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BackgroundBenfotiamine provides an important novel therapeutic direction in Alzheimer's disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches.ObjectiveTo conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD.MethodsThis is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA.ConclusionThe BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose.Trial registrationClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360.

ObjectivesTo make projections of cigarette consumption that incorporate state-specific trends in smoking behaviors, assess the potential for states to reach an ideal target, and identify State-specific targets for cigarette consumption.MethodsWe used 70 years (1950-2020) of annual state-specific estimates of per capita cigarette consumption (expressed as packs per capita or "ppc") from the Tax Burden on Tobacco reports (N = 3550). We summarized trends within each state by linear regression models and the variation in rates across states by the Gini coefficient. Autoregressive Integrated Moving Average (ARIMA) models were used to make state-specific forecasts of ppc from 2021 through 2035.ResultsSince 1980, the average rate of decline in US per capita cigarette consumption was 3.3% per year, but rates of decline varied considerably across US states (SD = 1.1% per year). The Gini coefficient showed growing inequity in cigarette consumption across US states. After reaching its lowest level in 1984 (Gini = 0.09), the Gini coefficient began increasing by 2.8% (95% CI: 2.5%, 3.1%) per year from 1985 to 2020 and is projected to continue to increase by 48.1% (95% PI = 35.3%, 64.2%) from 2020 to 2035 (Gini = 0.35; 95% PI: 0.32, 0.39). Forecasts from ARIMA models suggested that only 12 states have a realistic chance (≥50%) of reaching very low levels of per capita cigarette consumption (≤13 ppc) by 2035, but that all US states have opportunity to make some progress.ConclusionWhile ideal targets may be out of reach for most US states within the next decade, every US state has the potential to lower its per capita cigarette consumption, and our identification of more realistic targets may provide a helpful incentive.

BackgroundStatins have anti-inflammatory and immunomodulatory effects that may reduce the severity of coronavirus disease 2019 (COVID-19), in which organ dysfunction is mediated by severe inflammation. Large studies with diverse populations evaluating statin use and outcomes in COVID-19 are lacking.Methods and resultsWe used data from 10,541 patients hospitalized with COVID-19 through September 2020 at 104 US hospitals enrolled in the American Heart Association's COVID-19 Cardiovascular Disease (CVD) Registry to evaluate the associations between statin use and outcomes. Prior to admission, 42% of subjects (n = 4,449) used statins (7% on statins alone, 35% on statins plus anti-hypertensives). Death (or discharge to hospice) occurred in 2,212 subjects (21%). Outpatient use of statins, either alone or with anti-hypertensives, was associated with a reduced risk of death (adjusted odds ratio [aOR] 0.59, 95% CI 0.50-0.69), adjusting for demographic characteristics, insurance status, hospital site, and concurrent medications by logistic regression. In propensity-matched analyses, use of statins and/or anti-hypertensives was associated with a reduced risk of death among those with a history of CVD and/or hypertension (aOR 0.68, 95% CI 0.58-0.81). An observed 16% reduction in odds of death among those without CVD and/or hypertension was not statistically significant.ConclusionsPatients taking statins prior to hospitalization for COVID-19 had substantially lower odds of death, primarily among individuals with a history of CVD and/or hypertension. These observations support the continuation and aggressive initiation of statin and anti-hypertensive therapies among patients at risk for COVID-19, if these treatments are indicated based upon underlying medical conditions.

BackgroundMore smokers report using e-cigarettes to help them quit than FDA-approved pharmacotherapy.ObjectiveTo assess the association of e-cigarettes with future abstinence from cigarette and tobacco use.DesignCohort study of US sample, with annual follow-up.ParticipantsUS adult (ages 18+) daily cigarette smokers identified at Wave 1 (W1; 2013-14) of the PATH Study, who reported a quit attempt before W2 and completed W3 (n = 2443).ExposuresUse of e-cigarettes, pharmacotherapy (including nicotine replacement therapy), or no product for last quit attempt (LQA), and current daily e-cigarette use at W2.AnalysisPropensity score matching (PSM) of groups using different methods to quit.Outcome measures12+ months abstinence at W3 from cigarettes and from all tobacco (including e-cigarettes). 30+ days abstinence at W3 was a secondary outcome.ResultsAmong daily smokers with an LQA, 23.5% used e-cigarettes, 19.3% used pharmacotherapy only (including NRT) and 57.2% used no product. Cigarette abstinence for 12+ months at W3 was ~10% in each group. Half of the cigarette abstainers in the e-cigarette group were using e-cigarettes at W3. Different methods to help quitting had statistically comparable 12+ month cigarette abstinence at W3 (e-cigarettes vs no product: Risk Difference (RD) = 0.01, 95% CI: -0.04 to 0.06; e-cigarettes vs pharmacotherapy: RD = 0.02, 95% CI:-0.04 to 0.09). Likewise, daily e-cigarette users at W2 did not show a cessation benefit over comparable no-e-cigarette users and this finding was robust to sensitivity analyses. Abstinence for 30+ days at W3 was also similar across products.LimitationsThe frequency of e-cigarette use during the LQA was not assessed, nor was it possible to assess continuous abstinence from the LQA.ConclusionAmong US daily smokers who quit cigarettes in 2014-15, use of e-cigarettes in that attempt compared to approved cessation aids or no products showed similar abstinence rates 1-2 years later.

BACKGROUND:Lower rates of successful quitting among low-income populations in the United States may be from slower dissemination of smoke-free homes, a predictor of cessation. OBJECTIVES:To explore the role of smoke-free homes in cessation behavior across income levels. PARTICIPANTS:Current smokers who were ≥18 years and who participated in the longitudinal 2002-2003 (n = 2801) or 2010-2011 (n = 2723) Tobacco Use Supplements to the Current Population Survey. MEASUREMENTS:We categorized income as multiples of the federal poverty level (FPL) (300%FPL). Although similar in 2002, the prevalence of smoke-free homes was 33% lower among individuals living

[This corrects the article DOI: 10.1371/journal.pone.0201467.].

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

Nerve degeneration after transection injury decreases intraoperative visibility under white light (WL), complicating surgical repair. We show here that the use of fluorescently labeled nerve binding probe (F-NP41) can improve intraoperative visualization of chronically (up to 9 months) denervated nerves. In a mouse model for the repair of chronically denervated facial nerves, the intraoperative use of fluorescent labeling decreased time to nerve identification by 40% compared to surgeries performed under WL alone. Cumulative functional post-operative recovery was also significantly improved in the fluorescence guided group as determined by quantitatively tracking of the recovery of whisker movement at time intervals for 6 weeks post-repair. To our knowledge, this is the first description of an injectable probe that increases visibility of chronically denervated nerves during surgical repair in live animals. Future translation of this probe may improve functional outcome for patients with chronic denervation undergoing surgical repair.

Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal) pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC) mutations/ # total HC mutations).Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas.We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48) and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value 0.99), supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair.We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in both adult and children. Currently there are no reliable methods to determine disease severity, monitor disease progression, or efficacy of therapy, other than an invasive liver biopsy.Choline Deficient L-Amino Acid (CDAA) and high fat diets were used as physiologically relevant mouse models of NAFLD. Circulating extracellular vesicles were isolated, fully characterized by proteomics and molecular analyses and compared to control groups. Liver-related microRNAs were isolated from purified extracellular vesicles and liver specimens.We observed statistically significant differences in the level of extracellular vesicles (EVs) in liver and blood between two control groups and NAFLD animals. Time-course studies showed that EV levels increase early during disease development and reflect changes in liver histolopathology. EV levels correlated with hepatocyte cell death (r2 = 0.64, p

Although it is well-established that the macrophage M1 to M2 transition plays a role in tumor progression, the molecular basis for this process remains incompletely understood. Herein, we demonstrate that the small GTPase, Rac2 controls macrophage M1 to M2 differentiation and the metastatic phenotype in vivo. Using a genetic approach, combined with syngeneic and orthotopic tumor models we demonstrate that Rac2-/- mice display a marked defect in tumor growth, angiogenesis and metastasis. Microarray, RT-PCR and metabolomic analysis on bone marrow derived macrophages isolated from the Rac2-/- mice identify an important role for Rac2 in M2 macrophage differentiation. Furthermore, we define a novel molecular mechanism by which signals transmitted from the extracellular matrix via the α4β1 integrin and MCSF receptor lead to the activation of Rac2 and potentially regulate macrophage M2 differentiation. Collectively, our findings demonstrate a macrophage autonomous process by which the Rac2 GTPase is activated downstream of the α4β1 integrin and the MCSF receptor to control tumor growth, metastasis and macrophage differentiation into the M2 phenotype. Finally, using gene expression and metabolomic data from our Rac2-/- model, and information related to M1-M2 macrophage differentiation curated from the literature we executed a systems biologic analysis of hierarchical protein-protein interaction networks in an effort to develop an iterative interactome map which will predict additional mechanisms by which Rac2 may coordinately control macrophage M1 to M2 differentiation and metastasis.

Activin receptor 2 (ACVR2) is commonly mutated in microsatellite unstable (MSI) colon cancers, leading to protein loss, signaling disruption, and larger tumors. Here, we examined activin signaling disruption in microsatellite stable (MSS) colon cancers.Fifty-one population-based MSS colon cancers were assessed for ACVR1, ACVR2 and pSMAD2 protein. Consensus mutation-prone portions of ACVR2 were sequenced in primary cancers and all exons in colon cancer cell lines. Loss of heterozygosity (LOH) was evaluated for ACVR2 and ACVR1, and ACVR2 promoter methylation by methylation-specific PCR and bisulfite sequencing and chromosomal instability (CIN) phenotype via fluorescent LOH analysis of 3 duplicate markers. ACVR2 promoter methylation and ACVR2 expression were assessed in colon cancer cell lines via qPCR and IP-Western blots. Re-expression of ACVR2 after demethylation with 5-aza-2'-deoxycytidine (5-Aza) was determined. An additional 26 MSS colon cancers were assessed for ACVR2 loss and its mechanism, and ACVR2 loss in all tested cancers correlated with clinicopathological criteria.Of 51 MSS colon tumors, 7 (14%) lost ACVR2, 2 (4%) ACVR1, and 5 (10%) pSMAD2 expression. No somatic ACVR2 mutations were detected. Loss of ACVR2 expression was associated with LOH at ACVR2 (p