Citations

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Background and Aims: Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the biliary epithelium with limited therapeutic options and poor long-term survival rates. To address the limitations of CCA treatment, we investigated cell-targeted nanovesicles as a delivery platform for transcriptome-targeting therapeutics. Approach and Results: Milk-derived nanovesicles were loaded with short interfering RNAs targeting Yes-associated protein (YAP), the downstream effector of the Hippo pathway; LCK, an upstream regulator of YAP; and tafazzin, a protein critical for the integrity of the inner mitochondrial membrane. These transcriptome-targeting nanovesicles were decorated with a lipid-coupled RNA aptamer to epithelial cell adhesion molecule, including a tracking fluorophore. In vitro studies were conducted using multiple CCA cell lines. In vivo studies were performed using C57BL/6 and non-obese diabetic/severe combined immunodeficient mice to evaluate delivery and efficacy in both an immunocompetent syngeneic murine and a patient-derived xenograft model. We demonstrated that transcriptome-targeting nanovesicles were selectively taken up by liver tumor cells, which was augmented by the incorporation of a targeting aptamer, and that milk-derived nanovesicles loaded with short interfering RNA effectively downregulated target gene expression, both in vitro and in vivo. Downstream effects of target gene inhibition were observed, including downregulation of YAP-TEAD target genes and an increase in reactive oxygen species production at the mitochondrial level. Administration of transcriptome-targeting nanovesicles targeting YAP, LCK, and tafazzin inhibited CCA growth and further synergized with chemotherapy in 2 preclinical CCA models. Conclusions: Herein, we show that aptamer-directed, nanovesicle-mediated targeting of YAP, LCK, and tafazzin potentiates chemosensitivity in 2 CCA models when delivered using aptamer-guided milk-derived nanovesicles.

Abstract Background Coccidioidomycosis (cocci) is a fungal infection caused by Coccidioides and a common cause of community acquired pneumonia in endemic regions. Disseminated cocci occurs in ≤ 1% of persons with cocci, and among these, disseminated cutaneous coccidioidomycosis (DCC) is estimated to occur in 15 to 67% of cases, however little data exists to describe its frequency and timing of recurrence. Limited small studies show recurrence rates from 17 to 50% and often do not distinguish skin dissemination from other soft tissues. Our aim was to determine the frequency, timeframe and risk factors for relapsed DCC. Methods Potential cases of disseminated cocci were identified by ICD-10 codes 38.3, 38.7, 38.9 (& ICD-9 equivalents) and keyword-based search of pathology reports from 1/1/2008 - 3/31/2024. We included patients with proven or probable DCC. We excluded patients with primary cutaneous cocci or reactive rash. We performed a retrospective review to identify episodes of recurrence, comorbidities, and antifungal regimen. Results We identified 44 proven and 3 probable cases of DCC (33 males, 14 females), median age 48 years, 66.0% white, 21.3% black, 5.4% Hispanic. 18 (38.3%) were immunosuppressed and 6 (13.6%) had diabetes mellitus. Median follow-up duration was 68 months; 12 (25.5%) patients had ≥1 recurrence, 7 (14.9%) of whom relapsed ≥2 times. Median interval off of antifungals until recurrence was 14 months (range: 1 - 96). 3 (6.4%) patients had recurrence within three months of diagnosis, and 6 (13.0%) and 11 (23.9%) had a recurrence by the 1st and 5th follow-up year, respectively. 21 (87.5%) recurrences were at the same site as a prior occurrence, 4 (18.2%) occurred on antifungal therapy. There were no significant differences in recurrence rates by race or diabetes. Of the 18 immunosuppressed cases, there was 1 (5.6%) recurrence, though 14 (77.8%) continued antifungal therapy throughout follow-up. Conclusion Once antifungal treatment was discontinued, recurrence of disseminated cutaneous cocci was common, and among those whose DCC relapsed, multiple relapses were noted. Longer follow up is needed to better characterize the risk of long-term recurrence. Disclosures All Authors: No reported disclosures

Background: Randomized controlled trials (RCTs) evaluating the efficacy of platelet-rich plasma (PRP) for the management of lateral epicondylitis (LE) have been characterized by substantial variability in reported outcomes. The source of this heterogeneity is uncertain. Purpose: To determine the effect of estimated platelet concentration on the efficacy of PRP for the management of LE. Study Design: Systematic review and meta-analysis; Level of evidence, 2. Methods: All RCTs evaluating the efficacy of PRP in managing LE were identified. RCTs were classified according to whether the study documented a platelet concentration factor of PRP representing a greater than 3-fold increase over whole blood or a supraphysiological platelet dose (high-dose vs low-dose PRP). The primary outcome was the mean difference (MD) in the visual analog scale (VAS) score at latest follow-up. Random-effects and mixed-effects meta-analyses were performed, and meta-regression was used to evaluate whether differences in outcomes after treatment with PRP could be explained by differences in the concentration of PRP used. Results: Overall, 13 RCTs with a total of 791 patients were included in this analysis, with 5 that utilized low-dose PRP and 8 that used high-dose PRP. Meta-analysis of VAS scores reported by studies that used high-dose PRP resulted in an MD of −1.31 (95% CI, −1.87 to −0.75) in favor of PRP over all alternative treatment strategies ( P < .001). Meta-analysis of VAS scores reported by studies that used low-dose PRP resulted in an MD of 0.08 (95% CI, −0.51 to 0.68), suggesting no difference in the effect between PRP and all alternative treatment strategies ( P = .79). The platelet concentration factor of PRP used in each RCT was found to be strongly predictive of the VAS score at final follow-up in meta-regression ( P < .001), with 58.5% of the heterogeneity in the outcomes of PRP between studies explained by the platelet concentration factor alone. Conclusion: The platelet concentration of PRP may play a significant role in the outcomes of patients with LE. A direct linear relationship was observed between the platelet concentration factor of PRP used and the magnitude of patient-reported symptom relief after the management of LE with PRP. Clinicians should ensure a supraphysiological platelet concentration when preparing PRP for the management of LE.