Immunotherapy for triple-negative breast cancer (TNBC) is hindered by its immunologically "cold" microenvironment, reducing treatment efficacy. Converting cold tumors into hot ones can significantly enhance the efficacy of immunotherapy. Nevertheless, the tumor extracellular matrix-associated physical barriers impede the infiltration of immunomodulating agents. Our previous research suggested that extracellular vesicles (EVs) secreted in situ by tumor cells could mediate the intercellular transport and deep infiltration of antitumor drugs. However, EVs' application faces obstacles such as inefficient delivery, lack of specificity, low production yields, and manufacturing inconsistencies. Based on this, we explored artificial cytomembrane nanovesicles (NVs) as the biomimetics of EVs. Herein, NVs are genetically engineered with membrane fusion-promoting protein VSVG to form VSVG-NVs (V-NVs). The calcium ionophore A23187 and plasmid encoding TNF-alpha with Lamp2b are loaded into V-NVs (V-NVs/T+A) using electroporation technology. The fusogenic VSVG component facilitates the integration of NVs with the target cancer cells and further incorporation into secreted EVs. The A23187 enhances EVs secretion by increasing intracellular calcium level. This synergistic approach ensures efficient intracellular delivery of TNF-alpha through EVs, facilitating deep tumor infiltration and remodeling of the immune microenvironment. As expected, the EV-hitchhiking strategy for cascade tumor deep penetration and immune microenvironment modulation demonstrates significant potential to enhance cancer immunotherapy.

BACKGROUND:It remains unclear whether adding CTLA-4 blockade to PD-1/PD-L1 blockade improves clinical outcomes in cervical cancer (CC). METHODS:In this randomized, double-blind, placebo-controlled, phase 2 study (ClinicalTrials.gov: NCT04590599), patients with recurrent/metastatic CC (R/M CC) who experienced disease progression after or during platinum-based chemotherapy were enrolled from 37 centers across China and randomly assigned (1:1), stratified by PD-L1 expression and prior treatment lines, to receive either IBI310 plus sintilimab or placebo plus sintilimab intravenously every 3 weeks for 12 weeks, followed by sintilimab alone. The primary endpoint was the objective response rate (ORR). Pivotal secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. FINDINGS:205 patients were randomized to receive IBI310-sintilimab (n = 103) or placebo-sintilimab (n = 102). The ORR difference between the IBI310-sintilimab arm (32.3%, 95% confidence interval [CI]: 23.3%-42.5%) and the placebo-sintilimab arm (23.5%, 95% CI: 15.5%-33.1%) was not significant (p = 0.17). IBI310-sintilimab and placebo-sintilimab exhibited median PFS values of 3.6 (95% CI: 2.7-6.3) and 4.2 months (95% CI: 2.8-6.2), respectively (hazard ratio [HR] = 0.91, 95% CI: 0.65-1.27; p = 0.58). The median OSs were 13.9 months (95% CI: 11.5-25.6) in the IBI310-sintilimab arm and 17.2 months (95% CI: 13.7-25.9) in the placebo-sintilimab arm (HR = 1.12, 95% CI: 0.79-1.58; p = 0.54). Adding IBI310 to sintilimab increased the incidence of grade ≥3 treatment-related adverse events (55% versus 19%). CONCLUSIONS:Compared to single-agent PD-1/PD-L1 blockade, dual blockade of CTLA-4 and PD-1/PD-L1 did not significantly improve clinical outcomes in R/M CC. FUNDING:This work was funded by Innovent Biologics (Suzhou).

BACKGROUND:Chemotherapy, targeted therapy, and immunotherapy have all been shown to achieve some efficacy in treating intrahepatic cholangiocarcinoma (ICC). However, these systemic treatments have not provided optimal results for some patients. Therefore, the combination of transarterial chemoembolization (TACE) and hepatic artery infusion chemotherapy or other local interventional therapy methods is being considered for the treatment of liver tumors. AIM:To evaluate the efficacy and safety of combining chemotherapy, targeted therapy, and immunotherapy, with or without TACE, in patients with ICC. METHODS:We recruited 83 patients with unresectable ICC from July 2021 to December 2023 at the Affiliated Hospital of Xuzhou Medical University. Forty-one patients received TACE combined with chemotherapy, tyrosine kinase inhibitors, and programmed death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors (experimental group), whereas 42 patients were treated with chemotherapy, tyrosine kinase inhibitors, and PD-1/PD-L1 inhibitors (control group). Short-term efficacy was assessed using the modified response evaluation criterion, and the objective response rate, disease control rate, progression-free survival, and incidence of adverse events were compared between groups. RESULTS:The objective response rate in the experimental group was greater than that in the control group (39.0% vs 19.0%, P < 0.05). The disease control rate in the experimental group was significantly greater than that in the control group (75.6% vs 52.4%, P < 0.05). The median progression-free survival times were 14.3 months in the experimental group and 12.7 months in the control group (P < 0.05). All 41 patients in the experimental group developed postembolization syndrome. Among the symptoms, fever and pain were significantly more common in the experimental group than in the control group (85.4% vs 11.9%, P < 0.001 and 58.5% vs 9.5%, P < 0.001). No grade 4 or 5 treatment-related adverse events were observed in either group. CONCLUSION:In patients with unresectable ICC, TACE combined with chemotherapy, tyrosine kinase inhibitors, and PD-1/PD-L1 inhibitors has good efficacy and high safety, indicating potential benefits for these patients.

ObjectivesTo assess the efficacy and safety of nimotuzumab in combination with radiotherapy or chemoradiotherapy for locally advanced head and neck squamous cell carcinoma.MethodsSystematic searches were performed on PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biomedical Medicine, Wanfang, VIP databases. Seven eligible randomized controlled trials (n = 1012) were selected through rigorous inclusion and exclusion criteria.ResultsA total of 1012 cases were included. including 508 (50.2%) in the nimotuzumab combination treatment group; There were 504 cases (49.8%) in the control group. The results of meta-analysis showed that the overall survival (Hazard Ratio [HR]=0.75, 95% Confidence Interval [CI]: 0.62-0.90, P<0.05), progression-free survival (HR=0.69, 95% CI: 0.54-0.87, P<0.05), complete response rate (Risk Ratio [RR]=1.52, 95% CI: 1.24-1.86, P<0.05), and objective response rate (RR=1.32, 95% CI: 1.17-1.48, P<0.05) were significantly improved in the nimotuzumab combination treatment group compared with the control group. In terms of the incidence of adverse effects, only the incidence of rash was the nimotuzumab combination group higher than in the treatment alone group, and there was no significant difference between the remaining adverse reactions (neutropenia, anemia, nausea/vomiting, mucositis, dermatitis, dysphagia).ConclusionNimotuzumab combined with radiotherapy or chemoradiotherapy is more effective than radiotherapy alone or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck, and the safety profile is controllable. Therefore, the addition of nimotuzumab to treatment is expected to be an effective treatment option for this disease. However, more prospective randomized controlled trials are needed to fully explore the effectiveness of this treatment in patients with locally advanced head and neck squamous cell carcinoma.Systematic Review Registrationidentifier PROSPERO (CRD: 42022383313).

Peptide salicylaldehyde esters are the requisite coupling partner in Ser/Thr ligation reactions towards chemical protein synthesis. In general, it would be cost-effective and efficient to use side-chain-protected peptide acids, after Fmoc solid-phase peptide synthesis, for direct C-terminal derivatization; however, this has yet to be achieved, due to an intrinsic epimerization pathway. Here we report the development of 2-(dichloromethyl)phenol as a reagent that can directly form peptide salicylaldehyde esters in an epimerization-free manner. Mechanistic studies reveal that the 2-(dichloromethyl)phenol reagent serves as a source of highly reactive quinone methide species that can be trapped by the peptide C-terminal carboxylate to give alpha-chloroesters, followed by an O-benzylic-to-O-phenolic acyl transfer and chloride extrusion process. The peptide salicylaldehyde ester reaction products have been applied in the convergent total chemical synthesis of linker histone H1.2 using sequential Ser/Thr ligation reactions.

Chimeric antigen receptor engineered T (CAR T) cell therapy has developed rapidly in recent years, leading to profound developments in oncology, especially for hematologic malignancies. However, given the pressure of immunosuppressive tumor microenvironments, antigen escape, and diverse other factors, its application in solid tumors is less developed. Urinary system tumors are relatively common, accounting for approximately 24% of all new cancers in the United States. CAR T cells have great potential for urinary system tumors. This review summarizes the latest developments of CAR T cell therapy in urinary system tumors, including kidney cancer, bladder cancer, and prostate cancer, and also outlines the various CAR T cell generations and their pathways and targets that have been developed thus far. Finally, the current advantages, problems, and side effects of CAR T cell therapy are discussed in depth, and potential future developments are proposed in view of current shortcomings.

In recent decades, the pursuit of drug delivery systems has led to the development of numerous synthetic options aimed at enhancing drug efficacy while minimizing side effects. However, the practical application of these systems is often hindered by challenges such as inefficiency, cytotoxicity, and immunogenicity. Extracellular vesicles, natural carriers for drugs, emerge as promising alternatives with distinct advantages over synthetic carriers. Notably, EVs exhibit biocompatibility, low immunogenicity, and inherent tissue-targeting capabilities, thus opening new avenues for drug delivery strategies. This review provides an overview of EVs, including their biogenesis and absorption mechanisms. Additionally, we explore the current research efforts focusing on harnessing their potential as drug carriers, encompassing aspects such as purification techniques, drug loading, and bioengineering for targeted delivery. Finally, we discuss the existing challenges and future prospects of EVs as therapeutic agents in clinical settings. This comprehensive analysis aims to shed light on the potential of EVs as versatile and effective tools for drug delivery, particularly in the realm of cancer therapy.

Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignant tumors globally. Despite considerable advancements in HCC therapies, therapeutic resistance remains a significant challenge that compromises patient prognosis. Increasing evidence indicates that exosomes, which are secreted by cells in the tumor microenvironment (TME), are pivotal players in the development of therapeutic resistance in HCC. These nano-sized vesicles mediate intercellular communication in TME through the transfer of bioactive molecules such as nucleic acids, lipids, and proteins. A comprehensive understanding of the role of exosomes in therapeutic resistance could provide promising strategies for both the diagnosis and treatment of HCC. This review mainly summarizes the involvement of exosomal cargos and elucidates their underlying mechanisms in resistance to therapeutic treatments for HCC, and further discusses the potential clinical applications of exosomes as diagnostic biomarkers and therapeutic targets to overcome drug resistance in HCC.

This study aimed to conduct a bibliometric analysis in the field of bladder cancer (BC) immunotherapy, and explore the research trends, hotspots and frontiers from 2000 to 2022. VOSviewer software was used to analyze the collaborative relationships between authors, institutions, countries/regions, and journals through citation, co-authorship, and co-citation analysis, to identify research hotspots and frontiers in this field. Researchers based in the United States of America have published a total of 627 papers with 27,308 citations. Indeed, the USA ranked first among the top 10 most active countries and showed the most extensive collaboration with other countries. The University of Texas MD Anderson CANC CTR has published 58 articles, making it the top most institution in terms of published articles and active collaborative research. Kamat AM and Lamm DL were the most active and co-cited authors with 28 papers and 980 co-citations, respectively. Chang Yuan and Xu le were the most active collaborative authors with a total link strength of 195. The J UROLOGY was the most active and frequently co-cited journal, with 100 papers and 6,668 co-citations. Studies of BC immunotherapy can be broadly classified into three categories: "basic research", "clinical trial", and "prognosis". Our findings provide an overview of the research priorities and future directions of BC immunotherapy. Tumor microenvironment and immune checkpoint inhibitors (ICIs) of BC, as well as the combination of ICIs with other drugs, may become the main direction of future research.

Review question / Objective: To Systematicly evaluate of the clinical efficacy and safety of the combination of anti-angiogenesis and simultaneous radiotherapy in the treatment of cervical cancer. Condition being studied: Locally advanced cervical cancer. We searched databases including PubMed, Cochrane Library, Embase, Web of Science CNKI, Wanfang, VIP and CBM, and the International Clinical Trial Registry Platform (ICTRP) and the Chinese Clinical Registry(ChiCTR) to collect the clinical studies about the randomized controlled trial (RCTS) of anti-angiogenic drugs (mainly Endu, apatinib and bevacizumab) combined with chemoradiotherapy in the treatment of cervical cancer. The time limit is from the establishment of the database to April 2022. RevMan 5.4 software was used to analyze the short-term efficacy and the incidence of adverse reactions.

Chemotherapy has been one of the most important treatments for advanced cancer in recent decades. Although the sensitivity rate of initial chemotherapy is high, patients with chemotherapy resistant tumors, experience tumor recurrence. In recent years, many studies have shown that homeobox transcript antisense intergenic RNA (HOTAIR) is involved in many pathological processes including carcinogenesis. The abnormal regulation of a variety of cell functions by HOTAIR, such as apoptosis, the cell cycle, epithelial-mesenchymal transition, autophagy, self-renewal, and metabolism, is associated with chemotherapy resistance. Therefore, there is an urgent need to understand the biology and mechanism underlying the role of HOTAIR in tumor behavior and its potential as a biomarker for predicting the effect of chemotherapy. In this manuscript, we review the mechanisms underlying HOTAIR-related drug resistance and discuss the limitations of current knowledge and propose potential future directions.

Background Prostate cancer (PCa) is a serious threat to the health of elderly aged groups. It is very important to understand the occurrence and development of PCa for early diagnosis, treatment and metastasis control. This study aims to elucidate the international frontier research direction and literature distribution through bibliometric and visual analyses of PCa bone metastasis. Methods Data were obtained from the Web of Science core collection database, which collected 2,246 papers related to PCa bone metastasis from 1 January 2012 to 31 December 2021. The collected data were analyzed using the VOSviewer software for citation, co-authorship, co-citation, bibliometric coupling, and co-occurrence. Results Over the past decade, published papers have increased annually. The United States of America has published 890 papers with 29,161 citations, far more than any other country, and it has the most extensive collaboration with other countries. For example, 33 articles by Saad Fred were cited 2,721 times, and 91 articles from the University of Texas MD Anderson CANC CTR were cited 3,037 times, the most cited author and organization. Peng Xinsheng and Duke UNIV comprise the most active collaborative author and organization, respectively. The most co-cited journal was CANCER RES, with 3,195 citations. Studies of PCa bone metastasis can be divided into four categories: “basic research,” “auxiliary diagnosis and treatment,” “clinical trial,” and “prognosis.” Conclusion Our results provide a comprehensive overview of the research priorities and future directions of PCa bone metastasis, which can further accurately guide researchers in diagnosis, treatment, and personalized prevention.

Long non-coding RNAs (lncRNAs) are a series of non-coding RNAs that lack open reading frameworks. Accumulating evidence suggests important roles for lncRNAs in various diseases, including cancers. Recently, lncRNA H19 (H19) became a research focus due to its ectopic expression in human malignant tumors, where it functioned as an oncogene. Subsequently, H19 was confirmed to be involved in tumorigenesis and malignant progression in many tumors and had been implicated in promoting cell growth, invasion, migration, epithelial-mesenchymal transition, metastasis, and apoptosis. H19 also sequesters some microRNAs, facilitating a multilayer molecular regulatory mechanism. In this review, we summarize the abnormal overexpression of H19 in human cancers, which suggests wide prospects for further research into the diagnosis and treatment of cancers.

N6-methyladenosine (m6A) in messenger RNA (mRNA) is regulated by m6A methyltransferases and demethylases. Modifications of m6A are dynamic and reversible, may regulate gene expression levels and serve vital roles in numerous life processes, such as cell cycle regulation, cell fate decision and cell differentiation. In recent years, m6A modifications have been reported to exhibit functions in human cancers via regulation of RNA stability, microRNA processing, mRNA splicing and mRNA translation, including lung cancer, breast tumor and acute myeloid leukemia. In the present review, the roles of m6A modifications in the onset and progression of cancer were summarized. These modifications display an oncogenic role in certain types of cancer, whereas in other types of cancer they exhibit a tumor suppressor role. Therefore, understanding the biological functions performed by m6A in different types of tumors and identifying pivotal m6A target genes to deduce the potential mechanisms underlying the progression of cancer may assist in the development of novel therapeutics.

6032 Background: GLS-010 is a novel fully human anti-PD-1 mAb. Previous Phase I study exhibited favorable result of tolerance, preliminary efficacy and 240mg fixed dose q2w was selected as Recommended Phase II Dose (RP2D). This Phase II clinical trial is aimed to further evaluate the safety and anti-tumor activity of GLS-010 in patients with recurrent or metastatic cervical cancer. Methods: PD-L1 positive (combined positive score (CPS) ≥1) patients with recurrent or metastatic cervical cancer who had received one or more lines of chemotherapy were enrolled and received GLS-010 240mg every 2 weeks. Primary endpoint was the objective response rate (ORR) per RECIST 1.1, secondary endpoints included duration of response (DoR) and safety. Results: From May 16 th 2019 to December 24 th 2019, 44 pts were enrolled and treated in the study. As of December 24 th 2019,the median line of prior systemic chemotherapy was 2(range: 1~4), and 59% (26/44) of pts had received ≥2 previous lines of chemotherapy. The median number of GLS-010 doses was 1.5(range: 1~4). 25 pts received response evaluation per investigator review. With a median follow-up of 2.9 months, 7 of 25 evaluable pts achieved a partial response (PR). The ORR was 28% (95% CI, 12.07-49.39), with 7 pts achieving a PR ( 3 of 7 confirmed), 3 pts achieving stable disease (SD) and 15 pts with progressive disease (PD), 1 of which was assessed as dissociated response with treatment ongoing. Median duration of response had not been reached yet. 33 of 44 patients (75%) experienced one or more treatment-related adverse events (TRAEs) per NCI CTCAE v4.03, most of which were grade 1 or 2. The most common TRAEs were Anaemia (15/44), and 73.3% of them were grade 1 or 2. The most common ≥grade 3 TRAE included Anaemia (4/44). As data cut off, only 1 pt discontinued treatment due to adverse event. Conclusions: GLS-010 showed impressive therapeutic activity and manageable safety profile in Chinese recurrent or metastatic cervical cancer patients. Current evidence support further development of GLS-010 in this and more indications. This trial is still ongoing, and we are looking forward to further results. Clinical trial information: NCT03972722.

Objective To compare the clinical effects of transurethral prostatectomy (TUERP) and suprapubic prostatectomy(SP) in the treatment of massive prostatic hyperplasia.Methods The clinical data of 40 patients with benign prostatic hyperplasia ( BPH) with a volume range of 80 －150 mL from October 2015 to October 2017 in Shengjing Hospital of China Medical University were retrospectively analyzed .They were divided into two groups :TUERP group(20 cases) and SP group(20 cases).The length and distribution of large prostate were measured.The degree of hemoglobin decrease ,bladder irrigation time,operation time,indwelling catheter time ,maximum urine flow rate ( Qmax), international prostate symptom score ( IPSS), prostate specific antigen ( PSA), residual urine volume (PVR) and the incidence of complications were compared between the two groups before and after operation .Results It was found that the length of the prostatic fossa was less than 5 cm in patients with large prostatic hyperplasia whose volume ranged from 80 to 150 mL.After operation,the degree of hemoglobin decrease ,bladder irrigation time,indwelling catheter time and the incidence of complications in the TUERP group were (7.9 ±2.3)g／L,(42.5 ±3.6)h,(5.3 ± 1.1)d,15%(3／20),respectively,while in the SP group were (14.2 ±4.4)g／L,(62.6 ±6.0)h,(7.8 ±0.8)d and 50%(10／20),respectively,there were statistically significant differences between the two groups (t＝－5.7,－12.8,－8.6,χ2 ＝5.6,all P＜0.05).There were no statistically significant differences in operation time ,Qmax,IPSS,PSA and PVR between the two groups (all P＞0.05).Conclusion After TUERP treatment of large prostate hyperplasia , the improvement of urination and the decrease of PSA is similar to SP ,and the hemostasis effect is good ,the complica－tions are less and the recovery is faster.

Upregulation of the forkhead box protein Q1 (FOXQ1) promotes bladder cancer (BCa) cell growth and metastasis. Factors affecting FOXQ1 expression at the post-transcriptional level have not yet been identified. We performed cell proliferation, cell invasion, and tumorigenesis experiments to characterize the relationship between FOXQ1 and miR-140-3p. We found that FOXQ1 was significantly upregulated and miR-140-3p was significantly downregulated in BCa tissues. We also identified an inverse correlation between miR-140-3p and FOXQ1 expression in BCa tissues. Overexpression of miR-140-3p reduced FOXQ1 expression, suppressing BCa cell proliferation and invasion. A luciferase assay confirmed that miR-140-3p bound to the 3'-UTR of FOXQ1 mRNA and decreased its expression. In addition, we used a mouse xenograft model to demonstrate that miR-140-3p suppressed tumor cell growth in vivo. Our findings suggest that miR-140-3p suppresses BCa cell proliferation and invasion by directly decreasing FOXQ1 expression.

Hypoxia plays a key role in tumour cell survival, invasion, and metastasis. An increasing number of studies have attempted to characterize the tumour response to hypoxia and to identify predictive markers of disease. Here we show that hypoxia increases tumour cell invasion and migration by the modulation of Rab11, an important molecule for vesicular trafficking. In our study, we found that Rab11, together with the activation of Rac1, could stimulate invasion and migration of cervical cancer cell lines HeLa/SiHa in hypoxia. Activation of Rac1 activity by hypoxia seems to be central to carcinoma invasion. We also found that these effects could be related to the integrin αvβ3. In addition, we studied the molecular pathway for this process. Our results showed that in cervical cancer cell lines HeLa/SiHa, Rac1 activation in hypoxia could stimulate invasion and migration, and this process was mediated by integrin αvβ3-mediated FAK and PI3K phosphorylation. Furthermore, hypoxia induced a dramatic increase in αvβ3 integrin surface expression, and this increase is dependent on Rab11. In conclusion, our study might provide a new mechanism for the effect of hypoxia on stimulating cervical carcinoma invasion.