Erratum: Ophiopogonin-B Suppresses Epithelial-mesenchymal Transition in Human Lung Adenocarcinoma Cells via the Linc00668/miR-432-5p/EMT Axis: Erratum.

[This corrects the article DOI: 10.7150/jca.31338.].

PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

Domestication of rice may have changed its arbuscular mycorrhizal properties by modifying phosphorus nutrition-related traits and decreasing symbiotic compatibility.

Modern cultivated rice (Oryza sativa) typically experiences limited growth benefits from arbuscular mycorrhizal (AM) symbiosis. This could be due to the long-term domestication of rice under favorable phosphorus conditions. However, there is limited understanding of whether and how the rice domestication has modified AM properties. This study compared AM properties between a collection of wild (Oryza rufipogon) and domesticated rice genotypes and investigated the mechanisms underlying their differences by analyzing physiological, genomic, transcriptomic, and metabolomic traits critical for AM symbiosis. The results revealed significantly lower mycorrhizal growth responses and colonization intensity in domesticated rice compared to wild rice, and this change of AM properties may be associated with the domestication modifications of plant phosphorus utilization efficiency at physiological and genomic levels. Domestication also resulted in a decrease in the activity of the mycorrhizal phosphorus acquisition pathway, which may be attributed to reduced mycorrhizal compatibility of rice roots by enhancing defense responses like root lignification and reducing carbon supply to AM fungi. In conclusion, rice domestication may have changed its AM properties by modifying P nutrition-related traits and reducing symbiotic compatibility. This study offers new insights for improving AM properties in future rice breeding programs to enhance sustainable agricultural production.

Erratum: Ophiopogonin B inhibits migration and invasion in non-small cell lung cancer cells through enhancing the interaction between Axin and ß-catenin: Erratum.

[This corrects the article DOI: 10.7150/jca.60066.].

Symptom-to-balloon time and risk of ventricular arrhythmias in patients with STEMI undergoing percutaneous coronary intervention: The VERY-STEMI study.

Background: Ventricular arrhythmias (VAs) mainly occur in the early post-myocardial infarction (MI) period. However, studies examining the association between total myocardial ischemia time interval and the risk of new-onset VAs during a long-term follow-up are scarce. Methods: This study (symptom-to-balloon time and VEntricular aRrhYthmias in patients with STEMI, VERY-STEMI study) was a multicenter, observational cohort and real-world study, which included patients with ST-segment elevation MI (STEMI) undergoing percutaneous coronary intervention (PCI). The primary endpoint was cumulative new-onset VAs during follow-up. The secondary endpoints were the major adverse cardiovascular events (MACE) and changes in left ventricular ejection fraction (ΔLVEF, %). Results: A total of 517 patients with STEMI were included and 236 primary endpoint events occurred. After multivariable adjustments, compared to patients with S2BT of 24 h-7d, those with S2BT ≤ 24 h and S2BT > 7d had a lower risk of primary endpoint. RCS showed an inverted U-shaped relationship between S2BT and the primary endpoint, with an S2BT of 68.4 h at the inflection point. Patients with S2BT ≤ 24 h were associated with a lower risk of MACE and a 4.44 increase in LVEF, while there was no significant difference in MACE and LVEF change between the S2BT > 7d group and S2BT of 24 h-7d group. Conclusions: S2BT of 24 h-7d in STEMI patients was associated with a higher risk of VAs during follow-up. There was an inverted U-shaped relationship between S2BT and VAs, with the highest risk at an S2BT of 68.4 h.

Efficacy and safety of novel multifunctional M10 CAR-T cells in HIV-1-infected patients: a phase I, multicenter, single-arm, open-label study.

Chimeric antigen receptor T (CAR-T) cells have been proposed for HIV-1 treatment but have not yet demonstrated desirable therapeutic efficacy. Here, we report newly developed anti-HIV-1 CAR-T cells armed with endogenic broadly neutralizing antibodies (bNAbs) and the follicle-homing receptor CXCR5, termed M10 cells. M10 cells were designed to exercise three-fold biological functions, including broad cytotoxic effects on HIV-infected cells, neutralization of cell-free viruses produced after latency reversal, and B-cell follicle homing. After demonstrating the three-fold biological activities, M10 cells were administered to treat 18 HIV-1 patients via a regimen of two allogenic M10 cell infusions with an interval of 30 days, with each M10 cell infusion followed by two chidamide stimulations for HIV-1 reservoir activation. Consequently, 74.3% of M10 cell infusions resulted in significant suppression of viral rebound, with viral loads declining by an average of 67.1%, and 10 patients showed persistently reduced cell-associated HIV-1 RNA levels (average decrease of 1.15 log10) over the 150-day observation period. M10 cells were also found to impose selective pressure on the latent viral reservoir. No significant treatment-related adverse effects were observed. Overall, our study supported the potential of M10 CAR-T cells as a novel, safe, and effective therapeutic option for the functional cure of HIV-1/AIDS.

20(S)-Protopanaxadiol Exerts Antidepressive Effects in Chronic Corticosterone-Induced Rodent Animal Models as an Activator of Brain-Type Creatine Kinase.

20(S)-Protopanaxadiol (PPD) is one of the bioactive ingredients in ginseng and possesses neuroprotective properties. Brain-type creatine kinase (CK-BB) is an enzyme involved in brain energy homeostasis via the phosphocreatine-creatine kinase system. We previously identified PPD as directly bound to CK-BB and activated its activity in vitro. In this study, we explored the antidepressive effects of PPD that target CK-BB. First, we conducted time course studies on brain CK-BB, behaviors, and hippocampal structural plasticity responses to corticosterone (CORT) administration. Five weeks of CORT injection reduced CK-BB activity and protein levels and induced depression-like behaviors and hippocampal structural plasticity impairment. Next, a CK inhibitor and an adeno-associated virus-targeting CKB were used to diminish CK-BB activity or its expression in the brain. The loss of CK-BB in the brain led to depressive behaviors and morphological damage to spines in the hippocampus. Then, a polyclonal antibody against PPD was used to determine the distribution of PPD in the brain tissues. PPD was detected in the hippocampus and cortex and observed in astrocytes, neurons, and vascular endotheliocytes. Finally, different PPD doses were used in the chronic CORT-induced depression model. Treatment with a high dose of PPD significantly increased the activity and expression of CK-BB after long-term CORT injection. In addition, PPD alleviated the damage to depressive-like behaviors and structural plasticity induced by repeated CORT injection. Overall, our study revealed the critical role of CK-BB in mediating structural plasticity in CORT-induced depression and identified CK-BB as a therapeutic target for PPD, allowing us to treat stress-related mood disorders.

Retrospective analysis of preoperative application of triple-modal pre-rehabilitation on postoperative recovery of colorectal cancer patients.

PURPOSE: To retrospectively analyze the difference between triple-modal pre-rehabilitation and common treatment in patients with colorectal cancer (CRC). METHODS: A total of 145 patients with CRC diagnosed by pathology and admitted to our hospital for surgery between June 2020 and June 2022 were included in the study. All patients were divided into two groups: the triple-modal pre-rehabilitation group (pre-rehabilitation group) and the common treatment group. The triple-modal pre-rehabilitation strategy included exercise (3-5 times per week, with each session lasting more than 50 min), nutritional support, and psychological support. The study was designed to assess the potential of the pre-rehabilitation intervention to accelerate postoperative recovery by assessing the 6-min walk test, nutritional indicators, and HADS score before and after surgery. RESULTS: The pre-rehabilitation intervention did not reduce the duration of initial postoperative recovery or the incidence of postoperative complications, but it did increase the patients' exercise capacity (as determined by the 6-min walk test), with the pre-rehabilitation group performing significantly better than the common group (433.0 (105.0) vs. 389.0 (103.5), P < 0.001). The study also found that triple-modal pre-rehabilitation was beneficial for the early recovery of nutritional status in surgical patients and improved anxiety and depression in patients after surgery, especially in those who had not received neoadjuvant therapy. CONCLUSION: The triple-modal pre-rehabilitation strategy is of significant importance for reducing stress and improving the functional reserve of patients with colorectal cancer (CRC) during the perioperative period. The results of our study provide further support for the integration of the triple-modal pre-rehabilitation strategy into the treatment and care of CRC patients.

Correlation between blood albumin and hospital death and long-term death in ICU patients with heart failure: data from the medical information mart for intensive care III database.

BACKGROUND: Elevated circulating levels of albumin (ALB) are often associated with improved prognosis in patients with heart failure (HF). However, investigations of its association with hospital death and long-term death in HF patients in the intensive care unit (ICU) are limited. AIM: We examined whether increased blood ALB levels (first value at admission and maximum and minimum values in the ICU) were related to a greater risk of hospital death and long-term death in ICU patients with HF. METHODS: For the first time, we analyzed 4084 ICU patients with HF admitted to the ICU in The Medical Information Mart for Intensive Care III (MIMIC-III) database. RESULTS: Among 4084 HF patients, 774 (18.95%), 1056 (25.86%) and 1720 (42.12%) died in the hospital, within 30 days and 1 year, respectively. We conducted a logistic regression analysis and found significant inverse associations between blood ALB concentration and risk of hospital death, 30-day death and 1-year death when the covariates including age, sex, myocardial infarction (MI), hypertension, diabetes, valvular diseases, atrial fibrillation, stroke and chronic kidney disease (CKD) were adjusted. We additionally used a smooth curve for univariate analysis to establish an association between blood ALB concentration and death risk. Surprisingly, we observed U-shaped correlations between blood ALB concentration and hospital mortality, 30-day mortality and 1-year mortality. We found that the "inflection point" for the blood ALB concentration at the lowest risk of death was 3.5 g/dL. We further observed that a higher blood ALB concentration (albumin-max) did not contribute to a reduced risk of death (hospital death, 30-day death and 1-year death) in HF patients with an albumin concentration >3.5 g/dL. CONCLUSIONS: A lower blood ALB concentration contributed to a greater risk of hospital death and long-term death in HF patients admitted to the ICU, further suggesting that nutritional support in the ICU is highly important for improving the short-term and long-term mortality of HF patients. However, in HF patients without hypoproteinaemia (>3.5 g/dL), the impact of increased serum ALB on patient prognosis still needs to be demonstrated.

Characterization of metabolic patterns in porcine cumulus cells during meiotic maturation.

Metabolic coupling between oocytes and the surrounding somatic cells allows for normal two-way communication, and their interactions is necessary for generating developmentally competent eggs. However, the metabolic framework that support oocyte maturation in surrounding cumulus cells is still lacking. Herin, we established a temporal metabolome profile of porcine cumulus cells at three key stages during oocyte maturation, illustrating the picture of global metabolic network in cumulus cells. Importantly, we discovered the novel metabolic signature in cumulus cells during meiotic maturation, in specific, significant consumption of fatty acids, elevated activity of hexosamine biosynthetic pathway (HBP), and enhanced polyamine biosynthesis. Meanwhile, we observed the different utilization of tryptophan, active biosynthesis of progesterone, and progressive decrease in purine and pyrimidine metabolism as the oocytes progress through meiosis. Collectively, our metabolomic data serves an entree to elaborate on the dynamic changes in these metabolic pathways, which not only reveals the metabolic networks controlling oocyte development, but also lays a foundation for the discovery of biomarkers in the improvement in porcine oocyte culture system.

Combined analysis of temporal metabolomics and transcriptomics reveals the metabolic patterns in goat oocytes during maturation.

Well-balanced and orderly metabolism is a crucial prerequisite for promoting oogenesis. Involvement of single metabolites in oocyte development has been widely reported; however, the comprehensive metabolic framework controlling oocyte maturation is still lacking. In the present study, we employed an integrated temporal metabolomic and transcriptomic method to analyze metabolism in goat oocytes at GV, GVBD, and MII stages (GV, fully-grown immature oocyte; GVBD, stage of meiotic resumption; MII, mature oocyte) during in vitro maturation, revealing the global picture of the metabolic patterns during maturation. In particular, several significantly altered metabolic pathways during goat oocyte meiosis have been identified, including active serine metabolism, increased utilization of tryptophan, and marked accumulation of purine nucleotide. In summary, the current study provides transcriptomic and metabolomic datasets for goat oocyte development that can be applied in cross-species comparative studies.

Discovery and validation of COX2 as a target of flavonoids in Apocyni Veneti Folium: Implications for the treatment of liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Apocyni Veneti Folium (AVF), a popular traditional Chinese medicine (TCM), is known for its effects in soothing the liver and nerves and eliminating heat and water. It is relevant from an ethnopharmacological perspective. Pharmacological research has confirmed its benefits on antihypertension, antihyperlipidemia, antidepression, liver protection, immune system boosting, antiaging, and diabetic vascular lesions. Previous studies have shown that flavonoids, the active ingredients, have a hepatoprotective effect. However, the exact mechanism has not been clarified. AIM OF THE STUDY: This study aimed to identify the active flavonoids in AVF and their corresponding targets for liver injury. Multiple methods were introduced to confirm the targets. MATERIAL AND METHODS: AVF compounds were analyzed using liquid chromatography-mass spectrometry (LC-MS). Then, network pharmacology was utilized to screen potential hepatoprotection targets of the compounds. An enzyme activity assay was performed to determine the effect of the compounds on the targets. Biolayer interferometry (BLI) was applied to confirm the direct interaction between the compounds and the targets. RESULTS: A total of 71 compounds were identified by LC-MS and 19 compounds and 112 shared targets were screened using network pharmacology. These common targets were primarily involved in the TNF signaling pathway, cancer pathways, hepatitis B, drug responses, and negative regulation of the apoptotic process. Flavonoids were the primary pharmacological substance basis of AVF. The cyclooxygenase 2 (COX2) protein was one of the direct targets of flavonoids in AVF. The enzyme activity assay and BLI-based intermolecular interactions demonstrated that the compounds astragalin, isoquercitrin, and hyperoside exhibited stronger inhibition of enzyme activity and a higher affinity with COX2 compared to epigallocatechin, quercetin, and catechin. CONCLUSIONS: COX2 was preliminarily identified as a target of flavonoids, and the mechanism of the hepatoprotective effect of AVF might be linked to flavonoids inhibiting the activity of COX2. The findings can establish the foundation for future research on the traditional hepatoprotective effect of AVF on the liver and for clinical studies on liver disorders.

A multistage Sendai virus vaccine incorporating latency-associated antigens induces protection against acute and latent tuberculosis.

One-quarter of the world's population is infected with Mycobacterium tuberculosis (Mtb). After initial exposure, more immune-competent persons develop asymptomatic latent tuberculosis infection (LTBI) but not active diseases, creates an extensive reservoir at risk of developing active tuberculosis. Previously, we constructed a novel recombinant Sendai virus (SeV)-vectored vaccine encoding two dominant antigens of Mtb, which elicited immune protection against acute Mtb infection. In this study, nine Mtb latency-associated antigens were screened as potential supplementary vaccine candidate antigens, and three antigens (Rv2029c, Rv2028c, and Rv3126c) were selected based on their immune-therapeutic effect in mice, and their elevated immune responses in LTBI human populations. Then, a recombinant SeV-vectored vaccine, termed SeV986A, that expresses three latency-associated antigens and Ag85A was constructed. In murine models, the doses, titers, and inoculation sites of SeV986A were optimized, and its immunogenicity in BCG-primed and BCG-naive mice were determined. Enhanced immune protection against the Mtb challenge was shown in both acute-infection and latent-infection murine models. The expression levels of several T-cell exhaustion markers were significantly lower in the SeV986A-vaccinated group, suggesting that the expression of latency-associated antigens inhibited the T-cell exhaustion process in LTBI infection. Hence, the multistage quarter-antigenic SeV986A vaccine holds considerable promise as a novel post-exposure prophylaxis vaccine against tuberculosis.

Recent Advance of S100B Proteins in Spontaneous Intracerebral Hemorrhage and Aneurysmal Subarachnoid Hemorrhage.

Human health is seriously endangered by spontaneous intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). Because the majority of ICH and aSAH survivors experience disability, increased risk of stroke recurrence, cognitive decline, and systemic vascular disease, ICH and aSAH assume special importance in neurological disease. Early detection and prediction of neurological function and understanding of etiology and correction are the basis of successful treatment. ICH and aSAH cause complex inflammatory cascades in the brain. In order to establish precise staging and prognosis, as well as provide a basis for treatment selection and monitoring, it is imperative to determine appropriate biological markers according to pathological and physiological mechanisms. In this review, we focus on the research progress of S100B, an endogenous danger signaling molecule, as a potential biomarker for ICH and aSAH, assisting in the development of further basic research and clinical translational studies.

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.

Melatonin ameliorates histone modification disorders in mammalian aged oocytes by neutralizing the alkylation of HDAC1.

Aging-associated histone modification changes in oocytes have been sporadically reported, but the underlying mechanisms remain elusive. Here, we systematically characterize multiple histone modifications in oocytes during aging. We find that maternal and postovulatory aging markedly alter the status of histone modifications, specifically H4K12ac and H3K4me3, in both mouse and porcine oocytes. Meanwhile, we identify a substantial reduction in HDAC1 (histone deacetylase 1) protein in aged oocytes, which contributes to the changes in H4K12ac and H3K4me3. Moreover, by employing methylglyoxal (MG) and site-directed mutagenesis, we demonstrate that the elevated reactive carbonyl species (RCS) level induces HDAC1 degradation, likely through attacking the cysteine residues, thereby influences histone modification state. Importantly, supplementation of melatonin not only prevents the loss of HDAC1 protein, but also partially corrects the H4K12ac and H3K4me3 status in aged oocytes. To sum up, this study established the link between redox disequilibrium and histone modification alterations during mammalian oocyte aging.

Association between urinary cadmium level and subclinical myocardial injury in the general population without cardiovascular disease aged ≥ 50 years.

Cadmium (Cd) is a toxic heavy metal linked to an increased risk of cardiovascular disease (CVD). But the relationship between urinary Cd (U-Cd) and electrocardiographic subclinical myocardial injury (SC-MI) in older people is unclear. This study evaluated the connection between U-Cd and SC-MI in people who did not have CVD. The study involved 4269 participants from the National Health and Nutrition Examination Survey III(NHANES III) aged ≥ 50 years and had no history of CVD. The relationship between U-Cd and cardiac infarction/injury score (CIIS) was assessed by multivariable linear regression. Whether U-Cd and SC-MI were correlated was determined by multivariate logistic regression, restricted cubic spline, and subgroup analysis. There was a significant association between U-Cd and CIIS (ß, 1.04, 95% confidence interval (CI): 0.39-1.69; P = 0.003) in the highest quartile and fully adjusted model. After adjusting for relevant confounders, multivariable logistic regression showed that participants in the highest quartile of U-Cd had a greater chance of having SC-MI than those in the first ( OR (95% CI), 1.37(1.13,1.66), P for trend = 0.003), and this relationship was especially strong among hypertensive participants. And a positive linear correlation between U-Cd and the prevalence of SC-MI was shown by restricted cubic spline analysis. U-Cd may be a novel risk element for SC-MI because it is independently and linearly linked to CIIS and SC-MI.

Myeloid-derived suppressor cells and pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic pulmonary vascular disorder characterized by an increase in pulmonary vascular resistance and pulmonary arterial pressure. The detailed molecular mechanisms remain unclear. In recent decades, increasing evidence shows that altered immune microenvironment, comprised of immune cells, mesenchymal cells, extra-cellular matrix and signaling molecules, might induce the development of PH. Myeloid-derived suppressor cells (MDSCs) have been proposed over 30 years, and the functional importance of MDSCs in the immune system is appreciated recently. MDSCs are a heterogeneous group of cells that expand during cancer, chronic inflammation and infection, which have a remarkable ability to suppress T-cell responses and may exacerbate the development of diseases. Thus, targeting MDSCs has become a novel strategy to overcome immune evasion, especially in tumor immunotherapy. Nowadays, severe PH is accepted as a cancer-like disease, and MDSCs are closely related to the development and prognosis of PH. Here, we review the relationship between MDSCs and PH with respect to immune cells, cytokines, chemokines and metabolism, hoping that the key therapeutic targets of MDSCs can be identified in the treatment of PH, especially in severe PH.

Use of programmed cell death protein 1 (PD-1) inhibitor therapy in HIV-infected patients with advanced cancer: a single-center study from China.

BACKGROUND: Anti-PD-1 antibodies have been approved for treating several cancer. However, data regarding the safety and efficacy of these agents in HIV-infected patients with cancer is lacking, because these patients are frequently omitted from clinical trials. OBJECTIVES: The primary aim of our research is to assess the safety, activity, and long-term outcomes of PD-1 inhibitors in the treatment of HIV-infected patients with advanced cancer. METHOD: We retrospectively analyzed data from HIV-infected patients with advanced cancers who were treated with PD-1 inhibitors at Shanghai Public Health Clinical Center, Shanghai, China. RESULTS: Fifteen HIV-infected patients (all are men; asian; median age, 44) with cancer who were treated with chemotherapy and/or combined the other oncology treatments [along with combined antiretroviral therapy (cART)] prior to Sintilimab (12 out of 15) or Nivolumab (1 out of 11) or Camrelizumab (2 out of 11) injection were identified. Eight patients responded to treatment (disease control rate 53.3%), with 1 got partial response (PR) and 7 were stable. Most treatment-emergent adverse events (TEAEs) were grade 1 or 2 including anemia, leukopenia, hyperglycemia, granulocytopenia, and thrombocytopenia. Eight patients (53.3%) experienced treatment-related AEs (TRAEs) with grades 3/4including myelosuppression, infection, and neurological disorders. CD4+ T cell count and plasma HIV RNA remained stable throughout the treatment. CONCLUSIONS: When used in HIV-infected patients with advanced malignancies, PD-1 inhibitors tend to have favorable efficacy, manageable side effects, and no deteriorated impacts on plasma HIV-RNA and CD4+ T cell count.