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Translational strategies to characterize and monitor extracellular vesicles such as exosome (EX) shedding and the clinical impact of this data within hepatocellular carcinoma (HCC) remains unclear. In this study, EX shedding was assessed in early-stage HCC and evaluated as a stratification factor for time to progression (TTP) following first-cycle liver-directed therapy (LDT). Plasma EXs were isolated from HCC patients undergoing LDT using ultracentrifugation. Purified EXs were stained using markers CD9 and CD63 and quantified using an ImageStreamX flow cytometer. Circulating EXs expressing CD9 were isolated at 10-fold higher levels compared to CD63. The intensity of CD9+ EX shedding following LDT was positively correlated with treatment response. High post-LDT CD9+ EX shedding stratified TTP risk with a 30% lower frequency of disease progression at 1 year following LDT. Post-LDT high CD9+ EX shedding was observed in 100% (10/10) of patients successfully bridged to liver transplantation while only 22% (2/9) of patients with tumor progression had high CD9+ EX shedding post-LDT. CD9+ EX shedding also stratified TTP risk within the first cycle objective response rate (ORR) group, identifying patients still at higher disease progression. EX shedding was concordant with imaging response rate, stratified TTP in early-stage HCC, and may have important implications for assessing post-LDT viable, biologically aggressive HCC.

Priyanka Kolli,1 Grace Kelley,1 Marianela Rosales,2 Justin Faden,1 Ryan Serdenes3 1Department of Psychiatry, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 2Department of Psychiatry and Human Behavior, Thomas Jefferson University Hospital, Philadelphia, PA, USA; 3Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USACorrespondence: Ryan Serdenes, Email rserdenes@gmail.comAbstract: Olanzapine is one of the most widely used antipsychotics since its initial approval by the US Food and Drug Administration in 1996 and has undergone extensive pharmacokinetic study. Despite being utilized in clinical psychiatry for decades, there remain questions regarding the variety of available formulations, the utility of therapeutic drug monitoring, altered kinetic properties in special populations/medical illnesses, the use of high-dose olanzapine, and drug interactions, among many others. We performed a narrative literature review of olanzapine pharmacokinetics in June 2023 using the US National Library of Medicine’s PubMed.gov resource (https://www.ncbi.nlm.nih.gov/pubmed) and Google Scholar. Herein, we review clinically relevant aspects of olanzapine pharmacokinetic data while highlighting knowledge gaps and potential areas of future study.Keywords: olanzapine, pharmacokinetics, drug-drug interactions, pharmacodynamics, clinical psychopharmacology

Disruptive variants in lysine methyl transferase 5B (KMT5B/SUV4-20H1) have been identified as likely-pathogenic among humans with neurodevelopmental phenotypes including motor deficits (i.e., hypotonia and motor delay). However, the role that this enzyme plays in early motor development is largely unknown. Using a Kmt5b gene trap mouse model, we assessed neuromuscular strength, skeletal muscle weight (i.e., muscle mass), neuromuscular junction (NMJ) structure, and myofiber type, size, and distribution. Tests were performed over developmental time (postnatal days 17 and 44) to represent postnatal versus adult structures in slow- and fast-twitch muscle types. Prior to the onset of puberty, slow-twitch muscle weight was significantly reduced in heterozygous compared to wild-type males but not females. At the young adult stage, we identified decreased neuromuscular strength, decreased skeletal muscle weights (both slow- and fast-twitch), increased NMJ fragmentation (in slow-twitch muscle), and smaller myofibers in both sexes. We conclude that Kmt5b haploinsufficiency results in a skeletal muscle developmental deficit causing reduced muscle mass and body weight.

BackgroundHepatocellular carcinoma is a heterogeneous tumor that accumulates a mutational burden and dysregulated signaling pathways that differ from early to advanced stages. Liver transplant candidates with early-stage hepatocellular carcinoma (HCC) undergo liver-directed therapy (LDT) to delay disease progression and serve as a bridge to liver transplantation (LT). Unfortunately, >80% of LDT-treated patients have viable HCC in the explant liver, dramatically increasing recurrence risk. Understanding the effect of LDT on early-stage HCC could help identify therapeutic targets to promote complete pathologic necrosis and improve recurrence-free survival. In this study, transcriptomic data from viable HCC in LDT-treated bridged to transplant patients were investigated to understand how treatment may affect tumor signaling pathways.MethodsMultiplex transcriptomic gene analysis was performed with mRNA extracted from viable tumors of HCC patients bridged to transplant using LDT. The NanoString nCounter® Tumor Signaling 360 panel was used that contained 780 genes from 48 pathways involved in tumor biology within the microenvironment as well as antitumoral immune responses.ResultsHierarchical clustering separated tumors into three subtypes (HCC-1, HCC-2, and HCC-3) each with distinct differences in anti-tumoral signaling and immune infiltration within the tumor microenvironment. Immune infiltration (neutrophils, T cells, and macrophages) were all lowest in subtype HCC-3. The tumor inflammatory signature consisting of 18 genes associated with PD-1/PD-L1 inhibition, antigen presentation, chemokine secretion, and adaptive immune responses was highest in subtype HCC-1 and lowest in HCC-3. History of decompensation and etiology were associated with HCC subtype favoring downregulations in inflammation and immune infiltration with upregulation of lipid metabolism. Gene expression among intrahepatic lesions was remarkably similar with >85% of genes expressed in both lesions. Genes differentially expressed (

Introduction: It is widely accepted that pathophysiological changes to the central nervous system of persons with Parkinson’s disease (PD) result in negative effects on motor function. However, less information is known regarding the pathology of PD on skeletal muscle. The purpose of this study was to determine the effect of a fatiguing isometric knee extension protocol on muscle mechanics using evoked twitch contractions in persons with PD and in non-impaired older adults (OLD). Methods: Evoked twitch contractions were examined during a fatiguing protocol in PD (66 ± 9 yr, n = 8) and OLD (65 ± 10 yr, n = 5). Participants performed 5-sec maximal isometric voluntary contractions of the quadriceps femoris with 5-sec rest for 3-min. Every 30-sec during rest intervals, a maximal transcutaneous electrical stimulus was administered to the quadriceps femoris to quantify evoked peak twitch torque (pTT), peak relaxation rate (pRR), and peak rate of torque development (pRTD). Results: A large effect of voluntary fatigue (%decline) was observed (g = 1.58). There were no significant differences in pTT (p = 0.09; 95% CI:-3.6, 0.28) or pRR (p = 0.11; 95% CI:-31, 3.6). However, the slope decline of pRTD in OLD (-35.4 ± 24.7) was greater than PD (-11.5 ± 11.4; p = 0.03), indicating that skeletal muscle in persons with PD is less fatigable compared to non-impaired older adults. Conclusion: The rate, not the maximum capacity, of torque generation of the muscle during a fatiguing knee extension protocol was affected by PD. Future studies are warranted to identify the mechanism(s) responsible for the observed differences in skeletal muscle contractile characteristics and potential myofiber distribution variation in PD.

When entry-level designers transition into the workplace, new responsibilities and adjustments to organizational procedures may cause uncertainty, even prior to COVID-19. Studies have shown that positive mentorship relationships can help newer protégés advance in their professional and individual career goals. This study employed a mixed-methods survey to understand the mentorship opportunities available to emerging designers and the impact of remote work on these dynamics. Quantitative and qualitative data were analyzed from eighty-five respondents using Ragins and McFarlin's RMMRI instrument. Participants reported an average of 1.84 formal mentors and 4.01 informal mentors, which were significantly positively associated with overall average mentor role scores. Participants indicated that they were most likely to receive individual categories of "acceptor" and "friend." Yet, contextual factors (i.e., firm size and market sector) did not significantly influence mentor roles. Further, those from underrepresented groups scored "acceptor" significantly worse than their counterparts, yet they did not score mentor quality significantly differently. Qualitative insights indicated "coaching," "acceptance," and "counselor" were the primary mentor roles received by the participants. Other quantitative findings revealed that remote work had little impact on mentorship perceptions during COVID-19. Together, these findings help build understanding surrounding mentorship in design praxis. [ABSTRACT FROM AUTHOR]

Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%). Animals underwent diet withdrawal to control chow and/or underwent ischemia reperfusion and partial hepatectomy injury (I/R-PHx) and reperfused out to 7 days on control chow. For animals with severe macrosteatosis, hepatic levels of IL-33 decreased while Cyclin D1 levels increased in the absence of NF-κB p65 phosphorylation. Animals with high levels of nuclear Cyclin D1 prior to I/R-PHx either did not survive or had persistent macrosteatosis after 7 days on control chow. Survival 7 days after I/R-PHx fell to 57% which correlated with increased Cyclin D1 and decreased liver IL-33 levels. In the absence of I/R-PHx, withdrawing the MCD diet normalized IL-33, Cyclin D1 levels, and I/R-PHx survival back to baseline. In transplanted grafts with macrosteatosis, higher Cyclin D1 mRNA expression was observed. Shifts in Cyclin D1 and IL-33 expression may identify severely macrosteatotic livers with increased failure risk if subjected to I/R injury. Clinical validation of the panel in donor grafts with macrosteatosis revealed increased Cyclin D1 expression corresponding to delayed graft function. This pre-surgical biomarker panel may identify the subset of livers with increased susceptibility to PNF.

Ferreira, LC, Weiss, LW, Hammond, KG, and Schilling, BK. Structural and functional predictors of drop vertical jump. J Strength Cond Res 24(9): 2456-2467, 2010--This investigation was designed to determine if relatively small manipulations of squat load and the inclusion of selected morphologic variables might augment the explained variance in vertical jump (VJ) displacement. Fifty-two university students (27 women and 25 men) with weight training experience served as subjects. All were assessed for body fat percentage (BF%), height, body wei9ht (BW), leg length (LL), ankle range of motion, and quadriceps angle (Q-angle). Additionally, subjects performed drop vertical jumps (DVJs) and both countermovement jump (CMJ) squats and static jump (S J) squats at 20, 30, and 40% of their back squat 1 repetition maximum (1RM). A preliminary analysis revealed that [DVJ.sub.cm] for all subjects (28.1 [+ or -] 6.64; mean [+ or -] SD) was most highly correlated with both CMJ @ 30% 1RM (CMJ30PP) and SJ @ 20% 1RM (SJ20PP) (r = 0.84, p < 0.001). Forced multiple regression was then used to determine which variables contributed to VJ displacement. The greatest variability explained (83%) used a CMJ: [DVJ.sub.cm] = 20.311 + (0.008) (CMJ30PP) (0.346) (BW). When the same variables were used to calculate separate gender-based regressions, the explained variance in [DVJ.sub.cm] (men = 33.0 [+ or -] 5.34 cm; women = 23.4 [+ or -] 3.79 cm) was 68% for men and 64% for women. These findings suggest that jump squat peak power at a light load is a good predictor of VJ and that its training-induced augmentation would likely improve VJ. The addition of BW to the equation explained slightly more variability in [DVJ.sub.cm] than in BF%. Because excess amounts of either would be an additional load to be moved against gravity (fat in general or skeletal muscle in the upper torso), it follows that relatively high levels of either might be expected to attenuate VJ performance. KEY WORDS jump performance, muscular strength, muscular power morphologic characteristics