Carbon ions trigger DNA damage response to overcome radioresistance by regulating ß-catenin signaling in quiescent HeLa cells.

Quiescent cancer cells are major impediments to effective radiotherapy (RT) and exhibit limited sensitivity to traditional photon therapy. Herein, the functional role and underlying mechanism of carbon ions in overcoming the radioresistance of quiescent cervical cancer HeLa cells were determined. Briefly, serum withdrawal was used to induce synchronized quiescence in HeLa cells. Quiescent HeLa cells displayed strong radioresistance and DNA repair potential. After irradiation with carbon ions, the DNA damage repair pathway may markedly rely on error-prone nonhomologous end-joining in proliferating cells, whereas the high-precision homologous recombination pathway is more relevant in quiescent cells. This phenomenon could be explained by the ionizing radiation (IR)-induced cell cycle re-entry of quiescent cancer cells. There are three strategies for eradicating quiescent cancer cells using high-linear energy transfer (LET) carbon ions: direct cell death through complex DNA damage; apoptosis via an enhanced mitochondria-mediated intrinsic pathway; forced re-entry of quiescent cancer cells into the cell cycle, thereby improving their susceptibility to IR. Silencing ß-catenin signaling is essential for maintaining the dormant state in quiescent cells. Herein, carbon ions activated the ß-catenin pathway in quiescent cells, and inhibition of this pathway improved the resistance of quiescent HeLa cells to carbon ions by alleviating DNA damage, improving DNA damage repair, maintaining quiescent depth, and inhibiting apoptosis. Collectively, carbon ions conquer the radioresistance of quiescent HeLa cells by activating ß-catenin signaling, which provides a theoretical basis for improved therapeutic effects in patients with middle-advanced-stage cervical cancer with radioresistance.

LLPSDB v2.0: an updated database of proteins undergoing liquid-liquid phase separation in vitro.

SUMMARY: Emerging evidences have suggested that liquid-liquid phase separation (LLPS) of proteins plays a vital role both in a wide range of biological processes and in related diseases. Whether a protein undergoes phase separation not only is determined by the chemical and physical properties of biomolecule themselves, but also is regulated by environmental conditions such as temperature, ionic strength, pH, as well as volume excluded by other macromolecules. A web accessible database LLPSDB was developed recently by our group, in which all the proteins involved in LLPS in vitro as well as corresponding experimental conditions were curated comprehensively from published literatures. With the rapid increase of investigations in biomolecular LLPS and growing popularity of LLPSDB, we updated the database, and developed a new version LLPSDB v2.0. In comparison of the previously released version, more than double contents of data are curated, and a new class 'Ambiguous system' is added. In addition, the web interface is improved, such as that users can search the database by selecting option 'phase separation status' alone or combined with other options. We anticipate that this updated database will serve as a more comprehensive and helpful resource for users. AVAILABILITY AND IMPLEMENTATION: LLPSDB v2.0 is freely available at: http://bio-comp.org.cn/llpsdbv2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The burden of anemia among Chinese HIV-infected patients following the initiation of antiretroviral therapy in the treat-all era: a nationwide cohort study.

BACKGROUND: To assess the prevalence of anemia before and after antiretroviral therapy (ART) initiation and to identify impact of anemia on mortality among HIV-infected patients in China during the Treat-All era. METHODS: All HIV-infected patients who newly initiated ART between January 1, 2017 and December 31, 2020 were enrolled and followed up to December 31, 2021 in China. We analyzed the prevalence of anemia before and after ART initiation. Generalized estimating equations were fitted to determine factors associated with anemia after ART. Time-dependent cox proportional hazards models were performed to estimate the effect of anemia on death. RESULTS: Of 436,658 patients at the baseline of ART initiation, the overall prevalence of anemia was 28.6%. During a median 2.65 (IQR: 1.80-3.51) years of follow-up after ART initiation, 376,325 (86.2%) patients had at least one Hb measurement (a total of 955,300 hemoglobin measurements). The annual prevalence of anemia after ART was 17.0%, 14.1%, 13.4%, 12.6% and 12.7%, respectively. Being anemic at the baseline of ART initiation (adjusted odds ratio, aOR = 6.80, 95% confidence interval (CI): 6.67-6.92) was the strongest factor associated with anemia after ART. Anemia status after ART showed a strong association with death after multivariable adjustment (mild anemia: adjusted hazard ratio (aHR) = 2.65, 95% CI: 2.55-2.76; moderate anemia: aHR = 4.60; 95% CI:4.40-4.81; severe anemia: aHR = 6.41; 95% CI:5.94-6.91). CONCLUSIONS: In the era of ART universal access, pre-ART anemia was common among HIV-infected patients. Notably, a certain proportion of anemia still persisted after ART, and was significantly associated with death. We recommend strengthening the monitoring of patients at risk of anemia, especially in patients with baseline anemia or during the first year of ART, and timely treatment for correcting anemia.

Heavy ion radiation-induced DNA damage mediates apoptosis via the Rpl27a-Rpl5-MDM2-p53/E2F1 signaling pathway in mouse spermatogonia.

The risk of exposure to ionizing radiation (IR) environments has increased with the development of nuclear technology. IR exposure induces excessive apoptosis of the spermatogonia, which leads to male infertility. Spermatogonia apoptosis may be involved in ribosomal stress triggered by DNA damage following exposure to IR because ribosomal proteins (RPs) directly interact with mouse double minute 2 homolog (MDM2) to induce apoptosis. This study aimed to use comparative proteomics and transcriptomics approach to screen the differential RPs and ribosomal mRNAs in mouse testes following high linear energy transfer (LET) carbon ion radiation (CIR). The expression of ribosomal large subunit protein 27a (Rpl27a) decreased at both protein and mRNA levels in the spermatogonia in vivo. After 6 h of CIR, the immunofluorescence signal of 8-oxo-dG and phosphorylated ataxia-telangiectasia-mutated protein (ATM)/histone H2Ax increased, but that of Rpl27a decreased in the spermatogonia of p53 wild-type and knockout mouse testes. Moreover, the nucleolin was scattered throughout the nucleoplasm after CIR. These results suggested that CIR-induced DNA damage might trigger ribosomal stress, and the reduction in the expression of Rpl27a was associated with DNA damage in the spermatogonia. Similarly, in vitro, the immunofluorescence signal of 8-oxo-dG increased in the GC-1 cells after CIR. Moreover, the expression of Rpl27a was regulated by DNA damage because the co-transfection of ATM and Rpl27a or inhibition of ATM-treated CIR could restore the expression of Rpl27a. Furthermore, the reduction in the expression of Rpl27a led to weakened binding of E2F transcription factor 1 (E2F1) and p53 to MDM2, causing p53 activation and E2F1 degradation in p53 wild-type and knockdown GC-1 cells. This study proposed that heavy ion radiation-induced DNA damage mediated spermatogonia apoptosis via the Rpl27a-Rpl5-MDM2-p53/E2F1 signaling pathway. The results provided the underlying molecular mechanisms of spermatogonia apoptosis following exposure to high LET radiation.

Protein Databases Related to Liquid-Liquid Phase Separation.

Liquid-liquid phase separation (LLPS) of biomolecules, which underlies the formation of membraneless organelles (MLOs) or biomolecular condensates, has been investigated intensively in recent years. It contributes to the regulation of various physiological processes and related disease development. A rapidly increasing number of studies have recently focused on the biological functions, driving, and regulating mechanisms of LLPS in cells. Based on the mounting data generated in the investigations, six databases (LLPSDB, PhaSePro, PhaSepDB, DrLLPS, RNAgranuleDB, HUMAN CELL MAP) have been developed, which are designed directly based on LLPS studies or the component identification of MLOs. These resources are invaluable for a deeper understanding of the cellular function of biomolecular phase separation, as well as the development of phase-separating protein prediction and design. In this review, we compare the data contents, annotations, and organization of these databases, highlight their unique features, overlaps, and fundamental differences, and discuss their suitable applications.

The Human Immunodeficiency Virus Care Continuum in China: 1985-2015.

Background: Human immunodeficiency virus (HIV) care continuum attrition is a major global public health challenge. Few studies have examined this problem in resource-limited settings. We aimed to assess cumulative, current, and historical achievement along China's HIV continuum of care. Methods: A nationwide, serial cross-sectional study of all individuals with HIV infection diagnosed in China between 1 January 1985 and 31 December 2015 was conducted using data from China's HIV/AIDS information systems. Biennial estimates of the number of persons living with HIV were also used. We defined 7 steps in HIV care continuum as infected (estimated), diagnosed, linked, retained, enrolled, receiving antiretroviral therapy (ART), and virally suppressed. Cumulative, 30-year performance, and biennial performance during the most recent 10 years were examined. Results: A total of 573529 persons diagnosed with HIV infection were included. Cumulatively, 94% were linked, 88% were retained, 73% were enrolled, 67% were receiving ART, and 44% were suppressed. Greatest attrition was observed for adolescents, minorities, and those who reported injecting drug use as their route of infection. Improvement was observed from 2005 to 2015. As of the end of 2015, 68% among those infected were diagnosed, 67% among diagnosed were receiving ART, and 65% among those receiving ART were virally suppressed. After adjusting for those without viral load testing, the proportion suppressed increased to 89%. Conclusions: Despite dramatic improvements, China faces serious challenges in achieving the Joint United Nations Programme on HIV/AIDS 90-90-90 targets, because of substantial attrition along its continuum of HIV care.

Immediate Antiretroviral Therapy Decreases Mortality Among Patients With High CD4 Counts in China: A Nationwide, Retrospective Cohort Study.

Background: Clinical trials have demonstrated that immediate initiation of antiretroviral therapy (ART) reduces AIDS-related morbidity and mortality. We tested the hypothesis that initiating ART ≤30 days after human immunodeficiency virus (HIV) diagnosis would be associated with reduced mortality among people living with HIV (PLWH) with CD4 counts >500 cells/µL. Methods: PLWH enrolled in the Chinese National HIV Information System between January 2012 and June 2014 with CD4 counts >500 cells/µL were followed for 12 months. Cox proportional hazards model was used to determine hazard ratios (HRs) for PLWH who initiated ART after HIV diagnosis. ART initiation was treated as a time-dependent variable. Results: We enrolled 34581 PLWH with CD4 >500 cells/µL; 1838 (5.3%) initiated ART ≤30 days after diagnosis (immediate ART group), and 19 deaths were observed with a mortality rate of 1.04 per 100 person-years (PY). Fifty-eight deaths were documented among the 5640 PLWH in the delayed ART group with a mortality rate of 2.25 per 100 PY. There were 713 deaths among the 27103 PLWH in the no ART group with a mortality rate of 2.39 per 100 PY. After controlling for potential confounding factors, ART initiation at ≤30 days (adjusted HR, 0.37 [95% confidence interval, .23-.58]) was a statistically significant protective factor. Conclusions: We found that immediate ART is associated with a 63% reduction in overall mortality among PLWH with CD4 counts >500 cells/µL in China, supporting the recommendation to initiate ART immediately following HIV diagnosis.

Cotrimoxazole prophylaxis and antiretroviral therapy: an observational cohort study in China.

OBJECTIVE: To assess if cotrimoxazole prophylaxis administered early during antiretroviral therapy (ART) reduces mortality in Chinese adults who are infected with human immunodeficiency virus (HIV). METHODS: We did a retrospective observational cohort study using data from the Chinese national free antiretroviral database. Patients older than 14 years who started ART between 1 January 2010 and 31 December 2012 and had baseline CD4+ T-lymphocyte (CD4+ cell) count less than 200 cells/µL were followed until death, loss to follow-up or 31 December 2013. Hazard ratios (HRs) for several variables were calculated using multivariate analyses. FINDINGS: The analysis involved 23 816 HIV-infected patients, 2706 of whom died during the follow-up. Mortality in patients who did and did not start cotrimoxazole during the first 6 months of ART was 5.3 and 7.0 per 100 person-years, respectively. Cotrimoxazole was associated with a 37% reduction in mortality (hazard ratio, HR: 0.63; 95% confidence interval, CI: 0.56-0.70). Cotrimoxazole in addition to ART reduced mortality significantly over follow-up lasting 6 months (HR: 0.65; 95% CI: 0.59-0.73), 12 months (HR: 0.58; 95% CI: 0.49-0.70), 18 months (HR: 0.49; 95% CI: 0.38-0.63) and 24 months (HR: 0.66; 95% CI: 0.48-0.90). The mortality reduction was evident in patients with baseline CD4+ cell counts less than 50 cells/µL (HR: 0.60; 95% CI: 0.54-0.67), 50-99 cells/µL (HR: 0.66; 95% CI: 0.56-0.78) and 100-199 cells/µL (HR: 0.78; 95% CI: 0.62-0.98). CONCLUSION: Cotrimoxazole prophylaxis started early during ART reduced mortality and should be offered to HIV-infected patients in low- and middle-income countries.

Antiretroviral therapy to prevent HIV transmission in serodiscordant couples in China (2003-11): a national observational cohort study.

BACKGROUND: On the basis of the results of the randomised clinical trial HPTN 052 and observational studies, WHO has recommended that antiretroviral therapy be offered to all HIV-infected individuals with uninfected partners of the opposite sex (serodiscordant couples) to reduce the risk of transmission. Whether or not such a public health approach is feasible and the outcomes are sustainable at a large scale and in a developing country setting has not previously been assessed. METHODS: In this retrospective observational cohort study, we included treated and treatment-naive HIV-positive individuals with HIV-negative partners of the opposite sex who had been added to the national HIV epidemiology and treatment databases between Jan 1, 2003 and Dec 31, 2011. We analysed the annual rate of HIV infection in HIV-negative partners during follow-up, stratified by treatment status of the index partner. Cox proportional hazards analyses were done to examine factors related to HIV transmission. FINDINGS: Based on data from 38,862 serodiscordant couples, with 101,295·1 person-years of follow-up for the seronegative partners, rates of HIV infection were 2·6 per 100 person-years (95% CI 2·4-2·8) among the 14,805 couples in the treatment-naive cohort (median baseline CD4 count for HIV-positive partners 441 cells per µl [IQR 314-590]) and 1·3 per 100 person-years (1·2-1·3) among the 24,057 couples in the treated cohort (median baseline CD4 count for HIV-positive partners 168 cells per µl [62-269]). We calculated a 26% relative reduction in HIV transmission (adjusted hazard ratio 0·74, 95% CI 0·65-0·84) in the treated cohort. The reduction in transmission was seen across almost all demographic subgroups and was significant in the first year (0·64, 0·54-0·76), and among couples in which the HIV-positive partner had been infected by blood or plasma transfusion (0·76, 0·59-0·99) or heterosexual intercourse (0·69, 0·56-0·84), but not among couples in which the HIV-positive partner was infected by injecting drugs (0·98, 0·71-1·36). INTERPRETATION: Antiretroviral therapy for HIV-positive individuals in serodiscordant couples reduced HIV transmission across China, which suggests that the treatment-as-prevention approach is a feasible public health prevention strategy on a national scale in a developing country context. The durability and generalisability of such protection, however, needs to be further studied. FUNDING: Chinese Government's 12th Five-Year Plan, the National Natural Science Foundation of China, and the Canadian International Development Research Centre.

Incidence and associated factors of pulmonary tuberculosis in HIV-infected children after highly active antiretroviral therapy (HAART) in China: a retrospective study.

China is a country with high tuberculosis (TB) incidence but relatively low HIV prevalence. However, due to difficulties in diagnosis and reporting, true burden of HIV-associated TB in children is unknown. The objective of this study was to describe the incidence of pulmonary TB (PTB) after antiretroviral therapy (ART) and to study risk factors. A retrospective study was performed based on routinely collected data from China national pediatric free antiretroviral treatment database. A total of 3365 children under 15 years on ART from July 2005 to October 2012 were included. Multivariable logistic regression was used to detect associated factors. Two thousand nine hundred and ninety (89%) children got infected from HIV-positive mother, with median age of 6.7 (4.1, 10.0) years at highly active antiretroviral therapy (HAART) initiation in this program. Seventy-seven (2.3%) children were diagnosed with PTB after ART during 7.3 years cohort observation. Median time of occurrence was 212 (30-514) days. Overall incidence was 0.83 (0.65-1.01)/100 person-years (py), with the peak of 3.6/100 py in the first 3 months after antiretroviral treatment. WHO stage IV at baseline showed 2 (95% CI 1.0-6.8) times more risk for developing TB. Late clinical stage at ART initiation was shown to relate with TB incidence. PTB coinfection leads to higher mortality. Early diagnosis and treatment of HIV are highly required to reduce HIV-associated morbidity and mortality due to TB.

[The prevalence and relevant factors of hyperglycemia in AIDS patients receiving antiretroviral therapy in a single center].

OBJECTIVE: To investigate the prevalence of hyperglycemia and its associated factors in AIDS patients receiving antiretroviral therapy (ART). METHODS: A cross-sectional survey was conducted to obtain the prevalence of hyperglycemia among AIDS patients in a single center. Univariate and multivariate non-conditional logistic regression analysis were used to determine influencing factors of hyperglycemia. RESULTS: A total of 504 AIDS patients participated in the survey, who have received ART for at least three months. The prevalence of hyperglycemia was 15.7%. Multivariate analysis showed that age (OR = 1.03, 95%CI 1.00-1.05), family history of diabetes (OR = 2.70, 95%CI 1.55-4.69), overweight (OR = 2.13, 95%CI 1.24-3.67), nadir CD4 cell counts 50-199 cells/µl (OR = 1.95, 95%CI 1.08-3.51) and less than 50 cells/µl (OR = 2.95, 95%CI 1.47-5.91) were relevant factors associated with hyperglycemia. CONCLUSIONS: Blood glucose should be monitored regularly in AIDS patients receiving ART , especially among patients with old age, family history of diabetes, overweight and nadir CD4 T cell counts less than 200 cells/µl.

Modification of BCLX pre-mRNA splicing has antitumor efficacy alone or in combination with radiotherapy in human glioblastoma cells.

Dysregulation of anti-apoptotic and pro-apoptotic protein isoforms arising from aberrant splicing is a crucial hallmark of cancers and may contribute to therapeutic resistance. Thus, targeting RNA splicing to redirect isoform expression of apoptosis-related genes could lead to promising anti-cancer phenotypes. Glioblastoma (GBM) is the most common type of malignant brain tumor in adults. In this study, through RT-PCR and Western Blot analysis, we found that BCLX pre-mRNA is aberrantly spliced in GBM cells with a favored splicing of anti-apoptotic Bcl-xL. Modulation of BCLX pre-mRNA splicing using splice-switching oligonucleotides (SSOs) efficiently elevated the pro-apoptotic isoform Bcl-xS at the expense of the anti-apoptotic Bcl-xL. Induction of Bcl-xS by SSOs activated apoptosis and autophagy in GBM cells. In addition, we found that ionizing radiation could also modulate the alternative splicing of BCLX. In contrast to heavy (carbon) ion irradiation, low energy X-ray radiation-induced an increased ratio of Bcl-xL/Bcl-xS. Inhibiting Bcl-xL through splicing regulation can significantly enhance the radiation sensitivity of 2D and 3D GBM cells. These results suggested that manipulation of BCLX pre-mRNA alternative splicing by splice-switching oligonucleotides is a novel approach to inhibit glioblastoma tumorigenesis alone or in combination with radiotherapy.

Carrier systems of radiopharmaceuticals and the application in cancer therapy.

Radiopharmaceuticals play a vital role in cancer therapy. The carrier of radiopharmaceuticals can precisely locate and guide radionuclides to the target, where radionuclides kill surrounding tumor cells. Effective application of radiopharmaceuticals depends on the selection of an appropriate carrier. Herein, different types of carriers of radiopharmaceuticals and the characteristics are briefly described. Subsequently, we review radiolabeled monoclonal antibodies (mAbs) and their derivatives, and novel strategies of radiolabeled mAbs and their derivatives in the treatment of lymphoma and colorectal cancer. Furthermore, this review outlines radiolabeled peptides, and novel strategies of radiolabeled peptides in the treatment of neuroendocrine neoplasms, prostate cancer, and gliomas. The emphasis is given to heterodimers, bicyclic peptides, and peptide-modified nanoparticles. Last, the latest developments and applications of radiolabeled nucleic acids and small molecules in cancer therapy are discussed. Thus, this review will contribute to a better understanding of the carrier of radiopharmaceuticals and the application in cancer therapy.

Trends in Mortality and Prevalence of Reported HIV/AIDS Cases - China, 2002-2021.

What is already known about this topic?: Annually, only the incidence and mortality for Acquired Immune Deficiency Syndrome (AIDS) patients are officially disclosed. What is added by this report?: For the first time, information detailing the reported rate, mortality rate, and prevalence rate trends of HIV, AIDS, and HIV/AIDS in China's entire population over the past two decades has been provided. What are the implications for public health practice?: Our research overcomes the longstanding limitation of HIV/AIDS analysis as the sole denominator. Rather, it incorporates a comprehensive examination of the overall population, utilizing indicators and analytic methods from chronic disease analyses.

Changing Mortality and Patterns of Death Causes in HIV Infected Patients - China, 2013-2022.

What is already known about this topic?: The advent of antiretroviral therapy (ART) has markedly decreased mortality rates among patients infected with human immunodeficiency virus (HIV). Globally, there has been a 43% reduction in acquired immunodeficiency syndrome (AIDS)-related deaths from 2010 to 2022. Additionally, prior research indicates that the initiation of ART at an early stage within China has substantially lowered mortality rates. What is added by this report?: Over the previous decade, following the implementation of China's universal ART access strategy, the patterns of mortality causes among HIV-infected individuals across the country have undergone significant alterations. In 2022, the all-cause mortality rate among this population was reported at 2.7%, with the non-AIDS-related mortality rate at 1.8%. However, it is important to consider that the accuracy of death reporting could contribute to potential misclassification of the underlying causes of death. What are the implications for public health practice?: Efforts to enhance health outcomes should persist in emphasizing the advancement of ART strategies, with a particular focus on mitigating non-AIDS-related mortality in the future.

Indisulam exerts anticancer effects via modulation of transcription, translation and alternative splicing on human cervical cancer cells.

Indisulam is a synthetic sulfonamides drug with anticancer activity in various tumors. However, the effect and molecular mechanism of indisulam have still not been studied in human cervical cancer. We treated human cervical cancer cell lines (HeLa and C33A) with indisulam, evaluated its efficacy, and investigated its molecular targets. Indisulam inhibited tumor growth and induced RBM39 degradation in a dose-dependent manner. RNA-seq and proteomics analysis revealed that indisulam disrupted transcriptional regulation pathways related to mRNA splicing and apoptosis. More importantly, indisulam caused mis-splicing of RNA transcripts including p73 isoforms ΔNp73 and TAp73 which have opposite roles in apoptosis regulation. Indisulam increased TAp73 expression and triggered mitochondrial apoptosis independent of p53 status in HeLa cells. In summary, our data suggests that indisulam has therapeutic potential in cervical cancer, representing an attractive strategy in p53-disrupted cancers and should be further investigated.

Mitochondrial-Targeted Antioxidant MitoQ-Mediated Autophagy: A Novel Strategy for Precise Radiation Protection.

Radiotherapy (RT) is one of the most effective cancer treatments. However, successful radiation protection for normal tissue is a clinical challenge. Our previous study observed that MitoQ, a mitochondria-targeted antioxidant, was adsorbed to the inner mitochondrial membrane and remained the cationic moiety in the intermembrane space. The positive charges in MitoQ restrained the activity of respiratory chain complexes and decreased proton production. Therefore, a pseudo-mitochondrial membrane potential (PMMP) was developed via maintenance of exogenous positive charges. This study identified that PMMP constructed by MitoQ could effectively inhibit mitochondrial respiration within normal cells, disrupt energy metabolism, and activate adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling to induce autophagy. As such, it could not lead to starvation-induced autophagy among tumor cells due to the different energy phenotypes between normal and tumor cells (normal cells depend on mitochondrial respiration for energy supply, while tumor cells rely on aerobic glycolysis). Therefore, we successfully protected the normal cells from radiation-induced damage without affecting the tumor-killing efficacy of radiation by utilizing selective autophagy. MitoQ-constructed PMMP provides a new therapeutic strategy for specific radiation protection.

Impact factors of Blastocystis hominis infection in persons living with human immunodeficiency virus: a large-scale, multi-center observational study from China.

BACKGROUND: Blastocystis hominis (Bh) is zoonotic parasitic pathogen with a high prevalent globally, causing opportunistic infections and diarrhea disease. Human immunodeficiency virus (HIV) infection disrupts the immune system by depleting CD4+ T lymphocyte (CD4+ T) cell counts, thereby increasing Bh infection risk among persons living with HIV (PLWH). However, the precise association between Bh infection risk and HIV-related biological markers and treatment processes remains poorly understood. Hence, the purpose of the study was to explore the association between Bh infection risk and CD4+ T cell counts, HIV viral load (VL), and duration of interruption in antiviral therapy among PLWH. METHODS: A large-scale multi-center cross-sectional study was conducted in China from June 2020 to December 2022. The genetic presence of Bh in fecal samples was detected by real-time fluorescence quantitative polymerase chain reaction, the CD4+ T cell counts in venous blood was measured using flowcytometry, and the HIV VL in serum was quantified using fluorescence-based instruments. Restricted cubic spline (RCS) was applied to assess the non-linear association between Bh infection risk and CD4+ T cell counts, HIV VL, and duration of interruption in highly active antiretroviral therapy (HARRT). RESULTS: A total of 1245 PLWH were enrolled in the study, the average age of PLWH was 43 years [interquartile range (IQR): 33, 52], with 452 (36.3%) being female, 50.4% (n = 628) had no immunosuppression (CD4+ T cell counts > 500 cells/µl), and 78.1% (n = 972) achieved full virological suppression (HIV VL < 50 copies/ml). Approximately 10.5% (n = 131) of PLWH had interruption. The prevalence of Bh was found to be 4.9% [95% confidence interval (CI): 3.8-6.4%] among PLWH. Significant nonlinear associations were observed between the Bh infection risk and CD4+ T cell counts (Pfor nonlinearity < 0.001, L-shaped), HIV VL (Pfor nonlinearity < 0.001, inverted U-shaped), and duration of interruption in HARRT (Pfor nonlinearity < 0.001, inverted U-shaped). CONCLUSIONS: The study revealed that VL was a better predictor of Bh infection than CD4+ T cell counts. It is crucial to consider the simultaneous surveillance of HIV VL and CD4+ T cell counts in PLWH in the regions with high level of socioeconomic development. The integrated approach can offer more comprehensive and accurate understanding in the aspects of Bh infection and other opportunistic infections, the efficacy of therapeutic drugs, and the assessment of preventive and control strategies.

Mutant p53 in cancer: from molecular mechanism to therapeutic modulation.

TP53, a crucial tumor suppressor gene, is the most commonly mutated gene in human cancers. Aside from losing its tumor suppressor function, mutant p53 (mutp53) often acquires inherent, novel oncogenic functions, which is termed "gain-of-function". Emerging evidence suggests that mutp53 is highly associated with advanced malignancies and poor prognosis, which makes it a target for development of novel cancer therapies. Herein, we provide a summary of our knowledge of the mutp53 types and mutp53 spectrum in cancers. The mechanisms of mutp53 accumulation and gain-of-function are also summarized. Furthermore, we discuss the gain-of-function of mutp53 in cancers: genetic instability, ferroptosis, microenvironment, and stemness. Importantly, the role of mutp53 in the clinic is also discussed, particularly with regard to chemotherapy and radiotherapy. Last, emphasis is given to emerging strategies on how to target mutp53 for tumor therapy. Thus, this review will contribute to better understanding of the significance of mutp53 as a target for therapeutic strategies.