Promising Experimental Treatment in Animal Models and Human Studies of Interstitial Cystitis/Bladder Pain Syndrome.

Interstitial cystitis/bladder pain Syndrome (IC/BPS) remains a mysterious and intricate urological disorder, presenting significant challenges to healthcare providers. Traditional guidelines for IC/BPS follow a hierarchical model based on symptom severity, advocating for conservative interventions as the initial step, followed by oral pharmacotherapy, intravesical treatments, and, in refractory cases, invasive surgical procedures. This approach embraces a multi-tiered strategy. However, the evolving understanding that IC/BPS represents a paroxysmal chronic pain syndrome, often involving extravesical manifestations and different subtypes, calls for a departure from this uniform approach. This review provides insights into recent advancements in experimental strategies in animal models and human studies. The identified therapeutic approaches fall into four categories: (i) anti-inflammation and anti-angiogenesis using monoclonal antibodies or immune modulation, (ii) regenerative medicine, including stem cell therapy, platelet-rich plasma, and low-intensity extracorporeal shock wave therapy, (iii) drug delivery systems leveraging nanotechnology, and (iv) drug delivery systems assisted by energy devices. Future investigations will require a broader range of animal models, studies on human bladder tissues, and well-designed clinical trials to establish the efficacy and safety of these therapeutic interventions.

Comparison of the Efficacy, Safety, and Quality of Life of Pegylated Liposomal Doxorubicin-Cyclophosphamide versus Epirubicin-Cyclophosphamide in Patients with Early-Stage HER2-Negative Breast Cancer: A Prospective, Randomized, Multicenter, Phase II Study.

INTRODUCTION: This multicenter, phase II randomized, non-inferiority study reports from the first prospective two-armed randomized control trial that compared the efficacy, safety, and quality of life (QoL) of pegylated liposomal doxorubicin (PLD)-based and epirubicin-based as adjuvant chemotherapy for stage I-II human epidermal growth factor receptor 2 (HER2)-negative breast cancer. METHODS: Patients with stage I/II HER2-negative breast cancer received PLD (37.5 mg/m2, Q3W, 5 cycles, LC arm) plus cyclophosphamide (600 mg/m2) or epirubicin (90 mg/m2, Q3W, 4 cycles, EC arm) plus cyclophosphamide (600 mg/m2). Randomization was stratified by lymph node and ER and PR status. The primary endpoint was disease-free survival (DFS), and secondary endpoints were overall survival (OS), safety profiles, and QoL. QoL was assessed using the EORTC-QLQ-C30 and QLQ-BR23 questionnaires. RESULTS: A total of 256 patients were assigned to LC (n = 148) and EC (n = 108). There was no difference in 5-year DFS and OS rate between the two groups. LC-based adjuvant regimens had significantly less alopecia and low-grade 3-4 hematologic adverse events (AEs). Significantly improved QoL was observed in the LC arm during and after treatment for symptoms including fatigue, nausea and vomiting, and systemic therapy side effects. CONCLUSION: Comparable efficacy and safety between adjuvant PLD and epirubicin for stage I-II HER2-negative breast cancer was observed. There was no difference in the 5-year DFS and OS rates between the two treatment arms. However, low-grade 3-4 AEs and a trend of favorable QoL symptom scales were observed in the LC arm, suggesting that PLD-containing regimen could become a new standard treatment for early-stage HER2-negative breast cancer patients.

Carbohydrate-Mediated Pregnancy Gut Microbiota and Neonatal Low Birth Weight.

The effects of gut microbiota on the association between carbohydrate intake during pregnancy and neonatal low birth weight (LBW) were investigated. A prospective cohort study was conducted with 257 singleton-born mother-child pairs in Taiwan, and maternal dietary intake was estimated using a questionnaire, with each macronutrient being classified as low, medium, or high. Maternal fecal samples were collected between 24 and 28 weeks of gestation, and gut microbiota composition and diversity were profiled using 16S rRNA amplicon gene sequencing. Carbohydrates were the major source of total energy (56.61%), followed by fat (27.92%) and protein (15.46%). The rate of infant LBW was 7.8%, which was positively correlated with maternal carbohydrate intake. In the pregnancy gut microbiota, Bacteroides ovatus and Dorea spp. were indirectly and directly negatively associated with fetal growth, respectively; Rosenburia faecis was directly positively associated with neonatal birth weight. Maternal hypertension during pregnancy altered the microbiota features and was associated with poor fetal growth. Microbiota-accessible carbohydrates can modify the composition and function of the pregnancy gut microbiota, thus providing a potential marker to modulate deviations from dietary patterns, particularly in women at risk of hypertension during pregnancy, to prevent neonatal LBW.

Impact of Transgenerational Nutrition on Nonalcoholic Fatty Liver Disease Development: Interplay between Gut Microbiota, Epigenetics and Immunity.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent pediatric liver disorder, primarily attributed to dietary shifts in recent years. NAFLD is characterized by the accumulation of lipid species in hepatocytes, leading to liver inflammation that can progress to steatohepatitis, fibrosis, and cirrhosis. Risk factors contributing to NAFLD encompass genetic variations and metabolic disorders such as obesity, diabetes, and insulin resistance. Moreover, transgenerational influences, resulting in an imbalance of gut microbial composition, epigenetic modifications, and dysregulated hepatic immune responses in offspring, play a pivotal role in pediatric NAFLD development. Maternal nutrition shapes the profile of microbiota-derived metabolites in offspring, exerting significant influence on immune system regulation and the development of metabolic syndrome in offspring. In this review, we summarize recent evidence elucidating the intricate interplay between gut microbiota, epigenetics, and immunity in fetuses exposed to maternal nutrition, and its impact on the onset of NAFLD in offspring. Furthermore, potential therapeutic strategies targeting this network are also discussed.

Overexpression of malic enzyme is involved in breast cancer growth and is correlated with poor prognosis.

Malic enzyme (ME) genes are key functional metabolic enzymes playing a crucial role in carcinogenesis. However, the detailed effects of ME gene expression on breast cancer progression remain unclear. Here, our results revealed ME1 expression was significantly upregulated in breast cancer, especially in patients with oestrogen receptor/progesterone receptor-negative and human epidermal growth factor receptor 2-positive breast cancer. Furthermore, upregulation of ME1 was significantly associated with more advanced pathological stages (p < 0.001), pT stage (p < 0.001) and tumour grade (p < 0.001). Kaplan-Meier analysis revealed ME1 upregulation was associated with poor disease-specific survival (DSS: p = 0.002) and disease-free survival (DFS: p = 0.003). Multivariate Cox regression analysis revealed ME1 upregulation was significantly correlated with poor DSS (adjusted hazard ratio [AHR] = 1.65; 95% CI: 1.08-2.52; p = 0.021) and DFS (AHR, 1.57; 95% CI: 1.03-2.41; p = 0.038). Stratification analysis indicated ME1 upregulation was significantly associated with poor DSS (p = 0.039) and DFS (p = 0.038) in patients with non-triple-negative breast cancer (TNBC). However, ME1 expression did not affect the DSS of patients with TNBC. Biological function analysis revealed ME1 knockdown could significantly suppress the growth of breast cancer cells and influence its migration ability. Furthermore, the infiltration of immune cells was significantly reduced when they were co-cultured with breast cancer cells with ME1 knockdown. In summary, ME1 plays an oncogenic role in the growth of breast cancer; it may serve as a potential biomarker of progression and constitute a therapeutic target in patients with breast cancer.

A novel approach has been developed to produce pure plant-based gel soy yogurt by combining soy proteins (7S/11S), high pressure homogenization, and glycation reaction.

This research sought to examine how the physicochemical characteristics of soy globulins and different processing techniques influence the gel properties of soy yogurt. The goal was to improve these gel properties and rectify any texture issues in soy yogurt, ultimately aiming to produce premium-quality plant-based soy yogurt. In this research study, the investigation focused on examining the impact of 7S/11S, homogenization pressure, and glycation modified with glucose on the gel properties of soy yogurt. A plant-based soy yogurt with superior gel and texture properties was successfully developed using a 7S/11S globulin-glucose conjugate at a 1:3 ratio and a homogenization pressure of 110 MPa. Compared to soy yogurt supplemented with pectin or gelatin, this yogurt demonstrated enhanced characteristics. These findings provide valuable insights into advancing plant protein gels and serve as a reference for cultivating new soybean varieties by soybean breeding experts.

A retrospective study of inpatients diagnosed with degloving skin and soft tissue injuries.

The overall picture of degloving skin and soft tissue injuries (DSTI) remains a blank space in China. Therefore, a retrospective study was designed to summarize the current situation of this injury. Patients diagnosed with DSTI hospitalized between 2013 and 2018 were identified from the Hospital Quality Monitoring System (HQMS) database, of whom demographics, injury characteristics, hospitalization and cost information were analyzed. A total of 62,709 patients were enrolled in this study. Male sex predominated, with a mean age of 43.01 ± 19.70 years. Peasants seemed to be the most vulnerable. East China and Hubei province had the most patients. The most and least frequently injured anatomic site were lower extremity and torso, respectively. Traffic-related accidents and summer accounted for the highest proportion in terms of injury mechanism and season. The operation rate of DSTI roughly showed a growing trend, and the average length of stay was 22.02 ± 29.73 days. At discharge, 0.93% of DSTI patients ended up in death. Medicine accounted mostly for hospitalization cost, while the proportion decreased year by year. More than half DSTI patients paid at their own charge. This study made a relatively detailed description of DSTI patients nationwide, and might provide enlightenments for better prevention and treatment.

Efficacy and Safety of Moderate-Intensity Continuous Training on the Improvement of Cardiopulmonary Function in Patients After Transcatheter Aortic Valve Replacement (ENERGY): A Randomized Controlled Trial.

OBJECTIVES: To investigate the effect of moderate-intensity continuous training (MICT) on the improvement of cardiopulmonary function for patients undergoing transcatheter aortic valve replacement (TAVR). DESIGN: Randomized controlled study. SETTING AND PARTICIPANTS: Between August 20, 2021, and February 28, 2022, a total of 66 patients after TAVR were screened for inclusion and randomly divided into the MICT and control groups at a ratio of 1:1. MICT was scheduled 3 times per week for 3 months in the intervention group. Patients in the control group received one-time advice on physical activity according to the current guideline. METHODS: The primary endpoint was the 3-month change in peak oxygen consumption (peak VO2) assessed by cardiopulmonary exercise testing. The secondary endpoints included the 3-month change in 6-minute walk test (6MWT), the 12-Item Short Form Health Survey (SF-12), New York Heart Association (NYHA) class, echocardiographic parameters, and laboratory parameters. RESULTS: After 3 months, the change in peak VO2 was higher in the MICT group than that in the control group (1.63 mL/kg/min, 95% CI 0.58-2.67, P = .003). Change in 6MWT (21.55 m, 95% CI 0.38-42.71, P = .046) was higher in the MICT group compared with the control group. A significant change in favor of MICT was also observed for low-density lipoprotein cholesterol (-0.62 mmol/L, 95% CI -1.00 to -0.23, P = .002). However, there were no significant changes in other echocardiographic indices, laboratory parameters, and SF-12 between the 2 groups (all P > .05). CONCLUSIONS AND IMPLICATIONS: MICT had a positive effect on the cardiopulmonary function and physical capacity of patients after TAVR.

Reprogramming Effects of Postbiotic Butyrate and Propionate on Maternal High-Fructose Diet-Induced Offspring Hypertension.

Maternal nutrition has a key role in the developmental programming of adult disease. Excessive maternal fructose intake contributes to offspring hypertension. Newly discovered evidence supports the idea that early-life gut microbiota are connected to hypertension later in life. Short-chain fatty acids (SCFAs), butyrate, and propionate are microbiota-derived metabolites, also known as postbiotics. The present study aimed to determine whether maternal butyrate or propionate supplementation can protect offspring from hypertension using a maternal high-fructose (HF) diet rat model. Female Sprague Dawley rats were allocated during pregnancy and lactation to (1) regular chow (ND); (2) 60% high-fructose diet (HF); (3) HF diet plus butyrate (HFB, 400 mg/kg/day); and (4) HF diet plus propionate (HFP, 200 mmol/L). Male offspring were sacrificed at 12 weeks of age. The maternal HF diet impaired the offspring's BP, which was prevented by perinatal butyrate or propionate supplementation. Both butyrate and propionate treatments similarly increased plasma concentrations of propionic acid, isobutyric acid, and valeric acid in adult offspring. Butyrate supplementation had a more profound impact on trimethylamine N-oxide metabolism and nitric oxide parameters. Whilst propionate treatment mainly influenced gut microbiota composition, it directly altered the abundance of genera Anaerovorax, Lactobacillus, Macellibacteroides, and Rothia. Our results shed new light on targeting gut microbiota through the use of postbiotics to prevent maternal HF intake-primed hypertension, a finding worthy of clinical translation.

Evaluation of efficacy and safety for compound kushen injection combined with intraperitoneal chemotherapy for patients with malignant ascites: A systematic review and meta-analysis.

Objectives: Compound Kushen injection (CKI) combined with intraperitoneal chemotherapy (IPC) is widely used in the treatment of malignant ascites (MA). However, evidence about its efficacy and safety remains limited. This review aimed to evaluate the efficacy and safety of CKI combined with IPC for the treatment of MA. Methods: Protocol of this review was registered in PROSPERO (CRD42022304259). Randomized controlled trials (RCTs) on the efficacy and safety of IPC with CKI for the treatment of patients with MA were searched through 12 electronic databases and 2 clinical trials registration platforms from inception until 20 January 2023. The Cochrane risk-of-bias tool was used to assess the quality of the included trials through the risk of bias assessment. We included RCTs that compared IPC single used or CKI combined with IPC for patients with MA schedule to start IPC. The primary outcome was identified as an objective response rate (ORR), while the secondary outcomes were identified as the quality of life (QoL), survival time, immune functions, and adverse drug reactions (ADRs). The Revman5.4 and Stata17 software were used to calculate the risk ratio (RR) at 95% confidence intervals (CI) for binary outcomes and the mean difference (MD) at 95% CI for continuous outcomes. The certainty of the evidence was assessed according to the GRADE criteria. Results: A total of 17 RCTs were assessed, which included 1200 patients. The risk of bias assessment of the Cochrane risk-of-bias tool revealed that one study was rated high risk and the remaining as unclear or low risk. Meta-analysis revealed that CKI combined with IPC had an advantage in increasing ORR (RR = 1.31, 95% CI 1.20 to 1.43, p < 0.00001) and QoL (RR = 1.50, 95% CI 1.23 to 1.83, p < 0.0001) when compared with IPC alone. Moreover, the combined treatment group showed a lower incidence of myelosuppression (RR = 0.51, 95%CI 0.40-0.64, p < 0.00001), liver dysfunction (RR = 0.33, 95%CI 0.16 to 0.70, p = 0.004), renal dysfunction (RR = 0.39, 95%CI 0.17 to 0.89, p = 0.02), and fever (RR = 0.51, 95%CI 0.35 to 0.75, p = 0.0007) compared to those of the control group. The quality of evidence assessment through GRADE criteria showed that ORR, myelosuppression, and fever were rated moderate, renal dysfunction and liver dysfunction were rated low, and QoL and abdominal pain were rated very low. Conclusion: The efficacy and safety of CKI combined with IPC were superior to that with IPC alone for the treatment of MA, which indicates the potentiality of the treatment. However, more high-quality RCTs are required to validate this conclusion. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304259], identifier [PROSPERO 2022 CRD42022304259].

Tumor Vasculature as an Emerging Pharmacological Target to Promote Anti-Tumor Immunity.

Tumor vasculature abnormality creates a microenvironment that is not suitable for anti-tumor immune response and thereby induces resistance to immunotherapy. Remodeling of dysfunctional tumor blood vessels by anti-angiogenic approaches, known as vascular normalization, reshapes the tumor microenvironment toward an immune-favorable one and improves the effectiveness of immunotherapy. The tumor vasculature serves as a potential pharmacological target with the capacity of promoting an anti-tumor immune response. In this review, the molecular mechanisms involved in tumor vascular microenvironment-modulated immune reactions are summarized. In addition, the evidence of pre-clinical and clinical studies for the combined targeting of pro-angiogenic signaling and immune checkpoint molecules with therapeutic potential are highlighted. The heterogeneity of endothelial cells in tumors that regulate tissue-specific immune responses is also discussed. The crosstalk between tumor endothelial cells and immune cells in individual tissues is postulated to have a unique molecular signature and may be considered as a potential target for the development of new immunotherapeutic approaches.

Lymphocyte Subpopulations Associated with Neutralizing Antibody Levels of SARS-CoV-2 for COVID-19 Vaccination.

The comprehensive knowledge regarding the immune response during coronavirus disease 2019 (COVID-19) vaccination is limited. The aim of this study was to longitudinally investigate not only the dynamic changes of peripheral lymphocyte subpopulations and cytokine levels but parallel changes of antibody levels against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Blood samples of 20 healthcare workers with two doses of COVID-19 vaccine were prospectively collected. The percentages of lymphocyte subpopulations from peripheral blood and cytokine production in lymphocytes with in vitro stimulation were assessed using eight-color flow cytometry. SARS-CoV-2 spike antibodies (anti-S Abs) and functional neutralizing antibodies (nAbs) were also measured. The relation between pre- and post-vaccination immunity was analyzed. There are 7 men and 13 women with a median age of 44.0 years (range: 25.7−59.5 years). The individuals had an increased percentage of lymphocytes at post-vaccination with statistical significance post first dose (p = 0.031). The levels of transitional cells (p = 0.001), such as plasmablasts (p < 0.001) and plasma cells (p = 0.031), were increased compared with pre-vaccination. Recent thymic emigrants of CD4+ T cells subsets were significantly higher at post-vaccination than those at pre-vaccination (p = 0.029). Intracellular levels of tumor necrosis factor-alpha, interferon-γ, interleukin (IL)-2, IL-21, transforming growth factor-beta and IL-17 produced by CD4+ T, CD8+ T, and natural killer cells were increased. All individual samples showed reactivity to anti-S Abs and the levels of nAbs were elevated after vaccination. The magnitude of adaptive immunity was associated with vaccine types and doses. Alterations of total memory B cells (p < 0.001), non-switched memory B cells (p = 0.016), and memory Treg cells (p < 0.001) were independent predictors for nAb levels. These findings might be helpful in elucidating the immune response of COVID-19 vaccination and in developing new strategies for immunization.

Dysregulation of Cytoskeleton Remodeling Drives Invasive Leading Cells Detachment.

Detachment of cancer cells is the first step in tumor metastasis and malignancy. However, studies on the balance of initial tumor anchoring and detachment are limited. Herein, we revealed that the regulation of cytoskeleton proteins potentiates tumor detachment. The blockage of TGF-ß1 using neutralizing antibodies induced cancer cell detachment in the Boyden chamber and 3D in-gel spheroid models. Moreover, treatment with latrunculin B, an actin polymerization inhibitor, enhanced cell dissociation by abolishing actin fibers, indicating that TGF-ß1 mediates the formation of actin stress fibers, and is likely responsible for the dynamics of anchoring and detachment. Indeed, latrunculin B disrupted the formation of external TGF-ß1-induced actin fibers and translocation of intracellular vinculin, a focal adhesion protein, resulting in the suppression of cell adhesion. Moreover, the silencing of vimentin substantially reduced cell adhesion and enhanced cell detachment, revealing that cell adhesion and focal adhesion protein translocation stimulated by TGF-ß1 require vimentin. Using the 3D in-gel spheroid model, we found that latrunculin B suppressed the cell adhesion promoted by external TGF-ß1, increasing the number of cells that penetrated the Matrigel and detached from the tumor spheres. Thus, cytoskeleton remodeling maintained the balance of cell anchoring and detachment, and the TGF-ß1/vimentin/focal adhesion protein assembly axis was involved in the control dynamics of initial tumor detachment.

Ultralight, Conductive Ti3C2Tx MXene/PEDOT:PSS Hybrid Aerogels for Electromagnetic Interference Shielding Dominated by the Absorption Mechanism.

MXene aerogels with a porous microstructure are a promising electromagnetic interference (EMI) shielding material due to its low density and excellent electrical conductivity, which has attracted widespread attention. Compared with traditional EMI shielding materials that rely on reflection as the primary mechanism, MXene aerogels with absorption as the dominant mechanism have greater potential for development as a novel EMI shielding material because of its ability to reduce environmental contamination from reflected electromagnetic (EM) waves from materials. In this study, a novel Ti3C2Tx MXene/PEDOT:PSS hybrid aerogel was presented by freeze-drying and thermal annealing using few-layered Ti3C2Tx MXene and the conductive polymer poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT:PSS). PEDOT:PSS not only improved the gelling ability of Ti3C2Tx but also successfully established a conductive bridge between MXene nanosheets. The experimental results demonstrated that the hybrid aerogel exhibited an obvious porous microstructure, which was beneficial for the multiple scattering of EM waves within the materials. The EMI shielding effectiveness and specific shielding effectiveness reached up to 59 dB and 10,841 dB·cm2·g-1, respectively, while the SER/SET ratio value was only 0.05, indicating superior wave absorption performance. Furthermore, the good impedance matching, due to the electrical conductance loss and polarization loss effect of the composites, plays a critical role in their excellent wave absorption and EMI shielding performance. Therefore, this work provides a practical approach for designing and fabricating lightweight absorption-dominated EMI shielding materials.

The AST-120 Recovers Uremic Toxin-Induced Cognitive Deficit via NLRP3 Inflammasome Pathway in Astrocytes and Microglia.

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immunohistochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astrocytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.

Targeting the JAK-STAT pathway in autoimmune diseases and cancers: A focus on molecular mechanisms and therapeutic potential.

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is characterized by diverse immune regulatory systems involving cell proliferation, survival, and inflammation and immune tolerance. Aberrant JAK/STAT transduction activates proinflammatory cytokine signaling that jeopardize the immune balance and thus contributes to the development of autoimmune diseases and cancer progression. The success of several small-molecule JAK inhibitors in the treatment of rheumatologic diseases demonstrates that targeting the JAK/STAT pathway is efficient in suppressing inflammation and sheds light on their therapeutic potential in several autoimmune diseases and cancers. In this review, we discuss the signal transduction and molecular mechanism involving immune function through the JAK-STAT pathway, outline the role of this pathway in autoimmunity and oncoimmunology, and explain the preclinical and clinical trial evidence for the therapeutic potential of targeting the JAK-STAT signaling pathway. Issues regarding the safety and clinical efficacy of JAK inhibitors are reviewed. Ongoing studies are addressed with a focus on emerging indications for JAK inhibition and explanations of the novel mechanisms of JAK-STAT signaling blockade.

Encapsulation mechanism of α-mangostin by ß-cyclodextrin: Methods of molecular docking and molecular dynamics.

The study aimed to investigate the interaction of host-guest between α-mangostin and ß-cyclodextrin (ßCD) and also to calculate the energy of the complex system between α-mangostin with ßCD for drug delivery using methods of 15 molecular dynamics and molecular docking. Simulation of molecular docking and molecular dynamics was utilized to determine molecular interactions and the complex system's bond energy. The docking simulation results showed that α-mangostin-ßCD complex has a Gibbs energy value (ΔG) of -6.69 kcal/mol. The Gibbs energy value (ΔG) of molecular dynamics simulation from MMGBSA calculation showed the binding energy of α-mangostin-ßCD - 11.73 kcal/mol.

Multidisciplinary Care after Acute Care for Stroke: A Prospective Comparison between a Multidisciplinary Post-Acute Care Group and a Standard Group Matched by Propensity Score.

In this large-scale prospective cohort study, a propensity score matching method was applied in a natural experimental design to investigate how post-acute care (PAC) after stroke affects functional status and to identify predictors of functional status. The main objective of this study was to examine longitudinal changes in various measures of functional status in stroke patients and predictors of scores for these measures before and after PAC. A group of patients who had received PAC for stroke at one of two medical centers (PAC group, n = 273) was compared with a group who had received standard care for stroke at one of four hospitals (three regional hospital and one district hospital; non-PAC group, n = 273) in Taiwan from March, 2014, to October, 2018. The patients completed the functional status measures before rehabilitation, the 12th week and the 1st year after rehabilitation. Generalized estimating equations were used to estimate differences-in-differences models for examining the effects of PAC. The average age was 68.0 (SD = 8.1) years, and males accounted for 57.9%. During the follow-up period, significant risk factors for poor functional outcomes were advanced age, hemorrhagic stroke, and poor function scores before rehabilitation (p < 0.05). Between-group comparisons at subsequent time points revealed significantly higher functional status scores in the PAC group versus the non-PAC group (p < 0.001). Notably, for all functional status measures, between-group differences in total scores significantly increased over time from baseline to 1 year post-rehabilitation (p < 0.001). The contribution of this study is its further elucidation of the clinical implications and health policy implications of rehabilitative care after stroke. Specifically, it improves understanding of the effects of PAC in stroke patients at different follow-up times. Therefore, a policy implication of this study is that standard care for stroke should include intensive rehabilitative PAC to maximize recovery of overall function.

The role of the primary cilium in cancer.

As a common lethal disease, cancer is now responsible for the majority of deaths worldwide and has been the single most important barrier to increasing life expectancy in the world. The pathogenesis of cancer has been the key point of cancer therapeutics research. The primary cilium, a solitary microtubule-based organelle, is considered to be an important sensor for receiving mechanical and chemical stimulation from other cells and environments; it plays an important role in a variety of signal transduction and disease processes. More importantly, the primary cilium can also function as an elaborate structure to regulate cell proliferation because ciliogenesis regulates cell division by sequestering the centriole. Recently, many new findings have suggested that the length and incidence of the primary cilium are closely connected to carcinogenesis and responses to cancer therapy. Here, we review relevant evidences proving that the primary cilium plays a key role in the occurrence and treatment of cancer. We also summarize the primary cilium-associated signaling pathways in cancer, including Wnt signaling, Hedgehog signaling, PDGFR signaling, and Notch signaling, and anticipate that targeting proteins localized in the primary cilium may be a potential anti-cancer strategy.

Converged Rab37/IL-6 trafficking and STAT3/PD-1 transcription axes elicit an immunosuppressive lung tumor microenvironment.

Background: Increased IL-6 level, M2 macrophages and PD-1+CD8+ T cells in tumor microenvironments (TME) have been identified to correlate with resistance to checkpoint blockade immunotherapy, yet the mechanism remains poorly understood. Rab small GTPase-mediated trafficking of cytokines is critical in immuno-modulation. We have previously reported dysregulation of Rab37 in lung cancer cells, whereas the roles of Rab37 in tumor-infiltrating immune cells and cancer immunotherapy are unclear. Methods: The tumor growth of the syngeneic mouse allograft in wild type or Rab37 knockout mice was analyzed. Imaging analyses and vesicle isolation were conducted to determine Rab37-mediated IL-6 secretion. STAT3 binding sites at PD-1 promoter in T cells were identified by chromatin immunoprecipitation assay. Multiplex fluorescence immunohistochemistry was performed to detect the protein level of Rab37, IL-6 and PD-1 and localization of the tumor-infiltrating immune cells in allografts from mice or tumor specimens from lung cancer patients. Results: We revealed that Rab37 regulates the secretion of IL-6 in a GTPase-dependent manner in macrophages to trigger M2 polarization. Macrophage-derived IL-6 promotes STAT3-dependent PD-1 mRNA expression in CD8+ T cells. Clinically, tumors with high stromal Rab37 and IL-6 expression coincide with tumor infiltrating M2-macrophages and PD1+CD8+ T cells that predicts poor prognosis in lung cancer patients. In addition, lung cancer patients with an increase in plasma IL-6 level are found to be associated with immunotherapeutic resistance. Importantly, combined blockade of IL-6 and CTLA-4 improves survival of tumor-bearing mice by reducing infiltration of PD1+CD8+ T cells and M2 macrophages in TME. Conclusions: Rab37/IL-6 trafficking pathway links with IL-6/STAT3/PD-1 transcription regulation to foster an immunosuppressive TME and combined IL-6/CTLA-4 blockade therapy exerts potent anti-tumor efficacy.