Explore the vast range of titles available.

Tislelizumab, an anti‐programmed death protein‐1 (PD‐1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody‐dependent phagocytosis, a mechanism of T‐cell clearance and potential resistance to anti‐PD‐1 therapy. This single‐arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD‐L1‐positive urothelial carcinoma who progressed during/following platinum‐containing therapy and had no prior PD‐(L)1 inhibitor treatment. Patients were considered PD‐L1 positive if ≥ 25% of tumor/immune cells expressed PD‐L1 when using the VENTANA™ PD‐L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow‐up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy‐evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression‐free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment‐related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3‐4 treatment‐related adverse events and occurred in ≥ 5% of patients. Three investigator‐assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD‐L1‐positive urothelial carcinoma and had a manageable safety profile. Tislelizumab is a unique anti‐PD‐1 antibody that was engineered specifically to minimize FcγR binding in order to limit antibody‐dependent phagocytosis, a potential mechanism of resistance to anti‐PD‐1 therapy. In the current study, tislelizumab demonstrated clinically meaningful antitumor activity in patients with previously treated locally advanced or metastatic PD‐L1‐positive urothelial carcinoma and had a manageable safety profile with no new safety signals compared with other anti‐PD‐L1/PD‐1 therapies. A phase 3 study of tislelizumab as treatment for urothelial carcinoma (NCT03967977) is currently ongoing and is recruiting patients.

Background SOX (oxaliplatin and S1, every 3 weeks) is one of the most common first-line chemotherapy for advanced or metastatic G/GEJ (gastric or gastroesophageal junction) cancer in Asia, but it has noticeable hematological and neurological toxicity. In China, the majority of gastric cancer patients are middle-aged and elderly with poor tolerance to 3-weekly chemotherapy. Therefore, we aimed to assess efficacy and safety of biweekly SOX for Chinese advanced G/GEJ cancer patients aged ≥ 60 years as the first-line treatment in a single arm phase 2 study. Methods Oxaliplatin was administered intravenously on day 1 at 85 mg/m 2 . S-1 was given at 80, 100 or 120 mg/day, depending on the body surface area (< 1.25 m 2 , 1.25 to < 1.5 m 2 , or ≥ 1.5 m 2 ), twice daily, on day 1–10, every 2 weeks. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Results Between May 2016 and Sep 2018, 42 patients were enrolled. The median follow-up was 43.6 months. The ORR and DCR were 52.4% and 85.7%, respectively. The median PFS was 4.6 months (95%CI 2.486–6.714), and the median OS was 11.1 months (95%CI 8.001–14.199). The most common treatment-related adverse events (TRAEs) of any grade included thrombocytopenia (59.5%), neutropenia (57.1%), appetite loss (57.1%) and nausea (54.8%). Only two patients suffered from grade 3 TRAEs (4.8%), including neutropenia (1 patient, [2.4%]) and diarrhea (1 patient, [2.4%]). No ≥ grade 4 TRAEs occurred. Conclusions Biweekly SOX seemed to have favorable tolerance without compromising the efficacy as the first-line therapy in Chinese elderly patients aged ≥ 60 years with advanced G/GEJ cancer. Trial registration ClinicalTrials.gov ID: NCT04694404 (5/1/2021). This study was approved by the Ethical Committee of National Cancer Center/ National Clinical Research Center for Cancer/ Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, (17–048/1303).

To overcome the obstacles of maintaining covert transmissions in wireless networks employing collaborative wardens, we develop a reinforcement learning framework that jointly optimizes cooperative jamming strategies and relay selection mechanisms. The study focuses on a multi-relay-assisted two-hop network, where potential relays dynamically act as information relays or cooperative jammers to enhance covertness. A reinforcement learning-based relay selection scheme (RLRS) is employed to dynamically select optimal relays for signal forwarding and jamming; the framework simultaneously maximizes covert throughput and guarantees warden detection failure probability, subject to rigorous power budgets. Numerical simulations reveal that the developed reinforcement learning approach outperforms conventional random relay selection (RRS) across multiple performance metrics, achieving (i) higher peak covert transmission rates, (ii) lower outage probabilities, and (iii) superior adaptability to dynamic network parameters including relay density, power allocation variations, and additive white Gaussian noise (AWGN) fluctuations. These findings validate the effectiveness of reinforcement learning in optimizing relay and jammer selection for secure covert communications under colluding warden scenarios.

This study tackles the issue of ensuring secure communications in vehicular ad hoc networks (VANETs) under dynamic eavesdropping threats, where eavesdroppers adaptively reposition to intercept transmissions. We introduce a scheme utilizing a partitioned reconfigurable intelligent surface (RIS) to assist in the joint transmission of confidential signals and artificial noise (AN) from a source station. The RIS is divided into segments: one enhances legitimate signal reflection toward the intended vehicular receiver, while the other directs AN toward eavesdroppers to degrade their reception. To maximize secrecy performance in rapidly changing environments, we introduce a joint optimization framework integrating meta-learning for RIS partitioning and reinforcement learning (RL) for reflection matrix optimization. The meta-learning component rapidly determines the optimal RIS partitioning ratio when encountering new eavesdropping scenarios, leveraging prior experience to adapt with minimal data. Subsequently, RL is employed to dynamically optimize both beamforming vectors as well as RIS reflection coefficients, thereby further improving the security performance. Extensive simulations demonstrate that the suggested approach attain a 28% higher secrecy rate relative to conventional RIS-assisted techniques, along with more rapid convergence compared to traditional deep learning approaches. This framework successfully balances signal enhancement with jamming interference, guaranteeing robust and energy-efficient security in highly dynamic vehicular settings.

Significant cardinality change is an important sign of the beginning of network attacks. Hosts associated with significant cardinality changes usually exhibit abnormal behavior. Identifying abnormal hosts is meaningful for many applications such as anomaly detection. High‐speed data streams remain a great challenge to accurately estimate cardinality changes and detect abnormal hosts in real‐time. Sketches are a type of probability data structure, which are widely used to compress high‐rate data streams and estimate their statistics. However, most existing studies cannot simultaneously measure two kinds of cardinality changes in a distributed manner and efficiently reconstruct addresses of abnormal hosts in a centralized manner because of high calculation and memory overhead. In this paper, we propose reversible sketch‐based abnormal host identification. It constructs a reversible data structure and estimates cardinality changes using a probabilistic counting approach, so that abnormal sources and destinations are simultaneously identified based on their cardinality changes between consecutive measurement periods. Moreover, addresses of abnormal hosts can be reconstructed by only simple inverse calculation to find out attackers and victims. The experimental results illustrate that the proposed approach obtains superior performance for cardinality change estimation and addresses of abnormal host reconstruction in accuracy and performance compared with the existing approaches. In this paper, we have proposed a reversible and distributed sketch data structure to simultaneously trace two types of network‐wide abnormal hosts by simple computation, while improving the abnormal host recovery efficiency. This algorithm can be used as a crucial function module of network devices to monitor traffic anomaly in high‐speed networks.

Although immune checkpoint inhibitors (ICIs) have greatly improved the prognosis of some cancer patients, the majority still fail to respond adequately, and the available biomarkers cannot reliably predict drug efficacy. The gut microbiota has received widespread attention among the various intrinsic and extrinsic factors contributing to drug resistance. As an essential regulator of physiological function, the impact of gut microbiota on host immunity and response to cancer therapy is increasingly recognized. Several studies have demonstrated significant differences in gut microbiota between responders and nonresponders. The gut microbiota associated with better clinical outcomes is called ‘favorable gut microbiota’. Significantly, interventions can alter the gut microbiota. By shifting the gut microbiota to the ‘favorable’ one through various modifications, preclinical and clinical studies have yielded more pronounced responses and better clinical outcomes when combined with ICIs treatment, providing novel approaches to improve the efficacy of cancer immunotherapy. These findings may be attributed to the effects of gut microbiota and its metabolites on the immune microenvironment and the systemic immune system, but the underlying mechanisms remain to be discovered. In this review, we summarize the clinical evidence that the gut microbiota is strongly associated with the outcomes of ICI treatment and describe the gut microbiota characteristics associated with better clinical outcomes. We then expand on the current prevalent modalities of gut microbiota regulation, provide a comprehensive overview of preclinical and clinical research advances in improving the therapeutic efficacy and prognosis of ICIs by modulating gut microbiota, and suggest fundamental questions we need to address and potential directions for future research expansion.

Background Nasopharyngeal carcinoma (NPC) is not common in most parts of the world but is particularly prevalent in southern China. This study analyzed NPC incidence, mortality, years of life lost (YLL), and survival rates in Xiamen from 2011 to 2020. Methods This study mainly utilized data from the Xiamen City Cancer Registry, and cancer follow-up cohort, covering the period from 2011 to 2020. Crude and age-standardized incidence, mortality, YLL, and survival rates, as well as their trends were analyzed using annual percent change (APC) and average annual percent change (AAPC), stratified by sex and residency status. Results From 2011 to 2020, Xiamen reported 996 new NPC cases (733 males, 263 females) and 513 deaths (396 males, 117 females). Age-standardized incidence, mortality, and YLL rates were 3.58/100,000, 1.83/100,000, and 65.10/100,000, respectively. The AAPC in incidence and mortality rates of NPC was − 5.48% (95% CI: −9.25, −1.54, P  < 0.05) and − 0.82% (95% CI: −6.01, 4.65, P  > 0.05), respectively. The 5-year age-standardized relative survival rate was 55.98% (95%CI: 52.08, 60.17). Conclusion Over the recent decade, a consistent decline in the incidence of NPC has been observed, accompanied an insignificant decreasing mortality trend in Xiamen. Future efforts could focus on enhancing prevention, screening, and treatment strategies to potentially reinforcing these positive trends.

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

Accurate presurgical prediction of pathological complete response (pCR) can guide treatment decisions, potentially avoiding unnecessary surgeries and improving the quality of life for cancer patients. We developed a minimal residual disease (MRD) profiling approach with enhanced sensitivity and specificity for detecting minimal tumor DNA from cell-free DNA (cfDNA). The approach was validated in two independent esophageal squamous cell carcinoma (ESCC) cohorts. In a cohort undergoing neoadjuvant, surgical, and adjuvant therapy (NAT cohort), presurgical MRD status precisely predicted pCR. All MRD-negative cases (10/10) were confirmed as pCR by pathological evaluation on the resected tissues. In contrast, MRD-positive cases included all the 27 non-pCR cases and only one pCR case (10/10 vs 1/28, P < 0.0001, Fisher’s exact test). In a definitive radiotherapy cohort (dRT cohort), post-dRT MRD status was closely correlated with patient prognosis. All MRD-negative patients (25/25) remained progression-free during the follow-up period, while 23 of the 26 MRD-positive patients experienced disease progression (25/25 vs 3/26, P < 0.0001, Fisher’s exact test; progression-free survival, P < 0.0001, log-rank test). The MRD profiling approach effectively predicted the ESCC patients who would achieve pCR with surgery and those likely to remain progression-free without surgery. This suggests that the cancer cells in these MRD-negative patients have been effectively eliminated and they could be suitable candidates for a watch-and-wait strategy, potentially avoiding unnecessary surgery.

Background The immune checkpoint protein programmed cell death ligand 1 (PD‐L1) binds to PD1 to promote tumor cell escape from the killing effect of the immune system. However, there are few studies on the regulatory mechanisms of PD‐L1 in tumors. Although PD‐L1 has been reported to undergo ubiquitination in some cancers, its regulatory mechanisms in oral squamous cell carcinoma (OSCC) are unclear. Therefore, we aimed to investigate this phenomenon. Methods We examined the expression and function of USP9X and PD‐L1 in human oral keratinocytes (HOK) and OSCC cell lines (HN4 and HN30) as the control and relevant cancer cells using western blotting, immunoprecipitation, immunohistochemistry (IHC), T‐cell‐mediated tumor cell killing assay, and liquid chromatography‐mass spectrometry. Results Programmed cell death ligand 1 was highly expressed in OSCC by the regulation of the ubiquitin‐proteasome pathway. Furthermore, we discovered that ubiquitin‐specific peptidase 9, X‐linked (USP9X) could be combined with PD‐L1 to induce its deubiquitination and stabilize its protein expression in OSCC. Conclusion Our data indicate that USP9X deubiquitinates and stabilizes PD‐L1. Suppressing the expression of USP9X blocks tumor cell growth. The results provide a theoretical basis for USP9X as a therapeutic target. (i) USP9X and PD‐L1 are highly expressed in OSCC; (ii) USP9X can stabilize PD‐L1 by reducing its ubiquitination in OSCC; (iii) Targeting PD‐L1 through blocking USP9X seems as a promising strategy to treat OSCC.