Long non-coding RNA-encoded micropeptides: functions, mechanisms and implications.

Long non-coding RNAs (lncRNAs) are typically described as RNA transcripts exceeding 200 nucleotides in length, which do not code for proteins. Recent advancements in technology, including ribosome RNA sequencing and ribosome nascent-chain complex sequencing, have demonstrated that many lncRNAs retain small open reading frames and can potentially encode micropeptides. Emerging studies have revealed that these micropeptides, rather than lncRNAs themselves, are responsible for vital functions, including but not limited to regulating homeostasis, managing inflammation and the immune system, moderating metabolism, and influencing tumor progression. In this review, we initially outline the rapidly advancing computational analytical methods and public tools to predict and validate the potential encoding of lncRNAs. We then focus on the diverse functions of micropeptides and their underlying mechanisms in the pathogenesis of disease. This review aims to elucidate the functions of lncRNA-encoded micropeptides and explore their potential applications as therapeutic targets in cancer.

Bilayer MOF nanomachine for precision breast cancer cell fluorescent imaging and therapy.

A bilayer MOF reporter (ZIF-67@FAM-mRNA@ZIF-8) was synthesized, and the ZIF-67 was used as a carrier and fluorescent quencher to connect the FAM reporter through electrostatic adsorption and coordination effect. The ZIF-8 covering the outer layer can improve the stability of the probe and cell permeability, which helps the FAM reporter effectively release. After entering the cancer cells, the acidic environment in the cells induced the decomposition of ZIF-8. The excess ATP in the tumor cells competitively binds ZIF-67, causing the FAM reporter to shed and restore fluorescence. The shed FAM reporter was specifically bound to the overexpressed miRNA-21 in breast cancer cells to achieve fluorescence imaging and therapy of breast cancer. The results of specific imaging and apoptosis experiments of breast cancer cells indicate that bilayer MOF nanomachine provides an effective nanotherapy platform for accurate fluorescence imaging.

Establishing the homologous recombination score threshold in metastatic prostate cancer patients to predict the efficacy of PARP inhibitors.

Background: The homologous recombination deficiency (HRD) score serves as a promising biomarker to identify patients who are eligible for treatment with PARP inhibitors (PARPi). Previous studies have suggested a 3-biomarker Genomic Instability Score (GIS) threshold of ≥ 42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer. However, the GIS threshold for prostate cancer (PCa) is still lacking. Here, we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients. Methods: A total of 181 patients with metastatic castration-resistant PCa were included in this study. Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair (HRR) genes and copy number variation (CNV) analysis. The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors. The relationship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed. Results: Genomic testing was succeeded in 162 patients. In our cohort, 61 patients (37.7%) had HRR mutations (HRRm). BRCA mutations occurred in 15 patients (9.3%). The median HRD score was 4 (ranged from 0 to 57) in the total cohort, which is much lower than that in breast and ovarian cancers. Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores. CNV occured more frequently in patients with HRRm. The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores ≥ 43. In the 16 patients who received PARPi in our cohort, 4 patients with a high HRD score achieved an objective response rate (ORR) of 100% while 12 patients with a low HRD score achieved an ORR of 8.3%. Progression-free survival (PFS) in HRD high patients was longer compared to HRD low patients, regardless of HRRm. Conclusions: A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study. Future studies are needed to further verify this threshold.

Synergistic Elimination of Chlorophenols Using a Single-Atom Nickel with Single-Walled Carbon Nanotubes: The Roles of Adsorption, Hydrodechlorination, and the Electro-Fenton Process.

Electrocatalytic degradation enables the efficient treatment of chlorinated pollutants (COPs); however, its application has been significantly hindered by the large amounts of unsafe intermediate products. In this study, we present a single-atom nickel with single-walled carbon nanotubes (SWCNTs) as an electrochemical reactor for the complete elimination of chlorophenols. Distinct products and reductive mechanisms were observed for Ni-N-C compared to Cu-N-C. Ni-N-C incorporation has a novel degradation pathway for efficient chlorophenol degradation involving hydrodechlorination and the electro-Fenton process. Most importantly, the weak adsorption between the chlorophenols and the SWCNTs promoted their dechlorination by the attached active atomic hydrogen (H*) formed on the Ni-N-C. Meanwhile, the SWCNTs improved the reduction of O2 to H2O2, which was subsequently decomposed by Ni-N-C to form hydroxyl radicals (·OH) for phenol oxidation. As a result, the degradation rate of 4-chlorophenol was increased by 5 and 10 times compared with those of the Ni-N-C and SWCNTs alone, respectively. The first-order reaction rate constant was 2.7 h-1, and the metal mass kinetics constant was 1956.5 min-1g-1. Aromatic COPs containing benzene rings could be degraded, but chloroacetic acids could not. This study demonstrates a new design for multifunctional electrochemical degradation that functions via dechlorination and the ·OH activation mechanism.

The potential treatment of N-acetylcysteine as an antioxidant in the radiation-induced heart disease.

Background: Radiation-induced heart disease (RIHD) is a serious complication of thoracic tumor radiotherapy that substantially affects the quality of life of cancer patients. Oxidative stress plays a pivotal role in the occurrence and progression of RIHD, which prompted our investigation of an innovative approach for treating RIHD using antioxidant therapy. Methods: We used 8-week-old male Sprague-Dawley (SD) rats as experimental animals and H9C2 cells as experimental cells. N-acetylcysteine (NAC) was used as an antioxidant to treat H9C2 cells after X-ray irradiation in this study. In the present study, the extent of cardiomyocyte damage caused by X-ray exposure was determined, alterations in oxidation/antioxidation levels were assessed, and changes in the expression of genes related to mitochondria were examined. The degree of myocardial tissue and cell injury was also determined. Dihydroethidium (DHE) staining, reactive oxygen species (ROS) assays, and glutathione (GSH) and manganese superoxide dismutase (Mn-SOD) assays were used to assess cell oxidation/antioxidation. Flow cytometry was used to determine the mitochondrial membrane potential and mitochondrial permeability transition pore (mPTP) opening. High-throughput transcriptome sequencing and bioinformatics analysis were used to elucidate the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure. Polymerase chain reaction (PCR) was used to verify the expression of differentially expressed genes. Results: X-ray irradiation damaged myocardial tissue and cells, resulting in an imbalance of oxidative and antioxidant substances and mitochondrial damage. NAC treatment increased cell counting kit-8 (CCK-8) levels (P=0.02) and decreased lactate dehydrogenase (LDH) release (P=0.02) in cardiomyocytes. It also reduced the level of ROS (P=0.002) and increased the levels of GSH (P=0.04) and Mn-SOD (P=0.01). The mitochondrial membrane potential was restored (P<0.001), and mPTP opening was inhibited (P<0.001). Transcriptome sequencing and subsequent validation analyses revealed a decrease in the expression of mitochondria-related genes in myocardial tissue induced by X-ray exposure, but antioxidant therapy did not reverse the related DNA damage. Conclusions: Antioxidants mitigated radiation-induced myocardial damage to a certain degree, but these agents did not reverse the associated DNA damage. These findings provide a new direction for future investigations by our research group, including exploring the treatment of RIHD-related DNA damage.

Budget Impact Analysis of Circulating Tumor DNA Testing for Colon Cancer in Commercial Health and Medicare Advantage Plans.

Importance: In a randomized clinical trial, treatment guided by tumor-informed circulating tumor (ct)DNA testing reduced adjuvant chemotherapy use without compromising recurrence-free survival in patients with stage II colon cancer. The potential effects of adopting ctDNA testing into routine patient care is unknown. Objective: To compare the total cost of patient care scenarios with and without the adoption of ctDNA testing. Design, Setting, and Participants: This budget impact analysis was conducted from the perspectives of US commercial health and Medicare Advantage payers. A decision-analytical model was populated with age-specific incidence of colon cancer, use of adjuvant chemotherapy, and use of single-agent or multiagent regimens. Total cost was estimated with the costs of ctDNA testing, drug acquisition, administration, surveillance, and adverse events. The analysis was conducted from September 2023 to January 2024. Exposures: The adoption of ctDNA testing. Main Outcomes and Measures: The incremental cost in the first year following the adoption of ctDNA testing, where testing will affect patient treatment and costs. Results: In hypothetical plans with 1 million individuals covered, 35 commercial health plan members and 102 Medicare Advantage members aged 75 years and younger were eligible for ctDNA testing. In the base case with a 50% adoption rate, total cost savings were $221 684 (equivalent to $0.02 per member per month [PMPM]) for a commercial payer and $116 720 (equivalent to $0.01 PMPM) for a Medicare Advantage payer. Cost savings were robust to variations in assumptions of all parameters in the commercial population but sensitive to variations in assumptions of adjuvant chemotherapy use rates in the Medicare Advantage population. The number needed to test to avoid 1 patient receiving adjuvant chemotherapy was 4 in the commercial population and 10 in the Medicare Advantage population. The budget-neutral cost for ctDNA testing was $16 202 for a commercial payer and $5793 for a Medicare Advantage payer. Conclusions and Relevance: Use of tumor-informed ctDNA testing to guide adjuvant chemotherapy in postsurgery patients with stage II colon cancer was projected to result in cost savings for both commercial and Medicare Advantage payers. Adoption of ctDNA testing is therefore advantageous from a budgetary perspective.

TSPO-induced degradation of the ethylene receptor RhETR3 promotes salt tolerance in rose (Rosa hybrida).

The gaseous plant hormone ethylene regulates plant development, growth, and responses to stress. In particular, ethylene affects tolerance to salinity; however, the underlying mechanisms of ethylene signaling and salt tolerance are not fully understood. Here, we demonstrate that salt stress induces the degradation of the ethylene receptor ETHYLENE RESPONSE 3 (RhETR3) in rose (Rosa hybrid). Furthermore, the TspO/MBR (Tryptophan-rich sensory protein/mitochondrial benzodiazepine receptor) domain-containing membrane protein RhTSPO interacted with RhETR3 to promote its degradation in response to salt stress. Salt tolerance is enhanced in RhETR3-silenced rose plants but decreased in RhTSPO-silenced plants. The improved salt tolerance of RhETR3-silenced rose plants is partly due to the increased expression of ACC SYNTHASE1 (ACS1) and ACS2, which results in an increase in ethylene production, leading to the activation of ETHYLENE RESPONSE FACTOR98 (RhERF98) expression and, ultimately accelerating H2O2 scavenging under salinity conditions. Additionally, overexpression of RhETR3 increased the salt sensitivity of rose plants. Co-overexpression with RhTSPO alleviated this sensitivity. Together, our findings suggest that RhETR3 degradation is a key intersection hub for the ethylene signalling-mediated regulation of salt stress.

[Incidence and risk factors of deep vein thrombosis in patients with rheumatoid arthritis].

OBJECTIVE: To investigate the incidence and risk factors of deep vein thrombosis (DVT) in patients with rheumatoid arthritis (RA). METHODS: The clinical data of RA patients who were hospi-talized in the Department of Rheumatology and Immunology of Aerospace Center Hospital from May 2015 to September 2021 was retrospectively analyzed, including demographic characteristics, concomitant diseases, laboratory examinations (blood routine, biochemistry, coagulation, inflammatory markers, rheumatoid factor, antiphospholipid antibodies and lupus anticoagulant, etc.) and treatment regimens. The patients were compared according to the presence or absence of DVT, and the t test, Mann-Whitney U test or Chi-square test were applied to screen for relevant factors for DVT, followed by Logistic regression analysis to determine risk factors for DVT in patients with RA. RESULTS: The incidence of DVT in the RA patients was 9.6% (31/322); the median age of RA in DVT group was significantly older than that in non-DVT group [64 (54, 71) years vs. 50 (25, 75) years, P < 0.001]; the level of disease activity score using 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) in DVT group was higher than that in non-DVT group [5.2 (4.5, 6.7) vs. 4.5(4.5, 5.0), P < 0.001]; the incidence of hypertension, chronic kidney disease, fracture or surgery history within 3 months, and varicose veins of the lower extremities in DVT group was higher than that in non-DVT group (P < 0.001). The levels of hemoglobin and albumin in DVT group were significantly lower than that in non-DVT group (P=0.009, P=0.004), while the D-dimer level and rheumatoid factor positive rate in DVT group were significantly higher than that in non-DVT group (P < 0.001). The use rate of glucocorticoid in DVT group was higher than that in non-DVT group (P=0.009). Logistic regression analysis showed that the age (OR=1.093, P < 0.001), chronic kidney disease (OR=7.955, P=0.005), fracture or surgery history within 3 months (OR=34.658, P=0.002), DAS28-ESR (OR=1.475, P=0.009), and the use of glucocorticoid (OR=5.916, P=0.003) were independent risk factors for DVT in RA patients. CONCLUSION: The incidence of DVT in hospitalized RA patients was significantly increased, in addition to traditional factors, such as age and chronic kidney disease, increased DAS28-ESR level and the use of glucocorticoid were also independent risk factors for DVT.

Low-Level miR-199 Contribute to Neuropathic Low Back Pain via TRPV1 by Regulating the Production of Pro-Inflammatory Cytokines on Macrophage.

AIM: To explore the post-translational regulation of TRPV1, which plays an important role in neuropathic low back pain (NLBP). MATERIAL AND METHODS: qPCR was used to examine the gene mRNA levels. Western blot was used to examine the protein level. NLBP rat model was established for confirming what we observed in clinical samples. Dual-luciferase assay was used to verify the miR-199 targets on the 3'UTR of TRPV1. Cell coculture was used to explore the interaction between macrophages and nerve cells. RESULTS: We found the mRNA level of TRVP1 decreased in the sinuvertebral nerve biopsy of NLBP. With bioinformatics prediction, miR199 would involve the post-transcription regulation of TRPV1. As the prediction, the miR199 level decreased in the clinical samples. Correlation regression analysis showed a negative correlation between miR-199 and TRPV1. The same phenomenon was confirmed in the rat NLBP model. With dual-luciferase assay, we confirmed that miR199 directly binds to the 3'UTR of TRPV1. Through co-culture of macrophage (THP1) and sNF96.2, we found that up or down-regulates miR-199 in macrophage and sNF96.2 could relieve or aggravate the injury of nerve cells strain. CONCLUSION: These results suggest that the occurrence of NLBP may be caused by the lower expression of miR-199 in macrophages and nerve via TRPV1.

The Transcriptome Analysis of Circular RNAs Between the Doxorubicin- Induced Cardiomyocytes and Bone Marrow Mesenchymal Stem Cells- Derived Exosomes Treated Ones.

AIM: To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOX-induced cardiotoxicity for further study. METHODS: The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing. RESULTS: Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing. CONCLUSION: mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).

Prognostic value and immunological role of PD-L1 gene in pan-cancer.

OBJECTIVE: PD-L1, a target of immune checkpoint blockade, has been proven to take the role of an oncogene in most human tumors. However, the role of PD-L1 in human pan-cancers has not yet been fully investigated. MATERIALS AND METHODS: Pan-cancer analysis was conducted to analyze expression, genetic alterations, prognosis analysis, and immunological characteristics of PD-L1. Estimating the correlation between PD-L1 expression and survival involved using pooled odds ratios and hazard ratios with 95% CI. The Kaplan-Meier (K-M) technique, COX analysis, and receiver operating characteristic (ROC) curves were applied to the survival analysis. Additionally, we investigated the relationships between PD-L1 and microsatellite instability (MSI), tumor mutational burden (TMB), DNA methyltransferases (DNMTs), the associated genes of mismatch repair (MMR), and immune checkpoint biomarkers using Spearman's correlation analysis. Also, immunohistochemical analysis and qRT-PCR were employed in evaluating PD-L1's protein and mRNA expression in pan-caner. RESULTS: PD-L1 showed abnormal mRNA and protein expression in a variety of cancers and predicted prognosis in cancer patients. Furthermore, across a variety of cancer types, the aberrant PD-L1 expression was connected to the MSI, MMR, TMB, drug sensitivity, and tumor immune microenvironment (TIME). Moreover, PD-L1 was significantly correlated with infiltrating levels of immune cells (T cell CD8 + , neutrophil, and so on). CONCLUSION: Our study provides a better theoretical basis and guidance for the clinical treatment of PD-L1.

Comparing the efficacy and safety of three surgical approaches for total hysterectomy (TSATH): protocol for a multicentre, single-blind, parallel-group, randomised controlled trial.

INTRODUCTION: Hysterectomy is the most common surgical procedure in the field of gynaecology. The traditional multiport laparoscopy, transumbilical laparoendoscopic single-site surgery (TU-LESS) and transvaginal natural orifice transluminal endoscopic surgery (vNOTES) hysterectomy approaches have been implemented to varying degrees in clinical practice. At present, although their feasibility has been proven, there are no large randomised controlled studies on postoperative rehabilitation. This study aims to evaluate postoperative recovery and assess the safety and effectiveness of these three surgical approaches for total laparoscopic hysterectomy. METHOD AND ANALYSIS: This is a multicentre, randomised, single-blind, three-arm, parallel-group, interventional clinical trial. Recruitment will be carried out in five tertiary hospitals in China. Patients diagnosed with benign uterine disease or precancerous lesions will be assigned to the vNOTES group, TU-LESS group and conventional laparoscopy group at a 1:1:1 ratio. The achievement rate of comprehensive indices of enhanced recovery after surgery (ERAS) within 24 hours postoperatively will be considered the primary outcome (the comprehensive indicators of ERAS include fluid intake, passing flatus, urination after catheter removal, ambulation and a Visual Analogue Scale score ≤3.) This study will use a non-inferiority test, with a power (1-ß) of 80% and a margin of -0.15, at a one-sided α of 0.0125. The sample size will be 480 patients (including an assumed 15% dropout rate), calculated according to the primary outcome. ETHICS AND DISSEMINATION: This study was approved on 25 April 2022 by the Medical Ethics Committee of West China Second University Hospital (2022(057)), Sichuan University, Chengdu, China. All participants will be required to provide informed consent before their participation in the study. The results of the trial will be submitted for publication in a peer-reviewed journal and presented at international conferences. PROTOCOL VERSION: V.3.0, 31 August 2023. TRIAL REGISTRATION NUMBER: ChiCTR2200057405.

Extraperitonealization of the ileal conduit decreases the risk of parastomal hernia: A single-center, randomized clinical trial.

Parastomal hernia (PSH) is a common complication in patients receiving ileal conduit urinary diversion after radical cystectomy. In this randomized controlled clinical trial, we validate our previous finding that extraperitonealization of ileal conduit decreases incidence of PSH. In total, 104 consecutive patients undergoing radical cystectomy at Sun Yat-sen University Cancer Center are randomized 1:1 to receive either modified (extraperitonealized) ileal conduit (n = 52) or conventional ileal conduit (n = 52). Primary endpoint is incidence of radiological PSH during follow-up. Incidence of radiological PSH is lower in the modified group than in the conventional group (11.5% vs. 28.8%; p = 0.028) after a median follow-up of 32 months, corresponding to a hazard ratio of 0.374 (95% confidence interval: 0.145-0.965, p = 0.034) in the modified conduit group. The results support our previous finding that extraperitonealization of the ileal conduit is effective for reducing risk of PSH in patients receiving ileal conduit diversion.

CAR-NK cells for acute myeloid leukemia immunotherapy: past, present and future.

Acute myeloid leukemia (AML) is a deadly disease and the most common leukemia in adult with clonal heterogeneity and abnormity in myeloid lineages, which has been recognized with high morbidity and mortality attributes to the recurrence and resistance to chemotherapy. Numerous literatures have indicated the encouraging progress in allogeneic hematopoietic stem cell transplantation (allo-HSCT) and chimeric antigen receptor-transduced T (CAR-T) cells. However, the outcomes of recurrent and refractory AML (r/rAML) patients with current strategies are still unsatisfactory, which largely due to the matching restriction as well as adverse reactions, including graft-versus-host disease (GvHD), neurotoxicity and cytokine release syndrome (CRS). State-of-the-art literatures have indicated CAR-transduced NK (CAR-NK) cells for the management of diverse hematologic malignancies including AML, which are recognized as novel weapons for reinforcing the specificity and cytotoxicity of autogenous and allogeneic "off-the-shelf" NK cells dispense with prior sensitization. Therefore, in this review, we mainly focus on the latest updates of alternative cell sources, therapeutic targets, CAR-modification and delivery strategies, standardization and productization, together with prospective and challenges of CAR-NK cell-based cytotherapy, which will collectively benefit the further development of novel treatment paradigms for combating AML via both CAR-dependent and NK cell receptor-dependent signaling cascades in future.

CBSX2 is required for the efficient oxidation of chloroplast redox-regulated enzymes in darkness.

Thiol/disulfide-based redox regulation in plant chloroplasts is essential for controlling the activity of target proteins in response to light signals. One of the examples of such a role in chloroplasts is the activity of the chloroplast ATP synthase (CFoCF1), which is regulated by the redox state of the CF1γ subunit and involves two cysteines in its central domain. To investigate the mechanism underlying the oxidation of CF1γ and other chloroplast redox-regulated enzymes in the dark, we characterized the Arabidopsis cbsx2 mutant, which was isolated based on its altered NPQ (non-photochemical quenching) induction upon illumination. Whereas in dark-adapted WT plants CF1γ was completely oxidized, a small amount of CF1γ remained in the reduced state in cbsx2 under the same conditions. In this mutant, reduction of CF1γ was not affected in the light, but its oxidation was less efficient during a transition from light to darkness. The redox states of the Calvin cycle enzymes FBPase and SBPase in cbsx2 were similar to those of CF1γ during light/dark transitions. Affinity purification and subsequent analysis by mass spectrometry showed that the components of the ferredoxin-thioredoxin reductase/thioredoxin (FTR-Trx) and NADPH-dependent thioredoxin reductase (NTRC) systems as well as several 2-Cys peroxiredoxins (Prxs) can be co-purified with CBSX2. In addition to the thioredoxins, yeast two-hybrid analysis showed that CBSX2 also interacts with NTRC. Taken together, our results suggest that CBSX2 participates in the oxidation of the chloroplast redox-regulated enzymes in darkness, probably through regulation of the activity of chloroplast redox systems in vivo.

Effect of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma: a real-world retrospective study.

BACKGROUND: Genitourinary small cell carcinoma is rare, and has a poor prognosis. However, effective treatment options for this disease are limited. We present a study to assess the efficacy of chemotherapy alone or combined with immunotherapy for locally advanced or metastatic genitourinary small cell carcinoma (GSCC). METHODS: We performed a retrospective analysis of patients with locally advanced or metastatic GSCC from Jan 2013 to September 2022 at Sun Yat-sen University Cancer Center. The survival and safety profiles were analyzed. RESULTS: Forty-two GSCC patients were enrolled, which included 20 with chemotherapy plus immunotherapy and 22 with chemotherapy alone. The median follow-up time was 15.13 months (95% CI, 8.84-21.42). The addition of immunotherapy to chemotherapy demonstrated no significant difference in median progression-free survival (p = 0.37). However, the median overall survival (OS) was 22.97 and 14.03 months with immunotherapy plus chemotherapy and chemotherapy alone, respectively (HR = 0.69, 95%CI 0.08-0.55, p = 0.017). Two patients with immunotherapy plus chemotherapy achieved clinical complete remission. The overall response rate for patients receiving chemotherapy combined with immunotherapy was 65%, which was higher in comparison to those treated with chemotherapy alone (50%). Univariate and multivariate analyses demonstrated that chemotherapy combined with immunotherapy independently achieved favorable OS. Four patients experienced immunotherapy-related adverse events, with one developing grade 3 hypothyroidism. CONCLUSIONS: Among patients with locally advanced or metastatic GSCC, immunotherapy combined with chemotherapy might be thought of as a potentially effective treatment option for patients with GSCC.

Incidence and factors associated with hepatitis B surface antigen seroclearance in patients co-infected with HBV/HIV during antiretroviral therapy in Guangdong, China.

BACKGROUND: Hepatitis B surface antigen (HBsAg) clearance is vital for a functional cure of hepatitis B virus (HBV) infection. However, the incidence and predictors of HBsAg seroclearance in patients co-infected with HBV and human immunodeficiency virus (HIV) remain largely unknown in Guangdong, China. METHODS: Between 2009 and 2019, patients co-infected with HBV/HIV undergoing antiretroviral therapy (ART) in Guangzhou Eighth People's Hospital affiliated to Guangzhou Medical University were retrospectively reviewed with the endpoint on December 31, 2020. The incidence and risk factors for HBsAg seroclearance were evaluated using Kaplan-Meier and multivariate Cox regression analyses. RESULTS: A total of 1550 HBV/HIV co-infected patients were included in the study, with the median age of 42 years and 86.0% (1333/1550) males. Further, 98.3% (1524/1550) received ART containing tenofovir disoproxil fumarate (TDF) plus lamivudine (3TC). HBV DNA was examined in 1283 cases at the last follow-up. Over the median 4.7 years of follow-up, 8.1% (126/1550) patients achieved HBsAg seroclearance, among whom 50.8% (64/126) obtained hepatitis B surface antibody, 28.1% (137/488) acquired hepatitis B e antigen seroconversion, and 95.9% (1231/1283) undetectable HBV DNA. Compared with patients who maintained HBsAg positive, cases achieving HBsAg seroclearance showed no differences in age, gender, CD4 + T cell count, alanine aminotransferase (ALT) level, or fibrosis status; however, they presented lower HBV DNA levels, lower HBsAg levels, and higher rates of HBV genotype B at the baseline. Multivariate analysis showed that baseline HBsAg <1500 cutoff index (COI) (adjusted hazard ratio [aHR], 2.74, 95% confidence interval [95% CI]: 1.48-5.09), ALT elevation >2 × upper limit of normal during the first six months after receiving ART (aHR, 2.96, 95% CI: 1.53-5.77), and HBV genotype B (aHR, 3.73, 95% CI: 1.46-9.59) were independent predictors for HBsAg seroclearance (all P <0.01). CONCLUSIONS: Long-term TDF-containing ART has high anti-HBV efficacy including relatively high overall HBsAg seroclearance in HBV/HIV co-infected patients. Lower baseline HBsAg levels, HBV genotype B, and elevated ALT levels during the first six months of ART are potential predictors of HBsAg seroclearance.

SAVE Testis-sparing score: a multicenter retrospective study of a novel predictive tool for quantifying testicular tumors.

BACKGROUND: Testis-sparing surgery (TSS) is a safe treatment for patients with benign testicular tumors. Presently, assessments for evaluating the suitability of TSS are poorly standardized, partially because testicular anatomical elements cannot be quantitatively described. MATERIALS AND METHODS: The authors developed a scoring method known as the SAVE testis-sparing score based on four critical and accessible anatomical features of a testicular tumor. The SAVE score ranges from 0 to 8 and is divided into four risk classes ( low , medium , high , and extremely high ) to evaluate the feasibility of TSS, wherein low-risk indicates high feasibility and vice versa. This study included 444 testicular tumor patients from eight centers. Among them, 216 patients (model group: 151 patients, validation group: 65 patients) were included in the modeling analysis, and the other 228 patients from children's centers were included in the proportion analysis. Using retrospective data, patient characteristics associated with surgical methods were identified. Furthermore, a multivariate logistic regression model was built quantify the associations between these characteristics and the surgery method. The receiver operator characteristic curve was used to evaluate the classification efficiency of SAVE. RESULTS: The SAVE testis-sparing score includes size (tumor size as maximal diameter), available testicular tissue volume, volume ratio of the tumor to the testis, and the exophytic / endophytic properties of the tumor. The SAVE scoring system accurately classified the suitability of TSS based on the complexity of benign testicular tumors. CONCLUSION: The SAVE score is a reproducible and robust tool for quantitatively describing the anatomical characteristics of benign testicular tumors and guide the preoperative evaluation of TSS.

Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling.

The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14-3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer. SIGNIFICANCE: PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.

Occurrence and potential release of heavy metals in female underwear manufactured in China: Implication for women's health.

Underwear is a potential source of women's exposure to heavy metals owing to its direct contact with the skin, especially the skin of the vagina and vulva, which has a strong absorptive capacity. However, information regarding the prevalence of metals in female underwear, and its potential hazards, remains scarce. In the present study, we examined the concentrations and potential release of Cr, Co, Ni, Cu, As, Cd, Sb, and Pb in brassieres and briefs manufactured in China. We detected higher levels of Pb and moderate levels of other metals, relative to the metal levels reported for other textiles in the literature. Cu, As, Ni and Cd, had higher migration rates (MRs) from the underwear, with medians of 100%, 100%, 30.1%, and 20.7%, respectively. The median MRs of the other metals were in the range 1.07%-15.7%. On the whole, the total and extractable concentrations of these metals differed by item and fabric type. The pollution of raw materials and the use of chemical additives containing metals commonly contributed to the metals in the underwear. On the basis of the exposure estimation, the non-carcinogenic risks posed by the underwear metals were acceptable, but the carcinogenic risks from the metals in 5.18% of brassiere samples exceeded the acceptable level.