Selective inhibition of overactive warmth-sensitive Ca2+-permeable TRPV3 channels by antispasmodic agent flopropione for alleviation of skin inflammation.

The temperature-sensitive Ca2+-permeable TRPV3 ion channel is robustly expressed in the skin keratinocytes, and its gain-of-function mutations are involved in the pathology of skin lesions. Here, we report the identification of an antispasmodic agent flopropione that alleviates skin inflammation by selective inhibition of TRPV3. In whole-cell patch clamp recordings, flopropione selectively inhibits macroscopic TRPV3 currents in a concentration-dependent manner with an IC50 value of 17.8 ± 3.5 µM. At the single-channel level, flopropione inhibits TRPV3 channel open probability without alteration of its unitary conductance. In an in vivo mouse model of skin inflammation induced by the skin sensitizer DNFB, flopropione also alleviates dorsal skin lesions and ear skin swelling. Further molecular docking combined with site-directed mutagenesis reveals that two residues E501 and I505 in the channel S2-helix are critical for flopropione-mediated inhibition of TRPV3. Taken together, our findings demonstrate that the spasmolytic drug flopropione as a selective inhibitor of TRPV3 channel not only provides a valuable tool molecule for understanding of TRPV3 channel pharmacology but also holds repurposing potential for therapy of skin disorders, such as dermatitis and pruritus.

Inhibition of cutaneous heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 channels alleviates UVB-induced skin lesions in mice.

Ultraviolet B (UVB) radiation causes skin injury by trigging excessive calcium influx and signaling cascades in the skin keratinocytes. The heat-sensitive Ca2+ -permeable transient receptor potential vanilloid 3 (TRPV3) channels robustly expressed in the keratinocytes play an important role in skin barrier formation and wound healing. Here, we report that inhibition of cutaneous TRPV3 alleviates UVB radiation-induced skin lesions. In mouse models of ear swelling and dorsal skin injury induced by a single exposure of weak UVB radiation, TRPV3 genes and proteins were upregulated in quantitative real-time PCR and Western blot assays. In accompany with TRPV3 upregulations, the expressions of proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were also increased. Knockout of the TRPV3 gene alleviates UVB-induced ear swelling and dorsal skin inflammation. Furthermore, topical applications of two selective TRPV3 inhibitors, osthole and verbascoside, resulted in a dose-dependent attenuation of skin inflammation and lesions. Taken together, our findings demonstrate the causative role of overactive TRPV3 channel function in the development of UVB-induced skin injury. Therefore, topical inhibition of TRPV3 may hold potential therapy or prevention of UVB radiation-induced skin injury.

Enhancing catalytic activity of Cr2O3 in CO2-assisted propane dehydrogenation with effective dopant engineering: a DFT-based microkinetic simulation.

Using CO2 as a mild oxidizing agent in propane dehydrogenation (PDH) presents an attractive pathway for the generation of propene while maintaining high selectivity. Cr2O3 is one of the most important catalysts used for the CO2-assisted PDH process. In this study, the doping of Cr2O3 with single atoms such as Ge, Ir, Ni, Sn, Zn, and Zr was used for the PDH process. The introduction of dopants significantly modifies the electronic structure of pristine Cr2O3, leading to substantial alterations in its catalytic capabilities. The dehydrogenation reactions were explored both in the absence and presence of CO2. The addition of CO2 introduces two distinct pathways for PDH. On physisorbed CO2 surfaces, Ge and Ni-Cr2O3 enhance dehydrogenation. On the dissociated surface, the CO* and O* species actively participate in the reaction. All doped surfaces exhibit low energy barriers for dehydrogenation, except undoped Cr2O3 on dissociated CO2 surfaces. The Ni-Cr2O3 surface emerges as the most active surface for dehydrogenation of propane in all scenarios. Additionally, the catalytic surface is re-oxidized through H2 release, and doped surfaces facilitate coke removal via the reverse Boudouard reaction more efficiently than undoped Cr2O3. Microkinetics simulations identify the removal of the first H-atom as the rate-determining step. CO2 reduces the apparent activation energy, directly impacting C3H8 conversion and C3H6 formation. This study offers a decisive description of Cr2O3 modification for the CO2-assisted PDH process.

The impact of intimate partner violence on PrEP adherence among U.S. Cisgender women at risk for HIV.

BACKGROUND: Cisgender women account for 1 in 5 new HIV infections in the United States, yet remain under-engaged in HIV prevention. Women experiencing violence face risk for HIV due to biological and behavioral mechanisms, and barriers to prevention, such as challenges to Pre-Exposure Prophylaxis for HIV Prevention (PrEP) adherence. In this analysis, we aim to characterize intimate partner violence (IPV) among cisgender heterosexual women enrolled in a PrEP demonstration project and assess the associations with PrEP adherence. METHODS: Adherence Enhancement Guided by Individualized Texting and Drug Levels (AEGiS) was a 48-week single-arm open-label study of PrEP adherence in HIV-negative cisgender women in Southern California (N = 130) offered daily tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). From 6/2016 to 10/2018, women completed a survey reporting HIV risk behavior and experiences of any IPV (past 90-days) and IPV sub-types (past-year, lifetime) and biological testing for HIV/STIs at baseline, and concentrations of tenofovir-diphosphate (TFV-DP) in dried blood spots at weeks 4, 12, 24, 36, and 48. Outcomes were TFV-DP concentrations consistent with ≥ 4 or ≥ 6 doses/week at one or multiple visits. Multivariable logistic regression models were conducted to examine associations. RESULTS: Past-90-day IPV was reported by 34.4% of participants, and past-year and lifetime subtypes reported by 11.5-41.5%, and 21.5-52.3%, respectively. Women who engaged in sex work and Black women were significantly more likely to report IPV than others. Lifetime physical IPV was negatively associated with adherence at ≥ 4 doses/week at ≥ 3 of 5 visits, while other relationships with any IPV and IPV sub-types were variable. CONCLUSION: IPV is an indication for PrEP and important indicator of HIV risk; our findings suggest that physical IPV may also negatively impact long-term PrEP adherence. CLINICAL TRIALS REGISTRATION: NCT02584140 (ClinicalTrials.gov), registered 15/10/2015.

Molecular determinants for the chemical activation of the warmth-sensitive TRPV3 channel by the natural monoterpenoid carvacrol.

Transient receptor potential vanilloid 3 (TRPV3), robustly expressed in the skin, is a nonselective calcium-permeable cation channel activated by warm temperature, voltage, and certain chemicals. Natural monoterpenoid carvacrol from plant oregano is a known skin sensitizer or allergen that specifically activates TRPV3 channel. However, how carvacrol activates TRPV3 mechanistically remains to be understood. Here, we describe the molecular determinants for chemical activation of TRPV3 by the agonist carvacrol. Patch clamp recordings reveal that carvacrol activates TRPV3 in a concentration-dependent manner, with an EC50 of 0.2 mM, by increasing the probability of single-channel open conformation. Molecular docking of carvacrol into cryo-EM structure of TRPV3 combined with site-directed mutagenesis further identified a unique binding pocket formed by the channel S2-S3 linker important for mediating this interaction. Within the binding pocket consisting of four residues (Ile505, Leu508, Arg509, and Asp512), we report that Leu508 is the most critical residue for the activation of TRPV3 by carvacrol, but not 2-APB, a widely used nonspecific agonist and TRP channel modulator. Our findings demonstrate a direct binding of carvacrol to TRPV3 by targeting the channel S2-S3 linker that serves as a critical domain for chemical-mediated activation of TRPV3. We also propose that carvacrol can function as a molecular tool in the design of novel specific TRPV3 modulators for the further understanding of TRPV3 channel pharmacology.

Selective activation of TRPA1 ion channels by nitrobenzene skin sensitizers DNFB and DNCB.

2, 4-dinitrofluorobenzene (DNFB) and 2, 4-dinitrochlorobenzene (DNCB) are well known as skin sensitizers that can cause dermatitis. DNFB has shown to more potently sensitize skin; however, how DNFB and DNCB cause skin inflammation at a molecular level and why this difference in their sensitization ability is observed remain unknown. In this study, we aimed to identify the molecular targets and mechanisms on which DNFB and DNCB act. We used a fluorescent calcium imaging plate reader in an initial screening assay before patch-clamp recordings for validation. Molecular docking in combination with site-directed mutagenesis was then carried out to investigate DNFB and DNCB binding sites in the TRPA1 ion channel that may be selectively activated by these tow sensitizers. We found that DNFB and DNCB selectively activated TRPA1 channel with EC50 values of 2.3 ± 0.7 µM and 42.4 ± 20.9 µM, respectively. Single-channel recordings revealed that DNFB and DNCB increase the probability of channel opening and act on three residues (C621, E625, and Y658) critical for TRPA1 activation. Our findings may not only help explain the molecular mechanism underlying the dermatitis and pruritus caused by chemicals such as DNFB and DNCB, but also provide a molecular tool 7.5-fold more potent than the current TRPA1 activator allyl isothiocyanate (AITC) used for investigating TRPA1 channel pharmacology and pathology.

Aberrant promoter methylation of Wnt inhibitory factor-1 gene is a potential target for treating psoriasis.

Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a critical role in psoriasis, but how the Wnt pathway is regulated in psoriatic skin and whether it can be exploited for therapeutic benefits is unclear. By comparing biopsies from healthy and psoriatic skin, we found that Wnt inhibitory factor 1 (WIF1), an inhibitor of Wnt signaling, showed reduced expression at both mRNA and protein levels in psoriatic skin. We then quantified methylation of the WIF1 gene promoter by DNA methylation sequencing and found that the WIF1 promoter region was hypermethylated. We further showed that recombinant WIF1 injection ameliorates the imiquimod (IMQ) mouse model of psoriasis. We also revealed that treatment with the DNA methylation inhibitor, decitabine, inhibited proliferation of immortalized human keratinocytes (HaCaT) in a psoriasis-like inflammatory environment. Finally, we applied decitabine to the IMQ mouse model and demonstrated that treatment of mice with decitabine ameliorates the disease. Therefore, our study reveals that methylation of the WIF1 gene is associated with the pathogenesis of psoriasis, and suggests that pharmacological targeting of DNA methylation is a potential treatment strategy for psoriasis.

Spatiotemporal evolution of AML immune microenvironment remodeling and RNF149-driven drug resistance through single-cell multidimensional analysis.

BACKGROUND: The composition of the bone marrow immune microenvironment in patients with acute myeloid leukaemia (AML) was analysed by single-cell sequencing and the evolutionary role of different subpopulations of T cells in the development of AML and in driving drug resistance was explored in conjunction with E3 ubiquitin ligase-related genes. METHODS: To elucidate the mechanisms underlying AML-NR and Ara-C resistance, we analyzed the bone marrow immune microenvironment of AML patients by integrating multiple single-cell RNA sequencing datasets. When compared to the AML disease remission (AML-CR) cohort, AML-NR displayed distinct cellular interactions and alterations in the ratios of CD4+T, Treg, and CD8+T cell populations. RESULTS: Our findings indicate that the E3 ubiquitin ligase RNF149 accelerates AML progression, modifies the AML immune milieu, triggers CD8+T cell dysfunction, and influences the transformation of CD8+ Navie.T cells to CD8+TExh, culminating in diminished AML responsiveness to chemotherapeutic agents. Experiments both in vivo and in vitro revealed RNF149's role in enhancing AML drug-resistant cell line proliferation and in apoptotic inhibition, fostering resistance to Ara-C. CONCLUSION: In essence, the immune microenvironments of AML-CR and AML-NR diverge considerably, spotlighting RNF149's tumorigenic function in AML and cementing its status as a potential prognostic indicator and innovative therapeutic avenue for countering AML resistance.

Association of obesity with mild traumatic brain injury symptoms, inflammatory profile, quality of life and functional outcomes: a TRACK-TBI Study.

OBJECTIVES: Obesity is associated with chronic inflammation, which may impact recovery from mild traumatic brain injury (mTBI). The objective was to assess the role of obesity in recovery of symptoms, functional outcome and inflammatory blood biomarkers after mTBI. METHODS: TRACK-TBI is a prospective study of patients with acute mTBI (Glasgow Coma Scale=13-15) who were enrolled ≤24 hours of injury at an emergency department of level 1 trauma centres and followed for 12 months. A total of 770 hospitalised patients who were either obese (body mass index (BMI) >30.0) or healthy mass (BMI=18.5-24.9) were enrolled. Blood concentrations of high-sensitivity C reactive protein (hsCRP), interleukin (IL) 6, IL-10, tumour necrosis factor alpha; Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Quality of Life After Brain Injury and Glasgow Outcome Score-Extended reflecting injury-related functional limitations at 6 and 12 months were collected. RESULTS: After adjusting for age and gender, obese participants had higher concentrations of hsCRP 1 day after injury (mean difference (MD)=0.65; 95% CI: 0.44 to 0.87, p<0.001), at 2 weeks (MD=0.99; 95% CI: 0.74 to 1.25, p<0.001) and at 6 months (MD=1.08; 95% CI: 0.79 to 1.37, p<0.001) compared with healthy mass participants. Obese participants had higher concentrations of IL-6 at 2 weeks (MD=0.37; 95% CI: 0.11 to 0.64, p=0.006) and 6 months (MD=0.42; 95% CI: 0.12 to 0.72, p=0.006). Obese participants had higher RPQ total score at 6 months (MD=2.79; p=0.02) and 12 months (MD=2.37; p=0.049). CONCLUSIONS: Obesity is associated with higher symptomatology at 6 and 12 months and higher concentrations of blood inflammatory markers throughout recovery following mTBI.

Social network size and personality traits independently and prospectively predict distress disorders and suicidal behavior in U.S. Army soldiers.

BACKGROUND: Personality traits (e.g. neuroticism) and the social environment predict risk for internalizing disorders and suicidal behavior. Studying these characteristics together and prospectively within a population confronted with high stressor exposure (e.g. U.S. Army soldiers) has not been done, yet could uncover unique and interactive predictive effects that may inform prevention and early intervention efforts. METHODS: Five broad personality traits and social network size were assessed via self-administered questionnaires among experienced soldiers preparing for deployment (N = 4645) and new soldiers reporting for basic training (N = 6216). Predictive models examined associations of baseline personality and social network variables with recent distress disorders or suicidal behaviors assessed 3- and 9-months post-deployment and approximately 5 years following enlistment. RESULTS: Among the personality traits, elevated neuroticism was consistently associated with increased mental health risk following deployment. Small social networks were also associated with increased mental health risk following deployment, beyond the variance accounted for by personality. Limited support was found for social network size moderating the association between personality and mental health outcomes. Small social networks also predicted distress disorders and suicidal behavior 5 years following enlistment, whereas unique effects of personality traits on these more distal outcomes were rare. CONCLUSIONS: Heightened neuroticism and small social networks predict a greater risk for negative mental health sequelae, especially following deployment. Social ties may mitigate adverse impacts of personality traits on psychopathology in some contexts. Early identification and targeted intervention for these distinct, modifiable factors may decrease the risk of distress disorders and suicidal behavior.

Effects of prior deployments and perceived resilience on anger trajectories of combat-deployed soldiers.

BACKGROUND: Problematic anger is frequently reported by soldiers who have deployed to combat zones. However, evidence is lacking with respect to how anger changes over a deployment cycle, and which factors prospectively influence change in anger among combat-deployed soldiers. METHODS: Reports of problematic anger were obtained from 7298 US Army soldiers who deployed to Afghanistan in 2012. A series of mixed-effects growth models estimated linear trajectories of anger over a period of 1-2 months before deployment to 9 months post-deployment, and evaluated the effects of pre-deployment factors (prior deployments and perceived resilience) on average levels and growth of problematic anger. RESULTS: A model with random intercepts and slopes provided the best fit, indicating heterogeneity in soldiers' levels and trajectories of anger. First-time deployers reported the lowest anger overall, but the most growth in anger over time. Soldiers with multiple prior deployments displayed the highest anger overall, which remained relatively stable over time. Higher pre-deployment resilience was associated with lower reports of anger, but its protective effect diminished over time. First- and second-time deployers reporting low resilience displayed different anger trajectories (stable v. decreasing, respectively). CONCLUSIONS: Change in anger from pre- to post-deployment varies based on pre-deployment factors. The observed differences in anger trajectories suggest that efforts to detect and reduce problematic anger should be tailored for first-time v. repeat deployers. Ongoing screening is needed even for soldiers reporting high resilience before deployment, as the protective effect of pre-deployment resilience on anger erodes over time.

Associations of polygenic risk scores with posttraumatic stress symptom trajectories following combat deployment.

BACKGROUND: Identification of genetic risk factors may inform the prevention and treatment of posttraumatic stress disorder (PTSD). This study evaluates the associations of polygenic risk scores (PRS) with patterns of posttraumatic stress symptoms following combat deployment. METHOD: US Army soldiers of European ancestry (n = 4900) provided genomic data and ratings of posttraumatic stress symptoms before and after deployment to Afghanistan in 2012. Latent growth mixture modeling was used to model posttraumatic stress symptom trajectories among participants who provided post-deployment data (n = 4353). Multinomial logistic regression models tested independent associations between trajectory membership and PRS for PTSD, major depressive disorder (MDD), schizophrenia, neuroticism, alcohol use disorder, and suicide attempt, controlling for age, sex, ancestry, and exposure to potentially traumatic events, and weighted to account for uncertainty in trajectory classification and missing data. RESULTS: Participants were classified into low-severity (77.2%), increasing-severity (10.5%), decreasing-severity (8.0%), and high-severity (4.3%) posttraumatic stress symptom trajectories. Standardized PTSD-PRS and MDD-PRS were associated with greater odds of membership in the high-severity v. low-severity trajectory [adjusted odds ratios and 95% confidence intervals, 1.23 (1.06-1.43) and 1.18 (1.02-1.37), respectively] and the increasing-severity v. low-severity trajectory [1.12 (1.01-1.25) and 1.16 (1.04-1.28), respectively]. Additionally, MDD-PRS was associated with greater odds of membership in the decreasing-severity v. low-severity trajectory [1.16 (1.03-1.31)]. No other associations were statistically significant. CONCLUSIONS: Higher polygenic risk for PTSD or MDD is associated with more severe posttraumatic stress symptom trajectories following combat deployment. PRS may help stratify at-risk individuals, enabling more precise targeting of treatment and prevention programs.

Effect of Different Types of Hypoglycemic Medications on Psoriasis: An Analysis of Current Evidence.

BACKGROUND: Psoriasis is a chronic recurrent inflammatory skin disease with a high risk of diabetes based on disease severity. OBJECTIVES: The aim of the study was to evaluate the efficacy of different hypoglycemic medications in patients with psoriasis. METHODS: A systematic review and meta-analysis of studies were conducted to evaluate the efficacy of hypoglycemic medications in patients with psoriasis. The primary outcome was of changes in the psoriasis area and severity index (PASI) score, and a 75% improvement in PASI from baseline (PASI75). Subgroup analysis was used to investigate associations among the types of hypoglycemic medicines, combination therapy, patient characteristics, course of treatment, and curative effect. RESULTS: We included 3,286 patients from 19 studies to explore the effects of hypoglycemic medications. Patients randomized to receive hypoglycemic medicines showed a more significant decrease in the PASI score (standard mean difference = -0.55, 95% confidence interval (CI): -0.87 to -0.23, p = 0.0007) and a higher PASI75 ratio (RR: 1.80, 95% CI: 1.20-2.71, p = 0.0046). Patients consuming thiazolidinediones (TZDs) were more likely to reach PASI75 than those consuming glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase 4 inhibitors. The combined use of hypoglycemic medicines had an add-on effect on the standard psoriasis treatment, and the proportion of PASI75 in the combination group was nearly four times that in the noncombination group (p = 0.0216). In addition, hypoglycemic medications can reduce body weight, waist circumference, triglyceride, total cholesterol, low-density lipoprotein, and systolic blood pressure. CONCLUSIONS: Certain hypoglycemic drugs, such as GLP-1 RAs and TZDs, are beneficial for treating psoriasis. Multidisciplinary collaboration is recommended for the management of systemic inflammation in patients with psoriasis and diabetes.

Assessment of peripapillary retinal nerve fiber layer thickness and vessel density in newly diagnosed SLE patients without ocular symptoms.

PURPOSE: This study aims to assess peripapillary retinal nerve fiber layer thickness (pRNFLT) and peripapillary vessel density (PVD) in patients with newly diagnosed active and inactive systemic lupus erythematosus (SLE) by optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: This is a cross-sectional study, in which 77 newly diagnosed SLE patients without ocular symptoms (including 36 active SLE patients and 41 inactive SLE patients) and 72 age- and gender-matched healthy subjects were recruited. All participants underwent OCT and OCTA to evaluate pRNFLT, PVD, and radial peripapillary capillary density (RPCD), respectively. Clinical data at the time of initial diagnosis of SLE, including erythrocyte, leukocyte, platelet, albumin-globulin ratio, erythrocyte sedimentation rate, C-reactive protein, serum complement 3, serum complement 4, anti-dsDNA antibody, and 24-h proteinuria, were collected. RESULTS: No difference was found in pRNFLT between active SLE patients, and healthy controls, average pRNFLT, superonasal RNFLT, and inferonasal pRNFLT were reduced in inactive SLE patients than in healthy controls (p≤0.008). Temporal PVD, inferotemporal PVD, and inferotemporal RPCD in active SLE patients were significantly lower than those in healthy controls (p≤0.043). There also was a trend towards lower temporal RPCD in active SLE than healthy controls (p=0.089). Average PVD, average RPCD, superonasal RPCD, inferonasal RPCD, and inferotemporal RPCD were decreased in inactive SLE patients than in healthy controls (p≤0.047). Additionally, inferotemporal RPCD in active SLE patients was positively associated with albumin-globulin ratio (p=0.041). Temporal RPCD was negatively correlated with anti-dsDNA antibody (p=0.012) and 24-h proteinuria (p=0.006). CONCLUSIONS: PRNFL and PVD damage existed in newly diagnosed SLE patients without ocular symptoms. Temporal and inferotemporal RPCD were associated with the laboratory indicators of impaired renal function in active SLE patients, respectively.

Very Low Driving-Pressure Ventilation in Patients With COVID-19 Acute Respiratory Distress Syndrome on Extracorporeal Membrane Oxygenation: A Physiologic Study.

OBJECTIVES: To determine in patients with acute respiratory distress syndrome (ARDS) on venovenous extracorporeal membrane oxygenation (VV ECMO) whether reducing driving pressure (ΔP) would decrease plasma biomarkers of inflammation and lung injury (interleukin-6 [IL-6], IL-8, and the soluble receptor for advanced glycation end-products sRAGE). DESIGN: A single-center prospective physiologic study. SETTING: At a single university medical center. PARTICIPANTS: Adult patients with severe COVID-19 ARDS on VV ECMO. INTERVENTIONS: Participants on VV ECMO had the following biomarkers measured: (1) pre-ECMO with low-tidal-volume ventilation (LTVV), (2) post-ECMO with LTVV, (3) during low-driving-pressure ventilation (LDPV), (4) after 2 hours of very low driving-pressure ventilation (V-LDPV, main intervention ΔP = 1 cmH2O), and (5) 2 hours after returning to LDPV. MAIN MEASUREMENTS AND RESULTS: Twenty-six participants were enrolled; 21 underwent V-LDPV. There was no significant change in IL-6, IL-8, and sRAGE from LDPV to V-LDPV and from V-LDPV to LDPV. Only participants (9 of 21) with nonspontaneous breaths had significant change (p < 0.001) in their tidal volumes (Vt) (mean ± SD), 1.9 ± 0.5, 0.1 ± 0.2, and 2.0 ± 0.7 mL/kg predicted body weight (PBW). Participants with spontaneous breathing, Vt were unchanged-4.5 ± 3.1, 4.7 ± 3.1, and 5.6 ± 2.9 mL/kg PBW (p = 0.481 and p = 0.065, respectively). There was no relationship found when accounting for Vt changes and biomarkers. CONCLUSIONS: Biomarkers did not significantly change with decreased ΔPs or Vt changes during the first 24 hours post-ECMO. Despite deep sedation, reductions in Vt during V-LDPV were not reliably achieved due to spontaneous breaths. Thus, patients on VV ECMO for ARDS may have higher Vt (ie, transpulmonary pressure) than desired despite low ΔPs or Vt.

The longitudinal associations between perceived maternal parenting practices, mother-adolescent relationship quality, and friendship quality.

INTRODUCTION: As adolescents begin to expand their social networks beyond their family, they turn increasingly to their peers for support. Parenting practices present in the parent-child dyad are likely to extend to peer dyads. However, when considering the process involved in the transmission from parenting practices to friendships, the mediating role of parent-child relationships remains unclear. The current study explored the mediating effect of mother-adolescent relationship quality in the association between perceived maternal parenting practices (i.e., autonomy support and psychological control) and friendship quality using a three-wave longitudinal design, and also examined whether adolescents' gender moderates these associations. METHODS: A sample of 344 Chinese adolescents (12.01 to 15-year-old at Wave 1, M = 13.08, SD = 0.39; 153 boys and 191 girls) filled out questionnaires on perceived maternal parenting practices, mother-adolescent relationship quality, and friendship quality, separately in three waves. RESULTS: Perceived maternal autonomy support was associated with positive friendship quality through positive mother-adolescent relationship quality. However, perceived maternal psychological control was not associated with negative friendship quality. Moreover, marginal gender differences were only found in the associations between autonomy support and positive mother-adolescent relationship quality. CONCLUSIONS: These findings demonstrate the spillover effects existed only between autonomy support and positive friendship quality, and highlight the importance of positive mother-adolescent relationship quality when promoting positive friendship quality.

The prognostic impact of the immune microenvironment in small-cell neuroendocrine carcinoma of the uterine cervix: PD-L1 and immune cell subtypes.

BACKGROUND: We investigate the correlation between programmed cell death-ligand 1 (PD-L1) and tumor-associated immune cell (TAIC) density in small-cell neuroendocrine carcinoma of the uterine cervix (SCNEC) and their correlation with clinicopathologic features. METHODS: PD-L1 and mismatch repair protein (MMR) expression in cancer cells and the density of TAIC were evaluated by immunohistochemistry in 89 SCNEC patients. The combined positive score (CPS), tumor proportion score (TPS), and immune cell score (ICS) of PD-L1 were measured, along with their correlation with clinicopathologic features in SCNEC patients using statistical analyses. RESULTS: CPS of PD-L1 ≥ 1 was seen in 68.5% of patients, positive TPS and ICS of PD-L1 were detected in 59.6% and 33.7% of patients, respectively. PD-L1CPS was higher in tumor-infiltrating immune cells (r = 0.387, p = 0.001) and positively correlated with programmed cell death-1 and forkhead box P3 + regulatory T cell (FOXP3 + Treg) infiltration (r = 0.443, p < 0.001; r = 0.532, p < 0.001). There was no statistical correlation between PD-L1 and MMR status. PD-L1CPS and PD-L1ICS positivity were independent prognostic factors, correlating with a favorable survival (HR (95%CI) = 0.363(0.139-0.950), p = 0.039 and HR (95% CI) = 0.199(0.050-0.802), p = 0.023, respectively). PD-L1ICS positivity was an independent indicator of recurrence in SCNEC patients and associated with better disease-free survival (HR (95% CI) = 0.124(0.036-0425), p = 0.001). TAIC and MMR levels had no statistical impact on survival results. CONCLUSIONS: PD-L1 positivity was seen in over half of SCNEC tumors. It may work synergistically with FOXP3 + Treg and other infiltrating immune cells to support an adaptive immune response. PD-L1 positivity may be a favorable prognostic factor in SCNEC.

Clinical and genetic predictions of early-onset cardiac toxicity in adjuvant chemotherapy for breast cancer.

Aim: To identify clinical and genetic variants associated with early-onset cardiac toxicity with a low cumulative dose of chemotherapy drugs in breast cancer. Methods: A total of 388 recruited patients completed routine blood, liver and kidney function, D-dimer, troponin T, brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, ECG and echocardiography tests before and after adjuvant chemotherapy. 25 single-nucleotide polymorphisms (SNPs) were tested. Results: A total of 277 adjuvant chemotherapy-related cardiac toxicity events were recorded in 180 patients (46.4%). Anthracycline-containing chemotherapy (odds ratio: 1.848; 95% CI: 1.135-3.008; p = 0.014) and the SLC28A3 rs885004 GG genotype (odds ratio: 2.034; 95% CI: 1.189-3.479; p = 0.010) were found to be associated with overall cardiac toxicity. The final predictive risk model consisting of clinical risk factors and SNPs was better than SNP alone (p = 0.006) or clinical risk factor alone (p = 0.065). Conclusion: On the basis of clinical factors, a prediction model with genetic susceptibility factors can better predict early-onset cardiac toxicity.

Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11.

BACKGROUND: Acute myeloid leukemia (AML) is a malignant clonal disease of hematopoietic stem- and progenitor-cell origin. AML features massive proliferation of abnormal blasts and leukemia cells in the bone marrow and the inhibition of normal hematopoiesis at onset. Exosomes containing proteins or nucleic acids are secreted by cells; they participate in intercellular communication and serve as key modulators of hematopoiesis. The purpose of this study was to investigate the effects of exosomes derived from bone marrow mesenchymal stem cells (BMSCs) on the regulation of AML and the underlying mechanisms mediated by microRNA (miRNA). METHODS: Dysregulated miR-7-5p in AML patients was identified using qRT-PCR and its clinical significance was explored. Bioinformatic analysis revealed the target gene OSBPL11 that could be regulated by miR-7-5p. The findings were validated using a dual-luciferase reporter assay and western blotting. The functional genes of the PI3K/AKT/mTOR signaling pathway were identified, and the functional significance of miR-7-5p in AML cells was determined using a functional recovery assay. AML cells were co-cultured with exosomes originating from BMSCs overexpressing miR-7-5p to determine cell-cell regulation by Exo-miR-7-5p, as well as in vitro and in vivo functional validation via gain- and loss-of-function methods. RESULTS: Expression of miR-7-5p was decreased in AML patients and cells. Overexpression of miR-7-5p curbed cellular proliferation and promoted apoptosis. Overexpression of OSBPL11 reversed the tumorigenic properties of miR-7-5p in AML cells in vitro. Exo-miR-7-5p derived from BMSCs induced formation of AML cells prone to apoptosis and a low survival rate, with OSBPL11 expression inhibited through the PI3K/AKT/mTOR signaling pathway. Exo-miR-7-5p derived from BMSCs exhibited tumor homing effects in vitro and in vivo, and inhibited AML development. CONCLUSIONS: Exo-miR-7-5p derived from BMSCs negatively regulates OSBPL11 by suppressing the phosphorylation of the PI3K/AKT/mTOR signaling pathway, thereby inhibiting AML proliferation and promoting apoptosis. The data will inform the development of AML therapies based on BMSC-derived exosomes.

Clinical value of next-generation sequencing in guiding decisions regarding endocrine therapy for advanced HR-positive/HER-2-negative breast cancer.

Objective: The mechanism of acquired gene mutation plays a major role in resistance to endocrine therapy in hormone receptor (HR)-positive advanced breast cancer. Circulating tumor DNA (ctDNA) has been allowed for the assessment of the genomic profiles of patients with advanced cancer. We performed this study to search for molecular markers of endocrine therapy efficacy and to explore the clinical value of ctDNA to guide precise endocrine therapy for HR-positive/human epidermal growth factor receptor-2 (HER-2)-negative metastatic breast cancer patients. Methods: In this open-label, multicohort, prospective study, patients were assigned to four parallel cohorts and matched according to mutations identified in ctDNA: 1) activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway preferred mTOR inhibitor combined with endocrine therapy; 2) estrogen receptor 1 (ESR1) mutation preferred fulvestrant; 3) HER-2 mutations preferred pyrotinib; and 4) no actionable mutations received treatment according to the clinical situation. In all cohorts, patients were divided into compliance group and violation group. The primary outcome measure was progression-free survival (PFS), and the secondary outcome measure was overall survival (OS). Results: In all cohorts, the combined median PFS was 4.9 months, and median PFS for the compliance and violation groups was 6.0 and 3.0 months, respectively [P=0.022, hazard ratio (HR)=0.57]. Multivariate Cox regression model showed the risk of disease progression was lower in compliance group than in violation group (P=0.023, HR=0.55). Among the patients with HER-2 mutations, the median PFS was 11.1 months in the compliance group and 2.2 months in the violation group (P=0.011, HR=0.20). There was no significant difference in the median PFS between patients who did and did not comply with the treatment protocol in patients with activation of the PI3K/AKT/mTOR or ESR1 mutation. Conclusions: The results suggest that ctDNA may help to guide the optimal endocrine therapy strategy for metastatic breast cancer patients and to achieve a better PFS. Next-generation sequencing (NGS) detection could aid in distinguishing patients with HER-2 mutation and developing new treatment strategies.