CD163+ macrophages in the triple-negative breast tumor microenvironment are associated with improved survival in the Women's Circle of Health Study and the Women's Circle of Health Follow-Up Study.

BACKGROUND: Tumor-associated macrophages (TAMs) are a prominent immune subpopulation in the tumor microenvironment that could potentially serve as therapeutic targets for breast cancer. Thus, it is important to characterize this cell population across different tumor subtypes including patterns of association with demographic and prognostic factors, and breast cancer outcomes. METHODS: We investigated CD163+ macrophages in relation to clinicopathologic variables and breast cancer outcomes in the Women's Circle of Health Study and Women's Circle of Health Follow-up Study populations of predominantly Black women with breast cancer. We evaluated 611 invasive breast tumor samples (507 from Black women, 104 from White women) with immunohistochemical staining of tissue microarray slides followed by digital image analysis. Multivariable Cox proportional hazards models were used to estimate hazard ratios for overall survival (OS) and breast cancer-specific survival (BCSS) for 546 cases with available survival data (median follow-up time 9.68 years (IQR: 7.43-12.33). RESULTS: Women with triple-negative breast cancer showed significantly improved OS in relation to increased levels of tumor-infiltrating CD163+ macrophages in age-adjusted (Q3 vs. Q1: HR = 0.36; 95% CI 0.16-0.83) and fully adjusted models (Q3 vs. Q1: HR = 0.30; 95% CI 0.12-0.73). A similar, but non-statistically significant, association was observed for BCSS. Macrophage infiltration in luminal and HER2+ tumors was not associated with OS or BCSS. In a multivariate regression model that adjusted for age, subtype, grade, and tumor size, there was no significant difference in CD163+ macrophage density between Black and White women (RR = 0.88; 95% CI 0.71-1.10). CONCLUSIONS: In contrast to previous studies, we observed that higher densities of CD163+ macrophages are independently associated with improved OS and BCSS in women with invasive triple-negative breast cancer. Trial registration Not applicable.

Association between Neighborhood Stressors and Allostatic Load in Breast Cancer Survivors: The Pathways Study.

Allostatic load (AL) is an intermediary outcome through which neighborhood drivers of health may impact cancer survivorship outcomes. We examined associations of neighborhood stressors and AL in 2,553 women with breast cancer recruited into the Pathways Study in 2006-2013. AL score was derived from biomarkers in the cardiovascular, metabolic, and immune domains of physiological stress measured within 3 years after baseline. Neighborhood data were appended to participants' geocoded baseline addresses. Odds ratios (OR) and 95% confidence intervals (CI) were used to estimate associations between neighborhood stressors and risk of higher AL score. Adjusting for age and stage, high AL was positively associated with low versus high neighborhood socioeconomic status (nSES; OR=2.24, 95% CI=1.61-3.12) and green space (OR=1.55, 95% CI=1.18-2.03); high versus low traffic (OR=1.32, 95% CI=1.01-1.72), crime (OR=1.32, 95% CI=1.05-1.67), and household crowding (OR=1.57, 95% CI=1.22-2.01); and more versus no fast-food restaurants (OR=1.50, 95% CI=1.21-1.84). Associations remained for nSES and fast-food restaurants after co-adjustment with other neighborhood stressors, and for fast-food restaurants after additional adjustment with individual sociodemographic and lifestyle factors. Our preliminary findings can inform further studies of the physiological effects of neighborhood stressors, which collectively may help improve survivorship outcomes for the growing population of breast cancer survivors.

Functional cure of hepatitis B in patients with cancer undergoing immune checkpoint inhibitor therapy.

BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) can restore exhausted T cell immunity not only for cancer treatment but also potentially for curing chronic hepatitis B (CHB). The impact of ICIs on Hepatitis B surface antigen (HBsAg) seroclearance in cancer patients was unclear. METHODS: Consecutive cancer patients from 2016 to 2020 (Cohort 1, n=118), and hepatocellular carcinoma (HCC) patients from 2020 to 2022 (Cohort 2, n=44, as validation) receiving ICIs and positive for HBsAg were retrospectively recruited. An additional hepatitis B virus (HBV)-HCC cohort (Cohort 3, n=85) without ICI served as a control group. Factors associated with HBsAg loss or combining HBsAg decline >1 log were analyzed. RESULTS: With median follow-up of 17.5 months, 8 (6.8%) in cohort 1 and 4 (9.1%) in cohort 2 achieved HBsAg seroclearance, and additional 4 in cohort 1 and 1 in cohort 2 had HBsAg decline >1 log. In multivariate analysis, HBsAg <100 IU/mL was associated with HBsAg seroclearance (HR=6.274, p=0.028). In the validation cohort, the cumulative incidence of HBsAg loss at months 12 and 24 was 13.0% and 38.4% for baseline HBsAg <100 IU/ml, which were significantly higher than those in the control group (p=0.0267). While no case in cohort 3 achieved HBsAg within 24 months. Of the 17 cases achieved HBsAg loss and decline >1 log, 16 (94.1%) had nucleos(t)ide analogs treatment. The median time to HBsAg loss or HBsAg decline was 16.5 months (ranged 9.6 to 27.5). CONCLUSIONS: ICIs may accelerate HBsAg seroclearance in cancer patients with baseline HBsAg <100 IU/ml. This finding provides important information for the design of future ICI trials to achieve functional cure in patients with CHB.

A prospective study of vitamin D, proinflammatory cytokines, and risk of fragility fractures in women on aromatase inhibitors for breast cancer.

BACKGROUND: Vitamin D is critical to bone health by regulating intestinal absorption of calcium, whereas proinflammatory cytokines, including IL-1, IL-6, IL-12, and TNF-α, are known to increase bone resorption. We hypothesized that vitamin D and these cytokines at the time of breast cancer diagnosis were predictive for fragility fractures in women receiving aromatase inhibitors (AIs). METHODS: In a prospective cohort of 1,709 breast cancer patients treated with AIs, we measured the levels of 25-hydroxyvitamin D (25OHD), IL-1ß, IL-6, IL-12, and TNF-α from baseline blood samples. The associations of these biomarkers were analyzed with bone turnover markers (BALP and TRACP), bone regulatory markers (OPG and RANKL), bone mineral density (BMD) close to cancer diagnosis, and risk of fragility fractures during a median of 7.5 years of follow up. RESULTS: Compared to patients with vitamin D deficiency, patients with sufficient levels had higher bone turnover, lower BMD, and higher fracture risk; the latter became non-significant after controlling for covariates including BMD and no longer existed when patients taking vitamin D supplement or bisphosphonates or with history of fracture or osteoporosis were excluded. There was a non-significant trend of higher levels of IL-1ß and TNF-α associated with higher risk of fracture (highest vs. lowest tertile, IL-1ß: adjusted HR=1.37, 95% CI=0.94-1.99; TNF-α: adjusted HR=1.38, 95% CI=0.96-1.98). CONCLUSIONS: Our results do not support proinflammatory cytokines or vitamin D levels as predictors for risk of fragility fractures in women receiving AIs for breast cancer.

Sciatic nerve stimulation alleviates neuropathic pain and associated neuroinflammation in the dorsal root ganglia in a rodent model.

BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.

Dendritic cell vaccine for glioblastoma: an updated meta-analysis and trial sequential analysis.

BACKGROUND: Dendritic cell (DC) vaccine is an emerging immunotherapy that could potentially improve glioblastoma survival. The first phase III clinical trial of DC vaccine was recently published. This meta-analysis aims to update and reappraise existing evidence on the efficacy of DC vaccine in patients with glioblastoma. METHODS: We searched PubMed, Embase, and Cochrane Library for clinical trials of DC vaccine for glioblastoma. The quality of the studies was assessed using the RoB 2.0 and ROBINS-I tools. The results of overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Summary effects were evaluated using random effects models. Trial sequential analysis (TSA) was performed. RESULTS: Seven clinical trials involving 3,619 patients were included. DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - 0.98). In the subgroup of newly diagnosed glioblastoma, DC vaccine was associated with improved PFS (HR = 0.59; 95% CI, 0.39 - 0.90). TSA of OS showed that the cumulative z-score line for the DC vaccine crossed the benefit boundary and reached the required sample size. TSA of PFS and subgroup analysis of newly diagnosed glioblastoma showed that the required sample size was not reached. CONCLUSIONS: This updated meta-analysis, which included the first phase III trial of a DC vaccine for glioblastoma, demonstrated that the DC vaccine was associated with improved OS. Moreover, TSA showed that the required sample size was reached, indicating a true-positive result. Future studies are required for patient subgroups with newly diagnosed and recurrent glioblastoma.

Interleukin-1 receptor 1 deficiency worsens hepatocellular carcinoma, while gemcitabine treatment alleviates the hepatocellular carcinoma-induced increase in intra-hepatic immune cells.

BACKGROUND AND AIM: Primary liver cancer, particularly hepatocellular carcinoma (HCC), represents a substantial global health challenge. Although immune checkpoint inhibitors are effective in HCC treatment, several patients still experience disease progression. Interleukin-1 (IL-1) regulates immunity and inflammation. We investigate the role of IL-1 in HCC development and progression and determine the potential therapeutic impact of gemcitabine in treating HCC. METHODS: Hydrodynamics-based transfection, employing the sleeping beauty transposase system, delivered surrogate tumor antigens, NRAS (NRAS proto-oncogene, GTPase), ShP53, and SB100 to C57BL/6 mice. A basic HCC mouse model was established. Pathogen-free animals were tested for serum and hepatotoxicity. The HCC prognosis was monitored using alanine aminotransferase and aspartate aminotransferase levels. Liver histology immunohistochemistry and mouse splenocyte/intra-hepatic immune cell flow cytometry were conducted. IL-1ß levels in human and mouse serum were assessed. RESULTS: Interleukin-1ß levels were elevated in patients with HCC compared with those in non-HCC controls. Hepatic IL-1ß levels were higher in HCC mouse models than those in non-HCC mice, suggesting localized hepatic inflammation. IL-1 receptor type 1 (IL-1R1) knockout (IL-1R1-/-) mice exhibited less severe HCC progression than that in wild-type mice, despite the high intra-hepatic IL-1ß concentration. IL-1R1-/- mice exhibited increased hepatic levels of myeloid-derived suppressor cells and regulatory T cells, which may exacerbate HCC. Gemcitabine significantly reduced the HCC tumor burden, improved liver conditions, and increased survival rates in HCC mouse models. Gemcitabine reduced the hepatic levels of myeloid-derived suppressor cells and regulatory T cells, potentially alleviating immune suppression in the liver. CONCLUSIONS: Targeting IL-1 or combining gemcitabine with immunotherapy is a promising approach for treating advanced-stage HCC.

The effect of childhood depression trajectories on sugar-sweetened beverage habit trajectories in adolescence: Exploring sleep problems as a mediator.

Although depression has been linked to the habit of consuming sugar-sweetened beverages (SSBs), little is known about their long-term relationships and the mediating role of sleep problems. This study examines the associations between childhood depressive symptoms trajectories and adolescent SSB-habit trajectories and whether these associations were mediated by sleep problems. Data came from 1560 adolescents participating in a longitudinal study across grades 1 through 12 in northern Taiwan. Group-based trajectory modeling was used to identify development of childhood depressive symptoms and an SSB habit in adolescence. Multinomial logistic regression was conducted to examine the influence of childhood depressive symptoms and adolescent SSB habit. Mediation analysis was conducted to test whether sleep problems mediated the associations examined. Four distinct trajectories of childhood depressive symptoms were identified: low-stable (30.79%), moderate-stable (42.32%), increasing (12.29%), and high-stable (11.60%). Three distinct trajectories of SSB habit in adolescence were identified: low-stable (44.32%), increasing (15.02%), and high-stable (40.65%). Children who had moderate-stable (aOR = 1.35; CI: 1.04-1.77), high-stable (aOR = 2.01; CI: 1.28-3.15), or increasing (aOR = 1.97; CI: 1.26-3.06) trajectories of depressive symptoms relative to those in the low-stable group were significantly more likely to belong to the high-stable trajectory of SSBs than to the low-stable SSBs group. The Z-mediation test showed that sleep problems significantly mediated the associations between trajectories of childhood depressive symptoms and trajectories of SSBs during adolescence (all p < 0.05). Childhood depressive symptoms conferred risks for adolescent SSB habits; and the effects were seen, in part, through increasing sleep problems.

Association of organ damage with predicted fat mass in a community-dwelling elderly: the Northern Shanghai study.

BACKGROUND: Body fat mass (FM) is associated with multiple organ damage. However, data regarding the relationship between various organ damage and FM are rare in the elderly. Therefore, we aim to perform an analysis on the relationship between organ damage and FM in a geriatric cohort. METHODS: 3331 participants were included in this analysis. Based on age, body height, body weight, waist circumference, and race, we calculated FM with the established formula. Organ damage, including arterial stiffening, lower extremity atherosclerosis, left ventricular hypertrophy (LVH), micro-albuminuria, and chronic kidney disease (CKD), were measured and calculated with standard methods. RESULTS: All organ damage parameters were significantly related to FM (all p < 0.001). In univariate logistics regression, the highest quartile of FM was tied to the increased risk of arterial stiffening, lower extremity atherosclerosis, LVH, micro-albuminuria, and CKD (all p < 0.05). After adjustment, participants with higher quantiles of FM had a significantly increased odd ratio (OR) for arterial stiffening [OR = 1.51, 95% confidence interval (CI): 1.15-1.99, p = 0.002] and LVH (OR = 1.99, 95% CI: 1.48-2.67, p < 0.001). Moreover, FM was linearly associated with arterial stiffening and LVH in total population and gender subgroups. Independent of confounders, FM was significantly correlated with arterial stiffening, lower extremity atherosclerosis, LVH and CKD in female, while was only related to LVH in male. CONCLUSIONS: Among various organ damage, elevated FM is significantly and independently associated with arterial stiffening and LVH in the elderly. Compared with men, women with increased FM are more likely to have multiple organ damage.

Associations between social loneliness trajectories and chronotype among adolescents.

Late chronotype during adolescence is a critical risk factor for poor physical and mental health among adolescents. While social loneliness is confirmed to negatively influence sleep behaviors, the long-term effect of social loneliness on chronotype remains unknown. This study aims to investigate whether social loneliness trajectories from middle childhood to adolescence are associated with chronotype in late adolescence and examine the potential sex differences in these associations. Data were obtained from 2398 adolescents who participated in the Child and Adolescent Behaviors in Long-Term Evolution project. Chronotype was calculated as the midpoint of sleep on free days adjusted for sleep debt. Group-based trajectory modeling and multiple linear regression were employed to establish social loneliness trajectories and determine their associations with chronotype. Social loneliness trajectories were significantly associated with chronotype and varied by sex. Specifically, boys following a high-decreasing trajectory had earlier chronotype during late adolescence than did those following a low-decreasing trajectory (B = - 0.07; p < 0.05). By contrast, girls following a low-to-moderate-increasing trajectory exhibited later chronotype than did those following a low-stable trajectory (B = 0.07; p < 0.01). Social loneliness trajectories, especially those displaying significant fluctuations over time, are critical indicators influencing chronotype among adolescents. Furthermore, these trajectories and their associations with chronotype display sex differences. These findings highlight the need for early interventions for psychological factors such as social loneliness to ensure that the late chronotype can be prevented. In addition, sex variations must be considered.

Sustainable flood control strategies under extreme rainfall: Allocation of flood drainage rights in the middle and lower reaches of the yellow river based on a new decision-making framework.

Climate change has exacerbated the frequency and magnitude of extreme rainfall, which has led to the perpetuation of flooding as a hazard to humans and society. China has begun to consider introducing Flood drainage rights (FDR), a sustainable flood control measure, into non-engineering measures as a complement to engineering measures for flood control. FDR represent the right of regions to discharge regional floodwaters caused by extreme rainfall into the river, and are the primary means of controlling the amount of floodwaters from regions when regional flood capacity is exceeded. However, existing studies on quantitative FDR allocation still have limitations, and some previous methods have resulted in allocation schemes that are not entirely reasonable and fair because they do not comprehensively consider the influencing factors of FDR or the allocation method is unreasonable. This paper explores the impact of flooding on rural and agricultural areas. We incorporate the factors of agricultural economy and security and construct a system of the allocation indicators of FDR composed of five principles: Natural Environmental Endowment, General Economic and Social Development, Agricultural Economy and Security, Macro policy regulation, and Respect for Historical Background. Second, considering the influence of expert judgment and data of different time nodes on the allocation of FDR, we introduce the concepts of expert weight and time weight into the allocation model of FDR, and construct a new set of framework for the allocation of FDR, i.e., "[(expert weight + subjective weight)+(time weight + objective weight)]+decision making model ". To reduce the loss of information during the transformation of subjective judgments, we also introduced triangular fuzzy numbers for the transformation between expert judgments and numbers. Finally, we take the five provinces in the middle and lower reaches of the Yellow River as an example. Using the data from 2010 to 2021, we obtain the final allocation scheme (proportion) of FDR as Henan (33.26%) > Shaanxi (23.08%) > Inner Mongolia (21.31%) > Shanxi (14.44%) > Shandong (7.91%). On this basis, this paper utilizes sensitivity analysis and comparative validation to demonstrate the rationality and effectiveness of the method, and identifies several indicators that have a greater impact on the results of the allocation of FDR. FDR can form part of a set of integrated flood management system together with flood control projects, which greatly alleviates the drainage conflicts arising from flooding caused by extreme precipitation. Under extreme rainfall conditions, FDR improves drainage efficiency and minimizes the overall damage caused by flooding in the watershed. This study can contribute to the sustainable development of the watershed and provide a reference for the promotion and utilization of sustainable flood control measures.

[Factors Related to Musculoskeletal Disorders Among Hospital Nurses].

BACKGROUND: Nurses are a high-risk group for musculoskeletal disorders. Few studies conducted in Taiwan have been published regarding the relationships among work characteristics, psychological well-being, and musculoskeletal discomfort in nursing personnel. PURPOSE: This study was designed to investigate musculoskeletal discomfort among hospital nursing staff, as well as its associated factors. METHODS: A secondary data analysis design was used to examine hospital staff health survey data for 2018 from two regional hospitals in southern Taiwan. Data from 328 full-time nurses who had passed their probationary period and been employed for more than 6 months were included in the analysis, which was conducted using a logistic regression model. RESULTS: The prevalence of musculoskeletal disorders was found to be highest in the shoulders (73.8%), lower back (72.9%), and neck (64.0%), respectively. Number of sleep hours, work stress, confidence in dealing with work stress, workload, supervisor support, workplace justice, and depression level differed significantly between the groups with and without full-body musculoskeletal disorders (p < .05). The results of the logistic regression model analysis showed individuals with severe depression have 4.27 times higher odds of experiencing musculoskeletal discomfort compared to those without depression (odds ratio 4.27, 95% confidence interval [1.27, 14.41]). Severe depression was found to be a significant predictor of musculoskeletal disorders. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: Nurses are at high risk for musculoskeletal disorders. The results of this study indicate that level of risk is influenced significantly by psychological well-being, work environment, and workload. Efforts should be made to improve the relevant risk factors in the workplace to reduce the incidence of musculoskeletal disorders among nurses.

Synergistic Al-Al Dual-Atomic Site for Efficient Artificial Nitrogen Fixation.

Synthesis of ammonia by electrochemical nitrogen reduction reaction (NRR) is a promising alternative to the Haber-Bosch process. However, it is commonly obstructed by the high activation energy. Here, we report the design and synthesis of an Al-Al bonded dual atomic catalyst stabilized within an amorphous nitrogen-doped porous carbon matrix (Al2NC) with high NRR performance. The dual atomic Al2-sites act synergistically to catalyze the complex multiple steps of NRR through adsorption and activation, enhancing the proton-coupled electron transfer. This Al2NC catalyst exhibits a high Faradaic efficiency of 16.56±0.3 % with a yield rate of 29.22±1.2 µg h-1 mgcat -1. The dual atomic Al2NC catalyst shows long-term repeatable, and stable NRR performance. This work presents an insight into the identification of synergistic dual atomic catalytic site and mechanistic pathway for the electrochemical conversion of N2 to NH3.

Design of Near-Infrared-Triggered Metallo-Photosensitizers via a Self-Assembly-Induced Vibronic Decoupling Strategy.

Development of highly efficient near-infrared (NIR)-excited photosensitizers is hampered by the fast nonradiative vibrational relaxation process regulated by the energy gap law. Here, from the fundamental perspective we propose that the intermolecular coupling of well-designed photosensitizers has the potential to facilitate exciton delocalization and hence reduce the exciton-vibration coupling, thereby boosting their phototherapeutic efficacy via inhibition of the vibrational relaxation pathway. Such conceived NIR-excited metallo-photosensitizers (IrHA1 and IrHA2) were prepared and studied for experimental validation. The resulting iridium complexes exhibited a little singlet oxygen (1O2) production in the monomeric state, but produced substantially enhanced 1O2 generation efficiency via benefiting from the exciton-vibration decoupling in the self-assembly state. Particularly, IrHA2 exhibits an unprecedented high 1O2 quantum yield of 54.9% (FDA-approved NIR dye indocyanine green: ΦΔ = 0.2%) under 808 nm laser irradiation with negligible heat generation, probably attributed to the suppression of vibronic couplings from the stretching mode of the acceptor ligand. In phototherapy, IrHA2-NPs with high biocompatibility and low dark toxicity can induce substantial tumor regression with 92.9% tumor volume reduction in vivo. This self-assembly-induced vibronic decoupling strategy would offer an effective approach to the design of high-performance NIR-excited photosensitizers.

Highly Distorted Multiple Helicenes: Syntheses, Structural Analyses, and Properties.

A series of hexapole helicenes (HHs) and nonuple helicenes (NHs) were prepared from 1,3,5-tris[2-(arylethynyl)phenyl]benzene through two steps, namely, iodocyclization and subsequent palladium-catalyzed annulation with ortho-bromoaryl carboxylic acids. The crucial advantages of this synthetic method are the facile introduction of substituents, high regioselectivity, and efficient backbone extension. Three-dimensional structures of three C1-symmetric HHs and one C3-symmetric NH were elucidated using X-ray crystallography. Unlike most conventional multiple helicenes, the HHs and NHs investigated herein possess a unique structural feature where some double helical moieties share a terminal naphthalene unit. Chiral resolution of a HH and an NH was successfully achieved, and the enantiomerization barrier (ΔH‡) of the HH was experimentally determined to be 31.2 kcal/mol. A straightforward method for predicting the most stable diastereomer was developed based on density functional theory calculations and structural considerations. It was found that the relative potential energies (ΔHrs) of all diastereomers for two HHs and one NH can be obtained using minimal computational effort to analyze the types, helical configurations, numbers, and ΔH(MP-MM)s [= H(M,P/P,M) - H(M,M/P,P)] of the double helicenyl fragments.

Mitochondrial transplantation attenuates traumatic neuropathic pain, neuroinflammation, and apoptosis in rats with nerve root ligation.

Traumatic neuropathic pain (TNP) is caused by traumatic damage to the somatosensory system and induces the presentation of allodynia and hyperalgesia. Mitochondrial dysfunction, neuroinflammation, and apoptosis are hallmarks in the pathogenesis of TNP. Recently, mitochondria-based therapy has emerged as a potential therapeutic intervention for diseases related to mitochondrial dysfunction. However, the therapeutic effectiveness of mitochondrial transplantation (MT) on TNP has rarely been investigated. Here, we validated the efficacy of MT in treating TNP. Both in vivo and in vitro TNP models by conducting an L5 spinal nerve ligation in rats and exposing the primary dorsal root ganglion (DRG) neurons to capsaicin, respectively, were applied in this study. The MT was operated by administrating 100 µg of soleus-derived allogeneic mitochondria into the ipsilateral L5 DRG in vivo and the culture medium in vitro. Results showed that the viable transplanted mitochondria migrated into the rats' spinal cord and sciatic nerve. MT alleviated the nerve ligation-induced mechanical and thermal pain hypersensitivity. The nerve ligation-induced glial activation and the expression of pro-inflammatory cytokines and apoptotic markers in the spinal cord were also repressed by MT. Consistently, exogenous mitochondria reversed the capsaicin-induced reduction of mitochondrial membrane potential and expression of pro-inflammatory cytokines and apoptotic markers in the primary DRG neurons in vitro. Our findings suggest that MT mitigates the spinal nerve ligation-induced apoptosis and neuroinflammation, potentially playing a role in providing neuroprotection against TNP.

A Fc-VEGF chimeric fusion enhances PD-L1 immunotherapy via inducing immune reprogramming and infiltration in the immunosuppressive tumor microenvironment.

BACKGROUND: Immunotherapy is an emerging cancer therapy with potential great success; however, immune checkpoint inhibitor (e.g., anti-PD-1) has response rates of only 10-30% in solid tumor because of the immunosuppressive tumor microenvironment (TME). This affliction can be solved by vascular normalization and TME reprogramming. METHODS: By using the single-cell RNA sequencing (scRNAseq) approach, we tried to find out the reprogramming mechanism that the Fc-VEGF chimeric antibody drug (Fc-VFD) enhances immune cell infiltration in the TME. RESULTS: In this work, we showed that Fc-VEGF121-VEGF165 (Fc-VEGF chimeric antibody drug, Fc-VFD) arrests excess angiogenesis and tumor growth through vascular normalization using in vitro and in vivo studies. The results confirmed that the treatment of Fc-VFD increases immune cell infiltration including cytotoxic T, NK, and M1-macrophages cells. Indeed, Fc-VFD inhibits Lon-induced M2 macrophages polarization that induces angiogenesis. Furthermore, Fc-VFD inhibits the secretion of VEGF-A, IL-6, TGF-ß, or IL-10 from endothelial, cancer cells, and M2 macrophage, which reprograms immunosuppressive TME. Importantly, Fc-VFD enhances the synergistic effect on the combination immunotherapy with anti-PD-L1 in vivo. CONCLUSIONS: In short, Fc-VFD fusion normalizes intratumor vasculature to reprogram the immunosuppressive TME and enhance cancer immunotherapy.

mTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.

BACKGROUND: Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women. METHODS: The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression. RESULTS: AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings.

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.

BACKGROUND: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.

mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.

BACKGROUND: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk. METHODS: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term. RESULTS: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons. CONCLUSION: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings.