Flexible and Compressible Nanostructure-Assembled Aramid Nanofiber/Silica Composites Aerogel.

The Applications of silica aerogel are limited due to its brittleness and low strength. As a result, it is essential to strengthen and toughen it. Organic nanofibers are one of the preferred reinforcement materials. In this work, we designed and fabricated flexible and compressible nanostructure-assembled aramid nanofiber/silica composites aerogel (ANF/SiO2 aerogel) to improve the mechanical strength and flexibility of silica aerogel without compromising thermal insulation properties. The aramid nanofiber/silica composite aerogels were prepared by immersing the aramid nanofiber wet gel into the silica sol for a certain period of time followed by freeze drying without solvent replacement. The surface modifier 3-aminopropyltriethoxysilane (APTES) was used as a coupling agent to form chemical linkage between the ANF fiber and silica gel. It was observed that APTES can effectively drive the silica sol to infuse into ANF hydrogel, promoting the assembly of silica gel onto the fiber surface and a uniform distribution in the network of ANF. The compressive resilience, thermal stability, and thermal insulation properties of the composite aerogels were evaluated by inducing the silica aerogel into the ANF network to form a protective layer on the fiber and change the pore structure in the ANF network.

Genetic Causal Relationship Between Alanine Aminotransferase Levels and Risk of Gestational Diabetes Mellitus: Mendelian Randomization Analysis Based on Two Samples.

Gestational diabetes mellitus (GDM) is a frequent complication of pregnancy. The specific mechanisms underlying GDM have not yet been fully elucidated. Contemporary research indicates a potential association between liver enzyme irregularities and an increased risk of metabolic disorders, including diabetes. The alanine aminotransferase (ALT) level is recognized as a sensitive marker of liver injury. An increase in ALT levels is hypothesized to be linked to the pathogenesis of insulin resistance and diabetes. Nonetheless, the definitive causal link between ALT levels and GDM still needs to be determined. This investigation utilized two-sample Mendelian randomization (MR) to examine the genetic causation between alanine aminotransferase (ALT) and GDM. We acquired alanine aminotransferase (ALT)-related GWAS summary data from the UK Biobank, Million Veteran Program, Rotterdam Study, and Lifeline Study. Gestational diabetes data were obtained from the FinnGen Consortium. We employed various MR analysis techniques, including inverse-variance weighted (IVW), MR Egger, weighted median, simple, and weighted weighting. In addition to MR-Egger intercepts, Cochrane's Q test was also used to assess heterogeneity in the MR data, and the MR-PRESSO test was used to assess horizontal pleiotropy. To assess the association's sensitivity, a leave-one-out approach was employed. The IVW results confirmed the independent risk factor for GDM development, as indicated by the ALT level (p = .011). As shown by leave-one-out analysis, horizontal pleiotrophy did not significantly skew the causative link (p > .05). Our dual-sample MR analysis provides substantiated evidence of a genetic causal relationship between alanine aminotransferase (ALT) levels and gestational diabetes.

Allogeneic haematopoietic stem cell transplantation for adult T-lymphoblastic lymphoma: A real-world multicentre analysis in China.

In this multicentre, real-world study, we aimed to identify the clinical outcomes and safety of allogeneic haematopoietic stem cell transplantation (allo-HSCT) in T-lymphoblastic lymphoma (T-LBL). A total of 130 Ann Arbor stage III or IV T-LBL patients (>16 years) treated with allo-HSCT across five transplant centres were enrolled. The 2-year cumulative incidence of disease progression, the probabilities of progression-free survival (PFS), overall survival (OS) and non-relapse mortality (NRM) after allo-HSCT were 21.0%, 69.8%, 79.5% and 9.2% respectively. Patients with central nervous system (CNS) involvement had a higher cumulative incidence of disease progression compared with those without CNS involvement (57.1% vs. 18.9%, HR 3.78, p = 0.014). Patients receiving allo-HSCT in non-remission (NR) had a poorer PFS compared with those receiving allo-HSCT in complete remission (CR) or partial remission (49.2% vs. 72.7%, HR 2.21, p = 0.041). Particularly for patients with bone marrow involvement and achieving CR before allo-HSCT, measurable residual disease (MRD) positivity before allo-HSCT was associated with a poorer PFS compared with MRD negativity (62.7% vs. 86.8%, HR 1.94, p = 0.036). On multivariate analysis, CNS involvement at diagnosis and receiving allo-HSCT in NR were associated with disease progression. Thus, our real-world data suggested that allo-HSCT appeared to be an effective therapy for adult T-LBL patients with Ann Arbor stage III or IV disease.

Measurable residual disease monitoring by ddPCR in the early posttransplant period complements the traditional MFC method to predict relapse after HSCT in AML/MDS: a multicenter retrospective study.

BACKGROUND: Droplet digital PCR (ddPCR) is widely applied to monitor measurable residual disease (MRD). However, there are limited studies on the feasibility of ddPCR-MRD monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially targeting multiple molecular markers simultaneously. METHODS: Our study collected samples from patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in complete remission after allo-HSCT between January 2018 and August 2021 to evaluate whether posttransplant ddPCR-MRD monitoring can identify patients at high risk of relapse. RESULTS: Of 152 patients, 58 (38.2%) were MRD positive by ddPCR within 4 months posttransplant, with a median variant allele frequency of 0.198%. The detectable DTA mutations (DNMT3A, TET2, and ASXL1 mutations) after allo-HSCT were not associated with an increased risk of relapse. After excluding DTA mutations, patients with ddPCR-MRD positivity had a significantly higher cumulative incidence of relapse (CIR, 38.7% vs. 9.7%, P < 0.001) and lower rates of relapse-free survival (RFS, 55.5% vs. 83.7%, P < 0.001) and overall survival (OS, 60.5% vs. 90.5%, P < 0.001). In multivariate analysis, ddPCR-MRD positivity of non-DTA genes was an independent adverse predictor for CIR (hazard ratio [HR], 4.02; P < 0.001), RFS (HR, 2.92; P = 0.002) and OS (HR, 3.12; P = 0.007). Moreover, the combination of ddPCR with multiparameter flow cytometry (MFC) can further accurately identify patients at high risk of relapse (F+/M+, HR, 22.44; P < 0.001, F+/M-, HR, 12.46; P < 0.001 and F-/M+, HR, 4.51; P = 0.003). CONCLUSION: ddPCR-MRD is a feasible approach to predict relapse after allo-HSCT in AML/MDS patients with non-DTA genes and is more accurate when combined with MFC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06000306. Registered 17 August 2023 -Retrospectively registered ( https://clinicaltrials.gov/study/NCT06000306?term=NCT06000306&rank=1 ).

ceRNA Network and WGCNA Analyses of Differentially Expressed Genes in Cervical Cancer Tissues for Association with Survival of Patients.

The study aims to search and identify differentially expressed genes (DEGs) in cervical cancer tissues as novel biomarkers to predict cervical cancer prognosis. The Cancer Genome Atlas (TCGA) data on gene expression profiles in cervical cancer were downloaded and analyzed using R software to identify DEGs in cervical cancer tissues. miRNAs targeted by differentially expressed long non-coding RNAs (DElncRNAs) and mRNAs targeted by microRNAs (miRNAs) were identified using the online miRcode, miRTarBase, TargetScan, and miRDB tools. The ceRNA network and lncRNA expression modules in cervical cancer tissues were constructed using weighted gene co-expression network analysis (WGCNA) and analyzed bioinformatically. The Kaplan-Meier analysis was performed to confirm these DEGs as prognostic markers. Immunohistochemical (IHC) analysis was used to verify expression of the hub genes in 10 paired cervical cancer and normal tissues. A total of 1914 DEmRNAs, 210 DElncRNAs, and 67 DEmiRNAs were identified in cervical cancer samples. There were 39 lncRNAs, 19 miRNAs, and 87 mRNAs involved in the ceRNA network and 25 DElncRNAs, three DEmiRNAs, and four mRNAs involved in the ceRNA sub-network. CACNA1C-AS1 was associated with the yellow and blue modules in the ceRNA sub-network, and LIFR-AS1 was associated with the blue module. The DEmRNAs were involved in cancer-related pathways, and three hub genes (i.e., E2F1, CCNB1, and CCNE1) were highly expressed in cervical squamous cell carcinoma and adenocarcinoma tissues and associated with the prognosis of patients. The ceRNA network and WGCNA analyses are useful to identify novel DEGs that can serve as prognostic markers in cervical cancer. The DEGs will be validated in future studies.

Investigating fear of cancer recurrence among female breast cancer survivors and their spouses in southwest China: a cross-sectional study.

OBJECTIVES: Examining fear of cancer recurrence (FCR) among breast cancer survivors and their spouses, and the protective effect of family resilience on FCR among couples affected by breast cancer. DESIGN: Cross-sectional survey design. SETTING: Ten general grade IIIa (>500 beds) hospitals in southwest China. PARTICIPANTS: Overall, 392 early breast cancer survivors and their spousal caregivers (N=392) were recruited from cancer centres in hospitals. PRIMARY AND SECONDARY OUTCOME MEASURES: Spouses' and survivors' FCR were the primary outcome measures. Family resilience and perceived stress were the secondary outcome measures. Using a convenience sampling method, we collected data on-site using paper questionnaires. The Chinese version of the Family Resilience Assessment Scale, Perceived Stress Scale, Fear of Progression Questionnaire Short Form and Fear of Progression Questionnaire-Short Form for spouses were used to evaluate the outcomes. RESULTS: The model accounted for 66.3% and 53.6% of the variance in spouses' FCR and survivors' FCR, respectively. Family resilience directly negatively affected perceived stress and spouses' and survivors' FCR (ß=-0.22; ß=-0.13; ß=-0.19). Perceived stress was a partial mediator of the association between family resilience and survivors' FCR (ß=-0.070; 95% CI :-0.151 to -0.022). Spouses' FCR partially mediated the association between family resilience and survivors' FCR (ß=-0.048; 95% CI= -0.092 to -0.015). Perceived stress and spouses' FCR played a significant chain-mediated role between family resilience and survivors' FCR (ß=-0.061; 95% CI: -0.119 to -0.022). CONCLUSIONS: Family-centred approaches to reducing survivors' perceived stress can improve the psychological well-being of couples affected by breast cancer and ultimately reduce FCR. Medical staff should consider the psychological feelings of survivors and their spousal caregivers when devising the intervention plan, which should address the families' potential and mobilise family and community resources for increasing family resilience.

COVID-19 in immunocompromised patients after hematopoietic stem cell transplantation: a pilot study.

Data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients at early stage of immune reconstitution after hematopoietic stem cell transplantation (HSCT) are limited. In the present study, we retrospectively investigated the incidence and clinical features of SARS-CoV-2 infection in patients who underwent HSCT in 2022. Patients (allo-HSCT, n = 80; auto-HSCT, n = 37) were consecutively included in the study. The SARS-CoV-2 infection rate was 59.8%, and the median interval of HSCT to coronavirus disease 2019 (COVID-19) was 4.8 (range: 0.5-12) months. Most patients were categorized as mild (41.4%) or moderate (38.6%), and 20% as severe/critical. No deaths were attributable to COVID-19. Further analysis showed that lower circulating CD8+ T-cell counts and calcineurin inhibitor administration increased the risk of SARS-CoV-2 infection. Exposure to rituximab significantly increased the probability of severe or critical COVID-19 compared with that of mild/moderate illness (P < .001). In the multivariate analysis, rituximab use was associated with severe COVID-19. Additionally, COVID-19 had no significant effect on immune reconstitution. Furthermore, it was found that Epstein-Barr virus infection and rituximab administration possibly increase the risk of developing severe illness. Our study provides preliminary insights into the effect of SARS-CoV-2 on immune reconstitution and the outcomes of allo-HSCT recipients.

Photochromic biomaterials: Synthesis and fluorescence properties of spiroxanthenes-grafted alginate derivatives.

Herein, we reported a general and green synthetic strategy for photochromic functional alginate derivatives grafting with isoindolinone spiroxanthenes. Under mild condition, diverse 2-aminoalkyl isoindolinone spiroxanthene derivatives have been prepared from organic photochromic isobenzofuranone spiroxanthenes (including rhodamine B, rhodamine 6G and fluorescein), and grafted on alginate chains through amidation reaction using diamine as a linkage with water as a green solvent at room temperature. The photochromic properties of the fluorophores-modified polymers and the effect of pH value have been explored. Under acid conditions, the spiroisoindolinone rings of alginate derivatives are opened resulting in showing absorption bands and fluorescence with orange to green emission, while the alginate derivatives turned to colourless under basic conditions which is reversibly. In addition to biodegradability and biocompatibility, the polymers exhibit good film-forming properties simultaneously. The films and fibers produced from the alginate derivatives also project good fluorescence properties.

Ultrahigh Degree of Cationic Disorder, Configurational Entropy in New Type of High-Entropy Pseudobrookite Phase.

High-entropy ceramics exhibit various excellent properties owing to their high configurational entropy, which is caused by multi-principal elements sharing one lattice site. The configurational entropy will further increase significantly if multi-principal elements randomly share two different lattice sites. For this purpose, pseudobrookite phase containing two cationic lattice sites (A and B sites) is selected, and corresponding high-entropy pseudobrookite (M2+ 0.4 M3+ 1.2 )Ti1.4 O5 is synthesized. Herein, the distribution of the 2-valent and 3-valent cations in the A and B sites are analysed in depth. The distance between the A and B sites in the crystal structure models which are constructed by the Rietveld analysis is calculated and defined as distance d. Meanwhile, the atomic column positions in the STEM images are quantified by a model-based mathematical algorithm, and the corresponding distance d are calculated. By comparing the distance d, it is determine that the 2-valent and 3-valent cations are jointly and disorderly distributed in the A and B sites in high-entropy (M2+ 0.4 M3+ 1.2 )Ti1.4 O5 . The density functional theory (DFT) simulations also demonstrate that this type of crystal structure is more thermodynamically stable. The higher degree of cationic disorder leads to a higher configurational entropy in high-entropy (M2+ 0.4 M3+ 1.2 )Ti1.4 O5 , and endows high-entropy (M2+ 0.4 M3+ 1.2 )Ti1.4 O5 with very low thermal conductivity (1.187-1.249 W m-1  K-1 ).

Essential oil from Fructus Alpiniae zerumbet ameliorates vascular endothelial cell senescence in diabetes by regulating PPAR-γ signalling: A 4D label-free quantitative proteomics and network pharmacology study.

ETHNOPHARMACOLOGICAL RELEVANCE: Vascular endothelial cell senescence is associated with cardiovascular complications in diabetes. Essential oil from Fructus Alpiniae zerumbet (Pers.) B.L.Burtt & R.M.Sm. (EOFAZ) has potentially beneficial and promising diabetes-related vascular endothelial cell senescence-mitigating effects; however, the underlying molecular mechanisms remain unclear. AIM OF THE STUDY: To investigate the molecular effects of EOFAZ on vascular endothelial cell senescence in diabetes. MATERIALS AND METHODS: A diabetes mouse model was developed using a high-fat and high-glucose diet (HFD) combined with intraperitoneal injection of low-dose streptozotocin (STZ, 30 mg/kg) and oral treatment with EOFAZ. 4D label-free quantitative proteomics, network pharmacology, and molecular docking techniques were employed to explore the molecular mechanisms via which EOFAZ alleviates diabetes-related vascular endothelial cell senescence. A human aortic endothelial cells (HAECs) senescence model was developed using high palmitic acid and high glucose (PA/HG) concentrations in vitro. Western blotting, immunofluorescence, SA-ß-galactosidase staining, cell cycle, reactive oxygen species (ROS), cell migration, and enzyme linked immunosorbent assays were performed to determine the protective role of EOFAZ against vascular endothelial cell senescence in diabetes. Moreover, the PPAR-γ agonist rosiglitazone, inhibitor GW9662, and siRNA were used to verify the underlying mechanism by which EOFAZ combats vascular endothelial cell senescence in diabetes. RESULTS: EOFAZ treatment ameliorated abnormal lipid metabolism, vascular histopathological damage, and vascular endothelial aging in diabetic mice. Proteomics and network pharmacology analysis revealed that the differentially expressed proteins (DEPs) and drug-disease targets were associated with the peroxisome proliferator-activated receptor gamma (PPAR-γ) signalling pathway, a key player in vascular endothelial cell senescence. Molecular docking indicated that the small-molecule compounds in EOFAZ had a high affinity for the PPAR-γ protein. Western blotting and immunofluorescence analyses confirmed the significance of DEPs and the involvement of the PPAR-γ signalling pathway. In vitro, EOFAZ and rosiglitazone treatment reversed the effects of PA/HG on the number of senescent endothelial cells, expression of senescence-related proteins, the proportion of cells in the G0/G1 phase, ROS levels, cell migration rate, and expression of pro-inflammatory factors. The protective effects of EOFAZ against vascular endothelial cell senescence in diabetes were aborted following treatment with GW9662 or PPAR-γ siRNA. CONCLUSIONS: EOFAZ ameliorates vascular endothelial cell senescence in diabetes by activating PPAR-γ signalling. The results of the present study highlight the potential beneficial and promising therapeutic effects of EOFAZ and provide a basis for its clinical application in diabetes-related vascular endothelial cell senescence.

Minimally Invasive and Innovative Management of Prosthesis Infections in Endoscopic-Assisted Breast Reconstruction.

BACKGROUND: Implant infection continues to be the most common complication of breast reconstruction, and it can lead to serious consequences of implant loss. Recently, endoscopic-assisted nipple-sparing mastectomy with direct-to-implant breast reconstruction is being performed more frequently, with similar prosthetic infection incidence compared to conventional techniques. But there is little information published in the literature on the management of periprosthetic infection in endoscopic-assisted breast reconstruction. METHODS: A retrospective review was performed of patients who underwent endoscope-assisted breast reconstruction and developed periprosthetic infection between January 2020 and December 2022. Prosthesis infection was defined as any case where antibiotics were given, beyond the surgeon's standard perioperative period, in response to clinical signs such as swelling, pain, erythema, increased temperature, fever, etc. We summarized our clinical approach and treatment protocol for periprosthetic infection patients. Collected data include preoperative basic information, surgical details, postoperative data, and outcomes. RESULTS: A total of 580 patients (713 reconstructions) underwent endoscopic-assisted immediate breast reconstruction. There were 58 patients developed periprosthetic infection, 14 of whom had bilateral prosthesis reconstruction with unilateral prosthesis infection. The incidence of infection was 10.0%. Average follow-up was 17.3 ± 8.9 months (range = 2-37 months). Of the 58 patients, 53 (91.4%) patients successful salvaged implant and 5(8.6%) patients removed prosthesis. During follow-up, Baker III capsular contracture occurred in 2 patients (3.8%) who had radiotherapy. CONCLUSION: Our management of prosthesis infections in endoscopic-assisted breast reconstruction is easy, minimally invasive, and inexpensive. This method can be repeated if the implant infection does not improve after the first drainage. What's more, our data suggest that our prosthesis salvage of periprosthetic infection is effective. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The impact of pre-transplant anti-HLA antibodies in transplants from HLA-identical sibling donors: A multicenter study.

Few studies have performed comparative analysis of the outcome of hematopoietic stem cell transplantation from HLA-identical sibling donors (ISD-HSCT) in patients with or without anti-HLA Abs. In this study we retrospectively collected data from a multicenter study to analyze the distribution and impact of the pre-existing anti-HLA Abs in ISD-HSCT. Among 402 recipients, 111 were positive for anti-HLA Abs. Gender, time from diagnosis to transplantation and distribution of primary disease might be risk factors for the occurrence of anti-HLA Abs. We found that patients with anti-HLA Abs had delayed neutrophil engraftment and were more vulnerable to experience Cytomegalovirus (CMV) reactivation. The presence of anti-HLA Abs was proved to be an independent risk factor for neutrophil engraftment (HR 1.42 95% CI 1.13-1.80, p = 0.003) and CMV reactivation (HR 2.03 95% CI 1.19-3.46, p = 0.009). We found that anti-HLA Abs have a negative impact on the prognosis in the early period after transplantation from sibling donors and anti-HLA Abs was also an independent risk factor for the overall survival (OS) at 180 days (HR 2.32, 95% CI 1.03-5.27, p = 0.042) among female recipients. In conclusion, anti-HLA Abs have a negative impact on the prognosis early after ISD-HSCT.

Relationships between Attachment Style, Emotional Self-Disclosure, and Quality of Life among Young Breast Cancer Survivors: A Cross-Sectional Study.

OBJECTIVES: This investigation aims to explore relationships between adult attachment, emotional self-disclosure, and quality of life (QoL). DATA SOURCES: The study sample completed the Chinese versions of the Experiences in Close Relationships Inventory, the Functional Assessment of Cancer Therapy-Breast Scale, and the Distress Disclosure Index between October 2021 and March 2022. The relationships between adult attachment, emotional self-disclosure, and QoL were investigated using a multiple mediation effects test and structural equation modeling. CONCLUSION: Attachment anxiety and avoidance were risk factors for young Chinese breast cancer survivors' emotional self-disclosure and QoL. Emotional self-disclosure mediates the association between attachment anxiety or avoidance and QoL. Assessing and easing attachment anxiety and avoidance may improve the emotional self-disclosure and QoL of young breast cancer survivors. IMPLICATIONS FOR NURSING PRACTICE: This study confirms that adult attachment plays an important role in young breast cancer patients' adaptation to the disease and that high adult anxiety and avoidance levels can significantly reduce emotional self-disclosure and QoL in young breast cancer survivors. Identifying attachment patterns can help caregivers better understand patients' responses, adaptation, and treatment adherence to cancer, thereby helping caregivers develop targeted and personalized cancer care practice programs or psychotherapy interventions to improve patients' physical and mental health outcomes.

Essential oil from Fructus Alpinia zerumbet ameliorates atherosclerosis by activating PPARγ-LXRα-ABCA1/G1 signaling pathway.

BACKGROUND: Atherosclerosis (AS) is a progressive chronic disease. Currently, cardiovascular diseases (CVDs) caused by AS is responsible for the global increased mortality. Yanshanjiang as miao herb in Guizhou of China is the dried and ripe fruit of Fructus Alpinia zerumbet. Accumulated evidences have confirmed that Yanshanjiang could ameliorate CVDs, including AS. Nevertheless, its effect and mechanism on AS are still largely unknown. PURPOSE: To investigate the role of essential oil from Fructus Alpinia zerumbet (EOFAZ) on AS, and the potential mechanism. METHODS: A high-fat diet (HFD) ApoE-/- mice model of AS and a oxLDL-induced model of macrophage-derived foam cells (MFCs) were reproduced to investigate the pharmacological properties of EOFAZ on AS in vivo and foam cell formation in vitro, respectively. The underlying mechanisms of EOFAZ were investigated using Network pharmacology and molecular docking. EOFAZ effect on PPARγ protein stability was measured using a cellular thermal shift assay (CETSA). Pharmacological agonists and inhibitors and gene interventions were employed for clarifying EOFAZ's potential mechanism. RESULTS: EOFAZ attenuated AS progression in HFD ApoE-/- mice. This attenuation was manifested by the reduced aortic intima plaque development, increased collagen content in aortic plaques, notable improvement in lipid profiles, and decreased levels of inflammatory factors. Moreover, EOFAZ inhibited the formation of MFCs by enhancing cholesterol efflux through activiting the PPARγ-LXRα-ABCA1/G1 pathway. Interestingly, the pharmacological knockdown of PPARγ impaired the beneficial effects of EOFAZ on MFCs. Additionally, our results indicated that EOFAZ reduced the ubiquitination degradation of PPARγ, and the chemical composition of EOFAZ directly bound to the PPARγ protein, thereby increasing its stability. Finally, PPARγ knockdown mitigated the protective effects of EOFAZ on AS in HFD ApoE-/- mice. CONCLUSION: These findings represent the first confirmation of EOFAZ's in vivo anti-atherosclerotic effects in ApoE-/- mice. Mechanistically, its chemical constituents can directly bind to PPARγ protein, enhancing its stability, while reducing PPARγ ubiquitination degradation, thereby inhibiting foam cell formation via activation of the PPARγ-LXRα-ABCA1/G1 pathway. Simultaneously, EOFAZ could ameliorates blood lipid metabolism and inflammatory microenvironment, thus synergistically exerting its anti-atherosclerotic effects.

Shikonin reverses cancer-associated fibroblast-induced gemcitabine resistance in pancreatic cancer cells by suppressing monocarboxylate transporter 4-mediated reverse Warburg effect.

BACKGROUND: Gemcitabine is a first-line chemotherapeutic agent for pancreatic cancer (PC); however, most patients who receive adjuvant gemcitabine rapidly develop resistance and recurrence. Cancer-associated fibroblasts (CAFs) are a crucial component of the tumor stroma that contribute to gemcitabine-resistance. There is thus an urgent need to find a novel therapeutic strategy to improve the efficacy of gemcitabine in PC cells under CAF-stimulation. PURPOSE: To investigate if shikonin potentiates the therapeutic effects of gemcitabine in PC cells with CAF-induced drug resistance. METHODS: PC cell-stimulated fibroblasts or primary CAFs derived from PC tissue were co-cultured with PC cells to evaluate the ability of shikonin to improve the chemotherapeutic effects of gemcitabine in vitro and in vivo. Glucose uptake assay, ATP content analysis, lactate measurement, real-time PCR, immunofluorescence staining, western blot, and plasmid transfection were used to investigate the underlying mechanism. RESULTS: CAFs were innately resistant to gemcitabine, but shikonin suppressed the PC cell-induced transactivation and proliferation of CAFs, reversed CAF-induced resistance, and restored the therapeutic efficacy of gemcitabine in the co-culture system. In addition, CAFs underwent a reverse Warburg effect when co-cultured with PC cells, represented by enhanced aerobic glycolytic metabolism, while shikonin reduced aerobic glycolysis in CAFs by reducing their glucose uptake, ATP concentration, lactate production and secretion, and glycolytic protein expression. Regarding the mechanism underlying these sensitizing effects, shikonin suppressed monocarboxylate transporter 4 (MCT4) expression and cellular membrane translocation to inhibit aerobic glycolysis in CAFs. Overexpression of MCT4 accordingly reversed the inhibitory effects of shikonin on PC cell-induced transactivation and aerobic glycolysis in CAFs, and reduced its sensitizing effects. Furthermore, shikonin promoted the effects of gemcitabine in reducing the growth of tumors derived from PC cells and CAF co-inoculation in BALB/C mice, with no significant systemic toxicity. CONCLUSION: These results indicate that shikonin reduced MCT4 expression and activation, resulting in inhibition of aerobic glycolysis in CAFs and overcoming CAF-induced gemcitabine resistance in PC. Shikonin is a promising chemosensitizing phytochemical agent when used in combination with gemcitabine for PC treatment. The results suggest that disrupting the metabolic coupling between cancer cells and stromal cells might provide an attractive strategy for improving gemcitabine efficacy.

The effect of ritonavir on the pharmacokinetics of clonidine in vivo and in vitro.

This project aims to explore the repercussions of ritonavir on both the drug kinetics of clonidine in rats and clonidine metabolism in liver micro somes. Eighteen healthy male laboratory rats were haphazardly placed into groups: Group A, the control, Group B, got 20mg/kg ritonavir and Group C, got 180 mg/kg ritonavir. Ritonavir was administered to the rats by oral gavage and 30 minutes later, clonidine at 0.25mg/kg was administered for once. Moreover, rat and human liver micro somes, along with recombinant human CYP2D6*1, were used to study the inhibition effect of ritonavir on clonidine in vitro. The concentrations of clonidine and its metabolite were determined by the UPLC-MS/MS. The area under the curve (AUC) of clonidine increased (P<0.01) and clearance (CL) decreased significantly (P<0.01), after co-administration with 180mg/kg ritonavir. The half-maximal inhibitory concentration (IC50) of ritonavir was 11.48µmol/L in rat liver micro somes, 3.52µmol/L in human liver micro somes and 18.04µmol/L in CYP2D6*1. Our findings demonstrate that ritonavir exhibited an inhibitory effect on clonidine metabolism in vitro and in vivo. It suggests that concurrent use of clonidine with ritonavir required close monitoring of the clonidine plasma concentration to alert drug adverse reactions.

Diagnostic efficiency of metagenomic next-generation sequencing for suspected infection in allogeneic hematopoietic stem cell transplantation recipients.

Introduction: Immunosuppression predisposes allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients to infection. Prompt and accurate identification of pathogens is crucial to optimize treatment strategies. This multi-center retrospective study aimed to assess the ability of metagenomic next-generation sequencing (mNGS) to detect causative pathogens in febrile allo-HSCT recipients and examined its concordance with conventional microbiological tests (CMT). Methods: We performed mNGS and CMT on samples obtained from 153 patients with suspected infection during allo-HSCT. Patients were grouped based on their neutropenic status at the time of sampling. Results: The mNGS test was more sensitive than CMT (81.1% vs. 53.6%, P<0.001) for diagnosing clinically suspected infection, especially in the non-neutropenia cohort. mNGS could detect fungi and viruses better than bacteria, with a higher sensitivity than CMT. Immune events were diagnosed in 57.4% (35/61) of the febrile events with negative mNGS results, and 33.5% (48/143) with negative CMT results (P=0.002). The treatment success rate of the targeted anti-infection strategy was significantly higher when based on mNGS than on empirical antibiotics (85% vs. 56.5%, P=0.004). Conclusion: The mNGS test is superior to CMT for identifying clinically relevant pathogens, and provides valuable information for anti-infection strategies in allo-HSCT recipients. Additionally, attention should be paid to immune events in patients with negative mNGS results.

Development and Validation of a Novel Prognosis Model Based on a Panel of Three Immunogenic Cell Death-Related Genes for Non-Cirrhotic Hepatocellular Carcinoma.

Purpose: The accurate prediction of non-cirrhotic hepatocellular carcinoma (NCHCC) risk facilitates improved surveillance strategy and decreases cancer-related mortality. This study aimed to explore the correlation between immunogenic cell death (ICD) and NCHCC prognosis using The Cancer Genome Atlas (TCGA) datasets, and the potential prognostic value of ICD-related genes in NCHCC. Methods: Clinical and transcriptomic data of patients with NCHCC patients were retrieved from TCGA database. Weighted gene co-expression network analysis was performed to obtain the NCHCC phenotype-related module genes. Consensus clustering analysis was performed to classify the patients into two clusters based on intersection genes among differentially expressed genes (DEGs) between cancer and adjacent tissues, NCHCC phenotype-related genes, and ICD-related genes. NCHCC-derived tissue microarray was used to evaluate the correlation of the expression levels of key genes with NCHCC prognosis using immunohistochemical staining. Results: Cox regression analyses were performed to construct a prognostic risk score model comprising three genes (TMC7, GRAMD1C, and GNPDA1) based on DEGs between two clusters. The model stratified patients with NCHCC into two risk groups. The overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group. Univariable and multivariable Cox regression analyses revealed that these signature genes are independent predictors of OS. Functional analysis revealed differential immune status between the two risk groups. Next, a nomogram was constructed, which demonstrated the potent distinguishing ability of the developed model based on receiver operating characteristic curves. In vitro functional validation revealed that the migration and invasion abilities of HepG2 and Huh7 cells were upregulated upon GRAMD1C knockdown but downregulated upon TMC7 knockdown. Conclusion: This study developed a prognostic model comprising three genes, which can aid in predicting the survival of patients with NCHCC and guide the selection of drugs and molecular markers for NCHCC.

Analysis of the expression and mechanism of follistatin­like protein 1 in cervical cancer.

The abnormal expression of follistatin­like protein 1 (FSTL1) in various tumors is a crucial regulator of the biological process of tumorigenesis. Nonetheless, the regulatory role of FSTL1 in cervical cancer is yet to be elucidated. Hence, the present study aimed to explore the expression, function, and molecular mechanism of FSTL1 in cervical cancer. The expression of FSTL1 in normal and cervical cancer tissues was examined using quantitative reverse transcription­polymerase chain reaction and immunohistochemistry assays. The effects of abnormal expression of FSTL1 on cervical cancer cells were assessed using colony formation, MTT, wound­healing, Transwell, apoptosis, and nude mouse tumorigenicity assays. FSTL1­related molecular mechanisms were screened using gene chip analysis. Western blotting analysis was used to verify the regulatory mechanisms of FSTL1 in cervical cancer. The results indicated that the expression of FSTL1 was downregulated in cervical cancer tissues and that its downregulation was associated with tumor differentiation, pathologic type, and infiltration depth. Moreover, FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells as well as xenograft tumor growth and promoted cell apoptosis. In addition, the findings of gene chip analysis suggested that the differentially expressed genes of FSTL1 were predominantly enriched in multiple signaling pathways, of which the insulin­like growth factor (IGF)­1 signaling pathway was significantly activated. Western blotting suggested the involvement of FSTL1 in the regulation of the IGF­1R/PI3K/AKT/BCL­2 signaling pathway. These data establish the downregulation of FSTL1 in cervical cancer tissues. FSTL1 inhibited the proliferation, migration, and invasion of cervical cancer cells and promoted their apoptosis. Furthermore, xenograft tumor growth in nude mice was inhibited. FSTL1 may be involved in the regulation of the IGF­1R/PI3K/AKT/BCL­2 signaling pathway in cervical cancer. Therefore, FSTL1 may be employed as a novel biomarker to determine the extent of disease progression in patients with cervical cancer.