Following the coronavirus disease-2019 outbreak caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), there is an ongoing need to seek drugs that target COVID-19. First off, novel drugs have a long development cycle, high investment cost, and are high risk. Second, novel drugs must be evaluated for activity, efficacy, safety, and metabolic performance, contributing to the development cycle, investment cost, and risk. We searched the Cochrane COVID-19 Study Register (including PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and WHO COVID-19 Coronaviral Disease Global Literature to identify completed and ongoing studies as of February 20, 2024. We evaluated the pharmacological effects, in vivo and in vitro data of the 16 candidates in the paper. The difficulty of studying these candidates in clinical trials involving COVID-19 patients, dosage of repurposed drugs, etc. is discussed in detail. Ultimately, Metformin is more suitable for prophylactic administration or mildly ill patients; the combination of Oseltamivir, Tamoxifen, and Dexamethasone is suitable for moderately and severely ill patients; and more clinical trials are needed for Azvudine, Ribavirin, Colchicine, and Cepharanthine to demonstrate efficacy.

The proven efficacy of immunotherapy in fighting tumors has been firmly established, heralding a new era in harnessing both the innate and adaptive immune systems for cancer treatment. Despite its promise, challenges such as inefficient delivery, insufficient tumor penetration, and considerable potential toxicity of immunomodulatory agents have impeded the advancement of immunotherapies. Recent endeavors in the realm of tumor prophylaxis and management have highlighted the use of living biological entities, including bacteria, oncolytic viruses, and immune cells, as a vanguard for an innovative class of live biotherapeutic products (LBPs). These LBPs are gaining recognition for their inherent ability to target tumors. However, these LBPs must contend with significant barriers, including robust immune clearance mechanisms, cytotoxicity and other in vivo adverse effects. Priority must be placed on enhancing their safety and therapeutic indices. This review consolidates the latest preclinical research and clinical progress pertaining to the exploitation of engineered biologics, spanning bacteria, oncolytic viruses, immune cells, and summarizes their integration with combination therapies aimed at circumventing current clinical impasses. Additionally, the prospective utilities and inherent challenges of the biotherapeutics are deliberated, with the objective of accelerating their clinical application in the foreseeable future.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).
METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).
RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC.
CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

Despite remarkable progress in the treatment of hepatitis C virus (HCV) infection, it remains a significant global health burden, necessitating the development of an effective prophylactic vaccine. This review paper presents the current landscape of HCV vaccine candidates and approaches, including more traditional, based on inactivated virus, and more modern, such as subunit protein, vectored, based on nucleic acids (DNA and mRNA) and virus-like particles. The concept of the HCV vaccine is first put in the context of viral genetic diversity and adaptive responses to HCV infection, an understanding of which is crucial in guiding the development of an effective vaccine against such a complex virus. Because ethical dimensions are also significant in vaccine research, development, and potential deployment, we also address them in this paper. The road to a safe and effective vaccine to prevent HCV infection remains bumpy due to the genetic variation of HCV and its ability to evade immune responses. The progress in cell-culture systems allowed for the production of an inactivated HCV vaccine candidate, which can induce cross-neutralizing antibodies in vitro, but whether this could prevent infection in humans is unknown. Subunit protein vaccine candidates that entered clinical trials elicited HCV-specific humoral and cellular responses, though it remains to be shown whether they translate into effective prevention of HCV infection or progression of infection to a chronic state. Such responses were also induced by a clinically tested vector-based vaccine candidate, which decreased the viral HCV load but did not prevent chronic HCV infection. These disappointments were not readily predicted from preclinical animal studies. The vaccine platforms employing virus-like particles, DNA, and mRNA provide opportunities for the HCV vaccine, but their potential in this context has yet to be shown. Ensuring the designed vaccine is based on conserved epitope(s) and elicits broadly neutralizing immune responses is also essential. Given failures in developing a prophylactic HCV vaccine, it is crucial to continue supporting national strategies, including funding for screening and treatment programs. However, these actions are likely insufficient to permanently control the HCV burden, encouraging further mobilization of significant resources for HCV vaccine research as a missing element in the elimination of viral hepatitis as a global public health.

Non-alcoholic fatty liver disease (NAFLD) is a pressing global health concern that is associated with metabolic syndrome and obesity. On the basis of the insights provided by Jiang et al, this editorial presents an exploration of the potential of mesenchymal stem cells (MSCs) for NAFLD treatment. MSCs have numerous desirable characteristics, including immunomodulation, anti-inflammatory properties, and tissue regeneration promotion, rendering them attractive candidates for NAFLD treatment. Recent preclinical and early clinical studies have highlighted the efficacy of MSCs in improving liver function and reducing disease severity in NAFLD models. However, MSC heterogeneity, long-term safety concerns, and unoptimized therapeutic protocols remain substantial challenges. Addressing these challenges through standardized protocols and rigorous clinical trials is essential to the safe and successful application of MSCs in NAFLD management. Continued research into MSC mechanisms and therapeutic optimization is required to improve treatments for NAFLD and related liver diseases.

Food processing unavoidably introduces various risky ingredients that threaten food safety. N-Nitrosamines (NAs) constitute a class of food contaminants, which are considered carcinogenic to humans. According to the compiled information, pretreatment methods based on solid-phase extraction (SPE) were widely used before the determination of volatile NAs in foods. The innovation of adsorbents and hybridization of other methods have been confirmed as the future trends of SPE-based pretreatment methods. Moreover, technologies based on liquid chromatography and gas chromatography were popularly applied for the detection of NAs. Recently, sensor-based methods have garnered increasing attention due to their efficiency and flexibility. More portable sensor-based technologies are recommended for on-site monitoring of NAs in the future. The application of artificial intelligence can facilitate data processing during high-throughput detection of NAs. Natural bioactive compounds have been confirmed to be effective in mitigating NAs in foods through antioxidation, scavenging precursors, and regulating microbial activities. Meanwhile, they exhibit strong protective activities against hepatic damage, pancreatic cancer, and other NA injuries. Further supplementation of data on the bioavailability of bioactives can be achieved through encapsulation and clinical trials. The utilization of bioinformatics tools rooted in various omics technologies is suggested for investigating novel mechanisms and finally broadening their applications in targeted therapies.

Nicotinamide mononucleotide (NMN), a crucial intermediate in NAD + synthesis, can rapidly transform into NAD + within the body after ingestion. NMN plays a pivotal role in several important biological processes, including energy metabolism, cellular aging, circadian rhythm regulation, DNA repair, chromatin remodeling, immunity, and inflammation. NMN has emerged as a key focus of research in the fields of biomedicine, health care, and food science. Recent years have witnessed extensive preclinical studies on NMN, offering valuable insights into the pathogenesis of age- and aging-related diseases. Given the sustained global research interest in NMN and the substantial market expectations for the future, here, we comprehensively review the milestones in research on NMN biotherapy over the past 10 years. Additionally, we highlight the current research on NMN in the field of digestive system diseases, identifying existing problems and challenges in the field of NMN research. The overarching aim of this review is to provide references and insights for the further exploration of NMN within the spectrum of digestive system diseases.

BACKGROUND: Excessive intraoperative bleeding remains a challenge in limb surgeries. The exsanguination tourniquet ring has emerged as a potential solution for effective exsanguination and hemostasis. This study aims to evaluate its efficacy and safety compared to the conventional exsanguination and hemostasis approach (pneumatic tourniquet combined with Esmarch bandage).
METHODS: This randomized controlled trial evaluates the exsanguination tourniquet ring\'s effectiveness and safety versus the conventional approach in 220 participants undergoing various limb surgeries. Allocation included experimental and control groups, assesses through efficacy (including intraoperative and total blood loss, hemoglobin levels, and exsanguination and hemostasis effectiveness) and safety (adverse event occurrence) indicators.
RESULTS: The experimental group (n = 110) utilizes the exsanguination tourniquet ring, while the control group (n = 110) employs the conventional approach. As for intraoperative blood loss, the experimental group is non-inferior to the control group (p-value < 0.001). While no significant difference is found in total blood loss (for the full analysis set, p-value = 0.442; for the per protocol set, p-value = 0.976) and differences in postoperative and preoperative hemoglobin levels (for the full analysis set, p-value = 0.502; for the per protocol set, p-value = 0.928). Regarding exsanguination and hemostasis effectiveness, the full analysis set reveals significantly superior ratings in the experimental group compared to the control group (p-value = 0.002 < 0.05), while the per protocol set analysis indicates no significant difference between the groups (p-value = 0.504). As for safety indicators, adverse events related to the device are minimal in two groups, with only one severe event unrelated to the device.
CONCLUSIONS: The exsanguination tourniquet ring is an effective and safe device for intraoperative blood loss control in various limb surgeries.
BACKGROUND: Comparison of Exsanguination and Hemostasis Devices for Limb Surgery A Prospective Multicenter Randomized Controlled Study, ChiCTR2300077998, 11/27/2023.

Alzheimer\'s disease (AD) remains the foremost cause of dementia and represents a significant unmet healthcare need globally. The complex pathogenesis of AD, characterized by various pathological and physiological events, has historically challenged the development of anti-AD drugs. However, recent breakthroughs in AD drug development, including the approvals of aducanumab, lecanemab, and sodium oligomannate (GV-971), have ended a nearly two-decade hiatus in the introduction of new AD drugs. These developments have addressed long-standing challenges in AD drug development, marking a substantial shift in the therapeutic landscape of AD. Moreover, natural products (NPs) have shown promise in AD drug research, with several currently under clinical investigation. Their distinct properties and mechanisms of action offer new avenues to complement and enhance existing AD treatment approaches. This review article aims to provide an overview of the recent advancements and prospects in AD therapeutics, focusing on both NPs and approved drugs.

PI3K inhibitors have emerged as promising therapeutic agents due to their critical role in various cellular processes, particularly in cancer, where the PI3K pathway is frequently dysregulated. This review explores the evolutionary path of PI3K inhibitors from laboratory discovery to clinical application. The journey begins with early laboratory investigations into PI3K signaling and inhibitor development, highlighting fundamental discoveries that laid the foundation for subsequent advancements. Optimization strategies, including medicinal chemistry approaches and structural modifications, are scrutinized for their contributions to enhancing inhibitor potency, selectivity, and pharmacokinetic properties. The translation from preclinical studies to clinical trials is examined, emphasizing pivotal trials that evaluated efficacy and safety profiles. Challenges encountered during clinical development are critically assessed. Finally, the review discusses ongoing research directions and prospects for PI3K inhibitors, underscoring these agents\' continuous evolution and therapeutic potential.