Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis

Abstract

Background

The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results.

Objective

To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens.

Patients and Methods

Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle.

Results

Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9–13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6–39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5–14.3) and 30.6 months (95% CI 25.2–36.1) for cohort A, 9.7 (95% CI 9.1–10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8–13.2) and 37.9 months (95% CI 28.6–47.3) for cohort C, respectively.

Conclusions

Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.

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Pilot trial of inosine to elevate urate levels in amyotrophic lateral sclerosis

Annals of Clinical and Translational Neurology, EarlyView.


https://ift.tt/2CX4lzS

Ethanol from olive paste during malaxation, exploratory experiments

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2CAyGDC

NMR studies on Italian PDO olive oils and their potential in olive tree‐derived products characterization

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AnOmbR

Food genomics for the characterization of PDO and PGI virgin olive oils

European Journal of Lipid Science and Technology, Volume 0, Issue ja, -Not available-.


https://ift.tt/2CySfMh

Biomechanical parameters of the elbow stretch reflex in chronic hemiparetic stroke

Abstract

We sought to determine the relative velocity sensitivity of stretch reflex threshold angle and reflex stiffness during stretches of the paretic elbow joint in individuals with chronic hemiparetic stroke, and to provide guidelines to streamline spasticity assessments. We applied ramp-and-hold elbow extension perturbations ranging from 15 to 150°/s over the full range of motion in 13 individuals with hemiparesis. After accounting for the effects of passive mechanical resistance, we modeled velocity-dependent reflex threshold angle and torque–angle slope to determine their correlation with overall resistance to movement. Reflex stiffness exhibited substantially greater velocity sensitivity than threshold angle, accounting for ~ 74% (vs. ~ 15%) of the overall velocity-dependent increases in movement resistance. Reflex stiffness is a sensitive descriptor of the overall velocity-dependence of movement resistance in spasticity. Clinical spasticity assessments can be streamlined using torque–angle slope, a measure of reflex stiffness, as their primary outcome measure, particularly at stretch velocities greater than 100°/s.

https://ift.tt/2JbhDt0

EVI1 expression is associated with aggressive behavior in intrahepatic cholangiocarcinoma

Abstract

Ecotropic virus integration site 1 protein homolog (EVI1), a well-known oncogenic transcriptional factor of hematopoietic cells, contributes to pancreatic cancer oncogenicity through increased expression of KRAS. Because EVI1 was upregulated in cholangiocarcinoma by referring The Cancer Genome Atlas, we investigated the importance of EVI1 in intrahepatic cholangiocarcinoma (ICC) which has been regarded as a heterogeneous group of cancers. Immunohistochemical analysis results demonstrated that EVI1 was overexpressed in about half of ICC (53/101, 52.5%). Moreover, all intraductal papillary neoplasms of the bile duct cases expressed EVI1 regardless of histological grading and subtypes such as gastric, intestinal, pancreatobiliary, or oncocytic (20/20, 100%). EVI1-positive ICC showed higher frequencies of aggressive pathological indicators such as periductal infiltrative growth (p = 0.022), hilar invasion (p = 0.041), advanced UICC stage (p = 0.026), major vascular invasion (p = 0.026), and perineural invasion (p = 0.007) than EVI1-negative ICC. Patients with EVI1-positive ICC showed worse overall survival and recurrence-free survival in all resected cases and in curative resected cases. Recently, we proposed type 1/2 (large/small duct types) classification of ICC based on mucin productivity and immunophenotypes (S100P, N-cadherin, and NCAM). Type 1 predominantly consisted of EVI1-positive ICC (33/42 cases, 79%), and the frequency was significantly higher than type 2 (18/55 cases, 32.7%) (p < 0.0001). EVI1-positive ICC was likely to express stomach-specific claudin CLDN18 (correlation coefficient r = 0.55373) and mucin MUC5AC (r = 0.42718). EVI1-positive ICC is an aggressive ICC showing both large-duct and/or gastric phenotypes. Consequently, a transcriptional factor EVI1 is associated with aggressive behavior in ICC and can be a therapeutic target molecule, while EVI1 might be a key molecule for the development of intraductal papillary neoplasms of the bile duct.

https://ift.tt/2AniOCR

Genetic Variants in the Wingless Antagonist Genes (sFRP, DKK, and Axin2) Predict the Overall Survival and Prognosis of North Indian Lung Cancer Patients Treated with Platinum-Based Doublet Chemotherapy

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


https://ift.tt/2PbVLmL

Tox and Hound – Dust To Dust

by Howard Greller Sudden sniffing death and myocardial sensitization I will show you fear in a handful of dust. – T.S. Eliot Little Johnny was having a hard time. Dumped by his girlfriend of eight glorious weeks, he was despondent. There wasn't any alcohol in the house, and he didn't have a fake ID or the […]

EMCrit Project by Tox & Hound.

https://ift.tt/2AmUgcZ

Profiles of vagal withdrawal to challenging interactions: Links with preschoolers’ conceptual shifting ability

Developmental Psychobiology, EarlyView.


https://ift.tt/2yUl4j4

Case presentation: persistent adenovirus B3 infections associated with bronchiolitis obliterans treated with cidofovir in a child with mosaic tetrasomy 9p

Adenoviruses (AdV) are non-enveloped, double-stranded DNA viruses with multiple serotypes, which cause a variety of end-organ disease in both immunocompetent and immunocompromised individuals. Some adenoviruse...

https://ift.tt/2yRSWNo

The epidemiology of Taenia spp. infection and Taenia solium cysticerci exposure in humans in the Central Highlands of Vietnam

Vietnam is endemic for taeniasis and T. solium cysticercosis. Despite this, information on the epidemiological characteristics of the diseases in the Central Highlands of Vietnam are poorly described. The aims of...

https://ift.tt/2S8VZcQ

Risk of pregnancy complications and adverse birth outcomes after maternal A(H1N1)pdm09 influenza: a Norwegian population-based cohort study

The effects of maternal influenza infection on the fetus remain unclear. We studied mild influenza and influenza antibodies in relation to birth weight and risks of pre-eclampsia, preterm birth (PTB), and smal...

https://ift.tt/2yRSIWy

The role of socioeconomic and climatic factors in the spatio-temporal variation of human rabies in China

Rabies is a significant public health problem in China. Previous spatial epidemiological studies have helped understand the epidemiology of animal and human rabies in China. However, quantification of effects ...

https://ift.tt/2SaMCcM

Reactive plasmacytosis mimicking multiple myeloma associated with SFTS virus infection: a report of two cases and literature review

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by a novel bunyavirus named SFTS virus (SFTSV), which is classified into the genus Phlebovirus and family Phenuiviridae....

https://ift.tt/2yTQ9Dh

The E2F1-miR-520/372/373-SPOP axis modulates progression of renal carcinoma

Although renal cell carcinoma (RCC) is the most malignant urological cancer, its pathogenesis remains unclear, and effective treatments for advanced RCC are still lacking. Here we report that a novel E2F1-miR-520/372/373-SPOP axis controls RCC carcinogenesis. Speckle-type POZ protein (SPOP) was upregulated in over 90% of RCC tissues, whereas the miR-520/372/373 family was downregulated and correlated inversely with SPOP protein levels in RCC tissues. The miR-520/372/373 family targeted the SPOP 3'-UTR and suppressed SPOP protein expression, leading to elevation of PTEN and DUSP7 levels and, consequently, decreased proliferation, invasion/migration, and metastasis of RCC cells in vitro and in vivo. Tail vein delivery of therapeutic miR-520/372/373 family significantly decreased both tumor size and lung metastasis ratio in mice bearing orthotopic xenograft tumors. Decreased expression of miR-520/372/373 family was mediated by transcription factor E2F1. In conclusion, our results demonstrate that the E2F1-miR-520/372/373-SPOP axis functions as a key signalling pathway in RCC progression and metastasis and represents a promising opportunity for targeted therapies.

https://ift.tt/2S6dtqe

A novel germline variant in CSF3R reduces N-glycosylation and exerts potent oncogenic effects in leukemia

Mutations in the colony stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as AML. Here we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation.

https://ift.tt/2yTOgqb

Spatiotemporal loss of NF1 in Schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the Hippo pathway [Research Articles]

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor-suppressor Neurofibromin, a negative regulator of RAS signaling. NF1 patients present with a wide range of clinical manifestations and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that Hoxb7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the Hoxb7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today.

https://ift.tt/2Am9wqv

Cellular origin, tumour progression and pathogenic mechanisms of cutaneous neurofibromas revealed by mice with Nf1 knockout in boundary cap cells [Research Articles]

Patients carrying an inactive NF1 allele develop tumours of Schwann cell origin called neurofibromas (NFs). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNFs). However, this has not been the case for cutaneous neurofibromas (cNFs), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs, and provides insights on disease mechanisms, revealing a long, multistep pathological process in which inflammation-related signals play pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.

https://ift.tt/2CA9dKb

Impact of Combination Therapy vs Monotherapy on Mortality from Carbapenem-Resistant Enterobacteriaceae Bacteremia: A Retrospective Observational Study from a Chinese Network [Clinical Therapeutics]

A total of 164 bloodstream infection cases due to carbapenem-resistant Enterobacteriaceae (CRE) in 2013-2017 were retrospectively collected from 36 tertiary hospitals in 19 provinces in China to evaluate outcomes and risk factors for mortality by univariable and multivariable analysis. The most frequent infected species was Klebsiella pneumoniae (69.5%, 114/164). The overall in-hospital and 14-day mortality were 32.9% (54/164) and 31.1% (42/135), respectively. Multivariable analysis revealed that septic shock (adjusted odds ratio [aOR] 6.339, 95% confidence interval [CI] 1.586-25.332, P = 0.009), Pitt bacteremia score (aOR 1.300, 95% CI 1.009-1.676, P = 0.042), and Charlson comorbidity index (aOR 1.392, 95% CI 1.104-1.755, P = 0.005) were independently associated with hazard effect on mortality. Combination therapy, especially tigecycline-based combination therapy had the lowest in-hospital mortality and rates of bacterial clearance. Survival analysis revealed that appropriate therapy was associated with lower 14-day mortality than inappropriate therapy (including non-active therapy, P = 0.022); combination therapy was superior to monotherapy (P = 0.036); metallo-β-lactamase producers resulted in lower 14-day mortality than strains without carbapenemases or KPC-2 producers (P = 0.009); strains with minimum inhibitory concentrations (MICs) > 8 mg/L for meropenem were associated with higher 14-day mortality than that with MICs ≤ 8 mg/L (P = 0.037). Collectively, severity of illness, meropenem MICs > 8 mg/L, carbapenemase-producing types are associated with clinical outcome. Early detection of carbapenemase type and initiating appropriate combination therapy within 96 h might be helpful for improving survival.

https://ift.tt/2POboO9

Phylogenomic analysis of extraintestinal pathogenic Escherichia coli ST1193, an emerging multidrug-resistant clonal group [Epidemiology and Surveillance]

The fluoroquinolone-resistant ST1193 clonal group of Escherichia coli, from the ST14 clonal complex (STc14) within phylogenetic group B2, has appeared recently as an important cause of extraintestinal disease in humans. Although this emerging lineage has been characterized to some extent using conventional methods, it has not been studied extensively at the genomic level. Here, we used whole genome sequence analysis to compare 355 ST1193 isolates with 72 isolates from other STs within STc14. Using core genome phylogeny, the ST1193 isolates formed a tightly clustered clade with many genotypic similarities, as compared to ST14 isolates. All ST1193 isolates possessed the same set of three chromosomal mutations conferring fluoroquinolone resistance, carried the fimH64 allele, and were lactose non-fermenting. Analysis revealed an evolutionary progression from K1 to K5 capsular types and acquisition of an F-type virulence plasmid followed by changes in plasmid structure congruent with genome phylogeny. In contrast, the numerous identified antimicrobial resistance genes were distributed incongruently with the underlying phylogeny, suggesting frequent gain or loss of the corresponding resistance gene cassettes despite retention of the presumed carrier plasmids. Pangenome analysis revealed gains and losses of genetic loci occurring during the transition from ST14 to ST1193, and from the K1 to K5 capsular types. Using time-scaled phylogenetic analysis, we estimated that current ST1193 clades first emerged approximately 25 years ago. Overall, ST1193 appears to be a recently emerged clone in which both stepwise and mosaic evolution likely have contributed to epidemiologic success.

https://ift.tt/2Peft18

Emergence of Salmonella genomic island 1 variant SGI1-W in a clinical isolate of Providencia stuartii from Egypt [Letters]

Most of the variants of Salmonella genomic island 1 (SGI1) are multidrug resistance (MDR) DNA elements that can be transferred by horizontal gene transfer (HGT) (1)....

https://ift.tt/2PObC7X

Identification of functional MKK3/6 and MEK1/2homologs from Echinococcus granulosus and investigation of protoscolecidal activity of MAPK signaling pathway inhibitors in vitro and in vivo [Experimental Therapeutics]

Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of MAPK cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from E. granulosus sensu stricto. Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and co-immunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate, myelin basic protein. When sorafenib tosylate, PD184352 or U0126-EtOH were added to the medium for in vitro culture of E. granulosus protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Non-viability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassay, i.e. inoculation of treated and untreated protoscoleces into mice. In vivo treatment with sorafenib tosylate or U0126-EtOH for 4 weeks of E. granulosus s.s.-infected mice demonstrated a reduction in parasite weight, but the results did not show significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development and E. granulosus was efficiently inhibited by their inhibitors in vitro. The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.

https://ift.tt/2PiL01Q

THE REACTION MECHANISM OF METALLO-{beta}-LACTAMASES IS TUNED BY THE CONFORMATION OF AN ACTIVE SITE MOBILE LOOP [Mechanisms of Resistance]

Carbapenems are "last resort" β-lactam antibiotics, used to treat serious and life-threatening healthcare-associated infections caused by multidrug resistant Gram-negative bacteria. Unfortunately, the worldwide spread of genes coding for carbapenemases among these bacteria is threatening these life-saving drugs. Metallo-β-Lactamases (MβLs) are the largest family of carbapenemases. These are Zn(II)-dependent hydrolases that are active against almost all β-lactam antibiotics. Their catalytic mechanism and the features driving substrate specificity have been matter of intense debate. The active sites of MβLs are flanked by two loops, one of which, loop L3, was shown to adopt different conformations upon substrate or inhibitor binding, and thus being expected to play a role in substrate recognition. However, the sequence heterogeneity observed in this loop in different MβLs has limited the generalizations about its role. Herein we report the engineering of different loops within the scaffold of the clinically relevant carbapenemase NDM-1. We find that the loop sequence dictates its conformation in the unbound form of the enzyme, eliciting different degrees of active site exposure. However, these structural changes have a minor impact on the substrate profile. Instead, we report that the loop conformation determines the protonation rate of key reaction intermediates accumulated during the hydrolysis of different β-lactams in all MβLs. This study demonstrates the existence of a direct link between the conformation of this loop and the mechanistic features of the enzyme, bringing to light an unexplored function of active site loops on MβLs.

https://ift.tt/2PQkYjM

Ceftriaxone absorption enhancement for noninvasive administration as an alternative to injectable solutions [Clinical Therapeutics]

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop non-injectable formulations that can reduce treatment delays in resource limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via non-parenteral administration. This article presents all available ceftriaxone human and animal non-parenteral absorption data, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new rabbit pre-clinical data and discusses the importance of these data for the development of non-injectable formulations for non-invasive treatment. The combined results indicate that rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, Chenodeoxycholate sodium salt (Na-CDC) used as an absorption enhancer at a 125 mg dose together with a 500 mg dose of ceftriaxone, provided 24% rectal absorption of ceftriaxone and Cmax of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for bioavailability of other formulations before human assessment.

https://ift.tt/2PiYZ7K

OXA-23, a prevalent mechanism contributing to sulbactam resistance in diverse Acinetobacter baumannii clinical strains [Letters]

Acinetobacter baumannii is one of the most important and threatening pathogens for healthcare-associated infections (HAI), and the treatment for multidrug-resistant A. baumannii (MDRAB) are limited(1, 2)....

https://ift.tt/2PQkQAO

Promising new antifungal treatment targeting chorismate synthase from Paracoccidioides brasiliensis [Chemistry; Biosynthesis]

Paracoccidioidomycosis (PCM), caused by the Paracoccidioides species, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacologic criteria (adsorption-destribution-metabolism-excretion-toxicity) and was, therefore, used in in vitro experiments. Here, we demonstrate that CP1 binds with a dissociation constant of 64±1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity with an IC₅₀ value of 47±5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, the histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with less inflammatory response and is, therefore, a promising candidate and lead structure for the development of drugs useful in PCM treatment.

https://ift.tt/2PfTM0C

Unveiling the mechanisms of in vitro evolution towards fluconazole resistance of a Candida glabrata clinical isolate: a transcriptomics approach [Mechanisms of Resistance]

Candida glabrata is an emerging fungal pathogen. Its increased prevalence is associated to its ability to rapidly develop antifungal drug resistance, particularly to azoles.

In order to unravel new molecular mechanisms behind azole resistance, a transcriptomics analysis of the evolution of a C. glabrata clinical isolate (044) from azole susceptibility to posaconazole resistance (21^st day), clotrimazole resistance (31^st day) and fluconazole and voriconazole resistance (45^th day), induced by longstanding incubation with fluconazole, was carried out. All the evolved strains were found to accumulate lower concentrations of azole drugs, when compared to the parental strain, while the ergosterol concentration remained mostly constant. However, only the population displaying resistance to all azoles was found to have a GOF mutation in the CgPDR1 gene, leading to the up-regulation of genes encoding multidrug resistance transporters. Intermediate strains, exhibiting posacozole/clotrimazole-resistance and increased fluconazole/voriconazole MIC levels, were found to display alternative ways to resist azole drugs. Particularly, posacozole/clotrimazole-resistance after 31 days was correlated with increased expression of adhesin genes. This finding led us to identify the Epa3 adhesin as a new determinant of azole resistance. Besides being required for biofilm formation, Epa3 expression was found to decrease the intracellular accumulation of azole antifungal drugs.

Altogether, this work provides a glimps of the transcriptomics evolution of a C. glabrata population towards multi-azole resistance, highlighting the multifactorial nature of acquisition of azole resistance, and pointing out a new player in azole resistance.

https://ift.tt/2PdiDSQ

FK506 resistance of Saccharomyces cerevisiae Pdr5 and Candida albicans Cdr1 involves mutations in the transmembrane domains and extracellular loops [Mechanisms of Resistance]

The 23-membered-ring macrolide tacrolimus, a commonly used immunosuppressant, also known as FK506, is a broad-spectrum inhibitor and an efflux pump substrate of pleiotropic drug resistance (PDR) ATP-binding cassette (ABC) transporters. Little, however, is known about the molecular mechanism by which FK506 inhibits PDR transporter drug efflux. Thus, to obtain further insights we searched for FK506-resistant mutants of Saccharomyces cerevisiae cells overexpressing either the endogenous multidrug efflux pump, Pdr5, or its Candida albicans orthologue, Cdr1. A simple, but powerful, screen gave 69 FK506-resistant mutants with, between them, 72 mutations in either Pdr5 (37) or Cdr1 (35). Twenty mutations were in just three Pdr5/Cdr1 equivalent amino acid positions T550/T540 and T552/S542 of extracellular loop 1 (EL1) and A723/A713 of EL3. Sixty of the 72 mutations were either in the ELs or the extracellular halves of individual transmembrane spans (TMSs), while 11 mutations were found near the centre of individual TMSs, mostly in predicted TMS-TMS contact points, and only two mutations were in the cytosolic nucleotide-binding domains of Pdr5. We propose that FK506 inhibits Pdr5 and Cdr1 drug efflux by slowing transporter opening and/or substrate release, and that FK506-resistance of Pdr5/Cdr1 drug efflux is achieved by modifying critical intramolecular contact points that, when mutated, enable the co-transport of FK506 with other pump substrates. This may also explain why the 35 Cdr1 mutations that caused FK506-insensitivity of fluconazole efflux differed from the 13 Cdr1 mutations that caused FK506-insensitivity of cycloheximide efflux.

https://ift.tt/2PQpdvy

Analysis of Circulating Tumor DNA and Clinical Correlates in Patients with Esophageal, Gastroesophageal Junction and Gastric Adenocarcinoma

Purpose: Esophageal, gastro-esophageal junction and gastric adenocarcinoma (herein gastroesophageal adenocarcinomas) are associated with poor prognosis and limited systemic treatment options. To further understand the genomic landscape of gastroesophageal cancers and its clinical correlations, circulating tumor DNA (ctDNA) from patients' plasma was evaluated using next-generation sequencing (NGS). Methods: We analyzed genomic alterations of 55 patients (mostly advanced disease; nine, surgically resectable) with gastroesophageal adenocarcinomas using clinical-grade NGS performed on plasma-derived ctDNA (54-73 gene panel). The test detects single nucleotide variants, as well as copy number amplifications, fusions and indels in selected genes. Results: Seventy-six percent of patients (42/55) had ≥1 genomic alteration (including variants of unknown significance [VUSs]) and 69.1% (38/55) had ≥1 characterized alteration (excluding VUSs). The median number of alterations per patient was 2 (range, 0-15). TP53 (50.9%, 28/55), PIK3CA (16.4%, 9/55), ERBB2 (14.5%, 8/55) and KRAS (14.5%, 8/55) genes were most frequently affected characterized alterations. Thirty-one patients also had tissue NGS. Concordance between tissue and ctDNA ranged from 61.3% (TP53 alterations) to 87.1% (KRAS alterations). ERBB2 alterations were significantly associated with poor overall survival (HR: 14.06, 95% CI: 2.44 - 81.03, P=0.003 multivariate analysis). Among patients with ≥1 alteration, no two patients had identical molecular portfolios. All patients with ≥1 characterized alteration had theoretically targetable alterations by an FDA-approved agent (on- or off-label). Illustrative case treated with cognate agent is presented. Conclusions: Evaluation of ctDNA by NGS among gastroesophageal adenocarcinoma patients is feasible. Patients harbored heterogeneous patterns of genomics, with most having alterations that are potentially pharmacologically tractable.

https://ift.tt/2q6gpGN

Anti-PD-1 Antibody SHR-1210 combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study

Purpose: This study assessed the safety and efficacy of SHR-1210 (anti-PD-1 antibody) and apatinib (VEGFR2 inhibitor) as combination therapy in patients with advanced hepatocellular carcinoma (HCC), gastric or esophagogastric junction cancer (GC/EGJC). Experimental Design: This was an open-label, dose-escalation (phase Ia) and expansion study (phase Ib). In phase Ia, patients (n=15) received SHR-1210 200 mg every 2 weeks and apatinib 125-500 mg once daily until unacceptable toxicity or disease progression. In phase Ib, patients (n=28) received apatinib at the phase Ia-identified recommended phase II dose (RP2D) plus SHR-1210. The primary objectives were safety and tolerability and RP2D determination. Results: At data cut-off, 43 patients were enrolled. In Phase Ia, four dose-limiting toxicity events were observed (26.7%): one grade 3 lipase elevation (6.7%) in the apatinib 250 mg cohort and three grade 3 pneumonitis events (20%) in the apatinib 500 mg cohort. The maximum tolerated RP2D for apatinib was 250 mg. Of the 33 patients treated with the R2PD combination, 20 (60.6%) experienced a grade ≥3 treatment-related adverse event; adverse events in ≥10% of patients were hypertension (15.2%) and increased aspartate aminotransferase (15.2%). The ORR in 39 evaluable patients was 30.8% (95% CI: 17.0-47.6%). Eight of 16 evaluable HCC patients achieved a partial response (50.0%, 95% CI: 24.7-75.4%). Conclusions: SHR-1210 and apatinib combination therapy demonstrated manageable toxicity in HCC and GC/EGJC patients at recommended single-agent doses of both drugs. The RP2D for apatinib as combination therapy was 250 mg, which showed encouraging clinical activity in patients with advanced HCC.

https://ift.tt/2R8Bnjt

Pan-HDAC inhibitors restore PRDM1response to IL-21 in CREBBP mutated follicular lymphoma

Purpose: Follicular lymphoma (FL) arises from a germinal center B-cell proliferation supported by a bidirectional crosstalk with tumor microenvironment, in particular with follicular helper T cells (Tfh). We explored the relation that exist between the differentiation arrest of FL cells and loss-of-function of CREBBP acetyltransferase. Experimental design: The study used human primary cells obtained from either, FL tumors characterized for somatic mutations, or inflamed tonsils for normal germinal center B cells. Transcriptome and functional analyses were done to decipher the B and T cell crosstalk. Responses assessed by flow cytometry and molecular biology including ChIP-qPCR approaches. Results: Conversely to normal B cells, FL cells are unable to upregulate the transcription repressor PRDM1, required for plasma cell differentiation. This defect occurs although the FL microenvironment is enriched in the potent inducer of PRDM1, IL-21, highly produced by Tfhs. In FL carrying CREBBP loss-of-function mutations, we found a lack of IL-21-mediated PRDM1 response associated with an abnormal increased enrichment of the BCL6 protein repressor in PRDM1gene. Moreover, in these FL cells, pan-HDAC inhibitor Vorinostat restored their PRDM1 response to IL-21 by lowering BCL6 bound to PRDM1. This finding was reinforced by our exploration of FL patients treated with another pan-HDAC inhibitor. Patients showed an increase of plasma cell-identity genes, mainly PRDM1and XBP1, which underline the progression of FL B cells in the differentiation process. Conclusion: Our data uncover a new mechanism by which pan-HDAC inhibitors may act positively to treat FL patients through the induction of the expression of plasma cell genes.

https://ift.tt/2q3nZ4R

The Ewing family of tumors rely on BCL-2 and BCL-XL to escape PARP inhibitor toxicity

Purpose: It was recently demonstrated that EWS-FLI1 contributes to the hypersensitivity of Ewing Sarcoma (ES) to PARP inhibitors, prompting clinical evaluation of olaparib in a cohort of heavily pre-treated ES patients. Unfortunately, olaparib activity was disappointing, suggesting an underappreciated resistance mechanism to PARP inhibition in ES patients. We sought to elucidate the resistance factors to PARP inhibitor therapy in ES and identify a rational drug combination capable of rescuing PARP inhibitor activity. Experimental Design: By employing a pair of cell lines derived from the same ES patient prior to and following chemotherapy, a panel of ES cell lines, and several PDX and xenograft models. Results: We found olaparib sensitivity was diminished following chemoresistance. The matched cell line pair revealed increased expression of the anti-apoptotic protein BCL-2 in the chemotherapy-resistant cells, conferring apoptotic resistance to olaparib. Resistance to olaparib was maintained in this chemotherapy-resistant model in vivo, while the addition of the BCL-2/X_L inhibitor navitoclax led to complete tumor growth inhibition. In two patient-derived xenografts, olaparib and navitoclax were minimally effective as monotherapy, yet induced dramatic tumor growth inhibition when dosed in combination. We found that EWS-FLI1 increases BCL-2 expression; however, inhibition of BCL-2 alone by venetoclax is insufficient to sensitize ES cells to olaparib, revealing a dual necessity for BCL-2 and BCL-X_L in ES survival. Conclusion: These data reveal BCL-2 and BCL-X_L act together to drive olaparib resistance in ES and reveals a novel, rational combination therapy that may be put forward for clinical trial testing.

https://ift.tt/2R8BifF

Postnatal Education Increases Pain Relief Use at Vaccinations

MONDAY, Oct. 22, 2018 -- In-hospital postnatal education about infant pain management at vaccinations leads to more frequent use of pain relief interventions, according to a study published online Oct. 22 in CMAJ, the journal of the Canadian Medical...

https://ift.tt/2S9UTxB

Strong Link for Peds Obesity, Slipped Capital Femoral Epiphysis

MONDAY, Oct. 22, 2018 -- High childhood body mass index (BMI) is strongly correlated with slipped capital femoral epiphysis (SCFE), according to a study published online Oct. 22 in Pediatrics. Daniel C. Perry, Ph.D., from the University of Liverpool...

https://ift.tt/2PNAaOv

Diagnostic Strategy Can Rule Out PE in Pregnant Women

MONDAY, Oct. 22, 2018 -- A diagnostic strategy based on pretest clinical probability assessment, high-sensitivity D-dimer testing, bilateral lower-limb compression ultrasonography (CUS), and computed tomography pulmonary angiography (CTPA) can...

https://ift.tt/2S8bB09

Chemoimmunotherapy Ups Survival in Triple-Negative Breast Cancer

MONDAY, Oct. 22, 2018 -- For patients with metastatic triple-negative breast cancer, atezolizumab plus nanoparticle albumin-bound (nab)-paclitaxel prolongs progression-free survival compared with placebo plus nab-paclitaxel, according to a study...

https://ift.tt/2PPpy1J

American Society of Anesthesiologists, Oct. 13-17

ANESTHESIOLOGY 2018 The annual meeting of the American Society of Anesthesiologists was held from Oct. 13 to 17 in San Francisco and attracted approximately 15,000 participants from around the world, including anesthesiologists and other health care...

https://ift.tt/2S8bzW5

Primary Klebsiella pneumoniae Osteomyelitis with Bacteremia and Sepsis in a Patient with Cirrhosis

Osteomyelitis is commonly caused by Staphylococci, Streptococci, Escherichia coli, and anaerobes. There have been cases of rare organisms like Klebsiella pneumoniae (Kp) being initially overlooked as causes of osteomyelitis. We report a case of an elderly cirrhotic adult male transferred for further management of liver failure, who was subsequently diagnosed with Kp osteomyelitis and sepsis. He had a history of blunt leg trauma, and MRI of the leg revealed osteomyelitis, with a negative workup for other sources of infection. Kp osteomyelitis is reported in less than 100 cases, mainly in pediatric and sickle-cell patients. There are no pathognomonic imaging findings. Lesions may be metastatic, with rapid widespread destruction and exuberant periosteal reaction. Kp is a rare, under recognized cause of osteomyelitis in immune-suppressed adults. Given its pathogenicity, early identification is critical.

https://ift.tt/2D0hJDt

When timing and dose of nutrition support were examined, the modified Nutrition Risk in Critically Ill (mNUTRIC) score did not differentiate high-risk patients who would derive the most benefit from nutrition support: a prospective cohort study

The timing and dose of exclusive nutrition support (ENS) have not been investigated in previous studies aimed at validating the modified Nutrition Risk in Critically Ill (mNUTRIC) score. We therefore evaluated...

https://ift.tt/2Sa6eh5

Effect of the Composition of CAD/CAM Composite Blocks on Mechanical Properties

The aim of this study was to evaluate the effect of the composition of CAD/CAM blocks on their mechanical properties. Nine different CAD/CAM blocks, enamel and dentine, were tested. Sixteen samples of each material were separated for Vickers microhardness test (n=6, 5 readings per specimen), nanohardness test (n=6, 5 readings per specimen), filler weight (n=3), and SEM imaging (n=1). Data were statistically analysed using one-way ANOVA. Vita Mark II ceramic showed significantly higher values of hardness (in both nano- and microscale) and elastic modulus (6.83 GPa, 502 kg/mm2, and 47.7 GPa), respectively, than other materials. CAD/CAM composite blocks showed comparable values of hardness and elastic modulus to those of dentine but lower than those of enamel and ceramics. SEM images highlighted different filler-matrix microstructure of CAD/CAM composite blocks. It was concluded that hardness and elastic moduli are positively correlated with ceramic filler percentage and microstructure and CAD/CAM composite materials have comparable hardness and elastic moduli to tooth structure.

https://ift.tt/2OLroEo

Immunomodulatory Effects of Probiotics on Cytokine Profiles

Probiotics confer immunological protection to the host through the regulation, stimulation, and modulation of immune responses. Researchers have shifted their attention to better understand the immunomodulatory effects of probiotics, which have the potential to prevent or alleviate certain pathologies for which proper medical treatment is as yet unavailable. It has been scientifically established that immune cells (T- and B-cells) mediate adaptive immunity and confer immunological protection by developing pathogen-specific memory. However, this review is intended to present the recent studies on immunomodulatory effects of probiotics. In the early section of this review, concepts of probiotics and common probiotic strains are focused on. On a priority basis, the immune system, along with mucosal immunity in the human body, is discussed in this study. It has been summarized that a number of species of Lactobacillus and Bifidobacterium exert vital roles in innate immunity by increasing the cytotoxicity of natural killer cells and phagocytosis of macrophages and mediate adaptive immunity by interacting with enterocytes and dendritic, Th1, Th2, and Treg cells. Finally, immunomodulatory effects of probiotics on proinflammatory and anti-inflammatory cytokine production in different animal models have been extensively reviewed in this paper. Therefore, isolating new probiotic strains and investigating their immunomodulatory effects on cytokine profiles in humans remain a topical issue.

https://ift.tt/2NZ2SdB

Exam 1: Rebleeding vs Thromboembolism After Hospitalization for Gastrointestinal Bleeding in Patients on Direct Oral Anticoagulants

https://ift.tt/2Am4aeT

A novel intronic homozygous mutation in the AMT gene of a patient with nonketotic hyperglycinemia and hyperammonemia

Abstract

Nonketotic Hyperglycinemia is an autosomal recessive disorder characterized by defects in the mitochondrial glycine cleavage system. Most patients present soon after birth with seizures and hypotonia, and infants that survive the newborn period often have profound intellectual disability and intractable seizures. Here we present a case report of a 4-year-old girl with NKH as well as hyperammonemia, an uncommon finding in NKH. Genetic analysis found a previously unreported homozygous mutation (c.878–1 G > A) in the AMT gene. Maximum Entropy Principle modeling predicted that this mutation most likely breaks the splice site at the border of intron 7 and exon 8 of the AMT gene. Treatment with L-Arginine significantly reduced both the proband's glycine and ammonia levels, in turn aiding in control of seizures and mental status. This is the first time the use of L-Arginine is reported to successfully treat elevated glycine levels.

https://ift.tt/2CwkVWp

Top 10 not-so-altruistic ways to improve EMS with a billion dollars

The Ambulance Driver imagines a glorious future, funded by his Mega Millions winnings, as our EMS dear and fearless leader

https://ift.tt/2JaaSaM

Association between muscle strength, histopathology and MRI in sIBM

Acta Neurologica Scandinavica, Volume 0, Issue ja, -Not available-.


https://ift.tt/2NYeOMw

Isolated Gastric Varices in a Patient with Essential Thrombocythemia

https://ift.tt/2R7B4p8

Constitutive androstane receptor and pregnane X receptor cooperatively ameliorate DSS-induced colitis

Nuclear receptor pregnane X receptor (PXR) was shown to be protective in case of dextran sulfate sodium (DSS)-induced colitis. Constitutive androstane receptor (CAR) belongs to the same nuclear receptor subfamily with PXR. The roles of both receptors in DSS-induced colitis were evaluated.

https://ift.tt/2R2m2Ru

IBS clinical management in Italy: the AIGO survey

Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder, both in primary and secondary care.

https://ift.tt/2q4LL0r

Identification of a novel KLC1–ROS1 fusion in a case of pediatric low-grade localized glioma

Abstract

The proto-oncogene tyrosine-protein kinase ROS1 (ROS1) is a tyrosine kinase that is closely related to anaplastic lymphoma kinase receptor (ALK). We describe a novel KLC1–ROS1 fusion identified in a case of pediatric low-grade glioma. This was detected by RNA sequencing and confirmed by reverse-transcription PCR and fluorescent in situ hybridization. Immunohistochemical staining for ROS1 was positive in the tumor cytoplasm. In vitro analysis demonstrated the oncogenic activity of this fusion, which was suppressed by the ALK/ROS1 inhibitor, crizotinib. Our case and others suggest that various ROS1 fusions might be present in a subset of pediatric gliomas, which could be targeted for therapy.

https://ift.tt/2SakPt2

Capecitabine-Associated Terminal Ileitis

Capecitabine is an oral fluoropyrimidine used as adjuvant and palliative chemotherapy in patients with colorectal cancer. Diarrhea is a well-known side effect of capecitabine and 5-fluorouracil agents. We present a case with terminal ileitis as a rare adverse event of capecitabine treatment. Capecitabine-induced terminal ileitis is likely to be underreported. It should be considered more often as a cause of severe and atypical complaints of diarrhea during treatment with capecitabine or other 5-fluorouracil agents.
Case Rep Oncol 2018;11:654–659

https://ift.tt/2EBJHHe

Thromboembolic Events Related to Treatment with Checkpoint Inhibitors: Report of Two Cases

Despite the significant clinical benefits, checkpoint inhibition is associated with a unique spectrum of immune-related adverse events. It is sometimes difficult to distinguish some rare adverse effects from a cancer progression; thus, such effects should be reported in clinical trials to be diagnosed by physicians. Only a few cases of arterial embolic events have been described in studies related to patients treated by immunotherapy. In this article, we report the cases of 2 patients who presented rare and severe thromboembolic events after using checkpoint inhibitors. The first case describes multiple organ embolism at the same time, associated with other autoimmune symptoms. In the second case, distal digital necrosis emerged after the initiation of immunotherapy. There is insufficient data about the real incidence of thromboembolic and rheumatological events related to checkpoint inhibition. Future trials should be done to establish preventive strategies.
Case Rep Oncol 2018;11:648–653

https://ift.tt/2AnDEBP

Primary Gastrointestinal Kaposi’s Sarcoma in a Patient with Human Immunodeficiency Virus

Gastrointestinal bleeding in HIV patients secondary to coinfection by HHV8 and development of Kaposi's sarcoma (KS) is a rare complication even if no skin lesions are detected on physical examination. This article indicates which patients might develop this type of clinical sign and also tries to recall that absence of skin lesions never rules out the presence of KS, especially if gastrointestinal involvement is documented. Gastrointestinal bleeding in terms of hematemesis has rarely been reported in the literature. We review some important clinical findings, diagnosis, and treatment approach. We present the case of an HIV patient who presented to the emergency department with hematemesis and gastrointestinal signs of KS on upper gastrointestinal endoscopy without any dermatological involvement.
Case Rep Oncol 2018;11:638–647

https://ift.tt/2EBJG68

Diagnosis of Pulmonary Embolism During Pregnancy A Multicenter Prospective Management Outcome Study

Background:

Data on the optimal diagnostic management of pregnant women with suspected pulmonary embolism (PE) are limited, and guidelines provide inconsistent recommendations on use of diagnostic tests.

Objective:

To prospectively validate a diagnostic strategy in pregnant women with suspected PE.

Design:

Multicenter, multinational, prospective diagnostic management outcome study involving pretest clinical probability assessment, high-sensitivity D-dimer testing, bilateral lower limb compression ultrasonography (CUS), and computed tomography pulmonary angiography (CTPA). (ClinicalTrials.gov: NCT00740454)

Setting:

11 centers in France and Switzerland between August 2008 and July 2016.

Patients:

Pregnant women with clinically suspected PE in emergency departments.

Intervention:

Pulmonary embolism was excluded in patients with a low or intermediate pretest clinical probability and a negative D-dimer result. All others underwent lower limb CUS and, if results were negative, CTPA. A ventilation–perfusion (V/Q) scan was done if CTPA results were inconclusive. Pulmonary embolism was excluded if results of the diagnostic work-up were negative, and untreated pregnant women had clinical follow-up at 3 months.

Measurements:

The primary outcome was the rate of adjudicated venous thromboembolic events during the 3-month follow-up.

Results:

441 women were assessed for eligibility, and 395 were included in the study. Among these, PE was diagnosed in 28 (7.1%) (proximal deep venous thrombosis found on ultrasound [n = 7], positive CTPA result [n = 19], and high-probability V/Q scan [n = 2]) and excluded in 367 (clinical probability and negative D-dimer result [n = 46], negative CTPA result [n = 290], normal or low-probability V/Q scan [n = 17], and other reason [n = 14]). Twenty-two women received extended anticoagulation during follow-up, mainly for previous venous thromboembolic disease. The rate of symptomatic venous thromboembolic events was 0.0% (95% CI, 0.0% to 1.0%) among untreated women after exclusion of PE on the basis of negative results on the diagnostic work-up.

Limitation:

There were several protocol deviations, reflecting the difficulty of performing studies in pregnant women with suspected PE.

Conclusion:

A diagnostic strategy based on assessment of clinical probability, D-dimer measurement, CUS, and CTPA can safely rule out PE in pregnant women.

Primary Funding Source:

Swiss National Foundation for Scientific Research, Groupe d'Etude de la Thrombose de Bretagne Occidentale, and International Society on Thrombosis and Haemostasis.

https://ift.tt/2An8OJK

Time to Change the Way We Approach Opioid Use Disorder: A Challenge to the Status Quo

In their article, Martin and colleagues address buprenorphine treatment for opioid use disorder. The editorialists discuss the findings and why they believe that we need to disrupt current practice and change our approach to the treatment of persons with OUD.

https://ift.tt/2ECbuaD

Diagnosing Pulmonary Embolism During Pregnancy: Which Test Is Best?

In this issue, Righini and colleagues report the results of a large prospective study of an algorithm for the evaluation of pregnant women with suspected pulmonary embolism. The editorialists discuss the important lessons learned and how they should inform clinical practice and future study.

https://ift.tt/2AmTb4X

Kidney Damage Biomarkers and Incident Chronic Kidney Disease During Blood Pressure Reduction A Case–Control Study

Background:

Whether the increased incidence of chronic kidney disease (CKD) during intensive systolic blood pressure (SBP) lowering is accompanied by intrinsic kidney injury is unknown.

Objective:

To compare changes in kidney damage biomarkers between incident CKD case participants and matched control participants as well as between case participants in the intensive (<120 mm Hg) versus the standard (<140 mm Hg) SBP management groups of SPRINT (Systolic Blood Pressure Intervention Trial).

Design:

Nested case–control study within SPRINT.

Setting:

Adults with hypertension without baseline kidney disease.

Participants:

Case participants (n = 162), who developed incident CKD during trial follow-up (128 in the intensive and 34 in the standard group), and control participants (n = 162) without incident CKD, who were matched on age, sex, race, baseline estimated glomerular filtration rate, and randomization group.

Measurements:

9 urinary biomarkers of kidney damage were measured at baseline and at 1 year. Linear mixed-effects models were used to estimate 1-year biomarker changes.

Results:

Higher concentrations of urinary albumin, kidney injury molecule-1, and monocyte chemoattractant protein-1 at baseline were significantly associated with greater odds of incident CKD (adjusted odds ratio per doubling: 1.50 [95% CI, 1.14 to 1.98], 1.51 [CI, 1.05 to 2.17], and 1.70 [CI, 1.13 to 2.56], respectively). After 1 year of blood pressure intervention, incident CKD case participants in the intensive group had significantly greater decreases in albumin–creatinine ratio (ACR), interleukin-18, anti–chitinase-3-like protein 1 (YKL-40), and uromodulin than the matched control participants. Compared with case participants in the standard group, those in the intensive group had significantly greater decreases in ACR, β₂-microglobulin, α₁-microglobulin, YKL-40, and uromodulin.

Limitation:

Biomarker measurements were available only at baseline and 1 year.

Conclusion:

Incident CKD in the setting of intensive SBP lowering was accompanied by decreases, rather than elevations, in levels of kidney damage biomarkers and thus may reflect benign changes in renal blood flow rather than intrinsic injury.

Primary Funding Source:

National Institute for Diabetes and Digestive and Kidney Diseases.

https://ift.tt/2EEUJLY

Antiphospholipid Antibodies in Patients With Myocardial Infarction

https://ift.tt/2An8Npa

The Next Stage of Buprenorphine Care for Opioid Use Disorder

Buprenorphine has been used internationally for the treatment of opioid use disorder (OUD) since the 1990s and has been available in the United States for more than a decade. Initial practice recommendations were intentionally conservative, were based on expert opinion, and were influenced by methadone regulations. Since 2003, the American crisis of OUD has dramatically worsened, and much related empirical research has been undertaken. The findings in several important areas conflict with initial clinical practice that is still prevalent. This article reviews research findings in the following 7 areas: location of buprenorphine induction, combining buprenorphine with a benzodiazepine, relapse during buprenorphine treatment, requirements for counseling, uses of drug testing, use of other substances during buprenorphine treatment, and duration of buprenorphine treatment. For each area, evidence for needed updates and modifications in practice is provided. These modifications will facilitate more successful, evidence-based treatment and care for patients with OUD.

https://ift.tt/2EEUHUm

The possible Preventive Role of Pregabalin in Post-mastectomy Pain Syndrome: A Double-Blinded Randomized Controlled Trial

Chronic post-mastectomy pain syndrome (PMPS) has a considerable negative impact on the quality of life of breast cancer patients.

https://ift.tt/2AmZWUx

Long-term Clinical Outcomes of Nonoperative Management with Chemoradiotherapy for Locally Advanced Rectal Cancer in the Veterans Health Administration

Can appropriately selected locally advanced rectal cancer (LARC) patients be successfully managed with a nonoperative approach following chemoradiation? In this study, patients with a clinical complete responses (cCR) following concurrent chemoradiation (CRT) had similar OS and DSS versus patients treated with neoadjuvant chemoradiation and surgery (CRT+S) and had similar DSS versus CRT+S patients with a pCR. These data suggest that LARC patients with a cCR to CRT have an excellent prognosis and may be candidates for organ preservation.

https://ift.tt/2RderQv

Translating “Best Practices” To Meaningful Quality Measures: From Measure Conceptualization to Implementation

https://ift.tt/2EEf2Ju

A case of Behçet’s disease with esophageal ulcers

https://ift.tt/2q6n43O

Small-bowel hemangioma: rare and hard to find

https://ift.tt/2q5BoJC

African American Living Donors’ Attitudes About APOL1 Genetic Testing: A Mixed Methods Study

African American live kidney donors ("donors") have a greater risk for kidney failure than European American donors. Apolipoprotein L1 gene (APOL1) variants in African Americans may be associated with this disparity.

https://ift.tt/2yVaYOS

Familial Mediterranean Fever Is Commonly Diagnosed in Children in Israel with Periodic Fever Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome

To describe a cohort of pediatric patients diagnosed with periodic fever aphthous stomatitis, pharyngitis and adenitis (PFAPA) and familial Mediterranean fever (FMF) and compare them with children diagnosed solely with PFAPA (sPFAPA).

https://ift.tt/2OEtky8

An Optimized Rhizobox Protocol to Visualize Root Growth and Responsiveness to Localized Nutrients

Visualizing and measuring root growth in situ is extremely challenging. We present a customizable rhizobox method to track root development and proliferation over time in response to nutrient enrichment. This method is used to analyze maize genotypic differences in root plasticity in response to an organic nitrogen source.

https://ift.tt/2q5ISw9

Janus Membrane: Janus Membranes: Creating Asymmetry for Energy Efficiency (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2S6zG7E

3D Printing: Additive Manufacturing and Performance of Architectured Cement‐Based Materials (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2O0rv9A

Masthead: (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2OJq7xx

Contents: (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2NZ4unp

Wearable Health Monitoring: A Real‐Time Wearable UV‐Radiation Monitor based on a High‐Performance p‐CuZnS/n‐TiO2 Photodetector (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2ODDVJP

Microfluidic Bioprinting: Digitally Tunable Microfluidic Bioprinting of Multilayered Cannular Tissues (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2NY56tI

Black Phosphorus: Abnormal Near‐Infrared Absorption in 2D Black Phosphorus Induced by Ag Nanoclusters Surface Functionalization (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2ODDWNT

Nanoparticle Assembly: Revealing Driving Forces in Quantum Dot Supercrystal Assembly (Adv. Mater. 43/2018)

Advanced Materials, Volume 30, Issue 43, October 25, 2018.


https://ift.tt/2NWLIx9

Issue Information

Diagnostic Cytopathology, Volume 46, Issue 9, Page 723-724, September 2018.


https://ift.tt/2OGl68F

ASCO 2018 NSCLC highlights—combination therapy is key

Summary

Non-small cell lung cancer (NSCLC) treatment was booming at this year's ASCO 2018 meeting as several well-performed phase III trials with practice-changing potential were presented. Thereby immune checkpoint blockade (ICB) consolidated its major role in the treatment of NSCLC patients without genetic alterations and extended its use by showing impressive data on ICB combination therapies (mainly combined with chemotherapy). Furthermore the role of predictive biomarkers for ICB therapy (Programmed death-ligand 1 [PD-L1] expression, tumor mutational burden [TMB] testing and others) have been further developed and blood-based tests were presented with promising data revealing the potential of this minimally invasive method for treatment monitoring and guidance in the future. Nevertheless the best biomarker is still elusive and future research is ongoing and might be a multimodal approach combining different modalities. No major studies concerning new genetic alterations or innovative targets were presented and the focus in genetic driven NSCLC was the evaluation of combinational approaches (e.g. in epidermal growth factor receptor [EGFR] mutation positve patients, EGFR tyrosine kinase inhibitor [TKI] plus anti-angiogenic agent or chemotherapy backbone). The presented results showed some benefit for the combinational approach; however toxicity might be an issue and further validation is necessary. Summarizing, ASCO 2018 showed that combinational approaches will be the future standard treatment in NSCLC and that biomarker identification is more heterogeneous and complex than anticipated, but presented next generation techniques may pave the way to a more personalized cancer therapy.

https://ift.tt/2AnHcnY

Significance of genetic polymorphisms in hematological malignancies: implications of risk factors for prognosis and relapse

Summary

Background

Leukemia is one of the most important hematological malignancies. Despite progress in leukemia therapy, recurrence is still one of the main reasons for treatment failure. Recently, gene polymorphisms have been the focus of attention as important factors in the recurrence of leukemia.

Methods

Relevant literature was identified by an electronic database search (1996–2018) of English-language literature using the terms "polymorphism", "leukemia", "prognosis", "lymphoma", and "relapse."

Results

Polymorphisms of genes involved in cell cycle, apoptosis, immune system, and drug metabolism enzymes have been associated with progression of hematological malignancies. These genetic changes can be associated with relapse and unfavorable clinical outcomes through potential impact on leukemic cells survival.

Conclusion

Considering the fact that gene polymorphisms could significantly affect pathophysiology of hematological malignancies, these genetic changes may be considered as potential prognostic biomarkers and therapeutic agents in these disorders.

https://ift.tt/2CxZHHv

Cure in metastatic disease: how to manage and who is the right patient in colorectal cancer?

Summary

Metastatic colorectal cancer was long considered for palliative therapy, until significant improvement in surgical techniques and more effective chemotherapeutic regimens changed the way metastatic colon cancer patients are being treated today. Prospective trials were designed to answer the question which patient with metastatic disease could potentially be cured by a multidisciplinary approach with medical oncologists, surgeons and radiation oncology using an induction chemotherapy in combination with a targeted agent and being monitored for resectability in multidisciplinary tumor boards. Patients with oligometastatic disease should be treated with the goal of curative resection. This review will highlight studies conducted over the past 15 years addressing this issue. An algorithm is proposed illustrating how every newly diagnosed mCRC (metastatic colorectal cancer) patient could be discussed in the tumor board to decide the best treatment sequence with the best chance of cure.

https://ift.tt/2AnH4Vw

Cell Cycle Analysis in the C. elegans Germline with the Thymidine Analog EdU

An imaging-based method is described that can be used to identify S-phase and analyze cell cycle dynamics in the C. elegans hermaphrodite germline using the thymidine analog EdU. This method requires no transgenes and is compatible with immunofluorescent staining.

https://ift.tt/2CAWXth

CT Abdominal Aortic Calcification Score Predicts CV Event Risk

MONDAY, Oct. 22, 2018 -- A computed tomography (CT)-based abdominal aortic calcification (AAC) score is a strong predictor of future cardiovascular events in asymptomatic patients, according to a study published online Oct. 2 in Radiology. Stacey D....

https://ift.tt/2yVl1DD

Short Respiratory Event Duration Ups Mortality Risk in OSA

MONDAY, Oct. 22, 2018 -- For individuals with obstructive sleep apnea, those with short respiratory event duration have an increased risk for mortality, according to a study published online Oct. 19 in the American Journal of Respiratory and...

https://ift.tt/2SaWRxQ

Changes in Nomenclature for Perioperative Cognitive Disorders

MONDAY, Oct. 22, 2018 -- Recommendations have been developed for nomenclature of cognitive changes associated with anesthesia and surgery; the recommendations were published in the November issue of Anesthesiology. Lis Evered, Ph.D., from St....

https://ift.tt/2yUgl0x

Adolescent, Young Adult Pod-Based E-Cigarette Use Up

MONDAY, Oct. 22, 2018 -- Adolescents and young adults are increasingly using electronic cigarette (e-cigarette) products such as pod-based systems but have misperceptions and lack of knowledge about these products, according to a study published...

https://ift.tt/2S9B2i8

Guidelines Outlined to Ease Peds Transition to Adult Health Care

MONDAY, Oct. 22, 2018 -- Guidelines have been updated to support the health care transition from adolescence to adulthood, according to a clinical report published online Oct. 22 in Pediatrics. Patience H. White, M.D., from George Washington...

https://ift.tt/2yTUUwU

ACR: Ixekizumab Tops Placebo in Axial Spondyloarthritis

MONDAY, Oct. 22, 2018 -- For patients with active radiographic axial spondyloarthritis (r-axSpA) and prior inadequate response or intolerance to one or two tumor necrosis factor inhibitors (TNFi), ixekizumab treatment results in significant...

https://ift.tt/2S9AZms

ACR: Walking Each Day May Cut Risk for TKA Over Five Years

MONDAY, Oct. 22, 2018 -- For individuals with knee osteoarthritis (OA), replacing time not walking with walking at moderate-to-vigorous intensity is associated with reduced risk for total knee arthroplasty (TKA) over five years, according to a study...

https://ift.tt/2yQgyBS

Percent Weight Regain Predicts Health Risks Post-Bariatric Surgery

MONDAY, Oct. 22, 2018 -- Measuring the percentage of weight regained following the maximum amount of weight lost after Roux-en-Y gastric bypass (RYGB) surgery best predicts a patient's risk for several serious health problems, according to a study...

https://ift.tt/2S9AHvS

Glucose Dysregulation Seen Years Before Diabetes Diagnosis

MONDAY, Oct. 22, 2018 -- Individuals who develop diabetes or prediabetes have elevated fasting plasma glucose (FPG) at least 10 years before diagnosis, according to an observational study recently published in the Journal of the Endocrine...

https://ift.tt/2yVP2mL

High Uptake, Acceptability of Rapid Fentanyl Test Strips

MONDAY, Oct. 22, 2018 -- Young adults who report injecting drugs or using heroin, cocaine, or illicitly obtained prescription pills report high uptake and acceptability of fentanyl test strips to detect illicitly manufactured fentanyl, according to...

https://ift.tt/2Scwnfp

Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes

Genes, Chromosomes and Cancer, Volume 57, Issue 11, Page 573-583, November 2018.


https://ift.tt/2Sb4SCW

Table of Content Volume 57, Number 11, November 2018

Genes, Chromosomes and Cancer, Volume 57, Issue 11, Page 531-532, November 2018.


https://ift.tt/2yR4BvU

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

Genes, Chromosomes and Cancer, Volume 57, Issue 11, Page 557-563, November 2018.


https://ift.tt/2ScEY1F

Abstracts

https://ift.tt/2POED3k

First Responder Solutions to Showcase Medical Care Products at EMS World Expo

Visit EMS World Expo Booth 355 to see the all-new Trauma Beanie™ CARMEL, Oct. 19, 2018 – First Responder Solutions™, Inc. will attend the EMS World Expo in Nashville, Tennessee at the Music City Center from October 29th through November 2nd to showcase their specialty, and everyday use medical care products to the EMS first responder community. Their pioneering products, the...

https://ift.tt/2OCUfdI

Thalamic afferents to prefrontal cortices from ventral motor nuclei in decision making

European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.


https://ift.tt/2ySApR7

Suprachiasmatic Function in a Circadian Period Mutant: Duper alters light‐induced activation of Vasoactive Intestinal Peptide cells and PERIOD1 immunostaining

European Journal of Neuroscience, Volume 0, Issue ja, -Not available-.


https://ift.tt/2Sb1qYF

Synchrony surfacing: Epicortical recording of correlated action potentials

European Journal of Neuroscience, EarlyView.


https://ift.tt/2yUiIk2

Saccharomyces cerevisiae Metabolic Labeling with 4-thiouracil and the Quantification of Newly Synthesized mRNA As a Proxy for RNA Polymerase II Activity

The protocol described here is based on the genome-wide quantification of newly synthesized mRNA purified from yeast cells labeled with 4-thiouracil. This method allows to measure mRNA synthesis uncoupled from mRNA decay and, thus, provides an accurate measurement of RNA polymerase II transcription.

https://ift.tt/2Pibrog

Micromanipulation of Chromosomes in Insect Spermatocytes

In this protocol, we describe the selection and preparation of appropriate cells for micromanipulation and the use of a piezoelectric micromanipulator to reposition chromosomes within those cells.

https://ift.tt/2EBcA6o

Issue Information

Histopathology, Volume 73, Issue 5, Page 713-716, November 2018.


https://ift.tt/2PcOPpw

Safety of trifluridine/tipiracil in an open-label expanded-access program in elderly and younger patients with metastatic colorectal cancer

Abstract

Purpose

Trifluridine/tipiracil (FTD/TPI; TAS-102, Lonsurf®), a novel form of chemotherapy for metastatic colorectal cancer (mCRC), has shown clinical benefit in the global, phase III RECOURSE trial, regardless of patient age. Here, we report the safety and tolerability profile of FTD/TPI from an expanded-access program (EAP) in the US patients with mCRC whose disease has progressed on the standard therapies.

Methods

A total of 549 patients (≥ 18 years) with histologically confirmed mCRC following two or more regimens of standard therapy and an Eastern Cooperative Oncology Group performance status of 0 or 1 participated in this open-label EAP. During the 28-day treatment cycle, patients took FTD/TPI 35 mg/m² twice daily for 5 days followed by 2 days of rest for 2 weeks, with a 14-day rest period. Data were collected for therapy duration, treatment discontinuation, and adverse events. Age-based post hoc analysis was performed to determine the safety of FTD/TPI in elderly (≥ 65 years) versus younger (< 65 years) patients.

Results

FTD/TPI-treated patients in this EAP had a similar therapy duration and time to treatment discontinuation to those in the RECOURSE trial. The safety profile in elderly patients was consistent with that in younger patients, with no unexpected safety concerns.

Conclusions

This USA-based, open-label EAP has confirmed a similar safety and tolerability profile for FTD/TPI to that observed in the RECOURSE trial. Furthermore, FTD/TPI is well tolerated and can be considered as a treatment option in elderly patients with mCRC.

Trial registration

NCT02286492.

https://ift.tt/2R5lvi0

Krüppel-like factor 9 and histone deacetylase inhibitors synergistically induce cell death in glioblastoma stem-like cells

Abstract

Background

The dismal prognosis of patients with glioblastoma (GBM) is attributed to a rare subset of cancer stem cells that display characteristics of tumor initiation, growth, and resistance to aggressive treatment involving chemotherapy and concomitant radiation. Recent research on the substantial role of epigenetic mechanisms in the pathogenesis of cancers has prompted the investigation of the enzymatic modifications of histone proteins for therapeutic drug targeting. In this work, we have examined the function of Krüppel-like factor 9 (KLF9), a transcription factor, in chemotherapy sensitization to histone deacetylase inhibitors (HDAC inhibitors).

Methods

Since GBM neurosphere cultures from patient-derived gliomas are enriched for GBM stem-like cells (GSCs) and form highly invasive and proliferative xenografts that recapitulate the features demonstrated in human patients diagnosed with GBM, we established inducible KLF9 expression systems in these GBM neurosphere cells and investigated cell death in the presence of epigenetic modulators such as histone deacetylase (HDAC) inhibitors.

Results

We demonstrated that KLF9 expression combined with HDAC inhibitor panobinostat (LBH589) dramatically induced glioma stem cell death via both apoptosis and necroptosis in a synergistic manner. The combination of KLF9 expression and LBH589 treatment affected cell cycle by substantially decreasing the percentage of cells at S-phase. This phenomenon is further corroborated by the upregulation of cell cycle inhibitors p21 and p27. Further, we determined that KLF9 and LBH589 regulated the expression of pro- and anti- apoptotic proteins, suggesting a mechanism that involves the caspase-dependent apoptotic pathway. In addition, we demonstrated that apoptosis and necrosis inhibitors conferred minimal protective effects against cell death, while inhibitors of the necroptosis pathway significantly blocked cell death.

Conclusions

Our findings suggest a detailed understanding of how KLF9 expression in cancer cells with epigenetic modulators like HDAC inhibitors may promote synergistic cell death through a mechanism involving both apoptosis and necroptosis that will benefit novel combinatory antitumor strategies to treat malignant brain tumors.

https://ift.tt/2POz8lo

Issue Information

Experimental Dermatology, Volume 27, Issue 11, Page 1192-1192, November 2018.


https://ift.tt/2EDvjOT

Clinical Snippets

Experimental Dermatology, Volume 27, Issue 11, Page i-i, November 2018.


https://ift.tt/2PhW1R0

The Evaluation of Durative Transfusion of Endostar Combined with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

Background: The overall survival (OS) in non-small cell lung cancer (NSCLC) is poor, with median OS of advanced NSCLC with standard systemic chemotherapy being reported at 13.6 months and the 5-year survival rate at less than 15%. Therefore, the aim of this study was to evaluate Endostar combined with chemotherapy in patients with advanced NSCLC. Methods: Data on 116 cases of pathologically confirmed stage IIIB-IV NSCLC were retrospectively collected. The control group was treated with chemotherapy combined with intravenous infusion of Endostar while the test group received durative transfusion of Endostar. The short-term therapeutic effects including overall response rate (ORR), disease control rate (DCR), and safety were evaluated in both groups. In the follow-up, progression-free survival (PFS) and OS were also analysed. Results: In the test group, the ORR was 53.4%, which was similar to that in the control group (44.8%) (p #x3e; 0.05). However, the DCR in the test group (86.2%) was significantly higher than that in the control group (70.7%) (p #x3c; 0.01). The median time to progression in the test group (6 months) was also significantly longer than that in the control group (4 months). Importantly, the median OS in the test group (17.5 months) was improved compared to the control group (13.5 months). The 1-year survival rate in the test and control groups was 9.7 and 15.8%, respectively. There was no significant difference in side effects (including thrombocytopenia, leucopenia, nausea, and vomiting) between the two groups. Conclusions: Endostar durative transfusion combined with chemotherapy showed a higher DCR, longer PFS and OS time, and was well tolerated in patients with advanced NSCLC.
Chemotherapy 2018;63:214–219

https://ift.tt/2q2FEtr

Influence of the keratinized mucosa on the stability of peri‐implant tissues and brushing discomfort: a 4‐year follow‐up study

Clinical Oral Implants Research, Volume 0, Issue ja, -Not available-.


https://ift.tt/2AmrMjS

Accuracy of flapless immediate implant placement in anterior maxilla using computer‐assisted versus freehand surgery: a cadaver study

Clinical Oral Implants Research, Volume 0, Issue ja, -Not available-.


https://ift.tt/2EElUGN

Risk factors for transplant renal artery stenosis after live donor transplantation

BJS, EarlyView.


https://ift.tt/2S9v3da

Colorectal endoscopic submucosal dissection with a combination of a snare and endoclips

Digestive Endoscopy, Volume 0, Issue ja, -Not available-.


https://ift.tt/2yTEzIp

Plasma B‐vitamin and one‐carbon metabolites and risk of breast cancer before and after folic acid fortification in the US

International Journal of Cancer, Volume 0, Issue ja, -Not available-.


https://ift.tt/2PKgrPO

Disparities in human papillomavirus–related cancer incidence and survival among human immunodeficiency virus–infected hispanics living in the United States

Cancer, EarlyView.


https://ift.tt/2PdxnRE

BioEssays 11∕2018

BioEssays, Volume 40, Issue 11, November 2018.


https://ift.tt/2ECvOsd

BioEssays 11∕2018

BioEssays, Volume 40, Issue 11, November 2018.


https://ift.tt/2Pb0yov

Cancer Ecology: The Intracellular Interactome Makes Little Sense without the Intercellular One

BioEssays, Volume 40, Issue 11, November 2018.


https://ift.tt/2EF9myW

BioEssays 11∕2018

BioEssays, Volume 40, Issue 11, November 2018.


https://ift.tt/2PeXGa2

Influence of hepatitis C virus eradication with direct‐acting antivirals on the gut microbiota in patients with cirrhosis

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2z3QYK7

Persistent damage on magnetic resonance enterography in patients with Crohn’s disease in endoscopic remission

Alimentary Pharmacology &Therapeutics, EarlyView.


https://ift.tt/2S7c9U5

Questions concerning the role of amyloid-β in the definition, aetiology and diagnosis of Alzheimer’s disease

Abstract

The dominant hypothesis of Alzheimer's disease (AD) aetiology, the neuropathological guidelines for diagnosing AD and the majority of high-profile therapeutic efforts, in both research and in clinical practice, have been built around one possible causal factor, amyloid-β (Aβ). However, the causal link between Aβ and AD remains unproven. Here, in the context of a detailed assessment of historical and contemporary studies, we raise critical questions regarding the role of Aβ in the definition, diagnosis and aetiology of AD. We illustrate that a holistic view of the available data does not support an unequivocal conclusion that Aβ has a central or unique role in AD. Instead, the data suggest alternative views of AD aetiology are potentially valid, at this time. We propose that an unbiased way forward for the field, beyond the current Aβ-centric approach, without excluding a role for Aβ, is required to come to an accurate understanding of AD dementia and, ultimately, an effective treatment.

https://ift.tt/2S9TqHl

Identification of alcohol‐binding site(s) in proteins using diazirine‐based photoaffinity labeling and mass spectrometry

Chemical Biology &Drug Design, EarlyView.


https://ift.tt/2PmB0F7

Phenotypes of hypertrophic cardiomiopathy. An illustrative review of MRI findings

Abstract

Objective

The purpose of this article is to review how cardiac MRI provides the clinician with detailed information about the hypertrophic cardiomyopathy (HCM) phenotypes, assessing its morphological and functional consequences.

Conclusion

An understanding of cardiac MRI manifestations of HCM phenotypes will aid early diagnosis recognition and its functional consequences.

Teaching Points

• The phenotypic variability of HCM expands beyond myocardial hypertrophy, to include morphological and functional manifestations, ranging from subtle anomalies to remodelling of the LV with progressive dilatation and thinning of its wall.

• The stages of HCM, which are based on the clinical evidence of disease progression, include subclinical HCM, the classic HCM phenothype, adverse remodelling and overt dysfunction, or end-stage HCM.

• Cardiac MRI provides the clinician with detailed information regarding the HCM phenotypes and enables the assessment of its functional consequences.

https://ift.tt/2NZJj4G

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress, Published online: 22 October 2018; doi:10.1038/s41419-018-1123-7

APP promotes osteoblast survival and bone formation by regulating mitochondrial function and preventing oxidative stress

https://ift.tt/2OIRJmo

Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7

Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7

Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7, Published online: 22 October 2018; doi:10.1038/s41419-018-1116-6

Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7

https://ift.tt/2OEU0yR

Azithromycin promotes alternatively activated macrophage phenotype in systematic lupus erythematosus via PI3K/Akt signaling pathway

Azithromycin promotes alternatively activated macrophage phenotype in systematic lupus erythematosus via PI3K/Akt signaling pathway

Azithromycin promotes alternatively activated macrophage phenotype in systematic lupus erythematosus via PI3K/Akt signaling pathway, Published online: 22 October 2018; doi:10.1038/s41419-018-1097-5

Azithromycin promotes alternatively activated macrophage phenotype in systematic lupus erythematosus via PI3K/Akt signaling pathway

https://ift.tt/2OHVl7Y

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling, Published online: 22 October 2018; doi:10.1038/s41419-018-1138-0

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling

https://ift.tt/2NVMKJH

RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis

RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis

RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis, Published online: 22 October 2018; doi:10.1038/s41419-018-0979-x

RIT1 suppresses esophageal squamous cell carcinoma growth and metastasis and predicts good prognosis

https://ift.tt/2OKsujK

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks, Published online: 22 October 2018; doi:10.1038/s41419-018-1128-2

Chromatin-remodeling factor, RSF1, controls p53-mediated transcription in apoptosis upon DNA strand breaks

https://ift.tt/2NXpoTZ

The Zen of XEN: insight into differentiation, metabolism and genomic integrity

The Zen of XEN: insight into differentiation, metabolism and genomic integrity

The Zen of XEN: insight into differentiation, metabolism and genomic integrity, Published online: 22 October 2018; doi:10.1038/s41419-018-1120-x

The Zen of XEN: insight into differentiation, metabolism and genomic integrity

https://ift.tt/2NVO6nN

MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis

MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis

MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis, Published online: 22 October 2018; doi:10.1038/s41419-018-1117-5

MicroRNA-10a promotes granulosa cells tumor development via PTEN-AKT/Wnt regulatory axis

https://ift.tt/2NYg0zz

Colorectal cancer survivors: an investigation of symptom burden and influencing factors

Abstract

Background

Colorectal cancer is a significant issue internationally, with over 1.3 million people diagnosed annually. Survival rates are increasing as treatments improve, although physical symptoms can persist despite eradication of the tumour. In order to optimize survivorship care, further research is warranted in relation to symptom burden. Therefore, the objectives of this study are to (i) investigate frequency of physical symptoms in colorectal cancer survivors (ii) identify which symptoms occur together (iii) examine the associations between demographic and clinical variables, and symptoms.

Methods

Participants nine months to three years post diagnosis were identified from the population-based National Cancer Registry Ireland. Respondents completed the EORTC QLQ-C30 and EORTC QLQ-CR29. Reported physical symptom frequencies were transformed into continuous scale variables, which were then analysed using one way analysis of variance, general linear modelling and Spearman rank correlations.

Results

There were 496 participants. Fatigue, insomnia and flatulence were the most frequent symptoms, with ≥20% of respondents reporting these to be often present in the previous week. Eight other symptoms were experienced often by 10–20% of respondents. At least one of these eleven most common symptoms was experienced frequently by almost every respondent (99%). 66% of respondents experienced at least two of these symptoms together, and 16% experienced five or more together. Current stoma was the single most common variable associated with increased symptom scores, although statistically significant relationships (p ≤ 0.05) between symptom frequency scores and clinical/demographic variables were generally weak (R-sq value ≤0.08).

Conclusion

Findings may inform targeted interventions during the nine month to three year post diagnosis timeframe, which would enable supported self-management of symptoms.

https://ift.tt/2Amh10R

A case report of eyelid Merkel cell carcinoma occurring under treatment with nivolumab for a lung adenocarcinoma

Abstract

Background

Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin characterized by high aggressiveness. Four main factors are implicated in its development: immunosuppression, ultraviolet radiation, age and the Merkel cell polyomavirus (MCPyV). In recent years, immune checkpoint inhibitors have shown clinical activity in MCC treatment.

Case presentation

We report the case of an 82-year-old man with a lung adenocarcinoma diagnosis, who underwent immunotherapy with nivolumab as second-line treatment. Seven months after the diagnosis of lung cancer during the nivolumab treatment, the patient developed an eyelid MCC, initially misdiagnosed as a chalazion. A palliative radiotherapy was performed with clinical benefit. After a total of seven cycles of nivolumab, computed tomography showed a lung and cerebral disease progression. In addition, clinical conditions worsened leading to the patient's death 13 months after the initial lung cancer diagnosis.

Conclusions

Cases of co-occurrence of MCC and non-small cell lung cancer (NSCLC) have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.

https://ift.tt/2CxhheM

The hypermethylation of p16 gene exon 1 and exon 2: potential biomarkers for colorectal cancer and are associated with cancer pathological staging

Abstract

Background

Tumor suppressor gene p16 promoter hypermethylation has been widely studied in colorectal cancer (CRC), yet its clinicopathological significance remains controversial. The methylation alterations of other regions within p16 gene are still rarely researched. The present study aimed to explore the methylation changes of p16 gene body in CRC and to find whether they were associated with clinicopathological staging of CRC.

Methods

Paired colorectal cancer tissues and corresponding adjacent normal tissues from 30 CRC patients were collected. The methylation levels of two CpG islands within p16 gene body, exon 1 and exon 2, were accurately assessed simultaneously by a LC-MS/MS method. The p16 protein expressions were assessed by immunohistochemistry assay. Statistical analyses were carried out using SPSS 17.0 software. Heat-map analysis was carried out by HemI 1.0 software.

Results

In the present study, CRC tissues showed more highly methylated than adjacent normal tissues at both CpG islands of p16 gene. And exon 2 hypermethylation was higher and more frequent than exon 1. The ROC curve analysis showed that the simultaneous use of both indicators had excellent sensitivity and specificity for distinguishing CRC tissues and adjacent normal tissues. Following, the methylation level of p16 exon 1/2 was negatively related to p16 protein expression. Further correlation analysis revealed that p16 exon 1 hypermethylation was associated with N/Dukes staging (p = 0.033), and p16 exon 2 hypermethylaiton was associated with T staging (p = 0.035).

Conclusions

The p16 gene body was remarkably hyper-methylated in CRC tissues and associated with p16 protein expression and cancer clinicopathological staging. The combination of p16 exon 1 and exon 2 could better reflect the overall methylation status of p16 gene body and provide potential biomarkers of CRC.

https://ift.tt/2AlpWzp

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2R7XpmF

Prokaryotic communities of Indo-Pacific giant barrel sponges are more strongly influenced by geography than host phylogeny

ABSTRACT

Sponges harbor complex communities of microorganisms that carry out essential roles for the functioning and survival of their hosts. In some cases, genetically related sponges from different geographic regions share microbes, while in other cases microbial communities are more similar in unrelated sponges collected from the same location. To better understand how geography and host phylogeny cause variation in the prokaryotic community of sponges, we compared the prokaryotic community of 44 giant barrel sponges (Xestospongia spp.). These sponges belonged to six reproductively isolated genetic groups from eight areas throughout the Indo-Pacific region. Using Illumina sequencing, we obtained 440 000 sequences of the 16S rRNA gene V3V4 variable region that were assigned to 3795 operational taxonomic units (OTUs). The prokaryotic community of giant barrel sponges was characterized by 71 core OTUs (i.e. OTUs present in each specimen) that represented 57.5% of the total number of sequences. The relative abundance of these core OTUs varied significantly among samples, and this variation was predominantly related to the geographic origin of the sample. These results show that in giant barrel sponges, the variation in the prokaryotic community is primarily associated with geography as opposed to phylogenetic relatedness.

https://ift.tt/2q6rE1J

Energy-Dense versus Routine Enteral Nutrition in the Critically Ill

New England Journal of Medicine, Ahead of Print.


https://ift.tt/2R7XpmF

Leptomeningeal tumor response to combined MAPK/ERK inhibition in V600E mutated gliomas despite undetectable CSF drug levels

dabrafenibtrametinibBRAFleptomeningeal disseminationglioma

https://ift.tt/2OGISSg

Editorial on “Interpretation of time-to-event outcomes in randomized trials: an online randomized experiment” by I. R. Weir et al.

https://ift.tt/2NZfDVD

Comment on “Systematic Review and Meta-Analysis of Diagnostic Accuracy of miRNAs in Patients with Pancreatic Cancer”

https://ift.tt/2CZnxgv

7 keys to proper care and cleaning of your ballistic vest

Follow these do's and don'ts to prolong the life of this lifesaving investment

https://ift.tt/2CVIt80

Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer

Abstract

Background

Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer.

Materials and methods

This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer.

Results

Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit.

Conclusions

Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.

https://ift.tt/2NWpcEo

The risk factors for benign small bowel obstruction following curative resection in patients with rectal cancer

Abstract

Background

So far there have been limited studies about the risk factors for benign small bowel obstruction (SBO) after colorectal cancer surgery. This study aimed to determine the factors affecting the development of benign SBO following curative resection in patients with rectal cancer.

Methods

Patients (3472) receiving curative resection of rectal cancer at the Department of Colorectal Cancer, Tianjin Medical University Cancer Institute and Hospital, between January 2003 and December 2012 were retrospectively studied. The incidence of benign SBO and its risk factors were then determined.

Results

The incidence of benign SBO was 7.3% (253/3472) in follow-up studies with an average time of 68 months. Further, 27% (68/253) of the patients received operative treatment because of the signs of strangulation or the lack of clinical improvement with conservative management. Open surgery and radiotherapy were defined as the risk factors for benign SBO after curative resection in patients with rectal cancer (P <  0.001).

Conclusion

Open surgery plus radiotherapy led to an increased risk of benign SBO in rectal cancer patients receiving curative resection.

https://ift.tt/2CvMHCu

Statin use in cancer survivors versus the general population: cohort study using primary care data from the UK clinical practice research datalink

Abstract

Background

Cancer survivors may be at increased risk of cardiovascular diseases, but little is known about whether prescribing guidelines for the primary prevention of cardiovascular disease are adequately implemented in these patients. We compared levels of statin initiation and cessation among cancer survivors compared to the general population to determine differences in uptake of pharmaceutical cardiovascular risk prevention measures in these groups.

Methods

The study population included individuals aged ≥40 during 2005–13 within the UK Clinical Practice Research Datalink primary care database. Within this population we identified cancer survivors who were alive and under follow-up at least 1 year after diagnosis, and controls with no cancer history. Follow-up time prior to cancer diagnosis was included in the control cohort. Using logistic regression, we compared these groups with respect to uptake of statins within 1 month of a first high recorded cardiovascular risk score. Then, we used Cox modelling to compare persistence on statin therapy (time to statin cessation) between cancer survivors and controls from the main study population who had initiated on a statin.

Results

Among 4202 cancer survivors and 113,035 controls with a record indicating a high cardiovascular risk score, 23.0% and 23.5% respectively initiated a statin within 1 month (adjusted odds ratio 0.98 [91.8–1.05], p = 0.626). Cancer survivors appeared more likely to discontinue statin treatment than controls (adjusted hazard ratio 1.07 [1.01–1.12], p = 0.02). This greater risk of discontinuing was only evident after the first year of therapy (p-interaction < 0.001).

Interpretation

Although cardiovascular risk is thought to be higher in cancer survivors compared to the general population, cancer survivors were no more likely to receive statins, and marginally more likely to cease long-term therapy, than general population controls. There may be an opportunity to mitigate the suspected higher cardiovascular risk in the growing population of cancer survivors by improving uptake of lipid-lowering treatment and persistence on therapy.

https://ift.tt/2AnKK9F

Prognostic factors for survival after curative resection of gastric mixed adenoneuroendocrine carcinoma: a series of 80 patients

Abstract

Background

To assess the prognostic factors and investigate the optimal treatment of gastric mixed adenoneuroendocrine tumors.

Methods

We retrospectively analyzed clinical data from 80 patients with gastric mixed adenoneuroendocrine carcinoma that received radical resection in our department from January 2007 to December 2016. Risk factors for relapse and survival were analyzed using a multivariate Cox proportional hazards regression model. Gastric mixed adenoneuroendocrine carcinoma was divided into neuroendocrine carcinoma and adenocarcinoma based on the predominant type in the tumor.

Results

The 3-year overall survival was 40% in the neuroendocrine carcinoma group and 75% in the adenocarcinoma group (P = 0.006). The neuroendocrine carcinoma (NEC)-dominant tumors and a Ki-67-positive index ≥60% were independent risk factors for worse overall survival. The 3-year recurrence-free survival was 33% in the neuroendocrine carcinoma group and 68% in the adenocarcinoma group. NEC-dominant tumors and a Ki-67-positive index ≥60% were independent risk factors for gastric mixed adenoneuroendocrine carcinoma recurrence. Patients in the adenocarcinoma group that received adjuvant chemotherapy exhibited significantly better overall survival than patients that did not receive chemotherapy (median survival time 43 months vs. 13 months, P = 0.026).

Conclusion

The NEC-dominant tumors and a Ki-67-positive index ≥60% were significantly associated with worse survival and a higher recurrence rate for gastric mixed adenoneuroendocrine carcinoma patients. Patients in the adenocarcinoma group may benefit from gastric adenocarcinoma treatments.

https://ift.tt/2CAhMFd

High postoperative monocyte indicates inferior Clinicopathological characteristics and worse prognosis in lung adenocarcinoma or squamous cell carcinoma after lobectomy

Abstract

Background

Peripheral monocyte count is an assessable parameter. Recently, evidence suggested an elevated preoperative monocyte counts predicting poor prognosis in malignancies. The aim of this study was to determine the prognostic effect of early postoperative blood monocyte count in patients with lung adenocarcinoma or squamous cell carcinoma following lobectomy.

Methods

We retrospectively reviewed patients with operated lung adenocarcinoma or squamous cell carcinoma from 2006 to 2011 in Western China Lung Cancer database. Univariate analysis on disease-free survival (DFS) and overall survival (OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model.

Results

There were 433 patients enrolled in our analysis. High postoperative elevated monocyte was associated with male gender (P < 0.001), positive smoking history (P = 0.005), and higher N stage (P = 0.002) and higher tumor stage (P = 0.026). Two-tailed log-rank test indicated patients with an early postoperative elevated monocyte count predicted a poor DFS and OS overall (P < 0.001, P < 0.001, respectively) as well as in subgroup analysis, and further presented as a promising independent prognostic factor for both DFS and OS (HR = 2.991, 95%CI: 2.243–3.988, P < 0.001; HR = 2.705, 95%CI: 1.977–3.700, P < 0.001, respectively) on multivariate analysis. However, no significance was detected for preoperative monocyte in multivariate analysis.

Conclusions

Elevated early postoperative peripheral monocyte count was an independent prognostic factor of poor prognosis and inferior clinicopathological features for patients with operable lung adenocarcinoma or squamous cell carcinoma by lobectomy.

https://ift.tt/2Aml7pK

Comparison of the efficacies of first-generation epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in patients with advanced non-small-cell lung cancer harboring EGFR mutations

Abstract

Background

Compared with standard chemotherapy, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are more effective in patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, data comparing the efficacies of different EGFR−TKIs, especially regarding the presence of brain metastasis, are lacking.

Methods

EGFR-TKI naive patients with recurrent or stage IIIB/IV NSCLC harboring EGFR mutations, excluding resistance mutations, were enrolled in this study. We retrospectively determined progression-free survival (PFS) using the Kaplan−Meier method with log-rank test in patients treated with either gefitinib or erlotinib, cumulative incidence of central nervous system (CNS) progression using the Fine and Gray competing risk regression model, and favorable prognostic factors for CNS progression by multivariate analysis.

Results

Seventy-seven EGFR-TKI-naive patients were started on either gefitinib (n = 55) or erlotinib (n = 22) in our hospital from April 2010 to April 2016. Among the patients with brain metastasis, PFS tended to be longer in the erlotinib than in the gefitinib group. In the analysis of cumulative incidence, the probability of CNS progression was lower in the erlotinib group than in the gefitinib group. Particularly, in a subgroup analysis of the patients with brain metastasis, there was a significant difference between the erlotinib and gefitinib groups (hazard ratio 0.25; 95% confidence interval, 0.08–0.81; p = 0.021). Of the prognostic factors for CNS progression evaluated, the absence of brain metastasis before EGFR-TKI therapy and receiving erlotinib (vs gefitinib) had a significantly favorable effect on patient prognosis.

Conclusion

Although this was a retrospective analysis involving a small sample size, erlotinib is potentially more promising than gefitinib for treatment of brain metastasis in patients with EGFR-mutant NSCLC.

https://ift.tt/2CvhIGB

Recombinant PAPP-A resistant insulin-like growth factor binding protein 4 (dBP4) inhibits angiogenesis and metastasis in a murine model of breast cancer

Abstract

Background

The Insulin-like growth factor (IGF) pathway plays a role in tumour development and progression. In vivo, IGF1 activity is regulated by the IGF binding proteins (IGFBPs). IGFBP4 inhibits the activity of IGF1 but proteolytic cleavage by pregnancy-associated plasma protein-A (PAPP-A) releases active IGF1. A modified IGFBP4, dBP4, which was resistant to PAPP-A cleavage but retained IGF1 binding capacity, was engineered, expressed in Human Embryonic Kidney (HEK) 293 cells and purified. This study examined the effects of dBP4 on IGF1-induced cell migration, invasion and angiogenesis in vitro. The effect of intra-tumour injections of dBP4 on tumour angiogenesis and metastasis was examined using the 4T1.2luc orthotopic model of breast cancer.

Methods

PAPP-A resistance and IGF binding capacity of dBP4 were characterized by Western blot and surface plasmon resonance, respectively. 4T1.2luc are mouse mammary adenocarcinoma cells transfected with luciferase to allow in vivo imaging. The effect of dBP4 on IGF1-induced Akt activation in 4T1.2luc cells was assessed by Western blot. Cell migration and invasion assays were performed using 4T1.2luc cells. Angiokit™ assays and Matrigel® implants were used to assess the effects of dBP4 on angiogenesis in vitro and in vivo, respectively. An orthotopic breast cancer model – 4T1.2luc cells implanted in the mammary fat pad of BALB/c mice – was used to assess the effect of intra tumour injection of purified dBP4 on tumour angiogenesis and metastasis. Tumour growth and lung metastasis were examined by in vivo imaging and tumour angiogenesis was evaluated by CD31 immunohistochemistry.

Results

Our engineered, PAPP-A resistant IGFBP4 (dBP4) retained IGF1 binding capacity and inhibited IGF1 activation of Akt as well as IGF1-induced migration and invasion by 4T1.2 mammary adenocarcinoma cells. dBP4 inhibited IGF1-induced angiogenesis in vitro and in Matrigel implants in vivo. Direct intra-tumour injection of soluble dBP4 reduced angiogenesis in 4T1.2 luc mammary tumours tumour and reduced lung metastasis.

Conclusion

A PAPP-A resistant IGFBP4, dBP4, inhibits angiogenesis and metastasis in 4T1.2 mammary fat pad tumours. This study highlights the therapeutic potential of dBP4 as an approach to block the tumour-promoting actions of IGF1.

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