Factors influencing self-regulatory fatigue in patients undergoing chemotherapy for gynecologic cancer: a cross-sectional study.

Objective: To understand the current status of self-regulatory fatigue among gynecologic cancer chemotherapy patients and explore influencing factors. Methods: Using convenient sampling, a total of 232 gynecological cancer chemotherapy patients from two tertiary hospitals in Zhengzhou, Henan, China, were selected as study subjects from February 2023 to April 2023. General information questionnaire, Self-Regulatory Fatigue Scale (SRF-S), Strategies Used by People to Promote Health (SUPPH) Scale, Connor-Davidson resilience scale (CD-RISC) and Perceived Social Support Scale (PSSS) were employed for data collection. The data were analyzed using SPSS 26.0 software. Chi-square test and binary logistic regression were executed to explore the correlates of self-regulatory fatigue, the significance level (α) was set at 0.05. Results: The self-regulatory fatigue score of the 232 patients was 44 (36, 56). Binary logistic regression analyses revealed significant associations, demonstrating that residing in urban areas (OR=0.241, P=0.015), having no comorbidities (OR=0.158, P=0.015), increased perceived social support (OR=0.937, P=0.001), strong self-efficacy (OR=0.959, P=0.021), and heightened psychological resilience (OR=0.895, P<0.001) acted as protective factors against self-regulatory fatigue (P < 0.05). Conclusion: Patients residing in rural areas, having more than two comorbidities, lower self-efficacy and psychological resilience levels, and lower perceived social support are indicative of higher levels of self-regulatory fatigue. Identifying these influencing factors can provide references and support for developing individualized support and intervention measures to improve patients' physical and mental well-being.

The experiences of family resilience in patients with permanent colostomy and their spouses: A dyadic qualitative study.

PURPOSE: With the prolonged survival time of patients with permanent colostomy for colorectal cancer, they and their spouses face tremendous pressure and development dilemmas that can easily lead to family adaptation crises. This qualitative study amid to explore the dyadic experiences of family resilience among Chinese patients with permanent colostomy and their spouses. METHODS: A phenomenological research method was adopted. Semi-structured, in-depth, face-to-face interviews with 10 dyads of patients with permanent colostomy and their spouses were recruited through purposive sampling from a public tertiary hospital in China from March 2023 to July 2023.The Dyadic interview analysis and Colaizzi methods were used to analyze the interview data. RESULTS: Three themes and nine subthemes were developed. (1) family crisis and dichotomous coping with stress-family crisis and coping pressure caused by enterostomy; (2) Adjustment and adaptation within the family-Joint adjustment and adaptation within the couple's family; and (3) integration and utilization of multi-dimensional social external resources (micro-level, meso-level, and macro-level). CONCLUSIONS: Couples living with permanent colostomy often undergo a complex emotional journey, experiencing varied levels of individual stress as they navigate social interactions and daily activities, which can contribute to a decline in family adaptation. With the help of the perspective of family advantage, health practitioners should pay attention to the evaluation of individual factors and family environmental resources, to fully mobilize advantage resources and give effective interventions to improve the family and social adaptation level of patients and their spouses.

UFObow: A single-wavelength excitable Brainbow for simultaneous multicolor ex-vivo and in-vivo imaging of mammalian cells.

Brainbow is a genetic cell-labeling technique that allows random colorization of multiple cells and real-time visualization of cell fate within a tissue, providing valuable insights into understanding complex biological processes. However, fluorescent proteins (FPs) in Brainbow have distinct excitation spectra with peak difference greater than 35 nm, which requires sequential imaging under multiple excitations and thus leads to long acquisition times. In addition, they are not easily used together with other fluorophores due to severe spectral bleed-through. Here, we report the development of a single-wavelength excitable Brainbow, UFObow, incorporating three newly developed blue-excitable FPs. We have demonstrated that UFObow enables not only tracking the growth dynamics of tumor cells in vivo but also mapping spatial distribution of immune cells within a sub-cubic centimeter tissue, revealing cell heterogeneity. This provides a powerful means to explore complex biology in a simultaneous imaging manner at a single-cell resolution in organs or in vivo.

Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications.

Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC.

Synthesis, antibacterial activity, and 3D-QASR studies of matrine-indole derivatives as potential antibiotics.

Matrine and indole have antibacterial, anticancer, and other biological activities, in order to develop new antibiotics to solve the problem of multi-drug resistant bacteria. In this paper, we synthesized a series of 29 novel matrine derivatives as potential drug candidates by combining indole analogs and matrine. The antibacterial activity of these compounds was evaluated through minimum inhibitory concentration (MIC) assays against five bacterial strains (S. aureus, C. albicans, P. acnes, P. aeruginosa, and E. coli). The obtained results demonstrated promising antibacterial efficacy, particularly for compounds A20 and A18, which exhibited MICs.au values of 0.021 and 0.031 mg/ml, respectively, against S. aureus. Moreover, compounds A20 and A27 displayed remarkable MICc.al values of 2.806 and 4.519 mg/ml, respectively, against C. albicans, surpassing the performance of the clinical antibiotic penicillin G sodium (0.0368 mg/ml) and fluconazole (4.849 mg/ml). These findings underscore the significant bacteriostatic activity of the matrine derivatives. Furthermore, to gain a deeper understanding 3D-QSAR modeling was employed, revealing the critical influence of steric structure, charge distribution, hydrophobic interactions, and hydrogen bonding within the molecular structure on the bacteriostatic activity of the compounds. Additionally, molecular docking simulations shed light on the interaction between compound A20 and bacterial proteins, highlighting the involvement of hydrogen bonding, hydrophobic interactions, and π-π conjugation in the formation of stable complexes that inhibit the normal functioning of the proteins. This comprehensive analysis provided valuable insights into the antibacterial mechanism of the novel matrine derivatives, offering theoretical support for their potential application as antibiotics.

Letermovir Effectively Prevents Cytomegalovirus Infection in Patients with Aplastic Anemia After Hematopoietic Stem Cell Transplantation: A Real-World Retrospective Cohort Study.

INTRODUCTION: In this single-center retrospective cohort study, we investigated the efficacy of letermovir in preventing Cytomegalovirus (CMV) infection in patients with aplastic anemia (AA) who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Based on whether or not letermovir was used for preventing CMV infection, the patients were categorized into two groups: letermovir and control groups. The overall survival (OS) rate and cumulative incidence of CMV infection during the first 100 days after allo-HSCT were evaluated. The study included 21 matched pairs of patients, identified through propensity score matching analysis, to compare CMV infection rates, treatment efficacy, and regression. RESULTS: The incidence of CMV infection within 100 days after transplantation was significantly lower in the letermovir group than in the control group (26.5 vs. 77.4%, respectively; P < 0.001), among a total of 87 patients who underwent the transplant. In the matched cohort of 21 patients with AA, the letermovir group also showed a significantly reduced cumulative incidence of CMV infection (14.3 vs. 90.5% in the control group; P < 0.001). Compared to the control group, patients with CMV infection in the letermovir group had lower CMV-DNA load and a shorter clearance time. However, there was no significant difference in OS between both groups (P = 0.34). CONCLUSIONS: Letermovir effectively prevents CMV infection in allo-HSCT recipients with AA and demonstrates a high safety profile.

Analysis of the status and factors influencing physical activity in patients undergoing ovarian cancer chemotherapy.

Background: Ovarian cancer is a common gynecological malignancy, leading to approximately 200,000 deaths globally in 2020. Research has shown that regular physical activity can reduce the toxic side effects of cancer treatment, reduce morbidity and mortality, extend survival time, and improve quality of life. We aimed to evaluate physical activity regimens in patients undergoing chemotherapy for ovarian cancer and analyze the factors influencing physical activity levels. Methods: To facilitate the selection of patients with ovarian cancer hospitalized for chemotherapy in the Third Affiliated Hospital of Zhengzhou University and the First Affiliated Hospital of Zhengzhou University from August 2022 to February 2023, questionnaire surveys were conducted using the General Information Questionnaire, International Physical Activity Questionnaire, Hospital Anxiety and Depression Scale, and Revised Piper Fatigue Scale. Results: Data were collected from 167 patients with ovarian cancer. Overall, 96 (57.5%) patients had low physical activity levels, 53 (31.7%) had moderate physical activity levels, and 18 (10.8%) had high physical activity levels. Logistic regression analysis revealed that sleep status, social support, anxiety, depression, and cancer-related fatigue were the main factors influencing physical activity in patients undergoing chemotherapy for ovarian cancer. Conclusions: Physical activity levels of patients undergoing ovarian cancer chemotherapy were generally low. Therefore, healthcare professionals should pay greater attention to the physical activity in these patients. Targeted and individualized health guidance is recommended, and activity interventions should be implemented according to the influencing factors to promote disease understanding and increase physical activity levels.

Pluronic F-127 Hydrogel Loaded with Human Adipose-Derived Stem Cell-Derived Exosomes Improve Fat Graft Survival via HIF-1α-Mediated Enhancement of Angiogenesis.

Purpose: Autologous fat grafting is playing an increasingly important role in plastic surgery. However, high absorption and low survival of autologous fat grafts limit their clinical application. This study aimed to investigate whether human adipose-derived stem cell-derived exosomes (hASC-Exos) encapsulated in a PF-127 hydrogel can improve the survival of autologous fat grafts and to elucidate the underlying mechanisms. Patients and Methods: Exosomes were isolated from hASCs and identified using transmission electron microscopy, nanoparticle tracking analysis and Western blotting. We performed functional assays in vitro to assess the effect of hASC-Exos on proliferation, migration, and tube formation as well as their regulatory role in the HIF-1α/VEGF signaling pathway. hASC-Exos encapsulated in the PF-127 hydrogel were used as an in vivo autologous fat graft model. The effects of the PF-127 hydrogel/hASC-Exos and the role of the HIF-1α/VEGF signaling pathway in promoting angiogenesis in an autologous fat grafting model were assessed. Results: hASC-Exos were taken up by human umbilical vein endothelial cells and enhanced their proliferation, migration, and tubule formation in vitro. The effects of hASC-Exos on promoting angiogenesis were mediated by the HIF-1α/VEGF signaling pathway. Moreover, we fabricated a PF-127 hydrogel for the sustained release of hASC-Exos, and in vivo results showed that hASC-Exos encapsulated in PF-127 hydrogel improved the survival of autologous fat grafts. Conclusion: Our findings indicated that hASC-Exos encapsulated in PF-127 hydrogel serve as a key regulator of angiogenesis by activating the HIF-1α/VEGF signaling pathway and provide a promising strategy for autologous fat grafting treatment.

Neuron-secreted NLGN3 ameliorates ischemic brain injury via activating Gαi1/3-Akt signaling.

We here tested the potential activity and the underlying mechanisms of neuroligin-3 (NLGN3) against ischemia-reperfusion-induced neuronal cell injury. In SH-SY5Y neuronal cells and primary murine cortical neurons, NLGN3 activated Akt-mTOR and Erk signalings, and inhibited oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced cytotoxicity. Akt activation was required for NLGN3-induced neuroprotection. Gαi1/3 mediated NLGN3-induced downstream signaling activation. NLGN3-induced Akt-S6K1 activation was largely inhibited by Gαi1/3 silencing or knockout. Significantly, NLGN3-induced neuroprotection against OGD/R was almost abolished by Gαi1/3 silencing or knockout. In vivo, the middle cerebral artery occlusion (MCAO) procedure induced NLGN3 cleavage and secretion, and increased its expression and Akt activation in mouse brain tissues. ADAM10 (A Disintegrin and Metalloproteinase 10) inhibition blocked MCAO-induced NLGN3 cleavage and secretion, exacerbating ischemic brain injury in mice. Neuronal silencing of NLGN3 or Gαi1/3 in mice also inhibited Akt activation and intensified MCAO-induced ischemic brain injury. Conversely, neuronal overexpression of NLGN3 increased Akt activation and alleviated MCAO-induced ischemic brain injury. Together, NLGN3 activates Gαi1/3-Akt signaling to protect neuronal cells from ischemia-reperfusion injury.

DNMT1 mediates the disturbed flow-induced endothelial to mesenchymal transition through disrupting ß-alanine and carnosine homeostasis.

Background: Increasing evidence suggests that hemodynamic disturbed flow induces endothelial dysfunction via a complex biological process so-called endothelial to mesenchymal transition (EndoMT). Recently, DNA methyltransferases (DNMTs) was reported as a key molecular mediator to promote EndoMT. Our understanding of how DNMTs, particularly the maintenance DNMTs, DNMT1, coordinate EndoMT is still lacking. Methods: A parallel-plate flow apparatus and perfusion devices were used to apply fluid with endothelial protective pulsatile shear (PS, to mimic the laminar flow) or harmful oscillatory shear (OS, to mimic the disturbed flow) to cultured endothelial cells (ECs). Endothelial lineage tracing mice and conditional EC Dnmt1 knockout mice were subjected to a surgery of carotid partial ligation to generate the flow-accelerated atherogenesis models. Western blotting, quantitative RT-PCR, immunofluorescent staining, methylation-specific PCR, chromatin immunoprecipitation, endothelial functional assays, and assessments for neointimal formation and atherosclerosis were performed. Results: Inhibition of DNMTs with 5-aza-2'-deoxycytidine (5-Aza) suppressed the disturbed flow/OS-induced EndoMT, both in cultured cells and the endothelial lineage tracing mice. 5-Aza also ameliorated the downregulation of aldehyde dehydrogenases (ALDHs) and ß-alanine biosynthesis caused by disturbed flow/OS. Knockdown of the ALDH family proteins, ALDH2, ALDH3A1, and ALDH6A1, showed an EndoMT-induction effect as OS. Supplementation of cells with the functional metabolites of ß-alanine, carnosine and acetyl-CoA (acetate), reversed EndoMT, likely via inhibiting the phosphorylation of Smad2/3. Endothelial-specific knockout of Dnmt1 protected the vasculature from disturbed flow-induced remodeling and atherosclerosis. Conclusions: Endothelial DNMT1 acts as one of the key epigenetic factors to mediate the hemodynamically regulated EndoMT at least through repressing the expression of ALDH2, ALDH3A1, and ALDH6A1. Supplementation with carnosine and acetate may have a great potential in the prevention and treatment of atherosclerosis.

Three-dimensional spheroid formation of adipose-derived stem cells improves the survival of fat transplantation by enhance their therapeutic effect.

Adipose-derived stem cells (ADSCs) have important applications in basic research, especially in fat transplantation. Some studies have found that three-dimensional (3D) spheroids formed by mesenchymal stem cells have enhanced therapeutic potential. However, the fundamental basics of this effect are still being discussed. ADSCs were harvested from subcutaneous adipose tissues and 3D spheroids were formed by the automatic aggregation of ADSCs in a non-adhesive 6-well plate. Oxygen glucose deprivation (OGD) was used to simulate the transplantation microenvironment. We found that 3D culture of ADSCs triggered cell autophagy. After inhibiting autophagy by Chloroquine, the rates of apoptosis were increased. When the 3D ADSC-spheroids were re-planked, the number of senescent ADSCs decreased, and the proliferation ability was promoted. In addition, there were more cytokines secreted by 3D ADSC-spheroids including VEGF, IGF-1, and TGF-ß. After adding the conditioned medium with human umbilical vein endothelial cells (HUVECs), 3D ADSC-spheroids were more likely to promote migration, and tube formation, stimulating the formation of new blood vessels. Fat grafting experiments in nude mice also showed that 3D ADSC-spheroids enhanced survival and neovascularization of fat grafts. These results suggested that 3D spheroids culturing of ADSCs can increase the therapeutic potential in fat transplantation.

Comprehensive characterization of ferroptosis in hepatocellular carcinoma revealing the association with prognosis and tumor immune microenvironment.

Background: Ferroptosis is a type of regulatory cell death (RCD) mode that depends on iron-mediated oxidative damage. It has the potential to improve the efficacy of tumor immunotherapy by modulating the tumor microenvironment (TME). Currently, immunotherapy has significantly improved the overall treatment strategy for advanced hepatocellular carcinoma (HCC), but the distinct immune microenvironment and high tolerance to the immune make massive differences in the immunotherapy effect of HCC patients. As a result, it is imperative to classify HCC patients who may benefit from immune checkpoint therapy. Simultaneously, the predictive value of ferroptosis in HCC and its potential role in TME immune cell infiltration also need to be further clarified. Methods: Three ferroptosis molecular models were built on the basis of mRNA expression profiles of ferroptosis-related genes (FRGs), with notable variations in immunocyte infiltration, biological function, and survival prediction. In order to further investigate the predictive impact of immunotherapy response in HCC patients, the ferroptosis score was constructed using the principal component analysis (PCA) algorithm to quantify the ferroptosis molecular models of individual tumors. Results: In HCC, there were three totally different ferroptosis molecular models. The ferroptosis score can be used to assess genetic variation, immunotherapy response, TME characteristics, and prognosis. Notably, tumors with low ferroptosis scores have extensive tumor mutations and immune exhaustion, which are associated with a poor prognosis and enhanced immunotherapy response. Conclusions: Our study indicates that ferroptosis plays an indispensable role in the regulation of the tumor immune microenvironment. For HCC, the ferroptosis score is an independent prognostic indicator. Assessing the molecular model of ferroptosis in individual tumors will assist us in better understanding the characteristics of TME, predicting the effect of immunotherapy in HCC patients, and thus guiding a more reasonable immunotherapy program.

Preparation and cytotoxicity evaluation of folic acid-modified YF8-OA self-assembled lipid prodrug nanoparticles.

This study aimed to improve the use of YF8, a matrine derivative obtained through chemical transformation of matrine extracted from Sophora alopecuroides. YF8 has demonstrated improved cytotoxicity compared to matrine, but its hydrophobic nature hinders its application. To overcome this, the lipid prodrug YF8-OA was synthesized by linking oleic acid (OA) to YF8 through an ester bond. Although YF8-OA could self-assemble into unique nanostructures in water, it was not sufficiently stable. To enhance the stability of YF8-OA lipid prodrug nanoparticles (LPs), we employed the strategy of PEGylation using DSPE-mPEG2000 or DSPE-mPEG2000 conjugated with folic acid (FA). This resulted in the formation of uniform spherical nanoparticles with greatly improved stability and a maximum drug load capacity upto 58.63%. Cytotoxicity was evaluated in A549, HeLa, and HepG2 cell lines. The results showed that in HeLa cells, the IC50 value of YF8-OA/LPs with FA-modified PEGylation was significantly lower than that of YF8-OA/LPs modified by PEGylation alone. However, no significant enhancement was observed in A549 and HepG2 cells. In conclusion, the lipid prodrug YF8-OA can form nanoparticles in aqueous solution to address its poor water solubility. Modification with FA resulted in further enhanced cytotoxicity, providing a potential avenue for exerting the antitumor activity of matrine analogs.

Incorporation of mixed-dimensional palygorskite clay into chitosan/polyvinylpyrrolidone nanocomposite films for enhancing hemostatic activity.

Clay mineral-based hemostatic materials have attracted much attention in recent years, but it is scarce to report the hemostatic nanocomposite films containing natural mixed-dimensional clay composed of natural one-dimensional and two-dimensional clay minerals. In this study, the high-performance hemostatic nanocomposite films were facilely prepared by incorporating the natural mixed-dimensional palygorskite clay leached by oxalic acid (O-MDPal) into chitosan/polyvinylpyrrolidone (CS/PVP) matrix. By contrast, the obtained nanocomposite films exhibited the higher tensile strength (27.92 MPa), lower water contact angel (75.40°), better degradation, thermal stability and biocompatibility after incorporation of 20 wt% of O-MDPal, suggesting that O-MDPal contributed to enhancing the mechanical performance and water holding capacity of the CS/PVP nanocomposite films. Compared with the medical gauze and CS/PVP matrix groups, the nanocomposite films also indicated excellent hemostatic performance evaluated by blood loss and hemostasis time indexes based on the mouse tail amputation model, which might be ascribed to the enriched hemostatic functional sites, and hydrophilic surface, robust physical barrier role of nanocomposite films. Therefore, the nanocomposite film exhibited a promising practical application in wound healing.

Loss of Tumor Suppressor C9orf9 Promotes Metastasis in Colorectal Cancer.

The whole genome sequencing of tumor samples identifies thousands of somatic mutations. However, the function of these genes or mutations in regulating cancer progression remains unclear. We previously performed exome sequencing in patients with colorectal cancer, and identified one splicing mutation in C9orf9. The subsequent target sequencing of C9orf9 gene based on a validation cohort of 50 samples also found two function mutations, indicating that the loss of wild-type C9orf9 may participate in the tumorigenesis of colorectal cancer. In this research, we aimed to further confirm the function of C9orf9 in the CRC phenotype. Our Q-PCR analysis of the tumor and matched normal samples found that C9orf9 was downregulated in the CRC samples. Function assays revealed that C9orf9 exerts its tumor suppressor role mainly on cancer cell migration and invasion, and its loss was essential for certain tumor-microenvironment signals to induce EMT and metastasis in vivo. RNA-sequencing showed that stable-expressing C9orf9 can inhibit the expression of several metastasis-related genes and pathways, including vascular endothelial growth factor A (VEGFA), one of the essential endothelial cell mitogens which plays a critical role in normal physiological and tumor angiogenesis. Overall, our results showed that the loss of C9orf9 contributes to the malignant phenotype of CRC. C9orf9 may serve as a novel metastasis repressor for CRC.

Metal-Organic Frameworks (MOF)-Assisted Sonodynamic Therapy in Anticancer Applications.

Sonodynamic therapy (SDT) has emerged as a promising therapeutic modality for anticancer treatments and is becoming a cutting-edge interdisciplinary research field. This review starts with the latest developments of SDT and provides a brief comprehensive discussion on ultrasonic cavitation, sonodynamic effect, and sonosensitizers in order to popularize the basic principles and probable mechanisms of SDT. Then the recent progress of MOF-based sonosensitizers is overviewed, and the preparation methods and properties (e.g., morphology, structure, and size) of products are presented in a fundamental perspective. More importantly, many deep observations and understanding toward MOF-assisted SDT strategies were described in anticancer applications, aiming to highlight the advantages and improvements of MOF-augmented SDT and synergistic therapies. Last but not least, the review also pointed out the probable challenges and technological potential of MOF-assisted SDT for the future advance. In all, the discussions and summaries of MOF-based sonosensitizers and SDT strategies will promote the fast development of anticancer nanodrugs and biotechnologies.

Bad is essential for Bcl-xL-enhanced Bax shuttling between mitochondria and cytosol.

Although Bcl-xL has been shown to retrotranslocate Bax from mitochondria to cytosol, other studies have found that Bcl-xL also stabilizes the mitochondrial localization of Bax. It is still unclear what causes the difference in Bcl-xL-regulated Bax localization. Bad, a BH3-only protein with a high affinity for Bcl-xL, may play an important role in Bcl-xL-regulated Bax shuttling. Here, we found that Bcl-xL enhanced both translocalization and retrotranslocation of mitochondrial Bax, as evidenced by quantitative co-localization, western blots and fluorescence loss in photobleaching (FLIP) analyses. Notably, Bad knockdown prevented Bcl-xL-mediated Bax retrotranslocation, indicating Bad was essential for this process. Quantitative fluorescence resonance energy transfer (FRET) imaging in living cells and co-immunoprecipitation analyses showed that the interaction of Bcl-xL with Bad was stronger than that with Bax. The Bad mimetic ABT-737 dissociated Bax from Bcl-xL on isolated mitochondria, suggesting that mitochondrial Bax was directly liberated to cytosol due to Bad binding to Bcl-xL. In addition, MK-2206, an Akt inhibitor, decreased Bad phosphorylation while increasing cytosolic Bax proportion. Our data firmly demonstrate a notion that Bad binds to mitochondrial Bcl-xL to release Bax, resulting in retrotranslocation of Bax to cytosol, and that the amount of Bad involved is regulated by Akt signaling.

Molecular characterization and clinical investigation of patients with heritable thoracic aortic aneurysm and dissection.

OBJECTIVES: Thoracic aortic aneurysm and dissection has a genetic predisposition and a variety of clinical manifestations. This study aimed to investigate the clinical and molecular characterizations of patients with thoracic aortic aneurysm and dissection and further explore the relationship between the genotype and phenotype, as well as their postoperative outcomes. METHODS: A total of 1095 individuals with thoracic aortic aneurysm and dissection admitted to our hospital between 2013 and 2022 were included. Next-generation sequencing and multiplex ligation-dependent probe amplification were performed, and mosaicism analysis was additionally implemented to identify the genetic causes. RESULTS: A total of 376 causative variants were identified in 83.5% of patients with syndromic thoracic aortic aneurysm and dissection and 18.7% of patients with nonsyndromic thoracic aortic aneurysm and dissection, including 8 copy number variations and 2 mosaic variants. Patients in the "pathogenic" and "variant of uncertain significance" groups had younger ages of aortic events and higher aortic reintervention risks compared with genetically negative cases. In addition, patients with FBN1 haploinsufficiency variants had shorter reintervention-free survival than those with FBN1 dominant negative variants. CONCLUSIONS: Our data expanded the genetic spectrum of heritable thoracic aortic aneurysm and dissection and indicated that copy number variations and mosaic variants contributed to a small proportion of the disease-causing alterations. Moreover, positive genetic results might have a possible predictive value for aortic event severity and postoperative risk stratification.

Live-cell imaging analysis on the anti-apoptotic function of the Bcl-xL transmembrane carboxyl terminal domain.

The Transmembrane Carboxyl Terminal Domain (TMD) of some Bcl-2 family proteins has been demonstrated to play a key role in modulating apoptosis. We here ustilzed live-cell fluorescence imaging to evaluate how the Bcl-xL TMD (XT) regulate apoptosis. Cell viability assay revealed that XT had strong anti-apoptotic ability similarly to the full-length Bcl-xL. Fluorescence images of living cells co-expressing CFP-XT and Bad-YFP or YFP-Bax revealed that XT recruited Bad to mitochondria but prevented Bax translocation to mitochondria, and also significantly suppressed Bad/Bax-mediated apoptosis, indicating that XT prevents the pro-apoptotic function of Bad and Bax. Fluorescence Resonance Energy Transfer (FRET) analyses determined that XT directly interacted with Bad and Bax, and deletion of XT completely eliminated the mitochondrial localization and homo-oligomerization of Bcl-xL. Fluorescence images of living cells co-expressing CFP-XT and YFP-Bax revealed that XT significantly prevented mitochondrial Bax oligomerization, resulting in cytosolic Bax distribution. Collectively, XT is necessary for the mitochondrial localization and anti-apoptotic capacity of Bcl-xL, and XT, similarly to the full-length Bcl-xL, forms homo-oligomers on mitochondria to directly interact with Bad and Bax to inhibit their apoptotic functions.

Characterization of glucose metabolism in breast cancer to guide clinical therapy.

Background: Breast cancer (BRCA) ranks as a leading cause of cancer death in women worldwide. Glucose metabolism is a noticeable characteristic of the occurrence of malignant tumors. In this study, we aimed to construct a novel glycometabolism-related gene (GRG) signature to predict overall survival (OS), immune infiltration and therapeutic response in BRCA patients. Materials and methods: The mRNA sequencing and corresponding clinical data of BRCA patients were obtained from public cohorts. Lasso regression was applied to establish a GRG signature. The immune infiltration was evaluated with the ESTIMATE and CIBERSORT algorithms. The drug sensitivity was estimated using the value of IC50, and further forecasted the therapeutic response of each patient. The candidate target was selected in Cytoscape. A nomogram was constructed via the R package of "rms". Results: We constructed a six-GRG signature based on CACNA1H, CHPF, IRS2, NT5E, SDC1 and ATP6AP1, and the high-risk patients were correlated with poorer OS (P = 2.515 × 10-7). M2 macrophage infiltration was considerably superior in high-risk patients, and CD8+ T cell infiltration was significantly higher in low-risk patients. Additionally, the high-risk group was more sensitive to Lapatinib. Fortunately, SDC1 was recognized as candidate target and patients had a better OS in the low-SDC1 group. A nomogram integrating the GRG signature was developed, and calibration curves were consistent between the actual and predicted OS. Conclusions: We identified a novel GRG signature complementing the present understanding of the targeted therapy and immune biomarker in breast cancer. The GRGs may provide fresh insights for individualized management of BRCA patients.