Effects of physical exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy

Abstract

Purpose

Exercise has been shown to reduce fatigue during cancer treatment. Hypothesized mechanisms include inflammatory pathways. Therefore, we investigated effects of exercise on markers of inflammation in breast cancer patients during adjuvant chemotherapy.

Methods

We pooled data from two randomized controlled exercise intervention trials with breast cancer patients during adjuvant chemotherapy (n = 130), which had previously shown beneficial effects of exercise on fatigue. Exercise comprised a 12-week resistance training (BEATE study) or an 18-week combined resistance and aerobic training (PACT study). Serum IL-6, IL-1ra, and the IL-6/IL-1ra ratio were quantified at baseline, mid-intervention, post-intervention, and 6–9 months post-baseline.

Results

Mixed effect models showed significant increases in IL-6 and IL-6/IL-1ra ratio during chemotherapy and decreases afterwards. Differences between exercise and control group were not significant at any time point. Changes in total cancer-related fatigue were significantly correlated with changes in IL-6/IL-1ra ratio (partial correlation r = 0.23) and IL-6 (r = 0.21), and changes in physical cancer-related fatigue with changes in IL-6/IL-1ra ratio (r = 0.21).

Conclusions

Changes in fatigue were slightly correlated with changes in inflammatory markers, and there was a strong inflammatory response to adjuvant chemotherapy. The supervised exercise training did not counteract this increase in inflammation, suggesting that beneficial effects of exercise on fatigue during adjuvant chemotherapy for breast cancer are not essentially mediated by IL-6, IL-1ra, or the IL-6/IL-1ra ratio.

http://ift.tt/2jQBgv0

Tracking the Origin and Deciphering the Phylogenetic Relationship of Porcine Epidemic Diarrhea Virus in Ecuador

In 2010, new Chinese strains of porcine epidemic diarrhea virus (PEDV), clinically more severe than the classical strains, emerged. These strains were spread to United States in 2013 through an intercontinental transmission from China with further spreading across the world, evidencing the emergent nature of these strains. In the present study, an analysis of PEDV field sequences from Ecuador was conducted by comparing all the PEDV S gene sequences available in the GenBank database. Phylogenetic comparisons and Bayesian phylogeographic inference based on complete S gene sequences were also conducted to track the origin and putative route of PEDV. The sequence from the PED-outbreak in Ecuador was grouped into the clade II of PEDV genogroup 2a together with other sequences of isolates from Mexico, Canada, and United States. The phylogeographic study revealed the emergence of the Chinese PEDV strains, followed by spreading to US in 2013, from US to Korea, and later the introduction of PEDV to Canada, Mexico, and Ecuador directly from the US. The sources of imports of live swine in Ecuador in 2014 were mainly from Chile and US. Thus, this movement of pigs is suggested as the main way for introducing PEDV to Ecuador.

http://ift.tt/2l101bd

Note on the PCR threshold standard curve

The PCR threshold standard curve is based on an exponential model of the initial phase of a PCR run where template replication efficiency is constant cycle to cycle. As such it requires that a threshold is at ...

http://ift.tt/2jw9Zks

Patients’ attitudes regarding characteristics of physicians in ophthalmology

This retrospective cross-sectional study was performed to assess patient perceptions and attitudes towards physicians' physical appearance and education in the Vitreoretinal Specialist clinic setting. 295 cons...

http://ift.tt/2BchZxL

Cohort profile: the Saskatchewan Rural Health Study—adult component

Less is known about the respiratory health of general farming and non-framing populations. A longitudinal Saskatchewan Rural Health Study (SRHS) was conducted to explore the association between individual and con...

http://ift.tt/2jAwx3G

Central nervous system transcriptome of Biomphalaria alexandrina, an intermediate host for schistosomiasis

Globally, more than 200 million people live at risk of the neglected tropical disease schistosomiasis (or snail fever). Larval schistosomes require the presence of specific snail species that act as intermedia...

http://ift.tt/2BfyKrQ

Prediabetes and cardiovascular complications study (PACCS): international collaboration 4 years’ summary and future direction

The prediabetes and cardiovascular complications studies proposes to develop a screening protocol for diabetes cardiovascular risk, and strategies for holistic management amongst others. Over 500 participants ...

http://ift.tt/2jxSccG

Nevirapine- versus Efavirenz-based antiretroviral therapy regimens in antiretroviral-naive patients with HIV and Tuberculosis infections in India: a multi-centre study

According to World Health Organization (WHO) guidelines, which have also been adopted by the National AIDS Control Organization (NACO), India, Efavirenz-based Anti-Retroviral Therapy (ART) is better in Human-I...

http://ift.tt/2l1tRwi

Evaluation of the economic burden of leprosy among migrant and resident patients in Guangdong Province, China

A lot of time and money was needed during the diagnosis and treatment process of leprosy, the delayed leprosy would also impair the labor capability of patients as well, and these put a heavy burden for the le...

http://ift.tt/2iTi9zq

Composite neuroendocrine tumor and adenocarcinoma of the rectum

Although adenocarcinomas showing neuroendocrine differentiation or those mixed with high-grade neuroendocrine carcinoma (NEC) are sometimes encountered, composite tumors comprising neuroendocrine tumor (NET) G...

http://ift.tt/2kpWWgW

Placental abruption leading to hysterectomy

A 32-year-old multigravid patient at 21 weeks gestation presents with major concealed placental abruption and subsequent fetal demise. During an eventually failed misoprostol regime aiming for vaginal delivery she develops severe disseminated intravascular coagulopathy. Subsequent hysterotomy reveals Couvelaire uterus with major haemorrhage and requires subtotal hysterectomy for haemostasis. This case highlights the severity of the systemic response to abruption and fetal demise in utero and the multifactorial nature of its management.

http://ift.tt/2nPPuR5

Atypical chronic myeloid leukemia: a rare entity with management challenges

Future Oncology, Ahead of Print.


http://ift.tt/2Agkg7i

Survival prediction in pancreatic cancer patients with no distant metastasis: a large-scale population-based estimate

Future Oncology, Ahead of Print.


http://ift.tt/2z2P7GA

Endoscopic eradication therapy and the test of time

Endoscopic therapy for Barrett's esophagus (BE) has come a long way since 1992, when Brandt and Kauvar1 first demonstrated that BE metaplasia could be ablated by using endoscopically delivered laser irradiation. Early concerns regarding the feasibility and safety of endoscopic therapy were soon allayed, and attention shifted to finding the best endoscopic eradication technique. Endoscopic ablative modalities that have been studied include a variety of laser types, multipolar electrocoagulation, argon plasma coagulation, photodynamic therapy, radiofrequency ablation (RFA), and cryotherapy.

http://ift.tt/2jymU5D

Gastroscopy and gastric cancer–related mortality: Time to change recommendations regarding screening?

Gastric cancer is the third most common cause of cancer-related death worldwide,1 and most cases are locally advanced or metastatic at diagnosis. Widespread Helicobacter pylori eradication2 and radiologic or endoscopic screening,3 have been proved to decrease gastric cancer mortality in high-incidence countries. However, in countries with lower incidence, these strategies are probably not cost effective, and there are only recommendations regarding secondary prevention in high-risk patients, such as those with gastric preneoplastic conditions.

http://ift.tt/2jzwEMF

Unearthing the significance of buried intestinal metaplasia

Pre-cancerous Barrett's esophagus (BE) arises from columnar metaplasia of the squamous mucosa secondary to chronic reflux injury. If untreated, the metaplastic columnar epithelium may undergo a dysplastic transformation and in a subset of patients subsequently progresses to adenocarcinoma. New endoscopic modalities can successfully ablate the Barrett's mucosa to be replaced by neosquamous mucosa while the patients are taking a proton pump inhibitor. Although these advances have a positive impact on the conservation of the esophagus and treatment of early neoplasia, they have uncovered the issue of "buried BE" or "subsquamous intestinal metaplasia (SSIM)." SSIM is defined as the presence of esophageal subepithelial columnar epithelium underlying a restored squamous mucosal lining.

http://ift.tt/2BeQYKb

Sphincter of Oddi dysfunction: the never-ending story has come to a conclusion

In the late 1970s, during my fellowship in general surgery, my main scientific interest was the evaluation of the sphincter of Oddi status with intraoperative cholangiography during cholecystectomy. At that time, especially in Italy1 and in other locations, many cholecystectomies for gallstones were complemented by transduodenal sphincteroplasty whenever a dilatation of the common bile duct (CBD) or a tapering of the papillary contour was observed by intraoperative cholangiography. We assumed that these features were diagnostic for "papillitis," later more broadly renamed "sphincter of Oddi dysfunction" (SOD).

http://ift.tt/2jzYRTD

Post-ERCP pancreatitis in patients with type 2 diabetes mellitus

In their recent observational study, Zhao et al1 found similar incidence rates of post-ERCP pancreatitis (PEP) in patients with chronic pancreatitis (CP) versus other biliary diseases, and they reported lower PEP incidence rates as the severity of CP increased. The authors state that they "identified other possible risk and protective factors not examined before. The reduced incidence of PEP in CP patients was correlated with the presence of diabetes mellitus, pancreatic stones, and the use of ESWL (extracorporeal shock wave lithotripsy)." We would like to point out that our group had formerly evaluated the influence of type 2 diabetes mellitus (T2DM) on the short-term adverse events after ERCP in an 11-year (2003-2013) observational study that included 126,885 therapeutic procedures (23,002 [18.1%] in people with T2DM) in the overall Spanish population.

http://ift.tt/2BeQVht

Assessment of trainees’ performance in colonoscopy

The international competency-based medical education (CBME) collaborators proposed the following steps in planning a CBME curriculum: "(1) Identify the abilities needed of graduates. (2) Explicitly define the required competencies and their components. (3) Define milestones along a development path for the competencies. (4) Select educational activities, experiences, and instructional methods. (5) Select assessment tools to measure progress along the milestones. (6) Design an outcomes evaluation of the program."1

http://ift.tt/2jz28m2

Response:

We thank Nicosia and colleagues1 for their comments on our article "Asia-Pacific consensus guidelines for endoscopic management of benign biliary strictures."2 In that article, we highlighted the importance of a multidisciplinary approach to the management of benign biliary strictures (BBSs), not only in the diagnosis but in the treatment as well.2 The selection of treatment approaches to BBSs depends on the clinical setting, the patient's condition and willingness, and the availability of expertise, which mandate a multidisciplinary discussion among different specialties aimed at providing a patient with the appropriate treatment and the most optimal outcome.

http://ift.tt/2BeQSCj

Early ERCP for severe cholangitis? Of course!

Jean-Martin Charcot (1825-1893), a member of the Faculté de Médicin at the famous Hôpital Salpêtrière in Paris, a neurologist and professor of anatomic pathology, in 1877 brought attention to the "maladies du foie et des voie biliare"1 and the entity of "fièvre intermittente hépatique" characterized by the triad of jaundice, right upper quadrant pain, and fever, which came to be one of his eponymous legacies. This condition later became known as ascending cholangitis, based on the belief that infection always ascended from the duodenum through an incompetent sphincter of Oddi.

http://ift.tt/2jx0aTo

Information for readers

http://ift.tt/2Be0r4E

Response:

We highly appreciate the response from de Miguel-Yanes et al1 about the influence of diabetes mellitus (DM) on the incidence rate of post-ERCP pancreatitis (PEP). Because patients with chronic pancreatitis (CP) are at high risk for the development of DM, it is an important issue with significant implications for clinical practice.2

http://ift.tt/2Be0mxS

Guidewire cannulation in ERCP: from zero to hero!

For decades biliary cannulation during ERCP was done by lining up and advancing a catheter or a sphincterotome into the ampulla at what one believed was a "good" biliary angle and then gently (or not so gently) injecting contrast. This either resulted in a cholangiogram or a pancreatogram. If the bile duct was accessed, a wire was then advanced through the catheter into the biliary tree, and the procedure moved forward. If the pancreas was accessed, the catheter was pulled out and the maneuver was attempted again (and again and again) until ultimately successful or the biliary tree was not accessed.

http://ift.tt/2jwZZrc

Is it safe to wait 10 years after a negative baseline screening colonoscopy result?

Despite guidelines1 that recommend a 10-year interval after a negative screening colonoscopy result in average-risk individuals, many patients receive early examinations.2,3 This could be due to concerns about the adequacy of the baseline examination or to a fear of postcolonoscopy interval colorectal cancer (CRC). Prior studies suggest that if the baseline examination was less than adequate (poor preparation or uncertain cecal intubation), the yield of repeating the examination is high.4 However, in most cases, the baseline examination is adequate, and previous work has suggested that the risk of serious pathologic changes within 10 years is low.

http://ift.tt/2jwZT2O

Continuing Medical Education Exam: January 2018

http://ift.tt/2Be0duk

ASGE update

http://ift.tt/2kXLxbY

Suppression of reactive-oxygen-species accumulation accounts for paradoxical bacterial survival at high quinolone concentration [PublishAheadOfPrint]

When bacterial cells are exposed to increasing concentrations of quinolone-class antibacterials, survival drops, reaches a minimum, and then recovers, sometimes to 100%. Despite decades of study, events underlying the paradoxical, high-concentration survival remain obscure. Since reactive oxygen species (ROS) have been implicated in antimicrobial lethality, conditions generating paradoxical survival were examined for diminished ROS accumulation. Escherichia coli cultures were treated with various concentrations of nalidixic acid, followed by measurement of survival, rate of protein synthesis, and ROS accumulation. The latter measurement used a dye (carboxy-H2DCFDA) that fluoresces in the presence of ROS; fluorescence was assessed by microscopy (individual cells) and flow cytometry (batch cultures). High, non-lethal concentrations of nalidixic acid induced lower levels of ROS than moderate, lethal concentrations. Sub-lethal doses of exogenous hydrogen peroxide became lethal and eliminated the nalidixic acid-associated paradoxical survival. Thus, quinolone-mediated lesions needed for ROS-executed killing persist at high, non-lethal quinolone concentrations, thereby implicating ROS as a key factor in cell death. Chloramphenicol suppressed nalidixic acid-induced ROS accumulation and blocked lethality, further supporting a role for ROS in killing. Nalidixic acid also inhibited protein synthesis, with extensive inhibition at high concentrations correlating with lower ROS accumulation and paradoxical survival. A catalase deficiency, which elevated ROS levels, overcame the inhibitory effect of chloramphenicol on nalidixic acid-mediated killing, emphasizing the importance of ROS. The data collectively indicate that ROS play a dominant role in the lethal action of first-generation, quinolone-class compounds; a drop in ROS levels accounted for the quinolone tolerance observed at very high concentrations.

http://ift.tt/2ygixgx

Cystatin 9 and C: A novel immunotherapy that protects against multi-drug resistant New Delhi metallo-beta-lactamase-1 producing Klebsiella pneumoniae [PublishAheadOfPrint]

Multidrug-resistant (MDR) bacterial pneumonia can induce dysregulated pulmonary and systemic inflammation leading to morbidity and mortality. Antibiotics to treat MDR pathogens do not function to modulate the extent and intensity of inflammation and can have serious side effects. Herein, we evaluate the efficacy of two human cysteine proteinase inhibitors, cystatin 9 and cystatin C, as a novel immunotherapeutic treatment to combat MDR New Delhi metallo-beta-lactamase-1 (NDM-1) producing Klebsiella pneumoniae (Kp). Our results showed mice intranasally (i.n.) infected with an LD90 challenge of NDM-1 Kp then treated with the combination of human recombinant (r) rCST9 and rCSTC (rCSTs; 50 pg of each i.n. 1h post-infection (PI) and/or 500 pg of each intraperitoneal [i.p.] 3d PI) significantly improved survival compared to infected mice alone or infected mice treated with individual rCSTs (p<0.05). Results showed that both of our optimal rCST treatment regimens modulated pulmonary and systemic pro-inflammatory cytokine secretion in the serum, lungs, livers and spleens of infected mice (p<0.05). Treatment also significantly decreased bacterial burden (p<0.05), while preserving lung integrity with reduced inflammatory cell accumulation compared to infected mice. Further, rCST treatment regimens reduced lipid peroxidation and cell apoptosis in the lungs of infected mice. Additionally, in vitro studies showed that rCSTs (50 or 500 pg of each) directly decreased the viability of NDM-1 Kp. In conclusion, these data showed that rCST9/rCSTC worked synergistically to modulate host inflammation against MDR NDM-1 Kp pneumonia, which significantly improved survival. Therefore, rCST9/rCSTC are a promising therapeutic candidate for the treatment of bacterial pneumonia.

http://ift.tt/2AxDk5a

Elucidating the Pharmacokinetics/Pharmacodynamics of Aerosolized Colistin against Multidrug-resistant Acinetobacter baumannii and Klebsiella pneumoniae in a Mouse Lung Infection Model [PublishAheadOfPrint]

Pharmacokinetics/pharmacodynamics (PK/PD) of aerosolized colistin was investigated against Acinetobacter baumannii and Klebsiella pneumoniae over 24 h in a neutropenic mouse lung infection model. Dose fractionation studies were performed over 2.64 to 23.8 mg/kg/day, and the data were fitted to a sigmoid inhibitory model. AUC/MIC in the epithelial lining fluid was the most predictive PK/PD index for aerosolized colistin against both pathogens. Our study provides important pharmacological information for optimizing aerosolized colistin.

http://ift.tt/2yh3sLO

Hyperbaric Oxygen Reduces Aspergillus fumigatus Proliferation In Vitro and Influences In Vivo Disease Outcomes [PublishAheadOfPrint]

Recent estimates suggest that more than 3 million people have chronic or invasive fungal infections, causing more than 600,000 deaths every year. Aspergillus fumigatus causes invasive pulmonary aspergillosis (IPA) in patients with compromised immune systems and is a primary contributor to increases in human fungal infections. Thus, developing new clinical modalities as standalone or adjunctive therapy for improving IPA patient outcomes is critically needed. Here we test the in vitro and in vivo impact of hyperbaric oxygen (100% oxygen, >1 ATA) (HBO) on A. fumigatus proliferation and murine IPA outcomes. Our findings indicate that HBO reduces established fungal biofilm proliferation in vitro by over 50%. The effect of HBO under the treatment conditions was transient and fungistatic with A. fumigatus metabolic activity rebounding within six hours of HBO treatment being removed. In vivo, daily HBO provides a dose-dependent but modest improvement in murine IPA disease outcomes as measured by survival analysis. Intriguingly, no synergy was observed between sub-therapeutic voriconazole or amphotericin B and HBO in vitro or in vivo with daily HBO dosing, though loss of fungal superoxide dismutase genes enhanced HBO antifungal activity. Further studies are needed to optimize the HBO treatment regimen and better understand the effects of HBO on both the host and the pathogen during a pulmonary invasive fungal infection.

http://ift.tt/2AvHXNi

Sequencing of FKS Hot-Spot1 from Saprochaete capitata. Searching for a relationship with reduced echinocandin susceptibility. [PublishAheadOfPrint]

Saprochaete capitata, formerly known as Geotrichum capitatum, is an emerging fungal pathogen with low susceptibility to echinocandins. Here, we report the nucleotide sequence of the S. capitata Hot Spot 1 region of the FKS gene (FKS HS1) which codifies for the catalytic subunit of β-1,3-D-glucan synthase, the target of echinocandins. For that purpose, we firstly designed degenerated oligonucleotide primers derived from conserved flanking regions of the FKS1 HS1 segment of 12 different fungal species. Interestingly, the analysis of the translated FKS HS1 sequences of 12 isolates of S. capitata revealed that all of them exhibited the same substitution, F-to-L, in a position highly related to reduced echinocandins susceptibility.

http://ift.tt/2ygCAeK

Plasmodium falciparum Recrudescence Two Years after a First Treated Uncomplicated Infection without Return in a Malaria Endemic Area [PublishAheadOfPrint]

We report here evidence, confirmed by the lack of travel activity outside of France and genetic diversity analysis using polymorphic microsatellite markers, that Plasmodium falciparum malaria infection effectively treated with an artemisinin-based combination can remain dormant and relapse during pregnancy at least 2 years after treatment.

http://ift.tt/2l0hfWb

Topical antibiotic use co-selects for the carriage of mobile genetic elements conferring resistance to unrelated antimicrobials in Staphylococcus aureus [PublishAheadOfPrint]

Topical antibiotics such as mupirocin and fusidic acid are commonly used in the prevention and treatment of skin infections, particularly those caused by staphylococci. However, widespread use of these agents is associated with increased resistance to these agents, potentially limiting their efficacy. Of particular concern is the observation that resistance to topical antibiotics is often associated with multidrug resistance, suggesting that topical antibiotics may play a role in the emergence of multidrug-resistant (MDR) strains.

New Zealand (NZ) has some of the highest globally recorded rates of topical antibiotic usage and resistance. Using a combination of Pacific Biosciences Single Molecule Real Time (SMRT) whole genome sequencing, Illumina short read sequencing and Bayesian phylogenomic modelling on 118 new multilocus sequence type 1 (ST1) community Staphylococcus aureus isolates from New Zealand and 61 publically available international ST1 genome sequences, we demonstrate a strong correlation between the clinical introduction of topical antibiotics and the emergence of MDR ST1 S. aureus. We also provide in vitro experimental evidence showing that exposure to topical antibiotics can lead to the rapid selection of MDR S. aureus isolates carrying plasmids that confer resistance to multiple unrelated antibiotics, from within a mixed population of competitor strains. These findings have important implications regarding the impact of the indiscriminate use of topical antibiotics.

http://ift.tt/2iRy8xM

Adverse effects of intravenous vancomycin-based prophylaxis during therapy for pediatric acute myeloid leukemia [PublishAheadOfPrint]

Background Children and adolescents with acute myeloid leukemia (AML) are at risk of life-threatening bacterial infection, especially with viridans group streptococci. Primary antibacterial prophylaxis with vancomycin-based regimens reduces this risk, but might increase risk of renal or liver toxicity, or Clostridium difficile infection (CDI).

Methods A retrospective review was conducted of patients treated for newly diagnosed AML at St. Jude Children's Research Hospital from 2002 to 2008. Nephrotoxicity was classified according to pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease (RIFLE) criteria, and hepatotoxicity according to Common Terminology Criteria for Adverse Events criteria. The risks of nephrotoxicity, hepatotoxicity and CDI were compared between patients receiving vancomycin-based prophylaxis, no intravenous prophylaxis, or other prophylaxis. Generalized linear mixed models were used to address potential confounding.

Results 392 chemotherapy courses (108 with no intravenous prophylaxis, 218 with vancomycin-based prophylaxis, and 66 with other prophylaxis) in 111 patients were included. Development of pRIFLE risk, injury, or failure occurred in 190, 44, and 2 courses, respectively. An increase in ≥1, 2, or 3 grades for hepatotoxicity occurred in 189, 52, and 19 courses, respectively. After adjusting for confounders, vancomycin-based prophylaxis was not associated with nephrotoxicity or hepatotoxicity, and reduced the risk of CDI compared to no intravenous prophylaxis (0.9% vs. 6.5%; P= 0.007) or other prophylaxis regimens (0.9% vs. 3.0%; P= 0.23).

Summary Despite concerns about vancomycin toxicity, vancomycin-based prophylaxis in pediatric patients with AML did not increase the risk of nephrotoxicity or hepatotoxicity and reduced CDI. Caution is advised to avoid contributing to antibiotic resistance.

http://ift.tt/2l0G0BI

Whole cell screen of fragment library identifies gut microbiota metabolite indole propionic acid as antitubercular [PublishAheadOfPrint]

Several key tuberculosis drugs including pyrazinamide, with a molecular weight of 123.1 g/mol, are smaller than the usual drug like molecules. Current drug discovery efforts focus on the screening of larger compounds with molecular weights centered around 400-500 g/mol. Fragment (molecular weight < 300 g/mol) libraries have not been systematically explored for antitubercular activity. Here we screened a collection of 1000 fragments, present in the Maybridge Ro3 library, for whole cell activity against Mycobacterium tuberculosis. Twenty-nine primary hits showed dose-dependent growth inhibition equal or better than pyrazinamide. The most potent hit, indole propionic acid (IPA, 3-(1H-indol-3-yl)propanoic acid), a metabolite produced by the gut microbiota, was profiled in vivo. The molecule was well tolerated in mice and showed adequate pharmacokinetic properties. In an acute mouse model of tuberculosis infection, IPA reduced the bacterial load in the spleen 7 fold. Our results suggest that IPA should be evaluated as an add-on to current regimens and that fragment libraries should be further explored to identify antimycobacterial lead candidates.

http://ift.tt/2iRy0yi

Genomic insights into Colistin Resistant Klebsiella pneumoniae from a Tunisian teaching hospital [PublishAheadOfPrint]

The emergence of colistin-resistant Klebsiella pneumoniae (CoRKp) is a public health concern since this antibiotic has become the last line of treatment for infections caused by multidrug-resistant (MDR) gram-negatives. In this study, we have investigated the molecular basis of colistin-resistance in 13 MDR Kp isolated from 12 patients in a teaching hospital in Sousse, Tunisia. Whole-genome sequencing (WGS) was used to decipher the molecular mechanism of colistin-resistance and to identify the resistome of these CoRKp. It revealed a genome of ca. 5,5 Mbp in size with a G+C content of 57% corresponding to that commonly observed for K. pneumoniae. These isolates belonged the 5 different STs (ST11, ST15, ST101, ST147, and ST392) and their resistome was composed of acquired β-lactamases including ESBLs and carbapenemases (bla_CTX-M-15, bla_OXA-204, bla_OXA-48, bla_NDM-1 genes), aminoglycoside resistance genes (aac(6')Ib-cr, aph(3' ')-Ib, aph(6)-Id, aac(3)-IIa), fosfomycin (fosA), fluoroquinolone (qnr-like), chloramphenicol, trimethoprim and tetracyclin resistance genes. All the isolates were identified as having a mutated mgrB gene. Mapping reads with reference sequences of the most common genes involved in colistin-resistance revealed several modifications in mgrB, pmr and pho operons (deletions, insertion, susbstitution, ..) likely affecting the function of these proteins. Noteworthy, among the 12 patients, 10 were treated with colistin before the isolation of CoRKp. No plasmid encoding mcr-1-5 genes were found in these isolates.

This study corresponds to the first molecular characterization of a collection of CoRKp in Tunisia, and highlights that the small transmembrane protein MgrB is a main mechanism for colistin resistance in K. pneumoniae.

http://ift.tt/2kXH7lo

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy

No abstract available

http://ift.tt/2kmLbaY

Structural modification of histone deacetylase inhibitors with a phenylglycine scaffold

During the discovery of histone deacetylase inhibitors (HDACIs) as antitumor drugs, a series of potent phenylglycine-based HDACIs were developed. However, further development is restricted by the poor solubility. Therefore, structural modifications were performed in the present study in the development of potent HDACIs with improved pharmacokinetic properties. The synthesized molecules were designed by the substitution of fatty linkers for aromatic linkers, and showed good solubility profiles. Among the compounds derived, molecule HD9 showed a potent enzyme-inhibitory effect (IC50 values of 76 nmol/l) and in-vitro antiproliferative activities (IC50 values of 0.51, 0.83, and 0.76 µmol/l against U937, K562, and HL60 cells, respectively). Molecule HD9 showed selectivity of HDAC3 over HDAC6 in the isoform selectivity assays. Molecular docking studies showed good binding patterns of molecule HD9 to the active site of HDAC3. Results from the present work indicated that molecule HD9 is a promising lead compound for the tumor therapy. Correspondence to Dr Lei Zhang, Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, China Tel: +86 150 9208 5925; fax: +86 053 6846 2014; e-mail: leiqdu@foxmail.com Correspondence to Dr Weiguo Song, Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, China Fax: +86 053 6846 2014 Received February 13, 2017 Accepted November 8, 2017 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2jPejs6

Fusobacterium Travels with Colorectal Cancer Cells [News in Brief]

An innate tumor microbiome appears to drive tumor growth.

http://ift.tt/2BDPhqf

Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins

The statin family of drugs preferentially trigger tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for GGPP and FPP cannot explain increased statin sensitivity. While ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the anti-proliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity databases indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anti-cancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.

http://ift.tt/2AL8aEh

Race disparities in the contribution of miRNA isoforms and tRNA-derived fragments to triple-negative breast cancer

Triple-Negative Breast Cancer (TNBC) is a breast cancer subtype characterized by marked differences between White and Black/African-American women. We performed a systems-level analysis on datasets from The Cancer Genome Atlas (TCGA) to elucidate how the expression patterns of messenger RNAs (mRNAs) are shaped by regulatory non-coding RNAs (ncRNAs). Specifically, we studied isomiRs, i.e. isoforms of microRNAs (miRNAs), and tRNA-derived fragments (tRFs). In normal breast tissue, we observed a marked cohesiveness in both the ncRNA and mRNA layers and the associations between them. This cohesiveness was widely disrupted in TNBC: many mRNAs become either differentially expressed or differentially wired between normal breast and TNBC in tandem with isomiR or tRF dysregulation. The affected pathways included energy metabolism, cell signaling and immune responses. Within TNBC, the wiring of the affected pathways with isomiRs and tRFs differed in each race. Multiple isomiRs and tRFs arising from specific miRNA loci (e.g., miR-200c, miR-21, the miR-17/92 cluster, the miR-183/96/182 cluster) and from specific tRNA loci (e.g. the nuclear tRNAGly and tRNALeu, the mitochondrial tRNAVal and tRNAPro) were strongly associated with the observed race disparities in TNBC. We highlight the race-specific aspects of transcriptome wiring by discussing in detail the metastasis-related MAPK and the Wnt/β-catenin signaling pathways, two of the many key pathways that were found differentially wired. In conclusion, by employing a data- and knowledge-driven approach we comprehensively analyzed the normal and cancer transcriptomes to uncover novel key contributors to the race-based disparities of TNBC.

http://ift.tt/2BVS7mF

Coactivation of estrogen receptor and IKK-{beta} induces a dormant metastatic phenotype in ER-positive breast cancer

A growing body of evidence suggests that the inflammatory NFκB pathway is associated with the progression of ER+ tumors to more aggressive stages. However, it is unknown whether NFκB is a driver or a consequence of aggressive ER+ disease. To investigate this question, we developed breast cancer cell lines expressing an inducible, constitutively active form of IκB kinase β (CA-IKKβ), a key kinase in the canonical NFκB pathway. We found that CA-IKKβ blocked E2-dependent cell proliferation in vitro and tumor growth in vivo in a reversible manner, suggesting that IKKβ may contribute to tumor dormancy and recurrence of ER+ disease. Moreover, coactivation of ER and IKKβ promoted cell migration and invasion in vitro and drove experimental metastasis in vivo. Gene expression profiling revealed a strong association between ER and CA-IKKβ-driven gene expression and clinically relevant invasion and metastasis gene signatures. Mechanistically, the invasive phenotype appeared to be driven by an expansion of a basal/stem-like cell population rather than EMT. Taken together, our findings suggest that coactivation of ER and the canonical NFκB pathway promotes a dormant, metastatic phenotype in ER+ breast cancer and implicates IKKβ as a driver of certain features of aggressive ER+ breast cancer.

http://ift.tt/2AMLVOw

miR-204-5p and miR-211-5p contribute to BRAF inhibitor resistance in melanoma

Melanoma treatment with the BRAF V600E inhibitor vemurafenib (VMF) provides therapeutic benefits but the common emergence of drug resistance remains a challenge. We generated A375 melanoma cells resistant to VMF with the goal of investigating changes in miRNA expression patterns that might contribute to resistance. Increased expression of miR-204-5p and miR-211-5p occurring in VMF-resistant cells was determined to impact VMF response. Their expression was rapidly affected by VMF treatment through RNA stabilization. Similar effects were elicited by MEK and ERK inhibitors but not AKT or Rac inhibitors. Ectopic expression of both miRNA in drug-naive human melanoma cells was sufficient to confer VMF resistance and more robust tumor growth in vivo. Conversely, silencing their expression in resistant cells inhibited cell growth. Joint overexpression of miR-204-5p and miR-211-5p durably stimulated Ras and MAPK upregulation after VMF exposure. Overall, our findings show how upregulation of miR-204-5p and miR-211-5p following VMF treatment enables the emergence of resistance, with potential implications for mechanism-based strategies to improve VMF responses.

http://ift.tt/2BUyDP7

Transcription factor activities enhance markers of drug sensitivity in cancer

Transcriptional dysregulation induced by aberrant Transcription factors (TFs) is a key feature of cancer, but its global influence on drug sensitivity has not been examined. Here we infer the transcriptional activity of 127 TFs through analysis of RNA-seq gene expression data newly generated for 448 cancer cell lines, combined with publicly available datasets to survey a total of 1,056 cancer cell lines and 9,250 primary tumors. Predicted TF activities are supported by their agreement with independent shRNA essentiality profiles and homozygous gene deletions, and recapitulate mutant-specific mechanisms of transcriptional dysregulation in cancer. By analysing cell line responses to 265 compounds, we uncovered numerous TFs whose activity interacts with anti-cancer drugs. Importantly, combining existing pharmacogenomic markers with TF activities often improves the stratification of cell lines in response to drug treatment. Our results, which can be queried freely at dorothea.opentargets.io, offer a broad foundation for discovering opportunities to refine personalised cancer therapies.

http://ift.tt/2AMDJxI

VEGFR-2-mediated reprogramming of mitochondrial metabolism regulates the sensitivity of acute myeloid leukemia to chemotherapy

Metabolic reprogramming is central to tumorigenesis, but whether chemotherapy induces metabolic features promoting recurrence remains unknown. We established a mouse xenograft model of human acute myeloid leukemia (AML) that enabled chemotherapy-induced regressions of established disease followed by lethal regrowth of more aggressive tumor cells. Human AML cells from terminally ill mice treated with chemotherapy (chemoAML) had higher lipid content, increased lactate production and ATP levels, reduced expression of PPARG coactivator 1α (PGC-1α), and fewer mitochondria than controls from untreated AML animals. These changes were linked to increased vascular endothelial growth factor receptor 2 (VEGFR-2) signaling that counteracted chemotherapy-driven cell death; blocking of VEGFR-2 sensitized chemoAML to chemotherapy (re-)treatment and induced a mitochondrial biogenesis program with increased mitochondrial mass and oxidative stress. Accordingly, depletion of PGC-1α in chemoAML cells abolished such induction of mitochondrial metabolism and chemosensitization in response to VEGFR-2 inhibition. Collectively, this reveals a mitochondrial metabolic vulnerability with potential therapeutic applications against chemotherapy-resistant AML.

http://ift.tt/2BVhHIk

Genomic and Epigenomic Signatures in Ovarian Cancer Associated with Re-sensitization to Platinum Drugs

DNA methylation aberrations have been implicated in acquired resistance to platinum drugs in ovarian cancer (OC). In this study, we elucidated an epigenetic signature associated with platinum drug re-sensitization that may offer utility in predicting the outcomes of patients who are co-administered a DNA methyltransferase inhibitror. The OC specimens we analyzed were derived from a recent clinical trial that compared the responses of patients with recurrent platinum-resistant OC who received carboplatin plus the DNA methyltransferase inhibitor guadecitabine or a standard of care chemotherapy regimen selected by the treating physician. Tumor biopsies or malignant ascites were collected from patients before treatment (day 1, cycle 1) or after treatment (after 2 cycles) for epigenomic and transcriptomic profiling using the Infinium HumanMethylation450 BeadChip (HM450). We defined 94 gene promoters that were hypomethylated significantly by guadecitabine, with 1659 genes differentially expressed in pre-treatment vs. post-treatment tumors. Pathway analysis revealed that the experimental regimen significantly altered immune re-activation and DNA repair pathways. Progression-free survival correlated with baseline expression levels of 1155 genes involved in 25 networks. In functional investigations in OC cells, engineered upregulation of certain signature genes silenced by promoter methylation (DOK2, miR-293a and others) restored platinum drug sensitivity. Overall, our findings illuminate how inhibiting DNA methylation can sensitize OC cells to platinum drugs, in large part by altering gene expression patterns related to DNA repair and immune activation, with implications for improving the personalized care and survival outcomes of OC patients.

http://ift.tt/2AMaJpO

LNMICC promotes nodal metastasis of cervical cancer by reprogramming fatty acid metabolism

Cancer spread to lymph nodes (LN) predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long non-coding RNA LNMICC associates with LN metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted LN metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the pro-metastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of LN metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer.

http://ift.tt/2BVpbuS

Downregulating Neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies

Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. Nrp2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction.

http://ift.tt/2BVdbd9

CDKN2A/p16 deletion in head and neck cancer cells is associated with Cdk2 activation, replication stress, and vulnerability to Chk1 inhibition

Checkpoint kinase inhibitors (CHKi) exhibit striking single agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of Chk1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S phase arrest. Novel association between CDKN2A/p16 copy number loss, Cdk2 activation, replication stress and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated Cdk2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.

http://ift.tt/2BBkNVX

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non-Small-Cell Lung Cancer by Activating Src-Mediated Bypass Signaling

Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non-small-cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacological and molecular approaches rendered EGFR mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2-Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC.

http://ift.tt/2iTjGW3

Sterile water injections for childbirth pain: An evidenced based guide to practice

Publication date: Available online 11 December 2017
Source:Women and Birth
Author(s): Lena B. Mårtensson, Eileen K. Hutton, Nigel Lee, Sue Kildea, Yu Gao, Ingrid Bergh
BackgroundAbout 30% of women in labour suffer from lower back pain. Studies of sterile water injections for management of low back pain have consistently shown this approach to be effective. The objective of this evidence-based guide is to facilitate the clinical use of sterile water injections to relieve lower back pain in labouring women.MethodsTo identify relevant publications our search strategy was based on computerised literature searches in scientific databases. The methodological quality of each study was assessed using the modified version of the Jadad scale, 12 studies were included.FindingsRecommendations regarding the clinical use of sterile water injections for pain relief in labour are reported in terms of the location of injection administration, various injection techniques, number of injections used, amount of sterile water in each injection and adverse effects.DiscussionBoth injection techniques provide good pain relief for lower back pain during labour. The subcutaneous injection technique is possibly less painful than the intracutaneous technique administered, but we are unsure if this impacts on effectiveness. The effect seems to be related to the number of injections and the amount of sterile water in each injection.ConclusionThe recommendation at present, based on the current state of knowledge, is to give four injections. Notwithstanding the differences in injection technique and number of injections the method appears to provide significant levels of pain relief and can be repeated as often as required with no adverse effect (apart from the administration pain) on the woman or her foetus.



http://ift.tt/2BC4bxo

Telephone triage and midwifery: A scoping review

Publication date: Available online 11 December 2017
Source:Women and Birth
Author(s): Carolyn M. Bailey, Jennifer M. Newton, Helen G. Hall
BackgroundMidwives use telephone triage to provide advice and support to childbearing women, and to manage access to maternity services. Telephone triage practises are important in the provision of accurate, timely and appropriate health care. Despite this, there has been very little research investigating this area of midwifery practice.AimTo explore midwives and telephone triage practises; and to discuss the relevant findings for midwives managing telephone calls from women.MethodsA five-stage process for conducting scoping reviews was employed. Searches of relevant databases as well as grey literature, and reference lists from included studies were carried out.FindingsA total of 11 publications were included. Thematic analysis was used to identify key concepts. We grouped these key concepts into four emergent themes: purpose of telephone triage, expectations of the midwife, challenges of telephone triage, and achieving quality in telephone triage.DiscussionTelephone triage from a midwifery perspective is a complex multi-faceted process influenced by many internal and external factors. Midwives face many challenges when balancing the needs of the woman, the health service, and their own workloads. Primary research in this area of practice is limited.ConclusionFurther research to explore midwives' perceptions of their role, investigate processes and tools midwives use, evaluate training programs, and examine outcomes of women triaged is needed.



http://ift.tt/2B6qx8X

Septic Cardiomyopathy

Objectives: To describe, with an emphasis on clinical applications, what is known about the pathophysiology, management, and implications of septic cardiomyopathy in the adult ICU. Data Sources and Study Selection: A PubMed literature review was performed for relevant articles. Only articles in English that studied human adults with sepsis were included. Data Extraction and Data Synthesis: Multiple competing definitions for septic cardiomyopathy hinder understanding of this entity. Although many patients with sepsis develop cardiac dysfunction, the impact of septic cardiomyopathy on prognosis and therapy remains to be demonstrated. Treatment of septic cardiomyopathy is aimed at treating the underlying sepsis and providing specific supportive care for cardiogenic shock when present. Conclusions: Septic cardiomyopathy is an important contributor to organ dysfunction in sepsis. Guided treatment of septic cardiomyopathy may affect patients' prognosis, especially when their cardiac index is substantially decreased. The implication of septic cardiomyopathy for both short- and long-term outcomes is an important area for future investigation. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Dr. Sarge's institution received funding from the National Institutes of Health/National Heart, Lung, and Blood (UM1 NIH/NHLBI) as the site principal investigator for EPVent2: A Phase II study of Mechanical Ventilation Directed by Transpulmonary Pressures, and he received funding from Christie & Young P.C. (legal consulting) and the Society of Critical Care Medicine (SCCM) (speaking honoraria and travel expenses). Dr. Grissom received funding for teaching critical care ultrasound from SCCM (honorarium and travel expenses), the American Thoracic Society (honorarium), and the Beth Israel Deaconess Medical Center (honorarium and travel expenses). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: samuel.brown@imail.org Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2BbFE1j

Practice Patterns and Outcomes Associated With Early Sedation Depth in Mechanically Ventilated Patients: A Systematic Review and Meta-Analysis

Objectives: Emerging data suggest that early deep sedation may negatively impact clinical outcomes. This systematic review and meta-analysis defines and quantifies the impact of deep sedation within 48 hours of initiation of mechanical ventilation, as described in the world's literature. The primary outcome was mortality. Secondary outcomes included hospital and ICU lengths of stay, mechanical ventilation duration, and delirium and tracheostomy frequency. Data Sources: The following data sources were searched: MEDLINE, EMBASE, Scopus, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews and Effects, Cochrane Database of Systematic Reviews databases, ClinicalTrials.gov, conference proceedings, and reference lists. Study Selection: Randomized controlled trials and nonrandomized studies were included. Data Extraction: Two reviewers independently screened abstracts of identified studies for eligibility. Data Synthesis: Nine studies (n = 4,521 patients) published between 2012 and 2017 were included. A random effects meta-analytic model revealed that early light sedation was associated with lower mortality (9.2%) versus deep sedation (27.6%) (odds ratio, 0.34 [0.21–0.54]). Light sedation was associated with fewer mechanical ventilation (mean difference, –2.1; 95% CI, –3.6 to –0.5) and ICU days (mean difference, –3.0 (95% CI, –5.4 to –0.6). Delirium frequency was 28.7% in the light sedation group and 48.5% in the deep sedation group, odds ratio, 0.50 (0.22–1.16). Conclusions: Deep sedation in mechanically ventilated patients, as evaluated in a small number of qualifying heterogeneous randomized controlled trials and observational studies, was associated with increased mortality and lengths of stay. Interventions targeting early sedation depth assessment, starting in the emergency department and subsequent ICU admission, deserve further investigation and could improve outcome. This systematic review has been registered with the PROSPERO international prospective register of systematic reviews (#CRD42017057264). Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/29S62lw). Mr. Stephens received funding from Washington University Institute of Clinical; and supported by a Translational Sciences grant UL1TR000448, sub-award TL1TR000449, from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). Dr. Roberts was supported by a grant from the NIH/National Heart, Lung, and Blood Institute (K23HL126979). Dr. Ablordeppey was supported by the Washington University School of Medicine Faculty Scholars grant and the Foundation for Barnes-Jewish Hospital; and her institution received funding from Washington University School of Medicine and the BJH Foundation. Dr. Kollef is supported by the Foundation for Barnes-Jewish Hospital. Dr. Fuller was funded by the KL2 Career Development Award, and this research was supported by the Washington University Institute of Clinical and Translational Sciences (grants UL1 TR000448 and KL2 TR000450) from the NCATS. He was also funded by the Foundation for Barnes-Jewish Hospital Clinical and Translational Sciences Research Program (grant # 8041–88). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: stephensr@wustl.edu Copyright © by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

http://ift.tt/2BbFAP7

Risks of bleeding and thrombosis in intensive care unit patients with haematological malignancies

Patients with malignant haematological disease and especially those who require intensive care have an increased risk of bleeding and thrombosis, but none of these data were obtained in ICU patients only. We a...

http://ift.tt/2B87hIv

Relevant factors for the optimal duration of extended endocrine therapy in early breast cancer

Abstract

Purpose

For postmenopausal patients with hormone receptor-positive early breast cancer, the optimal subgroup and duration of extended endocrine therapy is not clear yet. The aim of this study using the IDEAL patient cohort was to identify a subgroup for which longer (5 years) extended therapy is beneficial over shorter (2.5 years) extended endocrine therapy.

Methods

In the IDEAL trial, 1824 patients who completed 5 years of adjuvant endocrine therapy (either 5 years of tamoxifen (12%), 5 years of an AI (29%), or a sequential strategy of both (59%)) were randomized between either 2.5 or 5 years of extended letrozole. For each prior therapy subgroup, the value of longer therapy was assessed for both node-negative and node-positive patients using Kaplan Meier and Cox regression survival analyses.

Results

In node-positive patients, there was a significant benefit of 5 years (over 2.5 years) of extended therapy (disease-free survival (DFS) HR 0.67, p = 0.03, 95% CI 0.47–0.96). This effect was only observed in patients who were treated initially with a sequential scheme (DFS HR 0.60, p = 0.03, 95% CI 0.38–0.95). In all other subgroups, there was no significant benefit of longer extended therapy. Similar results were found in patients who were randomized for their initial adjuvant therapy in the TEAM trial (DFS HR 0.37, p = 0.07, 95% CI 0.13–1.06), although this additional analysis was underpowered for definite conclusions.

Conclusions

This study suggests that node-positive patients could benefit from longer extended endocrine therapy, although this effect appears isolated to patients treated with sequential endocrine therapy during the first 5 years and needs validation and long-term follow-up.

http://ift.tt/2Avf6sk

PC-FACS December 1, 2017

Snyder Sulmasy L, Mueller PS. Ethics and the legalization of physician-assisted suicide: an American College of Physicians position paper. Ann Intern Med. 2017;167(8):576-578

http://ift.tt/2z2poxU

Chemotherapy use, end-of-life care, and costs of care among patients diagnosed with Stage IV pancreatic cancer

For patients with metastatic cancer and limited life-expectancy, potential benefits of chemotherapy must be balanced against harms to quality-of-life near death and increased out-of-pocket costs of care.

http://ift.tt/2iSHARC

MicroRNA 143-5p regulates alpaca melanocyte migration, proliferation, and melanogenesis

Abstract

microRNAs (miRNAs) have been shown to be closely involved in the control of melanogenesis and hair colour in mammals. Previous data also indicate that miR-143 regulates cell growth in melanoma. Here, we aimed to investigate the role of miR-143-5p in alpaca melanocytes. We found that miR-143-5p was highly expressed in the cytoplasm of alpaca melanocytes as demonstrated by an in situ hybridization assay. Prediction analysis revealed that miR-143-5p could regulate TGF-β-activated kinase 1 (TAK1) expression, which we confirmed by luciferase reporter assay, indicating that miR-143-5p controls TAK1 expression by directly targeting its 3′ untranslated region (UTR). miR-143-5p overexpression decreased TAK1 expression, which led to increased melanocyte migration and proliferation, and downregulation of microphthalmia-associated transcription factor (MITF), which regulates melanin production. These results support a functional role for miR-143-5p in regulating alpaca melanocyte migration, proliferation, and melanogenesis through direct targeting of TAK1.

This article is protected by copyright. All rights reserved.

http://ift.tt/2nN2aYW

Erratum to: Kanehira T, Matsuura T, Takao S, et al. Impact of Real-Time-Image Gating on Spot Scanning Proton Therapy for Lung Tumors: A Simulation Study. Int J Radiat Oncol Biol Phys 2016;97:173-181.

There was an error in the D5-D95 in Figure 4 on page 179. The data has been corrected here. The correction to this parameter still supports the conclusion if the criteria of D5-D95 was taken as 7%.

http://ift.tt/2yh1A5O

Radiation Oncology in The Netherlands

As part of the International Journal of Radiation Oncology, Biology, Physics "Around the Globe" section, we describe the current status of radiation oncology in The Netherlands. The Netherlands ranks highest in rate of acceptance of manuscripts of this journal (personal communication with A. Zietman, August 14, 2017) and has a large history in clinical studies and technological innovations in radiation therapy. We address the Dutch health care and insurance system, the history and organization of radiation therapy, the education and training, quality aspects, and the country's role in research and innovation.

http://ift.tt/2Au6Etl

Consider Surgery, but Not in This Case

We lack clear data regarding best management of Merkel cell carcinoma (MCC) with satellite metastases, given the rarity of presentation. Although wide excision for primary MCC is the standard of care, we advise against surgery here (1) because of the high probability that subclinical satellite metastases will prevent clear margins. Because MCC is highly sensitive to radiation therapy (RT), the added morbidity of surgery here is unlikely to provide further benefit. Radiation therapy fields would include the known primary and satellite lesions with a 5-cm margin, to a total dose of 50 to 60 Gy over 5 to 6 weeks (2 Gy/d) (2).

http://ift.tt/2yg3WSh

Breast Cancer Biology: Clinical Implications for Breast Radiation Therapy

Historically, prognosis and treatment decision making for breast cancer patients have been dictated by the anatomic extent of tumor spread. However, in recent years, "breast cancer" has proven to be a collection of unique phenotypes with distinct prognoses, patterns of failure, and treatment responses. Recent advances in biologically based assays and targeted therapies designed to exploit these unique phenotypes have profoundly altered systemic therapy practice patterns and treatment outcomes. Data associating locoregional outcomes with tumor biology are emerging.

http://ift.tt/2Av8hat

Primary Radiation Therapy for Merkel Cell Carcinoma

Satellite lesions (stage IIIB) represent poorly contained disease, and surgery cannot ensure clear margins. The patient (1) is immune-competent, and a complete response to radiation therapy (RT) is expected with <10% risk of local recurrence (2). Therefore, we recommend RT for the primary site and satellite lesions with a 3- to 5-cm margin to 50 Gy in 25 fractions, avoiding interruptions. Given the curved target volume, we favor tangential photons (with bolus) sparing the medial aspect of the leg.

http://ift.tt/2AvvEk4

Radiation Therapy Rather Than Surgery for Merkel Cell Carcinoma: The Advantages of Radiation Therapy

We recommend the following approach for this patient (1).

http://ift.tt/2ygnNkg

On the Fuzziness of Machine Learning, Neural Networks, and Artificial Intelligence in Radiation Oncology

Radiation oncology has been hailed as a potential vanguard for guiding Big Data applications into cancer research, quality assessment, and clinical care. This was emphasized by the joint American Society for Radiation Oncology/National Cancer Institute/American Association of Physicists in Medicine workshop held in Bethesda, Maryland in 2015 (1). Radiation therapy provides a unique combination of clinical patient demographics, physical use of radiation, application of image guidance ("radiomics"), and biological markers ("radiogenomics") generated over a treatment period that can span a few days to several weeks.

http://ift.tt/2ygFYX9

Intensity Modulated Radiation Therapy and Second Cancer Risk in Adults

Intensity modulated radiation therapy (IMRT) has been developed as an evolution of 3-dimensional conformal radiation therapy (3D-CRT) and was made possible by the enormous advances in the field of informatics and dose calculation algorithms (1, 2). Initially proposed by Brahme 30 years ago (3), IMRT has improved high-dose conformity around tumors with complex shapes, thus achieving maximal sparing of organs at risk. This "ideal" dose distribution can be achieved through an optimization process based on the definition of specific dose constraints for organs at risk and on the minimization of a so-called "cost function" (4).

http://ift.tt/2ygpCh9

Highlights

El Naqa et al

http://ift.tt/2AuQ0tV

Time-Driven Activity-Based Costing in Oncology: A Step in the Right Direction

The standard of care for locally advanced cervical cancer is the combination of chemotherapy, external beam radiation therapy (EBRT), and brachytherapy. The integration of magnetic resonance imaging–based planning and delivery for brachytherapy has resulted in local control rates of 80-90%, with a reduced risk of grade 3 morbidities (1). Despite these excellent results, a surprising number of patients with cervical cancer do not receive brachytherapy in favor of intensity modulated radiation therapy (IMRT) or stereotactic body radiation therapy boosts, resulting in inferior survival outcomes (2, 3).

http://ift.tt/2AuPWKH

In Regard to Chapman and Jagsi

To the Editor: The recent commentary by Chapman and Jagsi (1) highlights challenges to strengthen our subspecialty. To determine possible mechanisms of implicit bias, we conducted a prospective audit study (2). We hypothesized that prospective black (B) male doctoral students would experience greater disparity in responses when seeking access to National Cancer Institute–funded Principal Investigators (PIs) compared with prospective Caucasian (W) males. The specific aim was to explore response and acceptance rates for B (vs W) men seeking cancer research mentorship.

http://ift.tt/2yguMtE

Vasitis Nodosa and Related Lesions: A Modern Immunohistochemical Staining Profile with Special Emphasis on Novel Diagnostic Dilemmas

Vasitis nodosa is a benign proliferation of vas deferens epithelium, thought to be a response to trauma or obstruction, usually vasectomy. Although histologic features mimic malignancy, diagnosis is usually straightforward due to the clinical context. We analyzed 21 specimens with vasitis or epididymitis nodosa with antibodies to PAX8, CD10, p63, alpha-methyl-acyl-coA-racemase (AMACR), GATA3, prostein, NKX3.1, and prostate-specific antigen (PSA). Two diagnostically problematic cases included 1) florid bladder muscle involvement after prostatectomy and 2) involvement of the ampulla and ejaculatory duct in a radical prostatectomy specimen.

http://ift.tt/2z2lvJo

Diagnostic utility of histone H3.3G34 W, G34R, and G34 V mutant-specific antibodies for giant cell tumors of bone

Giant cell tumors of bone (GCTBs) are characterized by mononuclear stromal cells and osteoclast-like giant cells; up to 95% have H3F3A gene mutation. The RANKL inhibitor denosumab, when used for the treatment of GCTB, leads to histological changes such as new bone formation and giant cell depletion. Here we assessed the diagnostic utility of immunohistochemical staining with the antibodies against histone H3.3G34 W, G34R and G34 V mutant proteins for GCTB and other histologically similar bone and joint lesions.

http://ift.tt/2AcfaJq

Histone deacetylase inhibitor BG45-mediated HO-1 expression induces apoptosis of multiple myeloma cells by the JAK2/STAT3 pathway

Multiple myeloma (MM) is a hematological malignancy that is characterized by the clonal expansion of plasma cells in the bone marrow. Histone deacetylases (HDACs) represent a new type of molecular targeted therapy for different types of cancers and promising targets for myeloma therapy. We showed that HDAC3 mRNA and protein levels of CD138+ mononuclear cells from MM patients were higher than those in healthy donors. Therefore, we investigated the effects of a novel class I HDAC inhibitor BG45 on MM cells in vitro. BG45 downmodulated heme oxygenase 1 (HO-1) when class I HDACs decreased in MM cells. HO-1 is a target for the treatment of MM. Moreover, BG45 induced hyperacetylation of histone H3 and inhibited the growth, especially the apoptosis of MM cell lines. Treatment with BG45 induced apoptosis by downregulating bcl-2 and Bcl-xl, upregulating Bax and other antiapoptotic proteins and activating poly(ADP-ribose)polymerase, and decreasing protein levels of p-JAK2 and p-STAT3. These effects were partly blocked by HO-1. Correspondingly, BG45 led to an accumulation in the G0/G1 phase, accompanied by decreased levels of CDK4 and phospho-retinoblastoma protein, an increased level of p21, and a moderately reduced level of CDK2. Clinical use of single agents was limited because of toxic side effects and drug resistance. However, combining BG45 with lenalidomide exerted synergistic effects. In conclusion, we verified the potent antimyeloma activity of this novel HDAC inhibitor and that the combination of BG45 and lenalidomide is a new method for MM treatment. Thus, BG45 may be applicable to the treatment of MM and other hematological malignancies.

http://ift.tt/2BV1ZNm

A case of heavily pretreated metastatic cardiac angiosarcoma treated successfully using eribulin

Eribulin mesylate (eribulin) is a nontaxane microtubule inhibitor approved in Japan for treating soft tissue sarcoma irrespective of histological subtypes. Thus, our department routinely uses eribulin to treat any histological subtype of sarcoma for patients who have experienced disease progression during standard therapy. However, evidence on the efficacy of eribulin in treating sarcomas that are neither liposarcoma nor leiomyosarcoma is limited. Recently, we encountered a case of a heavily pretreated cardiac angiosarcoma that responded well to eribulin treatment. The patient was a 34-year-old Japanese woman with advanced angiosarcoma, who had been pretreated heavily using several lines of chemotherapy. Eribulin was administered as the eighth line of treatment and the dose was adjusted because of grade 4 neutropenia. After three cycles of treatment, contrast-enhanced computed tomography showed a partial tumor response, which was sustained for ~4 months. This case suggests that eribulin may be a potential therapeutic option for angiosarcoma. Further studies are needed to confirm the benefit of eribulin for patients with angiosarcoma and to establish predictive markers for eribulin sensitivity.

http://ift.tt/2BW2DKO

A genome-wide comprehensive analysis of alterations in driver genes in non-small-cell lung cancer

Lung cancer is one of the most common malignancies and the leading cause of cancer-related deaths worldwide. Although many oncogenes and tumor suppressors have been uncovered in the past decades, the pathogenesis and mechanisms of lung tumorigenesis and progression are unclear. The advancement of high-throughput sequencing technique and bioinformatics methods has led to the discovery of some unknown important protein-coding genes or noncoding RNAs in human cancers. In this study, we tried to identify and validate lung cancer driver genes to facilitate the diagnosis and individualized treatment of patients with this disease. To analyze distinct gene profile in lung cancer, the RNA sequencing data from TCGA and microarray data from Gene Expression Omnibus were used. Then, shRNA-pooled screen data and CRISPR-Cas9-based screen data in lung cancer cells were used to validate the functional roles of identified genes. We found that thousands of gene expression patterns are altered in lung cancer, and genomic alterations contribute to the dysregulation of these genes. Furthermore, we identified some potential lung cancer driver genes, such as TBX2, MCM4, SLC2A1, BIRC5, and CDC20, whose expression is significantly upregulated in lung cancer, and the copy number of these genes is amplified in the genome of patients with lung cancer. More importantly, overexpression of these genes is associated with poorer survival of patients with lung cancer, and knockdown or knockout of these genes results in decreased cell proliferation in lung cancer cells. Taken together, the genomewide comprehensive analysis combined with screen data analyses may provide a valuable help for identifying cancer driver genes for diagnosis and prevention of patients with lung cancer.

http://ift.tt/2BVnUEn

Histone deacetylase inhibitor SAHA-induced epithelial–mesenchymal transition by upregulating Slug in lung cancer cells

SAHA, a member of histone deacetylase inhibitors (HDACIs), which emerged as a class of novel antitumor drug, has been used in clinical treatment of cancers. However, clinical experience of SAHA in solid tumors has been disappointing. Nevertheless, the underlying mechanism of this deficiency is not clearly understood. In the present study, we found that SAHA could induce epithelial–mesenchymal transitions (EMT) in lung cancer A549 cells, which was associated with increased migration capability and cellular morphology changes. We showed that SAHA decreased epithelial marker E-cadherin's expression and increased the expression of mesenchymal marker vimentin. SAHA upregulated the protein and mRNA expression of transcription factor Slug in a time-dependent manner and promoted its nuclear translocation. We further demonstrated that SAHA upregulated Slug expression by promoting Slug acetylation but not influencing the phosphorylation of GSK-3β, a main kinase-controlled Slug expression. Finally, silencing of Slug by siRNA reversed EMT marker expressions and cellular morphology change induced by SAHA, suggesting that Slug plays a crucial role in SAHA-mediated EMT in A549 cells. Our research study provided a better understanding of treatment failure of SAHA in patients with solid tumors. Therefore, more attention should be paid to cancer treatment using SAHA and strategies for reversing EMT before using SAHA would be better if the value of SAHA in the treatment of solid tumors, especially lung cancer, is realized.

http://ift.tt/2BUg9yk

Cell cycle-dependent translocation and regulatory mechanism of CacyBP/SIP in gastric cancer cells

Our previous results showed that calcyclin-binding protein/Siah-1-interacting protein (CacyBP/SIP) inhibits the proliferation and tumorigenicity of gastric cancer; however, the exact mechanism remains unclear, especially from the aspect of cell cycle. The subcellular localization of CacyBP/SIP, Siah-1, and Skp1 in SGC7901 gastric cancer cells was assessed by immunofluorescence after cell cycle synchronization. Levels of CacyBP/SIP, Siah-1, Skp1, β-catenin, and p-ERK1/2 were analyzed by western blotting. CacyBP/SIP phosphorylation (p-CacyBP/SIP) and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP in nucleoprotein were determined by immunoprecipitation. CacyBP/SIP, Siah-1, and Skp1 were mainly in the cytoplasm in the G1 phase, but translocated to the nucleus during G2. Their expression in total protein was not altered, but elevated in the G2 phase in nucleoprotein. The CacyBP/SIP nucleus translocation of cells transfected with mutant CacyBP/SIP that does not bind S100 (CacyBP–ΔS100) was significantly increased compared with wild-type CacyBP/SIP. In the G2 phase, p-CacyBP/SIP expression and the combining capacity of Siah-1 and Skp1 with CacyBP/SIP were all increased, whereas levels of β-catenin and p-ERK1/2 reduced, compared with the G1 phase. CacyBP/SIP or CacyBP–ΔS100 overexpression was correlated with constitutively low β-catenin expression and affected its level through cell cycle. CacyBP/SIP overexpression led to retarded proliferation, G1 arrest, and β-catenin reduction, which could be abolished by lithium chloride, β-catenin activator, and further enhanced by the Wnt inhibitor XAV-939. In addition, CacyBP–ΔS100 further suppressed cell proliferation and induced G1 arrest compared with CacyBP/SIP. In conclusion, CacyBP/SIP nuclear localization, dependent on S100 protein, suppresses gastric cancer tumorigenesis through β-catenin degradation and the dephosphorylation of ERK1/2 during the G2 phase.

http://ift.tt/2BUg9hO

Autophagy and doxorubicin resistance in cancer

Doxorubicin (DOX), also known as adriamycin, is a DNA topoisomerase II inhibitor and belongs to the family of anthracycline anticancer drugs. DOX is used for the treatment of a wide variety of cancer types. However, resistance among cancer cells has emerged as a major barrier to effective treatment using DOX. Currently, the role of autophagy in cancer resistance to DOX and the mechanisms involved have become one of the areas of intense investigation. More and more preclinical data are being obtained on reversing DOX resistance through modulation of autophagy as one of the promising therapeutic strategies. This review summarizes the recent advances in autophagy-targeting therapies that overcome DOX resistance from in-vitro studies to animal models for exploration of novel delivery systems. In-depth understanding of the mechanisms of autophagy regulation in relation to DOX resistance and development of molecularly targeted autophagy-modulating agents will provide a promising therapeutic strategy for overcoming DOX resistance in cancer treatment.

http://ift.tt/2BTH2Te

Reversine induces autophagic cell death through the AMP-activated protein kinase pathway in urothelial carcinoma cells

Urothelial carcinoma is one of the most common malignancies of the urinary tract. Effective treatment of advanced urothelial carcinoma remains a clinical challenge with poor outcomes in these patients. Previous reports have shown that the expression of aurora kinase is associated with clinical stage and prognosis; hence, aurora kinases are potential targets in urothelial carcinoma therapy. Reversine, an aurora kinase inhibitor, was analyzed for its cytotoxicity in this study. Cell proliferation, flow cytometry, western blotting, and immunofluorescent assay were used to determine the effect of reversine on urothelial carcinoma cells. The results showed that reversine significantly inhibits the growth of urothelial carcinoma cell lines. Reversine induced cell cycle arrest at the G2/M phase, leading to autophagic cell death by activating the AMP-activated protein kinase pathway. Reversine induced significant cell death in urothelial carcinoma cells. Our results suggest that reversine may be a suitably small molecule for treating urothelial carcinoma in the future.

http://ift.tt/2BVb8p8

Influence of the alkylating function of aldo-Ifosfamide on the anti-tumor activity

The present work investigates the influence of different DNA damages caused by different isophosphoramide mustards on the 3-hydroxypropanal-assisted apoptotic antitumor activity of oxazaphosphorine cytostatics using I-aldophosphamide-perhydrothiazine (IAP) and mesyl-I-aldophosphamide-perhydrothiazine (SUM-IAP) for in-vitro and in-vivo experiments. IAP and SUM-IAP hydrolyze spontaneously to the corresponding I-aldophosphamide derivatives. They differ in the chemical structure of the alkylating moiety, whereas IAP has two chlorethyl groups in the SUM-IAP molecule, one chlorethyl group is substituted by a mesylethyl group. With both substances, cytotoxicity studies on P388 tumor cells in vitro and therapy experiments in mice bearing advanced growing P388 tumors were carried out. IAP was significantly more cytotoxic in-vitro than SUM-IAP, but the antitumor activity of SUM-IAP was by order of magnitude higher than the antitumor activity of IAP. The reason for these findings is discussed with respect to the enzymatic cleavage of the various I-aldophosphamide derivatives to the corresponding isophosphoramide mustards and 3-hydroxypropanal. Overall, the findings indicate that antitumor activity of ifosfamide and derivatives of ifosfamide can be improved considerably by altering the alkylating moiety of the molecule, but retaining the aldophosphamide structure.

http://ift.tt/2BVnRIH

A SRSF1 self-binding mechanism restrains Mir505-3p from inhibiting proliferation of neural tumor cell lines

Srsf1 has currently been demonstrated to be an oncogene that is precisely autoregulated for normal physiology. Although Mir505-3p has been reported as one of the regulatory miRNAs of Srsf1 in mouse embryonic fibroblast (MEF), the inhibitory effect of Mir505-3p on Srsf1 is poorly described in neural tumors. Whether SRSF1 autoregulation interferes with miRNA targeting on the Srsf1 transcript is unclear. In this work, we screened out one target site, out of three potential target sites on 3′ UTR of Srsf1 transcript, that was required for Mir505-3p targeting. We showed that Mir505-3p was capable of inhibiting tumor proliferation driven by SRSF1 in two neural tumor cell lines, Neuro-2a (N2a) and U251, exclusively in serum-reduced condition. We observed that the protein level of SRSF1 was gradually promoted by increasing concentration of serum. We also found that overexpressed exogenous SRSF1 protein abolished this RNA interfering related targeting, suggesting that serum-rich condition restrains Mir505-3p from inhibiting Srsf1 transcript after inducing SRSF1 protein overexpression. Moreover, by applying bioinformatic analysis, the SRSF1 self-binding motif was found proximal to the Mir505-3p target site, which was required for a SRSF1 competitive self-binding interaction. The interaction of overexpressed exogenous SRSF1 protein and the SRSF1 self-binding motif was sufficient to restrain Mir505-3p from targeting the Srsf1 transcript. These results provide a better understanding of how tumorous microenvironment influences anticancer therapy in the neural system, suggesting potential strategic design for anticancer drugs.

http://ift.tt/2BVnTjN

Integrated safety summary for trifluridine/tipiracil (TAS-102)

Trifluridine/tipiracil, an oral treatment combining trifluridine (an antineoplastic thymidine-based nucleoside analog) and tipiracil hydrochloride (a thymidine phosphorylase inhibitor), led to significant improvement in overall survival in metastatic colorectal cancer (mCRC) patients refractory to standard therapy in the phase III RECOURSE trial. Here, we report an integrated summary of the safety of trifluridine/tipiracil. The main safety analysis includes integrated data from the RECOURSE and J003 studies (safety data group 2) of patients with refractory mCRC receiving trifluridine/tipiracil at the recommended starting dose: 35 mg/m2 twice daily for 5 days with 2 days' rest for 2 weeks, followed by a 14-day rest (one cycle). Integrated data from a larger group of mCRC patients receiving trifluridine/tipiracil at the recommended starting dose (group 1) and nonintegrated data on serious adverse events (SAEs) representing all clinical experience with trifluridine/tipiracil as of the data cutoff date (group 3) are also summarized. In group 2, myelosuppressive and all-grade gastrointestinal adverse events (AEs) were more frequent in trifluridine/tipiracil patients than in placebo patients. The trifluridine/tipiracil and placebo patients had similar frequencies of AEs leading to discontinuation (9.0 vs. 11.5%) and SAEs (27.7 vs. 29.2%); fatal AEs were more frequent in placebo patients than in trifluridine/tipiracil patients (9.3 vs. 2.8%). AEs leading to interruptions/delays/reductions were more frequent in trifluridine/tipiracil patients (56.3 vs. 12.7%). Trifluridine/tipiracil was generally well tolerated, but over 50% of patients required interruptions/delays/reductions. There was a low rate of discontinuations, SAEs, and fatal AEs. This analysis confirms the safety profile observed in RECOURSE.

http://ift.tt/2BUUcPD

Anticancer effect of acid ceramidase inhibitor ceranib-2 in human breast cancer cell lines MCF-7, MDA MB-231 by the activation of SAPK/JNK, p38 MAPK apoptotic pathways, inhibition of the Akt pathway, downregulation of ERα

Acid ceramidase is the key enzyme of the ceramide metabolic pathway, which plays a vital role in regulating ceramide – sphingosine-1-phosphate rheostat. Ceramide acts as a proapoptotic molecule, but its metabolite sphingosine-1-phosphate, in contrast, signals for cell proliferation, cell survival, and angiogenesis. Acid ceramidase is highly upregulated in breast tumors and treatment with an acid ceramidase inhibitor, ceranib-2, significantly induced apoptosis in human breast cancer cell lines. However, the mechanisms underlying the induction of apoptosis remain ambiguous to date. Hence, in the present study, we have explored ceranib-2-mediated apoptotic signaling pathways in human breast cancer cell lines. MCF-7 and MDA MB-231 cells were treated with IC50 doses of ceranib-2 and tamoxifen. Nuclear changes showed the apoptotic effect of ceranib-2 in both the cell lines. Loss in the mitochondrial membrane potential was observed only in ceranib-2-treated MCF-7 cells. Ceranib-2 activated intrinsic and extrinsic apoptotic pathways in MCF-7 cells, but only the extrinsic apoptotic pathway was activated in MDA MB-231 cells. Further, ceranib-2 induced apoptosis by activating SAPK/JNK (stress-activated protein kinase/c-Jun N-terminal kinase), p38 MAPK (mitogen-activated protein kinase) apoptotic pathways and by inhibiting the Akt (antiapoptotic) pathway in both the cell lines. Most importantly, ERα (estrogen receptor-α) expression was highly downregulated after ceranib-2 treatment and a docking study predicted the highest binding affinity of ceranib-2 than tamoxifen with ERα in MCF-7 cells. Hence, ceranib-2 may have potential as a chemotherapeutic drug of breast cancer.

http://ift.tt/2ALNTyG

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.

http://ift.tt/2AOne4b

Pneumatosis Cystoides Intestinalis: An Unexpected Cause of Duodenal Nodules

N/A.

http://ift.tt/2C5oLmv

Isolated Polycystic Liver Disease

N/A.

http://ift.tt/2jz3Bci

Platypnea-Orthodeoxia Syndrome After Complicated Cholecystectomy: An Unsuspected Diagnosis

A 65-year-old woman with no significant prior medical history presented, in the postoperative course of a complicated cholecystectomy, several episodes of arterial desaturation. Pulmonary embolism was repeatedly suspected, but there was no evidence of pulmonary thrombus on the chest computed tomography angiographies obtained. As these episodes were mainly induced by postural changes, a platypnea-orthodeoxia syndrome was suspected. A transthoracic echocardiogram was performed and revealed a patent foramen ovale. A transesophageal echocardiography confirmed the presence of a significant right-to-left shunt exacerbated by the Valsalva manouver. The defect was repaired using a percutaneous transcatheter technique with complete resolution of the condition.

http://ift.tt/2C58fmI

Symptomatic Hyponatremia after Bowel Preparation: Report of Two Cases and Literature Review

Introduction: Bowel preparation for colonoscopy and/or colorectal surgery can cause electrolyte imbalances. The risk of electrolyte imbalances seems to be related to the type of bowel cleansing solution, age of patients and comorbidities.
Case Report: We report two cases of symptomatic hyponatremia (focal neurological signs and coma) after bowel preparation with sodium picosulfate/magnesium citrate for colonoscopy. In both cases, symptoms related to hyponatremia rapidly disappeared after sodium level correction with intravenous administration of hypertonic saline (3% NaCl).
Discussion: Electrolyte imbalances are more common with sodium phosphate-based solutions (NaP) and sodium picosulfate/magnesium citrate, in patients older than 65, in patients treated with thiazide diuretics, angiotensin-converting-enzyme inhibitor, betablockers or antidepressants and in gastrectomized patients. These patients should use macrogol-based solutions (polyethylene glycol).
Conclusion: In patients at risk (patient > 65 years old, patients taking thiazide diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers and antidepressants and with previous gastrectomy) we recommend macrogol-based solutions.

http://ift.tt/2jzenPD

Pregnancy after Breast Cancer: State of the Art

Breast cancer survivors have given rise to several issues of major relevance from a clinical and scientific point of view. In fact, breast cancer is the most prevalent malignancy in women of reproductive age. The effect of pregnancy on overall survival and in the recurrence after treatment of breast cancer, as well as the questions related to heredity continue to be matter of the highest timeliness and scientific interest. Most recent studies seem to agree in admitting that pregnancy after breast cancer appears to be potentially safe to both the women and her offspring, although this issue remains complex. Heredity and genetics seem to play an important role in this subject, but the conclusions lack absolute and unequivocal consistency. There is a need for meta-analysis, cohort and case-control studies, translational and prospective studies extended in time, in order to obtain greater safety in the establishment of strategies and guidelines for clinicians and adequate objective information for young breast cancer patients.

http://ift.tt/2C5Q2Fo

Metabolic Activity in the Visceral and Subcutaneous Adipose Tissues by FDG-PET/CT in Obese Patients

Introduction: The emerging role of the 18F-fluorodeoxyglucose-positron emission tomography/computed tomography in the study of the metabolic activity and inflammation in adipose tissue indicates that it might be a reliable tool to complement the risk stratification in obesity. The aims of this study were the evaluation of 18F-fluorodeoxyglucose uptake by visceral adipose tissues and subcutaneous adipose tissues and to determine eventual differences in patients with and without obesity.
Material and Methods: Retrospective study of adult patients who underwent whole body 18F-fluorodeoxyglucose-positron emission tomography/ computed tomography scanning between July and August of 2016. Statistical analysis: SPSS™ software v.20. Statistical
significance: p < 0.05.
Results: We assessed fluorodeoxyglucose-positron emission tomography/computed tomography scans from 156 patients (58.3% of males) with a mean age of 61.0 ± 14.1 years. Half of the patients had a body mass index ≥ 25.0 kg/m2 and 15.4% (n = 24) were obese. In both groups, the mean 18F-fluorodeoxyglucose uptake was higher in visceral adipose tissues. There were no differences in 18F-fluorodeoxyglucose uptake in visceral adipose tissues between the groups. Obese patients had lower density of adipose tissue,
both in subcutaneous adipose tissues and in visceral adipose tissues. Abdominal circumference and density of visceral adipose tissues
had a positive predictive value in the mean 18F-fluorodeoxyglucose uptake in visceral adipose tissues. 
Discussion: Through a non-invasive test, this study demonstrated a significant higher metabolic activity in visceral adipose tissues in both obese and non-obese patients. According to our results, abdominal circumference was an important determinant in 18F-fluorodeoxyglucose uptake in visceral adipose tissues. We also demonstrated that obese patients had differences in adipose tissue quality.
Conclusion: Our findings reinforce the importance of the adipose tissue quality and distribution for metabolic risk stratification.

http://ift.tt/2jv4JOe

Characterization of all Surgical Specimens Provided by a Portuguese Department of Ophthalmology over a 13 Year Period

Introduction: We intend to evaluate clinically, topographically and morphologically all surgical specimens sent by the Department of Ophthalmology of Hospital de Braga to the Department of Pathology of the same hospital.
Material and Methods: Two hundred and fifty eight surgically obtained specimens, from the Department of Ophthalmology of Hospital de Braga, analyzed in the Department of Pathology, from January 2002 to June 2015, were characterized. Data was arranged according to year, age, sex, topography and morphological diagnosis according to the SNOMED® coding system.
Results: Mean age at time of diagnosis was 54.6 years old; 52.3% were male subjects. The number of specimens was relatively stable until the year 2010, with a significant increase between 2011 and 2013. Most specimens sent corresponded to eyelid (54.7%), followed by conjunctiva (26.7%); the most common pathological diagnosis was malignant epithelial lesions (22.48%), followed by melanocytic tumours (22.09%) and benign epithelial lesions (17.05%).
Discussion: The results are distinct from previous publications presumably because of differences between the populations submitted to analysis.
Conclusion: This is the first indexed publication characterizing surgical specimens from a Department of Ophthalmology in Portugal; moreover, it also includes an extensive review of global epidemiological data about ophthalmic surgical specimens.

http://ift.tt/2C4zttK

Single Centre Prospective Study of Systematic Pain Evaluation in Portuguese Patients with Metastatic Prostate Cancer

Introduction: Pain is one of the most common symptoms reported by cancer patients and is associated with decreased quality of life. Assessment of pain with standardized questionnaires reduces variability in its interpretation and may increase effectiveness of medical interventions. Prostate cancer is the most frequent male neoplasm in Portugal. We designed this study to evaluate the impact of a standardized pain questionnaire on pain management in patients with metastatic prostate cancer.
Material and Methods: Single centre prospective observational study of patients with metastatic prostate cancer. The study was designed to evaluate the benefit of systematically evaluating pain with Brief Pain Inventory-Short Form prior to a scheduled medical oncology consult. Patients reporting pain were reassessed one week later by telephone. To assess the benefit two consecutive cohorts were established based on communication of questionnaire results to the treating physician.
Results: We recruited 207 patients of which 60% reported pain. Statistically significant decrease in mean pain intensity one week after the scheduled appointment was noted (3.95 vs 3.01; p < 0.001). Patients whose Brief Pain Inventory-Short Form was provided to their oncologist experienced greater reduction in pain, which was non-significant (p = 0.227). Using Brief Pain Inventory-Short Form assessment resulted in a higher probability of pain control (43.5% vs 30.9%; p = 0.193).
Discussion: The prevalence of pain founded was higher than described in the literature, probably because our sample was less selected than the published in clinical trials. After the scheduled appointment, there was a statistically significant reduction in mean pain intensity, but the explicit use of this questionnaire was not associated with a statistically significant reduction of pain.
Conclusion: Patients with metastatic prostate cancer have a high prevalence of pain. Evaluation and treatment by medical oncologists is associated with a reduction of mean pain intensity. The use of Brief Pain Inventory-Short Form was associated with a non-significant increased reduction of pain.

http://ift.tt/2jz3A8e

Cross-Cultural and Psychometric Properties Assessment of the Exercise Self-Efficacy Scale in Individuals with Spinal Cord Injury

Introduction: The Exercise Self-Efficacy scale (ESES) is a reliable measure, in the English language, of exercise self-efficacy in individuals with spinal cord injury. The aim of this study was to culturally adjust and validate the Exercise Self-Efficacy scale in the Portuguese language.
Material and Methods: The Exercise Self-Efficacy scale was applied to 76 subjects, with three-month intervals (three applications in total). The reliability was appraised using the intra-class correlation coefficient and Bland-Altman methods, and the internal consistency was evaluated using Cronbach´s alpha. The Exercise Self-Efficacy scale was correlated with the domains of the Quality of life Questionnaire SF-36 and Functional Independence Measure and tested using the Spearman rho coefficient.
Results: The Exercise Self-Efficacy scale-Brazil presented good internal consistency (alpha 1 = 0.856; alpha 2 = 0.855; alpha 3 = 0.822) and high reliability in the test-retest (intra-class correlation coefficient = 0.97). There was a strong correlation between the Exercise Self-Efficacy scale-Brazil and the SF-36 only in the functional capacity domain (rho = 0.708). There were no changes in Exercise Self-Efficacy scale-Brazil scores between the three applications (p = 0.796).
Discussion: The validation of the Exercise Self-Efficacy scale questionnaire permits the assessor to use it reliably in Portuguese speaking countries, since it is the first instrument measuring self-efficacy specifically during exercises in individuals with spinal cord injury. Furthermore, the questionnaire can be used as an instrument to verify the effectiveness of interventions that use exercise as an outcome.
Conclusion: The results of the Brazilian version of the Exercise Self-Efficacy scale support its use as a reliable and valid measurement of exercise self-efficacy for this population.

http://ift.tt/2juHaVs

Reconsidering the ‘Decline’ of Dental Student Empathy within the Course in Latin America

Introduction: The controversy over the presence of empathic decline within the course in students of medicine, dentistry and health sciences in general, has not fully been studied. This controversy could be partially solved if massive studies of empathy levels are made in similar cultural, social and economic contexts.
Material and Methods: Empathy levels within the course were studied in eighteen dental schools from six countries in Latin America (2013). The mean of the empathy levels were used to study the behavior between first and fifth academic years. The values of empathy levels within the course were observed by applying the Jefferson Scale of Physician Empathy, the Spanish version. All these studies were cross-sectional. The value of means observed, were subjected to regression studies and further adjustment curves were obtained and the coefficient of determination were calculated.
Results: Six different models of behavior were observed, which found that five of them suffer empathic decline within the course, but with different final results: in some the decline persists until the fifth academic year and in others, this decline 'recovers' persistently until the fifth academic year. The sixth model is characterized by a constant and persistent increase of levels of empathy within the course until the last academic year.
Discussion: There are six different models for the behavior of means of levels of empathy within the course evaluated by a common methodology in eighteen dental schools from six countries of Latin America. These findings support the existence of variability of empathic response and a comprehensive approach is needed to find the causes that give rise to this variability.
Conclusion: In dental students of Latin America, there is variability in the behavior of the distribution in means between the academic years of the dentistry schools examined in this study.

http://ift.tt/2C5jmvS

Readmission to an Adolescent Psychiatry Inpatient Unit: Readmission Rates and Risk Factors

Introduction: Most mental disorders have a chronic evolution and therefore a certain amount of psychiatric readmissions are inevitable. Several studies indicate that over 25% of child and adolescent inpatients were readmitted within one year of discharge. Several risk factors for psychiatric readmissions have been reported in the literature, but the history of repeated readmissions is the most consistent risk factor. Our aim is to calculate the readmission rates at 30 days and 12 months after discharge and to identify associated risk factors.
Material and Methods: The authors consulted the clinical files of patients admitted to the Inpatient Unit between 2010 and 2013, in order to calculate the readmission rates at 30 days and at 12 months. The demographic and clinical characteristics of the readmitted patients were analyzed and compared with a second group of patients with no hospital readmissions, in order to investigate possible predictors of readmission.
Results: A total of 445 patients were admitted to our inpatient unit between 2010 and 2013. Six adolescents were readmitted in a 30 days period (1.3%) and 52 were readmitted in a 12 month period after discharge (11.5%). Duration of the hospitalization and the previous number of mental health admissions were significant predictors of future hospital readmissions (p = 0.04 and p = 0.014).
Discussion: The low readmission rates may reflect the positive clinical and sociofamilial support being provided after discharge.
Conclusion: Rehospitalisation is considered a fundamental target for intervention concerning prevention and intervention in mental healthcare. Thus, knowledge regarding their minimisation is crucial.

http://ift.tt/2jv4vGS

Breast Cancer: Value-Based Healthcare, Costs and Financing

Introduction: Breast cancer is the second most common oncological disease worldwide. To analyse the new disease specific funding programme (breast cancer) implemented at the Francisco Gentil Portuguese Institute of Oncology, Lisbon Center (Instituto Português de Oncologia de Lisboa Francisco Gentil), the actual costs of the patients were examined using activity-based costing as a costing methodology. This study addresses the following question: "How much does it cost to treat breast cancer per 'patient-month' compared to the monthly fixed 'funding envelope'?".
Materials and Methods: The study cohort consisted of 807 patients, corresponding to all the patients eligible for the new disease specific funding programme and who were enrolled during the first year of implementation. Activity-based costing was used to calculate the total real costs per stage of disease and per 'patient-month' as well as the deviation from the monthly fixed 'funding envelope'.
Results: The total costs were 6.6 M€, whereas the total funding was 5.2 M€ for a total of 5648 'patient-months'. In 2014, the balance difference between the funding obtained and the actual costs was -1.4 €M for the cohort of 807 patients.
Discussion: The extreme cases of differences in cost per 'patient-month' compared to the monthly fixed 'funding envelope' were (i) stage 0/Tis, with higher funding at 415.23 € per 'patient-month', and (ii) stage IIIC, with lower funding at 1062.79 € per 'patient-month'.
Conclusion: The 'patient-month' cost, regardless of disease stage was 1170.29 €. The median deviation per 'patient-month' was negative (241.21 €) compared to the monthly fixed 'funding envelope' of 929.08 € in the first year. Establishing activity-based costing - funding models will be crucial for the future sustainability of the healthcare sector.

http://ift.tt/2C2nFYS