Interspecies Bombolitins exhibit structural diversity upon membrane binding lead to cell specificity

Bombolitins, a class of peptides produced by bees of the genus Bombus, target and disrupt cellular membranes, leading to lysis. Antimicrobial peptides (AMPs) exhibit various mechanisms of action resulting from the interplay between peptide structure, lipid composition, and cellular target membrane selectivity. Herein, two novel bombolitins displaying significant amino acid sequence similarity, BII and BL6, were assessed for antimicrobial activity as well as correlated dodecylphosphocholine (DPC) micelle binding and membrane-induced peptide conformational changes.

http://bit.ly/2N92qud

KRAS Prenylation is required for Bivalent Binding with CaM in a Nucleotide Independent Manner

Deregulation of KRAS4b signaling pathway has been implicated in 30% of all cancers. Membrane localization of KRAS4b is an essential step for initiation of the downstream signaling cascades that guides various cellular mechanisms. KRAS4b plasma membrane (PM) binding is mediated by insertion of a prenylated moiety that is attached to the terminal carboxy-methylated cysteine, in addition to electrostatic interactions of its positively charged hypervariable region (HVR) with anionic lipids. Calmodulin has been suggested to selectively bind KRAS4b to act as a negative regulator of the RAS/MAPK signaling pathway by displacing KRAS4b from the membrane.

http://bit.ly/2SNk9gg

Concurrent Versus Sequential Chemoradiation for Low-grade Gliomas Meeting RTOG 9802 Criteria

Purpose: Radiation Therapy Oncology Group (RTOG) 9802 has established postoperative radiation therapy (RT) and chemotherapy sequentially as the new standard of care for patients with high-risk low-grade glioma (LGG) meeting trial criteria. Although this trial investigated sequential chemoradiation therapy (sCRT) with RT followed by chemotherapy, it is unknown whether concurrent chemoradiation therapy (cCRT) may offer advantages over sCRT. Materials and Methods: The National Cancer Database (NCDB) was queried for newly diagnosed World Health Organization (WHO) grade II glioma. Patients with unknown surgery, RT, or chemotherapy status were excluded, along with patients below 40 years old who underwent gross total resection to coincide with RTOG 9802 exclusion criteria. The χ2, the Fisher exact, or Wilcoxon rank-sum tests evaluated differences in characteristics between groups. Kaplan-Meier analysis was used to evaluate overall survival (OS) between groups (sCRT vs. cCRT). Cox proportional hazards modeling determined variables associated with OS. Results: In total, 496 patients were analyzed (n=416 [83.9%] cCRT, n=80 [16.1%] sCRT). Sequencing or concurrency of therapy did not independently influence survival on univariable/multivariable analysis. Factors associated with worse OS on multivariable analysis included advanced age (P

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The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma

Objective and Background: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. Methods: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. Results: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9–27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6–30.4) months for 146 (12.7%) patients with R1

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Surgical management and prognostic factors in esophageal perforation caused by foreign body

Abstract

Objectives

Esophageal perforation is associated with multiple serious complications and high mortality. Herein, we identify some predictors for postoperative outcomes, compare the outcomes of various surgical approaches, and summarize our experience with esophageal perforation over the past 13 years.

Methods

We retrospectively analyzed 38 patients diagnosed with esophageal perforation caused by foreign body between November 2004 and May 2018. Univariate analysis and multivariate logistic regression analysis were performed to identify potential risk factors related to prognosis. Effects of different surgery were compared based on postoperative outcomes.

Results

Of the 38 patients, the number of females was equal to males with a mean age of 55.6 ± 14.9 (range 23–93) years; 22 had thoracic perforations and 16 had cervical perforations. The overall mortality rate was 5.3%. Univariate analysis revealed that sex (p = 0.049), type of foreign body (p = 0.042), abscess (p = 0.049), and site of perforation (p = 0.031) were associated with prognosis. The interval between perforation and surgery did not significantly influence prognosis (p = 0.929). No significant difference was found in postoperative outcomes among various surgeries.

Conclusions

The interval between perforation and treatment was not as important as previously reported. Surgical management should be performed early when feasible, even if the interval between perforation and surgery is 24 h or longer.

http://bit.ly/2DEe7oA

Single nucleotide polymorphisms in renal transplantation: Can’t see the wood for the trees.

No abstract available

http://bit.ly/2GsuxnW

Genotypic variants influencing acute allograft rejection; inherited susceptibility also matters

No abstract available

http://bit.ly/2IbV7TX

Clot Retraction: Lost in Interpretation?

No abstract available

http://bit.ly/2GsFu8K

Transient Tachypnea of Newborns Is Associated With Maternal Spinal Hypotension During Elective Cesarean Delivery: A Retrospective Cohort Study

BACKGROUND: The risk for transient tachypnea of newborns, a common cause of respiratory distress in the neonatal period, is 2- to 6-fold higher during elective cesarean delivery compared to vaginal delivery. Here, we evaluated the association between transient tachypnea of newborns and the degree and duration of predelivery maternal hypotension during spinal anesthesia for elective cesarean delivery. METHODS: Demographic data, details of anesthetic management, blood pressure measurements, and vasopressor requirement preceding delivery were compared between transient tachypnea newborns (n = 30) and healthy neonates (n = 151) with normal respiratory function born via elective cesarean delivery between July 2015 and February 2016. The degree and duration of hypotension were assessed using area under the curve for systolic blood pressure (SBP) ≤90 mm Hg and area under the curve for mean arterial pressure ≤65 mm Hg. After adjusting for confounders, multivariable logistic regression was used to evaluate the association between area under the curve for SBP and transient tachypnea of newborns. RESULTS: The median area under the curve for SBP was higher in cases of transient tachypnea of newborns (0.94; interquartile range, 0–28.7 mm Hg*min) compared to healthy controls (0; interquartile range, 0–3.30 mm Hg*min; P = .001). Similarly, median area under the curve for mean arterial pressure was also higher in cases of transient tachypnea of newborns (0; interquartile range, 0–18.6 mm Hg*min) compared to controls (0; interquartile range, 0–1.1 mm Hg*min; P = .01). Mothers of transient tachypnea newborns received significantly higher amounts of phenylephrine and ephedrine compared to controls (P = .001 and 0.01, respectively). Hence, the total vasopressor dose given to mothers in the transient tachypnea of newborn group was much higher than for the control group (P = .001). In the multivariable logistic regression, area under the curve for SBP was significantly associated with transient tachypnea of newborns (odds ratio, 1.02; 95% CI, 1.01–1.04, P = .005) after adjusting for gravidity and the type of anesthetic (spinal versus combined spinal epidural). CONCLUSIONS: Our results suggest that the degree and duration of maternal SBP

http://bit.ly/2GrRU0Y

Consensus Statement of the Malignant Hyperthermia Association of the United States on Unresolved Clinical Questions Concerning the Management of Patients With Malignant Hyperthermia

At a recent consensus conference, the Malignant Hyperthermia Association of the United States addressed 6 important and unresolved clinical questions concerning the optimal management of patients with malignant hyperthermia (MH) susceptibility or acute MH. They include: (1) How much dantrolene should be available in facilities where volatile agents are not available or administered, and succinylcholine is only stocked on site for emergency purposes? (2) What defines masseter muscle rigidity? What is its relationship to MH, and how should it be managed when it occurs? (3) What is the relationship between MH susceptibility and heat- or exercise-related rhabdomyolysis? (4) What evidence-based interventions should be recommended to alleviate hyperthermia associated with MH? (5) After treatment of acute MH, how much dantrolene should be administered and for how long? What criteria should be used to determine stopping treatment with dantrolene? (6) Can patients with a suspected personal or family history of MH be safely anesthetized before diagnostic testing? This report describes the consensus process and the outcomes for each of the foregoing unanswered clinical questions. Accepted for publication December 2, 2018. Funding: Travel, hotel, and some food expenses for the attendees at the consensus meeting were paid by the Malignant Hyperthermia Association of the United States The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Ronald S. Litman, DO, ML, Department of Anesthesiology & Critical Care, The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104. Address e-mail to litmanr@email.chop.edu. © 2019 International Anesthesia Research Society

http://bit.ly/2Ii8YIm

In Response

No abstract available

http://bit.ly/2GsTGi3

Perioperative Epidural Use and Risk of Delirium in Surgical Patients: A Secondary Analysis of the PODCAST Trial

BACKGROUND: Postoperative delirium is an important public health concern without effective prevention strategies. This study tested the hypothesis that perioperative epidural use would be associated with decreased risk of delirium through postoperative day 3. METHODS: This was a secondary, observational, nonrandomized analysis of data from The Prevention of Delirium and Complications Associated With Surgical Treatments Trial (PODCAST; NCT01690988). The primary outcome of the current study was the incidence of delirium (ie, any positive delirium screen, postanesthesia care unit through postoperative day 3) in surgical patients (gastrointestinal, hepatobiliary-pancreatic, gynecologic, and urologic) receiving postoperative epidural analgesia compared to those without an epidural. As a secondary outcome, all delirium assessments were then longitudinally analyzed in relation to epidural use throughout the follow-up period. Given the potential relevance to delirium, postoperative pain, opioid consumption, sleep disturbances, and symptoms of depression were also analyzed as secondary outcomes. A semiparsimonious multivariable logistic regression model was used to test the association between postoperative epidural use and delirium incidence, and generalized estimating equations were used to test associations with secondary outcomes described. Models included relevant covariates to adjust for confounding. RESULTS: In total, 263 patients were included for analysis. Epidural use was not independently associated with reduced delirium incidence (adjusted odds ratio, 0.65 [95% CI, 0.32–1.35]; P= .247). However, when analyzing all assessments over the follow-up period, epidural patients were 64% less likely to experience an episode of delirium (adjusted odds ratio, 0.36 [95% CI, 0.17–0.78]; P= .009). Adjusted pain scores (visual analog scale, 0–100 mm) were significantly lower in the epidural group on postoperative day 1 (morning, −16 [95% CI, −26 to −7], P

http://bit.ly/2IdBE56

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Management of Patients on Preoperative Opioid Therapy

Enhanced recovery pathways have quickly become part of the standard of care for patients undergoing elective surgery, especially in North America and Europe. One of the central tenets of this multidisciplinary approach is the use of multimodal analgesia with opioid-sparing and even opioid-free anesthesia and analgesia. However, the current state is a historically high use of opioids for both appropriate and inappropriate reasons, and patients with chronic opioid use before their surgery represent a common, often difficult-to-manage population for the enhanced recovery providers and health care team at large. Furthermore, limited evidence and few proven successful protocols exist to guide providers caring for these at-risk patients throughout their elective surgical experience. Therefore, the fourth Perioperative Quality Initiative brought together an international team of multidisciplinary experts, including anesthesiologists, nurse anesthetists, surgeons, pain specialists, neurologists, nurses, and other experts with the objective of providing consensus recommendations. Specifically, the goal of this consensus document is to minimize opioid-related complications by providing expert-based consensus recommendations that reflect the strength of the medical evidence regarding: (1) the definition, categorization, and risk stratification of patients receiving opioids before surgery; (2) optimal perioperative treatment strategies for patients receiving preoperative opioids; and (3) optimal discharge and continuity of care management practices for patients receiving opioids preoperatively. The overarching theme of this document is to provide health care providers with guidance to reduce potentially avoidable opioid-related complications including opioid dependence (both physical and behavioral), disability, and death. Enhanced recovery programs attempt to incorporate best practices into pathways of care. By presenting the available evidence for perioperative management of patients on opioids, this consensus panel hopes to encourage further development of pathways specific to this high-risk group to mitigate the often unintentional iatrogenic and untoward effects of opioids and to improve perioperative outcomes. Accepted for publication December 11, 2018. Conflicts of Interest: See Disclosures at the end of the article. Funding: D.A.E. has received research support from Semnur Inc and Grunenthal for research unrelated to the topic or production of this manuscript. T.E.M. received research funding and is a consultant for Edwards Lifesciences and for Mallinckrodt. M.D.E. received research funding from the GE Foundation, Edwards Lifesciences, and Cheetah Medical for projects unrelated to this manuscript. The Perioperative Quality Initiative-4 consensus conference was supported by unrestricted educational grants from the American Society for Enhanced Recovery and the Perioperative Quality Initiative, which have received grants from Baxter, Bev MD, Cadence, Cheetah Medical, Edwards, Heron Pharmaceutical, Mallinckrodt, Medtronic, Merck, Trevena, and Pacira 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://bit.ly/KegmMq). Reprints will not be available from the authors. Address correspondence to David A. Edwards, MD, PhD, Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN. Address e-mail to david.a.edwards@vanderbilt.edu. © 2019 International Anesthesia Research Society

http://bit.ly/2Ig8DWu

Randomized Trial Comparing Early and Late Administration of Rocuronium Before and After Checking Mask Ventilation in Patients With Normal Airways

BACKGROUND: During induction of general anesthesia, it is common practice to delay neuromuscular blockade until the ability to deliver mask ventilation has been confirmed. However, the benefits of this approach have never been scientifically validated. We thus compared the early and late administration of rocuronium before and after checking mask ventilation to investigate the efficiency of mask ventilation and the time to tracheal intubation in patients with normal airways. METHODS: Patients (n = 114) were randomized to receive IV rocuronium either before (early rocuronium group, n = 58) or after (late rocuronium group, n = 56) checking mask ventilation. Expiratory tidal volumes (VTs) were measured at 10, 20, 30, 40, 50, and 60 seconds after apnea during mask ventilation. We graded the ease of mask ventilation and measured the time from apnea to tracheal intubation. The primary outcome was the average of mask VTs measured at 10, 20, 30, 40, 50, and 60 seconds after apnea. The main secondary outcome was the time from apnea to tracheal intubation. STATA was used for statistical analysis. RESULTS: The average of mask VTs measured at 10, 20, 30, 40, 50, and 60 seconds after apnea was larger in the early rocuronium group than in the late rocuronium group (552 mL breath−1 [165 mL breath−1] vs 393 mL breath−1 [165 mL breath−1], mean difference, 160 mL breath−1; 95% CI, 98−221 mL breath−1; P

http://bit.ly/2IcWEcw

Managing Complications in Paediatric Anaesthesia

No abstract available

http://bit.ly/2GpbgDX

Drug Calculation Errors in Anesthesiology Residents and Faculty: An Analysis of Contributing Factors

BACKGROUND: Limited data exist regarding computational drug error rates in anesthesia residents and faculty. We investigated the frequency and magnitude of computational errors in a sample of anesthesia residents and faculty. METHODS: With institutional review board approval from 7 academic institutions in the United States, a 15-question computational test was distributed during rounds. Error rates and the magnitude of the errors were analyzed according to resident versus faculty, years of practice (or residency training), duration of sleep, type of question, and institution. RESULTS: A total of 371 completed the test: 209 residents and 162 faculty. Both groups committed 2 errors (median value) per test, for a mean error rate of 17.0%. Twenty percent of residents and 25% of faculty scored 100% correct answers. The error rate for postgraduate year 2 residents was less than for postgraduate year 1 (P = .012). The error rate for faculty increased with years of experience, with a weak correlation (R = 0.22; P = .007). The error rates were independent of the number of hours of sleep. The error rate for percentage-type questions was greater than for rate, dose, and ratio questions (P = .001). The error rates varied with the number of operations needed to calculate the answer (P

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Meet Our Regional Editor

http://bit.ly/2TM2ine

Enasidenib: First Mutant IDH2 Inhibitor for the Treatment of Refractory and Relapsed Acute Myeloid Leukemia

Background: Acute myeloid leukemia is the collective name for different types of leukemias of myeloid origin affecting blood and bone marrow. The overproduction of immature myeloblasts (white blood cells) is the characteristic feature of AML, thus flooding the bone marrow and reducing its capacity to produce normal blood cells. USFDA on August 1, 2017, approved a drug named Enasidenib formerly known as AG-221 which is being marketed under the name Idhifa to treat R/R AML with IDH2 mutation. The present review depicts the broad profile of enasidenib including various aspects of chemistry, preclinical, clinical studies, pharmacokinetics, mode of action and toxicity studies.

Methods: Various reports and research articles have been referred to summarize different aspects related to chemistry and pharmacokinetics of enasidenib. Clinical data was collected from various recently published clinical reports including clinical trial outcomes.

Result: The various findings of enasidenib revealed that it has been designed to allosterically inhibit mutated IDH2 to treat R/R AML patients. It has also presented good safety and efficacy profile along with 9.3 months overall survival rates of patients in which disease has relapsed. The drug is still under study either in combination or solely to treat hematological malignancies. Molecular modeling studies revealed that enasidenib binds to its target through hydrophobic interaction and hydrogen bonding inside the binding pocket. Enasidenib is found to be associated with certain adverse effects like elevated bilirubin level, diarrhea, differentiation syndrome, decreased potassium and calcium levels, etc.

Conclusion: Enasidenib or AG-221was introduced by FDA as an anticancer agent which was developed as a first in class, a selective allosteric inhibitor of the tumor target i.e. IDH2 for Relapsed or Refractory AML. Phase 1/2 clinical trial of Enasidenib resulted in the overall survival rate of 40.3% with CR of 19.3%. Phase III trial on the Enasidenib is still under process along with another trial to test its potency against other cell lines. Edasidenib is associated with certain adverse effects, which can be reduced by investigators by designing its newer derivatives on the basis of SAR studies. Hence, it may come in the light as a potent lead entity for anticancer treatment in the coming years.

http://bit.ly/2BzsxpO

Determination of Vulpinic Acid Effect on Apoptosis and mRNA Expression Levels in Breast Cancer Cell Lines

Objective: Breast cancer is one of the most common diseases among women worldwide and it is characterized by a high ratio of malignancy and metastasis and low rate of survival of patients. Due to limited treatment options, the discovery of alternative therapeutic agents and clarifying the molecular mechanism of breast cancer development may offer new hope for its treatment. Lichen secondary metabolites may be one of these therapeutic agents.

Methods: In this study, the effects of Vulpinic Acid (VA) lichen secondary metabolite on the cell viability and apoptosis of breast cancer cells and non-cancerous cell line were investigated. Quantitative polymerase chain reaction was also performed to determine changes in the expression of apoptosis-related genes at a molecular level.

Results: The results demonstrated that VA significantly inhibited the cell viability and induced apoptosis of human breast cancer cells. The highest rates of decreased growth were determined using the IC50 value of VA for 48h on MCF-7 breast cancer cell. Interestingly, VA treatment significantly reduced cell viability in all examined breast cancer cell lines compared to their non-cancerous human breast epithelial cell line. This is the first study on the investigation of the effects of VA on the molecular mechanisms associated with the expression of apoptosis-related genes in breast cancer cell lines. Results demonstrated that the gene expression of P53 genes was altered up to fourteen-fold levels in SK-BR-3 cell lines whereas it reached 2.5-fold in the MCF-12A cell line after treatment with VA. These observations support that VA induces apoptosis on the breast cancer cells compared with the non-cancerous human breast epithelial cell line.

Conclusion: It is implicated that VA may be a promising novel molecule for the induction of apoptosis on breast cancer cells.

http://bit.ly/2TPEC1d

Aberrant Sialylation in Cancer Pathology and Metastasis, a Putative Drug Target Candidate

Background Neoplasm metastasis is a multi-step and multi-level pathological feature causing 90% of cancer mortality due to a shortage of effective drugs and clinical therapeutics. To change this scenario, new drug targets and developments are required.

Method: Aberrant tumor sialylation as a putative drug target candidate has been evolving over the past halfcentury. Some specific agents and clinical events suggested some promising therapeutic potentiality and benefits against neoplasm metastasis in a number of cellular and animal tumor models.

Results: Since neoplasm tissues often contain higher levels and diverse sialic acids (sia) analogues and antigens, sia-related tumor biology/pathology are emerging as cancer diagnostic categories and a series of useful agents until now. Previously some compounds enabling to inhibit sia-related pathologic pathways were reported to exhibit therapeutic activity in cellular or animal tumor models. These types of cancer treatment agents can provide excellent therapeutic outcomes by glycome/metabolomics diagnostics first.

Conclusion: Taking together these experimental/clinical discoveries, the "Central Dogma" of glycobiology might be found out via all these principle discoveries. In addition, mathematic- or physics-majored talents might render new therapeutic discoveries by computational analysis of experimental and clinical data. Overall, therapeutic targets/benefits in the clinic should be pursued with earnest attitude.

http://bit.ly/2BAcurW

MMP7 Induces T-DM1 Resistance and Leads to the Poor Prognosis of Gastric Adenocarcinoma via a DKK1-Dependent Manner

Background: Gastric adenocarcinoma is one of the most common and lethal cancer types and is known as the second leading cause of cancer-related death of Asian adults, early diagnosis based on either pathology or molecular biology could be one of the most efficient ways to improve the outcomes of gastric adenocarcinoma patients Methods: Quantitative Real-Time PCR and Western-blot were used in detection of mRNA and protein expression.

Lentivirus infection was used to overexpression or knock down target gene. Alarma blue assay was used to monitor cells proliferation. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis.

Results: MMP7 as one of the most up-regulated genes in T-DM1 resistant NCI-N87 gastric adenocarcinoma cells compared to matched naïve cell lines. T-DM1 resistant NCI-N87 cell lines by exposed to T-DM1 in vitro. Exogenous overexpression of MMP7 promotes T-DM1 resistance and tumor growth in NCI-N87 cell lines while MMP7 knockdown enhanced sensitivity to T-DM1 in T-DM1 resistant NCI-N87 cell lines established previously. MMP7 was enriched in high WHO grade GC samples and implies poor outcomes for these patients. DKK1 as one of the most correlated genes to MMP7 in gastric adenocarcinoma and knock-down of DKK1 or inhibition of Wnt/β-catenin pathway led to a decreased expression of MMP7 and resistance to T-DM1.

Conclusion: DKK1 and Wnt/β-catenin-dependent activation of MMP7 induces T-DM1 resistance and leads to the poor prognosis of gastric adenocarcinoma, which might be a novel potential therapeutical target for T-DM1 resistant gastric adenocarcinoma.

http://bit.ly/2TM29Ac

Engineered Silver Nanoparticles, A New Nanoweapon Against Cancer

New modifications in nanoparticles changed their applications obviously. Green synthesis of nanoparticles and their biomedical utilizations have been the focus of increasing attention in recent years. Silver nanoparticles (AgNPs) demonstrated surprising effects and many advantageous features for cancer therapy. Investigations indicated the anticancer activity of AgNPs in different ways, comprising cell cycle arrest, DNA damaging and apoptosis, alteration of P53 function, up/down regulation of some important cytokine genes and so on. But some key inquiries like the ability to control the accidental effects of AgNPs, or encompassing process for parcels, which reduces the toxicological profile of nanoparticles, still remained. "Green synthesis" of nanoparticles has been shown to be a kind of approach to resolve the toxicity amounts in a range of 10-18 times. Using distinctive properties of this approach, i.e. as green synthesized silver nanoparticles (G-AgNPs), in order to raise potential therapeutic efficacy, even up to two-fold higher than cis-platin, is going to play a crucial role in cancer treatment and could be considered as a new insight in this field. The current review focuses on the antioxidant activity of G-AgNPs and potential impacts on cancer cells.

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A Comparison of the Inhibitory Effects of Anti-Cancer Drugs on Thioredoxin Reductase and Glutathione S-Transferase in Rat Liver

Background: While Thioredoxin Reductase (TrxR) plays an important role in regulation of the intracellular redox balance and various signalling pathways, Glutathione S-Transferase (GSTs) enzymes belong to the detoxification family that catalyse the conjugation of glutathione with various endogenous and xenobiotic electrophiles. Since TrxR and GSTs are overexpressed in many cancer cells, they have been identified as potential targets to develop chemotherapeutic strategies.

Method: The mitochondrial TrxR (TrxR2) enzyme and the cytosolic GST enzyme was purified from rat liver via affinity chromatography. After the purification, the in vitro inhibition effects of some anticancer drugs (cisplatin, calcium folinate, carboplatin, epirubicin hydrochloride, doxorubicin hydrochloride, paclitaxel, etoposide, fluorouracil, and methotrexate) were investigated on both enzymes. Since only methotrexate inhibits both enzymes among all the anticancer drugs, a molecular docking study was performed to determine the binding site and the binding affinity of methotrexate to the enzymes.

Results: Firstly, TrxR2 and GST were found to have a specific activity of 0.436, 1765 EU/mg proteins with a yield of 39.20%, 31.28% and 207.6, 3516.6 of purification fold, respectively. While TrxR2 was strongly inhibited by all of the anticancer drugs, GST was not inhibited by any of the anticancer drugs except methotrexate.

Conclusion: Both enzymes were inhibited by only methotrexate in rat liver, and methotrexate was well placed in the active sites of both proteins. Therefore, it may be argued that methotrexate may be a more effective anticancer drug than all other drugs used in this study against the multi drug resistance that will occur during chemotherapy.

http://bit.ly/2TPEv5N

Silimarin and Cancer

Background: Silimarin is the dry mixture of a whole family of natural substances, extracted after the addition of ethanol, methanol, and acetone. Silimarin consists mainly of silibin A and silibin B, as well as other less important compounds.

Methods: Silimarin has been demonstrated to "inhibit cell proliferation and to induce apoptosis, while also having anti-angiogenic properties." The induction of apoptosis in cancer cells has been mediated by the involvement of ER stress.

Results: Silibinin has the potential to operate as a STAT3-targeted inhibitor as well as an inhibitor of the upregulation of the immune checkpoint regulator PD-L1 and also EMT regulators, thus being a promising adjuvant in NSCLC. It has also been documented to suppress cancer cells be means of down- regulating actin cytoskeleton and PI3K / Akt molecular pathways. Several studies have demonstrated that silibinin exerts its protective potential partly through interacting with the tumor suppressor gene p53.

Conclusions: It is noteworthy that research has been carried out on the enhancement of silimarin's bioavailability, especially by the preparation of specific nanoformulas, and its probable additional use together with the chemotherapeutic regimens in the near future.

http://bit.ly/2BAKXqg

A Review on The Role of VEGF in Tamoxifen Resistance

Background: Certain molecular deviations can lead to the development of breast cancer. For instance, estrogen and estrogen receptors play a significant role in inducing tumor proliferation. However, the efficacy of endocrine therapy through the administration of anti-estrogen drugs, such as Tamoxifen, is challenged by acquired resistance.

Methods: Relevant articles were retrieved from Medline and google scholar. All were screened to select the ones discussing the molecular mechanisms of angiogenesis and Tamoxifen resistance. The molecular interactions contributing in the resistant network were studied from the eligible articles.

Results: Tamoxifen resistance occurs as a consequence of over-activated signal transduction pathways such as RTK s dependent cascades. It has been shown that microvessel count was greater in Tamoxifen resistant tissues than in responsive ones.

Conclusion: In this review, the interaction between estrogen, Tamoxifen, VEGF, and VEGF receptors (VEGFRs) in Tamoxifen resistant cells has been discussed. VEGF and estrogen-independent growth cascades, especially MAPK have a positive feedback loop in Tamoxifen resistant cells. It has been proposed that over-activated pathways in Tamoxifen resistant cells induce pin1 mediated VEGF over-expression, which in turn result in enhanced activation of MAPK.

http://bit.ly/2TPErmz

Protective Effects of Downregulating Estrogen Receptor Alpha Expression in Cervical Cancer

Background: The cause of cervical cancer can be traced to Human Papilloma Virus (HPV) along with other, nonviral factors. The uterine cervix is reactive to hormones, and female hormones have been implicated in cervical cancer pathogenesis. Previous studies have indicated that malignant cervical cells tend to lose Estrogen Receptor alpha (ER-α) expression in the cervical epithelium while maintaining ER-α expression in the stromal cells.

Method: We searched the Web of Science, Embase, PubMed, and Wiley Online Library databases to identify potentially relevant articles up to July 4, 2018. Keywords include uterine cervical neoplasms; receptors, estrogen; estrogen receptor alpha; estrogen receptor modulators; estrogens; cervical cancer and estrogen receptor.

Result: Discussions on molecular transitions and drug therapies offer insights into cervical cancer and the functions of estrogen receptors. We focus on molecular transitions and drug therapies for cervical cancer and ER-α targets. Finally, the targeting of downstream gene products and/or receptors to aid in cervical cancer prevention and therapy is discussed.

Conclusion: Downregulating ER-α expression may be a potential treatment regimen for cervical cancer patients and will be of great significance for patients with cervical cancer who are receiving conventional treatment for nonsurgical treatments.

http://bit.ly/2BActUU

Synthesis and In vitro/In vivo Characterization of Raloxifene Grafted Poly(Styrene Maleic Acid)-Poly(Amide-Ether-Ester-Imide) Micelles for Targeted Delivery of Docetaxel in G Protein-Coupled Estrogen Receptor Breast Cancer

Background: To reduce the nonspecifically distribution of chemotherapeutic agents throughout the whole body, which causes severe toxicity in normal tissues, targeting them towards a receptor overexpressed on tumor tissue, is a promising method for cancer therapy.

Objective: The aim of the present study was development of novel copolymeric micelles of raloxifene targeted Styrene Maleic Acid-Poly Amide Ether Ester Imide-Poly Ethylene Glycol (SMA-PAEEI-PEG-RA) and loading them with Docetaxel (DTX).

Methods: Successful synthesis of the targeted copolymer was confirmed by FTIR and C-NMR spectroscopy. The micelles physicochemical properties like morphology, particle size, poly dispersity index, zeta potential, drug loading, release, stability, in vitro cytotoxicity and cellular uptake were analyzed. The in vivo antitumor activity of DTX-loaded micelles were assessed and compared with free DTX and non-targeted micelles in breast cancer bearing Balb-c mice.

Results: Particle sizes, zeta potentials and the encapsulation efficiency of the drug in targeted micelles were 115.9- 142.8 nm, -4.9 to -12.9 mV, and 54.1-67.8%, respectively. Cell toxicity tests showed that IC50 of DTX-loaded SMAPAEEI- PEG-RA micelles increased five-fold as compared with free DTX. Survival rate of the mice improved more effectively than free DTX so that, the percentage of increase in lifespan (ILS%) and the tumor inhibition ratio (TIR) changed from 41.66% and 51.19% in free drug to 83.33% and 78.57% in the targeted micelles, respectively.

Conclusion: Therefore, the raloxifene conjugated PEG-derived micelles may provide a novel and effective delivery system for DTX in breast cancer.

http://bit.ly/2TM1WNq

Critical microRNAs in Lung Cancer: Recent Advances and Potential Applications

Background: MicroRNAs (miRNAs) play an important role in the regulation of various genes involved in cell growth, development and the maintenance of body homeostasis. They are closely linked to different human diseases, particularly in cancers. Amplification and overexpression of some miRNAs that are called 'oncomiRs' or down-regulation of tumor suppressor miRNAs are associated with genetic alterations that are sufficient to drive tumorigenesis in humans. Lung cancer is the leading cause of cancer-related deaths worldwide. The high mortality rate of lung cancer is not changed even with recent advances in cancer treatment. Several studies demonstrated that miRNAs are involved in the pathogenesis of lung cancer that they negatively or positively regulate gene and protein expression by acting as oncogenes or tumor suppressors.

Objective: This article reviewed the current knowledge on the role of miRNAs and their target genes in lung cancer and discussed the potential use of some miRNAs as novel therapeutic agents in lung cancer.

Method: Firstly, we collected and summarized all research and review and research articles in databases including Scopus and PubMed. Then, we used related keywords that are important to lung cancer target therapy and their diagnostic and prognostic values.

Results: Based on collected articles and research, recognizing critical microRNA and controlling the expression of this microRNA by antagonist oligonucleotides like antagomiRs or anti-miRs and microRNA mimicking will have a remarkable role in treating lung cancer.

Conclusion: Many research studies have shown that a combination of chemotherapy plus knockdown or mimicking microRNA is effective and useful in the cancers treatment like lung cancer.

http://bit.ly/2BEk04O

HOXA4-Dependent Transcriptional Activation of AXL Promotes Cisplatin- Resistance in Lung Adenocarcinoma Cells

Background: Lung cancer is one of the most leading causes of cancer-related deaths in adults worldwide. Non-Small Cell Lung Cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most lethal subtype of lung cancer with a 5-year survival of less than 13%. In this study, we identified a poorly-studied kinase PDK4 as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma.

Methods: In vitro cell viability assay and in vivo tumor xenograft assay were used in the detection of cell proliferation. RNA isolation, quantitative Real-Time PCR, Western blot analysis, immunohistochemistry were used to investigate the expression of RNA and protein. Lentivirus infection was used to regulate gene expression. Luciferase assays were used to monitor EPAS1 promoter activity.

Results: In vivo PDK4 expression was elevated in a Cisplatin-resistant population of lung adenocarcinoma cells, PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma in vivo and in vitro, clinically PDK4 expression was associated with poor prognosis in lung adenocarcinoma patients, mechanically PDK4 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of endothelial PAS domain-containing protein 1 (EPAS1).

Conclusion: PDK4 is the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma and PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma mainly through transcriptional regulation of EPAS1. Enriched PDK4 expression was correlated with the poor prognosis of lung cancer patients, indicating that PDK4 could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

http://bit.ly/2TOJNys

Delivering mobile eye care to underserved communities while providing training in ophthalmology to medical students: experience of the Guerrilla Eye Service

http://bit.ly/2RVGF1R

A phase 2 randomized, double-masked, placebo-controlled study of novel nonsystemic kinase inhibitor TOP1630 for the treatment of dry eye disease

http://bit.ly/2X4AA6Z

An experimental study of exenatide effects on renal injury in diabetic rats

Abstract Purpose: To investigate the effects of exenatide on renal injury in streptozotocin-induced diabetic rats. Methods: Fifty SD rats were randomly divided into normal control, model, exenatide-1, exenatide-2 and exenatide-3 groups, 10 rats in each group. The diabetic nephropathy model was constructed in later 4 groups. Then, the later 3 groups were treated with 2, 4 and 8 μg/kg exenatide for 8 weeks, respectively. The serum and urine biochemical indexes and oxidative stress and inflammatory indexes in renal tissue were determined. Results: Compared to the model group, in exenatide-3 group the serum fasting plasma glucose and hemoglobin A1c levels were significantly decreased, the fasting insulin level was significantly increased, the renal index and blood urea nitrogen, serum creatinine and 24 h urine protein levels were significantly decreased, the renal tissue superoxide dismutase and glutathione peroxidase levels were significantly increased, the malondialdehyde level was significantly decreased, and the renal tissue tumor necrosis factor alpha, interleukin 6, hypersensitive C-reactive protein and chemokine (C-C motif) ligand 5 levels were significantly decreased P<0.05). Conclusions: Exenatide can mitigate the renal injury in diabetic rats. The mechanisms may be related to its resistance of oxidative stress and inflammatory response in renal tissue.

http://bit.ly/2IggjIx

Bone callus formation is highly disrupted by dietary restriction in growing rats sustaining a femoral fracture

Abstract Purpose: To evaluate the effects of food restriction on fracture healing in growing rats. Methods: Sixty-eight male Wistar rats were assigned to two groups: (1) Control and (2) Dietary restriction. After weaning the dietary restricted animals were fed ad libitum for 42 days with 50% of the standard chow ingested by the control group. Subsequently, the animals underwent bone fracture at the diaphysis of the right femur, followed by surgical stabilization of bone fragments. On days 14 and 28 post-fracture, the rats were euthanized, and the fractured femurs were dissected, the callus was analyzed by dual-energy X-ray absorptiometry, micro-computed tomography, histomorphometry, mechanical tests, and gene expression. Results: Dietary restriction decreased body mass gain and resulted in several phenotypic changes at the bone callus (a delay in cell proliferation and differentiation, lower rate of newly formed bone and collagen deposition, reductions in bone callus density and size, decrease in tridimensional callus volume, deterioration in microstructure, and reduction in bone callus strength), together with the downregulated expression of osteoblast-related genes. Conclusion: Dietary restriction had detrimental effects on osseous healing, with a healing delay and a lower quality of bone callus formation.

http://bit.ly/2GwGjxJ

LBP reduces theinflammatory injuryof kidney in septic rat and regulates the Keap1-Nrf2∕ARE signaling pathway

Abstract Purpose: To investigate the influence of lycium barbarum polysaccharides (LBP), a functional derivative from lycium barbarum, on septic kidney injury. Methods: The SD male rats were randomly divided into 8 groups. The concentration of IL-1β, IL-6, IL-8, TNF-α, NF-κB and ROS, in kidney cortex homogenates after 12 h treatments were determined by enzyme-linked immunosorbent assay and ROS test kit, respectively. Morphology observation of kidney tissue was conducted with HE staining. The mRNA and protein expression levels of Nrf2, HO-1, NQO1, NF-κB, and Keap1 in kidney tissues were determined by qRT-PCR and Western blot, respectively. Results: LPS treatment significantly increased the oxidative stress. After LBP treatment, the ROS content reduced significantly in a dose-depend manner. However, the levels of HO-1, NQO1 and Nrf2 as molecular elements that respond to oxidative stress were further increased. Also, administration of LBP increased the levels of NF-κB and Keap1, and decreased the levels of Nrf2 in the Keap 1-Nrf2∕ARE signaling pathway. By administrating the brusatol, the inhibition of Nrf2 enhanced the expression of NF-κB, inhibits the antioxidant responses, and further reverse the protective effect of LBP on the LPS induced septic kidney injury. Conclusion: Lycium barbarum polysaccharides can reduce inflammation and activate the antioxidant responses via regulating the level of pro-inflammatory cytokines and the Keap1-Nrf2/ARE signaling pathway.

http://bit.ly/2IgghAp

Metronidazole concentration in the bloodstream following its topical application, at different concentration levels, on experimental skin wounds during healing by secondary intention

Abstract Purpose: To characterize qualitatively and quantitatively the absorption of metronidazole solution, in greater concentrations and for longer periods, when applied topically to an experimental open skin wound model. Methods: An open skin wound, 2 cm in diameter and total skin thickness was prepared, under anesthetic, in the dorsal region of 108 Wistar rats weighing between 300 and 350 grams. The animals were allocated to groups of 18 animals in accordance with the concentration of metronidazole in the solution to be applied daily to the wound. In the control group (CG), 0.9% sodium chloride solution was used for application, and in the experimental groups (GI, GII, GIII, GIV and GV) metronidazole solution at 4%, 6%, 8%, 10% and 12%, respectively, was applied. After 3, 7 and 14 days of treatment. Blood samples collected through cardiac puncture were examined for the existence or non-existence of metronidazole, using high performance liquid chromatography (HPLC). Detected metronidazole values were compared statistically within each group (temporal analysis 3 days X 7 days X 14 days) and between the groups that used topical metronidazole (4% X 6% X 8% X 10% and 12%) using the Kruskal-Wallis test, considering a statistical significance of 95% (p<0.05). Results: Metronidazole was detected in all the samples at all times in all the groups in which topical metronidazole was applied to the wounds. Characteristically, there was no significant difference between the doses obtained within each group over time (3 days X 7 days X 14 days) GI=0.461; GII=0.154; GIII=0.888; GIV= 0.264 and GV=0.152. In the evaluation between groups, a similar degree of absorption was found after 3 days (p=0.829) and 14 days (p=0.751). Conclusion: The serum concentration of metronidazole that was achieved was not influenced by the concentration of the solution applied to the skin wound, with similar extend, or by the duration of the application.

http://bit.ly/2GqWyfp

The role of PI3K/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion

Abstract Purpose: To investigate the role of PI3k/Akt signal pathway in the protective effects of propofol on intestinal and lung injury induced by intestinal ischemia/reperfusion(I/R). Methods: Male Sprague-Dawley rats were subjected to 45 min of ischemia by occluding the superior mesenteric artery and to 2h of reperfusion to establish the model of I/R. Twenty four rats were randomly divided into four groups: Sham, intestinal I/R (II/R), propofol (P), wortmannin (W). In groups P, W, propofol was injected intravenously and continuously at the onset of reperfusion via infusion pump. PI3K inhibitor (wortmannin) was administered intravenously in group W 25 min before ischemia. Intestinal tissues and lung tissues were obtained for determination of histologic injury, wet/dry weight ratio, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. Meanwhile, the expressions of caspase-3 and phosphorylated Akt (p-Akt) in intestines and lungs were detected by western blot. Results: Propofol treatment alleviated intestinal and lung morphological changes which were observed in II/R group，Moreover, wet/dry weight ratio, the MDA level, MPO activity and expression of caspase-3 were significantly decreased whereas the SOD activity and p-Akt expression were significantly increased. Notably, the protections were significantly reversed by pretreatment of wortmannin. Conclusion: PI3K/Akt pathway activation play a critical role in the protective effects of propofol on intestinal and lung injury induced by ischemia/reperfusion.

http://bit.ly/2IggTGd

The effect of hirudin on antagonisting thrombin induced apoptosis of human microvascular endothelial cells

Abstract Purpose: To investigate whether hirudin exerts its antithrombin action to decrease the ratio of Human Microvascular Endothelial Cells (HMVECs) apoptosis. Methods: Human microvascular endothelial cells (HMVECs) cultured in the third and fifth generations were used. HMVECs were divided into normal group, thrombin group (T group), natrual hirudin group (H group), thrombin + natrual hirudin group (T + H group), AG490 group, thrombin + AG490 group (T + AG490 group), natrual hirudin + AG490 group (H + AG490 group), thrombin + natural hirudin + AG490 (T + H + AG490 group).Apart from the normal group, the other groups were exposed to the relevant drugs for 24 hours.HMVEC apoptosis was assessed by flow cytometric and double Immunofluorescence of phosphorylation of JAK (P-JAK2) and TUNEL assay. Results: Compared with the normal group, in thrombin group the HMVECs apoptosis rate were significantly increased (P<0.05).The results indicated that the index of apoptosis and the apoptosis rate were improved in cultures treated by natural hirudin (T + H group), relative to cultures with thrombin only (T group). We found that the index of apoptosis and the apoptosis rate in the AG490 + thrombin group were higher than that in the hirudin + thrombin group (P<0.05). Double Immunofluorescence of p-JAK2 and TUNEL assays showed that cells were double positive for P-JAK2 uptake and TUNEL detection liquid binding. Conclusion: The natural hirudin and JAK2/STATs signal inhibitor AG490 could block the effects of thrombin. Natural hirudin could attenuate HMVECs apoptosis via antagonizing thrombin and it is suggested that this effect may occur by blocking the JAK2/STATs signaling pathway and this signaling pathways appears to be not the only pathway.

http://bit.ly/2GsjvPE

Ramipril can alleviate the accumulation of renal mesangial matrix in rats with diabetic nephropathy by inhibiting insulin-like growth factor-1

Abstract Purpose: To investigate the impact of Ramipril (RAM) on the expressions of insulin-like growth factor-1 (IGF-1) and renal mesangial matrix (RMM) in rats with diabetic nephropathy (DN). Methods: The Sprague Dawley rats were divided into normal control (NC) group (n = 12), DN group (n = 11), and DN+RAM group (n = 12). The ratio of renal weight to body weight (RBT), fasting blood glucose (FBG), HbA1c, 24-h urine protein (TPU), blood urea nitrogen (BUN), creatinine (Cr), renal pathological changes, the levels of IGF-1, fibronectin (FN), type IV collagen (Col-IV), and matrix metalloproteinases (MMP)-2 were compared among the groups. Results: Compared with NC group, the RBT, FBG, HbA1c, TPU, BUN, Cr, and RMM in DN group were significantly increased (P < 0.05), the IGF-1, FN, and Col-IV were significantly upregulated (P < 0.05), while MMP was significantly downregulated (P < 0.05). Compared with DN group, the indexes except for the FBG and HbA1c in DN+RAM group were significantly improved (P < 0.05), among which IGF-1 exhibited significant positive correlation with TPU(r=0.937), FN(r=0.896) and Col-IV(r=0.871), while significant negative correlation with MMP-2 (r=-0.826) (P<0.05). Conclusion: RAM may protect the kidneys by suppressing IGF-1 and mitigating the accumulation of RMM.

http://bit.ly/2IggcN7

Patents on hospital medical and dental equipment (EMHO). Question and answer tool

Abstract Purpose: To create a question and answer tool on patents on EMHO. Methods: Was used the Thinking Design methodology divided into four phases: Discovery, Definition, Development and Delivery. Discovery Phase: Desk research was carried out in: SciELO, Pubmed, LILACS, Google and Google Scholar. Once the target audience was selected, the interviews were conducted. Definition Phase: the interviewees' difficulties were mapped, on an Excel spreadsheet. Development Phase: a brainstorming was conducted with the public interviewed. Delivery Phase: the prototype, validation and final elaboration of the tool were made. Results: Discovery Phase: 10 inventors were identified and the interviews were carried out. Definition Phase: 80% of the interviewees determined lack of information as one of the problems. The main content was defined as: the patent process, from the beginning of the idea to the deposit (70%), search for precedence (40%) and informing partners (30%). Development Phase: with the brainstorming, the tool type was defined as an interactive site. Delivery Phase: a prototype with content framework and an interactive video was presented for validation. After approval, the interactive website was developed, which was made available to the public. Conclusion: A question and answer tool on patents in EMHO was developed.

http://bit.ly/2GpUKDF

Ursodeoxycholic acid in the prevention of gallstones in patients subjected to Roux-en-Y gastric bypass

Abstract Purpose: To evaluate the contribution of ursodeoxycholic acid (UDCA) in the first 12 months after Roux-en-Y gastric bypass in the prevention of gallstone formation. Methods: A community-based clinical trial was conducted. A total of 137 patients were included in the study; 69 were treated with UDCA, starting 30 days after the surgery, at a dose of 150 mg twice daily (300 mg/day) over a period of 5 consecutive months (GROUP A), and 68 were control patients (GROUP B). The patients were followed-up, and ultrasonography was performed to determine the presence of gallstones at various times during follow-up. Demographic, anthropometric and comorbid indicators were obtained. The data were subjected to normality tests and evaluated using appropriate tests. Results: Patients did not differ in their baseline characteristics. Of the 69 patients who used UDCA, only one patient developed cholelithiasis (1%), whereas 18 controls (26%) formed gallstones (OR = 24.4, p <0.001). Also, other factors were found not to influence the formation of calculi, such as pre-operative or postoperative hepatic steatosis or diabetes (p = 0.759, 0.468, 0.956). Conclusion: The results demonstrated that patients who did not use UDCA showed a 24.4-fold greater probability of developing cholelithiasis.

http://bit.ly/2Iggbc1

The role of laparoscopy in the propaedeutics of gynecological diagnosis

Abstract Purpose: To evaluate agreement between pre- and post-laparoscopy gynecological diagnosis in order to demonstrate the rationality of this minimally invasive technique use in gynecological propaedeutics. Methods: Retrospective chart review study conducted between March 2010 and October 2016 based on a convenience sample. 315 patients undergoing surgical laparoscopy at the Center of Gynecologic Endoscopy and Family Planning of Botucatu Medical School/UNESP. Pre- and postoperative diagnoses were compared by the diagnosis agreement test considering the proportions of events. Results: Laparoscopy contributed to diagnosis in 59.6% of infertility cases (P>0.05), in 93.7% of chronic pelvic pain of undetermined origin (P<0.01) and conclusively elucidated the diagnosis of acute abdomen and the ruling out of tubo-ovarian abcess (P<0.05). Laparoscopy also increased the diagnosis of pelvic-abdominal adhesions in 76.7% (P>0.05). Conclusion: The use of laparoscopy considerably contributed to diagnostic elucidation, especially in cases of undetermined chronic pelvic pain.

http://bit.ly/2GuRW8a

Erratum: The effect of metyrosine on oxidative gastric damage induced by ischemia/reperfusion in rats. Biochemical and histopathological evaluation

Abstract Purpose: To evaluate agreement between pre- and post-laparoscopy gynecological diagnosis in order to demonstrate the rationality of this minimally invasive technique use in gynecological propaedeutics. Methods: Retrospective chart review study conducted between March 2010 and October 2016 based on a convenience sample. 315 patients undergoing surgical laparoscopy at the Center of Gynecologic Endoscopy and Family Planning of Botucatu Medical School/UNESP. Pre- and postoperative diagnoses were compared by the diagnosis agreement test considering the proportions of events. Results: Laparoscopy contributed to diagnosis in 59.6% of infertility cases (P>0.05), in 93.7% of chronic pelvic pain of undetermined origin (P<0.01) and conclusively elucidated the diagnosis of acute abdomen and the ruling out of tubo-ovarian abcess (P<0.05). Laparoscopy also increased the diagnosis of pelvic-abdominal adhesions in 76.7% (P>0.05). Conclusion: The use of laparoscopy considerably contributed to diagnostic elucidation, especially in cases of undetermined chronic pelvic pain.

http://bit.ly/2Igg8gl

Erratum

Abstract Purpose: To evaluate agreement between pre- and post-laparoscopy gynecological diagnosis in order to demonstrate the rationality of this minimally invasive technique use in gynecological propaedeutics. Methods: Retrospective chart review study conducted between March 2010 and October 2016 based on a convenience sample. 315 patients undergoing surgical laparoscopy at the Center of Gynecologic Endoscopy and Family Planning of Botucatu Medical School/UNESP. Pre- and postoperative diagnoses were compared by the diagnosis agreement test considering the proportions of events. Results: Laparoscopy contributed to diagnosis in 59.6% of infertility cases (P>0.05), in 93.7% of chronic pelvic pain of undetermined origin (P<0.01) and conclusively elucidated the diagnosis of acute abdomen and the ruling out of tubo-ovarian abcess (P<0.05). Laparoscopy also increased the diagnosis of pelvic-abdominal adhesions in 76.7% (P>0.05). Conclusion: The use of laparoscopy considerably contributed to diagnostic elucidation, especially in cases of undetermined chronic pelvic pain.

http://bit.ly/2GsqSGI

In vitro antioxidant properties of golden grass (Syngonanthus nitens) by electron paramagnetic resonance

The high antioxidant activity of a Brazilian native grass‐like herb (Syngonanthus nitens) was investigated by electron paramagnetic resonance spectroscopy.

Abstract

The in vitro antioxidant properties of golden grass (GG), a grass‐like herb (Syngonanthus nitens), were investigated by electron paramagnetic resonance (EPR) spectroscopy. We measured the antioxidant capacity of methanolic extracts based on their ability to scavenge 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical. The kinetics of reaction between DPPH and GG extract was determined. This kinetics followed a biexponential decay, and this behavior was attributed to different flavonoids acting together as antioxidants. Isoorientin and luteolin, which are two of the eight flavonoids found in GG extract, were used to investigate kinetics of reaction between DPPH and both the flavonoids acting separately and together. The antioxidant activity of GG extract was determined in terms of the vitamin C equivalent antioxidant capacity (VCEAC). Compared to other well‐known plant‐based antioxidants, such as pulp and peels of fruit and vegetables, S. nitens presented a high antioxidant capacity (VCEAC = 1,485 ± 198 mg/100 g), indicating that it should be regarded as a valuable source of antioxidants and also that it may bestow health benefits when consumed.

http://bit.ly/2EbHcZV

Cancers, Vol. 11, Pages 225: The Value of Histological Algorithms to Predict the Malignancy Potential of Pheochromocytomas and Abdominal Paragangliomas—A Meta-Analysis and Systematic Review of the Literature

Cancers, Vol. 11, Pages 225: The Value of Histological Algorithms to Predict the Malignancy Potential of Pheochromocytomas and Abdominal Paragangliomas—A Meta-Analysis and Systematic Review of the Literature

Cancers doi: 10.3390/cancers11020225

Authors: Adam Stenman Jan Zedenius Carl Christofer Juhlin

Pheochromocytomas (PCCs) and abdominal paragangliomas (PGLs), collectively abbreviated PPGLs, are neuroendocrine tumors of the adrenal medulla and paraganglia, respectively. These tumors exhibit malignant potential but seldom display evidence of metastatic spread, the latter being the only widely accepted evidence of malignancy. To counter this, pre-defined histological algorithms have been suggested to stratify the risk of malignancy: Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) and the Grading system for Adrenal Pheochromocytoma and Paraganglioma (GAPP). The PASS algorithm was originally intended for PCCs whereas the GAPP model is proposed for stratification of both PCCs and PGLs. In parallel, advances in terms of coupling overtly malignant PPGLs to the underlying molecular genetics have been made, but there is yet no combined risk stratification model based on histology and the overall mutational profile of the tumor. In this review, we systematically meta-analyzed previously reported cohorts using the PASS and GAPP algorithms and acknowledge a &ldquo;rule-out&rdquo; way of approaching these stratification models rather than a classical &ldquo;rule-in&rdquo; strategy. Moreover, the current genetic panorama regarding possible molecular adjunct markers for PPGL malignancy is reviewed. A combined histological and genetic approach will be needed to fully elucidate the malignant potential of these tumors.

http://bit.ly/2ST15gu

5 ways to bring a culture of celebration to your EMS agency

Regardless of size or service model, here are a few ways your department can honor its employees throughout the year

http://bit.ly/2DEEyKR

Now Accepting Applications for Global Internships

Each year, the Foundation's Global Internship Program offers students who are interested in focused ultrasound the opportunity to work with esteemed mentors in the field.

http://bit.ly/2EbqBph

A combination of naso- and oropharyngeal swabs improves the diagnostic yield of respiratory viruses in adult emergency department patients

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http://bit.ly/2SxjvEa

Successful cure of daptomycin-non-susceptible, vancomycin-intermediate Staphylococcus aureus prosthetic aortic valve endocarditis directed by synergistic in vitro time-kill study

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http://bit.ly/2DEvCVQ

NAEMSP commends new 'Emergency Triage, Treat and Transport' model

The model policy will reimburse EMS agencies for the cost of providing Medicare beneficiaries with treatment-without-transportation and transporting patients to alternative destinations

http://bit.ly/2Grbrym

CMS announces Medicare reimbursement for certain non-transport treatment

The Emergency Triage, Treat and Transport Model makes Medicare reimbursement available for treatment without transport

http://bit.ly/2Gqbb2D

Genome Analyses of a New Mycoplasma Species from the Scorpion Centruroides vittatus

Arthropod Mycoplasma are little known endosymbionts in insects, primarily known as plant disease vectors. Mycoplasma in other arthropods such as arachnids are unknown. We report the first complete Mycoplasma genome sequenced, identified, and annotated from a scorpion, Centruroides vittatus, and designate it as Mycoplasma vittatus. We find the genome is at least a 683,827 bp single circular chromosome with a GC content of 42.7% and with 987 protein-coding genes. The putative virulence determinants include 11 genes associated with the virulence operon associated with protein synthesis or DNA transcription and ten genes with antibiotic and toxic compound resistance. Comparative analysis revealed that the M. vittatus genome is smaller than other Mycoplasma genomes and exhibits a higher GC content. Phylogenetic analysis shows M. vittatus as part of the Hominis group of Mycoplasma. As arthropod genomes accumulate, further novel Mycoplasma genomes may be identified and characterized.

http://bit.ly/2SzV09j

Clinicopathological characteristics associated with necrosis in pulmonary metastases from colorectal cancer

Abstract

Metastatic lung cancers from the colon and rectum (MLCR) frequently have necrotic components. The aim of this study is to elucidate clinicopathological factors associated with the amount of necrosis in MLCR. Ninety patients who underwent the first pulmonary metastasectomy for MLCR with a tumor diameter ≦ 3.0 cm and without chemotherapy were enrolled in this study. Analyzing digitally scanned pathological slides, we calculated the necrosis percentage (NP, the necrosis area divided by the tumor area). The relationship between NP and clinicopathological factors was analyzed. Moreover, to determine whether NP was affected by tissue hypoxia, vascularization, or tumor cell proliferation, tissues were analyzed by immunohistochemical staining using carbonic anhydrase IX (CAIX), CD34 antibodies, and Ki-67 antibodies, respectively. Median tumor area and NP were 0.69 cm² (0.11–3.01) and 13.1% (0–71.6), respectively. Although NP was not associated with the tumor area, it was significantly higher in the patients with a positive smoking history (8.14% vs 17.1%, p = 0.045). Other clinicopathological factors were not correlated with NP. Immunohistochemical analysis revealed that CA IX expression on tumor cells, CD34 micro-vessel density, CD34 micro-vessel area, and Ki-67 index were not significantly associated with NP. NP in the primary site was not associated with NP in the pulmonary metastasis. NP was not determined by tumor size, tissue hypoxia, vascularization, or tumor cell proliferation. Positive correlation of NP with smoking history suggests a unique lung microenvironment in smokers which makes necrosis of MLCR more likely to occur.

http://bit.ly/2DJ2pct

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells

Purpose: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies.

Patients and Methods: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5–1.0 x 10⁶/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism.

Results: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/μL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein–Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFN and IL-10. They peaked at 1,848 cells/μL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur.

Conclusions: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.

http://bit.ly/2N5C0cU

A Variant of a Killer Cell Immunoglobulin-like Receptor is Associated with Resistance to PD-1 Blockade in Lung Cancer

Purpose: PD-(L)1 blocking antibodies have clinical activity in metastatic non-small cell lung cancer (NSCLC) and mediate durable tumor remissions. However, the majority of patients are resistant to PD-(L)1 blockade.Understanding mechanisms of primary resistance may allow prediction of clinical response and identification of new targetable pathways. Experimental Design: Peripheral blood mononuclear cells were collected from 35 NSCLC patients receiving nivolumab monotherapy. Cellular changes, cytokine levels, gene expression, and polymorphisms were compared between responders and non-responders to treatment. Findings were confirmed in additional cohorts of NSCLC patients receiving immune checkpoint blockade. Results: We identified a genetic variant of a Killer Cell Immunoglobulin-like Receptor (KIR) KIR3DS1 that is associated with primary resistance to PD-1 blockade in NSCLC patients. This association could be confirmed in independent cohorts of patients with NSCLC. In a multivariate analysis of the pooled cohort of 135 patients the progression-free survival was significantly associated with presence of the KIR3DS1 allele (HR 1.72, 95 % CI 1.10 to 2.68, P=0.017). No relationship was seen in cohorts of NSCLC patients who did not receive immunotherapy. Cellular assays from patients before and during PD-1 blockade showed that resistance may be to NK cell reactivity. Conclusions:We identify an association of the KIR3DS1 allelic variant with response to PD-1 targeted immunotherapy in patients with NSCLC. This finding links NK cells with response to PD-1 therapy. While the findings are interesting, a larger analysis in a randomized trial will be needed to confirm KIRs as predictive marker for response to PD-1 immunotherapy.

http://bit.ly/2SU5i3B

BRAF targeting sensitizes resistant melanoma to cytotoxic T cells

Purpose: BRAF and MEK inhibitors (BRAFi, MEKi) are actively used for the treatment of metastatic melanoma in patients with BRAF^V600E mutation in their tumors. However, the development of resistance to BRAFi and MEKi remains a difficult clinical challenge with limited therapeutic options available to these patients. In this study we investigated the mechanism and potential therapeutic utility of combination BRAFi and adoptive T cells therapy (ACT) in melanoma resistant to BRAFi. Experimental design: Investigations were performed in vitro and in vivo with various human melanoma cell lines sensitive and resistant to BRAFi as well as PDXs derived from patients. In addition, samples were evaluated from patients on a clinical trial of BRAFi in combination with ACT. Results: Herein we report that in human melanoma cell lines senstitive and resistant to BRAFi and in PDXs from patients who progressed on BRAFi and MEKi therapy, BRAFi caused transient up-regulation of mannose-6-phosphate receptor (M6PR). This sensitized tumor cells to CTLs via uptake of granzyme B, a main component of the cytotoxic activity of CTLs. Treatment of mice bearing resistant tumors with BRAFi enhanced the antitumor effect of patients' TIL. A pilot clinical trial of 16 patients with metastatic melanoma who were treated with the BRAFi vemurafenib followed by therapy with TIL demonstrated significant increase of M6PR expression on tumors during vemurafenib treatment. Conclusions: BRAF targeted therapy sensitized resistant melanoma cells to CTLs, which opens new therapeutic opportunities for the treatment of patients with BRAF resistant disease.

http://bit.ly/2N5BZ8Q

Impact of Concomitant Administration of Gastric Acid-Suppressive Agents and Pazopanib on Outcomes in Soft-Tissue Sarcoma Patients Treated within the EORTC 62043/62072 Trials

Purpose: Pazopanib is active in soft-tissue sarcoma (STS). Because pazopanib absorption is pH-dependent, coadministration with gastric acid–suppressive (GAS) agents such as proton pump inhibitors could affect exposure of pazopanib, and thereby its therapeutic effects.

Experimental Design: The EORTC 62043 and 62072 were single-arm phase II and placebo-controlled phase III studies, respectively, of pazopanib in advanced STS. We first compared the outcome of patients treated with pazopanib with or without GAS agents for ≥80% of treatment duration, and subsequently using various thresholds. The impact of concomitant GAS therapy was assessed on progression-free survival (PFS) and overall survival (OS) using multivariate Cox models, exploring and comparing also the potential effect on placebo-treated patients.

Results: Of 333 eligible patients, 59 (17.7%) received concomitant GAS therapy for >80% of pazopanib treatment duration. Median PFS was shorter in GAS therapy users versus nonusers: 2.8 vs. 4.6 months, respectively [HR, 1.49; 95% confidence interval (CI), 1.11–1.99; P = 0.01]. Concomitant administration of GAS therapy was also associated with a shorter median OS: 8.0 vs. 12.6 months (HR, 1.81; 95% CI, 1.31–2.49; P < 0.01). The longer the overlapping use of GAS agents and pazopanib, the worse the outcome with pazopanib. These effects were not observed in placebo-treated patients (HR, 0.82; 95% CI, 0.51–1.34; P = 0.43 for PFS and HR, 0.84; 95% CI, 0.48–1.48; P = 0.54 for OS).

Conclusions: Coadministration of long-term GAS therapy with pazopanib was associated with significantly shortened PFS and OS. Withdrawal of GAS agents must be considered whenever possible. Therapeutic drug monitoring of pazopanib plasma concentrations may be helpful for patients on pazopanib and GAS therapy.

http://bit.ly/2SU5cJh

Lung Microbiota Promote Lung Cancer [News in Brief]

Mice treated with antibiotics or kept in bacteria-free conditions have fewer, smaller tumors.

http://bit.ly/2SySoIW

Antidepressive effects of kaempferol mediated by reduction of oxidative stress, proinflammatory cytokines and up-regulation of AKT/β-catenin cascade

Abstract

Kaempferol (KFL), the major constituent of various fruits and vegetables, could attenuate oxidaitve stress and inflammation. The aims of the present study were to explore the ameliorative abilities of KFL on the depressive-like behaviors in a chronic social defeat stress (CSDS) mouse model, and to determine the potential mechanisms on oxidative stress, neuroinflammation, and AKT/β-catenin signaling pathway. Three behavioral tests, sucrose preference test (SPT), social interaction test (SIT), and tail suspension test (TST), were used to evaluate the antidepressive effects of KFL in CSDS mice. Activity levels of antioxidant enzyme, superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione s-transferase (GST), and concentrations of malonaldehyde (MDA) and protein carbonylation in the prefrontal cortex were assessed by commercial kits, respectively. Elisa was used to detect the levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α). Q-PCR was used to determine the mRNA level of CD-11b. Furthermore, activity level of AKT/β-catenin signaling in the prefrontal cortex of CSDS mice was investigated by western blot. In addition, LY294002, a PI3-K inhibitor, was used to investigate the role of AKT/β-catenin signaling in the antidepressant effects of KFL. Social defeat stress reduced the bodyweights, sucrose consumptions, social interaction times, and the tail suspension mobility times in mice. CSDS mice were also exhibited remarkablely increased levels in oxidative stress markers, inflammatory mediators, and decreased activity of AKT/β-catenin cascade in the prefrontal cortex, which were reversed by treatment with KFL. Interestingly, LY294002 appeared to partly inhibit the overall KFL-mediated protective effects in the CSDS mice. These results confirmed that KFL exerted antidepressive effects, which might be mediated, at least in part, by enhanced antioxidant abilities and anti-inflammation effects via up-regulation AKT/β-catenin cascade activity in the prefrontal cortex of CSDS mice. Thus, KFL might be a promising, effective, and safe food medicine for depression treatment.

http://bit.ly/2SzePO9

Disruption of endolysosomal RAB5/7 efficiently eliminates colorectal cancer stem cells.

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSC remains a promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSC and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an anti-malarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSC.

http://bit.ly/2SMTEri

MDH1 and MPP7 regulate autophagy in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is driven by metabolic changes in pancreatic cells caused by oncogenic mutations and dysregulation of p53. PDAC cell lines and PDAC-derived xenografts grow as a result of altered metabolic pathways, changes in stroma, and autophagy. Selective targeting and inhibition of one of these may open avenues for the development of new therapeutic strategies. In this study, we performed a genome-wide siRNA screen in a PDAC cell line using endogenous autophagy as a readout and identified several regulators of autophagy that were required for autophagy-dependent PDAC cell survival. Validation of two promising candidates, MPP7 (MAGUK p55 subfamily member 7, a scaffolding protein involved in cell-cell contacts) and MDH1 (cytosolic Malate dehydrogenase 1), revealed their role in early stages of autophagy during autophagosome formation. MPP7 was involved in activation of YAP1 (a transcriptional coactivator in the Hippo pathway), which in turn promoted autophagy, whereas MDH1 was required for maintenance of the levels of the essential autophagy initiator serine-threonine kinase ULK1, and increased in activity upon induction of autophagy. Our results provide a possible explanation for how autophagy is regulated by MPP7 and MDH1, which adds to our understanding of autophagy regulation in PDAC.

http://bit.ly/2N8xVEI

Cytochrome c-deficiency Confers Apoptosome and Mitochondrial Dysfunction in African-American Men with Prostate Cancer

Although African-American (AA) prostate cancer (PCa) patients tend to develop greater therapeutic resistance and faster PCa recurrence compared to Caucasian-American men, the molecular mechanisms of this racial PCa disparity remain undefined. In this study, we provide the first comprehensive evidence that cytochrome c (CC) deficiency in AA primary tumors and cancer cells abrogates apoptosome-mediated caspase activation and contributes to mitochondrial dysfunction, thereby promoting therapeutic resistance and PCa aggressiveness in AA men. In AA PCa cells, decreased nuclear accumulation of Nrf1 and its subsequent loss of binding to the CC promoter mediated CC deficiency. Activation of c-Myc and NF-κB or inhibition of AKT prevented nuclear translocation of Nrf1. Genetic and pharmacological inhibition of c-Myc and NF-κB or activation of AKT promoted Nrf1 binding to CC promoter, CC expression, caspase activation, and cell death. The lack of p-Drp1S616 in AA PCa cells contributed to defective CC release and increased resistance to apoptosis, indicating that restoration of CC alone may be insufficient to induce effective apoptosis. CC-deficiency promoted acquisition of glycolytic phenotypes and mitochondrial dysfunction, whereas CC restoration via inhibition of c-Myc and NF-κB or activation of AKT attenuated glycolysis in AA PCa cells. Inhibition of c-Myc and NF-κB enhanced the efficacy of docetaxel in tumor xenografts. Therefore, restoring CC may overcome therapeutic resistance and PCa aggressiveness in AA men. Overall, this study provides the first comprehensive experimental, mechanistic, and clinical evidence for apoptosome and mitochondrial dysfunction in PCa racial disparity.

http://bit.ly/2SU11x5

Cancer Death Risk Up for Kidney Transplant, Dialysis Patients

THURSDAY, Feb. 14, 2019 -- Dialysis and kidney transplant patients have more than a 2.5-fold increased risk for cancer death, according to a study published online Feb. 14 in the Journal of the American Society of Nephrology. Eric H. Au, M.B.B.S.,...

http://bit.ly/2NbhEza

Wisdom Linked to Cognitive Performance in Schizophrenia

THURSDAY, Feb. 14, 2019 -- For people with schizophrenia (PwS), wisdom is associated with better cognitive performance, according to a study published online Feb. 14 in Schizophrenia Research. Ryan Van Patten, Ph.D., from the University of...

http://bit.ly/2SV81cY

Burnout Predicts Clinician Turnover in Primary Care

THURSDAY, Feb. 14, 2019 -- The prevalence rates of burnout, low engagement, and turnover are all high among primary care clinicians and staff, according to a study published in the January/February issue of the Annals of Family Medicine. Rachel...

http://bit.ly/2N7enAF

Hip Preservation Appropriateness Guidelines May Be Limited

THURSDAY, Feb. 14, 2019 -- The American Academy of Orthopaedic Surgeons (AAOS) hip preservation surgery appropriateness classification system is driven almost entirely by age and radiographic hip osteoarthritis (OA) evaluation, according to a study...

http://bit.ly/2SV8oEo

CDC: Severity of Influenza Season Low Through Feb. 2, 2019

THURSDAY, Feb. 14, 2019 -- The 2018 to 2019 influenza season has been low in severity so far, and overall vaccine effectiveness is about 47 percent, according to two reports published in the Feb. 15 issue of the U.S. Centers for Disease Control and...

http://bit.ly/2N7elZz

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α, Published online: 15 February 2019; doi:10.1038/s41416-019-0394-9

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

https://go.nature.com/2GJG3ui

Brivanib in combination with Notch3 silencing shows potent activity in tumour models

Brivanib in combination with Notch3 silencing shows potent activity in tumour models

Brivanib in combination with Notch3 silencing shows potent activity in tumour models, Published online: 15 February 2019; doi:10.1038/s41416-018-0375-4

Brivanib in combination with Notch3 silencing shows potent activity in tumour models

https://go.nature.com/2tnnwwb

Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma

Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma

Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma, Published online: 15 February 2019; doi:10.1038/s41416-018-0373-6

Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma

https://go.nature.com/2GIw5t7

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis, Published online: 15 February 2019; doi:10.1038/s41416-019-0400-2

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis

https://go.nature.com/2tmBgHi

TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer

TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer

TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer, Published online: 15 February 2019; doi:10.1038/s41416-019-0397-6

TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer

https://go.nature.com/2GHr7Nn

Needlescopic surgery for broad ligament hernia: A case report

Broad ligament hernia is a rare type of internal hernia. We herein report a case of broad ligament hernia successfully treated by needlescopic surgery. A 41‐year‐old woman was referred to our hospital with a complaint of nausea and vomiting. Abdominal contrast‐enhanced computed tomography showed diffuse dilatation of the small bowel accompanied by a caliber change at the right side of the uterus. She was thus diagnosed with small bowel obstruction due to incarceration through right broad ligament hernia. After bowel decompression, she underwent elective needlescopic surgery using 2‐ and 3‐mm instruments. The defect in the right broad ligament was closed with sutures, and she was discharged 2 days after surgery. In the treatment of broad ligament hernia without bowel ischemia, neither an abdominal incision nor any energy devices are required. In this respect, needlescopic surgery seems to be a promising approach among minimally invasive surgeries.

http://bit.ly/2tnBMVC

Incorporation of digital gene expression profiling for cell-of-origin determination (Lymph2Cx testing) into the routine work-up of diffuse large B cell lymphoma

Abstract

Diffuse large B cell lymphomas (DLBCL) represent a clinically heterogeneous group of lymphomas that are classified together based on similarities in morphology and immunophenotype. Gene expression profiling further classifies DLBCL into distinct molecular subgroups based on cell-of-origin (COO), including germinal center B cell type, activated B cell type, and unclassified type. COO assignment of DLBCL has important biological and prognostic significance, as well as emerging therapeutic implications. Herein, we describe the first clinical validation of a digital gene expression-profiling assay (Lymph2Cx) to perform COO assignment in the routine work-up of DLBCL using formalin-fixed paraffin-embedded (FFPE) tissue sections and describe the results of 90 consecutive DLBCL cases analyzed prospectively by a College of American Pathologists/Clinical Laboratory Improvement Amendments (CAP/CLIA)-certified clinical molecular diagnostics laboratory.

http://bit.ly/2DFSmEQ

Emergency Triage, Treatment and Transport reimbursement model is a watershed moment in modern EMS

EMS leaders react to ET3, HHS reimbursement model that recognizes the value of community paramedicine and emphasizes quality and outcomes

http://bit.ly/2TRcsD8

4 effective strategies to cope with drug shortages in EMS

Pharmaceutical shortages are an ongoing challenge for EMS providers, but agencies can take proactive steps to address the issue

http://bit.ly/2X3J4eE

5 ways to bring a culture of celebration to your EMS agency

Regardless of size or service model, here are a few ways your department can honor its employees throughout the year

http://bit.ly/2DFSsw5

Effect of Cotinine-verified Change in Smoking Status on Risk of Metachronous Colorectal Neoplasia After Polypectomy

Previous assessments of colorectal neoplasia (CRN) recurrence after polypectomy used self-report to determine smoking status. We evaluated the association between change in smoking status and metachronous CRN risk after polypectomy using cotinine level in urine to determine tobacco exposure.

http://bit.ly/2N5GhwZ

Improved Real-Time Optical Diagnosis of Colorectal Polyps Following a Comprehensive Training Program

The optimal training method for endoscopic characterization of colorectal polyps using narrow-band imaging is uncertain, and sessile serrated lesions (SSLs) optical diagnosis data are lacking. We aimed to evaluate a comprehensive training program for real-time optical diagnosis of colorectal polyps, including SSLs.

http://bit.ly/2SUEXSQ

Association Between Level of Fecal Calprotectin and Progression of Crohn's Disease

Mucosal healing is associated with improved outcomes in patients with Crohn's disease (CD), but assessment typically requires ileocolonoscopy. Calprotectin can be measured in fecal samples to determine luminal disease activity in place of endoscopy—this measurement is an important component of the treat to target strategy. We investigated whether levels of fecal calprotectin associate with subsequent CD progression.

http://bit.ly/2N5YxGA

For Whom is Hepatocellular Carcinoma Surveillance after Sustained Virologic Response Cost Effective?

http://bit.ly/2SPDa1p

Use of Doppler Probe in Non-Variceal Upper-Gastrointestinal Bleeding is Less Costly and More Effective Than Standard of Care

Upper gastrointestinal bleeding is a common emergency and rebleeding is associated with an increased risk of death. Proper assessment of high-risk lesions and appropriate endoscopic hemostasis are required for the best outcomes. The endoscopic Doppler probe exam (DPE) allows for a more complete assessment of the stigmata of hemorrhage, providing better evaluation of the need for endoscopic hemostasis and determination of its completeness. We aimed to evaluate whether use of the DPE provides an additional advantage in cost and effectiveness compared with traditional endoscopic visual assessment (TEA) of high-risk stigmata in patients with non-variceal upper gastrointestinal bleeding.

http://bit.ly/2SPFTYJ

Addition of Carvedilol to Gastric Variceal Obturation Does Not Decrease Recurrence of Gastric Variceal Bleeding in Patients With Cirrhosis

Gastric variceal bleeding (GVB) frequently recurs after hemostasis by gastric variceal obturation (GVO). We performed a multicenter, randomized controlled trial to determine the efficacy of carvedilol plus GVO in secondary prophylaxis of GVB.

http://bit.ly/2N8r9PE

Receipt of a survivorship care plan and self-reported health behaviors among cancer survivors

Abstract

Purpose

Our study aims to determine whether receipt of a written survivorship care plan (SCP) is associated with five self-reported health behaviors known to be correlated with positive long-term outcomes for cancer survivors: (1) attending a recent medical appointment, (2) exercise in the past month, (3) non-smoking status, (4) mammography in the past 2 years, and (5) up-to-date colorectal cancer screening.

Methods

In this secondary data analysis, we used data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS) cancer survivorship module for 1855 off-treatment cancer survivors. Multivariable logistic regression accounting for complex survey design was used to examine the association between SCP receipt and each of the five preventive health behaviors.

Results

Overall, 37% (669/1855) of survivors reported receiving a written survivorship care plan. In the logistic regression models adjusted for sociodemographic and disease-related factors, SCP receipt was associated with having a recent medical appointment (OR (95% CI) 2.81 (1.27–6.22)), exercise in the past month (1.78 (1.20–2.63)), non-smoking status (2.27 (1.26–4.12)), and up-to-date mammography (2.25 (1.30–3.88)). Receipt of a survivorship care plan was not associated with colorectal cancer screening (1.2 (0.73–2.03)).

Conclusions

This study provides preliminary evidence that SCPs may be helpful in promoting health behaviors among cancer survivors, including attending a regular medical appointment, mammography screening, exercise, and abstinence from smoking. Additionally, the low rates of SCP provision highlight an important missed opportunity and area for intervention.

Implications for Cancer Survivors

Providing survivors with SCPs may help to increase important health behaviors.

http://bit.ly/2SyYKYY

TYRO3 as a molecular target for growth inhibition and apoptosis induction in bladder cancer

https://go.nature.com/2Gsjqet

Integrated analysis of multiple receptor tyrosine kinases identifies Axl as a therapeutic target and mediator of resistance to sorafenib in hepatocellular carcinoma

https://go.nature.com/2Iei9JS

HAI-2 as a novel inhibitor of plasmin represses lung cancer cell invasion and metastasis

https://go.nature.com/2GrfXNm

Synergistic antitumour activity of HDAC inhibitor SAHA and EGFR inhibitor gefitinib in head and neck cancer: a key role for ΔNp63α

https://go.nature.com/2IfsDbY

Brivanib in combination with Notch3 silencing shows potent activity in tumour models

https://go.nature.com/2GrfVFe

Immunohistochemical Study of PD-1/PD-L1 Axis Expression in Oral Tongue Squamous Cell Carcinomas: Effect of Neoadjuvant Chemotherapy on Local Recurrence

Abstract

While neoadjuvant chemotherapy (NAC) for patients with oral tongue squamous cell carcinoma (OTSCC) may improve tumor microenvironment, it may lead to local immune suppression caused by residual cancer cells. The efficacy of NAC is therefore controversial. In our study, we investigated tumor microenvironments after NAC using immune checkpoint molecules, and evaluated the association between tumor microenvironments, clinicopathological factors and outcomes. We reviewed the records of 121 patients who underwent radical surgery for OTSCC between April 2001 and March 2015. Patients with a positive surgical margin and a follow up period of less than 6 months were excluded. For these patients, programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) expressions were immunohistochemically examined. The expression of PD-1 and PD-L1 were significantly associated with local recurrence in patients with OTSCC (P < 0.01 and P < 0.01, respectively). We found a significant decrease in 5-year disease specific survival rate for patients with combined PD-1+/PD-L1+ expressions (P < 0.05). In the subgroup analysis of local recurrence between the NAC treated group and those who received surgery alone, high levels of PD-1 and PD-L1 expressions were significantly found in the former, but not in the latter group. Local recurrence in the NAC-treated group may contribute to local immune suppression in OTSCC. NAC lead to local immune suppression and immune checkpoint molecules play an important role in local recurrence in patients with OTSCC who received NAC. NAC modality can't be recommended for patients with OTSCC at present.

http://bit.ly/2BBNDng

Erratum Regarding “Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial” (Am J Kidney Dis. 2018;71[1]:65-74)

In the Original Investigation entitled "Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial" that appeared in the January 2018 issue of AJKD (Bjornstad et al, volume 71, issue 1, pages 65-74), there was a labeling error in Tables 2 and 3. Specifically, the variables "HbA1c, per 1% lower" (in Tables 2 and 3) and "Δ HbA1c, per 1% decrease" (in Table 2) should have been listed as "HbA1c, per 1% higher" and "Δ HbA1c, per 1% increase," respectively.

http://bit.ly/2N4X2by

Erratum Regarding “Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report” (Am J Kidney Dis. 2017;70[6]:859-868)

In the Perspective entitled "Oral Anticoagulants to Prevent Stroke in Nonvalvular Atrial Fibrillation in Patients With CKD Stage 5D: An NKF-KDOQI Controversies Report" that appeared in the December 2017 issue of AJKD (Bansal et al, volume 70, issue 6, pages 859-868), some corrections are needed to resolve ambiguities in the content related to warfarin alternatives.

http://bit.ly/2STKKZ1

Is Metabolic Acidosis a Friend or Foe for Cardiovascular Disease in Kidney Transplant Recipients?

Metabolic acidosis, typically inferred from serum total carbon dioxide (tCO2) measurements, has emerged as a potentially modifiable determinant for a number of clinical outcomes. Low tCO2 levels are independently associated with chronic kidney disease (CKD) progression, incident functional limitation, poorer global cognition, and the development or exacerbation of bone disease.1-4 Supporting the notion that metabolic acidosis plays a causal role in these clinical outcomes, bicarbonate supplementation has been suggested to slow CKD progression, including progression to end-stage kidney disease, among patients with low tCO2 levels in small single-center interventional studies.

http://bit.ly/2N7inkN

Quantification of Complications of Tunneled Hemodialysis Catheters

Tunneled central venous catheters (CVCs) are widely regarded as a suboptimal form of vascular access for hemodialysis (HD), when compared with arteriovenous fistulas (AVFs) or grafts (AVGs).1 Nevertheless, CVCs are frequently used in patients who do not yet have an AVF or AVG suitable for dialysis or those who have exhausted all options for a permanent access. CVC use for HD varies greatly among countries.2 In the United States, a CVC is used in approximately 70% to 80% of patients initiating HD therapy and 15% to 20% of prevalent patients.

http://bit.ly/2SUyY0k

Elective Naloxone-Induced Opioid Withdrawal for Rapid Initiation of Medication-Assisted Treatment of Opioid Use Disorder

We present a case of elective naloxone-induced opioid withdrawal followed by buprenorphine rescue to initiate opioid use disorder treatment in the emergency department. This strategy may represent a safe alternative to prescribing buprenorphine for outpatient initiation, a method that puts the patient at risk for complications of unmonitored opioid withdrawal, including relapse. After confirmation that the naloxone-induced withdrawal was adequately treated with buprenorphine, the patient was discharged with prescribed buprenorphine to follow up in an addiction medicine clinic, where he was treated 2 days later.

http://bit.ly/2IcOHDS

Transesophageal Echocardiography During Cardiopulmonary Resuscitation Is Associated With Shorter Compression Pauses Compared With Transthoracic Echocardiography

Point-of-care ultrasonography provides diagnostic information in addition to visual pulse checks during cardiopulmonary resuscitation (CPR). The most commonly used modality, transthoracic echocardiography, has unfortunately been repeatedly associated with prolonged pauses in chest compressions, which correlate with worsened neurologic outcomes. Unlike transthoracic echocardiography, transesophageal echocardiography does not require cessation of compressions for adequate imaging and provides the diagnostic benefit of point-of-care ultrasonography.

http://bit.ly/2IdH7sW

What Is the Diagnostic Accuracy of Point-of-Care Ultrasonography in Patients With Suspected Blunt Thoracoabdominal Trauma?

Authors included 34 studies (8,635 patients) from an initial 2,872 publications. The setting for half of the studies was the United States. Twenty-two studies were prospective, 10 were retrospective, 1 was cross-sectional, and 1 was a cross-sectional validation study. Ten studies included only pediatric and adolescent patients, 2 included only adults, and 22 enrolled patients of all ages. Four studies evaluated thoracic trauma only. CT was the reference standard in 25 studies, and 7 studies used a combination of CT and laparotomy.

http://bit.ly/2EaKHju

Do Antibiotics Improve Patient Outcomes in Acute Exacerbations of Chronic Obstructive Pulmonary Disease?

Authors included 19 randomized controlled trials (11 outpatient, 7 inpatient, and 1 ICU) comprising 2,663 patients. Sample sizes ranged from 19 to 310 patients. Studies used amoxicillin-clavulanic acid, trimethoprim/sulfamethoxazole, doxycycline, levofloxacin, ciprofloxacin, piperacillin-sulbactam, amoxicillin, and penicillin, as well as several drugs not commonly used, such as oxytetracycline, tetracycline hydrochloride, cotrimoxazole, ofloxacin, chloramphenicol, streptomycin, and cefaclor. Low-quality evidence suggested current antibiotics reduced risk of treatment failure for patients with mild to moderate exacerbation who were treated as outpatients, with an absolute reduction approaching 8.3% (Table). Antibiotics for inpatients did not display statistically significant results, but trends suggested benefit in treatment failure (11% absolute reduction).

http://bit.ly/2EbyD1u

Breath Collection from Children for Disease Biomarker Discovery

This protocol describes a simple method for the acquisition of breath samples from children. Briefly, samples of mixed air are pre-concentrated in sorbent tubes prior to gas chromatography-mass spectrometry analysis. Breath biomarkers of infectious and non-infectious diseases can be identified using this breath collection method.

http://bit.ly/2Io9Ue6

Separation of Spinach Thylakoid Protein Complexes by Native Green Gel Electrophoresis and Band Characterization using Time-Correlated Single Photon Counting

Here we present a protocol to separate solubilized thylakoid complexes by Native Green Gel electrophoresis. Green gel bands are subsequently characterized by Time Correlated Single Photon Counting (TCSPC) and basic steps for data analysis are provided.

http://bit.ly/2SBD8Lg

Medicare Patients With MS Face Higher Out-of-Pocket Rx Costs

THURSDAY, Feb. 14, 2019 -- Medicare patients with multiple sclerosis (MS) face increasing out-of-pocket costs for disease-modifying therapies, according to a study published in the February issue of Health Affairs. Daniel M. Hartung, Pharm.D.,...

http://bit.ly/2N5mg9J

Safety and Effectiveness of Ipragliflozin for Type 2 Diabetes in Japan: 12-Month Interim Results of the STELLA-LONG TERM Post-Marketing Surveillance Study

Abstract

Introduction

The present interim report of the STELLA-LONG TERM study aimed to examine the safety and effectiveness of ipragliflozin in real-word clinical practice in Japan using data up to 12 months. We also evaluated the effect of ipragliflozin on aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with normal vs. abnormal liver function.

Methods

This is an ongoing 3-year post-marketing surveillance study. We analyzed data from Japanese type 2 diabetes mellitus (T2DM) patients who were first prescribed ipragliflozin between 17 July 2014 and 16 October 2015 at participating centers in Japan, and whose data were locked by 16 January 2018. The incidence of adverse drug reactions (ADRs) was evaluated for safety. Changes in glycemic control and body weight were evaluated for effectiveness. The effect on liver function was evaluated by changes in the fatty liver index, and changes in AST and ALT were evaluated in patients with normal and abnormal liver function.

Results

The safety analysis set comprised 11,051 patients and the efficacy analysis set comprised 8788 patients. The incidence rates of ADRs and serious ADRs were 14.6% (1616/11,051) and 0.97% (107/11,051), respectively. Significant reductions (all P < 0.001 vs. baseline, paired t test) in glycated hemoglobin (− 0.8%), fasting plasma glucose (− 31.9 mg/dL), body weight (− 2.9 kg), and fatty liver index (− 8.7) were observed. In patients with normal liver function at baseline, no clinically significant changes in AST and ALT were observed. In patients with abnormal liver function at baseline, clinically and statistically significant decreases (P < 0.05 vs. baseline, two-sample t test) in AST (− 9.0 U/L) and ALT (− 14.7 U/L) levels were observed.

Conclusion

Ipragliflozin was effective and well tolerated in Japanese patients with T2DM over 12 months in the real-world clinical setting. Improvements in liver function parameters (AST and ALT) were observed in T2DM patients with abnormal liver function.

Trial Registration

ClinicalTrials.gov identifier, NCT02479399.

Funding

Astellas Pharma Inc., Japan.

http://bit.ly/2GIvfNa