Cancers, Vol. 10, Pages 168: Mechanistic Target of Rapamycin (mTOR) in the Cancer Setting

Cancers, Vol. 10, Pages 168: Mechanistic Target of Rapamycin (mTOR) in the Cancer Setting

Cancers doi: 10.3390/cancers10060168

Authors: James T. Murray Andrew R. Tee

This special issue on mammalian target of rapamycin (mTOR) explores the importance of mTOR in cell growth control and cancer. Cancer cells often exploit mTOR as a mechanism to enhance their capacity to grow. While protein synthesis is by far the best-characterized mTOR-driven process, this special issue also describes a wider array of mTOR-driven biological processes that cancer cells benefit from, including autophagy, cell cycle control, metabolic transformation, angiogenic signaling, and anabolic processes such as nucleotide biosynthesis and ribosomal biogenesis. Other areas of mTOR signaling covered in these reviews delve into cell migration, inflammation, and regulation of transcription factors linked to cancer progression.

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You are measuring the decision to be fast, not inattention: the Sustained Attention to Response Task does not measure sustained attention

Abstract

The Sustained Attention to Response Task (SART) has been widely used in psychological literature as a measure of vigilance (the ability to sustain attention over a prolonged period of time). This task uses a Go/No-Go paradigm and requires the participants to repetitively respond to the stimuli as quickly and as accurately as possible. Previous literature indicates that performance in SART is subjected to a "speed–accuracy trade-off" (SATO) resulting from strategy choices and from the failures of controlling motor reflexes. In this study, 36 participants (n = 36) performed a series of four SARTs. The results support the perspective of strategy choice in SART and suggest that within-subjects SATO in SART should also be acknowledged in attempting to explain SART performance. The implications of the speed–accuracy trade-off should be fully understood when the SART is being used as a measure or tool.

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The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease

Abstract

Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain's cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer's disease. The cholinergic hypothesis of Alzheimer's disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer's disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer's disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer's disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer's disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.

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Su1433 LOW CLINICAL SUCCESS RATES AND HIGH COMPLICATION RATES IN PATIENTS UNDERGOING PERCUTANEOUS TRANSHEPATIC BILIARY DRAINAGE AFTER FAILED ERCP: RESULTS OF A LARGE TERTIARY CENTER

Percutaneous transhepatic biliary drainage (PTBD) has been the preferred modality for biliary drainage when ERCP is unsuccessful. Older studies have shown high complication rates, however this may have improved in the last few decades. As newer alternatives, including EUS guided drainage, are evolving quickly, updated results on the outcomes of PTBD are crucial. We aim to assess the success and complication rates of PTBD in a large tertiary hospital.

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Su1432 A COMPLETE ASSESSMENT OF THE ROLE OF EUS-GUIDANCE FOR BILIARY AND PANCREATIC DUCT ACCESS AND DRAINAGE

EUS-guided ductal access & drainage (EUS-D) of biliary (EUS-BD) or pancreatic duct (EUS-PD) has been used for 20 years. The need for EUS-BD is estimated at 3 in 1000 ERCPs (Holt, GIE-2016), excluding EUS-PD and prior biliary interventions. A complete assessment of the role of EUS-D requires considering the full spectrum of ERCP failure beyond failed cannulation, all patient populations & all indications. Data on concurrent institutional use of PTBD is required to interpret findings.

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Mo1675 RISK OF COLORECTAL CANCER FOR FECAL IMMUNOCHEMISTRY TEST (FIT)-POSITIVE PATIENTS WHO PREVIOUSLY UNDERWENT COLONOSCOPY

Colonoscopy is recommended for fecal immunochemistry test (FIT)-positive patients; however, the risk of colorectal cancer (CRC) has not been well examined in FIT-positive patients who previously underwent colonoscopy.

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ASGE Program

COMBINED CLINICAL SYMPOSIUM

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68 EUS-GUIDED GASTROJEJUNOSTOMY WITH LUMEN APPOSING METAL STENT VERSUS ENTERAL STENT PLACEMENT FOR PALLIATION OF MALIGNANT GASTRIC OUTLET OBSTRUCTION

Enteral stent placement is commonly performed for palliation of obstructive symptoms caused by malignant gastric outlet obstruction (GOO). EUS-guided gastrojejunostomy (EUS-GJ) with placement of a lumen-apposing metal stent (LAMS) is a novel procedure that may offer long lasting patency with fewer incidence of stent failure, however there is limited data comparing EUS-GJ to enteral stent placement.

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Mo1319 CORRELATION BETWEEN EUS-FNA AND SURGICAL SPECIMEN FOR KI67 INDEX AND TUMOR GRADING IN PANCREATIC NEUROENDOCRINE TUMORS:

Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms comprising of 2% of all pancreatic tumors. They exhibit an extremely variable natural history. Ki67, a marker of cell proliferation is a significant prognostic discriminator for pNETs and is used to grade these tumors based on a system implemented by European Neuroendocrine Tumor Society (ENETS) and by the WHO. Historically, Ki67 indices are measured using histological specimens obtained through surgery. However, in the last decade, there is increasing utilization of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) to obtain tumor specimens.

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73 A PROSPECTIVE MULTICENTER STUDY EVALUATING EUS AND ERCP COMPETENCE DURING ADVANCED ENDOSCOPY TRAINING AND SUBSEQUENT INDEPENDENT PRACTICE: THE RAPID ASSESSMENT OF TRAINEE ENDOSCOPY SKILLS (RATES2) STUDY

We have shown that AETs achieve EUS and ERCP competence at varying rates, validating the shift from defining competence based on an absolute number of procedures to well-defined metrics. However, there are no data to confirm that advanced endoscopy trainees (AETs) who achieve competence during training subsequently perform high quality EUS and ERCP in their 1st year of independent practice.

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76 PROCEDURALIST-DRIVEN FLUOROSCOPY SIGNIFICANTLY REDUCES IRRADIATION DURING ERCP

Fluoroscopy exposure should be reduced as much as possible for safety of staff and patients. Accumulated radiation exposure of busy ERCP proceduralists approaches risk of organ damage (eg: cataract formation1). Annual exposure of a busy proceduralist has been equated to a single fluoroscopic examination (3-5mSv) which involves a small but real increased risk of malignancy2. Proceduralist-driven fluoroscopy might reduce exposure.

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107 UNCOVERED VERSUS COVERED SELF-EXPANDABLE METAL STENTS IN PALLIATIVE ENDOSCOPIC TREATMENT OF MALIGNANT GASTRIC OUTLET OBSTRUCTION: A LARGE MULTICENTER RANDOMIZED TRIAL IN WEST JAPAN

The pathogenesis of gastric outlet obstruction (GOO) mainly involves extrinsic tumors (i.e. pancreatic carcinomas) or intrinsic tumors (i.e. gastric carcinomas). Self-expandable metal stents (SEMSs) are an effective treatment option for GOO. However, stent dysfunction due to tumor ingrowth is a frequent problem with uncovered SEMSs, while covered SEMSs are prone to migration. The aim of this study was to compare uncovered and covered SEMSs for palliation of malignant GOO.

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Mo1351 THE SAFETY AND FEASIBILITY OF ENDOSCOPIC ULTRASOUND-GUIDED PARENCHYMAL LIVER BIOPSY AT A LARGE COMMUNITY HOSPITAL

Parenchymal liver biopsy is important for diagnosis and management for many liver disease patients. Percutaneous image-guided liver biopsy is currently the most widely used method; however, endoscopic ultrasound (EUS)-guided liver biopsy with newer flexible large-bore core needles represents an emerging approach for sampling. EUS-guided liver biopsy (EUS-LB) offers certain advantages over traditional methods such as doppler assistance to avoid intervening vessels and the ability to image both hepatic lobes to minimize sampling error.

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108 COVERED STENTS AND ENDOSCOPIC SUTURING FOR BENIGN AND MALIGNANT GASTRIC OUTLET OBSTRUCTION: SAFETY AND EFFICACY.

Self-expandable metallic stents (SEMS) have a wide range of therapeutic application in the management of malignant gastric outlet obstruction (GOO), and in select cases, esophageal covered SEMS have been used for benign indications. Uncovered SEMS to relieve malignant GOO have a shorter recovery time compared to conventional surgical bypass. Covered SEMS (CSEMS) confer the benefit of minimizing tissue ingrowth but are prone to stent migration. Endoscopic suturing (ES) reduces esophageal stent migration.

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Mo1286 PREDICTING MALIGNANCY RISK IN GASTROINTESTINAL SUBEPITHELIAL TUMORS WITH CONTRAST-ENHANCED HARMONIC ENDOSCOPIC ULTRASOUND USING A PERFUSION ANALYSIS SOFTWARE

Contrast enhanced harmonic endoscopic ultrasound (CEH EUS) is a promising imaging modality that can identify subepithelial tumors (SETs) by detecting the degree of enhancement, but whether CEH EUS alone can predict the malignancy risk of gastrointestinal stromal tumors (GISTs) remains unclear. The aim of our study was to evaluate the ability of CEH EUS using a perfusion analysis software for the discrimination among SETs and the prediction of malignancy risk of GISTs.

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109 PER ORAL ENDOSCOPIC PYLOROMYOTOMY (POP) IS EFFICIOUS AND SAFE FOR REFRACTORY GASTROPARESIS: THE FIRST PROSPECTIVE STUDY (GASTRO-POP- NCT02779920)

Gastroparesis is a functionnal disorder defined by delayed gastric emptying without mechanical obstruction and cardinal symptoms (nausea, vomiting, early satiety). It's prevalence is high around 3% in USA. Treatment of gastroparesis is based on specific diet (frequent small meals with low fat and low fiber) and prokinetics drugs. However these drugs are concerned by a lot of cardiac side effect, and a lot of patients escape because of a tachyphylaxy effect. In case of failure of these treatments, there is no validated therapeutic alternative.

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Mo1112 SLICING VERSUS LOOPING-EFFICACY AND SAFETY OF ENDOSCOPIC SUBMUCOSAL DISSECTION(ESD) VERSUS ENDOSCOPIC MUCOSAL RESECTION(EMR) IN PATIENTS WITH NON-PEDUNCULATED POLYPS LARGER THAN 20MM

Large adenomas have a high risk of progression to invasive cancer. Endoscopic mucosal resection (EMR) is a widely effective and durable technique for managing large polyps. However, in adenomas larger than 20 mm in size, EMR is limited by the piecemeal technique with possible high adenoma recurrence rate. Endoscopic submucosal dissection (ESD) has emerged as a technique which offers complete en bloc resection of large polyps.

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110 CONTINUED VERSUS INTERRUPTED ASPIRIN USE AND BLEEDING RISK AFTER ENDOSCOPIC SUBMUCOSAL DISSECTION OF GASTRIC NEOPLASMS: A META-ANALYSIS

Balancing the risk of bleeding and thromboembolic events for patients who use aspirin and need to undergo endoscopic submucosal dissection (ESD) for gastric neoplasms is a delicate process. The current guidelines from different associations provide inconsistent recommendations. For instance, the American Society of Gastrointestinal Endoscopy recommends continuing aspirin peri-procedurally regardless of thrombotic risks, whereas the European Society of Gastrointestinal Endoscopy recommends that aspirin discontinuation should be considered for patients whose risk of hemorrhage outweighs the risk of thrombotic events.

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Su1697 TRANS-ANAL SUBMUCOSAL ENDOSCOPIC RESECTION (TASER) FOR COMPLEX RECTAL POLYPS: CLINICAL EXPERIENCE WITH THE FIRST 64 CASES

Trans-Anal Submucosal Endoscopic Resection (TASER) is a novel instrumental platform for resection of large (≥5cm) and/or complex rectal polyps (CRPs). It involves a multi-port trans-anal access (Gelport Path), enabling dynamic tissue retraction to assist endoscopic submucosal dissection (ESD), used alone or in conjunction with supplementary techniques [Endoscopic Mucosal Resection (EMR) or Ablation (EMA), Trans-Anal Excision (TAE)]. We report the clinical outcomes with TASER from two UK centers.

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Taytulla (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) by Allergan: Recall - Due to Out of Sequence Capsules

Audience: Patient, Pharmacy, Health Professional ISSUE: Allergan recently identified, through a physician report, that four placebo capsules were placed out of order in a sample pack of Taytulla and the first four days of therapy had four...

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Male patients with resected IIIA-N2 non-small-cell lung cancer may benefit from postoperative radiotherapy: a population-based survival analysis

Future Oncology, Ahead of Print.


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Lymph node ratio has prognostic value related to the number of positive lymph nodes in patients with vulvar cancer

Future Oncology, Ahead of Print.


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Miltefosine has post-antifungal effect and induces apoptosis in Cryptococcus yeasts [PublishAheadOfPrint]

Cryptococcus spp. are common opportunistic fungal pathogens, particularly in HIV patients. The approved drug miltefosine (MFS) has potential as an alternative antifungal against cryptococcosis; however, the mechanism of action of MFS in Cryptococcus is poorly understood. Here, we examined the effects of MFS on C. neoformans and C. gattii yeasts (planktonic and biofilm lifestyles), to clarify its mechanism of action. MFS presented inhibitory and fungicidal effects against planktonic Cryptococcus cells, with similar activity against dispersion biofilm cells, while sessile biofilm cells were less sensitive to MFS. Interestingly, MFS had post-antifungal effect on Cryptococcus, with a proliferation delay of up to 8.15 h after short exposure to fungicidal doses. MFS at fungicidal concentrations increased plasma membrane permeability, likely due to direct interaction with ergosterol, as suggested by competition assays with exogenous ergosterol. Moreover, MFS reduced the mitochondrial membrane potential, increased ROS production, and induced DNA fragmentation and condensation, all of which are hallmarks of apoptosis. Transmission electron microscopy analysis showed that MFS-treated yeasts had a reduced mucopolysaccharide capsule (confirmed by morphometry in light microscopy), plasma membrane irregularities, mitochondrial swelling and a less conspicuous cell wall. Our results suggest that MFS increases plasma membrane permeability in Cryptococcus via interaction with ergosterol, and also affects the mitochondrial membrane, eventually leading to apoptosis, in line with its fungicidal activity. These findings confirm the potential of MFS as an antifungal against C. neoformans and C. gattii, and warrants further studies to establish clinical protocols for MFS use against cryptococcosis.

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Fragments of the non-lytic proline-rich antimicrobial peptide Bac5 kill E. coli cells by inhibiting protein synthesis. [PublishAheadOfPrint]

Unlike most antimicrobial peptides (AMPs), the main mode of action of the subclass of proline-rich antimicrobial peptides (PrAMPs) is not based on disruption of the bacterial membrane. Instead, PrAMPs exploit the inner membrane transporters SbmA and YjiL/MdtM to pass through the bacterial membrane and enter the cytosol of specific Gram-negative bacteria, where they exert an inhibitory effect on protein synthesis. Despite sharing a high proline and arginine content with other characterized PrAMPs, the PrAMP Bac5 has a low sequence identity with them. Here we investigated the mode of action of three N-terminal Bac5 fragments, Bac5 (1-15), Bac5 (1-25) and Bac5 (1-31). We could show that Bac5 (1-25) and Bac5 (1-31) retain excellent antimicrobial activity towards Escherichia coli and low toxicity towards eukaryotic cells, whereas Bac5 (1-15) was inactive. Bac5 (1-25) and Bac5 (1-31) inhibited bacterial protein synthesis in vitro and in vivo. Competition assays suggest that the binding site of Bac5 is within the ribosomal tunnel, where it prevents the transition from the initiation to the elongation phase of translation, as reported for other PrAMPs, such as the bovine PrAMP Bac7. Surprisingly, unlike Bac7, Bac5 (1-25) exhibited species-specific inhibition, being an excellent inhibitor of protein synthesis on E. coli ribosomes but a poor inhibitor on Thermus thermophilus ribosomes. This indicates that while Bac5 most likely has an overlapping binding site with Bac7, the mode of interaction is distinct, suggesting that Bac5 fragments may be interesting alternative lead compounds for the development of new antimicrobial agents.

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Antibacterial spectrum of a tetrazole-based reversible inhibitor of serine {beta}-lactamases [PublishAheadOfPrint]

CTX-M is the most prevalent family of extended-spectrum β-lactamases. We recently developed a tetrazole-derived non-covalent inhibitor of CTX-M-9. Here, we present biochemical and microbiological activity of this inhibitor across a representative panel of serine β-lactamases and Gram-negative bacteria. The compound displayed significant activity against all major subgroups of CTX-M, including CTX-M-15, while exhibiting some low-level inhibition of other serine β-lactamases. Complex crystal structures with CTX-M-14 S237A mutant and CTX-M-27 illustrate the binding contribution of specific active site residues on the β3 strand. In vitro pharmacokinetic studies revealed drug-like properties and positive prospects for further optimization. These studies suggest that tetrazole-based compounds can provide novel chemotypes for future serine β-lactamase inhibitor discovery.

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Antimicrobial Efficacy and Safety of a Novel Gas Plasma-Activated Catheter Lock Solution [PublishAheadOfPrint]

Antimicrobial lock solutions are important for prevention of microbial colonization and infection of long-term central venous catheters. We investigated the efficacy and safety of a novel antibiotic-free lock solution formed from gas plasma-activated disinfectant (PAD). Using a luminal biofilm model, viable cells of methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Candida albicans in mature biofilms were reduced by 6 – 8 orders of magnitude with a PAD lock for 60 minutes. Subsequent 24-hour incubation of PAD-treated samples resulted in no detectable regrowth of viable bacteria or fungi. As a comparison, the use of a minocycline/EDTA/ethanol lock solution for 60 minutes led to regrowth of bacteria and fungi, up to 10⁷ – 10⁹ CFU/ml, in 24 hours. The PAD lock solution had minimal impact on human umbilical vein endothelial cell viability, whereas the minocycline/EDTA/ethanol solution elicited cell death in nearly half of human endothelial cells. Additionally, PAD treatment caused little topological change to catheter materials. In conclusion, PAD represents a novel antibiotic-free, non-cytotoxic lock solution that elicits rapid and broad-spectrum eradication of biofilm-laden microbes and which shows promise for the prevention and treatment of intravascular catheter infections.

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Recommendations to address the difficulties encountered when determining linezolid resistance from whole genome sequencing data [PublishAheadOfPrint]

Mutations associated with linezolid resistance within the V domain of 23S rRNA are annotated using an Escherichia coli numbering system. The 23S rRNA gene varies in length, nucleotide sequence and copy number between bacterial species. Consequently, this numbering system is not intuitive and can lead to confusion when locating mutation sites using whole genome sequencing data. Using the mutation G2576T as an example, we demonstrate the difficulties associated with using the E. coli numbering system.

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Chromosomally Encoded mcr-5 in Colistin non-susceptible Pseudomonas aeruginosa [PublishAheadOfPrint]

Whole genome sequencing (WGS) of historical Pseudomonas aeruginosa clinical isolates identified a chromosomal copy of mcr-5 within a Tn3-like transposon in P. aeruginosa MRSN 12280. The isolate was non-susceptible to colistin by broth microdilution and genome analysis revealed no mutations known to confer colistin resistance. To the best of our knowledge, this is the first report of mcr in colistin non-susceptible P. aeruginosa.

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Lipopeptide Paenipeptin Analogues Potentiate Clarithromycin and Rifampicin against Carbapenem-Resistant Pathogens [PublishAheadOfPrint]

Two paenipeptin analogues at 4 μg/ml potentiated clarithromycin and rifampicin against carbapenem-resistant Acinetobacter baumannii and Klebsiella pneumoniae strains. The combined treatment significantly increased their antibacterial efficacy in a microbiological medium and in human serum in vitro at therapeutically-relevant concentrations. Moreover, these two paenipeptins analogues showed low cytotoxicity against a human kidney cell line. Therefore, the combination therapy with paenipeptins may be an option for the treatment of antibiotic-resistant bacterial infections.

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Clofazimine for the treatment of Mycobacterium kansasii [PublishAheadOfPrint]

Mycobacterium kansasii pulmonary infection is global problem. Standard combination therapy consists of isoniazid 300 mg/day, rifampin 600 mg/day, and ethambutol 15 mg/kg/day for 18 months. Co-incubation of M. kansasii with different clofazimine concentrations over 7 days in test-tubes resulted in maximal kill (E_max) of 2.03 log₁₀ CFU/mL below day 0. The concentration associated with E_max was 110 times the minimum inhibitory concentration. Next, the effect of human-like concentration-time profiles of clofazimine human-equivalent doses ranging between 0 to 200 mg daily for 21 days were examined in the intracellular-infection hollow fiber model of M. kansasii (HFS-Mkn). On day 14, when clofazimine microbial effect was maximal, the E_max was 2.57 log₁₀ CFU/mL while dose associated with E_max was 100 mg/day. However, no dose killed M. kansasii to below day 0. Thus, the antimicrobial effect of clofazimine monotherapy in the HFS-Mkn was modest. Human equivalent concentration-time profiles of standard combination therapy and doses were used as comparator in the HFS-Mkn. On day 14, standard therapy had killed 2.32 log₁₀ CFU/mL below day 0. The effect of standard therapy was consistent with a bi-exponential decline with kill rate constants of 1.85 per day (half-life=0.37 days) and 0.06 per day (half-life=12.76 days), r²>0.99. This means that standard therapy would take 9.3-12 months to completely eliminate M. kansasii in the model, which is consistent with clinical observations. This observation for standard therapy means that the modest to poor effect of clofazimine on M. kansasii identified here is likely to be the same in the clinic.

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Comparison of in vitro activity and MIC distributions between the novel oxazolidinone delpazolid and linezolid against multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis in China [PublishAheadOfPrint]

Oxazolidinones are efficacious in treating mycobacterial infections, including tuberculosis (TB) caused by drug-resistant Mycobacterium tuberculosis (MTB). In this study, we compared in vitro activity and minimal inhibitory concentration (MIC) distributions between delpazolid, a novel oxazolidinone, and linezolid against multidrug-resistant (MDR) and extensively drug-resistant MTB (XDR-TB) in China. Additionally, genetic mutations in 23S rRNA, rplC and rplD genes were analyzed to reveal potential mechanism(s) underlying observed oxazolidinone resistance. A total of 240 MTB isolates were enrolled in this study, including 120 MDR-TB and 120 XDR-TB isolates. Overall, linezolid and delpazolid MIC₉₀ values for MTB isolates were 0.25 mg/L and 0.5 mg/L, respectively. Based upon visual inspection, we tentatively set epidemiological cutoff values (ECOFFs) for MIC determinations at 1.0 mg/L and 2.0 mg/L for linezolid and delpazolid, respectively. Although no significant difference in resistance rate was observed between linezolid and delpazolid among XDR-TB isolates (P > 0.05), statistical analysis revealed a significantly higher proportion of linezolid-resistant isolates than delpazolid-resistant isolates within the MDR group (P = 0.036). Seven (53.85%) of 13 linezolid-resistant isolates were found to harbor mutations within the three target genes. Additionally, one isolate exhibited an amino acid substitution (Arg126His) within the protein encoded by rplD that contributed to high-level resistance to linezolid (MIC > 16 mg/L) compared to a delpazolid MIC = 0.25. In conclusion, in vitro susceptibility testing revealed that delpazolid antibacterial activity is comparable to that of linezolid. A novel mutation within rplD was identified that endowed MTB with linezolid, but not delpazolid, resistance.

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Nephrotoxicity Associated with Intravenous Polymyxin B Once versus Twice Daily Dosing Regimen [PublishAheadOfPrint]

Nephrotoxicity is a known adverse effect of polymyxin B (PMB). Animal data suggests that once daily dosing may reduce the rate and delay the onset of acute kidney injury (AKI).

In a multicenter, retrospective study, we evaluated adult patients with a creatinine clearance (CrCl) ≥30 mL/min who received ≥48h of PMB therapy. The primary endpoint was the difference in rate of AKI comparing once and twice daily PMB dosing. Secondary endpoints included time to AKI and recovery of renal function.

Of 273 eligible patients, 100 from each group were matched based on propensity scores. In the matched groups, nephrotoxicity, defined according to RIFLE criteria, was more frequent with once versus twice daily dosing (47% vs. 17% P=0.0005). After adjusting for residual differences by multivariate conditional logistic regression, once daily dosing was more likely to result in nephrotoxicity (adjusted odds ratio 2.5, 95% CI 1.413-4.541, P=0.002). Among 64 patients who developed AKI, the median onset was similar between groups (7 days with once vs. 6 days with twice daily dosing, P=0.095). Of 37 patients who had their serum creatinine evaluated subsequently, 29/37 (78%) had recovery of renal function. No patient required renal replacement therapy.

Our findings suggest that AKI is significantly more common with PMB once daily as compared to twice daily dosing with no difference in time to AKI. Prospective randomized study is warranted to validate these results.

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Analysis of the tunicamycin biosynthetic gene cluster of Streptomyces chartreusis reveals new insights into tunicamycin production and immunity [PublishAheadOfPrint]

The tunicamycin biosynthetic gene cluster of Streptomyces chartreusis consists of 14 genes (tunA-N) with a high degree of apparent translational coupling. Transcriptional analysis revealed that all of these genes are likely to be transcribed as a single operon from two promoters, tunp1 and tunp2. In frame deletion analysis revealed that just six of these genes (tunABCDEH) are essential for tunicamycin production in the heterologous host Streptomyces coelicolor, while five (tunFGKLN) with likely counterparts in primary metabolism are not necessary, but presumably ensure efficient production of the antibiotic at the onset of tunicamycin biosynthesis. Three genes are implicated in immunity; tunIJ, which encode a two component ABC transporter presumably required for export of the antibiotic, and tunM, which encodes a putative SAM-dependent methyltransferase. Expression of tunIJ or tunM in S. coelicolor conferred resistance to exogenous tunicamycin. The results presented here provide new insights into tunicamycin biosynthesis and immunity.

https://ift.tt/2sidgoR

Iron restriction to clinical isolates of Candida albicans by the novel chelator DIBI inhibits growth and increases sensitivity to azoles in vitro and in vivo in a murine model of experimental vaginitis [PublishAheadOfPrint]

Candida albicans is an important opportunistic pathogen causing various human infections that are often treated with azole antifungals. The US CDC now regards developing candidal antifungal resistance as a threat, creating a need for new and more effective antifungal treatments. Iron is an essential nutrient for all living cells and there is growing evidence that interference with iron homeostasis of C. albicans can improve its response to antifungals. This study was aimed at establishing whether withholding iron by currently used medical iron chelators and the novel chelator DIBI could restrict growth and also enhance the activity of azoles against clinical isolates of C. albicans. DIBI but not deferoxamine or deferiprone, inhibited growth of C. albicans at relatively low concentrations in vitro and this inhibition was reversed by iron addition. DIBI in combination with various azoles demonstrated stronger growth inhibition than the azoles alone and greatly prolonged inhibition of cell multiplication. In addition, administration of DIBI along with fluconazole (FLC) to mice inoculated with a FLC-sensitive isolate in a model of experimental C. albicans vaginitis showed markedly improved clearance of infection. These results suggest that iron chelation by DIBI has the potential to enhance azole efficacy for the treatment of candidiasis.

https://ift.tt/2IWYtWB

Assessment of the Radiation Therapy Model in the Dominican Republic and Its Impact on the Caribbean Islands

The Dominican Republic (DR) is an upper-middle-income country that has taken several strides to address cancer care at the national level (1). The International Atomic Energy Agency (IAEA) performed an analysis of the radiation therapy resources in 2004 and noted 3 radiation therapy centers with deficiencies in equipment as there were only 3 cobalt (60Co) teletherapy units and 1 linear accelerator (2). Afterward, an effort was undertaken to characterize the resources available for cancer care by the Fundación Plenitud, though only the resources of 2 radiation therapy centers were analyzed (3).

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Supine or Prone Breast Radiation: Upsides and Downsides

The past decade has been accompanied by an increasing body of literature supporting the use of the prone position for patients undergoing whole-breast radiation (1-4). A brief informal review of PubMed reveals that in the 10 years before 2008 there were approximately 20 reports relating to prone breast irradiation, whereas in the 10 years from 2008 to 2018 there were more than 100 reports relating to prone breast irradiation.

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In Reply to Nevens et al

To the Editor: My co-authors and I appreciate the response of Nevens et al to the publication of our article, "Single-arm phase 2 trial of elective nodal dose reduction for patients with locoregionally advanced squamous cell carcinoma of the head and neck" (1, 2). We included in our discussion their group's randomized trial of 40 Gy versus 50 Gy elective nodal irradiation (ENI), in which "concurrent chemotherapy was allowed" but not further discussed and no analysis of elective nodal failures (ENF) was performed (3).

https://ift.tt/2H2Byrk

Atypical Meningioma: An Evolving Landscape and Moving Target

While World Health Organization (WHO) grade 2, or atypical, meningiomas comprise approximately 25% of meningiomas, they represent the population with increased propensity for local recurrence and even decreased survival (1). Unfortunately, there are a paucity of prospective data to guide clinical management, as the largely retrospective studies on this disease are fraught with patient selection bias, insufficient follow-up, and small numbers of events. Unanswered clinical questions for grade 2 meningiomas include the role of adjuvant radiation therapy for gross totally resected tumors (2, 3) and the use of stereotactic radiosurgery given the higher local and marginal failure rate after stereotactic radiosurgery (4). Proton radiation therapy is also being explored, allowing for treatment of larger volumes more suitable for conventional fractionation but with decreased integral dose than photon therapy.

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In Regard to Maguire et al

To the Editor: We read the article by Maguire et al (1) with great interest. The authors present a single-arm phase 2 trial of elective nodal dose reduction for patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC). Fifty-four patients were enrolled, with a median follow-up of 36 months. The dose to the elective nodal volume was lowered to 36 Gy. The authors conclude that this approach is feasible and needs to be further investigated in future clinical trials.

https://ift.tt/2spOWAr

Hippocampus-Sparing Radiation and Chemotherapy

Before Radiation Therapy Oncology Group (RTOG) protocol 9802, when there was no survival advantage associated with receipt of radiation therapy (European Organization for Research and Treatment of Cancer [EORTC] 22845), the debate regarding whether to treat with radiation therapy centered on which would lead to worse neurocognition and quality of life: progression of a patient's residual tumor or radiation side effects. Because the patient is high risk by EORTC criteria with a median survival of 3.5 years, we would have recommended radiation, because the potential late neurocognitive side effects of radiation are unfortunately less of a concern (1).

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Meetings

July 16-17, 2018

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Chemotherapy Plus Proton or Photon Radiation on a Trial

Up-front radiation offers improved disease-free survival. "Historic" indications for adjuvant therapy in this case would include size > 6 cm, age > 40 years, and an astrocytic component (1, 2). Regardless, many practitioners might hesitate to offer adjuvant radiation (or referral to radiation oncology), primarily out of fear of radiation-induced cognitive dysfunction. Indeed, the presence of an isocitrate dehydrogenase mutation portends long-term survival, presumably placing this patient at risk for long-term radiation-induced cognitive toxicities.

https://ift.tt/2ITNuBn

In Reply to Habr-Gama et al

To the Editor: We appreciate the comments made by Habr-Gama and colleagues regarding our recent publication in this journal (1, 2). First, we agree that the concept of organ preservation in rectal cancer is now less controversial than it used to be, owing to Dr. Habr-Gama's courage and leadership in changing the mindset of surgeons around the world regarding nonsurgical treatment options for rectal cancer.

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In Regard to Nantavithya et al

To the Editor: We read the interesting results from a phase 2 randomized study comparing the toxicity and efficacy of stereotactic body proton therapy (SBPT) and stereotactic body radiation therapy (SBRT) for high-risk medically inoperable early-stage non-small cell lung cancer (NSCLC) by Nantavithya et al (1). Although their study was closed early because of poor accrual and insurance issues, a total of 19 patients receiving 50 Gy (relative biologic effectiveness) in 4 fractions were included for analysis.

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In Reply to Hurmuz and Ozyigit

To the Editor: We thank Dr Hurmuz for expressing interest in our recent report (1) and her cogent comments (2). Stereotactic body radiation therapy (SBRT) has indeed become a standard treatment for peripherally located, medically inoperable stage I non-small cell lung cancer (NSCLC). Local control rates from SBRT for such patients have generally been >90%, with regional lymph node control rates ranging from 85% to 90% (3, 4). Our previous pooled analysis of the STARS and ROSEL randomized studies (3) revealed estimated rates of locoregional control and overall survival (OS) at 3 years of 90% and 95% in the SBRT arms—indeed, the OS rates were better for SBRT than for surgery (79%).

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In Regard to Dong et al

To the Editor: I would like to make a comment on the "4π radiotherapy" mentioned by Dong et al in 2013, in which 4π indicates the solid angle (1). Subsequently this concept was used by several other authors, and presently some institutions are recruiting patients in such studies (2-8). In geometry of 3-dimensional Euclidian space (solid geometry), angle, hence the solid angle at any point, is defined as , where ds is the surface area, and r is the radius vector.

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Issue Highlights

Chan et al

https://ift.tt/2sn27lG

Low-grade Glioma, High Stakes Controversy—When and How to Treat in the Molecular Era?

A previously healthy 43-year-old man presented with a history of 6 months of intermittent numbness and tingling in his right upper extremity and later experienced a single focal motor seizure in the same arm. Magnetic resonance imaging of the brain revealed a 5.6 × 5.5 × 6.2-cm mass in the left parietal lobe, which was T1 hypointense, T2 hyperintense, without enhancement, and with minimal surrounding edema (Fig. 1). Dexamethasone and levetiracetam were started with resolution of his symptoms and no further seizure activity.

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Immediate Radiation and Chemotherapy

We would recommend immediate adjuvant treatment with radiation and chemotherapy (1). Radiation therapy would be directed to the tumor bed and residual disease as indicated by the T2/fluid-attenuated inversion recovery signal with a 7- to 10-mm margin treated to 54 Gy at 1.8 Gy/fraction with at least sequential and optionally, concurrent temozolomide.

https://ift.tt/2H22SWv

Ki-67 Remains Solely a Prognostic Biomarker in Localized Prostate Cancer

The pursuit of personalized medicine has led to a surge in the development and approval of molecular diagnostic tests, with now >40 approved in the United States. These tests can generally be classified into 3 categories of biomarkers: diagnostic, prognostic, and predictive. Diagnostic biomarkers include those that assess an analyte (eg, DNA, RNA, or protein) that defines a diagnostic entity. For example, the ResponseDx Tissue of Origin test is a gene expression classifier that is used to identify the primary tumor type for tumors of unknown primary (1).

https://ift.tt/2IVpi1L

Phase II study of first-line intensity-modulated radiotherapy (IMRT) followed by gemcitabine, dexamethasone, and cisplatin for high-risk early-stage extranodal nasal-type NK/T-cell lymphoma: the GREEN study

Radiotherapy is the backbone for early-stage NKTCL, but relapses and systemic failures are common for patients with unfavorable factors. This is the first prospective phase II trial focusing on high-risk group of early-stage NKTCL, and also the first prospective study that applies IMRT to early-stage NKTCL. The present study suggests that first-line IMRT followed by GDP represents an effective and well-tolerated therapeutic approach with improved long-term survival and decreased failure rate for high-risk early-stage NKTCL.

https://ift.tt/2sdAdcC

MR-guided gated stereotactic radiotherapy delivery for lung, adrenal and pancreatic tumors: a geometric analysis

Tumor and organ motion poses a challenge to accurate delivery of stereotactic body radiotherapy (SBRT). We implemented MR-guided, breath-hold SBRT using visual feedback, in order to treat smaller target volumes. The accuracy of gated delivery and reproducibility of the positions of lung-, adrenal- and pancreatic tumors were studied using images acquired during treatment. Analysis of data from 15 patients (87 fractions) revealed 95% geometric GTV coverage in all cases.

https://ift.tt/2xlDBHz

Use of Radiation in Extramedullary Leukemia/Chloroma: Guidelines from the International Lymphoma Radiation Oncology Group

Survival times for patients with leukemia in general have improved in recent decades, and this improvement has been attributed to an enhanced understanding of the genetics driving the etiology of the disease and improved combination chemotherapy and targeted therapy. Durable control of systemic disease in blood and bone marrow has significantly improved survival, but extramedullary relapse can pose therapeutic challenges for which radiation therapy can have an important role. The objective of this document is to discuss the current role of radiation therapy for patients with leukemia, specifically the extramedullary manifestations of leukemia.

https://ift.tt/2xjeYLi

TMPRSS2-ERG controls luminal epithelial lineage and antiandrogen sensitivity in PTEN and TP53-mutated prostate cancer

Purpose: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN/TP53-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. Experimental Design: We generated a Pten-negative/Trp53-mutated/ERG-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin-immunoprecipitation sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of Pten/Trp53 alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin dependent kinases 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray. Results: Transgenic ERG expression in mice blocked Pten/Trp53 alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Conclusions: Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in PTEN/TP53-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of PTEN/TP53-altered, RB1-intact prostate cancer.

https://ift.tt/2J0ezyX

Glycosyltransferase gene expression identifies a poor prognostic colorectal cancer subtype associated with mismatch repair deficiency and incomplete glycan synthesis

Purpose: We aimed to discover glycosyltransferase gene (glycogene)-derived molecular subtypes of colorectal cancer (CRC) associated with patient outcomes. Experimental Design: Transcriptomic and epigenomic datasets of non-tumor, pre-cancerous, cancerous tissues and cell lines with somatic mutations, mismatch repair status, clinicopathological and survival information, were assembled (n=4223) and glycogene profiles were analyzed. Immunohistochemistry for a glycogene, GALNT6, was conducted in adenoma and carcinoma specimens (n=403). The functional role and cell surface glycan profiles were further investigated by in vitro loss-of-function assays and lectin microarray analysis. Results: We initially developed and validated a 15-glycogene signature that can identify a poor-prognostic subtype, which closely related to deficient mismatch repair (dMMR) and GALNT6 downregulation. The association of decreased GALNT6 with dMMR was confirmed in multiple datasets of tumors and cell lines, and was further recapitulated by immunohistochemistry, where approximately 15% tumors exhibited loss of GALNT6 protein. GALNT6 mRNA and protein was expressed in premalignant/preinvasive lesions but was subsequently downregulated in a subset of carcinomas, possibly through epigenetic silencing. Decreased GALNT6 was independently associated with poor prognosis in the immunohistochemistry cohort and an additional microarray meta-cohort, by multivariate analyses, and its discriminative power of survival was particularly remarkable in stage III patients. GALNT6 silencing in SW480 cells promoted invasion, migration, chemoresistance and increased cell surface expression of a cancer-associated truncated O-glycan, Tn-antigen. Conclusions: The 15-glycogene signature and the expression levels of GALNT6 mRNA and protein each serve as a novel prognostic biomarker, highlighting the role of dysregulated glycogenes in cancer-associated glycan synthesis and poor prognosis.

https://ift.tt/2skkW9Z

Detection of Gastric Cancer with Novel Methylated DNA Markers: Discovery, Tissue Validation, and Pilot Testing in Plasma

Purpose: Gastric adenocarcinoma (GAC) is the third most common cause of cancer mortality worldwide. Accurate and affordable non-invasive detection methods have potential value for screening and surveillance. Herein, we identify novel methylated DNA markers (MDMs) for GAC, validate their discrimination for GAC in tissues from geographically separate cohorts, explore marker acquisition through the oncogenic cascade, and describe distributions of candidate MDMs in plasma from GAC cases and normal controls. Experimental Design: Following discovery by unbiased whole methylome sequencing, candidate MDMs were validated by blinded methylation-specific PCR in archival case-control tissues from U.S. and South Korean patients. Top MDMs were then assayed by an analytically sensitive method (quantitative real-time allele-specific target and signal amplification) in a blinded pilot study on archival plasma from GAC cases and normal controls. Results: Whole methylome discovery yielded novel and highly discriminant candidate MDMs. In tissue, a panel of candidate MDMs detected GAC in 92-100% of U.S. and S. Korean cohorts at 100% specificity. Levels of most MDMs increased progressively from normal mucosa through metaplasia, adenoma, and GAC with variation in points of greatest marker acquisition. In plasma, a 3 marker panel (ELMO1, ZNF569, C13orf18) detected 86% (95% CI 71-95%) of GACs at 95% specificity. Conclusions: Novel MDMs appear to accurately discriminate GAC from normal controls in both tissue and plasma. The point of aberrant methylation during oncogenesis varies by MDM, which may have relevance to marker selection in clinical applications. Further exploration of these MDMs for GAC screening and surveillance is warranted.

https://ift.tt/2J2RBac

Phase Ib Study of Binimetinib with Paclitaxel in Patients with Platinum-Resistant Ovarian Cancer: Final Results, Potential Biomarkers, and Extreme Responders

Purpose: Epithelial ovarian cancer (EOC) is a molecularly diverse disease. Mitogen-activated protein kinase kinase (MEK) inhibition targets tumors harboring mitogen-activated protein kinase (MAPK) pathway alterations and enhances paclitaxel-induced apoptosis in EOC. This phase Ib study evaluated the MEK inhibitor binimetinib combined with paclitaxel in patients with platinum-resistant EOC. Experimental Design: Patients received intravenous (IV) weekly paclitaxel with oral binimetinib in three different administration schedules. Outcomes were assessed by RECIST and CGIC CA-125 response criteria. Tumor samples were analyzed using next-generation sequencing. Results: Thirty-four patients received ≥1 binimetinib dose. A 30-mg twice daily (BID) continuous or 45-mg BID intermittent binimetinib dose were deemed the recommended phase 2 doses (RP2Ds) in combination with 80 mg/m² IV weekly paclitaxel. Rate of grade 3/4 adverse events was 65%. The best overall response rate was 18%-1 complete (CR) and 4 partial responses (PRs)-among 28 patients with RECIST-measurable disease. Eleven patients achieved stable disease (SD), yielding a clinical benefit rate (CR+PR+SD) of 57%. Response rates, per both RECIST and CA-125 criteria, were highest in the 45-mg BID continuous cohort and lowest in the 45-mg BID intermittent cohort. All 4 evaluable patients with MAPK pathway-altered tumors experienced clinical benefit. Conclusions: The combination of binimetinib and IV weekly paclitaxel was tolerable in this patient population. The RP2D of binimetinib in combination with paclitaxel was 30 mg BID as a continuous or 45 mg BID as an intermittent dose. Although response rates were modest, a higher clinical benefit rate was seen in patients harboring alterations affecting the MAPK pathway.

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Target-Based Screening Against eIF4A1 Reveals the Marine Natural Compound Elatol as a Novel Inhibitor of Translation Initiation with In Vivo Anti-Tumor Activity

Purpose: The DEAD-box RNA helicase eIF4A1 carries out the key enzymatic step of cap-dependent translation initiation and is a well-established target for cancer therapy, but no drug against it has entered evaluation in patients. We identified and characterized a natural compound with broad antitumor activities that emerged from the first target-based screen to identify novel eIF4A1 inhibitors. Experimental Design: We tested potency and specificity of the marine compound elatol vs. eIF4A1 ATPase activity. We also assessed eIF4A1 helicase inhibition, binding between the compound and the target including binding-site mutagenesis, and extensive mechanistic studies in cells. Finally, we determined maximum tolerated dosing in vivo and assessed activity against xenografted tumors. Results: We found elatol is a specific inhibitor of ATP hydrolysis by eIF4A1 in vitro with broad activity against multiple tumor types. The compound inhibits eIF4A1 helicase activity and binds the target with unexpected 2:1 stoichiometry at key sites in its helicase core. Sensitive tumor cells suffer acute loss of translationally regulated proteins, leading to growth arrest and apoptosis. In contrast to other eIF4A1 inhibitors, elatol induces markers of an integrated stress response, likely an off-target effect, but these effects do not mediate its cytotoxic activities. Elatol is less potent in vitro than the well-studied eIF4A1 inhibitor silvestrol but is tolerated in vivo at ~100X relative dosing, leading to significant activity against lymphoma xenografts. Conclusions: Elatol's identification as an eIF4A1 inhibitor with in vivo anti-tumor activities provides proof-of-principle for target-based screening against this highly promising target for cancer therapy.

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Emma gets braces!

Book reviews in the AJO-DO usually focus on textbooks that present information on scientific and clinical matters. This new book is not really of value for its scientific content but, rather, is important because of its practical value. Emma gets braces! is a delightful little book written by an orthodontist that describes what it is like to get braces.

https://ift.tt/2LFCYeY

Interdisciplinary approach for a patient with unilateral cleft lip and palate

The oral rehabilitation of patients with cleft lip and palate is a challenge. The aim of this case report was to underline the importance of a sequential interdisciplinary approach to correct functional problems and improve facial esthetics for a patient with unilateral cleft lip and palate. Few clinical reports have described this treatment in a teenager. The patient, a girl, age 12.6 years, had a complete right cleft lip and palate with a Class II molar tendency and a full Class II canine relationship on the right side, and a full Class II molar relationship with a canine Class I on the left side.

https://ift.tt/2LDPb3D

Orthodontic trial outcomes: Plentiful, inconsistent, and in need of uniformity? A scoping review

The selection of appropriate outcomes that matter to both patients and operators is increasingly appreciated, with core outcome sets in clinical trials gaining in popularity. The first step in core outcome set development is the generation of a list of possible important outcomes based on a scoping literature review. Moreover, outcome heterogeneity is known to detract from the findings of systematic reviews and meta-analyses. The aim of this study was to identify the range of outcome domains and specific outcome measures in contemporary orthodontic research.

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Information for readers

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Periodontal health and compliance: A comparison between Essix and Hawley retainers

Many studies on removable retainers have focused on retention efficacy and characteristics. However, studies on plaque accumulation, periodontal health, breakages, and patient compliance are still lacking. Thus, in this study, we aimed at evaluating these parameters in 2 groups of young patients wearing Essix or Hawley retainers for a 6-month period.

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Editorial Board

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Three-dimensional assessment of the effect of micro-osteoperforations on the rate of tooth movement during canine retraction in adults with Class II malocclusion: A randomized controlled clinical trial

The purpose of this split-mouth trial was to investigate the effect of micro-osteoperforations (MOPs) on the rate of tooth movement.

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Table of Contents

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Fluid structure interaction simulations of the upper airway in obstructive sleep apnea patients before and after maxillomandibular advancement surgery

The purpose of this study was to analyze pharyngeal airflow using both computational fluid dynamics (CFD) and fluid structure interactions (FSI) in obstructive sleep apnea patients before and after maxillomandibular advancement (MMA) surgery. The airflow characteristics before and after surgery were compared with both CFD and FSI. In addition, the presurgery and postsurgery deformations of the airway were evaluated using FSI.

https://ift.tt/2xnEnUr

Effect of local administration of simvastatin on postorthodontic relapse in a rabbit model

Posttreatment relapse is a major challenging clinical issue. The objective of this study was to evaluate the effect of local administration of simvastatin on posttreatment relapse.

https://ift.tt/2xmkU6t

Operation Plowshare and the nuclear option

After World War II concluded, the United States government established a program called "Operation Plowshare."1 This program was intended to use nuclear explosions for peaceful purposes. The irony here is obvious: nuclear weapons were the most destructive option ever invented by man, and they were designed to solve the complex problems associated with fighting and the end of World War II. Subsequently, during a time of relative peace, the government sought to advance nuclear technology by promoting nuclear explosions to accomplish projects that would be viewed as useful by the public.

https://ift.tt/2LHBAbN

Tomographic evaluation of the maturation stage of the midpalatal suture in postadolescents

In this study, we aimed at evaluating the maturation stage of the midpalatal suture based on its morphology, using cone-beam computed tomography images in young postadolescents.

https://ift.tt/2xnEi35

A promise made is a promise kept

Jim was referred to you by an oral surgeon with whom you have had little previous experience. Jim's law firm is in your building, so treatment will be as convenient for him as a walk up a few flights of stairs. He had undergone full bonded nonextraction therapy during law school but has always objected to his facial convexity and lip incompetence. The surgeon has recommended bimaxillary surgery, and insurance predetermination for the procedures is pending. Since Jim expects to marry within the year, he and his fiancée are eager to initiate orthodontic preparation for the surgery.

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Directory: AAO Officers and Organizations

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Erratum

Correction to: Ortiz AJ, Fernández E, Vicente A, Calvo JL, Ortiz C. Metallic ions released from stainless steel, nickel-free, and titanium orthodontic alloys: toxicity and DNA damage. Am J Orthod Dentofacial Orthop. 2011;140:e115-22.

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Apical root resorption during orthodontic treatment with clear aligners: A retrospective study using cone-beam computed tomography

We aimed to investigate the incidence and severity of orthodontically induced inflammatory root resorption (OIIRR) on maxillary incisors with clear aligner therapy using cone-beam computed tomography and to identify possible risk factors.

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Orthodontic-periodontic treatment for periodontitis

We read the article by Zhang et al describing the authors' efforts to treat patients with periodontitis.1 The authors concluded that combined orthodontic-periodontic treatment has a favorable effect on periodontitis and could also decrease the levels of inflammatory cytokines.

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When apologies go too far

During treatment, pretend that one of the following things happened: your patient developed a significant periodontal compromise or a significant root resorption. You pick it. Remember, it's make believe, but, it also happens. The patient, let's call her Honey, may lose a few teeth; we'll have to see. It happened on your watch, but you didn't pick it up as early as you should have, and yes, you should have picked it up earlier. Bottom line? Not good, but hey, that's why you have malpractice insurance.

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June 2018:153(6)

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Atorvastatin inhibits osteoclastogenesis and arrests tooth movement

In addition to their cholesterol-lowering effects, the statin class of drugs appears to enhance osteogenesis and suppress bone resorption, which could be a clinical concern during orthodontic treatment. In this animal study, we aimed to determine whether atorvastatin (ATV) affects orthodontic tooth movement (OTM) through osteoclast inhibition. Furthermore, we analyzed the potential adverse effects of ATV on long-bone turnover and endochondral ossification.

https://ift.tt/2xozN8m

SNHG6 acts as a genome-wide hypomethylation trigger via coupling of miR-1297-mediated S-adenosylmethionine-dependent positive feedback loops

Aberrant genome-wide hypomethylation and long non-coding RNA (lncRNA) dysregulation are associated with hepatocarcinogenesis. However, whether a relationship between the two exists remains largely unknown. S-adenosylmethionine (SAMe)-dependent methylation is a critical factor in genomic methylation. We previously found that SNHG6 lncRNA acted as an oncogene in hepatocarcinogenesis and could be considered a potential prognostic indicator for hepatocellular carcinoma (HCC). Here we verify that SNHG6 leads to genome-wide hypomethylation in hepatoma cells and that SNHG6 negatively correlates with the steady-state SAMe concentration in vivo and in vitro. SNHG6 suppressed MAT1A protein expression by activating the miR-1297/FUS pathway to regulate nucleocytoplasmic shuttling of MAT1A mRNA. Additionally, SNHG6 promoted expression of MAT2A by suppressing direct binding of miR-1297 to the MAT2A 3'UTR. SNHG6 regulated steady-state SAMe levels via coupling of two miR-1297-mediated SAMe-dependent positive feedback loops. Interestingly, the effect of SNHG6 on genome-wide methylation was inhibited by exogenous SAMe within a certain concentration range. These results suggest that single lncRNA dysregulation can lead to aberrant genome-wide hypomethylation by inhibiting SAMe production in HCC and that exogenous SAMe may be beneficial in the treatment of HCC.

https://ift.tt/2LGGd5G

Twist1 regulates Vimentin through Cul2 circular RNA to promote EMT in hepatocellular carcinoma

Twist is a critical epithelial-mesenchymal transition (EMT)-inducing transcription factor that increases expression of Vimentin. How Twist1 regulates this expression remains unclear. Here we report that Twist1 regulates Cullin2 (Cul2) circular RNA to increase expression of Vimentin in EMT. Twist1 bound the Cul2 promoter to activate its transcription and selectively promote expression of Cul2 circular RNA (circ-10720), but not mRNA. circ-10720 positively correlated with Twist1, tumor malignance, and poor prognosis in hepatocellular carcinoma (HCC). Twist1 promoted Vimentin expression by increasing levels of circ-10720, which can absorb miRNAs that target Vimentin. circ-10720 knockdown counteracted the tumor-promoting activity of Twist1 in vitro and in patient-derived xenograft (PDX) and DEN-induced TetOn-Twist1 transgenic mouse HCC models. These data unveil a mechanism by which Twist1 regulates Vimentin during EMT. They also provide potential therapeutic targets for HCC treatment and provide new insight for circRNA-based diagnostic and therapeutic strategies.

https://ift.tt/2xyQnmb

The tumor suppressor CIC directly regulates MAPK pathway genes via histone deacetylation

Oligodendrogliomas (ODG) are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with ODG; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster orthologue of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in ODG tumors prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.

https://ift.tt/2LGG8io

FGFR1-activated Translation of WNT Pathway Components with Structured 5' UTRs is Vulnerable to Inhibition of EIF4A-dependent Translation Initiation

Cooperativity between WNT and FGF signaling is well documented in embryonic development and cancer progression, but the molecular mechanisms underlying this crosstalk remain elusive. In this study, we interrogated the dynamics of RNA levels, ribosome occupancy, and protein expression as a function of inducible FGF signaling in mouse mammary glands with constitutive WNT hyperactivation. Multi-omics correlation analysis revealed a substantial discrepancy between RNA and ribosome occupancy levels versus protein levels. However, this discrepancy decreased as cells became pre-malignant and dynamically responded to FGF signaling, implicating the importance of stringent gene regulation in non-transformed cells. Analysis of individual genes demonstrated that acute FGF hyperactivation increased translation of many stem cell self-renewal regulators, including WNT signaling components, and decreased translation of genes regulating cellular senescence. WNT pathway components translationally upregulated by FGF signaling had long and structured 5' UTRs with a high frequency of polypurine sequences, several of which harbored (CGG)4 motifs that can fold into either stable G-quadruplexes or other stable secondary structures. The FGF-mediated increase in translation of WNT pathway components was compromised by silvestrol, an inhibitor of EIF4A that clamps EIF4A to polypurine sequences to block 43S scanning and inhibits its RNA-unwinding activity important for translation initiation. Moreover, silvestrol treatment significantly delayed FGF-WNT-driven tumorigenesis. Taken together, these results suggest that FGF signaling selectively enhances translation of structured mRNAs, particularly WNT signaling components, and highlight their vulnerability to inhibitors that target the RNA helicase EIF4A.

https://ift.tt/2xs6PV6

Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in Glioblastoma

Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM. We show that both c-Met and TrkA-B pathways transactivate each other, and targeting both pathways simultaneously results in more efficient pathway suppression. Mechanistically, inhibition of CDK4/6 drove NF-κB-mediated upregulation of hepatocyte growth factor (HGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) that in turn activated both c-Met and TrkA-B pathways. Combining the CDK4/6 inhibitor abemaciclib with the c-Met/Trk inhibitor altiratinib or the corresponding siRNAs induced apoptosis, leading to significant synergy against GBM. Collectively, these findings demonstrate that the activation of c-Met/TrkA-B pathways is a novel mechanism involved in therapeutic resistance of GBM to CDK4/6 inhibition and that dual inhibition of c-Met/Trk with CDK4/6 should be considered in future clinical trials.

https://ift.tt/2LGFVvC

Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

A key tool of cancer therapy has been targeted inhibition of oncogene addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here we use Drosophila to dissect response to targeted therapies. Treatment with a range of kinase inhibitors led to hyperactivation of overall cellular networks, resulting in emergent resistance and expression of stem cell markers including Sox2. Genetic and drug screens revealed that inhibitors of histone deacetylases, proteasome, and Hsp90 family of proteins restrained this network hyperactivation. These 'network brake' cocktails, used as adjuncts, prevented emergent resistance and promoted cell death at subtherapeutic doses. Our results highlight a general response of cells-transformed and normal-to targeted therapies that leads to resistance and toxicity. Pairing targeted therapeutics with subtherapeutic doses of broad acting 'network brake' drugs may provide a means of extending therapeutic utility while reducing whole body toxicity.

https://ift.tt/2IWSrFr

Radiotherapy and CD40 activation separately augment immunity to checkpoint blockade in cancer

Immunotherapy in pancreatic ductal adenocarcinoma (PDA) remains a difficult clinical problem despite success in other disease types with immune checkpoint blockade (ICB) and chimeric antigen receptor T cell therapy. Mechanisms driving immunosuppression and poor T cell infiltration in PDA are incompletely understood. Here we use genetically engineered mouse models of PDA that recapitulate hallmarks of human disease to demonstrate that CD40 pathway activation is required for clinical response to radiotherapy (RT) and ICB with αCTLA-4 and αPD-1. The combination of an agonist αCD40 antibody, RT, and dual ICB eradicated irradiated and unirradiated (i.e. abscopal) tumors, generating long-term immunity. Response required T cells and also short-lived myeloid cells and was dependent on the long non-coding RNA myeloid regulator Morrbid. Using unbiased random forest machine learning, we built unique, contextual signatures for each therapeutic component, revealing that (i) RT triggers an early proinflammatory stimulus, ablating existing intratumoral T cells and upregulating MHC class I and CD86 on antigen presenting cells, (ii) αCD40 causes a systemic and intratumoral reorganization of the myeloid compartment, and (iii) ICB increases intratumoral T cell infiltration and improves the CD8 T cell:regulatory T cell ratio. Thus, αCD40 and RT non-redundantly augment anti-tumor immunity in PDA, which is otherwise refractory to ICB, providing a clear rationale for clinical evaluation.

https://ift.tt/2LGFL7u

Specific targeting of MTAP-deleted tumors with a combination of 2'-fluoroadenine and 5'-methylthioadenosine

Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogs such as 6′-thioguanine (6TG) or 2′-fluoroadenine (2FA) with the MTAP substrate 5′-deoxy-5′-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analog toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogs into nucleotides. However, in MTAP- tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivo. In vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-dependent manner, shifting the IC50 concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different MTAP- human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors.

https://ift.tt/2IYHcMT

Notch-induced myeloid reprogramming in spontaneous pancreatic ductal adenocarcinoma by dual genetic targeting

Despite advances in our understanding of the genetics of pancreatic ductal adenocarcinoma (PDAC), the efficacy of therapeutic regimens targeting aberrant signaling pathways remains highly limited. Therapeutic strategies are greatly hampered by the extensive desmoplasia that comprises heterogeneous cell populations. Notch signaling is a contentious pathway exerting opposite roles in tumorigenesis depending on cellular context. Advanced model systems are needed to gain more insights into complex signaling in the multi-layered tumor microenvironment. In this study, we employed a dual recombinase-based in vivo strategy to modulate Notch signaling specifically in myeloid cells to dissect the tumorigenic role of Notch in PDAC stroma. Pancreas-specific KrasG12D activation and loss of Tp53 was induced using a Pdx1-Flp transgene, while Notch signaling was genetically targeted using a myeloid-targeting Lyz2-Cre strain for either activation of Notch2-IC or deletion of Rbpj. Myeloid-specific Notch activation significantly decreased tumor infiltration by protumorigenic M2 macrophages in spontaneous endogenous PDAC, which translated into significant survival benefit. Further characterization revealed upregulated antigen presentation and cytotoxic T effector phenotype upon Notch-induced M2 reduction. This approach is the first proof-of-concept for genetic targeting and reprogramming of myeloid cells in a complex disease model of PDAC and provides evidence for a regulatory role of Notch signaling in intratumoral immune phenotypes.

https://ift.tt/2LHVN1d

Integrative modeling identifies key determinants of inhibitor sensitivity in breast cancer cell lines

Cancer cell lines differ greatly in their sensitivity to anticancer drugs as a result of different oncogenic drivers and drug resistance mechanisms operating in each cell line. Although many of these mechanisms have been discovered, it remains a challenge to understand how they interact to render an individual cell line sensitive or resistant to a particular drug. To better understand this variability, we profiled a panel of thirty breast cancer cell lines in the absence of drugs for their mutations, copy number aberrations, mRNA and protein expression and protein phosphorylation, and for response to seven different kinase inhibitors. We then constructed a knowledge-based, Bayesian computational model that integrates these data types and estimates the relative contribution of various drug sensitivity mechanisms. The resulting model of regulatory signaling explained the majority of the variability observed in drug response. The model also identified cell lines with an unexplained response, and for these we searched for novel explanatory factors. Among others, we found that 4E-BP1 protein expression - and not just the extent of phosphorylation - was a determinant of mTOR inhibitor sensitivity. We validated this finding experimentally and found that overexpression of 4E-BP1 in cell lines that normally possess low levels of this protein is sufficient to increase mTOR inhibitor sensitivity. Taken together, our work demonstrates that combining experimental characterization with integrative modeling can be used to systematically test and extend our understanding of the variability in anticancer drug response.

https://ift.tt/2xq0NEh

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?, Published online: 30 May 2018; doi:10.1038/s41416-018-0118-6

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

https://ift.tt/2kAaQh6

A Case of Recurrent Erysipelas Caused by Streptococcus mitis Group

The aetiology of erysipelas remains poorly defined though beta-haemolytic streptococci are considered as the main causative pathogens. We describe a case of a 70-year-old woman with recurrent erysipelas in her left arm due to infection with streptococci of the mitis group. Her past medical history includes lymphoedema of the left arm secondary to lymph node dissection due to breast cancer surgery. On seven different occasions during a decade, she has presented a clinical picture of erysipelas and in three of them with Streptococcus mitis group bacteraemia. The results indicate that two cases were caused by Streptococcus mitis and one case was caused by Streptococcus oralis. This is, to our knowledge, the first reported cases of S. mitis and of S. oralis as the causative agents of erysipelas.

https://ift.tt/2sijPaF

Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic?

https://ift.tt/2IXTWYp

Accuracy of Endoscopic Ultrasound Imaging in Distinguishing Celiac Ganglia from Celiac Lymph Nodes

Endoscopic ultrasound (EUS) allows visualization of celiac lymph nodes (CLNs) and celiac ganglia (CG). Reliably distinguishing these structures is important for tumor staging and CG ablative therapies. We aimed to evaluate the accuracy of EUS in distinguishing CLNs from CG using a strict cytopathology reference standard. We also determined the rate of detection of CLN and CG by conventional cross-sectional imaging.

https://ift.tt/2sfN7qK

Huge enterolithiasis in Crohn’s disease

https://ift.tt/2xpzVnT

Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis

In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas.

https://ift.tt/2JhjY8b

Myoepithelial hamartoma in the ampulla of Vater

https://ift.tt/2H0izxG

Evaluations of Lifestyle, Dietary, and Pharmacologic Treatments for Pediatric Non-Alcoholic Fatty Liver Disease—a Systematic Review

There are no approved treatments for pediatric non-alcoholic fatty liver disease (NAFLD) and there is a lack of consensus on the best outcome measure for randomized controlled trials. We performed a systematic review of treatments tested for pediatric NAFLD, the degree of heterogeneity in trial design, and endpoints analyzed in these studies.

https://ift.tt/2snYOM7

Emphysematous Gastritis in a Patient with Abdominal Pain after Dialysis

https://ift.tt/2xpzCtf

Diagnosis Related Group Assignment for Gastrointestinal Bleeding: The Devil is in the Details

https://ift.tt/2sjSOni

Von Meyenburg Complexes Found Incidentally in a Patient with Acute Cholangitis

https://ift.tt/2H0EG6U

Lugol’s Chromoendoscopy in the Screening of Esophageal Squamous Cell Carcinoma: Time to Take a Closer Look?

https://ift.tt/2kxrxJK

Mycophenolate Mofetil Induced Esophagitis

https://ift.tt/2L7hPZN

Barriers to Follow-Up Colonoscopies for Patients With Positive Results From Fecal Immunochemical Tests During Colorectal Cancer Screening

There are several reasons that patients do not receive diagnostic colonoscopies after positive results from FITs, and patients often decline the procedure. The incidence of CRC is high among patients with positive FIT results who are subsequently evaluated by colonoscopy, suggesting many missed cancers in patients that do not undergo follow-up colonoscopy.

https://ift.tt/2LG9ygL

Rapid response to vedolizumab therapy in biologic-naïve patients with inflammatory bowel diseases

Vedolizumab is an antibody against α4β7 integrin that is used to treat patients with ulcerative colitis or Crohn's disease. In an analysis of data from 3 clinical trials, we found that vedolizumab rapidly (within 2 weeks) improved some patient-reported symptoms, through the first 6 weeks of treatment.

https://ift.tt/2H0QIxh

Epidemiology, Clinical Characteristics, and Associations for Rome IV Functional Nausea and Vomiting Disorders in Adults

Functional nausea and vomiting disorders (FNVDs) are classified as chronic nausea and vomiting syndrome (CNVS) or cyclic vomiting syndrome (CVS) – CVS includes cannabinoid hyperemesis syndrome. We investigated the population prevalence of FNVDs, their characteristics, and associated factors.

https://ift.tt/2kA6FBW

Increased Risk of Herpes Zoster Infection in Patients with Inflammatory Bowel Diseases in Korea

Few data are available on risk of herpes zoster (HZ) infection in Asian patients with inflammatory bowel diseases (IBD). We investigated whether patients with IBD in Korea have an increased risk of HZ and sought to identify risk factors for infection.

https://ift.tt/2smfz9B

Risk of developing metachronous advanced colorectal neoplasia after colonoscopic polypectomy in patients aged 30 to 39 and 40 to 49 years

Current guidelines define postpolypectomy surveillance intervals in patients aged ≥50 years. The risk of metachronous colorectal neoplasia (CRN) and the optimal postpolypectomy surveillance interval in patients aged <50 years remain unclear. We compared the risk of metachronous CRN in patients aged 30 to 39, 40 to 49, and ≥50 years old.

https://ift.tt/2IWq9PG

The implementation of the free maternal health policy in rural Northern Ghana: synthesised results and lessons learnt

A free maternal health policy was implemented under Ghana's National Health Insurance Scheme to promote the use of maternal health services. Under the policy, women are entitled to free services throughout pre...

https://ift.tt/2GYKZYF

The effect of lipopolysaccharide on the expression level of immunomodulatory and immunostimulatory factors of human amniotic epithelial cells

Human amniotic epithelial cells (hAECs) are a novel source of stem cells and have immunomodulatory effects on both the innate and adoptive immune system. hAECs can differentiate into multiple cell lineages tha...

https://ift.tt/2kBvugG

Re-exploring the value of surveillance cultures in predicting pathogens of late onset neonatal sepsis in a tertiary care hospital in southern Sri Lanka

To identify the validity of surveillance cultures in predicting causative organism(s) of late onset neonatal sepsis.

https://ift.tt/2H1dvZM

Response to flutamide, as second-line therapy after bicalutamide, predicts efficacy of abiraterone, not that of enzalutamide

The objective of this retrospective study was to evaluate whether the effect of second-line therapy of flutamide after bicalutamide can predict the response to abiraterone.

https://ift.tt/2kzYipZ

The Spiritual Event of Serious Illness

Thought leaders in palliative care have long recognized the spiritual implications of illness, including Dame Cicely Saunders' groundbreaking concept of suffering as comprised of physical, emotional, social, and spiritual sources of pain. However despite such recognition, spirituality remains an oft-neglected component of the bio-psychosocial spiritual model of caregiving in serious illness. We aim in this manuscript to highlight, through an in depth account of patients' experiences and attitudes, the concept of illness as a "spiritual event."

https://ift.tt/2siRHUa

Risk Factors Associated With Chemotherapy-Induced Nausea in the Week Prior to the Next Cycle and Impact of Nausea on Quality of Life Outcomes

Despite current advances in antiemetic treatments, between 19% to 58% of oncology patients experience chemotherapy-induced nausea (CIN).

https://ift.tt/2kxBrv5

Spirituality and Quality of Life in Black Patients with Cancer Pain

The objective of this study was to examine the associations between spirituality and overall quality of life (QOL) and individual QOL domains in Black patients with cancer pain.

https://ift.tt/2H0jNch

The value of electrochemical skin conductance measurement using Sudoscan ® in the assessment of patients with familial amyloid polyneuropathy

Familial amyloid polyneuropathy (FAP) due to transthyretin (TTR) mutation results from an irreversible extracellular fibril protein deposits caused by mutated TTR and is a length-dependent small-fiber predominant neuropathy (Planté-Bordeneuve and Said, 2011). Because of this characteristic, the evaluation of the autonomic cutaneous innervation of the extremities by unmyelinated C fibers is particularly relevant in this disease. A few studies addressed this issue. At distal limb level, sudomotor innervation was assessed in patients with TTR-FAP by sympathetic skin reflex recording (Montagna et al., 1996; Alves et al., 1997; Shivji and Ashby, 1999; Conceição et al., 2008, 2014; Lefaucheur et al., 2013, 2015; Castro et al., 2016), quantitative sudomotor axon reflex testing (QSART) (Wang et al., 2008; Kim et al., 2009), and sweat gland quantitation in skin biopsy (Chao et al., 2015).

https://ift.tt/2GYJdHa

Quantitative EEG reflects Non-Dopaminergic Disease Severity in Parkinson’s Disease

Parkinson's Disease (PD) is a multisystem neurodegenerative disorder, caused by progressive degeneration of both dopaminergic and non-dopaminergic neurons (Jellinger, 2012). Dopaminergic neurons account primarily for the characteristic motor symptoms of PD, whilst non-dopaminergic neurons account for non-motor symptoms such as impaired cognition, psychiatric manifestations or sleep disturbances. PD is typically treated with oral dopaminergic medication, which alleviates motor symptoms. However, medication-related motor complications occur in the majority of patients within 10 years of disease (Ahlskog et al., 2001).

https://ift.tt/2IXOG77

Early differentiation of Dementia with Lewy bodies and Alzheimer’s disease: Heart rate variability at mild cognitive impairment stage

Dementia with Lewy bodies (DLB) is the second most common type of degenerative dementia after Alzheimer's disease (AD). Mild cognitive impairment (MCI) is well-known as a precursor of AD, but often also precedes DLB (Ferman et al., 2013; Jicha et al., 2010; McKeith et al., 2016; Yoshizawa et al., 2013). Early differentiation of DLB from AD at MCI stage is crucial for early intervention and prognosis (Bergstrom et al., 2016; Sevigny et al., 2016). However, clinical diagnosis of DLB in the early stages can be difficult because few patients display all of the core clinical features, which leads to low sensitivity of current DLB criteria (Nelson et al., 2010).

https://ift.tt/2so8aXd

Rapid Eye Movement Sleep Behavior Disorder and the Link to Alpha-Synucleinopathies

Rapid eye movement (REM) sleep, which occupies approximately 20-25% of total sleep time, is a cyclical sleep state, occurring in intervals of 90-120 minutes during the night. Normally, during REM sleep, there is active inhibition of motor activity, which results in complete or near- complete muscle atonia. Atonia results from an interplay of multiple neurotransmitter systems, with a decrease in excitatory activity and increase in the inhibitory glycinergic and GABAergic premotor neuronal input to motor neurons.

https://ift.tt/2IV1Fq5

Motor Unit Number Index (MUNIX) and the Chowkidar

Clinical neurophysiological techniques have been utilized in research for many years, ranging from the simplest measures, such as nerve conductions, to the more sophisticated, such as quantitative electromyography and motor unit number estimation (MUNE). Motor unit number index (MUNIX) is a relatively new and novel form of MUNE that combines the recording of a compound muscle action potential (CMAP) with surface-recorded EMG signal (Nandedkar et al 2004). Similar to other MUNE techniques, the CMAP is the conditio sine qua non of the technique (de Carvalho, et al 2018).

https://ift.tt/2spkF4L

TAYTULLA (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) by Allergan: Recall - Due to Out of Sequence Capsules

[Posted 05/29/2018] AUDIENCE: Patient, Pharmacy, Health Professional ISSUE: Allergan recently identified, through a physician report, that four placebo capsules were placed out of order in a sample pack of TAYTULLA and the first four days of...

https://ift.tt/2kxmxVF

Monthly News Roundup - May 2018

Aimovig Cleared as First-In-Class for Migraine Prevention Migraines are painful, debilitating headaches that can negatively affect a patient's work and quality-of-life. This month the U.S. Food and Drug Administration (FDA) approved Amgen's...

https://ift.tt/2sgsnPh

Hierarchical protein export mechanism of the bacterial flagellar type III protein export apparatus

Abstract

The bacterial flagellum is supramolecular motility machinery consisting of the basal body, the hook and the filament. Flagellar proteins are translocated across the cytoplasmic membrane via a type III protein export apparatus, diffuse down the central channel of the growing structure and assemble at the distal end. Flagellar assembly begins with the basal body, followed by the hook and finally the filament. The completion of hook assembly is the most important morphological checkpoint of the sequential flagellar assembly process. When the hook reaches its mature length of about 55 nm in Salmonella enterica, the type III protein export apparatus switches export specificity from proteins required for the structure and assembly of the hook to those responsible for filament assembly, thereby terminating hook assembly and initiating filament assembly. Three flagellar proteins, namely FliK, FlhB and FlhA, are responsible for this substrate specificity switching. Upon completion of the switching event, interactions among FlhA, the cytoplasmic ATPase complex and flagellar type III export chaperones establish the assembly order of the filament at the hook tip. Here, we describe our current understanding of a hierarchical protein export mechanism used in flagellar type III protein export.

https://ift.tt/2sjLpU8

Fatty acids and their amide derivatives from endophytes: new therapeutic possibilities from a hidden source

Abstract

Fatty acid and their amide derivatives are natural self-defense agents in plants. They have been observed to be broadly bioactive against a variety of disease agents. The mechanism of action understood so far being their targeting the protein synthesis and causing leakage of the intracellular components. Owing to their broad bioactivity, the fatty acids and their amides as therapeutics can cover a wide range of indications such as cancer, bacterial infections, parasitic infection, inflammations, diabetes and obesity to name a few. The microorganisms residing inside the healthy plant tissues are a unique niche for exploration of novel bioactive compounds. The recent identification of fatty acid amide derivatives as well as prior reports from endophytes have drawn fresh attention to this unique source for their isolation. Hence, they represent an exciting opportunity for the development of new therapeutic agents against existing disease causative agents. In this paper, we will discuss the production of fatty acids and amide derivatives by plants and their associated endophytes. Their reported bioactivities establishing their potential benefit as possible therapeutic agents will also be examined.

https://ift.tt/2IRbK7c

TAYTULLA (norethindrone acetate and ethinyl estradiol capsules and ferrous fumarate capsules) by Allergan: Recall - Due to Out of Sequence Capsules

[Posted 05/29/2018] AUDIENCE: Patient, Pharmacy, Health Professional ISSUE: Allergan recently identified, through a physician report, that four placebo capsules were placed out of order in a sample pack of TAYTULLA and the first four days of...

https://ift.tt/2kxmxVF

Bulk and Thin Film Synthesis of Compositionally Variant Entropy-stabilized Oxides

The synthesis of high quality bulk and thin film (Mg0.25(1-x)CoxNi0.25(1-x)Cu0.25(1-x)Zn0.25(1-x))O and (Mg0.25(1-x)Co0.25(1-x)Ni0.25(1-x)CuxZn0.25(1-x))O entropy-stabilized oxides is presented.

https://ift.tt/2JixNmY

Horizontal gaze palsy with progressive scoliosis: a case report with magnetic resonance tractography and electrophysiological study

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive congenital anomaly characterized by horizontal gaze limitation and progressive scoliosis. We investigated the underlying p...

https://ift.tt/2H00z6B

Dyke-Davidoff-Masson syndrome: a case report

Dyke-Davidoff-Masson syndrome is a rare condition of unknown frequency resulting from brain injury due to a multitude of causes; especially in early life. Characteristics include cerebral hemiatrophy/hypoplasi...

https://ift.tt/2kwieK2

Unusual presentation of a skull base mass lesion in sarcoidosis mimicking malignant neoplasm: a case report

Sarcoidosis is a multi-organ disease of unknown etiology characterised by the presence of epithelioid granulomas, without caseous necrosis. Systemic sarcoidosis is rare among children, while neurosarcoidosis i...

https://ift.tt/2snc6aR

Urine IP-10 as a biomarker of therapeutic response in patients with active pulmonary tuberculosis

Prior to clinical trials of new TB drugs or therapeutic vaccines, it is necessary to develop monitoring tools to predict treatment outcomes in TB patients. Urine interferon gamma inducible protein 10 (IP-10) i...

https://ift.tt/2L5RfQT

Lessons learned from the 2009–2010 H1N1 outbreak for the management of the 2013 silent polio outbreak

The Israeli Ministry of Health (MoH) encountered two substantial outbreaks during the past decade: the H1N1 swine flu outbreak during 2009–2010 and the silent polio outbreak during 2013. Although both outbreak...

https://ift.tt/2LG7ntx

A pill for the partner via the chlamydia patient? Results from a mixed method study among sexual health care providers in the Netherlands

Chlamydia prevalence in the Netherlands remains high despite targeted efforts. Effective Partner Notification (PN) and Partner Treatment (PT) can interrupt transmission and prevent re-infections. Patient Initi...

https://ift.tt/2L7vPCZ

Progression into sepsis: an individualized process varying by the interaction of comorbidities with the underlying infection

Development of sepsis is a process with significant variation among individuals. The precise elements of this variation need to be defined. This study was designed to define the way in which comorbidities cont...

https://ift.tt/2LIdo8X

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing Aβ deposition

It is well known that Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and synaptic dysfunction play importa...

https://ift.tt/2L6PWkz

Mortality in Puerto Rico after Hurricane Maria

The tropical cyclone Hurricane Maria made landfall in Puerto Rico, a territory of the United States, on September 20, 2017. It compounded the destruction caused by Hurricane Irma 2 weeks earlier, damaging roads and interrupting the water supply, electricity, telecommunications networks, and access…

https://ift.tt/2sczh8r

Experimental Cancer Drug Metarrestin Targets Metastatic Tumors

Researchers have struggled to develop therapies to treat tumors that have spread to other parts of the body. In a new study, researchers tested whether the experimental drug metarrestin can selectively shrink metastases in mouse models of aggressive pancreatic cancer.

https://ift.tt/2LIVhj8

Novel Techniques for Observing Structural Dynamics of Photoresponsive Liquid Crystals

Here, we present the protocols of differential-detection analyses of time-resolved infrared vibrational spectroscopy and electron diffraction which enable observations of the deformations of local structures around photoexcited molecules in a columnar liquid crystal, giving an atomic perspective on the relationship between the structure and the dynamics of this photoactive material.

https://ift.tt/2xxWIhJ

Mortality in Puerto Rico after Hurricane Maria

The tropical cyclone Hurricane Maria made landfall in Puerto Rico, a territory of the United States, on September 20, 2017. It compounded the destruction caused by Hurricane Irma 2 weeks earlier, damaging roads and interrupting the water supply, electricity, telecommunications networks, and access…

https://ift.tt/2sczh8r

Trans-inner Cell Mass Injection of Embryonic Stem Cells Leads to Higher Chimerism Rates

Here we present a protocol to increase chimera production without the use of new equipment. A simple orientation change of the embryo for injection can increase the number of embryos produced, and potentially reduce the timeline to germline transmission.

https://ift.tt/2LGI6j2

Predicting and Understanding Cancer Response to Treatment

https://ift.tt/2xkULF7

Mortality in Puerto Rico after Hurricane Maria

The tropical cyclone Hurricane Maria made landfall in Puerto Rico, a territory of the United States, on September 20, 2017. It compounded the destruction caused by Hurricane Irma 2 weeks earlier, damaging roads and interrupting the water supply, electricity, telecommunications networks, and access…

https://ift.tt/2sczh8r

Human Enteric α-Defensin 5 Promotes Shigella Infection by Enhancing Bacterial Adhesion and Invasion

How Shigella can be infectious in humans despite lacking clear mechanisms for mucosal adhesion remains a long-standing enigma concerning its pathogenesis. Xu et al. demonstrate that Shigella exploits the host defense peptide HD5 in the gut to attain its ability to colonize and destroy the intestinal epithelium.

https://ift.tt/2ITIfl9

The Tumor Necrosis Factor Superfamily Member RANKL Suppresses Effector Cytokine Production in Group 3 Innate Lymphoid Cells

Although signals that activate group 3 ILCs (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Bando et al. demonstrate that the TNF superfamily member RANKL suppresses the abundance and effector functions of intestinal CCR6+ ILC3s and that RANKL-mediated suppression occurs through ILC3-ILC3 interactions.

https://ift.tt/2ISCJzf

Transcription Factor IRF8 Orchestrates the Adaptive Natural Killer Cell Response

The link between human IRF8 mutations and immunodeficiency is poorly understood. Adams et al. demonstrate that IRF8 is required for NK-cell-mediated antiviral immunity by promoting proliferation of virus-specific NK cells.

https://ift.tt/2xoaNOs

Hemogenic Endothelial Fate Mapping Reveals Dual Developmental Origin of Mast Cells

Gentek et al. demonstrate that Cdh5-CreERT2 can be used to selectively fate map yolk sac and definitive hematopoiesis. Temporally defined Cdh5-CreERT2 lineage tracing reveals that mast cells are yolk sac derived in the embryo but replaced by definitive hematopoiesis in the adult, a feature they share with macrophages.

https://ift.tt/2ISCGn3

Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance

Extrathymically generated regulatory (pTreg) cells are induced by bacterial products at mucosal sites. In this issue, Campbell et al. show that pTreg cell deficiency impedes the establishment of a subset of intestinal bacteria due to heightened immune responses, with significant effects on host metabolites and fitness.

https://ift.tt/2IYuLRh

X-Jow and Acne Shave Products by Shadow Holdings: Voluntary Recall - Due to Possible Bacterial Contamination

[Posted 05/29/2018] AUDIENCE: Consumer ISSUE: The products may be contaminated with bacteria. Topical administration of the products could result in potentially serious bacterial infections in immunocompromised...

https://ift.tt/2xuqWSK

PD-L1-Expressing Radiation-Associated Angiosarcoma after Primary Breast Cancer

Radiation-associated angiosarcoma (RAAS) is a type of radiation-associated sarcoma (RAS) that develops at the previous field of radiation in breast cancer patients. Although several reports have suggested a poor prognosis for RAAS, the 5-year overall survival of RAAS is better than that of cutaneous angiosarcoma (CAS), suggesting that the prognostic factors of RAAS and CAS might be different, at least in part. In this report, we describe a case of RAAS, and employed immunohistochemical (IHC) staining of PD-L1 and MMP9 as well as periostin, IL-4, and CD163. Interestingly, IHC staining revealed that the RAAS in our case was positive for PD-L1 and negative for MMP9. Moreover, the predominant stromal factor of our case was periostin, suggesting that TAMs in the present case was not immunosuppressive, but an inflammatory subtype. These results might explain, at least in part, the better prognosis of RAAS compared to CAS.
Case Rep Oncol 2018;11:330–335

https://ift.tt/2IUJUqS

Small-Cell Carcinoma Transformation of Pulmonary Adenocarcinoma after Osimertinib Treatment: A Case Report

There are various mechanisms underlying the resistance of EGFR-mutant lung adenocarcinoma to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We herein report a case of pulmonary adenocarcinoma with EGFR mutation (exon 19 deletion and T790M) that acquired resistance to osimertinib treatment because of transformation into small-cell lung carcinoma (SCLC). A 67-year-old ex-smoking woman was diagnosed with left upper lobe adenocarcinoma of clinical stage IIIA (cT2bN2M0). She was treated with chemoradiotherapy (cisplatin and vinorelbine plus radiation), gefitinib, cisplatin, and pemetrexed followed by pemetrexed maintenance therapy and erlotinib. Since a sample extracted from the metastatic lung tumor taken obtained via a transbronchial lung biopsy was found to be positive for the T790M mutation at the time of disease progression during erlotinib treatment, she received osimertinib treatment for 15 months until progressive disease. She developed resistance to osimertinib due to the histologic transformation to SCLC. Although the standard chemotherapy of carboplatin and etoposide for SCLC was administered, she died due to metastatic liver failure.
Case Rep Oncol 2018;11:323–329

https://ift.tt/2IY0KRF

Intramammary Metastasis in a Patient with a History of Renal Cell Carcinoma: A Case Report

Intramammary metastasis of renal cell carcinoma (RCC) is extremely rare, accounting for only 1.5% of all intramammary metastases. Distinguishing intramammary metastases from benign tumors and breast cancer is clinically problematic. Some patients undergo excessive surgery after a misdiagnosis of breast cancer instead of a mammary tumor. We performed a core needle biopsy (CNB) of a breast mass that developed in a 71-year-old woman after surgeries for bilateral RCC and breast cancer, leading to a diagnosis of intramammary metastasis of RCC. In this case, the CNB and immunohistochemical examination were critical for reaching a definitive diagnosis. We conclude that, when examining patients with mammary tumors, establishing their history of malignant tumors may help diagnose intramammary metastasis and select the best treatment strategy.
Case Rep Oncol 2018;11:318–322

https://ift.tt/2LGmt2k

An Inguinal Perivascular Epithelioid Cell Tumor Metastatic to the Orbit

Malignant PEComas are rare mesenchymal neoplasms. These tumors harbor distinct myomelanocytic phenotype. The PEComa family of tumors includes lymphangioleiomyomatosis, angiomyolipoma, clear cell sugar tumor of the lung, and myomelanocytic tumor of the falciparum ligament/ligamentum teres. PEComas have no known normal cell counterpart. Majority of PEComas are benign and occur predominantly in the middle-age women. These tumors are commonly encountered in the uterus. Herein, we report a 20-year-old woman with a left inguinal mass metastatic to orbit, brain, lumbar spine, and skin at presentation. To our knowledge, this is the first case of metastatic PEComa to the orbit. This is the third case of primary PEComa of the inguinal area.

https://ift.tt/2sl89mQ

ESGAR 2018 Book of Abstracts

https://ift.tt/2GYQ6s7

X-Jow and Acne Shave Products by Shadow Holdings: Voluntary Recall - Due to Possible Bacterial Contamination

[Posted 05/29/2018] AUDIENCE: Consumer ISSUE: The products may be contaminated with bacteria. Topical administration of the products could result in potentially serious bacterial infections in immunocompromised...

https://ift.tt/2xuqWSK

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner, Published online: 29 May 2018; doi:10.1038/s41419-018-0697-4

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner

https://ift.tt/2sf6cZM

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats, Published online: 29 May 2018; doi:10.1038/s41419-018-0701-z

Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats

https://ift.tt/2xob4Rt

The kinase receptor-interacting protein 1 is required for inflammasome activation induced by endoplasmic reticulum stress

The kinase receptor-interacting protein 1 is required for inflammasome activation induced by endoplasmic reticulum stress

The kinase receptor-interacting protein 1 is required for inflammasome activation induced by endoplasmic reticulum stress, Published online: 29 May 2018; doi:10.1038/s41419-018-0694-7

The kinase receptor-interacting protein 1 is required for inflammasome activation induced by endoplasmic reticulum stress

https://ift.tt/2sfcgBI

Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment

Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment

Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-<i>trans</i> retinoic acid treatment, Published online: 29 May 2018; doi:10.1038/s41419-018-0699-2

Profiling and functional analysis of circular RNAs in acute promyelocytic leukemia and their dynamic regulation during all-trans retinoic acid treatment

https://ift.tt/2IWBFX3

Macrophage inducible nitric oxide synthase promotes the initiation of lung squamous cell carcinoma by maintaining circulated inflammation

Macrophage inducible nitric oxide synthase promotes the initiation of lung squamous cell carcinoma by maintaining circulated inflammation

Macrophage inducible nitric oxide synthase promotes the initiation of lung squamous cell carcinoma by maintaining circulated inflammation, Published online: 29 May 2018; doi:10.1038/s41419-018-0653-3

Macrophage inducible nitric oxide synthase promotes the initiation of lung squamous cell carcinoma by maintaining circulated inflammation

https://ift.tt/2sgJEbc

DSGOST regulates resistance via activation of autophagy in gastric cancer

DSGOST regulates resistance via activation of autophagy in gastric cancer

DSGOST regulates resistance via activation of autophagy in gastric cancer, Published online: 29 May 2018; doi:10.1038/s41419-018-0658-y

DSGOST regulates resistance via activation of autophagy in gastric cancer

https://ift.tt/2IWBuLn

CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma

CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma

CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma, Published online: 29 May 2018; doi:10.1038/s41419-018-0681-z

CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma

https://ift.tt/2JegWl6

Correction: MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

Correction: MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

Correction: MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy, Published online: 29 May 2018; doi:10.1038/s41419-018-0637-3

Correction: MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy

https://ift.tt/2IWBivD

Evaluation and Management of Hematopoietic Failure in Dyskeratosis Congenita

Dyskeratosis congenita (DC) is a rare, inherited bone marrow failure (BMF) syndrome characterized by variable manifestations and ages of onset, and predisposition to cancer. DC is one of a spectrum of diseases caused by mutations in genes regulating telomere maintenance, collectively referred to as telomere biology disorders (TBDs). Hematologic disease is common in children with DC/TBD. Timely diagnosis of underlying TBD in patients with BMF affects treatment and has been facilitated by increased awareness and availability of diagnostic tests in recent years. This article summarizes the pathophysiology, evaluation, and management of hematopoietic failure in patients with DC and other TBDs.

https://ift.tt/2kvGwEe

Germline GATA2 Mutation and Bone Marrow Failure

GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.

https://ift.tt/2H1fMEa