Evaluation of the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin, and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer: A study protocol of prospective single-center, randomized controlled and open label clinical trial (RNPLS-01).

Objective: Ramucirumab is a VEGFR2 antagonist. The aim of this trial is to evaluate the efficacy and safety of ramucirumab combined with nab-paclitaxel, lobaplatin and S-1 in neoadjuvant and conversion therapy for advanced gastric cancer. Methods: and analysis: This study is a prospective single-center, randomized controlled and open label clinical study, enrolling a total of 140 patients with advanced gastric cancer distributed across two distinct cohorts (Cohort A n = 70; Cohort B n = 70). The central focus of the study lies in evaluating the pathological complete response (pCR) of the cancer post-neoadjuvant or conversion therapy. Secondary endpoints encompass the assessment of the R0 resection rate subsequent to the aforementioned therapies, the occurrence of adverse events (AE), progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the total response rate and its duration, the disease control rate (DCR), and the duration of overall response (DOR). Ethics: Ethics approval has been obtained from the Ethics Committee at the First Affiliated Hospital (Xijing Hospital) of Air force Military Medical University (KY20232220-F-1). Trial registration: This trial has been registered at the ClinicalTrials.gov: NCT06169410 (registration date: December 5, 2023).

Human amniotic mesenchymal stem cells inhibit immune rejection injury from allogeneic mouse heart transplantation: A preliminary study on the microRNA expression.

BACKGROUND: Mesenchymal stem cell therapy is a new treatment for immune rejection in heart transplantation. The aim of this paper is to investigate the effect of human amniotic mesenchymal stem cells (hAMSCs) on alleviating immune rejection of allogeneic heart transplantation in mice and its possible underlying mechanism. METHODS: We injected hAMSCs into cervical ectopic heart transplantation model mice via tail vein to observe the survival time, the pathological changes of donor myocardium, and the fluorescent distribution of hAMSCs after the transplantation. MicroRNAs (miRs) with significantly differential expression were obtained by RNA sequencing and bioinformatic analysis, and a dual luciferase reporter gene assay together with real-time quantitative PCR (qRT-PCR) was performed to verify the relationship between miRs and their targeting genes. RESULTS: The intervention of hAMSCs prolonged the graft survival time and alleviated the pathological damage of the donor heart. The injected hAMSCs were distributed mainly in the liver, spleen, and kidney, only a very small portion in the donor and recipient hearts. In the allogeneic transplantation models, the expression of miR-34b-5p significantly increased after hAMSC treatment. MiR-34b-5p showed a knockdown effect on gene Fc gamma receptor 2B (FCGR2B). CONCLUSIONS: hAMSCs can reduce the immune rejection injury after allogeneic heart transplantation. This effect may be associated with the upregulation of miR-34b-5p expression to knock down its targeting gene FCGR2B.

Risk factors of early disease progression and decreased survival for multiple myeloma patients after upfront autologous stem cell transplantation.

Multiple myeloma (MM) stands as the second most prevalent hematological malignancy, constituting approximately 10% of all hematological malignancies. Current guidelines recommend upfront autologous stem cell transplantation (ASCT) for transplant-eligible MM patients. This study seeks to delineate factors influencing post-ASCT outcomes in MM patients. Our cohort comprised 150 MM patients from Taipei Veterans General Hospital, with progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint. A Cox proportional hazards model was employed to discern potential predictive factors for survival. ASCT age ≥ 65 (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.08-3.47) and the presence of extramedullary disease (HR 2.53, 95% CI 1.53-4.19) negatively impacted PFS. Conversely, treatment response ≥ VGPR before ASCT (HR 0.52, 95% CI 0.31-0.87) and total CD34+ cells collected ≥ 4 × 106 cells/kg on the first stem cell harvesting (HR 0.52, 95% CI 0.32-0.87) were positively associated with PFS. For OS, patients with ISS stage III (HR 2.06, 95% CI 1.05-4.04), the presence of extramedullary disease (HR 3.92, 95% CI 2.03-7.58), light chain ratio ≥ 100 before ASCT (HR 7.08, 95% CI 1.45-34.59), post-ASCT cytomegalovirus infection (HR 9.43, 95% CI 3.09-28.84), and a lower conditioning melphalan dose (< 140 mg/m2; HR 2.75, 95% CI 1.23-6.17) experienced shorter OS. In contrast, post-ASCT day + 15 absolute monocyte counts (D15 AMC) > 500/µl (HR 0.36, 95% CI 0.17-0.79) and post-ASCT day + 15 platelet counts (D15 PLT) > 80,000/µl (HR 0.48, 95% CI 0.24-0.94) were correlated with improved OS. Significantly, early PLT and AMC recovery on day + 15 predicting longer OS represents a novel finding not previously reported. Other factors also align with previous studies. Our study provides real-world insights for post-ASCT outcome prediction beyond clinical trials.

SEL1L3 as a link molecular between renal cell carcinoma and atherosclerosis based on bioinformatics analysis and experimental verification.

BACKGROUND: Renal cancer, the most common type of kidney cancer, develops in the renal tubular epithelium. Atherosclerosis of the aorta is the primary cause of atherosclerosis. However, the underlying mechanisms remain unclear. METHODS: The renal clear cell carcinoma RNA sequence profile was obtained from The Cancer Genome Atlas (TCGA) database, and the atherosclerosis datasets GSE28829 and GSE43292 based on GPL570 and GPL6244 was obtained from the Gene Expression Omnibus (GEO) database. The difference and hub genes were identified by the Limma protein-protein interaction (PPI) network in R software. Functional enrichment, survival, and immunoinfiltration analyses were performed. The role of SEL1L3 in the ErbB/PI3K/mTOR signaling pathway, apoptosis, invasion, cell cycle, and inflammation was analyzed using western blotting. RESULTS: 764 DEGs were identified from TCGA Kidney Renal Clear Cell Carcinoma (KIRC) dataset. A total of 344 and 117 DEGs were screened from the GSE14762 and GSE53757 datasets, respectively. Functional enrichment analysis results primarily indicated enrichment in the transporter complex, DNA-binding transcription activator activity, morphogenesis of the embryonic epithelium, stem cell proliferation, adrenal overactivity and so on. Fifteen common DEGs overlapped among the three datasets. The PPI network revealed that SEL1L3 was the core gene. Survival analysis showed that lower SEL1L3 expression levels led to a worse prognosis. Immune cell infiltration analysis showed that SEL1L3 expression was significantly correlated with antibody-drug conjugates (aDC), B cells, eosinophils, interstitial dendritic cells (iDC), macrophages, and more. CONCLUSIONS: SEL1L3 plays an important role in renal clear cell carcinoma and atherosclerosis and may be a potential link between them.

KIF20A as a potential biomarker of renal and bladder cancers based on bioinformatics and experimental verification.

BACKGROUND: Bladder cancer (BC) is a malignant tumor that occurs in the bladder wall and often appears in elderly individuals. Renal cancer (RC) arises from the renal tubular epithelium, but its molecular mechanism remains unclear. METHODS: We downloaded RC datasets (GSE14762 and GSE53757) and a BC dataset (GSE121711) to screen differentially expressed genes (DEGs). We also performed weighted gene coexpression network analysis (WGCNA). We created a protein-protein interaction (PPI) network and performed functional enrichment analysis, such as gene set enrichment analysis (GSEA). Heatmaps were made for gene expression. Survival analysis and immunoinfiltration analysis were performed. Comparative toxicogenomics database (CTD) analysis was performed to find the relationship between disease and hub genes. Western blotting was performed to verify the role of KIF20A in apoptosis. RESULTS: A total of 764 DEGs were identified. The GSEA showed that the DEGs were mainly enriched in organic acid metabolism, drug metabolism, mitochondria, and metabolism of cysteine and methionine. The PPI network in GSE121711 showed that KIF20A was a hub gene of renal clear cell carcinoma. Where the expression level of KIF20A was higher, the prognosis of patients was worse. CTD analysis showed that KIF20A was associated with inflammation, proliferation, and apoptosis. KIF20A expression in the RC group was upregulated, as shown by western blotting. The core proteins (including pRB Ser 780, CyclinA, E2F1, CCNE1, and CCNE2) in the pRB Ser 780/CyclinA signaling pathway were also upregulated in the RC group. CONCLUSIONS: KIF20A might be a novel biomarker for researching renal and bladder cancers.

Development and validation of a prognostic nomogram for gastrointestinal stromal tumors in the postimatinib era: A study based on the SEER database and a Chinese cohort.

BACKGROUND: After the standardization, recording and follow-up of imatinib use that significantly prolongs survival of gastrointestinal stromal tumors (GISTs), a comprehensive reassessment of the prognosis of GISTs is necessary and more conductive to treatment options. METHODS: A total of 2185 GISTs between 2013 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database and comprised our training (n = 1456) and internal validation cohorts (n = 729). The risk factors extracted from univariate and multivariate analyses were used to establish a predictive nomogram. The model was evaluated and tested in the validation cohort internally and in 159 patients with GIST diagnosed between January 2015 and June 2017 in Xijing Hospital externally. RESULTS: The median OS was 49 months (range, 0-83 months) in the training cohort and 51 months (0-83 months) in the validation cohort. The concordance index (C-index) of the nomogram was 0.777 (95% CI, 0.752-0.802) and 0.7787 (0.7785, bootstrap corrected) in training and internal validation cohorts, respectively, and 0.7613 (0.7579, bootstrap corrected) in the external validation cohort. Receiver operating characteristic curves and calibration curves for 1-, 3-, and 5-year overall survival (OS) showed a high degree of discrimination and calibration. The area under the curve showed that the new model performed better than the TNM staging system. In addition, the model could be dynamically visualized on a webpage. CONCLUSION: We developed a comprehensive survival prediction model for assessing the 1-, 3- and 5-year OS of patients with GIST in the postimatinib era. This predictive model outperforms the traditional TNM staging system and sheds light on the improvement of the prognostic prediction and the selection of treatment strategies for GISTs.

Foot-and-Mouth Disease Virus Induces Porcine Gasdermin E-Mediated Pyroptosis through the Protease Activity of 3Cpro.

Foot-and-mouth disease (FMD) is an acute, highly contagious disease of cloven-hoofed animals caused by FMD virus (FMDV). Currently, the molecular pathogenesis of FMDV infection remains poorly understood. Here, we demonstrated that FMDV infection induced gasdermin E (GSDME)-mediated pyroptosis independent of caspase-3 activity. Further studies showed that FMDV 3Cpro cleaved porcine GSDME (pGSDME) at the Q271-G272 junction adjacent to the cleavage site (D268-A269) of porcine caspase-3 (pCASP3). The inhibition of enzyme activity of 3Cpro failed to cleave pGSDME and induce pyroptosis. Furthermore, overexpression of pCASP3 or 3Cpro-mediated cleavage fragment pGSDME-NT was sufficient to induce pyroptosis. Moreover, the knockdown of GSDME attenuated the pyroptosis caused by FMDV infection. Our study reveals a novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the pathogenesis of FMDV and the design of antiviral drugs. IMPORTANCE Although FMDV is an important virulent infectious disease virus, few reports have addressed its relationship with pyroptosis or pyroptosis factors, and most studies focus on the immune escape mechanism of FMDV. GSDME (DFNA5) was initially identified as being associated with deafness disorders. Accumulating evidence indicates that GSDME is a key executioner for pyroptosis. Here, we first demonstrate that pGSDME is a novel cleavage substrate of FMDV 3Cpro and can induce pyroptosis. Thus, this study reveals a previously unrecognized novel mechanism of pyroptosis induced by FMDV infection and might provide new insights into the design of anti-FMDV therapies and the mechanisms of pyroptosis induced by other picornavirus infections.

Prognostic value of circWWC3 as a novel survival­related biomarker for clear cell renal cell carcinoma.

The aim of the present study was to assess the prognostic value of circular RNA WW and C2 domain-containing protein 3 (circWWC3) in patients with clear cell renal cell carcinoma (ccRCC). The clinicopathological data were collected for patients with ccRCC treated between January 1, 2012, and February 31, 2014, at The Fourth Hospital of Hebei Medical University Hospital (Shijiazhuang, China). A total of 150 patients who underwent nephrectomy were included in the study. Analysis of stored tissues and long-term follow-up data was performed. Fluorescence in situ hybridization was used to detect the relative circWWC3 expression in fresh-frozen cancerous and adjacent para-cancerous tissue samples from patients with ccRCC. A χ2 test was used to analyze the association between circWWC3 expression levels and the clinicopathological parameters of the patients. A Cox proportional risk regression model was used to analyze the clinical factors affecting patient prognosis. The survival curve was plotted using the Kaplan-Meier method, and the association between circWWC3 expression levels and patient survival status was tested using the log-rank test. circWWC3 expression in cancerous tissues was higher than that in the adjacent normal tissues. Additionally, circWWC3 expression was significantly associated with T stage (P=0.005) and pathological grade (P=0.033). Univariate Cox regression analysis showed that overall survival (OS) was associated with T stage, pathological Fuhrman grade and circWWC3 expression levels (all P<0.05). Multivariate Cox regression analysis also yielded similar results in patients with ccRCC (P<0.05). Moreover, the OS time of patients with high circWWC3 expression was significantly shorter than that of patients with low circWWC3 expression. In conclusion, high circWWC3 expression is an independent risk factor affecting patient prognosis, and is expected to be an important prognostic biomarker and novel therapeutic target for patients with ccRCC.

Role of CCT4/ErbB signaling in nephroblastoma: Implications for a biomarker of Wilms tumor.

Wilms tumor is a common abdominal malignant tumor in children. However, the molecular mechanism of Wilms tumor is unclear. GSE66405 and GSE197047 were obtained from the Gene Expression Omnibus database. To identify differentially expressed genes (DEGs) in Wilms tumor, the R package "limma" was used. Weighted gene co-expression network analysis was performed to identify the significant module. The list of DEGs was input into the Search Tool for the Retrieval of Interacting Genes database to construct a protein-protein interaction network for predicting core genes. Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes analysis are computational methods for assessing gene function and biological pathways. The genome was analyzed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes and developed by gene set enrichment analysis. Comparative Toxicogenomics Database analysis was performed to find the diseases most related to the core genes. TargetScan was used to screen for miRNAs that regulate hub genes. A total of 925 DEGs were identified. The differently expressed genes were mainly enriched in the metabolic pathway, AMPK signaling pathway, ErbB signaling pathway, mRNA detection pathway, and folded protein binding. A total of 16 core genes (HNRNPK, PABPC1, HNRNPD, NCL, YBX1, EIF4G1, KHDRBS1, HNRNPAB, HSPA4, EEF2, HSP90AA1, EEF1A1, A TP5A1, SDHA, CCT4, CCT5) were obtained. chaperonin containing TCP-1 subunit 4 (CCT4) was downregulated in tumor tissue samples, which may have reverse regulatory significance for Wilms tumor. CCT4, HSP90AA1, NCL, PABPC1, and YBX1 were found to be associated with kidney disease, acute kidney injury, edema, tumor metastasis, transitional cell carcinoma, necrosis, and inflammation. The research found that the related miRNA of the CCT4 gene was hsamiR-7-5p. CCT4 might play an essential role in the occurrence and development of Wilms tumor, and they may participate in the occurrence and development of Wilms tumor through the ERBB signal pathway. CCT4 may be a promising biomarker of Wilms tumor.

mRNA decoding in human is kinetically and structurally distinct from bacteria.

In all species, ribosomes synthesize proteins by faithfully decoding messenger RNA (mRNA) nucleotide sequences using aminoacyl-tRNA substrates. Current knowledge of the decoding mechanism derives principally from studies on bacterial systems1. Although key features are conserved across evolution2, eukaryotes achieve higher-fidelity mRNA decoding than bacteria3. In human, changes in decoding fidelity are linked to ageing and disease and represent a potential point of therapeutic intervention in both viral and cancer treatment4-6. Here we combine single-molecule imaging and cryogenic electron microscopy methods to examine the molecular basis of human ribosome fidelity to reveal that the decoding mechanism is both kinetically and structurally distinct from that of bacteria. Although decoding is globally analogous in both species, the reaction coordinate of aminoacyl-tRNA movement is altered on the human ribosome and the process is an order of magnitude slower. These distinctions arise from eukaryote-specific structural elements in the human ribosome and in the elongation factor eukaryotic elongation factor 1A (eEF1A) that together coordinate faithful tRNA incorporation at each mRNA codon. The distinct nature and timing of conformational changes within the ribosome and eEF1A rationalize how increased decoding fidelity is achieved and potentially regulated in eukaryotic species.

Surface TREM2 on circulating M-MDSCs as a novel prognostic factor for adults with treatment-naïve diffuse large B-cell lymphoma.

INTRODUCTION: Circulating monocytic myeloid-derived suppressive cells (M-MDSCs) are implicated as a poor prognostic factor and cause CAR T-cell failure in diffuse large B-cell lymphoma (DLBCL). Triggering receptors expressed on myeloid cells 2 (TREM2) are a transmembrane glycoprotein that polarize macrophages to anti-inflammation phenotype but have never been explored on M-MDSCs. This study aims to elucidate the expression and clinical impact of surface TREM2 on circulating M-MDSCs derived from DLBCL adults. METHODS: This prospective, observational study enrolled 100 adults with newly diagnosed and treatment-naïve DLBCL from May 2019 to October 2021. Human circulating M-MDSCs were obtained from freshly isolated peripheral blood, and each patient's surface-TREM2 level on M-MDSCs was normalized via a healthy control at the same performance of flow-cytometry analysis. Murine MDSCs derived from bone marrow (BM-MDSCs) were adopted to assess the link between Trem2 and cytotoxic T lymphocytes. RESULTS: More circulating M-MDSCs at diagnosis of DLBCL predicted worse progression-free (PFS) and overall survival (OS). Patients with higher IPI scores, bone marrow involvement, or lower absolute counts of CD4+ or CD8+ T cells in PB had significantly higher normalized TREM2 levels on M-MDSCs. Additionally, normalized TREM2 levels on M-MDSCs could be grouped into low (< 2%), medium (2-44%), or high (> 44%) levels, and a high normalized TREM2 level on M-MDSCs was proven as an independent prognostic factor for both PFS and OS via multivariate Cox regression analysis and associated with worst PFS and OS. Interestingly, normalized levels of surface TREM2 on M-MDSCs were negatively associated with absolute counts of PB CD8+ T cells and positively correlated with levels of intracellular arginase 1 (ARG1) within M-MDSCs. Wild-type BM-MDSCs had significantly higher mRNA levels of Arg1 and showed more prominent ability to suppress the proliferation of co-cultured CD8+ T cells than BM-MDSCs from Trem2 knockout mice, and the suppressive ability could be impaired by adding Arg1 inhibitors (CB1158) or supplementing L-arginine. CONCLUSION: In treatment-naïve DLBCL adults, a high surface-TREM2 level on circulating M-MDSCs is a poor prognostic factor for both PFS and OS and warrants further investigation for its potential as a novel target in immunotherapy.

Risk Factors and Outcomes of Stem Cell Mobilization Failure in Multiple Myeloma Patients.

Introduction: Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment for patients with multiple myeloma (MM), and adequate stem cell collection must be assured before ASCT. However, prediction of poor mobilizers (PMs) is still difficult despite several risk factors for mobilization failure having been identified. Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan who underwent stem cell collection between October 2006 and August 2020. A CD34+ cell collection of <1 × 106 cells/kg was defined as a mobilization failure. The primary endpoint was mobilization failure. The secondary endpoint was overall survival (OS). Odds ratios (ORs) and 95% confidence intervals (CIs) for mobilization failure were calculated using a logistic regression model. The cumulative incidence of mortality was estimated using the Kaplan-Meier method. Results: In the multivariate analysis, absolute monocyte count <500/µL (adjusted OR 10.75, 95% CI: 1.82-63.57, p = 0.009), platelet count <150,000/µL (adjusted OR 12.49, 95% CI: 2.65-58.89, p = 0.001) before mobilization, and time interval from diagnosis to stem cell harvest ≥180 days (adjusted OR 7.69, 95% CI: 1.61-36.87, p = 0.011) were risk factors for PMs. PM patients had poorer OS compared to patients with successful stem cell collection in the univariate analysis (log-rank test p = 0.027). The predicted probability of PMs was estimated by the multiple logistic regression model with a sensitivity of 84.6% and a specificity of 84.0%. Conclusion: Absolute monocyte count <500/µL, platelet count <150,000/µL, and treatment duration more than 180 days before stem cell mobilization are risk factors for unsuccessful stem cell collection. Our prediction models have high sensitivity and specificity for mobilization failure prediction and allow for early interventions for possible PMs.

Long-term outcomes of frontline intensification in primary CNS lymphoma: A real-world single-center experience.

BACKGROUND: Frontline intensification (including consolidative whole-brain radiotherapy or high-dose chemotherapy with autologous stem-cell transplantation after induction therapy) has been proposed to treat primary central nervous system lymphoma (PCNSL). However, no prospective randomized trials have answered whether frontline intensification can offer a survival benefit to PCNSL patients. We aim to clarify the outcomes and survival influence of frontline intensification on real-world patients with different risk-stratified PCNSLs. METHODS: Between January 2003 and December 2016, 110 PCNSL adults were retrospectively included, and 76 patients achieved at least PR after induction therapy, including 38 patients who received frontline intensification. The median follow-up with the 31 survivors was 7.52 years. RESULTS: Of the 38 induction-completed patients who had not received frontline intensification, 95% achieved post-induction therapy CR/CRu; however, all inevitably recurred. In the 38 who received frontline intensification, CR/CRu improved from 45% (pre-frontline intensification) to 84% (post-frontline intensification), and they achieved significantly better PFS (non-reach vs. 522 days, p < 0.001) and OS (non-reach vs. 899 days, p < 0.001). Additionally, patients had similar PFS and OS rates when receiving HDC-ASCT and/or WBRT as frontline intensification. Frontline intensification significantly improved PFS and OS survival in higher-risk patients (intermediate/high IELSG risk, MSKCC group 2/3, or Nottingham/Barcelona score ≥ 2 points) but did not improve OS in lower-risk patients. Among the 38 patients who received frontline intensification, two had treatment-related mortality; 14 recurred after frontline intensification. MTX-based chemotherapy was the main salvage modality, and the median OS was 295 days after recurrence. Progressive disease and infection (especially pneumonia) are two major causes of mortality in patients who receive frontline intensification. CONCLUSIONS: When achieving CR/CRu/PR after induction chemotherapy, frontline intensification should be adopted to improve PFS and OS in real-world PCNSL patients, especially higher-risk patients.

Prognostic factors in patients with bone marrow hemophagocytosis and its association with hematologic malignancies.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted.

Herpes zoster prophylaxis: Essential for treating newly diagnosed multiple myeloma patients.

BACKGROUND: Multiple myeloma (MM) is known for its immune disturbance and patients suffering from MM are thus vulnerable to opportunistic infections, including herpes zoster (HZ). As HZ infection remarkably affects patients' quality of life and poses huge economic burdens on the health system, we aim to identify the risk factors of HZ infection and evaluate the effects of different dosages, types, and durations of anti-HZ prophylaxis drugs to prevent HZ infection. METHODS: 551 MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2009 and August 31, 2021 were restrospectively analyzed. The patients' baseline characteristics were recorded. The primary endpoint of the study was the incidence of HZ infection among the studied patient population. Due to the lack of cost coverage from Taiwanese public health insurance on HZ prophylaxis drugs, the use of anti-HZ drugs mainly depends on physicians' preferences and patients' choices. RESULTS: In our study, prophylaxis was given to 283 of the patients. In the multivariate analysis, we included non-prophylaxis, age ≥ 60, corrected serum calcium ≥12 mg/dl, serum creatinine ≥2 mg/dl, serum ß2-microglobulin ≥5500 mg/L, autologous stem cell transplant (SCT), and allogeneic SCT for analysis. Our results demonstrated that the non-prophylaxis group (HR: 2.37, 95% CI 1.57-3.57) and patients receiving autologous SCT (HR: 2.22, 95% CI 1.28-3.86) and allogeneic SCT (HR: 5.12, 95% CI 1.13-23.22) had higher risk of HZ infection. The difference in dosage and types of anti-HZ drugs showed similar protective effects. In patients who stopped anti-HZ prophylaxis before active cancer-related treatment, a higher risk of getting HZ infection compared to the corresponding group was also observed (adjusted HR 3.09, 95% CI 1.35-7.07, p = 0.008). CONCLUSIONS: We concluded that MM patients should receive HZ prophylaxis drugs while receiving active cancer-related treatment. Patients receiving SCT are also at high risk of getting HZ infection, even under prophylaxis.

PLK1 as one novel target for the poor prognosis of bladder cancer: An observational study.

Bladder cancer (BC) is one of the most common male malignant tumors and the most common urological tumor. However, the molecular mechanism and role of PLK1 on bladder cancer were unclear. Therefore, the study aims to explore the potential part of the overall survival of bladder cancer through bioinformatics analysis. GSE121711 and GSE130598, from the Gene Expression Omnibus database. The GEO2R screened differently expressed genes, and DAVID and Metascape were used for functional annotation. The cytoHubba made hub genes identification and expression. A total of 50 BC participants were recruited. After surgery, 50 BC tumor samples from BC patients and 50 adjacent standard bladder tissue samples were obtained. The RT-qPCR assay was performed to verify the expression of hub genes. The Kaplan-Meier Plotter analyzed the effect of hub gene expression for overall survival of BC. The compulsory module of Molecular Complex Detection tool analysis was shown, which included CDK1, TTK, AURKB, MELK, PLK1, and BUB1. And the six hub genes were up-regulated in the BC compared with the normal tissues. The relative expression levels of CDK1, TTK, AURKB, MELK, PLK1, and BUB1 were significantly higher in BC samples compared with the regular kidney tissue groups. The result demonstrated that CDK1, TTK, AURKB, MELK, PLK1, and BUB1 might be considered biomarkers for BC. Overall survival analysis showed that BC patients with high expression level of PLK1 had poorer overall survival times than those with low expression level (P < .05). The expression levels of CDK1, TTK, AURKB, MELK, and BUB1 was not related to the overall survival of BC patients (P > .05). The PLK1 gene might provide new ideas and evidence for bladder cancer research.

Synthesis and single-molecule imaging reveal stereospecific enhancement of binding kinetics by the antitumour eEF1A antagonist SR-A3.

Ternatin-family cyclic peptides inhibit protein synthesis by targeting the eukaryotic elongation factor-1α. A potentially related cytotoxic natural product ('A3') was isolated from Aspergillus, but only 4 of its 11 stereocentres could be assigned. Here, we synthesized SR-A3 and SS-A3-two out of 128 possible A3 epimers-and discovered that synthetic SR-A3 is indistinguishable from naturally derived A3. Relative to SS-A3, SR-A3 exhibits an enhanced residence time and rebinding kinetics, as revealed by single-molecule fluorescence imaging of elongation reactions catalysed by eukaryotic elongation factor-1α in vitro. An increased residence time-stereospecifically conferred by the unique ß-hydroxyl in SR-A3-was also observed in cells. Consistent with its prolonged duration of action, thrice-weekly dosing with SR-A3 led to a reduced tumour burden and increased survival in an aggressive Myc-driven mouse lymphoma model. Our results demonstrate the potential of SR-A3 as a cancer therapeutic and exemplify an evolutionary mechanism for enhancing cyclic peptide binding kinetics via stereospecific side-chain hydroxylation.

KIF11: A potential prognostic biomarker for predicting bone metastasis-free survival of prostate cancer.

Most prostate cancer (PCa) cases remain indolent with a relatively good prognosis. However, bone metastasis of PCa can quickly worsen prognoses and lead to mortality. Metastasis-free survival (MFS), a strong surrogate for overall survival, is widely used in PCa prognosis research. The present study identified molecules that affect bone MFS in PCa, with clinical validation. Three datasets (GSE32269, GSE74367 and GSE77930) were downloaded from the Gene Expression Omnibus database. Hub genes most relevant to clinical traits (bone metastasis-associated morbidity) were identified by weighted gene co-expression network analysis (WGCNA) and subjected to logistic regression analysis. Patient samples were obtained between January 2014 and December 2016, with a clinically annotated follow-up in December 2021. Clinical data and follow-up information for 60 patients with PCa were used in MFS analysis. Tumor samples were retrieved, and immunohistochemistry was performed to detect vascular endothelial growth factor (VEGF). The prognostic potential of the two molecules was assessed using Cox proportional hazards regression analysis. A total of 16 gene modules were obtained via WGCNA, and the tan module, containing 147 genes, was most closely linked to bone metastasis. In total, 877 differentially expressed genes (DEGs) were detected. The DEG-tan module intersection yielded seven hub genes [BUB1, kinesin family member (KIF)2C, RACGAP1, CENPE, KIF11, TTK and KIF20A]. Using univariate and multivariate logistic regression analyses for independent risk factors of bone metastasis, KIF11 and VEGF were found to be significantly associated with a higher T stage, prostate-specific antigen level and Gleason score. In addition, KIF11 and VEGF expression levels were positively correlated (P<0.001). Using univariate Cox analysis, KIF11 and VEGF were found to exhibit a significant association with poor MFS (P<0.05). However, only KIF11 was significantly associated with MFS upon multivariate analysis (P=0.007; hazard ratio, 2.776; 95% confidence interval, 1.315-5.859). Markers of bone metastasis in PCa were identified. Overall, KIF11 is an independent indicator that can predict bone metastasis for patients with PCa, which could be used to guide clinical practice.

Porcine Sapelovirus 3Cpro Inhibits the Production of Type I Interferon.

Porcine sapelovirus (PSV) is the causative pathogen of reproductive obstacles, acute diarrhea, respiratory distress, or severe polioencephalomyelitis in swine. Nevertheless, the pathogenicity and pathogenic mechanism of PSV infection are not fully understood, which hinders disease prevention and control. In this study, we found that PSV was sensitive to type I interferon (IFN-ß). However, PSV could not activate the IFN-ß promoter and induce IFN-ß mRNA expression, indicating that PSV has evolved an effective mechanism to block IFN-ß production. Further study showed that PSV inhibited the production of IFN-ß by cleaving mitochondrial antiviral signaling (MAVS) and degrading melanoma differentiation-associated gene 5 (MDA5) and TANK-binding kinase 1 (TBK1) through viral 3Cpro. In addition, our study demonstrated that PSV 3Cpro degrades MDA5 and TBK1 through its protease activity and cleaves MAVS through the caspase pathway. Collectively, our results revealed that PSV inhibits the production of type I interferon to escape host antiviral immunity through cleaving and degrading the adaptor molecules.

Identifying the Cellular Target of Cordyheptapeptide A and Synthetic Derivatives.

Cordyheptapeptide A is a lipophilic cyclic peptide from the prized Cordyceps fungal genus that shows potent cytotoxicity in multiple cancer cell lines. To better understand the bioactivity and physicochemical properties of cordyheptapeptide A with the ultimate goal of identifying its cellular target, we developed a solid-phase synthesis of this multiply N-methylated cyclic heptapeptide which enabled rapid access to both side chain- and backbone-modified derivatives. Removal of one of the backbone amide N-methyl (N-Me) groups maintained bioactivity, while membrane permeability was also preserved due to the formation of a new intramolecular hydrogen bond in a low dielectric solvent. Based on its cytotoxicity profile in the NCI-60 cell line panel, as well as its phenotype in a microscopy-based cytological assay, we hypothesized that cordyheptapeptide was acting on cells as a protein synthesis inhibitor. Further studies revealed the molecular target of cordyheptapeptide A to be the eukaryotic translation elongation factor 1A (eEF1A), a target shared by other lipophilic cyclic peptide natural products. This work offers a strategy to study and improve cyclic peptide natural products while highlighting the ability of these lipophilic compounds to effectively inhibit intracellular disease targets.