Tumor-agnostic genomic and clinical analysis of BRAF fusions identify actionable targets.

BACKGROUND: Even though BRAF fusions are increasingly detected in standard multigene next-generation sequencing panels, few reports have explored their structure and impact on clinical course. PATIENTS/METHODS: We collected data from patients with BRAF fusion-positive cancers identified through a genotyping protocol of 97,024 samples. Fusions were characterized and reviewed for oncogenic potential (in-frame status, non-BRAF partner gene, intact BRAF kinase domain). RESULTS: We found 241 BRAF fusion-positive tumors from 212 patients with 82 unique 5' fusion partners spanning 52 histologies. 39 fusion partners were not previously reported, and 61 were identified once. BRAF fusion incidence was enriched in pilocytic astrocytomas, gangliomas, low-grade neuroepithelial tumors, and acinar cell carcinoma of the pancreas. 24 patients spanning multiple histologies were treated with MAPK-directed therapies of which 20 were evaluable for RECIST. Best response was partial response (N=2), stable disease (N=11), and progressive disease (N=7). The median time on therapy was 1 month with MEK plus BRAF inhibitors ([N=11], range 0-18 months) and 8 months for MEK inhibitors ([N=14], range 1-26 months). 9 patients remained on treatment for longer than 6 months [pilocytic astrocytomas (N=6), Erdheim-Chester disease (N=1), extraventricular neurocytoma (N=1), melanoma (N=1)]. Fifteen patients had acquired BRAF fusions. CONCLUSIONS: BRAF fusions are found across histologies and represent an emerging actionable target. BRAF fusions have a diverse set of fusion partners. Durable responses to MAPK therapies were seen, particularly in pilocytic astrocytomas. Acquired BRAF fusions were identified after targeted therapy underscoring the importance of post-progression biopsies to optimize treatment at relapse in these patients.

Rapid jail-based implementation of overdose education and naloxone distribution in response to the COVID-19 pandemic.

BACKGROUND: People incarcerated in jails are highly impacted by the opioid epidemic, and overdose education and naloxone distribution (OEND) is an effective strategy to reduce opioid overdose deaths. This study examines barriers and facilitators of fast-track OEND implementation within the jails in the Wave 1 Kentucky counties of the HEALing Communities Study during the COVID-19 pandemic. METHODS: Meeting minutes with jail stakeholders were qualitatively coded using the Practical, Robust Implementation and Sustainability Model (PRISM) as the coding framework. The analysis highlighted the top barriers and facilitators to fast-track OEND implementation within the PRISM framework. RESULTS: Space and staffing shortages related to the COVID-19 pandemic, disruptions in interorganizational programming from pandemic-related service suspensions, and a lack of technological solutions (e.g., reliable Internet access) for socially distanced delivery were the top barriers to fast-track OEND implementation. In addition, there were limitations on non-jail staff access to jails during COVID-19. Top facilitators included jail leadership support, the option to prioritize high-risk groups, and the incorporation of OEND processes into existing communications and management software. While the COVID-19 pandemic strained jail infrastructure, jail and partner agency collaboration led to creative implementation strategies for the successful integration of OEND into jail operations. Urban jails were more likely than rural jails to be early adopters of OEND during the public health emergency. CONCLUSIONS: Understanding the barriers to and facilitators of OEND within jails will improve implementation efforts seeking to curb opioid overdose deaths. Jail leadership support and interorganizational efforts were key facilitators to implementation; therefore, it is recommended to increase buy-in with multiple agencies to promote success. Challenges brought on by COVID-19 have resulted in a need for innovative solutions for implementation. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov, NCT04111939, Submitted 30 September 2019, https://clinicaltrials.gov/study/NCT04111939?titles=HEALing%20Communities%20Study&rank=1 .

Dexamethasone-Induced Insulin Resistance Attenuation by Oral Sulfur-Oxidovanadium(IV) Complex Treatment in Mice.

Vanadium compounds are known to exert insulin-enhancing activity, normalize elevated blood glucose levels in diabetic subjects, and show significant activity in models of insulin resistance (IR). Faced with insulin resistance, the present work investigates the antidiabetic performance of a known oxidovanadium(IV)-based coordination compound-[VIVO(octd)]-and effects associated with glucocorticoid-induced insulin resistance in mice. The effects of [VIVO(octd)] were evaluated in a female Swiss mice model of insulin resistance induced by seven days of dexamethasone treatment in comparison with groups receiving metformin treatment. Biological assays such as hematological, TyG index, hepatic lipids, glycogen, oxidative stress in the liver, and oral glucose tolerance tests were evaluated. [VIVO(octd)] was characterized with 51V NMR, infrared spectroscopy (FTIR), electron paramagnetic resonance (EPR), electronic absorption spectroscopy, and mass spectrometry (ESI-FT-MS). The [VIVO(octd)] oral treatment (50 mg/kg) had an antioxidant effect, reducing 50% of fast blood glucose (p < 0.05) and 25% of the TyG index, which is used to estimate insulin resistance (p < 0.05), compared with the non-treated group. The oxidovanadium-sulfur compound is a promising antihyperglycemic therapeutic, including in cases aggravated by insulin resistance induced by glucocorticoid treatment.

Insect meal in aquafeeds: A sustainable path to enhanced mucosal immunity in fish.

The mucosal surfaces of fish, including their intestines, gills, and skin, are constantly exposed to various environmental threats, such as water quality fluctuations, pollutants, and pathogens. However, various cells and microbiota closely associated with these surfaces work in tandem to create a functional protective barrier against these conditions. Recent research has shown that incorporating specific feed ingredients into fish diets can significantly boost their mucosal and general immune response. Among the various ingredients being investigated, insect meal has emerged as one of the most promising options, owing to its high protein content and immunomodulatory properties. By positively influencing the structure and function of mucosal surfaces, insect meal (IM) has the potential to enhance the overall immune status of fish. This review provides a comprehensive overview of the potential benefits of incorporating IM into aquafeed as a feed ingredient for augmenting the mucosal immune response of fish.

Warming and shifts in litter quality drive multiple responses in freshwater detritivore communities.

Aquatic detritivores are highly sensitive to changes in temperature and leaf litter quality caused by increases in atmospheric CO2. While impacts on detritivores are evident at the organismal and population level, the mechanisms shaping ecological communities remain unclear. Here, we conducted field and laboratory experiments to examine the interactive effects of changes in leaf litter quality, due to increasing atmospheric CO2, and warming, on detritivore survival (at both organismal and community levels) and detritus consumption rates. Detritivore community consisted of the collector-gathering Polypedilum (Chironomidae), the scraper and facultative filtering-collector Atalophlebiinae (Leptophlebiidae), and Calamoceratidae (Trichoptera), a typical shredder. Our findings reveal intricate responses across taxonomic levels. At the organismal level, poor-quality leaf litter decreased survivorship of Polypedilum and Atalophlebiinae. We observed taxon-specific responses to warming, with varying effects on growth and consumption rates. Notably, species interactions (competition, facilitation) might have mediated detritivore responses to climate stressors, influencing community dynamics. While poor-quality leaf litter and warming independently affected detritivore larvae abundance of Atalophebiinae and Calamoceratidae, their combined effects altered detritus consumption and emergence of adults of Atalophlebiinae. Furthermore, warming influenced species abundances differently, likely exacerbating intraspecific competition in some taxa while accelerating development in others. Our study underscores the importance of considering complex ecological interactions in predicting the impact of climate change on freshwater ecosystem functioning. Understanding these emergent properties contributes to a better understanding of how detritivore communities may respond to future environmental conditions, providing valuable insights for ecosystem management and conservation efforts.

Cancer diagnosis and treatment in working-age adults: Implications for employment, health insurance coverage, and financial hardship in the United States.

The rising costs of cancer care and subsequent medical financial hardship for cancer survivors and families are well documented in the United States. Less attention has been paid to employment disruptions and loss of household income after a cancer diagnosis and during treatment, potentially resulting in lasting financial hardship, particularly for working-age adults not yet age-eligible for Medicare coverage and their families. In this article, the authors use a composite patient case to illustrate the adverse consequences of cancer diagnosis and treatment for employment, health insurance coverage, household income, and other aspects of financial hardship. They summarize existing research and provide nationally representative estimates of multiple aspects of financial hardship and health insurance coverage, benefit design, and employee benefits, such as paid sick leave, among working-age adults with a history of cancer and compare them with estimates among working-age adults without a history of cancer from the most recently available years of the National Health Interview Survey (2019-2021). Then, the authors identify opportunities for addressing employment and health insurance coverage challenges at multiple levels, including federal, state, and local policies; employers; cancer care delivery organizations; and nonprofit organizations. These efforts, when informed by research to identify best practices, can potentially help mitigate the financial hardship associated with cancer.

Phase II Study of Osimertinib in Patients With Epidermal Growth Factor Receptor Mutations: Results From the NCI-MATCH ECOG-ACRIN (EAY131) Trial Subprotocol E.

PURPOSE: The National Cancer Institute Molecular Analysis for Therapy Choice trial is a signal-finding genomically driven platform trial that assigns patients with any advanced refractory solid tumor, lymphoma, or myeloma to targeted therapies on the basis of next-generation sequencing results. Subprotocol E evaluated osimertinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with EGFR mutations. METHODS: Eligible patients had EGFR mutations (T790M or rare activating) and received osimertinib 80 mg once daily. Patients with lung cancer with EGFR T790M were excluded. The primary end point was objective response rate (ORR), and the secondary end points were 6-month progression-free survival (PFS), overall survival, and toxicity. RESULTS: A total of 19 patients were enrolled: 17 were evaluable for toxicity and 13 for efficacy. The median age of the 13 included in the efficacy analysis was 63 years, 62% had Eastern Cooperative Oncology Group performance status 1, and 31% received >three previous systemic therapies. The most common tumor type was brain cancers (54%). The ORR was 15.4% (n = 2 of 13; 90% CI, 2.8 to 41.0) and 6-month PFS was 16.7% (90% CI, 0 to 34.4). The two confirmed RECIST responses were observed in a patient with neuroendocrine carcinoma not otherwise specified (EGFR exon 20 S768T and exon 18 G719C mutation) and a patient with low-grade epithelial carcinoma of the paranasal sinus (EGFR D770_N771insSVD). The most common (>20%) treatment-related adverse events were diarrhea, thrombocytopenia, and maculopapular rash. CONCLUSION: In this pretreated cohort, osimertinib did not meet the prespecified end point threshold for efficacy, but responses were seen in a neuroendocrine carcinoma with an EGFR exon 20 S768T and exon 18 G719C mutation and an epithelial carcinoma with an EGFR D770_N771insSVD mutation. Osimertinib was well tolerated and had a safety profile consistent with previous studies.

Alternatives to dental opioid prescribing after tooth extraction (ADOPT): protocol for a stepped wedge cluster randomized trial.

BACKGROUND: Dentists and oral surgeons are leading prescribers of opioids to adolescents and young adults (AYA), who are at high risk for developing problematic opioid use after an initial exposure. Most opioids are prescribed after tooth extraction, but non-opioid analgesics provide similar analgesia and are recommended by multiple professional organizations. METHODS: This multi-site stepped wedge cluster-randomized trial will assess whether a multicomponent behavioral intervention can influence opioid prescribing behavior among dentists and oral surgeons compared to usual practice. Across up to 12 clinical practices (clusters), up to 33 dentists/oral surgeons (provider participants) who perform tooth extractions for individuals 12-25 years old will be enrolled. After enrollment, all provider participants will receive the intervention at a time based on the sequence to which their cluster is randomized. The intervention consists of prescriber education via academic detailing plus provision of standardized patient post-extraction instructions and blister packs of acetaminophen and ibuprofen. Provider participants will dispense the blister packs and distribute the patient instructions at their discretion to AYA undergoing tooth extraction, with or without additional analgesics. The primary outcome is a binary, patient-level indicator of electronic post-extraction opioid prescription. Data for the primary outcome will be collected from the provider participant's electronic health records quarterly throughout the study. Provider participants will complete a survey before and approximately 3 months after transitioning into the intervention condition to assess implementation outcomes. AYA patients undergoing tooth extraction will be offered a survey to assess pain control and satisfaction with pain management in the week after their extraction. Primary analyses will use generalized estimating equations to compare the binary patient-level indicator of being prescribed a post-extraction opioid in the intervention condition compared to usual practice. Secondary analyses will assess provider participants' perceptions of feasibility and appropriateness of the intervention, and patient-reported pain control and satisfaction with pain management. Analyses will adjust for patient-level factors (e.g., sex, number of teeth extracted, etc.). DISCUSSION: This real-world study will address an important need, providing information on the effectiveness of a multicomponent intervention at modifying dental prescribing behavior and reducing opioid prescriptions to AYA. CLINICALTRIALS: GOV: NCT06275191.

Mucosal barrier status in Atlantic salmon fed rapeseed oil and Schizochytrium oil partly or fully replacing fish oil through winter depression.

The study was designed to investigate the effects of replacing fish oil by algal oil and rapeseed oil on histomorphology indices of the intestine, skin and gill, mucosal barrier status and immune-related genes of mucin and antimicrobial peptide (AMP) genes in Atlantic salmon (Salmo salar). For these purposes, Atlantic salmon smolts were fed three different diets. The first was a control diet containing fish oil but no Schizochytrium oil. In the second diet, almost 50 % of the fish oil was replaced with algal oil, and in the third diet, fish oil was replaced entirely with algal oil. The algal oil contained mostly docosahexaenoic acid (DHA) and some eicosapentaenoic acid (EPA). The study lasted for 49 days in freshwater (FW), after which some fish from each diet group were transferred to seawater (SW) for a 48-h challenge test at 33 ppt to test their ability to tolerate high salinity. Samples of skin, gills, and mid intestine [both distal (DI) and anterior (AI) portions of the mid intestine] were collected after the feeding trial in FW and after the SW-challenge test to assess the effects of the diets on the structure and immune functions of the mucosal surfaces. The results showed that the 50 % VMO (Veramaris® algal oil) dietary group had improved intestinal, skin, and gill structures. Principal component analysis (PCA) of the histomorphological parameters demonstrated a significant effect of the algal oil on the intestine, skin, and gills. In particular, the mucosal barrier function of the intestine, skin, and gills was enhanced in the VMO 50 % dietary group after the SW challenge, as evidenced by increased mucous cell density. Immunolabelling of heat shock protein 70 (HSP70) in the intestine (both DI and AI) revealed downregulation of the protein expression in the 50 % VMO group and a corresponding upregulation in the 100 % VMO group compared to 0 % VMO. The reactivity of HSP70 in the epithelial cells was higher after the SW challenge compared to the FW phase. Immune-related genes related to mucosal defense, such as mucin genes [muc2, muc5ac1 (DI), muc5ac1 (AI), muc5ac2, muc5b (skin), and muc5ac1 (gills)], and antimicrobial peptide genes [def3 (DI), def3 (AI), and cath1 (skin)] were significantly upregulated in the 50 % VMO group. PCA of gene expression demonstrated the positive influences on gene regulation in the 50 % VMO dietary group. In conclusion, this study demonstrated the positive effect of substituting 50 % of fish oil with algal oil in the diets of Atlantic salmon. The findings of histomorphometry, mucosal mapping, immunohistochemistry, and immune-related genes connected to mucosal responses all support this conclusion.

Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

Most of the escaped farmed salmon entering a river during a 5-year period were infected with one or more viruses.

Disease interactions between farmed and wild populations have been poorly documented for most aquaculture species, in part due to the complexities to study this. Here, we tested 567 farmed Atlantic salmon escapees, captured in a Norwegian river during 2014-2018, for five viral infections that are prevalent in global salmonid aquaculture. Over 90% of the escapees were infected with one or more viruses. Overall prevalences were: 75.7% for piscine orthoreovirus (PRV-1), 43.6% for salmonid alphavirus (SAV), 31.2% for piscine myocarditis virus (PMCV), 1.2% for infectious pancreatic necrosis virus (IPNV) and 0.4% for salmon anaemia virus (ISAV). A significantly higher prevalence of PMCV infection was observed in immature compared to mature individuals. The prevalence of both SAV and PMCV infections was higher in fish determined by fatty acid profiling to be 'recent' as opposed to 'early' escapees that had been in the wild for a longer period of time. This is the first study to establish a time-series of viral infection status of escapees entering a river with a native salmon population. Our results demonstrate that farmed escapees represent a continuous source of infectious agents which could potentially be transmitted to wild fish populations.

Major trauma in working-age adults in New Zealand.

AIM: To describe the demographic and injury profile of major trauma among 20-65-year-old New Zealanders. METHODS: A retrospective analysis of routinely collected data from the New Zealand Major Trauma Registry for the period 1 July 2017 to 30 June 2020 was conducted. Sex, age and ethnicity-based rates were then calculated using census-based population estimates to compare the rates of injury across different demographic groups. RESULTS: Of the 4,186 major trauma incidents among 20-65-year-olds in New Zealand during the 3-year period reviewed, 235 died (5.6%). Males accounted for 77% of those injured. Maori (New Zealand's Indigenous population) had significantly higher rates of major trauma (79.2 per 100,000; 95% confidence interval [CI] 74.4-84.3) compared to non-Maori (44.4 per 100,000; 95% CI 42.9-46.0). The most common cause of injury was transport-related incidents (63%; n=2,632/4,186), followed by falls (19%; n=788/4,186). CONCLUSIONS: Demographic characteristics have a significant relationship with major trauma injuries among 20-65-year-old New Zealanders. Continued injury prevention efforts focussing on males, Maori and transport incidents are required. Interventions that improve the safety of roads, such as lane separators, speed limits and raised intersections, should be implemented in high-crash-risk areas to reduce risk.

The Gender Minority Stress and Resilience Measure: Psychometric Validity for Use in Spanish.

Purpose: Stigma is a fundamental driver of HIV disparities among transgender women (TW). The gender minority stress and resilience (GMSR) measure has not been validated in Spanish-speaking, resource-limited settings. We examined the psychometric properties of a translated and abbreviated GMSR among TW in Tijuana, Mexico. Methods: From 2020 to 2021, 152 participants were recruited through social media and venue-based sampling. We collected information on the abbreviated GMSR, psychosocial factors (e.g., depressive symptoms), and sociodemographics. The abbreviated GMSR assessed 7 factors (Discrimination, Rejection, Internalized Transphobia, Negative Expectations, Nondisclosure, Pride, and Community Connectedness). Confirmatory factor analysis, Cronbach's alphas, and McDonald's omegas assessed structural validity. Pearson's partial correlations assessed criterion, convergent, and discriminant validities. Results: The 7-factor structure solution had acceptable fit (root mean square error of approximation [95% confidence interval]=0.05 [0.05-0.06]; comparative fit index/Tucker-Lewis index=0.92/0.91); and internal reliability (α=0.62-0.89; ω=0.62-0.89). Depressive (r=0.22-0.43; p<0.001-0.007), post-traumatic stress disorder (PTSD; r=0.20-0.34; p<0.001-0.017) symptoms, and perceived stress (r=0.19-0.41; p≤0.001-0.030) were all positively associated with all stress factors (e.g., Discrimination, Rejection, Internalized Transphobia, Negative Expectations, and Nondisclosure). The resilience factor Pride was associated with fewer PTSD symptoms (r=-0.18; p=0.027), lower perceived life stress (r=-0.21; p=0.012), and greater general resilience (r=0.26; p=0.002). The Community Connectedness resilience factor was associated with fewer depressive symptoms (r=-0.22; p=0.007). Constructs were conceptually distinct with factor correlations below 0.60. Conclusion: Findings suggest that the Spanish-translated, abbreviated GMSR is a reliable and valid measure. These data expand the usability of the GMSR to TW in a Latin American, Spanish-speaking context.

When Addressing Trauma Makes a Difference: A Case Report of Undiagnosed Complex Post-traumatic Stress Disorder.

Complex post-traumatic stress disorder (C-PTSD) is an emergent diagnosis, which acknowledges the impact of prolonged interpersonal abuse on affect regulation, interpersonal functioning, and self-concept. We present the case of a 59-year-old woman who remained undiagnosed and untreated for this condition for three decades while under follow-up in mental health services for the diagnosis of personality disorder and bipolar disorder. The patient suffered repeated sexual abuse in her childhood, resulting in intrusive traumatic memories she emotionally and cognitively avoided, dissociative amnesia, a persistent inability to experience positive emotions, a persistent sense of guilt, re-experiencing phenomena, and hypervigilance toward others and their intentions to harm her. She persistently believed herself to be worthless, defective, inferior, and lacking value; had a history of affective dysregulation resulting in suspicion of bipolar disorder; and displayed a pattern of relationship avoidance. Addressing chronic trauma and assessing its impact offered deeper contextualization of the patient's symptoms and proved pivotal in redefining her diagnosis and providing access to trauma-focused psychotherapy, which is the mainstay of treatment for C-PTSD.

Fluorimetric determination of aqueous formaldehyde employing heating and ultrasound-assisted approach through its derivatization with a ß-diketone-nickel(2+) complex immobilized in a PMMA flow cell.

Formaldehyde (FA) is a highly toxic substance present in many matrices, including freshwater as well as found in natural mechanisms such as rainfall and combustion of organic matter. Consumption of water contaminated with high levels of FA can cause severe short-term or long-term health problems. Due to these health risks, procedures are necessary to determine and quantify FA in aqua sources This paper reports on a study of fluorimetric determination of FA using a nickel(2 + )-diketonate coordination compound immobilized as a solid precursor. The compound was characterized by electronic absorption, Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), thermogravimetry (TG), optical microscopy (OM), and scanner electron microscopy (SEM). The methodology was based on the reaction of the synthesized compound with an ammoniacal buffer generating a selective reagent for formaldehyde: fluoral-P. The product of the reaction generates 3,5-diacetyl-1,4-dihydrolutidine (DDL), which is responsible for the fluorescence of the system. Several parameters such as temperature, duration of heating time, and dilution effect with the best effects were studied to carry out FA determination. Under the optimum experimental conditions, a linear response ranging from 1.0 to 10.0 mg/L FA (R = 0.997 and n = 10), and a detection (3σ criterion) and quantification (10 σ criterion) limit estimated at 0.129 and 0.389 mg/L, respectively were achieved. The FA analysis was able to be conducted in 05 min with a relative standard deviation estimated at 1.10 %.

Drug disposal deserts: An assessment of receptacle availability in Kentucky community pharmacies.

PURPOSE: The purpose of this study was to describe the county-level availability of drug disposal receptacles in Kentucky community pharmacies and show the relationship between installed receptacles and opioid analgesic (OA)/controlled substance dispensing rates, stratifying where possible by urban-rural classification. METHODS: Using 2020 data from the Kentucky All Schedule Prescription Electronic Reporting program and disposal receptacle data from the US Drug Enforcement Agency, county-level comparisons were made between number of receptacles and OA/controlled substance dispensing rates. Logistic and negative binomial regression models were used to assess for differences between rural/urban county designation and odds of ≥1 disposal receptacle and compare the rates of receptacles per dispensed OA dose in rural/urban counties. FINDINGS: While rural counties saw higher OA and controlled substance dispensing rates, the majority (55.6%) of disposal receptacles were in urban locations. The odds of having at least 1 receptacle were higher in urban counties (OR 2.60, 95% CI: 1.15, 5.92) compared to rural. The estimated rate of disposal receptacles per million dispensed OA doses was found to be 0.47 (95% CI: 0.36, 0.61) in urban counties compared to 0.32 (95% CI: 0.25, 0.42) in rural counties, with an estimated rate ratio of 1.45 (95% CI: 1.01, 2.10). CONCLUSIONS: A mismatch between the availability of county-level disposal receptacles in community pharmacies and the volume of dispensed OAs/controlled substances exists, resulting in fewer receptacles per dispensed OA in rural counties compared to urban counties. Future efforts are necessary to increase access to convenient disposal receptacles located in community pharmacies, particularly in rural communities.

Evaluation of the Treatment with Akkermansia muciniphila BAA-835 of Chemotherapy-induced Mucositis in Mice.

Mucositis is a high-incidence side effect in cancer patients undergoing chemotherapy. Next-generation probiotics are emerging as new therapeutic tools for managing various disorders. Studies have demonstrated the potential of Akkermansia muciniphila to increase the efficiency of anticancer treatment and to mitigate mucositis. Due to the beneficial effect of A. muciniphila on the host, we evaluated the dose-response, the microorganism viability, and the treatment protocol of A. muciniphila BAA-835 in a murine model of chemotherapy-induced mucositis. Female Balb/c mice were divided into groups that received either sterile 0.9% saline or A. muciniphila by gavage. Mucositis was induced using a single intraperitoneal injection of 5-fluorouracil. The animals were euthanized three days after the induction of mucositis, and tissue and blood were collected for analysis. Prevention of weight loss and small intestine shortening and reduction of neutrophil and eosinophil influx were observed when animals were pretreated with viable A. muciniphila at 1010 colony-forming units per mL (CFU/mL). The A. muciniphila improved mucosal damage by preserving tissue architecture and increasing villus height and goblet cell number. It also improved the integrity of the epithelial barrier, decreasing intestinal permeability and bacterial translocation. In addition, the treatment prevented the expansion of Enterobacteriaceae. The immunological parameters were also improved by decreasing the expression of pro-inflammatory cytokines (IL6, IL1ß, and TNF) and increasing IL10. In conclusion, pretreatment with 1010 CFU/mL of viable A. muciniphila effectively controlled inflammation, protected the intestinal mucosa and the epithelial barrier, and prevented Enterobacteriaceae expansion in treated mice.

A combined experimental-molecular modeling study of crown ether europium complexes: Effects of the coordinated anion on structural and luminescence properties.

It is reported the synthesis, characterization by elemental analysis, thermogravimetry; electronic absorption, infrared, excitation, and emission spectroscopies of the [Eu(12C4)(phen)2(X)n]X2 complexes, where 12C4 = 12-crown-4, phen = 1,10-phenanthroline, and X  = F-, Cl-, Br-, SCN-, ClO4-, and NO3-. It is verified that the polarizability of the anion X- exerts remarkable effects on the emission process. As a general trend, lower wavenumbers for the 7F0→5L6, 7F0→5D2 and 7F0→5D1 transitions are associated with the anions with higher volumes and, consequently, higher polarizability. The molecular modeling results performed with quantum methods (RHF and DFT) suggest some relationships between the calculated structures, electronic, and luminescence properties with the presence of the LMCT (ligand-to-metal charge transfer) states, which explains the differences in the emission spectra of these complexes due to the coordinated anion.

Brief Report: Tyrosine Kinase Inhibitors for Lung Cancers That Inhibit MATE-1 Can Lead to "False" Decreases in Renal Function.

INTRODUCTION: Select tyrosine kinase inhibitors (TKIs) used to treat oncogene-driven lung cancers also inhibit MATE-1. When MATE-1 is blocked, creatinine is retained in the serum. Elevated creatinine levels raise the specter of drug-induced intrarenal insufficiency despite the lack of true renal injury. We conducted a systematic analysis of MATE-1 inhibitor (MATEi)-treated patients to comprehensively characterize this phenomenon. METHODS: Patients with oncogene-driven lung cancer treated with a wide variety of MATEi TKIs (brigatinib, cabozantinib, capmatinib, crizotinib, entrectinib, lorlatinib, pralsetinib, selpercatinib, and tepotinib) were eligible for an analysis of renal dysfunction. Acute kidney injury was classified on the basis of creatinine levels (Kidney Disease: Improving Global Outcomes criteria) as stage 1 (≥1.5× but <2× baseline), stage 2 (≥2× but <3× baseline), or stage 3 (>3× baseline). When available, cystatin C, a marker of kidney function unaffected by MATE-1, was used to evaluate the glomerular filtration rate (GFR). RESULTS: We identified 863 patients receiving MATEi TKIs including crizotinib (39%, n = 333), lorlatinib (17%, n = 144), cabozantinib (10%, n = 87), selpercatinib (10%, n = 82), capmatinib (9%, n = 77), brigatinib (6%, n = 53), entrectinib (5%, n = 45), tepotinib (5%, n = 41), and pralsetinib (0.1%, n = 1). Of the 90 patients (10%) with acute kidney injury, Kidney Disease: Improving Global Outcomes stages 1, 2, and 3 were observed in 72% (n = 65), 21% (n = 19), and 7% (n = 6) of patients, respectively. Concurrently drawn creatinine and cystatin C levels on TKI therapy were available for 17 patients. In most cases (n = 15 of 17), the calculated GFR was higher using cystatin C versus creatinine. The percentage of patients whose GFR was higher using cystatin C versus creatinine by less than 10 mL/min, 10 to 19 mL/min, 20 to 29 mL/min, and more than or equal to 30 mL/min was 27% (n = four of 15), 20% (n = three of 15), 20% (n = three of 15), and 33% (n = five of 15), respectively. Long-term data in three patients that spanned 3 years revealed that GFR was higher using cystatin C versus creatinine in 96% (n = 49 of 51) of all time points. Using a virtual clinical trial GFR cutoff of 40 mL/min, the percentage of eligible patients rose from 41% (n = seven of 17) using creatinine calculations to 71% (n = 12 of 17) using cystatin C calculations. CONCLUSIONS: The calculated GFR in patients with cancer receiving MATEi TKIs was higher in almost all cases when using cystatin C. When serum creatinine level seems elevated in patients receiving MATE-1 inhibitors, we recommend recalculating GFR using cystatin C before searching for other etiologies of kidney injury and reducing or stopping TKI therapy.

HDAC specificity and kinase off-targeting by purine-benzohydroxamate anti-hematological tumor agents.

A series of hybrid inhibitors, combining pharmacophores of known kinase inhibitors bearing anilino-purines (ruxolitinib, ibrutinib) and benzohydroxamate HDAC inhibitors (nexturastat A), were generated in the present study. The compounds have been synthesized and tested against solid and hematological tumor cell lines. Compounds 4d-f were the most promising in cytotoxicity assays (IC50 ≤ 50 nM) vs. hematological cells and displayed moderate activity in solid tumor models (EC50 = 9.3-21.7 µM). Compound 4d potently inhibited multiple kinase targets of interest for anticancer effects, including JAK2, JAK3, HDAC1, and HDAC6. Molecular dynamics simulations showed that 4d has stable interactions with HDAC and members of the JAK family, with differences in the hinge binding energy conferring selectivity for JAK3 and JAK2 over JAK1. The kinase inhibition profile of compounds 4d-f allows selective cytotoxicity, with minimal effects on non-tumorigenic cells. Moreover, these compounds have favorable pharmacokinetic profiles, with high stability in human liver microsomes (e.g., see t1/2: >120 min for 4f), low intrinsic clearance, and lack of significant inhibition of four major CYP450 isoforms.