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.

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.

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.

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.

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.

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.

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.

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.

Death of HIV/AIDS cases within 1 year in Jingzhou City from 1996 to 2021 / 预防医学

Objective@#To investigate the characteristics of dead HIV/AIDS cases within 1 year after confirmatory testing in Jingzhou City, Hubei Province from 1996 to 2021, so as to provide the evidence for facilitating early identification and treatment of AIDS.@*Methods@#The basic and follow-up data of HIV/AIDS cases were retrieved from the HIV/AIDS Comprehensive Response Information System of Chinese Disease Prevention and Control Information System, and mortality density and its trend were evaluated within 1 year after confirmatory testing. The factors affecting death within 1 year after confirmatory testing were identified using a Cox proportional hazards model, and the demographics, detection, treatment and cause of death were analyzed among dead HIV/AIDS cases within 1 year after confirmatory testing.@*Results@#A total of 3 304 HIV/AIDS cases were included, with 508 deaths within 1 year after confirmatory testing. The overall mortality density was 17.43 per 100 person-years, and the mortality density appeared a tendency towards a reduction from 1996 to 2021 (χ2trend=21.053, P<0.001). Of all dead HIV/AIDS cases within 1 year after confirmatory testing, 77.76% were men, 67.72% at ages of 45 years and older, 83.86% with transmission by heterosexual contact, 83.66% identified in medical institutions, 62.20% without antiretroviral therapy, and 47.83% without detection of CD4+T cell count. Mortality that was not associated with AIDS was the predominant cause of death among dead HIV/AIDS cases within 1 year after confirmatory testing (58.86%). Age of 30 years and older (HR: 1.781-4.644, 95%CI: 1.073-7.784), identification in medical institutions (HR=2.130, 95%CI: 1.306-4.474), initial CD4+T cell count of <200 cells/μL (HR: 2.649-12.879, 95%CI: 1.669-19.189), no antiretroviral therapy (HR=7.945, 95%CI: 5.743-10.993) and initiation of antiretroviral therapy 4 to 12 months after confirmatory testing (HR=1.636, 95%CI: 1.005-2.662) resulted in a higher risk of mortality within 1 year after confirmatory testing.@*Conclusions@#The mortality density appeared a tendency towards a reduction among cases within 1 year after confirmatory testing in Jingzhou City from 1996 to 2021. Mortality within 1 year after confirmatory testing was associated with advanced age, heterosexual contact transmission, identification in medical institutions, low CD4+T cell counts, and delay or absence of antiretroviral therapy.

The pattern and magnitude of T cell subsets reconstitution during ten years of ART with viral suppression in HIV-infected patients.

BACKGROUND: The extent of immune reconstitution in human immunodeficiency virus (HIV) infected persons receiving long-term antiretroviral therapy (ART) with controlled viral load has been controversial. We studied the extent and speed of T cell subsets retrieval after long-term antiretroviral treatment. METHODS: 662 HIV-infected patients followed at least 2 years whose plasma HIV-1 RNA load <50 copies/mL were evaluated for longitudinal and functional phenotypic indices of immune restoration. Determinants of change in magnitude and importance of recovery have been evaluated using mixed linear regression models. RESULTS: Almost all robust immune restorations achieved occurred after 2-3 years of ART. The median CD4 lymphocyte count increased 449 cells/µl (IQR 303-604) from 226 cells/µl (IQR 83-336) at baseline during the third year (P < 0.001); CD4+T lymphocyte rises during the sixth and tenth years were not significant. Naive and memory CD4+T cells'reconstitution occurred in the sixth and eighth years of ART but no significant change thereafter. The change of CD45RA+Naïve and CD45RA-memory CD4+T cell reconstitution is different in baseline CD4+T cell counts <100 cells/µl group and in baseline CD4+T cell counts >100 cells/µl group. Activation antigen expression (CD38 or HLA-DR) on CD8 lymphocytes declined mostly during the first till second year, and after 4 years, activation antigen expression on patient lymphocytes showed no significant change. The proportion of CD4 cells expressing CD28 climbed during the first years and reached normal levels in the second year. CONCLUSIONS: Immune restoration was dependent on the capacity of immune system during the first 2-3 year of ART. But the significant change of CD4 and compartments of CD4+T cells could persist until 6-8 years. The pattern of CD38+CD8+, HLA-DR+CD8+, CD28+CD4+ T cells could quickly return to normal level and no significant change after sufficient time of ART. In general, the immune response compared to the baseline status may be the overall effect from the age and time of antiretroviral treatment.

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.

Overexpression of splicing factor poly(rC)-binding protein 1 elicits cycle arrest, apoptosis induction, and p73 splicing in human cervical carcinoma cells.

PURPOSE: Splicing factor poly(rC)-binding protein 1 (PCBP1) is a novel tumor suppressor that is downregulated in several cancers thereby regulating tumor formation and metastasis. However, the involvement of PCBP1 in apoptosis of cancer cells and the molecular mechanism remains elusive. On this basis, we sought to investigate the role of splicing factor PCBP1 in the apoptosis in human cervical cancer cells. METHODS: To investigate PCBP1 functions in vitro, we overexpressed PCBP1 in human cervical cancer cells. A series of cytological function assays were employed to study to the role of PCBP1 in cell proliferation, cell cycle arrest and apoptosis. RESULTS: Overexpression of PCBP1 was found to greatly repress proliferation of HeLa cells in a time-dependent manner. It also induced a significant increase in G2/M phase arrest and apoptosis. Furthermore, overexpressed PCBP1 favored the production of long isoforms of p73, thereby inducing upregulated ratio of Bax/Bcl-2, the release of cytochrome c and the expression of caspase-3. CONCLUSION: Our results revealed that PCBP1 played a vital role in p73 splicing, cycle arrest and apoptosis induction in human cervical carcinoma cells. Targeting PCBP1 may be a potential therapeutic strategy for cervical cancer therapy.

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.

Epidemiological trends of severely immunosuppressed people living with HIV at time of starting antiretroviral treatment in China during 2005-2018.

OBJECTIVES: High HIV-related mortality is mainly associated with severe immunosuppression (CD4 count < 50 cells/µL) in people living with HIV (PLWH). This study intended to explore the trends in epidemic and early mortality among PLWH with severe immunosuppression for further targeted intervention. METHODS: We extracted the data of treatment-naïve PLWH with severe immunosuppression from China's National Free Antiretroviral Treatment (ART) Program database. Early mortality (within 6 or 12 months after initiating ART) and spatial, temporal, and population distribution were analyzed during 2005-2018. RESULTS: Of 748,066 treatment-naïve PLWH, 105,785 (14.1%) were severely immunosuppressed PLWH aged more than 15-year-old. The proportion of severely immunosuppressed PLWH peaked at 31.4% and then decreased with time, leveling off at approximately 11-12% from 2015 onward. Early mortality rates of these PLWH declined significantly (from 17.0% to 8.1% after 6 months of initiating ART; 20.4% to 10.6% after 12 months; both p values < 0.01) from 2005-2007 to 2016-2018. In the South-central and Southwest, the number of these PLWH was larger than that in the other regions during 2005-2018, and it increased to 4780 (37.1%) and 3370 (26.2%) in 2018. The proportion of PLWH aged 30-44 years among all treatment-naïve severely immunosuppressed PLWH in each region was higher than that of other age groups during 2005-2018. After the proportion decreased during 2005-2007, the proportion of PLWH aged 45-59 years in Southwest and South-central were increased steadily from 11% (69/626) and 16.7% (358/2140) in 2007 to 33.8% (1138/3370) and 34.0% (1626/4780) in 2018, respectively; the proportion of PLWH aged ≥60 years showed an increasing trend during 2005-2018; while changes in the proportion of those age groups were less pronounced in North and Northeast. The proportion of PLWH infected by heterosexual contact was high at 83% (2798/3370) in Southwest, and 75.1% (3588/4780) in South-central in 2018; conversely, proportion of PLWH infected by homosexual contacts was largest in North (57.8% [500/865]) and Northeast (59.9% [561/936]). CONCLUSIONS: The persistent burden of treatment-naïve PLWH with severe immunosuppression remains challenging. Our results provide evidence for policy-makers to allocate resources and establish targeting strategies to identify early infection of PLWH.

RNA-binding protein 39: a promising therapeutic target for cancer.

RNA-binding motif protein 39 (RBM39), as a key factor in tumor-targeted mRNA and protein expression, not only plays a vital role in tumorigenesis, but also has broad development prospects in clinical treatment and drug research. Moreover, since RBM39 was identified as a target of sulfonamides, it has played a key role in the emerging field of molecule drug development. Hence, it is of great significance to study the interaction between RBM39 and tumors and the clinical application of drug-targeted therapy. In this paper, we describe the possible multi-level regulation of RBM39, including gene transcription, protein translation, and alternative splicing. Importantly, the molecular function of RBM39 as an important splicing factor in most common tumors is systematically outlined. Furthermore, we briefly introduce RBM39's tumor-targeted drug research and its clinical application, hoping to give reference significance for the molecular mechanism of RBM39 in tumors, and provide reliable ideas for in-depth research for future therapeutic strategies.

Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation.

Bcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

Influential factors and spatial-temporal distribution of tuberculosis in mainland China.

Tuberculosis (TB) is an infectious disease that threatens human safety. Mainland China is an area with a high incidence of tuberculosis, and the task of tuberculosis prevention and treatment is arduous. This paper aims to study the impact of seven influencing factors and spatial-temporal distribution of the relative risk (RR) of tuberculosis in mainland China using the spatial-temporal distribution model and INLA algorithm. The relative risks and confidence intervals (CI) corresponding to average relative humidity, monthly average precipitation, monthly average sunshine duration and monthly per capita GDP were 1.018 (95% CI 1.001-1.034), 1.014 (95% CI 1.006-1.023), 1.026 (95% CI 1.014-1.039) and 1.025 (95% CI 1.011-1.040). The relative risk for average temperature and pressure were 0.956 (95% CI 0.942-0.969) and 0.767 (95% CI 0.664-0.875). Spatially, the two provinces with the highest relative risks are Xinjiang and Guizhou, and the remaining provinces with higher relative risks were mostly concentrated in the Northwest and South China regions. Temporally, the relative risk decreased year by year from 2013 to 2015. It was higher from February to May each year and was most significant in March. It decreased from June to December. Average relative humidity, monthly average precipitation, monthly average sunshine duration and monthly per capita GDP had positive effects on the relative risk of tuberculosis. The average temperature and pressure had negative effects. The average wind speed had no significant effect. Mainland China should adapt measures to local conditions and develop tuberculosis prevention and control strategies based on the characteristics of different regions and time.

The crosstalk between HIFs and mitochondrial dysfunctions in cancer development.

Mitochondria are essential cellular organelles that are involved in regulating cellular energy, metabolism, survival, and proliferation. To some extent, cancer is a genetic and metabolic disease that is closely associated with mitochondrial dysfunction. Hypoxia-inducible factors (HIFs), which are major molecules that respond to hypoxia, play important roles in cancer development by participating in multiple processes, such as metabolism, proliferation, and angiogenesis. The Warburg phenomenon reflects a pseudo-hypoxic state that activates HIF-1α. In addition, a product of the Warburg effect, lactate, also induces HIF-1α. However, Warburg proposed that aerobic glycolysis occurs due to a defect in mitochondria. Moreover, both HIFs and mitochondrial dysfunction can lead to complex reprogramming of energy metabolism, including reduced mitochondrial oxidative metabolism, increased glucose uptake, and enhanced anaerobic glycolysis. Thus, there may be a connection between HIFs and mitochondrial dysfunction. In this review, we systematically discuss the crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Above all, the stability and activity of HIFs are closely influenced by mitochondrial dysfunction related to tricarboxylic acid cycle, electron transport chain components, mitochondrial respiration, and mitochondrial-related proteins. Furthermore, activation of HIFs can lead to mitochondrial dysfunction by affecting multiple mitochondrial functions, including mitochondrial oxidative capacity, biogenesis, apoptosis, fission, and autophagy. In general, the regulation of tumorigenesis and development by HIFs and mitochondrial dysfunction are part of an extensive and cooperative network.

Immune restoration in HIV-1-infected patients after 12 years of antiretroviral therapy: a real-world observational study.

Using normalization of CD4 counts as the main evaluation parameter of complete immune restoration for HIV-1 patients under antiretroviral therapy (ART) might be not enough. A comprehensive evaluation system more accurately reflecting immune restoration are urgently needed. Totally, 91,805 HIV-1 patients from 17 tertiary hospitals in China during 2005-2018 were included in this study. Immune restoration and mortality were assessed. Patients initiated ART with baseline CD4 counts <50, 50-199, 200-349, 350-499, and ≥500 cells/µL, and results showed an increase in the median CD4 counts to 445 (12-year), 467 (12-year), 581 (11-year), 644 (7-year), and 768 cells/µL (5-year), as well as the CD4/CD8 ratio to 0.59 (12-year), 0.65 (12-year), 0.79 (11-year), 0.82 (7-year), 0.9 (5-year), respectively. The median CD8 count was relatively high (median range 732-845 cells/µL), regardless of the baseline CD4 counts. Furthermore, the probabilities of death in patients achieving CD4 counts ≥500 cells/µL and CD4/CD8 ratio ≥0.8 simultaneously were significantly lower than those in patients achieving either CD4 counts ≥500 cells/µL (2.77% vs 3.50%, p=0.02) or CD4/CD8 ≥ 0.8 (2.77% vs 4.28%, p<0.001) after 12-year of ART. In this study, a new binary-indicator would accurately assess immune restoration in the era of "treat all."