SENP1 knockdown potentiates the apoptosis, cell cycle arrest, and reduces cisplatin resistance of diffuse large B cell lymphoma cells via inducing ferroptosis.

Ferroptosis has been regarded as a critical event in the process of diffuse large B cell lymphoma (DLBCL). Sentrin-specific protease 1 (SENP1) has emerged as an oncogene in multiple human malignancies. The present work was to investigate the effects of SENP1 on the progression of DLBCL and the possible regulatory mechanism involving ferroptosis. SENP1 expression in DLBCL tissues, parental and cisplatin-resistant DLBCL cells were, respectively, tested by GEPIA database, RT-qPCR, and Western blot. Cell viability was estimated via CCK-8 assay. Flow cytometry analysis estimated cell apoptosis and cycle. Western blot examined the expression of apoptosis-, cell cycle-, and ferroptosis-associated proteins. TBARS assay and BODIPY 581/591 C11 probe measured lipid peroxidation. Related assay kit assessed total iron levels. CCK-8 and flow cytometry evaluated cisplatin resistance. SENP1 expression was raised in DLBCL tissues and cells. SENP1 knockdown reduced cell viability, boosted cell apoptosis, cell cycle arrest, and elevated cisplatin sensitivity in DLBCL. SENP1 depletion drove the ferroptosis of both parental and cisplatin-resistant DLBCL cells and ferroptosis inhibitor Fer-1 reversed the influences of SENP1 inhibition on cell viability, apoptosis, cell cycle, and cisplatin resistance in DLBCL. Anyway, SENP1 absence might facilitate ferroptosis to obstruct the development of DLBCL and cisplatin resistance.

Cost-effectiveness of the combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer: a systematic review.

BACKGROUND: The combination of immunotherapy and chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC) was primarily carried out with a combination of immune checkpoint inhibitors (ICIs) and platinum-etoposide (EP). It is likely to be more effective in treating ES-SCLC than EP alone, but could result in high healthcare costs. The study aimed to investigate the cost-effectiveness of this combination therapy for ES-SCLC. METHODS: We searched literature from the following databases: PubMed, Embase, Cochrane Library, and Web of Science for studies on cost-effectiveness of immunotherapy combined with chemotherapy for ES-SCLC. The literature search period was up to April 20, 2023. The quality of the studies was evaluated using the Cochrane Collaboration's tool and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: A total of 16 eligible studies were included in the review. All studies met CHEERS recommendations, and all randomized controlled trials (RCTs) in these studies were rated as having low risk of bias using the Cochrane Collaboration's tool. The treatment regimens compared were ICIs plus EP or EP alone. All studies mainly used incremental quality-adjusted life year and incremental cost-effectiveness ratio as outcomes. Most ICIs plus EP treatment regimens were not cost-effective based on corresponding willingness-to-pay thresholds. CONCLUSIONS: Adebrelimab plus EP and serplulimab plus EP were probably cost-effective for ES-SCLC in China, and serplulimab plus EP was probably cost-effective for ES-SCLC in the U.S. Lowering the price of ICIs and selecting ES-SCLC patients who were sensitive to ICIs could improve the cost-effectiveness of the ICIs-combined treatment.

Colon cancer cells secreted CXCL11 via RBP-Jκ to facilitated tumour-associated macrophage-induced cancer metastasis.

Metastasis is the main cause of colon cancer-related deaths. RBP-Jκ is involved in colon cancer development, but its function in colon cancer metastasis is still unclear. Tumour-associated macrophages are the main cell components in tumour microenvironments. Here, we aimed to determine the function of RBP-Jκ in colon cancer metastasis and its underlying mechanisms for modulating interactions between colon cancer cell and tumour-associated macrophages. Through bioinformation analysis, we found that RBP-Jκ was overexpressed in colon cancer tissues and associated with advanced colon cancer phenotypes, macrophage infiltration and shorter survival overall as confirmed by our patients' data. And our patients' data show that RBP-Jκ expression and tumour-associated macrophages infiltration are associated with colon cancer metastasis and are independent prognostic factors for colon cancer patients. Tumour-associated macrophages induced colon cancer cell migration, invasion and epithelial-mesenchymal transition through secreting TGF-ß1. Colon cancer cells with high RBP-Jκ expression induced the expression of TGF-ß1 in tumour-associated macrophages by secreting CXCL11. Our research revealed that colon cancer cells secreted CXCL11 via overexpression of RBP-Jκ to enhance the expression of TGF-ß1 in tumour-associated macrophages to further promote metastasis of colon cancer cells.

De Novo Nano-Erythrocyte Structurally Braced by Biomimetic Au(I)-peptide Skeleton for MDM2/MDMX Predation toward Augmented Pulmonary Adenocarcinoma Immunotherapy.

In nature, cells rely on a structural framework called the "cytoskeleton" to maintain their shape and polarity. Based on this, herein a new class of cell-mimicking nanomedicine using bionic skeletons constituted by the oligomeric Au(I)-peptide complex is developed. The peptide function of degrading pathological MDM2 and MDMX is used to synthesize an oligomeric Au(I)-PMIV precursor capable of self-assembling into a clustered spherical bionic skeleton. Through coating by erythrocyte membrane, an erythrocyte-mimicking nano-cell (Nery-PMIV) is developed with depressed macrophage uptakes, increased colloidal stability, and prolonged blood circulation. Nery-PMIV potently restores p53 and p73 in vitro and in vivo by degrading MDM2/MDMX. More importantly, Nery-PMIV effectively augments antitumor immunity elicited by anti-PD1 therapy in a murine orthotopic allograft model for LUAD and a humanized patient-derived xenograft (PDX) mouse model for LUAD, while maintaining a favorable safety profile. Taken together, this work not only presents evidence showing that MDM2/MDMX degradation is a potentially viable therapeutic paradigm to synergize anti-PD1 immunotherapy toward LUAD carrying wild-type p53; it also suggests that cell-mimicking nanoparticles with applicable bionic skeletons hold tremendous promise in offering new therapies to revolutionize nanomedicine in the treatment of a myriad of human diseases.

Single cell RNA-seq data and bulk gene profiles reveal a novel signature of disease progression in multiple myeloma.

BACKGROUND: The development of multiple myeloma (MM) is considered to involve a multistep transformation process, but the role of cytogenetic abnormalities and molecular alterations in determining the cell fate of multiple myeloma (MM) remains unclear. Here, we have analyzed single cell RNA-seq data and bulk gene profiles to reveal a novel signature associated with MM development. METHODS: The scRNA-seq data from GSE118900 was used to profile the transcriptomes of cells from MM patients at different stages. Pseudotemporal ordering of the single cells was performed using Monocle package to feature distinct transcriptomic states of the developing MM cells. The bulk microarray profiles from GSE24080 and GSE9782 were applied to identify a signature associated with MM development. RESULTS: The 597 cells were divided into 7 clusters according to different risk levels. They were initiated mainly from monoclonal gammopathy of undetermined significance (MGUS), newly diagnosed MM (NDMM), or relapsed and/or refractory myeloma (RRMM) with cytogenetically favorable t(11;14), moved towards the cells from smoldering MM (SMM) or NDMM without t(11;14) or t(4;14), and then finally to cells from SMM or RRMM with t(4;14). Based on the markers identified in the late stage, the bulk data was used to develop a 20-gene signature stratifying patients into high and low-risk groups (GSE24080: HR = 3.759, 95% CI 2.746-5.145; GSE9782: HR = 2.612, 95% CI 1.894-3.603), which was better than the previously published gene signatures (EMC92, UAMS70, and UAMS17) and International Staging System. This signature also succeeded in predicting the clinical outcome of patients treated with bortezomib (HR = 2.884, 95% CI 1.994-4.172, P = 1.89e-8). The 20 genes were further verified by quantitative real-time polymerase chain reaction using samples obtained from the patients with MM. CONCLUSION: Our comprehensive analyses offered new insights in MM development, and established a 20-gene signature as an independent biomarker for MM.

Construction and Validation of a Novel Nomogram to Predict the Overall Survival of Patients With Combined Small Cell Lung Cancer: A Surveillance, Epidemiology, and End Results Population-Based Study.

INTRODUCTION: Combined small cell lung cancer (C-SCLC) represents a rare subtype of all small cell lung cancer cases, with limited studies investigated its prognostic factors. The aim of this study was to construct a novel nomogram to predict the overall survival (OS) of patients with C-SCLC. METHODS: In this retrospective study, a total of 588 C-SCLC patients were selected from the Surveillance, Epidemiology, and End Results database. The univariate and multivariate Cox analyses were performed to identify optimal prognostic variables and construct the nomogram, with concordance index (C-index), receiver operating characteristic curves, and calibration curves being used to evaluate its discrimination and calibration abilities. Furthermore, decision curve analysis (DCA), integrated discrimination improvement (IDI), and net reclassification index (NRI) were also adopted to assess its clinical utility and predictive ability compared with the classic TNM staging system. RESULTS: Seven independent predictive factors were identified to construct the nomogram, including T stage, N stage, M stage, brain metastasis, liver metastasis, surgery, and chemotherapy. We observed a higher C-index in both the training (.751) and validation cohorts (.736). The nomogram has higher area under the curve in predicting 6-, 12-, 18-, 24-, and 36-month survival probability of patients with C-SCLC. Meanwhile, the calibration curves also revealed high consistencies between the actual and predicted OS. DCA revealed that the nomogram could provide greater clinical net benefits to these patients. We found that the NRI for 6- and 12-month OS were .196 and .225, and the IDI for 6- and 12-month OS were .217 and .156 in the training group, suggesting that the nomogram can predict a more accurate survival probability. Similar results were also observed in the validation cohort. CONCLUSION: We developed and verified a novel nomogram that can help clinicians recognize high-risk patients with C-SCLC and predict their OS.

Tumor Mutation Burden, Immune Cell Infiltration, and Construction of Immune-Related Genes Prognostic Model in Head and Neck Cancer.

Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and the prognosis of HNSCC remains bleak. Numerous studies revealed that the tumor mutation burden (TMB) could predict the survival outcomes of a variety of tumors. Objectives: This study aimed to investigate the TMB and immune cell infiltration in these patients and construct an immune-related genes (IRGs) prognostic model. Methods: The expression data of 546 HNSCC patients were obtained from The Cancer Genome Atlas (TCGA) database. All patients were divided into high- and low- TMB groups, and the relationship between TMB and clinical relevance was further analyzed. The differentially expressed genes (DEGs) were identified using the R software package, limma. Functional enrichment analyses were conducted to identify the significantly enriched pathways between two groups. CIBERSORT algorithm was adopted to calculate the abundance of 22 leukocyte subtypes. The IRGs prognostic model was constructed via the multivariate Cox regression analysis. Results: Missense mutation and single nucleotide variants (SNV) were the most predominant mutation types in HNSCC. TP53, TTN, and FAT1 were the most frequently mutated genes. Patients with high TMB were observed with worse survival outcomes. The functional analysis of TMB associated DEGs showed that the identified DEGs mainly involved in spliceosome, RNA degradation, proteasome, and RNA polymerase pathways. We observed that macrophages, T cells CD8, and T cells CD4 memory were the most commonly infiltrated subtypes of immune cells in HNSCC. Finally, an IRGs prognostic model was constructed, and the AUC of the ROC curve was 0.635. Conclusions: Our results suggest that high TMB is associated with poor prognosis in HNSCC patients. The constructed model has potential prognostic value for the prognosis of these individuals, and it needs to be further validated in large-scale and prospective studies.

Vitamin D receptor gene polymorphism is associated with multiple myeloma.

OBJECTIVES: The aim of this study was to explore the Vitamin D receptor (VDR) gene polymorphism and its association with multiple myeloma (MM) development. METHODS: The peripheral blood of 40 MM cases and 84 healthy controls were collected. Polymerase chain reaction (PCR) and DNA sequencing were applied to detect VDR gene polymorphism (including: FokI, BsmI, ApaI, and TaqI). SHESIS biological information software was used to analyze genotypes, alleles, linkage disequilibrium (LD), haplotype distribution, and their association with MM. RESULTS: Compared with controls, the MM group had a significantly higher frequency of the A allele in BsmI site (8.7% vs 2.4%) and C allele in the TaqI site (10.5% vs 3.6%). These two alleles were closely associated with an increased risk of MM (P = .025; P = .030). The highly rare genotypes (BsmI-AA and TaqI-CC) were found in one patient with MM. CONCLUSION: VDR gene polymorphisms may be a molecular marker of MM risk.

Nosocomial infections due to multidrug-resistant bacteria in cancer patients: a six-year retrospective study of an oncology Center in Western China.

BACKGROUND: Bacterial infections are the most frequent complications in patients with malignancy, and the epidemiology of nosocomial infections among cancer patients has changed over time. This study aimed to evaluate the characteristics, antibiotic resistance patterns, and prognosis of nosocomial infections due to multidrug-resistant (MDR) bacteria in cancer patients. METHODS: This retrospective observational study analyzed cancer patients with nosocomial infections caused by MDR from August 2013 to May 2019. The extracted clinical data were recorded in a standardized form and compared based on the survival status of the patients after infection and during hospitalization. The data were analyzed using independent samples t-test, Chi-square test, and binary logistic regression. P-values < 0.05 were considered significant. RESULTS: One thousand eight patients developed nosocomial infections during hospitalization, with MDR strains detected in 257 patients. Urinary tract infection (38.1%), respiratory tract infection (26.8%), and bloodstream infection (BSI) (12.5%) were the most common infection types. Extended-spectrum ß-lactamase producing Enterobacteriaceae (ESBL-PE) (72.8%) members were the most frequently isolated MDR strains, followed by Acinetobacter baumannii (11.7%), and Stenotrophomonas maltophilia (6.2%). The results of multivariate regression analysis revealed that smoking history, intrapleural/abdominal infusion history within 30 days, the presence of an indwelling urinary catheter, length of hospitalization, and hemoglobin were independent factors for in-hospital mortality in the study population. The isolated MDR bacteria exhibited high rates of sensitivity to amikacin, meropenem, and imipenem. CONCLUSIONS: The burden of nosocomial infections due to MDR bacteria is considerably high in oncological patients, with ESBL-PE being the most predominant causative pathogen. Our findings suggest that amikacin and carbapenems actively against more than 89.7% of MDR isolates. The precise management of MDR bacterial infections in cancer patients may improve the prognosis of these individuals.

Clinical outcomes and prognostic factors in bloodstream infections due to extended-spectrum ß-lactamase-producing Enterobacteriaceae among patients with malignancy: a meta-analysis.

BACKGROUND: The colonization of Extended-spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) in bloodstream infections (BSIs) has been increased dramatically worldwide, and it was associated with worse clinical outcomes in patients with malignancy. We performed the meta-analysis to investigate the prognosis and risk factors in BSIs caused by ESBL-PE in oncological patients. METHODS: PubMed, EMBASE, and Cochrane Library were searched for related studies. All-cause mortality was considered as the primary outcome. Subgroup analyses, meta-regression analyses, and sensitivity analysis were used to investigate heterogeneity and reliability in results. RESULTS: 6,729 patients from 25 studies were eligible. Six studies enrolled oncological patients with BSIs caused by ESBL-PE only, while 19 studies both enrolled ESBL-PE and non-ESBL-PE infections. The results showed that BSIs caused by ESBL-PE in patients with malignancy was associated with higher mortality than non-ESBL-PE infections (RR = 2.21, 95% CI: 1.60-3.06, P < 0.001), with a significant between-study heterogeneity (I2 =78.3%, P < 0.001). Subgroup analyses showed that children (RR = 2.80, 95% CI: 2.29-3.43, P < 0.001) and hematological malignancy (RR = 3.20, 95% CI: 2.54-4.03, P < 0.001) were associated with a higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality. CONCLUSIONS: Our study identified that BSIs caused by ESBL-PE in patients with malignancy were associated with worse clinical outcomes compared with non-ESBL-PE infections. Furthermore, children and hematological malignancy were associated with higher mortality. Severe sepsis/ septic shock, pneumonia, and ICU admission were the most common predictors of mortality.

Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway.

Rab31 belongs to the Ras superfamily of small GTP-binding proteins, which has been found to regulate the vesicle transport from the Golgi apparatus to early and late endosomes. The investigation here detected the expression of Rab31 in 96 patients with hepatocellular carcinoma (HCC) and tried to identify its significance on outcome of HCCs after liver resection. By immunohistochemistry staining, it was found that Rab31 expression in HCC tissues was remarkably higher than that in adjacent liver tissues. Aberrant Rab31 overexpression in HCC tissues was identified to be associated with worse prognosis after liver resection. Univariate analysis showed that advanced tumor-nodes-metastasis (TNM) staging of HCC, intrahepatic metastases, portal vein invasion, and higher Rab31 were the predictive factors of poor prognosis. Multivariate analysis demonstrated that intrahepatic metastases and higher Rab31 were the independent prognostic factors. Furthermore, forced expression of Rab31 in Huh7 cells was found to promote cell growth via upregulation of Bcl-2/BAX ratio induced by PI3K/AKT. Correspondingly, silencing Rab31 induced cell apoptosis and in turn suppressed the growth capacity of MHCC97 cells in vitro. Taken together, this study provides the evidence of Rab31 overexpression in HCC, and Rab31 is potentially used as a novel biomarker of poor prognosis in patients with HCC. PI3K/AKT/Bcl-2/BAX axis was involved in Rab31-promoting HCC progression.

[Clinical Analysis of PEG-rhG-CSF in Mobilization of Autologous Hematopoietic Stem Cells in Hematological Tumors].

OBJECTIVE: To investigate the efficiency and optimal time of stem cell apheresis mobilized by pegylated recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) in autologous stem cell transplantation (ASCT) for hematological malignancies without monitoring pre-collection CD34+ cells. METHODS: Forty-six patients underwent stem cell mobilization were retrospectively analyzed between August 2017 and January 2022 at the First Affiliated Hospital of Fujian Medical University. 27 patients using high dose chemotherapy combined with PEG-rhG-CSF mobilization were enrolled in the PEG-rhG-CSF group, and other 19 patients mobilized with recombinant human granulocyte colony stimulating factor (G-CSF) were enrolled in G-CSF group. The mobilization and collection effects of the patients in two groups were compared. RESULTS: A total of 46 patients underwent 86 apheresis procedures, the median amount of mononuclear cell (MNC) in the PEG-rhG-CSF group and G-CSF group was 6.54（3.85-12.61）×108/kg and 6.15（1.13-11.58）×108/kg, respectively (P >0.05), the total CD34+ cells of the grafts were 11.44(1.33-65.02)×106/kg and 4.95(0.30-24.02)×106/kg (P < 0.05), with harvest timing of 14(10-20) days and 14(4-22) days, respectively (P >0.05). In the PEG-rhG-CSF group, there was a significant difference between the number of CD34+ cells collected when white blood cells (WBC) ≥10×109/L and WBC<10×109 /L, 19.04(2.85-65.02)×106/kg and 6.22(0.81-34.86)×106/kg, respectively (P < 0.05). CONCLUSION: Stem cells mobilization with PEG-rhG-CSF was highly efficient with a median mobilization time of 14 days. In the absence of peripheral blood CD34 monitoring, peripheral blood WBC≥10×109/L can be considered as a threshold for a single stem cell apheresis to collect sufficient stem cells.

Reversing MET-Mediated Resistance in Oncogene-Driven NSCLC by MET-Activated Wnt Condensative Prodrug.

The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR-mutant non-small-cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/ß-catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/ß-catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self-assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH-responsive peptide (Tyr-Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr-Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by ß-catenin,effectively overcoming acquired resistance to EGFR-TKIs caused by MET amplification in both cell line-derived and patient-derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/ß-catenin signaling pathway selectively, but also serves as an innovative example for pro-drug development through biologically responsive LLPS.

Advancing the Boundaries of Immunotherapy in Lung Adenocarcinoma with Idiopathic Pulmonary Fibrosis by a Biomimetic Proteinoid Enabling Selective Endocytosis.

The coexistence of lung adenocarcinoma (LUAD) with idiopathic pulmonary fibrosis (IPF), which has been extensively documented as a prominent risk factor for checkpoint inhibitor-related pneumonitis (CIP) in patients undergoing immunotherapy, has long been considered a restricted domain for the use of immune checkpoint inhibitors (ICIs). To overcome it, an approach was employed herein to specifically target PD-L1 within the cellular interior, surpassing the conventional focus solely on the cytomembrane, thereby facilitating the development of ICIs capable of distinguishing between LUAD cells and noncancerous cells based on their distinctive endocytic propensities. By exploiting the aurophilicity-driven self-assembly of a PD-L1 binding peptide (PDBP) and subsequently encapsulating it within erythrocyte membranes (EM), the resulting biomimetic ICIs protein EMS-PDBP exhibited extraordinary selectivity in internalizing LUAD cells, effectively targeting PD-L1 within cancer cells while hindering its membrane translocation. The EMS-PDBP treatment not only reactivated the antitumor immune response in the LUAD orthotopic allograft mouse model but also demonstrated a favorable safety profile by effectively eliminating any immune-related adverse events (irAEs). Most significantly, EMS-PDBP successfully and safely restored the antitumor immune response in a mouse model of LUAD with coexistent IPF, thus shattering the confines of ICIs immunotherapy. The reported EMS-PDBP collectively offers a potential strategy for immune reactivation to overcome the limitations of immunotherapy in LUAD coexisting with IPF.

Hydrogelation of peptides and carnosic acid as regulators of adaptive immunity against postoperative recurrence of cutaneous melanoma.

The in-situ activation of adaptive immunity at the surgical site has demonstrated remarkable efficacy in inhibiting various forms of tumour recurrence and even holds the promise of a potential cure. However, extensive research and bioinformatic analysis conducted in this study have unveiled the formidable challenge posed by melanoma-intrinsic ß-catenin signaling, which hinders the infiltration of cytotoxic T-lymphocytes (CTLs) and their subsequent anti-tumour action. To overcome this obstacle, a ß-catenin antagonist called carnosic acid (CA) was co-assembled with a RADA-rich peptide to create a nanonet-derived hydrogel known as Supra-gelδCA. This injectable hydrogel is designed to be retained at the surgical site while simultaneously promoting hemostasis. Importantly, Supra-gelδCA directly releases CA to the site of residual tumour lesions, thereby enhancing infiltration of CTLs and subsequently activating adaptive immunity. Consequently, it effectively suppresses postoperative recurrence of skin cutaneous melanoma (SKCM) in vivo. Collectively, the presented Supra-gelδCA not only provides an efficacious immunotherapy strategy for regulating adaptive immunity by overcoming the obstacle posed by melanoma-intrinsic ß-catenin signaling-induced absence of CTLs but also offers a clinically translatable hydrogel that revolutionizes post-surgical management of SKCM.

Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.

Objectives: To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods: A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-ß, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-ß and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results: NACT increased the expression of STING, IFN-ß and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. Conclusion: NACT stimulates STING/IFN-ß pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.

Sintilimab (anti-PD-1 antibody) combined with high-dose methotrexate, temozolomide, and rituximab (anti-CD20 antibody) in primary central nervous system lymphoma: a phase 2 study.

Primary central nervous system lymphoma (PCNSL) is a rare and frequently fatal lymphoma subtype. The programmed death-1 (PD-1) pathway has emerged as a potential therapeutic target, but the effectiveness of PD-1 antibody sintilimab in combination with immunochemotherapy as a frontline treatment for PCNSL remains to be determined. In this phase 2 trial (ChiCTR1900027433) with a safety run-in, we included patients aged 18-70 with newly diagnosed PCNSL. Participants underwent six 21-day cycles of a SMTR regimen, which includes sintilimab (200 mg, Day 0), rituximab (375 mg/m2, Day 0), methotrexate (3.0 g/m2, Day 1 or 1.0 g/m2 for patients aged ≥65 years), and temozolomide (150 mg/m2/d, Days 1-5). Among 27 evaluable patients, the overall response rate (ORR) was 96.3% (95% confidence interval: 81-99.9%), with 25 complete responses. At a median follow-up of 24.4 months, the medians for duration of response, progression-free survival (PFS), and overall survival were not reached. The most common grade 3-4 treatment-related toxicities were increased levels of alanine aminotransferase (17.9%) and aspartate aminotransferase (14.3%). Additionally, baseline levels of interferon-α and the IL10/IL6 ratio in cerebrospinal fluid emerged as potential predictors of PFS, achieving areas under the curve of 0.88 and 0.84, respectively, at 2 years. Whole-exome sequencing revealed a higher prevalence of RTK-RAS and PI3K pathway mutations in the durable clinical benefit group, while a greater frequency of Notch and Hippo pathway mutations in the no durable benefit group. These findings suggest the SMTR regimen is highly efficacious and tolerable for newly diagnosed PCNSL, warranting further investigation.

Patient-derived xenografts or organoids in the discovery of traditional and self-assembled drug for tumor immunotherapy.

In addition to the rapid development of immune checkpoint inhibitors, there has also been a surge in the development of self-assembly immunotherapy drugs. Based on the immune target, traditional tumor immunotherapy drugs are classified into five categories, namely immune checkpoint inhibitors, direct immune modulators, adoptive cell therapy, oncolytic viruses, and cancer vaccines. Additionally, the emergence of self-assembled drugs with improved precision and environmental sensitivity offers a promising innovation approach to tumor immunotherapy. Despite rapid advances in tumor immunotherapy drug development, all candidate drugs require preclinical evaluation for safety and efficacy, and conventional evaluations are primarily conducted using two-dimensional cell lines and animal models, an approach that may be unsuitable for immunotherapy drugs. The patient-derived xenograft and organoids models, however, maintain the heterogeneity and immunity of the pathological tumor heterogeneity.

Association of socioeconomic status with cardiovascular disease and cardiovascular risk factors: a systematic review and meta-analysis.

Aim: Cardiovascular disease (CVD) remains one of the leading causes of mortality worldwide, and several studies have indicated the association between socioeconomic status (SES) with CVD and cardiovascular risk factors (CVRFs). It is necessary to elucidate the association of SES and CVRFs with CVD. Subject and methods: We searched PubMed, Embase, Web of Science, and the Cochrane Library for publications, using "socioeconomic status," "cardiovascular disease," and corresponding synonyms to obtain literature. The quality of studies was evaluated using the National Institutes of Health Quality Assessment Tool (NIH-QAT). All analyses were performed using Stata V.12.0. Results: There were 31 eligible studies included in this meta-analysis. All studies presented a low risk of bias via NIH-QAT assessment. As for CVD incidence/mortality, pooled hazard ratios (HR) of low and middle vs. high income were [HR = 1.22 (1.17-1.28); HR = 1.12 (1.09-1.16)] and [HR = 1.37 (1.21-1.56); HR = 1.19 (1.06-1.34)]. The HR of education were [HR = 1.44 (1.28-1.63); HR = 1.2 (1.11-1.3)] and [HR = 1.5 (1.22-1.83); HR = 1.13 (1.05-1.22)]. The HR of deprivation were [HR = 1.28 (1.16-1.41); HR = 1.07 (1.03-1.11)] and [HR = 1.19 (1.11-1.29); HR = 1.1 (1.02-1.17)]. SES was negatively correlated with CVD outcomes. A subgroup analysis of gender and national income level also yielded a negative correlation, and additional details were also obtained. Conclusions: SES is inversely correlated with CVD outcomes and the prevalence of CVRFs. As for CVD incidence, women may be more sensitive to income and education. In terms of CVD mortality, men may be more sensitive to income and education, and people from low- and middle-income countries are sensitive to income and education. Supplementary Information: The online version contains supplementary material available at 10.1007/s10389-023-01825-4.

Retrospective Analysis of the Expression of CD56 in Multiple Myeloma with Bone-Related Extramedullary Diseases.

OBJECTIVE: To identify the clinical characteristics and tissue CD56 expression pattern in patients with multiple myeloma (MM) with bone-related extramedullary disease (b-EMD), not connected to or isolated from the bone marrow. METHODS: We reviewed consecutive patients with MM hospitalised at the First Affiliated Hospital of Fujian Medical University between 2016 and 2019. Patients with b-EMD were identified, and the clinical and laboratory features of patients with and without b-EMD were compared. Immunohistochemistry of extramedullary lesions was performed based on b-EMD histology. RESULTS: Ninety-one patients were included in the study. Among them, 19 (20.9%) were found to have b-EMD at initial diagnosis. Median age was 61 years (range, 42-80 years), with a female/male ratio of 6/13. The most common site of b-EMD was the paravertebral space (11/19; 57.9%). Compared to those without b-EMD, patients with b-EMD had lower levels of serum ß2-microglobulin and similar levels of lactate dehydrogenase. Immunophenotype analysis based on histopathology showed that CD56 was expressed in 9/10 (90.0%) patients with b-EMD. CONCLUSION: A considerable number of MM patients presented with b-EMD at the time of initial diagnosis, and most patients with b-EMD exhibited CD56 expression, highlighting a potential new therapeutic target in the future.