Cross-cueing cannot explain unified control in split-brain patients

Sir,

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WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells

Abstract

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.

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Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation

Sir,

http://ift.tt/2y741sP

Evidence-Based Guidelines for Interface Design for Data Entry in Electronic Health Records.

Electronic health records use a variety of data entry methods that are often customized to clinician needs. Data entry interfaces must be appropriately designed to maximize benefits and minimize unintended consequences. There was relatively little evidence in the literature to guide the selection of specific data entry methods according to the type of data documented. This literature review summarizes existing data entry design recommendations to guide data entry interface design. Structured data entry uses predefined charting elements to limit acceptable data entry to standard coded data and improve completeness and data reuse at the expense of correctness. Unstructured data entry methods use natural language and improve correctness, at the expense of completeness and data reusability. Semistructured data entry uses a combination of these data entry methods to complement the strengths and minimize the weaknesses of each method. Documentation quality is influenced by the method of data entry. It is important to choose data entry methods based on the type of data to be documented. This literature review summarizes data entry design guidelines to inform clinical practice and future research. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Molecular profile of atypical hyperplasia of the breast

Abstract

Purpose

Atypical ductal and atypical lobular hyperplasia (AH) of the breast are important proliferative lesions which are associated with a significantly increased risk for breast cancer. The breast cancer which develops in association with AH may occur synchronously, representing local progression, or metachronously at a later date in either the ipsilateral or contralateral breast. These high-risk characteristics of AH suggest they contain significant genomic changes.

Methods

To define the genomic changes in AH, a comprehensive review of the literature was conducted to identify the numerical chromosomal and structural chromosomal changes, DNA methylation, and gene expression abnormalities in atypical ductal and atypical lobular hyperplasia.

Results

AHs are characterized by advanced genomic changes including aneuploidy, loss of heterozygosity, gross chromosomal rearrangements such as amplifications and large-scale deletions, DNA methylation of tumor suppressor and other genes, and gene expression differences between AH and surrounding normal breast tissue including significant estrogen receptor expression. Many of these changes are shared by an associated synchronous breast cancer, consistent with an important precursor role for AH. At the same time, many of the genomic changes of AHs are also shared by common sporadic breast cancer, consistent with a high risk for future development of metachronous breast cancer.

Conclusions

This molecular profile should help clarify the genomic characteristics and malignant predisposition of AH, and aid in the identification of new targets for the prevention of breast cancer

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Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients

Abstract

Purpose

Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility.

Methods

In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O).

Results

The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial β-oxidation and ATP production (P = 4.16 × 10⁻⁴) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10⁻³). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10⁻⁴, 95% CI 2.83–28.6).

Conclusions

We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

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Early tumor shrinkage indicates a favorable response to bevacizumab-based first-line chemotherapy for metastatic colorectal cancer.

A close correlation between early tumor shrinkage (ETS) and overall survival (OS) has been shown in antiepidermal growth factor receptor antibody-based chemotherapies for metastatic colorectal cancer (mCRC), but the clinical impact of ETS in bevacizumab-based chemotherapy has not been adequately clarified. Clinical data of mCRC patients who started initial chemotherapy without antiepidermal growth factor receptor antibody from 2005 to 2010 were retrospectively evaluated. The relative change in tumor size after 8 weeks of chemotherapy expected from the first image assessment [estimated ETS (EETS)] and the relative change in the tumor size at the nadir compared with the baseline [depth of response (DPR)] were examined. Seventy-three patients were enrolled and 61 patients were evaluable for survival by simple regression analysis. Bevacizumab-based chemotherapies were administered to 40 (66%) patients. The median EETS, DPR, progression-free survival, and OS were 16.1%, 27.2%, 8.0 months, and 19.5 months, respectively. Progression-free survival showed a positive correlation with OS (R2=0.429), whereas EETS and DPR were less correlated with OS (R2=0.0682, 0.186). EETS was well correlated with DPR (R2=0.659). Patients with EETS greater than 16.12% were predicted to achieve tumor shrinkage of more than 30% at the maximum response. EETS in bevacizumab-treated mCRC showed a close correlation with DPR, which suggested that EETS might be useful, indicating a favorable response in treatment with bevacizumab-based chemotherapy. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Corticosteroids as co-analgesics with opioids for cancer related pain: A feasibility study

Corticosteroids as co-analgesics with opioids for cancer related pain: A feasibility study

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The effects of climate, catchment land use and local factors on the abundance and community structure of sediment ammonia-oxidizing microorganisms in Yangtze lakes

Ammonia-oxidizing archaea (AOA) and bacteria (AOB) play important roles in regulating the nitrification process in lake ecosystems. However, the relative effects of climate, catchment land use and local condit...

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Genetic algorithm with a crossover elitist preservation mechanism for protein–ligand docking

Protein–ligand docking plays an important role in computer-aided pharmaceutical development. Protein–ligand docking can be defined as a search algorithm with a scoring function, whose aim is to determine the c...

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Study on the removal and transport and migration mechanism for As with activated sludge system

In this paper, the removal of As and the transport and migration of As at the process of activated sludge system was studied. The results showed that the activated sludge system has high removal efficiency for...

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A novel diagnostic method for malaria using loop-mediated isothermal amplification (LAMP) and MinION™ nanopore sequencer

A simple and accurate molecular diagnostic method for malaria is urgently needed due to the limitations of conventional microscopic examination. In this study, we demonstrate a new diagnostic procedure for hum...

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Routine monitoring and assessment of adults living with HIV: results of the British HIV Association (BHIVA) national audit 2015

The clinical care of people living with HIV changed fundamentally as a result of the development of effective antiretroviral therapy (ART). HIV infection is now a long-term treatable condition. We report a nat...

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Factors associated with syphilis treatment failure and reinfection: a longitudinal cohort study in Shenzhen, China

The treatment failure and reinfection rates among syphilis patients are high, and relevant studies in China are limited. The aim of this study was to detect the rates of treatment failure and reinfection after...

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Tumor Biology and Response to Chemotherapy Impact Breast Cancer-specific Survival in Node-positive Breast Cancer Patients Treated With Neoadjuvant Chemotherapy: Long-term Follow-up From ACOSOG Z1071 (Alliance)

Background: Women with node-positive breast cancer are at high risk for recurrence. We evaluate the impact of approximated tumor subtype and response to chemotherapy on long-term outcomes in a node-positive cohort receiving neoadjuvant chemotherapy. Methods: ACOSOG Z1071 enrolled cT0-4N1-2 breast cancer patients treated with neoadjuvant chemotherapy from 2009 to 2011. Factors impacting breast cancer-specific survival (BCSS) and overall survival (OS) were analyzed. Results: Median follow-up of 701 eligible patients was 4.1 years (0.4–6.5). Ninety patients (12.8%) died from breast cancer. Approximated subtype and chemotherapy response were significantly associated with BCSS and OS (P 95% in HER2-positive disease independent of chemotherapy response.

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Failure to Diagnose Hyperparathyroidism in 10,432 Patients With Hypercalcemia: Opportunities for System-level Intervention to Increase Surgical Referrals and Cure

Objective: To determine whether a significant number of patients with hyperparathyroidism remain undiagnosed and untreated. Background: Failure to diagnose primary hyperparathyroidism and refer patients to surgeons leads to impaired quality of life and increased costs. We hypothesized that many patients with hyperparathyroidism would be untreated due to not considering the diagnosis, inadequate evaluation of hypercalcemia, and under-referral to surgeons. Methods: We reviewed administrative data on 682,704 patients from a tertiary referral center between 2011 and 2015, and identified hypercalcemia (>10.5 mg/dL) in 10,432 patients. We evaluated whether hypercalcemic patients underwent measurement of parathyroid hormone (PTH), had documentation of hypercalcemia/hyperparathyroidism, or were referred to surgeons. Results: The mean age of our cohort was 54 years, with 61% females, and 56% whites. Only 3200 (31%) hypercalcemic patients had PTH levels measured, 2914 (28%) had a documented diagnosis of hypercalcemia, and 880 (8%) had a diagnosis of hyperparathyroidism in the medical record. Only 592 (22%) out of 2666 patients with classic hyperparathyroidism (abnormal calcium and PTH) were referred to surgeons. Conclusions: A significant proportion of patients with hyperparathyroidism do not undergo appropriate evaluation and surgical referral. System-level interventions which prompt further evaluation of hypercalcemia and raise physician awareness about hyperparathyroidism could improve outcomes and produce long-term cost savings.

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American Surgical Association Presidential Forum: A Lifetime of Surgical Education: Can We Do better?

No abstract available

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Wide Variation and Overprescription of Opioids After Elective Surgery

Objective: We aimed to identify opioid prescribing practices across surgical specialties and institutions. Background: In an effort to minimize the contribution of prescription narcotics to the nationwide opioid epidemic, reductions in postoperative opioid prescribing have been proposed. It has been suggested that a maximum of 7 days, or 200 mg oral morphine equivalents (OME), should be prescribed at discharge in opioid-naïve patients. Methods: Adults undergoing 25 common elective procedures from 2013 to 2015 were identified from American College of Surgeons National Surgical Quality Improvement Program data from 3 academic centers in Minnesota, Arizona, and Florida. Opioids prescribed at discharge were abstracted from pharmacy data and converted into OME. Wilcoxon Rank-Sum and Kruskal-Wallis tests assessed variations. Results: Of 7651 patients, 93.9% received opioid prescriptions at discharge. Of 7181 patients who received opioid prescriptions, a median of 375 OME (interquartile range 225–750) were prescribed. Median OME varied by sex (375 men vs 390 women, P = 0.002) and increased with age (375 age 18–39 to 425 age 80+, P 200 OME (80.9%). Significant variations in opioid prescribing practices were seen within each procedure and between the 3 medical centers. Conclusions: The majority of patients were overprescribed opioids. Significant prescribing variation exists that was not explained by patient factors. These data will guide practices to optimize opioid prescribing after surgery.

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Individualized Metabolic Surgery Score: Procedure Selection Based on Diabetes Severity

Objective: To construct and validate a scoring system for evidence-based selection of bariatric and metabolic surgery procedures according to severity of type 2 diabetes (T2DM). Background: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) account for >95% of bariatric procedures in United States in patients with T2DM. To date, there is no validated model to guide procedure selection based on long-term glucose control in patients with T2DM. Methods: A total of 659 patients with T2DM who underwent RYGB and SG at an academic center in the United States and had a minimum 5-year follow-up (2005–2011) were analyzed to generate the model. The validation dataset consisted of 241 patients from an academic center in Spain where similar criteria were applied. Results: At median postoperative follow-up of 7 years (range 5–12), diabetes remission (HbA1C 95), when clinical features suggest limited functional β-cell reserve, both procedures had similarly low efficacy for diabetes remission. There was an intermediate group, however, in which RYGB was significantly more effective than SG, likely related to its more pronounced neurohormonal effects. Findings were externally validated and procedure recommendations for each severity stage were provided. Conclusions: This is the largest reported cohort (n = 900) with long-term postoperative glycemic follow-up, which, for the first time, categorizes T2DM into 3 validated severity stages for evidence-based procedure selection.

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Health-related Quality of Life and Functional Outcomes in 5-year Survivors After Pancreaticoduodenectomy

Objective: Our aim was to assess quality of life (QOL) and functionality in a large cohort of patients ≥5-years after pancreaticoduodenectomy (PD). Background: Long-term QOL outcomes after PD for benign or malignant disease are largely undocumented. Methods: We administered the EORTC QLQ-C30 questionnaire to patients who underwent PD for neoplasms from 1998 to 2011 and compared their scores with an age- and sex-matched normal population. Clinical relevance (CR) of differences was scored as small (5–10), moderate (10–20), or large (>20) based on validated interpretation of clinically important differences. Results: Of 305 PD survivors, 245 (80.3%) responded, of whom 157 (64.1%) underwent PD for nonmalignant lesions. Median follow-up was 9.1 years (range 5.1 –21.2 yrs). New-onset diabetes developed in 10.6%; 50.4% reported taking pancreatic enzymes; 54.6% reported needing antacids. Compared with the age- and sex-adjusted controls, PD survivors demonstrated higher global QOL (78.7 vs 69.7, CR small, P

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Readiness of US General Surgery Residents for Independent Practice

Objective: This study evaluates the current state of the General Surgery (GS) residency training model by investigating resident operative performance and autonomy. Background: The American Board of Surgery has designated 132 procedures as being "Core" to the practice of GS. GS residents are expected to be able to safely and independently perform those procedures by the time they graduate. There is growing concern that not all residents achieve that standard. Lack of operative autonomy may play a role. Methods: Attendings in 14 General Surgery programs were trained to use a) the 5-level System for Improving and Measuring Procedural Learning (SIMPL) Performance scale to assess resident readiness for independent practice and b) the 4-level Zwisch scale to assess the level of guidance (ie, autonomy) they provided to residents during specific procedures. Ratings were collected immediately after cases that involved a categorical GS resident. Data were analyzed using descriptive statistics and supplemented with Bayesian ordinal model-based estimation. Results: A total of 444 attending surgeons rated 536 categorical residents after 10,130 procedures. Performance: from the first to the last year of training, the proportion of Performance ratings for Core procedures (n = 6931) at "Practice Ready" or above increased from 12.3% to 77.1%. The predicted probability that a typical trainee would be rated as Competent after performing an average Core procedure on an average complexity patient during the last week of residency training is 90.5% (95% CI: 85.7%–94%). This falls to 84.6% for more complex patients and to less than 80% for more difficult Core procedures. Autonomy: for all procedures, the proportion of Zwisch ratings indicating meaningful autonomy ("Passive Help" or "Supervision Only") increased from 15.1% to 65.7% from the first to the last year of training. For the Core procedures performed by residents in their final 6 months of training (cholecystectomy, inguinal/femoral hernia repair, appendectomy, ventral hernia repair, and partial colectomy), the proportion of Zwisch ratings (n = 357) indicating near-independence ("Supervision Only") was 33.3%. Conclusions: US General Surgery residents are not universally ready to independently perform Core procedures by the time they complete residency training. Progressive resident autonomy is also limited. It is unknown if the amount of autonomy residents do achieve is sufficient to ensure readiness for the entire spectrum of independent practice.

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Surgical Management of Gallbladder Cancer: Simple Versus Extended Cholecystectomy and the Role of Adjuvant Therapy

Objective: To assess if simple cholecystectomy with adjuvant therapy could provide outcomes comparable to extended cholecystectomy. Background: Current guidelines recommend extended/radical cholecystectomy for T2/T3 gallbladder cancer; however, many tumors are discovered incidentally at laparoscopic cholecystectomy. Methods: The national Cancer Data Base 2004 to 2014 was queried for patients with pT2/T3 gallbladder adenocarcinoma who underwent resection. Adjuvant therapy was defined as chemotherapy, with or without radiotherapy, within 90 days of surgery. Baseline characteristics and overall survival were compared by χ2 and Kaplan-Meier method, respectively. One-to-one propensity score matching for receipt of adjuvant therapy was used to account for potential selection bias. Results: A total of 6825 patients were identified. Diagnosis was made predominantly (78.9%) at the time of surgery or on pathology; 31.8% (2168) received adjuvant therapy. The majority, 88.8% (6060), had a simple cholecystectomy. Patients who received adjuvant therapy versus surgery alone were more likely to: be younger, privately insured, have no comorbidities, pT3 disease, positive lymph nodes, positive resection margins, and extended cholecystectomy. After matching, median survival was significantly longer for extended cholecystectomy with adjuvant therapy (23.3 months) than cholecystectomy with adjuvant therapy (16.4 months), which was significantly longer than either simple (12.4 months) or extended (10.7 months) cholecystectomy alone (all log-rank P

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Transfusion Requirement in Burn Care Evaluation (TRIBE): A Multicenter Randomized Prospective Trial of Blood Transfusion in Major Burn Injury

Objective: Our objective was to compare outcomes of a restrictive to a liberal red cell transfusion strategy in 20% or more total body surface area (TBSA) burn patients. We hypothesized that the restrictive group would have less blood stream infection (BSI), organ dysfunction, and mortality. Background: Patients with major burns have major (>1 blood volume) transfusion requirements. Studies suggest that a restrictive blood transfusion strategy is equivalent to a liberal strategy. However, major burn injury is precluded from these studies. The optimal transfusion strategy in major burn injury is thus needed but remains unknown. Methods: This prospective randomized multicenter trial block randomized patients to a restrictive (hemoglobin 7–8 g/dL) or liberal (hemoglobin 10–11 g/dL) transfusion strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes. Results: Eighteen burn centers enrolled 345 patients with 20% or more TBSA burn similar in age, TBSA burn, and inhalation injury. A total of 7054 units blood were transfused. The restrictive group received fewer blood transfusions: mean 20.3 ± 32.7 units, median = 8 (interquartile range: 3, 24) versus mean 31.8 ± 44.3 units, median = 16 (interquartile range: 7, 40) in the liberal group (P 0.05) were similar. In addition, there was no 30-day mortality difference: 9.5% restrictive versus 8.5% liberal (P = 0.892, χ2 test). Conclusions: A restrictive transfusion strategy halved blood product utilization. Although the restrictive strategy did not decrease BSI, mortality, or organ dysfunction in major burn injury, these outcomes were no worse than the liberal strategy (Clinicaltrials.gov identifier NCT01079247).

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Anatomical Resections Improve Disease-free Survival in Patients With KRAS-mutated Colorectal Liver Metastases

Objective: To investigate the potential clinical advantage of anatomical resection versus nonanatomical resection for colorectal liver metastases, according to KRAS mutational status. Background: KRAS-mutated colorectal liver metastases (CRLM) are known to be more aggressive than KRAS wild-type tumors. Although nonanatomical liver resections have been demonstrated as a viable approach for CRLM patients with similar oncologic outcomes to anatomical resections, this may not be the case for the subset of KRAS-mutated CRLM. Methods: 389 patients who underwent hepatic resection of CRLM with known KRAS mutational status were identified. Survival estimates were calculated using the Kaplan-Meier method, and multivariable analysis was conducted using the Cox proportional hazards regression model. Results: In this study, 165 patients (42.4%) underwent nonanatomical resections and 140 (36.0%) presented with KRAS-mutated CRLM. Median disease-free survival (DFS) in the entire cohort was 21.3 months, whereas 1-, 3-, and 5-year DFS was 67.3%, 34.9%, and 31.5% respectively. Although there was no difference in DFS between anatomical and nonanatomical resections in patients with KRAS wild-type tumors (P = 0.142), a significant difference in favor of anatomical resection was observed in patients with a KRAS mutation (10.5 vs. 33.8 months; P

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Perception of Safety of Surgical Practice Among Operating Room Personnel From Survey Data Is Associated With All-cause 30-day Postoperative Death Rate in South Carolina

Objective: To evaluate whether the perception of safety of surgical practice among operating room (OR) personnel is associated with hospital-level 30-day postoperative death. Background: The relationship between improvements in the safety of surgical practice and benefits to postoperative outcomes has not been demonstrated empirically. Methods: As part of the Safe Surgery 2015: South Carolina initiative, a baseline survey measuring the perception of safety of surgical practice among OR personnel was completed. We evaluated the relationship between hospital-level mean item survey scores and rates of all-cause 30-day postoperative death using binomial regression. Models were controlled for multiple patient, hospital, and procedure covariates using supervised principal components regression. Results: The overall survey response rate was 38.1% (1793/4707) among 31 hospitals. For every 1 point increase in the hospital-level mean score for respect [adjusted relative risk (aRR) 0.78, 95% CI 0.65–0.93, P = 0.0059], clinical leadership (aRR 0.86, 95% CI 0.74–0.9932, P = 0.0401), and assertiveness (aRR 0.71, 95% CI 0.54–0.93, P = 0.01) among all survey respondents, there were associated decreases in the hospital-level 30-day postoperative death rate after inpatient surgery ranging from 14% to 29%. Higher hospital-level mean scores for the statement, "I would feel safe being treated here as a patient," were associated with significantly lower hospital-level 30-day postoperative death rates (aRR 0.83, 95% CI 0.70–0.97, P = 0.02). Although most findings seen among all OR personnel were seen among nurses, they were often absent among surgeons. Conclusions: Perception of OR safety of surgical practice was associated with hospital-level 30-day postoperative death rates.

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Understanding and Resetting Radiation Sensitivity in Rectal Cancer

Objective: The aim of the study was to explore specific microRNAs (miRs) in rectal cancer that would predict response to radiation and identify target pathways that may be exploited for neoadjuvant therapies. Summary Background Data: Chemoradiotherapy (CRT) response is a predictor of survival in rectal cancer. Studies have demonstrated changes in RNA expression correlate with chemoradiation sensitivity across cancers. Methods: Forty-five rectal cancer patients, partial responders (PR = 18), nonresponders (NR = 13), and complete responders (CR = 14) to CRT, as defined by a tumor regression score, were examined. miRs differentially expressed, using NanoString microArray profiling, were validated with qPCR. We quantified 1 miR and its downstream targets in patient samples. Chemosensitivity was measured in HCT-116, a human colorectal carcinoma cell line, using inhibitors of SHP2 and RAF. Results: miR-451a, 502-5p, 223-3p, and 1246 were the most upregulated miRs (>1.5-fold change) in a NanoString profiling miR panel. qPCR revealed a decrease in expression of miR-451a in NRs. EMSY and CAB39, both downstream targets of miR-451a and involved in carcinogenesis (shown in TCGA) were increased in NRs (qPCR). Both targets are associated with worse survival in colorectal cancer. Inhibition of miR-451a in HCT-116 cells significantly decreased cell proliferation with treatment of SHP2 and RAF inhibitors. Conclusions: An integrated analysis of rectal cancer miRs may yield biomarkers of radioresistance and offer treatment targets for resensitization.

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Molecular Adsorbent Recirculating System Effectively Replaces Hepatic Function in Severe Acute Liver Failure

Summary Background Data: Patients with severe acute liver failure (ALF) have extreme physiologic dysfunction and often die if transplantation is not immediately available. Patients may be supported with MARS (Baxter International Inc., Deerfield, IL) until transplantation or spontaneous recovery occurs. We present the largest series in the United States of MARS therapy as temporary hepatic replacement for ALF. Methods: MARS was used to support patients with severe liver trauma (SLT), in ALF patients as a bridge to transplantation (BTT), and as definitive therapy for toxic ingestion or idiopathic liver failure (DT) in a level 1 trauma center and large transplant center. Patient demographics, etiology of ALF, and laboratory values were recorded. Endpoints were patient survival ± liver transplant and/or recovery of liver function. Results: Twenty-seven patients with severe ALF received MARS therapy. Five patients with SLT had a 60% survival with recovery of liver and renal function. Thirteen patients received MARS as a BTT, of which 9 were transplanted with a 1-year survival of 78% (program overall survival 85% at 1 year). All 4 who were not transplanted expired. Nine patients with ALF from toxic ingestion received MARS as DT with liver recovery and survival in 67%. MARS therapy resulted in significant improvement in liver function, coagulation, incidence of encephalopathy, and creatinine. Conclusions: MARS therapy successfully replaced hepatic function in ALF allowing time for spontaneous recovery or transplantation. Spontaneous recovery was remarkably common if support can be sustained.

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Impact of the Hospital Readmission Reduction Program on Surgical Readmissions Among Medicare Beneficiaries

Objective: To understand the impact of the Hospital Readmission Reduction Program on both future targeted and nontargeted surgical procedures. Background: The Hospital Readmission Reduction Program, established under the Affordable Care Act in March of 2010, placed financial penalties on hospitals with higher than expected rates of readmission beginning in 2012 for targeted medical conditions. Multiple studies have suggested a "spill-over" effect into other conditions, but the extent of that effect for specific surgical procedures is unknown. Methods: A retrospective review 5,122,240 Medicare beneficiaries who underwent future targeted procedures (total hip replacement, total knee replacements) or nontargeted procedures (colectomy, lung resection, abdominal aortic aneurysm repair, coronary artery bypass graft, aortic valve replacement, mitral valve repair) using an interrupted time series model to assess the rates of readmission before the Hospital Readmission Reduction Program was announced (2008–2010), whereas the program was being implemented (2010–2012) and after penalties were initiated (2012–2014). We also explored if the change in readmission rates were correlated with changes in index length of stay, use of observation status, or discharge to a skilled nursing facility. Results: From 2008 to 2014 rates of readmission declined for both target conditions (6.8%–4.8%; slope change −0.07 to −0.10, P

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Prediction of Hepatocellular Carcinoma Recurrence Beyond Milan Criteria After Resection: Validation of a Clinical Risk Score in an International Cohort

Objective: This study aims to validate a previously reported recurrence clinical risk score (CRS). Summary of Background Data: Salvage transplantation after hepatocellular carcinoma (HCC) resection is limited to patients who recur within Milan criteria (MC). Predicting recurrence patterns may guide treatment recommendations. Methods: An international, multicenter cohort of R0 resected HCC patients were categorized by MC status at presentation. CRS was calculated by assigning 1 point each for initial disease beyond MC, multinodularity, and microvascular invasion. Recurrence incidences were estimated using competing risks methodology, and conditional recurrence probabilities were estimated using the Bayes theorem. Results: From 1992 to 2015, 1023 patients were identified, of whom 613 (60%) recurred at a median follow-up of 50 months. CRS was well validated in that all 3 factors remained independent predictors of recurrence beyond MC (hazard ratio 1.5–2.1, all P

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Weight gain in hormone receptor-positive (HR+) early-stage breast cancer: is it menopausal status or something else?

Abstract

Purpose

This study investigates weight trajectories in pre- versus postmenopausal breast cancer (BC) survivors diagnosed with hormone receptor-positive tumors, with a specific focus on discerning menopausal status and type of endocrine treatment (ET) as risk factors for weight gain during ET.

Methods

We conducted a retrospective review of electronic medical records. Descriptive statistics and Chi-squared and t tests were used to compare pre- and postmenopausal women. Chi-squared tests and ANOVA were used for within-group associations between patient characteristics and weight trajectories. Log-binomial regression models were used to estimate relative risk for weight gain.

Results

The final sample was 32% premenopausal (n = 140) and 68% postmenopausal (n = 298). Relative risk (RR) for weight gain during ET was highest in women who were premenopausal (RR = 1.29, 1.03–1.52) and had Stage 3 BC (RR = 2.12, 1.59–2.82), mastectomy (RR = 1.49, 1.19–1.88), axillary node dissection (RR = 1.39, 1.11–1.73), and chemotherapy (RR = 1.80, 1.37–2.36). For each kg of weight gained between BC diagnosis and start of ET, and for each additional year of age, RR of gaining weight during ET decreased (RR = 0.98, 0.97–0.99, and RR = 0.99, 0.98–0.99, respectively). Menopausal status and type of ET were not significant predictors of weight gain. In multivariable analysis, only weight loss between BC diagnosis and start of ET was significant.

Conclusion

The association of weight loss prior to ET and subsequent substantial weight gain during ET warrants further investigation.

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Evaluation of delivery costs for external beam radiation therapy and brachytherapy for locally advanced cervical cancer using time-driven activity-based costing

Time-driven activity-based costing methodology was applied to calculate the delivery costs of definitive radiation therapy for locally advanced cervical cancer. Brachytherapy was more costly and consumed more attending radiation oncologist time than external beam radiation therapy. Comparison of the delivery costs and physician time requirements to current reimbursement revealed a financial disincentive against brachytherapy, which should be studied as a potential contributor to the reported national poor compliance rates for cervical cancer brachytherapy.

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Bowel Dilation Diagnosed Prenatally

A 29-year-old woman gravida 2 para 2 was referred at 22 weeks of gestation following the observation of dilated fetal bowel loops and polyhydramnios. First trimester fetal ultrasound was normal. There was no history of drug ingestion or radiography exposure. No familial history or consanguinity was noted.

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Lidocaine Gel for Urethral Catheterization in Children: A Meta-Analysis

To compare the efficacy and safety of lidocaine gel vs nonanesthetic gel (NAG) in reducing transurethral bladder catheterization (TUBC) procedural pain in children.

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“Striatal Toe Sign”: False-Positive “Extensor Plantar Response” in Dystonia

Plantar response is a nociceptive protective reflex elicited classically by the Babinski method. This method involves stimulation of the sole from the posterolateral aspect, advancing forward and medially up to the ball of the great toe. A normal response would be flexor, in which all the toes including the great toe flex.1 The abnormal response is termed as "extensor toe sign," which is characterized by extension of the great toe and fanning of all other toes. This abnormal response is seen in presence of corticospinal (pyramidal tract) dysfunction as a result of either physiologic immaturity in infancy or pathology of the tract (upper motor neuron), anywhere from the motor cortex to the spinal cord anterior horn cell level.

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21st Surgical Research Days. Section of Surgical Research of the German Society of Surgery. September 21-23, 2017, Cologne, Germany: Abstracts

Eur Surg Res 2017;58:275-328

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Introduction to special section on digital technology and cancer survivorship

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Eribulin in advanced breast cancer: safety, efficacy and new perspectives

Future Oncology, Ahead of Print.


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Mapping Loci That Control Tuber and Foliar Symptoms Caused by PVY in Autotetraploid Potato (Solanum tuberosum L.)

Potato tuber necrotic ringspot disease (PTNRD) is a tuber deformity associated with infection by the tuber necrotic strain of Potato virus Y (PVY^NTN). PTNRD negatively impacts tuber quality and marketability and poses a serious threat to seed and commercial potato production worldwide. PVY^NTN symptoms differ in the cultivars Waneta and Pike: Waneta expresses severe PTNRD and foliar mosaic with vein and leaf necrosis, whereas Pike does not express PTNRD and mosaic is the only foliar symptom. To map loci that influence tuber and foliar symptoms, 236 F₁ progeny of a cross between Waneta and Pike were inoculated with PVY^NTN isolate NY090029 and genotyped using 12,808 Potato SNPs. Foliar symptom type and severity were monitored for 10 weeks, while tubers were evaluated for PTNRD expression at harvest and again after 60 days in storage. Pairwise correlation analyses indicate a strong association between PTNRD and vein necrosis ( = 0.4195). QTL analyses revealed major-effect QTLs on chromosomes 4 and 5 for mosaic, 4 for PTNRD, and 5 for foliar-necrosis symptoms. Locating QTLs associated with PVY-related symptoms provides a foundation for breeders to develop markers that can be used to screen out potato clones with undesirable phenotypes, e.g., those likely to develop PTNRD or to be symptomless carriers of PVY.

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Serotonin Drives Predatory Feeding Behavior via Synchronous Feeding Rhythms in the Nematode Pristionchus pacificus

Feeding behaviors in a wide range of animals are regulated by the neurotransmitter serotonin, although the exact neural circuits and associated mechanism are often unknown. The nematode Pristionchus pacificus can kill other nematodes by opening prey cuticles with movable teeth. Previous studies showed that exogenous serotonin treatment induces a predatory-like tooth movement and slower pharyngeal pumping in the absence of prey, however, physiological functions of serotonin during predation and other behaviors in P. pacificus remained completely unknown. Here, we investigate the roles of serotonin by generating mutations in Ppa-tph-1 and Ppa-bas-1, two key serotonin biosynthesis enzymes and by genetic ablation of pharynx-associated serotonergic neurons. Mutations in Ppa-tph-1 reduced the pharyngeal pumping rate during bacterial feeding compared to wild type. Moreover, the loss of serotonin or a subset of serotonergic neurons decreased the success of predation, but did not abolish the predatory feeding behavior completely. Detailed analysis using high-speed camera revealed that the elimination of serotonin or the serotonergic neurons disrupted the timing and coordination of predatory tooth movement and pharyngeal pumping. This loss of synchrony significantly reduced the efficiency of successful predation events. These results suggest that serotonin has a conserved role in bacterial feeding and in addition drives the feeding rhythm of predatory behavior in Pristionchus.

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Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy

In 2010, 5-year-old Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL). Though her parents were told that if you had to have a kid with cancer, ALL was the best one to have, Emily's course was hardly typical. After two rounds of chemotherapy, necrotizing fasciitis developed in…

http://ift.tt/2f6EM56

PD-1 status in CD8+ T cells associates with survival and anti-PD-1 therapeutic outcomes in head and neck cancer

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV- patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

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ANGPTL1 interacts with integrin {alpha}1{beta}1 to suppress HCC angiogenesis and metastasis by inhibiting JAK2/STAT3 signaling

Downregulation of tumor suppressor signaling plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). Here we report that downregulation of the angiopoietin-like protein ANGPTL1 is associated with vascular invasion, tumor thrombus, metastasis and poor prognosis in HCC. Ectopic expression of ANGPTL1 in HCC cells effectively decreased their in vitro and in vivo tumorigenicity, cell motility and angiogenesis. shRNA-mediated depletion of ANGPTL1 exerted opposing effects. ANGPTL1 promoted apoptosis via inhibition of the STAT3/Bcl-2 mediated anti-apoptotic pathway and decreased cell migration and invasion via downregulation of transcription factors SNAIL and SLUG. Furthermore, ANGPTL1 inhibited angiogenesis by attenuating ERK and AKT signaling and interacted with integrin α1β1 receptor to suppress the downstream FAK/Src-JAK-STAT3 signaling pathway. Taken together, these results suggest ANGPTL1 as a prognostic biomarker and novel therapeutic agent in HCC.

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Structurally novel antiestrogens elicit differential responses from constitutively active mutant estrogen receptors in breast cancer cells and tumors

Many ERα-positive breast cancers develop resistance to endocrine therapy via mutation of estrogen receptors (ER) whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ER, we describe here our development and characterization of three chemically novel AE that effectively suppress proliferation of breast cancer cells and tumors. Our AE are effective against wild type and Y537S and D538G ER, the two most commonly occurring constitutively active ER. The 3 new AE suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared to WT ER, mutants exhibited ~10 to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER-containing MCF7 and T47D cells revealed that AE responses were compound, cell-type and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER-expressing tumor xenografts in NOD/SCID-gamma mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ER to different AE and make clear the value of having a toolkit of AE for treatment of endocrine therapy-resistant tumors driven by different constitutively active ER.

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Anti-Jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance.

Myeloid-derived suppressor cells (MDSCs) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti-Jagged1/2 blocking antibody CTX014 on MDSC-mediated T cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, impacted the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T cell tolerance, increased the infiltration of reactive CD8+ T-cells into tumors, and enhanced the efficacy of T cell-based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas co-injection of MDSC-like cells from anti-Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy.

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Optical coherence tomography detects necrotic regions and volumetrically quantifies multicellular tumor spheroids

Three-dimensional (3D) tumor spheroid models have gained increased recognition as important tools in cancer research and anti-cancer drug development. However, currently available imaging approaches employed in high-throughput screening drug discovery platforms e.g. bright field, phase contrast, and fluorescence microscopies, are unable to resolve 3D structures deep inside (>50 μm) tumor spheroids. In this study, we established a label-free, non-invasive optical coherence tomography (OCT) imaging platform to characterize 3D morphological and physiological information of multicellular tumor spheroids (MCTS) growing from ~250 μm up to ~600 μm in height over 21 days. In particular, tumor spheroids of two cell lines glioblastoma (U-87 MG) and colorectal carcinoma (HCT 116) exhibited distinctive evolutions in their geometric shapes at late growth stages. Volumes of MCTS were accurately quantified using a voxel-based approach without presumptions of their geometries. In contrast, conventional diameter-based volume calculations assuming perfect spherical shape resulted in large quantification errors. Furthermore, we successfully detected necrotic regions within these tumor spheroids based on increased intrinsic optical attenuation, suggesting a promising alternative of label-free viability tests in tumor spheroids. Therefore, OCT can serve as a promising imaging modality to characterize morphological and physiological features of MCTS, showing great potential for high-throughput drug screening.

http://ift.tt/2jqZzlr

Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency

Mismatch repair (MMR)–deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 1–8. ©2017 AACR.

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Liquid Biopsy Technique May Allow Early Screening [News in Brief]

Method detects mutations in small amounts of tumor DNA present in early-stage cancer.

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Obesity modulates diaphragm curvature in subjects with and without COPD

Background: Obesity is a common co-morbidity of COPD and has been associated with worse outcomes. However, it is unknown whether the interaction between obesity and COPD modulates diaphragm shape and consequently its function. The body mass index has been used as a correlate of obesity. We tested the hypothesis that the shape of the diaphragm muscle and size of the ring of its insertion in Non-COPD and COPD subjects are modulated by BMI. Methods: We recruited 48 COPD patients with post-bronchiodilator FEV1/FVC < 0.7 and 29 age-matched smoker/ex-smoker control (Non-COPD) subjects, who underwent chest CT at lung volumes ranging from FRC to TLC. We then computed maximum principle diaphragm curvature in the midcostal region of the left hemidiaphragm at end of inspiration during quiet breathing (EI) and at total lung capacity (TLC). Results: The radius of maximum curvature of diaphragm muscle increased with BMI in both COPD and Non-COPD subjects. The size of diaphragm ring of insertion on the chest wall also increased significantly with increasing BMI. Surprisingly, COPD severity did not appear to cause significant alteration in diaphragm shape except in normal weight subjects at TLC. Conclusion: Our data uncovered important factors such as BMI, the size of the diaphragm ring of insertion, and disease severity that modulate the structure of the ventilatory pump in Non-COPD and COPD subjects.

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Long-term treatment with the ghrelin receptor antagonist, [D-Lys3]-GHRP-6 does not improve glucose homeostasis in non-obese diabetic MKR mice

Ghrelin secretion has been associated with increased caloric intake and adiposity. The expressions of ghrelin and its receptor (GHS-R1a) in pancreas have raised the interest about the role of ghrelin in glucose homeostasis. Most of the studies showed that ghrelin promoted hyperglycaemia and inhibited insulin secretion. This raised the interest in using GHS-R1a antagonists as therapeutic targets for type 2 diabetes. Available data of GHS-R antagonists are on a short-term basis. Moreover, the complexity of GHS-R1a signalling makes it difficult to understand the mechanism of action of GHS-R1a antagonists. This study examined the possible effects of long-term treatment with a GHS-R1a antagonist, [D-Lys3]-GHRP-6 on glucose homeostasis, food intake and indirect calorimetric parameters in non-obese diabetic MKR mice. Our results showed that [D-Lys3]-GHRP-6 (200nmol/mouse), reduced pulsatile growth hormone secretion and body fat mass as expected, but worsened glucose and insulin intolerances and increased cumulative food intake unexpectedly. In addition, a significant increase in blood glucose and decreases in plasma insulin and c-peptide levels were observed in MKR mice following long-term [D-Lys3]-GHRP-6 treatment, suggested a direct inhibition of insulin secretion. Immunofluorescence staining of pancreatic islets showed a proportional increase in somatostatin positive cells and a decrease in insulin positive cells in [D-Lys3]-GHRP-6 treated mice. Furthermore, [D-Lys3]-GHRP-6 stimulated food intake on long-term treatment via reduction of POMC gene expression and antagonized GH secretion via reduced GHRH gene expression in hypothalamus. These results demonstrate that [D-Lys3]-GHRP-6 is not completely opposite to ghrelin and may not be a treatment option for type 2 diabetes.

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Advances in Nanoparticles Vol.6,No.3 (August 2017)

Nanotechnology in Diagnosis: A Review
Nanodiagnostics, Biosensors, Microelectromechanical Systems
Paper Information Full Paper: PDF (Size:584KB)
DOI: 10.4236/anp.2017.63008

Interaction of Immune System Protein with PEGylated and Un-PEGylated Polymeric Nanoparticles
Nanoparticles, Mannose-Binding Protein, Poly (L-Lactic-Co-Glycolic Acid), Nanoparticle Protein Interaction
Paper Information Full Paper: PDF (Size:696KB)
DOI: 10.4236/anp.2017.63009

Boosted Photoactivity of Titania Nanotube Layers Doped with a Suspension of Gold Nanoparticles
Gold Nanoparticle, TiO₂-NT, Photocurrent, Photodegradation
Paper Information Full Paper: PDF (Size:3076KB)
DOI: 10.4236/anp.2017.63010

Comparative Study of the Silver Nano-/Microstructures Deposited from Aerosol and Fog
Aerosol, Fog, Silver, Deposition, Janus-Nanoparticle, Fractal Aggregate
Paper Information Full Paper: PDF (Size:1609KB)
DOI: 10.4236/anp.2017.63011

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Dreams Deferred — The Public Health Consequences of Rescinding DACA

After months of conflicting statements, President Donald Trump has announced that the Deferred Action for Childhood Arrivals (DACA) program, a landmark immigration program introduced during the Obama administration, will be rescinded as of March 2018. The announcement was made in the face of…

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Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy

In 2010, 5-year-old Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL). Though her parents were told that if you had to have a kid with cancer, ALL was the best one to have, Emily's course was hardly typical. After two rounds of chemotherapy, necrotizing fasciitis developed in…

http://ift.tt/2f6EM56

Serum 8-hydroxydeoxyguanosine and aldose reductase C-106T polymorphism in type 2 diabetes mellitus and its relation to complications in Egyptian patients

Abstract

Diabetes mellitus (DM) is an inherited disease, which can affect every organ in the body. 8-hydroxydeoxyguanosine (8-OHdG) is a biomarker for oxidative DNA damage. Occurrence of C-106T polymorphism of the aldose reductase (ALR) gene in type II diabetic patients suffering from diabetic microvascular complications has been reported. The aim of the present work was to assess the association between oxidative stress and C(-106)T ALR gene polymorphism and the incident of type 2 diabetes (T2D) and its complications. The current study was conducted on 200 subjects classified into 150 T2D patients and 50 healthy control subjects. Quantitative determination of human 8-OHdG was done using enzyme-linked immunosorbent assay (ELISA) technique. ALR C(-106)T polymorphism was assessed by PCR/RFLP method. Levels of 8-OHdG were significantly increased in diabetic patients when compared to control subjects and in diabetic patients with complications when compared to those without complications (P < 0.001 or all). CT genotype was associated with susceptibility to development of T2D in Egyptian population. Nevertheless, this association has not been observed in diabetic complications. 8-OHdG level is significantly increased in diabetic group when compared to the control group and in diabetic patients with complications when compared to diabetic patients without complications. C(-106)T gene polymorphisms were associated with susceptibility to development diabetes, but it has no associations in development of complications.

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Phenotypic variation of thymic epithelial cells and partial spontaneous regression in thymoma of a cow

Abstract

Thymoma was recognized in a 12-year-old Holstein dairy cow presenting with no significant clinical signs. The animal was conventionally slaughtered at an abattoir and, on postmortem examination, a spherical tumor mass was found in the anterior region of the mediastinum. Histologically, the tumor was fibrously encapsulated and exhibiting varying-sized cystoid cavities containing serous fluid and necrotic and hemorrhagic foci. No architectural features showing distinct characteristics to a sufficient degree to allow identification of the thymus or other organs could be seen. The tumor showed diffuse solid sheet-like or nodular patterns of proliferation and consisted of a dual cell population: one was neoplastic epithelial cells that were immunohistochemically positive for cytokeratin, and the other was T lymphocytes that exhibited positive immunohistochemical staining with CD3. This finding enabled a diagnosis of mixed thymoma to be made. Neoplastic epithelial cells represented a wide spectrum of phenotypic expression, including (1) spindle shaped cells with a chiasmus-like, interlacing fascicular, or storiform growth pattern; (2) small, round to oval cells with scant cytoplasm showing indistinct boundary of cells; (3) large cells arranged in a solid sheet-like pattern; (4) vacuolated cells similar to signet ring cells; (5) clear cells that had defined cell membranes; and (6) occasional formation of micronodules composed of neoplastic epithelial cells. In addition, some areas of the tumor exhibited features of partial spontaneous regression characterized by collapse or disintegration of tumor tissues in close association with fibrocollagenous connective tissue deposition. Even if the morphology of thymic epithelial cells in thymoma is known to display variable appearance, it is likely to be unusual that, in the current bovine case, such thymic epithelial cells exhibited a wider spectrum of phenotypic expression within a single tumor. This salient histomorphological heterogeneity shown by thymic epithelial cells might have presumably been associated with innate characteristics specific to pluripotent thymic epithelial cells during thymoma tumorigenesis.

http://ift.tt/2eWgas9

What factors are associated with reporting lacking interest in sex and how do these vary by gender? Findings from the third British national survey of sexual attitudes and lifestyles

Objectives

To investigate factors associated with reporting lacking interest in sex and how these vary by gender.

Setting

British general population.

Design

Complex survey analyses of data collected for a cross-sectional probability sample survey, undertaken 2010–2012, specifically logistic regression to calculate age-adjusted OR (AOR) to identify associated factors.

Participants

4839 men and 6669 women aged 16–74 years who reported ≥1 sexual partner (opposite-sex or same-sex) in the past year for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3).

Main outcome measure

Lacking interest in sex for ≥3 months in the past year.

Results

Overall, 15.0% (13.9–16.2) of men and 34.2% (32.8–35.5) of women reported lacking interest in sex. This was associated with age and physical and mental health for both men and women, including self-reported general health and current depression. Lacking interest in sex was more prevalent among men and women reporting sexually transmitted infection diagnoses (ever), non-volitional sex (ever) and holding sexual attitudes related to normative expectations about sex. Some gender similarities in associated relationship and family-related factors were evident, including partner having had sexual difficulties in the last year (men: AOR 1.41 (1.07–1.86); women: AOR 1.60 (1.32–1.94)), not feeling emotionally close to partner during sex (men: 3.74 (1.76–7.93); women: 4.80 (2.99–7.69) and ease of talking about sex (men: 1.53 (1.23–1.90);women: 2.06 (1.77–2.39)). Among women only, lack of interest in sex was higher among those in a relationship of >1 year in duration and those not sharing the same level of interest (4.57 (3.87–5.38)) or preferences (2.91 (2.22–3.83)) with a partner.

Conclusions

Both gender similarities and differences were found in factors associated with lacking interest in sex, with the most marked differences in relation to some relationship variables. Findings highlight the need to assess, and if appropriate, treat lacking interest in sex in a holistic and relationship-specific way.

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Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy

In 2010, 5-year-old Emily Whitehead was diagnosed with acute lymphoblastic leukemia (ALL). Though her parents were told that if you had to have a kid with cancer, ALL was the best one to have, Emily's course was hardly typical. After two rounds of chemotherapy, necrotizing fasciitis developed in…

http://ift.tt/2f6EM56

In the Next Issue

No abstract available

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Valorization of CO 2 -rich off-gases to biopolymers through biotechnological process

Abstract

As one of the Key Enabling Technologies, industrial biotechnology has a high potential to tackle harmful CO₂ emissions and to turn CO₂ into a valuable commodity. So far, experimental work mainly focused on the bioconversion of pure CO₂ to chemicals and plastics and little is known about the tolerance of the bioprocesses to the presence of impurities. This work is the first to investigate the impact of real CO₂-rich off gases on autotrophic production of polyhydroxybutyrate (PHB). To this end, two-phase heterotrophic-autotrophic fermentation experiments were set up, consisting of heterothrophic cell mass growth using glucose as substrate followed by autotrophic biopolymer production using either pure synthetic CO₂ or industrial off-gases sampled at 2 point sources. The use of real off-gases did not affect the bacterial performance. High biopolymer content (up to 73%) and productivities (up to 0.227 g/lh) were obtained. Characterization of the polymers showed that all biopolymers had similar properties, independent of the CO₂ source. Moreover, the CO₂-derived biopolymers' properties were comparable to commercial ones and biopolymers reported in literature, which are all produced from organic carbon sources.

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Identification of a fabZ gene essential for flexirubin synthesis in Cytophaga hutchinsonii

Abstract

Cytophaga hutchinsonii, an aerobic soil bacterium which could degrade cellulose, produces yellow flexirubin pigments. In this study, fabZ, annotated as a putative β-hydroxyacyl-(acyl carrier protein) (ACP) dehydratase gene, was identified by insertional mutation and gene deletion as an essential gene for flexirubin pigment synthesis. The availability of a FabZ-mutant that fails to produce flexirubin allowed us to investigate the biological role of the pigment in C. hutchinsonii. Loss of flexirubin made the FabZ-mutant more sensitive to UV radiation, oxidative stress and alkaline stress than the wild-type.

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Typing and Comparative Genome Analysis of Brucella melitensis Isolated from Lebanon

Abstract

Brucella melitensis is the main causative agent of the zoonotic disease brucellosis. This study aimed at typing and characterizing genetic variation in 33 Brucella isolates recovered from patients in Lebanon. Bruce-ladder multiplex PCR and PCR-RFLP of omp31, omp2a and omp2b were performed. Sixteen representative isolates were chosen for draft-genome sequencing and analyzed to determine variations in virulence, resistance, genomic islands, prophages and insertion sequences. Comparative whole-genome SNPs analysis was also performed. The isolates were confirmed to be B. melitensis. Genome analysis revealed multiple virulence determinants and efflux pumps. Genome comparisons and SNPs divided the isolates based on geographical distribution but revealed high levels of similarity between the strains. Sequence divergence in B. melitensis was mainly due to lateral gene transfer of mobile elements. This is the first report of an in-depth genomic characterization of B. melitensis in Lebanon.

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Fit for duty: How to be a resilient responder

Fit for duty does not always mean being physically fit; it also refers to being resilient to the stress and emotional impacts of the job

http://ift.tt/2jo07IJ

OriGen VV28F Reinforced Dual Lumen ECMO Catheters: Recall - Potential for Separation of Extension Tube From Hub

Audience: Risk Manager, Emergency Medicine, Surgery [Posted 09/13/2017] ISSUE: OriGen Biomedical initiated a nationwide recall for two (2) lots of VV28F Reinforced Dual Lumen ECMO Catheters. These VV28F Reinforced Dual Lumen ECMO Catheters have...

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Measurement of cortisol in saliva: a comparison of measurement error within and between international academic-research laboratories

Hundreds of scientific publications are produced annually that involve the measurement of cortisol in saliva. Intra- and inter-laboratory variation in salivary cortisol results has the potential to contribute ...

http://ift.tt/2xxCx2B

OriGen VV28F Reinforced Dual Lumen ECMO Catheters: Recall - Potential for Separation of Extension Tube From Hub

Audience: Risk Manager, Emergency Medicine, Surgery [Posted 09/13/2017] ISSUE: OriGen Biomedical initiated a nationwide recall for two (2) lots of VV28F Reinforced Dual Lumen ECMO Catheters. These VV28F Reinforced Dual Lumen ECMO Catheters have...

http://ift.tt/2x1wCkA

Development of a Human Preclinical Model of Osteoclastogenesis from Peripheral Blood Monocytes Co-cultured with Breast Cancer Cell Lines

This protocol describes development of an in vitro human preclinical model of osteoclastogenesis from peripheral blood monocytes cultured with breast cancer cell lines to mimic the cancer cell-osteoclast interaction. The model could be used to further our understanding of bone metastasis formation and improve therapeutic options.

http://ift.tt/2x1hWAA

Superwettability of Gas Bubbles and Its Application: From Bioinspiration to Advanced Materials

Gas bubbles in aqueous media are common and inevitable in, for example, agriculture and industrial processes. The behaviors of gas bubbles on solid interfaces, including generation, growth, coalescence, release, transport, and collection, are crucial to gas-bubble-related applications, which are always determined by gas-bubble wettability on solid interfaces. Here, the recent progress regarding the study of interfaces with gas-bubble superwettability in aqueous media, i.e., superaerophilicity and superaerophobicity, is summarized. Some examples illustrate how to design microstructures and chemical compositions to achieve reliable and effective manipulation of gas-bubble wettability on artificial interfaces. These designed interfaces exhibit excellent performance in gas-evolution reactions, gas-adsorption reactions, and directional gas-bubble transportation. Moreover, progress in the theoretical investigation of gas-bubble superwettability is reported. Lastly, some challenges are presented, such as the reliable manipulation of gas-bubble wettability and the establishment of mature theory for exactly and systematically explaining gas-bubble wetting phenomena.

Recent progress on interfaces with gas-bubble superwettability in aqueous media, i.e., superaerophilicity and superaerophobicity, is summarized. Some examples are provided with regard to how to design microstructures and chemical compositions to achieve reliable and effective manipulation of gas-bubble wettability on artificial interfaces.

http://ift.tt/2joFHPM

Fourier-Based Diffraction Analysis of Live Caenorhabditis elegans

This manuscript describes how to distinguish different nematodes using far-field diffraction signatures. We compare the locomotion of 139 wild type and 108 "Roller" C. elegans by averaging frequencies associated with the temporal Fraunhofer diffraction signature at a single location using a continuous wave laser.

http://ift.tt/2vUazcG

Should we blame our genes for the bacteria behind tooth decay?

While human host genes may influence oral microbiome composition, it is unlikely that they control the bacteria that promote tooth decay, says a new study.

http://ift.tt/2w8Hn5S

Contribution of Astroglial Cx43 Hemichannels to the Modulation of Glutamatergic Currents by D-Serine in the Mouse Prefrontal Cortex

Astrocytes interact dynamically with neurons by modifying synaptic activity and plasticity. This interplay occurs through a process named gliotransmission, meaning that neuroactive molecules are released by astrocytes. Acting as a gliotransmitter, D-serine, a co-agonist of the NMDA receptor at the glycine-binding site, can be released by astrocytes in a calcium [Ca²⁺]_i-dependent manner. A typical feature of astrocytes is their high expression level of connexin43 (Cx43), a protein forming gap junction channels and hemichannels associated with dynamic neuroglial interactions. Pharmacological and genetic inhibition of Cx43 hemichannel activity reduced the amplitude of NMDA EPSCs in mouse layer 5 prefrontal cortex pyramidal neurons without affecting AMPA EPSC currents. This reduction of NMDA EPSCs was rescued by addition of D-serine in the extracellular medium. LTP of NMDA and AMPA EPSCs after high-frequency stimulation was reduced by prior inhibition of Cx43 hemichannel activity. Inactivation of D-serine synthesis within the astroglial network resulted in the reduction of NMDA EPSCs, which was rescued by adding extracellular D-serine. We showed that the activity of Cx43 hemichannels recorded in cultured astrocytes was [Ca²⁺]_I dependent. Accordingly, in acute cortical slices, clamping [Ca²⁺]_i at a low level in astroglial network resulted in an inhibition of NMDA EPSC potentiation that was rescued by adding extracellular D-serine. This work demonstrates that astroglial Cx43 hemichannel activity is associated with D-serine release. This process, occurring by direct permeation of D-serine through hemichannels or indirectly by Ca²⁺ entry and activation of other [Ca²⁺]_i-dependent mechanisms results in the modulation of synaptic activity and plasticity.

SIGNIFICANCE STATEMENT We recorded neuronal glutamatergic (NMDA and AMPA) responses in prefrontal cortex (PFC) neurons and used pharmacological and genetic interventions to block connexin-mediated hemichannel activity specifically in a glial cell population. For the first time in astrocytes, we demonstrated that hemichannel activity depends on the intracellular calcium concentration and is associated with D-serine release. Blocking hemichannel activity reduced the LTP of these excitatory synaptic currents triggered by high-frequency stimulation. These observations may be particularly relevant in the PFC, where D-serine and its converting enzyme are highly expressed.

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STIM1 Regulates Somatic Ca2+ Signals and Intrinsic Firing Properties of Cerebellar Purkinje Neurons

Control of Ca²⁺ flux between the cytosol and intracellular Ca²⁺ stores is essential for maintaining normal cellular function. It has been well established in both neuronal and non-neuronal cells that stromal interaction molecule 1 (STIM1) initiates and regulates refilling Ca²⁺ into the ER. Here, we describe a novel, additional role for STIM1, the regulation of free cytosolic Ca²⁺, and the consequent control of spike firing in neurons. Among central neurons, cerebellar Purkinje neurons express the highest level of STIM1, and they fire continuously in the absence of stimulation, making somatic Ca²⁺ homeostasis of particular importance. By using Purkinje neuron-specific STIM1 knock-out (STIM1^PKO) male mice, we found that the deletion of STIM1 delayed clearance of cytosolic Ca²⁺ in the soma during ongoing neuronal firing. Deletion of STIM1 also reduced the Purkinje neuronal excitability and impaired intrinsic plasticity without affecting long-term synaptic plasticity. In vestibulo-ocular reflex learning, STIM1^PKO male mice showed severe deficits in memory consolidation, whereas they were normal in memory acquisition. Our results suggest that STIM1 is critically involved in the regulation of the neuronal excitability and the intrinsic plasticity of the Purkinje neurons as well as cerebellar memory consolidation.

SIGNIFICANCE STATEMENT Stromal interaction molecule 1 (STIM1), which regulates the refilling of ER Ca²⁺, has been investigated in several systems including the CNS. In addition to a previous study showing that STIM1 regulates dendritic ER Ca²⁺ refilling and mGluR1-mediated synaptic transmission, we provide compelling evidence describing a novel role of STIM1 in spike firing Purkinje neurons. We found that STIM1 regulates cytosolic Ca²⁺ clearance of the soma during spike firing, and the interruption of this cytosolic Ca²⁺ clearing disrupts neuronal excitability and cerebellar memory consolidation. Our results provide new insights into neuronal functions of STIM1 from single neuronal Ca²⁺ dynamics to behavior level.

http://ift.tt/2xyYhuG

Confocal Imaging of Neuropeptide Y-pHluorin: A Technique to Visualize Insulin Granule Exocytosis in Intact Murine and Human Islets

We describe a protocol for visualization of insulin exocytosis in intact islets using pHluorin, a pH-sensitive green fluorescent protein. Isolated islets are infected with adenovirus encoding pHluorin coupled to the vesicle cargo neuropeptide Y. This allows for the detection of insulin granule fusion events by confocal microscopy.

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High Fat Diet Feeding and High Throughput Triacylglyceride Assay in Drosophila Melanogaster

This is a high fat diet feeding protocol to induce obesity in Drosophila, a model for understanding fundamental molecular mechanisms implicated in lipotoxicity. It also provides a high throughput triacylglyceride assay for measuring fat accumulation in Drosophila and potentially other (insect) models under various dietary, environmental, genetic or physiological conditions.

http://ift.tt/2vUFq94

Outcomes after sofosbuvir-containing regimens for hepatitis C virus in patients with decompensated cirrhosis: a real-world study

Abstract

Background

Direct-acting antivirals have been used for decompensated cirrhotic patients with hepatitis C virus (HCV) infection. However, the benefits in Chinese patients with decompensated cirrhosis are unclear.

Methods

Thirty patients with HCV infection and decompensated cirrhosis were administered sofosbuvir-containing regimens at our hospital between April and December 2015. The efficacy and safety of the treatments was determined by sustained virological response at week 12 (SVR 12), change of liver function and adverse events.

Results

The cohort included 13 treatment-experienced and 17 treatment-naïve patients. A total of 27 patients (90%) achieved SVR 12. No baseline characteristics (sex, age, treatment-experience, genotype, viral load, liver function or splenectomy) was association with achievement of SVR 12. Patients achieved SVR 12 had significantly improved liver function by post-treatment week 12 (P < 0.05). Of the 30 patients, six developed anemia, one developed hepatic decompensation, two developed impaired renal function and one developed a severe upper respiratory tract infection during the treatment. There was no death or HCC development during 12 months of follow-up off-therapy. Two patients (7.4%) with SVR 12 experienced new decompensated episodes during the follow-up.

Conclusion

Sofosbuvir-containing regimens are effective in Chinese HCV patients with decompensated cirrhosis, regardless of baseline characteristics, as demonstrated by a high rate of SVR 12, as well as improvement in liver function. Although antiviral therapy is generally well tolerated, a vigilant monitoring of anemia and renal function should be mandatory.

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Identified GABAergic and Glutamatergic Neurons in the Mouse Inferior Colliculus Share Similar Response Properties

GABAergic neurons in the inferior colliculus (IC) play a critical role in auditory information processing, yet their responses to sound are unknown. Here, we used optogenetic methods to characterize the response properties of GABAergic and presumed glutamatergic neurons to sound in the IC. We found that responses to pure tones of both inhibitory and excitatory classes of neurons were similar in their thresholds, response latencies, rate-level functions, and frequency tuning, but GABAergic neurons may have higher spontaneous firing rates. In contrast to their responses to pure tones, the inhibitory and excitatory neurons differed in their ability to follow amplitude modulations. The responses of both cell classes were affected by their location regardless of the cell type, especially in terms of their frequency tuning. These results show that the synaptic domain, a unique organization of local neural circuits in the IC, may interact with all types of neurons to produce their ultimate response to sound.

SIGNIFICANCE STATEMENT Although the inferior colliculus (IC) in the auditory midbrain is composed of different types of neurons, little is known about how these specific types of neurons respond to sound. Here, for the first time, we characterized the response properties of GABAergic and glutamatergic neurons in the IC. Both classes of neurons had diverse response properties to tones but were overall similar, except for the spontaneous activity and their ability to follow amplitude-modulated sound. Both classes of neurons may compose a basic local circuit that is replicated throughout the IC. Within each local circuit, the inputs to the local circuit may have a greater influence in determining the response properties to sound than the specific neuron types.

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Individual Movement Variability Magnitudes Are Explained by Cortical Neural Variability

Humans exhibit considerable motor variability even across trivial reaching movements. This variability can be separated into specific kinematic components such as extent and direction that are thought to be governed by distinct neural processes. Here, we report that individual subjects (males and females) exhibit different magnitudes of kinematic variability, which are consistent (within individual) across movements to different targets and regardless of which arm (right or left) was used to perform the movements. Simultaneous fMRI recordings revealed that the same subjects also exhibited different magnitudes of fMRI variability across movements in a variety of motor system areas. These fMRI variability magnitudes were also consistent across movements to different targets when performed with either arm. Cortical fMRI variability in the posterior–parietal cortex of individual subjects explained their movement–extent variability. This relationship was apparent only in posterior-parietal cortex and not in other motor system areas, thereby suggesting that individuals with more variable movement preparation exhibit larger kinematic variability. We therefore propose that neural and kinematic variability are reliable and interrelated individual characteristics that may predispose individual subjects to exhibit distinct motor capabilities.

SIGNIFICANCE STATEMENT Neural activity and movement kinematics are remarkably variable. Although intertrial variability is rarely studied, here, we demonstrate that individual human subjects exhibit distinct magnitudes of neural and kinematic variability that are reproducible across movements to different targets and when performing these movements with either arm. Furthermore, when examining the relationship between cortical variability and movement variability, we find that cortical fMRI variability in parietal cortex of individual subjects explained their movement extent variability. This enabled us to explain why some subjects performed more variable movements than others based on their cortical variability magnitudes.

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Visual Receptive Field Heterogeneity and Functional Connectivity of Adjacent Neurons in Primate Frontoparietal Association Cortices

The basic organization principles of the primary visual cortex (V1) are commonly assumed to also hold in the association cortex such that neurons within a cortical column share functional connectivity patterns and represent the same region of the visual field. We mapped the visual receptive fields (RFs) of neurons recorded at the same electrode in the ventral intraparietal area (VIP) and the lateral prefrontal cortex (PFC) of rhesus monkeys. We report that the spatial characteristics of visual RFs between adjacent neurons differed considerably, with increasing heterogeneity from VIP to PFC. In addition to RF incongruences, we found differential functional connectivity between putative inhibitory interneurons and pyramidal cells in PFC and VIP. These findings suggest that local RF topography vanishes with hierarchical distance from visual cortical input and argue for increasingly modified functional microcircuits in noncanonical association cortices that contrast V1.

SIGNIFICANCE STATEMENT Our visual field is thought to be represented faithfully by the early visual brain areas; all the information from a certain region of the visual field is conveyed to neurons situated close together within a functionally defined cortical column. We examined this principle in the association areas, PFC, and ventral intraparietal area of rhesus monkeys and found that adjacent neurons represent markedly different areas of the visual field. This is the first demonstration of such noncanonical organization of these brain areas.

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Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research

Abstract

The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically track tumor evolution and to adapt molecularly targeted therapy according to the emergence of tumor clonal variants is shaping modern medical oncology., In order to better describe this new therapeutic paradigm we propose the term "Liquid dynamic medicine" in the place of "Personalized or Precision medicine". Clinical validation of the "Liquid dynamic medicine" approach is best captured by N-of-1 trials where each patient acts as tester and control of truly personalized therapies.

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Variation in the use of active surveillance for low-risk prostate cancer

BACKGROUND

This study assessed the use of active surveillance in men with low-risk prostate cancer and evaluated institutional factors associated with the receipt of active surveillance.

METHODS

A retrospective, hospital-based cohort of 115,208 men with low-risk prostate cancer diagnosed between 2010 and 2014 was used. Multivariate and mixed effects models were used to examine variation and factors associated with active surveillance.

RESULTS

During the study period, the use of active surveillance increased from 6.8% in 2010 to 19.9% in 2014 (estimated annual percentage change, +28.8%; 95% confidence interval [CI], + 19.6% to + 38.7%; P = .002). The adjusted probability of active-surveillance receipt by institution was highly variable. Compared with patients treated at comprehensive community cancer centers, patients treated at community cancer programs (odds ratio [OR], 2.00; 95% CI, 1.50-2.67; P < .001) and academic institutions (OR, 2.47; 95%, CI, 1.81-3.37; P < .001) had higher odds of receiving active surveillance. Compared with patients treated at very low-volume facilities, patients treated at very high-volume facilities had higher odds of receiving active surveillance (OR, 3.57; 95% CI, 1.94-6.55; P < .001). Patient and hospital characteristics accounted for 60.2% of the overall variation, whereas the treating institution accounted for 91.5% of the unexplained variability.

CONCLUSIONS

Within this hospital-based cohort, the use of active surveillance for low-risk prostate cancer increased significantly over time. Significant variation was found in the use of active surveillance. Most of the variation was attributable to facility-related factors such as the facility type, facility volume, and institution. Policies to achieve consistent and higher rates of active surveillance, when appropriate, should be a priority of professional societies and patient advocacy groups. Cancer 2017. © 2017 American Cancer Society.

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Quality of life after surgery for intracranial meningioma

BACKGROUND

To the authors' knowledge, limited data exist regarding long-term quality of life (QOL) for patients diagnosed with intracranial meningioma.

METHODS

The data in the current study concerned 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013, and 1622 controls who were frequency matched to the cases by age, sex, and geography. These individuals were participants in a large, population-based, case-control study. Telephone interviews were used to collect data regarding QOL at the time of initial diagnosis or contact, using the Medical Outcomes Study Short-Form 36 Health Survey. QOL outcomes were compared by case/control status.

RESULTS

Patients diagnosed with meningioma reported levels of physical, emotional, and mental health functioning below those reported in a general healthy population. Case participants and controls differed most significantly with regard to the domains of Physical and Social Functioning, Role-Physical, Role-Emotional, and Vitality.

CONCLUSIONS

In the current study, patients with meningioma experienced statistically significant decreases in QOL compared with healthy controls of a similar demographic breakdown, although these differences were found to vary in clinical significance. Cancer 2017. © 2017 American Cancer Society.

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Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis

BACKGROUND

There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL).

METHODS

Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study.

RESULTS

Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study.

CONCLUSIONS

Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2017. © 2017 American Cancer Society.

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Parental distress 6 months after a pediatric cancer diagnosis in relation to family psychosocial risk at diagnosis

BACKGROUND

This study was aimed at assessing fathers' and mothers' distress 6 months after a pediatric cancer diagnosis and at determining whether this is related to the level of family psychosocial risk 1 month after the diagnosis.

METHODS

A sample of 192 families completed the electronic Psychosocial Assessment Tool (ePAT) 1 month after the diagnosis. At 6 months after the diagnosis, 119 mothers and 98 fathers completed the Distress Thermometer for Parents (DT-P; of which n=132 had also completed the ePAT at baseline). The DT-P consists of a thermometer score ranging from 0 to 10 (with a score ≥ 4 indicating clinical distress), problem domains (total, practical, social, emotional, physical, cognitive, and parenting for children < 2 years old and for children ≥ 2 years old), and a desire for a referral. The DT-P scores of mothers and fathers were compared with the scores of a reference group of 671 mothers and 463 fathers with healthy children. Within the pediatric cancer group, the DT-P scores of families with elevated total ePAT-scores were compared with the DT-P scores of parents with universal ePAT scores.

RESULTS

Parents of children with cancer more often reported clinical distress on the DT-P than parents of healthy children (fathers, 59.2% vs 32.3%; P < .001; mothers, 63% vs 42.3%; P < .001) and reported more problems on all DT-P domains (P < .001 to P = .042) except for the parenting domain for children < 2 years old. Furthermore, the ePAT predicted parental distress 6 months after the diagnosis because parents with elevated ePAT scores reported more problems than parents with universal scores on the DT-P thermometer and most of the DT-P domains (P < .001 to P = 1.00).

CONCLUSIONS

Initial ePAT risk scores at diagnosis are predictive of future mean levels of parental distress. Cancer 2017. © 2017 American Cancer Society.

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Safety-net versus private hospital setting for brain metastasis patients treated with radiosurgery alone: Disparities in follow-up care and outcomes

BACKGROUND

Stereotactic radiosurgery (SRS) alone is an increasingly accepted treatment for brain metastases, but it requires adherence to frequently scheduled follow-up neuroimaging because of the risk of distant brain metastasis. The effect of disparities in access to follow-up care on outcomes after SRS alone is unknown.

METHODS

This retrospective study included 153 brain metastasis patients treated consecutively with SRS alone from 2010 through 2016 at an academic medical center and a safety-net hospital (SNH) located in Los Angeles, California. Outcomes included neurologic symptoms, hospitalization, steroid use and dependency, salvage SRS, salvage whole-brain radiotherapy, salvage neurosurgery, and overall survival.

RESULTS

Ninety-three of the 153 patients were private hospital (PH) patients, and 60 were SNH patients. The median follow-up time was 7.7 months. SNH patients received fewer follow-up neuroimaging studies (1.5 vs 3; P = .008). In a multivariate analysis, the SNH setting was a significant risk factor for salvage neurosurgery (hazard ratio [HR], 13.65; P < .001), neurologic symptoms (HR, 3.74; P = .002), and hospitalization due to brain metastases (HR, 6.25; P < .001). More clinical visits were protective against hospitalizations due to brain metastases (HR, 0.75; P = .002), whereas more neuroimaging studies were protective against death (HR, 0.65; P < .001).

CONCLUSIONS

SNH patients with brain metastases treated with SRS alone had fewer follow-up neuroimaging studies and were at higher risk for neurologic symptoms, hospitalization for brain metastases, and salvage neurosurgery in comparison with PH patients. Clinicians should consider the practice setting and patient access to follow-up care when they are deciding on the optimal strategy for the treatment of brain metastases. Cancer 2017;. © 2017 American Cancer Society.

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Two-step EUS-guided antegrade treatment of a difficult bile duct stone in a surgically altered anatomy patient

Abstract

EUS-guided antegrade (EUS-AG) treatment is a treatment option for bile duct stones (BDS) in surgically altered anatomy patients[1, 2] but can be technically demanding due to the limitation of stone extraction devices[3, 4]. Herein, we presented a case of a difficult BDS successfully removed by two-step EUS-AG treatment after enterobiliary fistula maturation.A 73 year-old male with a history of gastrectomy and Roux-en-Y reconstruction for gastric cancer presented with 12-mm BDS on CT scan (Figure1).

This article is protected by copyright. All rights reserved.

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Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls

Abstract

Purpose

The fusion gene BRC–ABL has an important role to the progression of chronic myeloid leukemia (CML) and several signaling pathways have been characterized as responsible for the terminal blastic phase (BP). However, the initial phase, the chronic phase (CP), is long lasting and there is much yet to be understood about the critical role of BRC–ABL in this phase. This study aims to evaluate transcriptional deregulation in CD34+ hematopoietic cells (CD34+ cells) from patients with untreated newly diagnosed CML compared with CD34+HC from healthy controls.

Methods

Gene expression profiling in CML-CD34 cells and CD34 cells from healthy controls were used for this purpose with emphasis on five main pathways important for enhanced proliferation/survival, enhanced self-renewal and block of myeloid differentiation.

Results

We found 835 genes with changed expression levels (fold change ≥ ±2) in CML-CD34 cells compared with CD34 cells. These include genes belonging to PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways. Four of these pathways converge to MYC activation. We also identified five transcripts upregulated in CD34-CML patients named OSBPL9, MEK2, p90RSK, TCF4 and FZD7 that can be potential biomarkers in CD34-CML-CP.

Conclusion

We show several mRNAs up- or downregulated in CD34-CML during the chronic phase.

http://ift.tt/2xZywAb

Facilitatory effect of insulin treatment on hepatocellular carcinoma development in diabetes

To evaluate the effect of insulin treatment on the incidence and/or severity of hepatocellular carcinoma (HCC) in a mouse model of HCC based on diabetes.

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Neonatal hemolytic anemia does not always indicate thalassemia: a case report

Congenital erythropoietic porphyria is a rare autosomal recessive disorder that affects heme-porphyrin synthesis. This disorder is due to the genetic defect of uroporphyrinogen III cosynthase. This defect resu...

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Sauna bathing reduces the risk of respiratory diseases: a long-term prospective cohort study

Abstract

Sauna bathing has been linked with numerous health benefits. Sauna bathing may reduce the risk of respiratory diseases; however, no prospective evidence exists to support this hypothesis. We aimed to assess the association of frequency of sauna bathing with risk of respiratory diseases (defined as chronic obstructive pulmonary disease, asthma, or pneumonia). Baseline sauna bathing habits were assessed in a prospective cohort of 1935 Caucasian men aged 42–61 years. During a median follow-up of 25.6 years, 379 hospital diagnosed incident cases of respiratory diseases were recorded. In adjustment for several major risk factors for respiratory conditions and other potential confounders, the hazard ratios (HRs) 95% confidence intervals (CIs) of respiratory diseases were 0.73 (0.58–0.92) and 0.59 (0.37–0.94) for participants who had 2–3 and ≥4 sauna sessions per week respectively compared with participants who had ≤1 sauna session per week. The multivariate adjusted HR (95% CI) for pneumonia was 0.72 (0.57–0.90) and 0.63 (0.39–1.00) for participants who had 2–3 and ≥4 sauna sessions per week respectively. Frequent sauna baths may be associated with a reduced risk of acute and chronic respiratory conditions in a middle-aged male Caucasian population.

http://ift.tt/2joBAmN

FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway

Abstract

Background

FOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in human hepatocellular carcinoma (HCC).

Methods

Expression profile of FOXP3 was analyzed using real-time RT-PCR, western blotting and immunofluorescence on HCC cell lines, and immunostaing of a tissue microarray containing of 240 primary HCC samples. The potential regulatory roles of FOXP3 were dissected by an integrated approach, combining biochemical assays, analysis of patient survival, genetic manipulation of HCC cell lines, mouse xenograft tumor models and chromatin immunoprecipitation (ChIP) sequencing.

Results

FOXP3 was constitutively expressed in HCC cells with the existence of splice variants (especially exon 3 and 4 deleted, Δ3,4-FOXP3). High expression of FOXP3 significantly correlated with low serum α-fetoprotein (AFP) level, absence of vascular invasion and early TNM stage. Survival analyses revealed that increased FOXP3 expression was significantly associated with better survival and reduced recurrence, and served as an independent prognosticator for HCC patients. Furthermore, FOXP3 could potently suppress the proliferation and invasion of HCC cells in vitro and reduce tumor growth in vivo. However, Δ3,4-FOXP3 showed a significant reduction in the tumor-inhibiting effect. The inhibition of FOXP3 on HCC aggressiveness was acted probably by enhancing the TGF-β/Smad2/3 signaling pathway.

Conclusion

Our findings suggest that FOXP3 suppresses tumor progression in HCC via TGF-β/Smad2/3 signaling pathway, highlighting the role of FOXP3 as a prognostic factor and novel target for an optimal therapy against this fatal malignancy.

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Can you un-ring the bell? A qualitative study of how affect influences cancer screening decisions

Abstract

Background

The belief that early detection is the best protection against cancer underlies cancer screening. Emerging research now suggests harms associated with early detection may sometimes outweigh the benefits. Governments, cancer agencies, and organizations that publish screening guidelines have found it is difficult to "un-ring the bell" on the message that "early detection is your best protection" because of its widespread communication and enduring resonance. This study explores affective factors—and their interplay with relevant analytical factors—in public/laypersons' decision making about cancer screening.

Methods

A total of 93 people (47 men, 46 women) attended focus groups about, respectively, prostate cancer screening and breast cancer screening in two Canadian cities.

Results

Affective factors were a major influence on many focus group participants' decision making about cancer screening, including fear of cancer and a generalized enthusiasm for prevention/screening, and they were often inspired by anecdotes about the cancer experiences of family and friends. Affect also existed alongside more analytical factors including assessments of reduced risk in the management of any cancer diagnosis if caught early, and, for men, the belief that an unreliable test is "better than nothing," and that men deserve prostate cancer screening because women have breast and cervical cancer screening. Affective factors were particularly noticeable in the sub-groups most supportive of screening and the "early detection" message: older women who felt that mammogram screening should begin at age 40 rather than 50, and older men who felt that prostate cancer screening should be expanded beyond its current unorganized, opportunistic usage. In contrast, younger participants displayed less affective attachments to "early detection" messages and had greater concerns about harms of screening and were more receptive to nuanced messages informed by evidence.

Conclusion

Policymakers attempting to communicate more nuanced versions of the "early detection" message need to understand the role of affect alongside other judgments brought into laypersons' decision making processes and anticipate how affective responses to their messages will be shaped, transformed, and potentially subverted by external forces beyond their control. Particularly overt external factors are campaigns by cancer advocacy organizations actively promoting breast and prostate cancer awareness and screening to younger women and men using affectively-charged messages.

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