Detection of elusive DNA copy-number variations in hereditary disease and cancer through the use of noncoding and off-target sequencing reads.

Copy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we developed OFF-PEAK, a user-friendly CNV detection tool that builds on a denoising approach and the use of "off-target" DNA reads, which are usually discarded by sequencing pipelines. We benchmarked OFF-PEAK on data from targeted sequencing of 96 cancer samples, as well as 130 exomes of individuals with inherited retinal disease from three different populations. For both sets of data, OFF-PEAK demonstrated excellent performance (>95% sensitivity and >80% specificity vs. experimental validation) in detecting CNVs from in silico data alone, indicating its immediate applicability to molecular diagnosis and genetic research.

Survival and cancer recurrence after short-course perioperative probiotics in a randomized trial.

BACKGROUND & AIMS: The long-term impact of perioperative probiotics remains understudied while mounting evidence links microbiome and oncogenesis. Therefore, we analyzed overall survival and cancer recurrence among patients enrolled in a randomized trial of perioperative probiotics. METHODS: 6-year follow-up of surgical patients participating in a randomized trial evaluating short-course perioperative oral probiotic VSL#3 (n = 57) or placebo (n = 63). RESULTS: Study groups did not differ in age, preoperative hemoglobin, ASA status, and Charlson comorbidity index. There was a significant difference in preoperative serum albumin (placebo group 4.0 ± 0.1 vs. 3.7 ± 0.1 g/dL in the probiotic group, p = 0.030). Thirty-seven deaths (30.8 %) have occurred during a median follow-up of 6.2 years. Overall survival stratified on preoperative serum albumin and surgical specialty was similar between groups (p = 0.691). Age (aHR = 1.081, p = 0.001), serum albumin (aHR = 0.162, p = 0.001), and surgical specialty (aHR = 0.304, p < 0.001) were the only predictors of overall survival in the multivariate model, while the placebo/probiotic group (aHR = 0.808, p = 0.726) was not predictive. The progression rate among cancer patients was similar in the probiotic group (30.3 %, 10/33) compared to the placebo group (21.2 %, 7/33; p = 0.398). The progression-free survival was not significantly different (unstratified p = 0.270, stratified p = 0.317). CONCLUSIONS: Perioperative short-course use of VSL#3 probiotics does not influence overall or progression-free survival after complex surgery for visceral malignancy.

Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology.

Preventing tau aggregation is a potential therapeutic strategy in Alzheimer's disease and other tauopathies. Recently, liquid-liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid-liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

Treatment of Pyogenic Flexor Tenosynovitis in the Emergency Department Setting With WALANT Technique.

BACKGROUND: The standard of care for treatment of pyogenic flexor tenosynovitis (PFT) involves antibiotic therapy and prompt irrigation of the flexor tendon sheath, traditionally performed in the operating room. With the acceptance of wide-awake local anesthesia no tourniquet (WALANT) hand surgery and its potential ability to minimize time to flexor tendon sheath irrigation, we sought to determine whether closed irrigation of the flexor tendon sheath could be safely and effectively performed in the emergency department setting with WALANT technique. METHODS: A retrospective review was conducted of the senior author's hand surgery consultations over a 12-month period. Six patients were identified who were diagnosed with PFT and subsequently underwent irrigation of the flexor tendon sheath using WALANT technique. Patient outcomes such as length of hospital stay, need for reoperation, infectious etiology, perioperative complications, and postprocedure range of motion (ROM) were identified. RESULTS: Six patients with diagnosis of PFT underwent irrigation of the flexor tendon sheath in the emergency department with local anesthesia only. The irrigation procedures were all well-tolerated. One patient required reoperation due to lack of appropriate clinical improvement following initial irrigation. Four of 6 patients regained their preinjury ROM while the remaining 2 patients had mild proximal interphalangeal joint extension lag. There were no complications associated with the procedures. CONCLUSIONS: Surgical treatment of PFT with closed irrigation of the flexor tendon sheath in the emergency department utilizing WALANT technique was safe, effective, and well-tolerated. Local anesthesia alone can be used effectively for irrigation procedures of the flexor tendon sheath.

Damage assessment in structures using artificial neural network working and a hybrid stochastic optimization.

Artificial neural network (ANN) has been commonly used to deal with many problems. However, since this algorithm applies backpropagation algorithms based on gradient descent (GD) technique to look for the best solution, the network may face major risks of being entrapped in local minima. To overcome those drawbacks of ANN, in this work, we propose a novel ANN working parallel with metaheuristic algorithms (MAs) to train the network. The core idea is that first, (1) GD is applied to increase the convergence speed. (2) If the network is stuck in local minima, the capacity of the global search technique of MAs is employed. (3) After escaping from local minima, the GD technique is applied again. This process is applied until the target is achieved. Additionally, to increase the efficiency of the global search capacity, a hybrid of particle swarm optimization and genetic algorithm (PSOGA) is employed. The effectiveness of ANNPSOGA is assessed using both numerical models and measurement. The results demonstrate that ANNPSOGA provides higher accuracy than traditional ANN, PSO, and other hybrid ANNs (even a higher level of noise is employed) and also considerably decreases calculational cost compared with PSO.

Rising Incidence of Peri-Operative Bactibilia among Patients Undergoing Complex Biliopancreatic Surgery.

Background: Biliary instrumentation is associated with bactibilia and post-operative infection. Bactibilia incidence over time remains unknown. Patients and Methods: Consecutive patients with bilioenteric anastomosis surgery and available surveillance intra-operative bile duct cultures were evaluated for post-operative infection. The study period (2008-2019) was divided into quartiles to examine time-based trends. Results: Among 101 cases, 60 intra-operative bile duct cultures had no growth and 41 patients had documented at least one culture-positive isolate in their bile. Frequency of patients with culture-positive intra-operative bile increased over the study period (period 1, 1/28, 3.6% vs. period 2, 7/21, 33.3% vs. period 3, 15/26, 57.7% vs. period 4, 18/26, 69.2%; p < 0.001). Culture-positive post-operative infection (17/101; 16.8%) was not associated with intra-operative bile duct culture (p = 0.552), however, the same micro-organism isolate was identified on post-operative infection and intra-operative culture of bile duct bile among six of 17 patients (35.3%). Conclusions: We found an increasing incidence of bactibilia and post-operative culture-positive infections over the last decade. One-third of patients with a positive intra-operative bile duct culture experienced post-operative infection with the same organism, yet a clear link between bile colonization and post-operative infection was not established.

Opposite nonlinear effects of unemployment and sentiment on male and female suicide rates: Evidence from Australia.

We investigate gender differences in the effects of unemployment and sentiment on suicide rates. Using monthly Australian data, we find a positive relationship between the unemployment rate and the suicide rate, and a negative relationship between consumer sentiment and the suicide rate. However, there is strong evidence of nonlinearity in the effects of both unemployment and sentiment on suicide rates, with substantial gender differences. For men, an increase in the unemployment rate increases the suicide rate, but an unemployment decrease has no effect; we find the opposite for women. For men, an increase in sentiment has stronger effects on the suicide rate than a decrease in sentiment. Again, we observe the opposite effect for women. Among sentiment components, forward-looking expectations are stronger predictors of suicide rates than present conditions. Sentiment has a much stronger effect on male suicide rates than on female suicide rates.

Recent progress in general force fields of small molecules.

Recent advances in computational hardware and free energy algorithms enable a broader application of molecular simulation of binding interactions between receptors and small-molecule ligands. The underlying molecular mechanics force fields (FFs) for small molecules have also achieved advancements in accuracy, user-friendliness, and speed during the past several years (2018-2020). Besides the expansion of chemical space coverage of ligand-like molecules among major popular classical additive FFs and polarizable FFs, new charge models have been proposed for better accuracy and transferability, new chemical perception of avoiding predefined atom types have been applied, and new automated parameterization toolkits, including machine learning approaches, have been developed for users' convenience.

Signet ring cell carcinoma of the gastrointestinal tract: National trends on treatment effects and prognostic outcomes.

BACKGROUND: Signet ring cell carcinoma (SRCC) is a distinct malignancy occurring across the tubular gastrointestinal tract (tGIT). We comprehensively examined the outcomes of patients diagnosed with SRCC across tGIT. METHODS: SRCC and not-otherwise-specified adenocarcinoma (NOS) patients reported to the National Cancer Database from 2004 to 2015 were included. Baseline characteristics, outcomes and site-specific adjusted hazard ratios (aHR) derived from Cox models of SRCC patients were compared to those of NOS patients. Overall survival (OS) was primary endpoint. RESULTS: A total of 41,686 SRCC (4.6%) and 871,373 NOS patients (95.4%) were included. SRCC patients were younger (63.1 ± 14.7 vs. 67.0 ± 13.4 y, p < 0.001) and more likely to present with Stage IV disease than NOS patients (42.5% vs. 24.5%, p < 0.001). Stomach (n = 24,433) and colon (n = 9,914) contributed highest frequency of SRCC. SRCC histology was associated with shorter OS (aHR = 1.377, p < 0.001) in multivariate model. There was an interaction between SRCC and chemotherapy effects on risk of death (interaction aHR = 1.072, pinteraction< 0.001) and between SRCC histology and disease site, suggesting that the effect of SRCC on OS is site-dependent, with a higher increased risk of death in patients with rectal SRCC (aHR = 2.378, pinteraction< 0.001). CONCLUSION: Significant negative prognostic effect associated with SRCC is site-dependent across the GIT. Surgical and or systemic therapy was associated with improved OS among SRCC patients, but remained lower than NOS patients. Further understanding of gastrointestinal SRCC molecular profile is needed to better inform future treatment strategies.

Chemotherapy-induced early transient increase and surge of CA 19-9 level in patients with pancreatic Adenocarcinoma✰.

This study aimed to characterize chemotherapy-induced transient increase and surge of CA 19-9 level to treatment response in patients with advanced pancreatic ductal adenocarcinoma (PDAC). A retrospective case series was performed of advanced PDAC patients treated with first-line chemotherapy at City of Hope Comprehensive Cancer Center from Jan 2017 to May 2020. CA 19-9 surge was defined as an increase of >20% from baseline followed by a >20% drop in one or more subsequent CA 19-9 levels compared to baseline. Out of 106 advanced PDAC patients, 38 were evaluable for CA 19-9 surge. Fourteen (51.9%) patients treated with FOLFIRINOX and 3 (27.3%) patients treated with nab-P + Gem chemotherapy demonstrated an early transient rise in CA 19-9 level. A CA 19-9 surge was documented in 9 (23.7%) patients, all with duration of surge lasting < 16 weeks. Five out of 9 (55.6%) patients (4: FOLFIRINOX, 1: nab-P + Gem) with CA 19-9 surge demonstrated partial objective response rate on surveillance cross-sectional imaging. One patient (FOLFIRINOX) had stable disease, and 2 patients (1: FOLFIRINOX, 1: nab-P + Gem) were found to have disease progression after treatment interruption. The initial early rise of CA 19-9 levels during chemotherapy in patients with advanced PDAC may not indicate tumor progression. Rather, it may represent a chemotherapy-induced transient increase or surge phenomenon of the tumor marker in patients responding to treatment.

Metachronous peritoneal metastases following curative resection for colon cancer: Understanding risk factors and patterns of recurrence.

BACKGROUND: A subset of metachronous colon cancer recurrence manifests as peritoneal metastases (PM). Risk factors for metachronous PM recurrence are not well-defined in patients with stage II or III colon cancers after curative resection and standard adjuvant treatments. METHODS: Population data from the California Cancer Registry for patients with Stage II or III colon cancer were collected between 2004 and 2012. Multivariate analysis was used to identify factors associated with metachronous PM. RESULTS: Of the 2077 patients with stage II or III colon cancer, female patients (odds ratio [OR] = 1.84, p = 0.02), T4 primary tumor (OR = 2.36, p = 0.02), mucinous (OR = 3.97, p < 0.01) or signet-ring histology (OR = 6.01, p = 0.01), and right-sided cancer (OR = 2.2, p < 0.01) were found with increased risk of metachronous isolated PM recurrence after curative resection. Median survival after diagnosis for patients without PM recurrence was 22 months, compared with 12 months for PM recurrence (p < 0.001). CONCLUSION: PM recurrence groups have a worse overall survival than patients with recurrent disease in other sites. A better understanding of the tumor biology and molecular characteristics of colon cancers likely to recur as PM is needed to explain behavior and identify potential targeted therapy.

Outcomes of neoadjuvant therapy for cholangiocarcinoma: A review of existing evidence assessing treatment response and R0 resection rate.

Adjuvant chemotherapy for cholangiocarcinoma (CCA) has not been shown to gain significant improvements in survival. Factors contributing to suboptimal treatment response include aggressive disease biology and late clinical presentation. When feasible, surgical resection is the first line of treatment. Yet, recurrence remains high and long-term survival is rare. Neoadjuvant therapy is an appealing approach, with oncologic advantages in allowing the treatment of occult systemic disease and selection of patients most likely to benefit from radical surgery. However, given the surgery-first treatment paradigm for CCA, there is a paucity of data supporting neoadjuvant therapy. This review summarizes the current evidence on treatment response and margin-negative (R0) resection rate associated with neoadjuvant therapy for CCA.

A fast and high-quality charge model for the next generation general AMBER force field.

The General AMBER Force Field (GAFF) has been broadly used by researchers all over the world to perform in silico simulations and modelings on diverse scientific topics, especially in the field of computer-aided drug design whose primary task is to accurately predict the affinity and selectivity of receptor-ligand binding. The atomic partial charges in GAFF and the second generation of GAFF (GAFF2) were originally developed with the quantum mechanics derived restrained electrostatic potential charge, but in practice, users usually adopt an efficient charge method, Austin Model 1-bond charge corrections (AM1-BCC), based on which, without expensive ab initio calculations, the atomic charges could be efficiently and conveniently obtained with the ANTECHAMBER module implemented in the AMBER software package. In this work, we developed a new set of BCC parameters specifically for GAFF2 using 442 neutral organic solutes covering diverse functional groups in aqueous solution. Compared to the original BCC parameter set, the new parameter set significantly reduced the mean unsigned error (MUE) of hydration free energies from 1.03 kcal/mol to 0.37 kcal/mol. More excitingly, this new AM1-BCC model also showed excellent performance in the solvation free energy (SFE) calculation on diverse solutes in various organic solvents across a range of different dielectric constants. In this large-scale test with totally 895 neutral organic solvent-solute systems, the new parameter set led to accurate SFE predictions with the MUE and the root-mean-square-error of 0.51 kcal/mol and 0.65 kcal/mol, respectively. This newly developed charge model, ABCG2, paved a promising path for the next generation GAFF development.

Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein-Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF.

Accurate prediction of the absolute or relative protein-ligand binding affinity is one of the major tasks in computer-aided drug design projects, especially in the stage of lead optimization. In principle, the alchemical free energy (AFE) methods such as thermodynamic integration (TI) or free-energy perturbation (FEP) can fulfill this task, but in practice, a lot of hurdles prevent them from being routinely applied in daily drug design projects, such as the demanding computing resources, slow computing processes, unavailable or inaccurate force field parameters, and difficult and unfriendly setting up and post-analysis procedures. In this study, we have exploited practical protocols of applying the CPU (central processing unit)-TI and newly developed GPU (graphic processing unit)-TI modules and other tools in the AMBER software package, combined with ff14SB/GAFF1.8 force fields, to conduct efficient and accurate AFE calculations on protein-ligand binding free energies. We have tested 134 protein-ligand complexes in total for four target proteins (BACE, CDK2, MCL1, and PTP1B) and obtained overall comparable performance with the commercial Schrodinger FEP+ program (WangJ. Am. Chem. Soc.2015, 137, 2695-2703). The achieved accuracy fits within the requirements for computations to generate effective guidance for experimental work in drug lead optimization, and the needed wall time is short enough for practical application. Our verified protocol provides a practical solution for routine AFE calculations in real drug design projects.

Metabolic and the Surgical Stress Response Considerations to Improve Postoperative Recovery.

PURPOSE OF REVIEW: Enhanced recovery pathways are a multimodal, multidisciplinary approach to patient care that aims to reduce the surgical stress response and maintain organ function resulting in faster recovery and improved outcomes. RECENT FINDINGS: A PubMed literature search was performed for articles that included the terms of metabolic surgical stress response considerations to improve postoperative recovery. The surgical stress response occurs due to direct and indirect injuries during surgery. Direct surgical injury can result from the dissection, retraction, resection, and/or manipulation of tissues, while indirect injury is secondary to events including hypotension, blood loss, and microvascular changes. Greater degrees of tissue injury will lead to higher levels of inflammatory mediator and cytokine release, which ultimately drives immunologic, metabolic, and hormonal processes in the body resulting in the stress response. These processes lead to altered glucose metabolism, protein catabolism, and hormonal dysregulation among other things, all which can impede recovery and increase morbidity. Fluid therapy has a direct effect on intravascular volume and cardiac output with a resultant effect on oxygen and nutrient delivery, so a balance must be maintained without excessively loading the patient with water and salt. All in all, attenuation of the surgical stress response and maintaining organ and thus whole-body homeostasis through enhanced recovery protocols can speed recovery and reduce complications. The present investigation summarizes the clinical application of enhanced recovery pathways, and we will highlight the key elements that characterize the metabolic surgical stress response and improved postoperative recovery.

Calculate protein-ligand binding affinities with the extended linear interaction energy method: application on the Cathepsin S set in the D3R Grand Challenge 3.

We participated in the Cathepsin S (CatS) sub-challenge of the Drug Design Data Resource (D3R) Grand Challenge 3 (GC3) in 2017 to blindly predict the binding poses of 24 CatS-bound ligands, the binding affinity ranking of 136 ligands, and the binding free energies of a subset of 33 ligands in Stage 1A and Stage 2. Our submitted predictions ranked relatively well compared to the submissions from other participants. Here we present our methodologies used in the challenge. For the binding pose prediction, we employed the Glide module in the Schrodinger Suite 2017 and AutoDock Vina. For the binding affinity/free energy prediction, we carried out molecular dynamics simulations of the complexes in explicit water solvent with counter ions, and then estimated the binding free energies with our newly developed model of extended linear interaction energy (ELIE), which is inspired by two other popular end-point approaches: the linear interaction energy (LIE) method, and the molecular mechanics with Poisson-Boltzmann surface area solvation method (MM/PBSA). Our studies suggest that ELIE is a good trade-off between efficiency and accuracy, and it is appropriate for filling the gap between the high-throughput docking and scoring methods and the rigorous but much more computationally demanding methods like free energy perturbation (FEP) or thermodynamics integration (TI) in computer-aided drug design (CADD) projects.