Correction: Winter cover crops increase readily decomposable soil carbon, but compost drives total soil carbon during eight years of intensive, organic vegetable production in California.

[This corrects the article DOI: 10.1371/journal.pone.0228677.].

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

Infigratinib for the Treatment of Metastatic or Locally Advanced Cholangiocarcinoma With Known FGFR2 Gene Fusions or Rearrangements.

Cholangiocarcinoma (CCA) is an aggressive and diverse malignancy with a poor prognosis. Related to a typical indolent course of progression, most cases of CCA are metastatic or locally advanced at the time of presentation. For patients with nonresectable tumors or metastatic disease, the mainstay of treatment is comprehensive with combination chemotherapy. The first-line chemotherapeutic combination for the treatment of CCA are cisplatin and gemcitabine-based chemotherapies. However, many locally advanced and progressive CCA cases are refractory to first-line management. Within the past few years, the increase in the incidence of metastatic CCA and its poor prognosis has brought to light the need for novel therapeutic approaches to treatment. With advancements in next-generation genome sequencing, multiple molecular pathways have been identified in the pathogenesis of CCA and have shown great potential as alternative treatments in cases of CCA refractory to surgical resection. FGFR2 fusions or rearrangements have been identified in 10-16% of all intrahepatic CCA and are thought to serve as a pathway of resistance for a number of nonresectable and refractory cases of cholangiocarcinoma. A novel therapeutic agent that has been discussed is infigratinib, a selective, ATP-competitive inhibitor of fibroblast growth factor receptor 2 (FGFR2). In a phase 1 trial, infigratinib showed a safe profile and showed remarkable clinical efficacy in advanced CCA with FGFR2 fusions or rearrangements in phase II trials. As of May 2021, the Food and Drug Administration (FDA) approved infigratinib for CCA largely based on tumor response and duration of response. As of 2021, infigratinib, futibatinib, and pemigatinib, similar novel selective FGFR inhibitors, have been approved by the FDA for the treatment of locally advanced or metastatic CCA harboring FGFR2 gene mutations. The present investigation reviews the development of infigratinib in particular and its clinical efficacy compared to other available treatment options for cholangiocarcinoma. While the side effect profile of infigratinib is minimal, particularly GI side effects, when compared with futibatinib and pemigatinib, the overall response rate (ORR) and median overall survival (mOS) for infigratinib (ORR=23.1%, mOS=3.8 months) was significantly lower than futibatinib (ORR=35.8%, mOS=21.1 months) and pemigatinib (ORR=35.5%, mOS=21.1 months). While there is ample promise for the use of infigratinib as molecular-directed therapy in the treatment of CCA harboring FGFR2 mutations, there is an appropriate concern for patient-acquired resistance. The heterogeneous nature of FGFR mutations and the emergence of different resistance mechanisms emphasize a need for more agents to inhibit FGFR rearrangements effectively.

Data quantifying interseeded cover crops effects on soil water and corn productivity in corn-soybean-wheat no-till cropping systems.

The data described support the research article entitled "Interseeded cover crop mixtures influence soil water storage during the corn phase of corn-soybean-wheat no-till cropping systems". Data were collected during the corn (Zea mays L.) phase from rotations with four different cover crop (CC) treatments. The study was conducted at the USDA research facility in Beltsville, MD from 2017 through 2020. The data are available from a repository at Ag Data Commons. Descriptions of crop rotations, soil water and temperature sensors, placement, and frequency of measurements are provided in the manuscript and repository. Hourly volumetric soil water content (m3 m-3) (VWC) and soil temperature (°C) data for each soil depth (0-12, 25-35, 50-60, 75-85 cm) are available from the repository. In the manuscript, daily values of soil water storage were used to estimate daily evapotranspiration (ET) and infiltration. A text file of meta information is provided in the repository describing data collection procedures, estimation of ET and infiltration, and methods used to replace sensor data having errors. Daily precipitation, maximum and minimum temperatures, net solar radiation, and windspeed collected at a nearby weather station are provided for estimating growing degree days and potential ET. Cover crop biomass (kg ha-1) prior to corn planting and corn yields are provided by replication and cover crop system treatment for the four years.

The Emerging Role of Ketamine in Acute Postoperative Pain Management.

PURPOSE OF REVIEW: Postoperative pain (POP) is among the most unpleasant experiences that patients face after surgery. Interest in and use of N-methyl-D-aspartate (NMDA) receptor antagonists for the management of POP has increased over the years with ketamine being the most popular drug of this class. RECENT FINDINGS: Several randomized controlled trials found that the use of ketamine either alone or in combination with other medications leads to decreased postoperative pain and opioid consumption. However, there are other studies that have not found these benefits. The results as of now suggest that the role of intraoperative ketamine in postoperative pain control varies among different operative procedures. While some studies have shown promise in ketamine's potential use as a postoperative analgesic, there is still a great deal of proposed research and randomized controlled trials needed to deduce the most efficacious and tolerable form and dose of ketamine.

Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis.

Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these combination therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 synergized with VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, an inhibitor of purine biosynthesis, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired resistance to AraC showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. These results translated into significantly prolonged survival upon combination of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.

Exploratory assessment: Nurse-led community health worker delivered HCV intervention for people experiencing homelessness.

BACKGROUND: Getting and maintaining Hepatitis C Virus (HCV) cure is challenging among people experiencing homelessness (PEH) as a result of critical social determinants of health such as unstable housing, mental health disorders, and drug and alcohol use. OBJECTIVES: The purpose of this exploratory pilot study was to compare a registered nurse/community health worker (RN/CHW)-led HCV intervention tailored for PEH, "I am HCV Free," with a clinic-based standard of care (cbSOC) for treating HCV. Efficacy was measured by sustained virological response at 12 weeks after stopping antivirals (SVR12), and improvement in mental health, drug and alcohol use, and access to healthcare. METHODS: An exploratory randomized controlled trial design was used to assign PEH recruited from partner sites in the Skid Row Area of Los Angeles, California, to the RN/CHW or cbSOC programs. All received direct-acting antivirals. The RN/CHW group received directly observed therapy in community-based settings, incentives for taking HCV medications, and wrap-around services, including connection to additional healthcare services, housing support, and referral to other community services. For all PEH, drug and alcohol use and mental health symptoms were measured at month 2 or 3 and 5 or 6 follow-up, depending on HCV medication type, while SVR12 was measured at month 5 or 6 follow-up. RESULTS: Among PEH in the RN/CHW group, 75% (3 of 4) completed SVR12 and all three attained undetectable viral load. This was compared with 66.7% (n = 4 of 6) of the cbSOC group who completed SVR12; all four attained undetectable viral load. The RN/CHW group, as compared to the cbSOC, also showed greater improvements in mental health, and significant improvement in drug use, and access to healthcare services. DISCUSSION: While this study shows significant improvements in drug use and health service access among the RN/-CHW group, the sample size of the study limits the validity and generalizability of the results. Further studies using larger sample sizes are necessitated.

Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist.

The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.

Identification of actionable targets for breast cancer intervention using a diversity outbred mouse model.

HER2-targeted therapy has improved breast cancer survival, but treatment resistance and disease prevention remain major challenges. Genes that enable HER2/Neu oncogenesis are the next intervention targets. A bioinformatics discovery platform of HER2/Neu-expressing Diversity Outbred (DO) F1 Mice was established to identify cancer-enabling genes. Quantitative Trait Loci (QTL) associated with onset ages and growth rates of spontaneous mammary tumors were sought. Twenty-six genes in 3 QTL contain sequence variations unique to the genetic backgrounds that are linked to aggressive tumors and 21 genes are associated with human breast cancer survival. Concurrent identification of TSC22D3, a transcription factor, and its target gene LILRB4, a myeloid cell checkpoint receptor, suggests an immune axis for regulation, or intervention, of disease. We also investigated TIEG1 gene that impedes tumor immunity but suppresses tumor growth. Although not an actionable target, TIEG1 study revealed genetic regulation of tumor progression, forming the basis of the genetics-based discovery platform.

Correlates of SARS-CoV-2 anti-RBD IgG antibody titers among persons experiencing homelessness in Los Angeles.

OBJECTIVES: People experiencing homelessness (PEH) have been especially impacted by the COVID-19 pandemic, likely due to increased vulnerabilities stemming from chronic diseases, substance use, and mental health conditions. DESIGN: A case-control study to assess the presence of antibodies against SARS-CoV-2 among PEH and associations with key variables. SAMPLE: A convenience sample of 97 PEH in Skid Row, Los Angeles. MEASUREMENTS: A structured questionnaire assessing socio-demographic, mental health, drug and alcohol use, health care access, pandemic stress, and other COVID-19-specific questions. RESULTS: We found high anti-receptor binding domain (RBD) IgG titers among five of 15 PEH who reported no prior COVID-19 diagnosis or being vaccinated, suggesting undiagnosed and/or asymptomatic COVID-19. While anti-RBD IgG titers across vaccination categories were not statistically significant (p = .069), participants vaccinated with Janssen had the lowest mean anti-RBD IgG titers. In multivariable analysis, we found negative associations between level of SARS-CoV-2 antibody titers with the Janssen vaccine and depression; thus, a need for integrated care for PEH with depression and COVID-19. CONCLUSIONS: Further research is warranted to confirm the immune response, initial and over time, to SARS-CoV-2 infection and to COVID-19 vaccinations, particularly among PEH whose immune systems may be impacted by multiple health conditions.

Pharmacological Approaches in Managing Symptomatic Relief of Benign Prostatic Hyperplasia: A Comprehensive Review.

Benign Prostatic Hyperplasia (BPH) is a prevalent condition that affects aging men, leading to the development of lower urinary tract symptoms (LUTS) and potentially severe complications such as complete obstruction. The management of BPH typically involves the use of medications from different classes, including alpha-1 antagonists, 5-alpha reductase inhibitors, and anticholinergics. Combination therapy utilizing drugs from different classes can also effectively manage the BPH-LUTS complex. Recent research has revealed that phosphodiesterase 5 (PDE5) inhibitors, including Tadalafil and Sildenafil, are highly effective in treating LUTS associated with BPH. Tadalafil as a monotherapy has recently been shown to significantly improve LUTS in BPH patients. Additionally, the use of herbal remedies as a treatment option for BPH has also been widely debated. Previous research suggests that saw palmetto can reduce BPH symptoms through several proposed mechanisms, but recent trials have found inconsistencies in its efficacy. In this literature review, we conducted an extensive PubMed database search to provide current and comprehensive insights into BPH treatment options. This review comprehensively evaluates available treatments for managing BPH, highlighting the effectiveness of different classes of medications and combination therapies in managing associated symptoms. The present investigation also discusses recent research on the efficacy of PDE5 inhibitors in treating LUTS associated with BPH and the uncertain efficacy of herbal remedies. The insights provided by this study can guide healthcare professionals in making informed decisions about managing BPH, ultimately improving patient outcomes.

Winter cover crops increased nitrogen availability and efficient use during eight years of intensive organic vegetable production.

Efficient use of nitrogen (N) is essential to protect water quality in high-input organic vegetable production systems, but little is known about the long-term effects of organic management on N mass balances. We measured soil N and tabulated N inputs (organic fertilizers, compost, irrigation water, atmospheric deposition, cover crop seed, vegetable transplant plugs and fixation by legume cover crops) and exports in harvested crops (lettuce, broccoli) over eight years to calculate soil surface and soil system N mass balances for the Salinas Organic Cropping Systems study in Salinas, CA. Our objectives were to 1) quantify the long-term effects of compost, cover crop frequency and cover crop type on soil N, cover crop and vegetable crop N uptake, and yield, and 2) tabulate N balances to assess the effects of these factors on N export in harvested crops, soil N storage and potential N loss. Results show that across all systems only 13 to 23% of N inputs were exported in harvest. Annual compost applications increased soil N stocks but had little effect on vegetable N uptake or yield, increasing the cumulative soil system N balance surplus over eight years by 999 kg ha-1, relative to the system receiving organic fertilizers alone. Annually planted winter cover crops increased N availability, crop uptake and export; however, biological N fixation by legumes negated the positive effect of increased harvest exports on the balance surplus in the legume-rye cover cropped system. Over eight years, rye cover crops improved system performance and reduced the cumulative N surplus by 384 kg ha-1 relative to the legume-rye mixture by increasing N retention and availability without increasing N inputs. Reduced reliance on external compost inputs and increased use of annually planted non-legume cover crops can improve efficient N use and cropping system yield, consequently improving environmental performance.

Nurse-led intervention to decrease drug use among LTBI positive homeless adults.

BACKGROUND: People experiencing homelessness (PEH) are disproportionately diagnosed with active tuberculosis. While promoting latent tuberculosis infection (LTBI) treatment has been a call to action, PEH engaging in substance use often experience challenges in completing LTBI treatment. METHODS: In this non-randomized single arm study, we tested an innovative, community-based, nurse-led community health worker (RN-CHW) model, on reducing drug use among 50 PEH, residing in homeless shelters or living on the streets in Los Angeles. Follow-up was at 3- and 6- months. RESULTS: Findings revealed significant and ongoing decrease in any drug use (odds ratio [OR] = 0.30; 95% confidence interval [CI] = 0.14-0.68); p = .004), amphetamine use (OR = 0.14; 95% CI = 0.02-0.81; p = .029), cannabis use (OR = 0.26; 95% CI = 0.12-0.57; p = .001) and methamphetamine use (OR = 0.30; 95% CI = 0.10-0.90; p = .031) at 6-month follow-up. CONCLUSIONS: To our knowledge, this pilot study is the first to evaluate the impact a RN-CHW delivered intervention on reduction in drug use among PEH enrolled in a LTBI intervention. LTBI interventions may serve as an entryway into reduction in drug use among this underserved population.

Correlates of depression and anxiety among homeless adults with latent tuberculosis infection.

Homeless persons have disproportionate rates of latent tuberculosis infection (LTBI). LTBI treatment can prevent and reduce active tuberculosis spread. We examined associations between mental health, social support, and perceptions of general health in 50 LTBI-positive, homeless adults enrolled in LTBI treatment. Depression and anxiety prevalence were 40% and 48%, respectively. Depression was negatively associated with general health, positive social interaction, and tangible, emotional/informational, and total social support, and positively associated with severe substance use (ps < 0.05). Anxiety was negatively associated with emotional/informational, tangible and total social support, and positively associated with severe substance use (ps < 0.05). Mental health services may help improve LTBI interventions.

Development and Application of a Semi quantitative Scoring Method for Ultrastructural Assessment of Acute Stress in Pancreatic Islets.

BACKGROUND: Pancreas and islet transplantation outcomes are negatively impacted by injury to the endocrine cells from acute stress during donor death, organ procurement, processing, and transplant procedures. Here, we report a novel electron microscopy scoring system, the Newcastle Pancreas Endocrine Stress Score (NPESS). METHODS: NPESS was adapted and expanded from our previously validated method for scoring pancreatic exocrine acinar cells, yielding a 4-point scale (0-3) classifying ultrastructural pathology in endocrine cell nuclei, mitochondria, endoplasmic reticulum, cytoplasmic vacuolization, and secretory granule depletion, with a maximum additive score of 15. We applied NPESS in a cohort of deceased organ donors after brainstem (DBD) and circulatory (DCD) death with a wide range of cold ischemic times (3.6-35.9 h) including 3 donors with type 1 and 3 with type 2 diabetes to assess islets in situ (n = 30) in addition to pancreata (n = 3) pre- and postislet isolation. RESULTS: In DBD pancreata, NPESS correlated with cold ischemic time (head: r = 0.55; P = 0.02) and mirrored exocrine score (r = 0.48; P = 0.01). When stratified by endocrine phenotype, cells with granules of heterogeneous morphology had higher scores than α, ß, and δ cells (P < 0.0001). Cells of mixed endocrine-exocrine morphology were observed in association with increased NPESS (P = 0.02). Islet isolation was associated with improved NPESS (in situ: 8.39 ± 0.77 [Mean ± SD]; postisolation: 5.44 ± 0.31; P = 0.04). CONCLUSIONS: NPESS provides a robust method for semiquantitative scoring of subcellular ultrastructural changes in human pancreatic endocrine cells in situ and following islet isolation with utility for unbiased evaluation of acute stress in organ transplantation research.

Nutritional status and skeletal muscle status in patients with head and neck cancer: Impact on outcomes.

BACKGROUND: Computed tomography (CT)-defined skeletal muscle depletion and malnutrition are demonstrated as poor prognostic factors in patients with head and neck cancer (HNC), however to date, have only been explored in isolation. We aimed to describe body composition profile and examine the impact of nutritional status as well as independently and concurrently occurring body composition features on overall survival, treatment completion, unplanned admissions and length of stay (LOS) in patients undergoing radiotherapy (RT) or chemoradiotherapy (CRT) of curative intent for HNC. METHODS: This work is a retrospective, observational study of patients who had completed treatment of curative intent for HNC. Scored Patient-Generated Subjective Global Assessment (PG-SGA) was used to determine nutritional status. Tissue-density data were derived at the third lumbar vertebra (L3) with sarcopenia and myosteatosis defined by published, sex-specific threshold values stratified by body mass index for skeletal muscle index (cm2 /m2 ) and skeletal muscle radiodensity (SMR, Hounsfield Unit). RESULTS: Pre-treatment data (n = 277: 78% male, mean (SD) age 60 (13) years) revealed the prevalence of malnutrition (24.9%), sarcopenia (52.3%), myosteatosis (82.3%), and concurrently occurring sarcopenia and myosteatosis (39.7%). Malnutrition was independently associated with reduced OS for patients with moderate [hazard ratio (HR) 2.57; 95% confidence interval (CI) 1.45-4.55, P = 0.001] and severe (HR 3.19; 95% CI 1.44-7.07, P = 0.004) malnutrition on multivariable analysis but not sarcopenia (HR 1.09; 95% CI 0.70-1.71), P = 0.700 or myosteatosis (HR 1.28; 95% CI 0.57-2.84), P = 0.500). Malnutrition was associated with treatment discontinuation (P < 0.001), not completing RT as planned (P < 0.001), unplanned hospital admission (P = 0.021), and greater LOS (P < 0.001). Skeletal muscle status features were associated with unplanned hospital admissions for those with no features (32%), with sarcopenia only (50%), myosteatosis only (25%), and concurrent sarcopenia and myosteatosis (50%), P < 0.001. Similarly, a clinically relevant greater median (Q1, Q3) LOS was observed for those with sarcopenia only [5 (3, 32)], myosteatosis only [10 (5, 30)], concurrent sarcopenia, and myosteatosis [14 (4, 33)] days vs. those with no features [3 (2, 11)] days, P = 0.2. CONCLUSIONS: Malnutrition was a more powerful prognostic indicator than CT-defined skeletal muscle depletion and was independently associated with reduced OS in patients undergoing RT or CRT of curative intent for HNC. CT-defined skeletal muscle depletion studies should recognize the multifaceted nature of human body composition and also measure nutritional status using validated methods in order to move towards developing a typology of high risk criteria for this complex patient group.

3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus.

The brain's ability to process complex information relies on the constant supply of energy through aerobic respiration by mitochondria. Neurons contain three anatomically distinct compartments-the soma, dendrites, and projecting axons-which have different energetic and biochemical requirements, as well as different mitochondrial morphologies in cultured systems. In this study, we apply quantitative three-dimensional electron microscopy to map mitochondrial network morphology and complexity in the mouse brain. We examine somatic, dendritic, and axonal mitochondria in the dentate gyrus and cornu ammonis 1 (CA1) of the mouse hippocampus, two subregions with distinct principal cell types and functions. We also establish compartment-specific differences in mitochondrial morphology across these cell types between young and old mice, highlighting differences in age-related morphological recalibrations. Overall, these data define the nature of the neuronal mitochondrial network in the mouse hippocampus, providing a foundation to examine the role of mitochondrial morpho-function in the aging brain.