Novel humanized monoclonal antibodies against ROR1 for cancer therapy.

BACKGROUND: Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. METHODS: ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. RESULTS: ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. CONCLUSIONS: Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.

The addition of nimotuzumab during concurrent chemoradiotherapy improved survival outcomes in locally advanced nasopharyngeal carcinoma patients with optimal response to induction chemotherapy.

OBJECTIVE: To investigate the impact of response to induction chemotherapy (IC) on survival outcomes in patients with locally advanced nasopharyngeal carcinoma (LANPC) and evaluate the efficacy of adding nimotuzumab to concurrent chemoradiotherapy (CCRT) based on different responses to IC. METHODS: We retrospectively included patients with stage III-IVA NPC who underwent IC with and without nimotuzumab during CCRT. Statistical analysis included the chi-square test, propensity score matching, Kaplan-Meier survival analysis, and Cox proportional hazards model. RESULTS: Among 383 identified patients, 216 (56.4%) received nimotuzumab during CCRT, while 167 (43.6%) did not. Following IC, 269 (70.2%) patients showed a complete response (CR) or partial response (PR), and 114 (29.8%) had stable disease (SD) or progressive disease (PD). The response to IC independently influenced disease-free survival (DFS) and overall survival (OS). Patients achieving CR/PR demonstrated significantly higher 3-year DFS (80.3% vs. 70.6%, P = 0.031) and OS (90.9% vs. 83.2%, P = 0.038) than those with SD/PD. The addition of nimotuzumab during CCRT significantly improved DFS (P = 0.006) and OS (P = 0.037) for CR/PR patients but not for those with SD/PD. CONCLUSIONS: This study emphasizes the importance of IC response in LANPC and highlights the potential benefits of nimotuzumab during CCRT for improving survival outcomes in CR/PR patients. Tailored treatment approaches for SD/PD patients warrant further investigation.

Use of pressure muscle index to guide pressure support ventilation setting: a study protocol and statistical plan for a prospective randomised controlled proof-of-concept trial.

INTRODUCTION: Although pressure support ventilation is one of the most commonly used assisted ventilation modes in intensive care units, there is still a lack of precise strategies for setting pressure support. By performing an end-inspiratory airway occlusion, the difference between the peak and plateau airway pressure, which is defined as pressure muscle index (PMI), can be easily measured on the ventilator screen. Previous studies have shown that PMI is accurate in detecting high and low inspiratory effort. No study has been conducted to investigate the use of PMI as an indicator for setting inspiratory pressure support. METHOD AND ANALYSIS: This is a study protocol for a prospective, single-centre, randomised controlled, pilot trial. Sixty participants undergoing pressure support ventilation will be randomly assigned in a 1:1 ratio to the control group or intervention group, with pressure support adjusted according to standard care or guided by the PMI strategy for 48 hours, respectively. The feasibility of the PMI-guided strategy will be evaluated. The primary endpoint is the proportion of inspiratory effort measurements within a well-accepted 'normal' range, which is predefined as oesophageal pressure-time product per minute between 50 and 200 cmH2O⋅s/min, for each patient during 48 hours of pressure support adjustment. ETHICS AND DISSEMINATION: The study protocol has been approved by Beijing Tiantan Hospital (KY2023-005-02). The data generated in the present study will be available from the corresponding author on reasonable request. The results of the trial will be submitted to international peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05963737; ClinicalTrials.org.

Small-molecule-based targeted therapy in liver cancer.

Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.

Employing the International Classifications of Functioning, Disability, and Health to identify relevant categories for disability evaluation in older adults from the research perspective: a systematic review.

INTRODUCTION: The objective of this study was to identify relevant aspects for disability evaluation used in scientific literature for older adults. EVIDENCE ACQUISITION: We employed a systematic review methodology as outlined by the ICF Research Branch. The methodology consists of four steps: 1) identifying studies that focus on disability evaluation among older adults; 2) identifying disability measures used in these studies; 3) linking the concepts contained in these measures to ICF categories; 4) conducting frequency analysis. EVIDENCE SYNTHESIS: A total of 1942 concepts contained in disability measures from 137 studies were extracted. About 97.7% of the concepts could be linked, and 1862 concepts were linked to 52 second-level ICF categories. Of these, 44 categories found in at least 5% of the studies (range 5.1-85.4%) were selected to develop an outcome set that represents the relevant categories, including five categories in the Body Functions component and 39 categories from the Activities and Participation component. CONCLUSIONS: The relevant categories identified in our study reflect the essential areas that measure disability for older adults, providing a scientific basis for developing an ICF Core Set for disability evaluation, in combination with further empirical study and expert survey. Information from the outcome set is also valuable for providing a standardized minimal set for disability measurement, which can be used for data comparison across different studies and the development of an ICF-based disability measurement tool.

Clinical effects of detailed nursing management interventions on medication adherence and disease perception in patients with drug-resistant tuberculosis.

BACKGROUND: Tuberculosis (TB) is a chronic respiratory infectious disease that considerably jeopardizes human health, and there is no effective vaccine suitable for its prevention in the entire population. AIM: To investigate the promotion of medication adherence and disease cognition in patients with drug-resistant (DR-)TB using detailed nursing management. METHODS: In total, 114 patients with DR-TB who were diagnosed and treated at our hospital between January 2019 and January 2023 were included in this study. Patients in the control group (n = 57) were managed with conventional nursing care, while those in the observation group (n = 57) were managed with detailed nursing care. Medication adherence, disease awareness scores, medication safety, and nursing satisfaction were compared between the two groups after the intervention. RESULTS: The post-intervention medication compliance rate was 91.23% in the observation group and 75.44% in the control group, with the former being 15.79% higher than the latter (P < 0.05). There was no statistically significant difference in the disease awareness scores between the two groups before the intervention; the disease awareness scores of the observation group were significantly higher than those of the control group after the intervention (P < 0.05). The incidence of gastrointestinal reactions, joint swelling and pain, hearing loss, electrolyte disorders, and liver and kidney function abnormalities were lower in the observation group than those in the control group. The total nursing satisfaction of the observation group was higher than that of the control group (P < 0.05). CONCLUSION: Implementation of detailed nursing management for patients with DR-TB can effectively improve medication adherence, enhance awareness of the disease, ensure safety of medication, and improve satisfaction with nursing care.

Chromosome-level genome assembly and sex chromosome identification of the pink stem borer, Sesamia inferens (Lepidoptera: Noctuidae).

The pink stem borer, Sesamia inferens Walker (Lepidoptera: Noctuidae), is one of the most notorious pest insects of rice and maize crops in the world. Here, we generated a high-quality chromosome-level genome assembly of S. inferens, using a combination of Illumina, PacBio HiFi and Hi-C technologies. The total assembly size was 973.18 Mb with a contig N50 of 33.39 Mb, anchored to 31 chromosomes, revealing a karyotype of 30 + Z. The BUSCO analysis indicated a high completeness of 98.90% (n = 5286), including 5172 (97.8%) single-copy BUSCOs and 58 (1.1%) duplicated BUSCOs. The genome contains 58.59% (564.58 Mb) repeat elements and 26628 predicted protein-coding genes. The chromosome-level genome assembly of S. inferens provides in-depth knowledge and will be a helpful resource for the Lepidoptera and pest control research communities.

Study of Factors Influencing the Oral Bioaccessibility of Commonly Used and Detected Pesticides in Bananas and Mangoes Based on in vitro Methods.

Estimating the impact of pesticide residue bioaccessibility in fruits on dietary exposure is a complex task in human health risk assessment. This research investigated the bioaccessibility of ten commonly used and detected pesticides in bananas and mangoes, as well as the factors influencing it, using an in vitro model. The highest bioaccessibility was observed at pH levels of 2.5 and 6.5 in the gastric and intestinal stages, respectively. Bioaccessibility decreased significantly with increasing solid/liquid ratios for most pesticides. The consumption of protein and four dietary components (carbohydrates, protein, lipids, and dietary fiber) could significantly reduce pesticide bioaccessibility by 9.89-48.32% (p < 0.05). Bioaccessibility in oral and gastric stages among four populations followed the order of adults/the elderly > children > infants, due to decreasing concentrations of α-amylase and pepsin. Pesticides in bananas generally exhibited a higher bioaccessibility (18.65-82.97%) compared to that in mangoes (11.68-87.57%). Bioaccessibility showed a negative correlation with the Log P values of the target pesticide, while no clear relationship was found between bioaccessibility and initial pesticide concentrations. Incorporating bioaccessible pesticide concentrations into risk assessments could lower dietary risk estimates by 11.85-79.57%. Assessing human exposure to pesticides based on bioaccessibility would greatly improve the accuracy of the risk assessment.

Tumor-associated macrophages in anti-PD-1/PD-L1 immunotherapy for hepatocellular carcinoma: recent research progress.

Hepatocellular carcinoma (HCC) is one of the cancers that seriously threaten human health. Immunotherapy serves as the mainstay of treatment for HCC patients by targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis. However, the effectiveness of anti-PD-1/PD-L1 treatment is limited when HCC becomes drug-resistant. Tumor-associated macrophages (TAMs) are an important factor in the negative regulation of PD-1 antibody targeted therapy in the tumor microenvironment (TME). Therefore, as an emerging direction in cancer immunotherapy research for the treatment of HCC, it is crucial to elucidate the correlations and mechanisms between TAMs and PD-1/PD-L1-mediated immune tolerance. This paper summarizes the effects of TAMs on the pathogenesis and progression of HCC and their impact on HCC anti-PD-1/PD-L1 immunotherapy, and further explores current potential therapeutic strategies that target TAMs in HCC, including eliminating TAMs in the TME, inhibiting TAMs recruitment to tumors and functionally repolarizing M2-TAMs (tumor-supportive) to M1-TAMs (antitumor type).

Integration of High-Resolution LC-Q-TOF Mass Spectrometry and Multidimensional Chemical-Biological Analysis to Detect Nanomolar-Level Acetylcholinesterase Inhibitors from Different Parts of Zanthoxylum nitidum.

Zanthoxyli radix is a popular tea among the elderly, and it is believed to have a positive effect on Alzheimer's disease. In this study, a highly effective three-step strategy was proposed for comprehensive analysis of the active components and biological functions of Zanthoxylum nitidum (ZN), including high-resolution LC-Q-TOF mass spectrometry (HRMS), multivariate statistical analysis for heterogeneity (MSAH), and experimental and virtual screening for bioactivity analysis (EVBA). A total of 117 compounds were identified from the root, stem, and leaf of ZN through HRMS. Bioactivity assays showed that the order of acetylcholinesterase (AChE) inhibitory activity from strong to weak was root > stem > leaf. Nitidine, chelerythrine, and sanguinarine were found to be the main differential components of root, stem, and leaf by OPLS-DA. The IC50 values of the three compounds are 0.81 ± 0.02, 0.14 ± 0.01, and 0.48 ± 0.01 µM respectively, indicating that they are potent and high-quality AChE inhibitors. Molecular docking showed that pi-pi T-shaped interactions and pi-lone pairs played important roles in AChE inhibition. This study not only explains the biological function of Zanthoxyli radix in alleviating Alzheimer's disease to some extent, but also lays the foundation for the development of stem and leaf of ZN.

Survey of physicians' knowledge about pediatric nonalcoholic fatty liver disease in China.

OBJECTIVES: To evaluate physicians' awareness and knowledge towards pediatric nonalcoholic fatty liver disease (NAFLD) and their attitude toward change in nomenclature from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) in China. METHODS: The questionnaire survey contained five parts (characteristics of the participants, epidemiology, diagnosis, management of NAFLD, and attitudes toward the nomenclature of MAFLD/MASLD). The participants included 53 hepatologists, 88 gastroenterologists (GEs), 74 endocrinologists (ENDOs), 61 primary care physicians (PCPs), and 157 pediatricians across 31 municipalities, provinces and autonomous regions of China's mainland. RESULTS: Hepatologists saw the largest number of pediatric NAFLD patients annually (median 9 [range 1-20]), with the lowest number by PCPs (even notwithstanding one patient annually). The primary sources of pediatric NAFLD knowledge were acquired via guidelines. Hepatologists had the highest total knowledge score among all five types of physicians. Approximately one-third of nonspecialists (ENDOs and PCPs) considered liver biopsy necessary for pediatric NAFLD patients, and this percentage increased to half in specialists (hepatologists and GEs). For nonspecialists, the major barriers to the management of pediatric NAFLD were poor patient adherence to lifestyle modifications and lacking confidence in managing NAFLD. Above 90% physicians agreed to change the nomenclature NAFLD to MAFLD; however, they were not sure whether it could reduce the economic burden. CONCLUSIONS: Despite the epidemic of pediatric NAFLD in China, a significant knowledge gap remains in the identification, diagnosis, and treatment of pediatric NAFLD, particularly among frontline workers such as pediatricians and PCPs. More education programs should be carried out in the future.

Interaction of Th17 differentiations-related gene polymorphisms and environmental factors contributing to the disease classification, complications, and surgical risks of Crohn's disease in the Chinese Han population.

OBJECTIVES: Few studies have been conducted on gene-environment interactions in the Chinese population with Crohn's disease (CD). We aimed to investigate the association between single nucleotide polymorphisms (SNPs) on the T helper 17 (Th17) cell and CD susceptibility/performance in Chinese individuals. METHODS: We conducted a case-control and case-only study at the Peking Union Medical College Hospital. Four SNPs related to the Th17 cell pathway genes were prioritized, including rs2284553 (interferon gamma receptor 2), rs7517847 (interleukin 23 receptor), rs7773324 (interferon regulatory factor 4), and rs4263839 (tumor necrosis factor superfamily 15). SNP frequency was calculated, and gene-environment interaction was assessed by multifactor dimensionality reduction analysis. RESULTS: Altogether 159 CD patients and 316 healthy controls were included. All analyzed SNPs were found in Hardy-Weinberg equilibrium (P > 0.05). The frequency of rs2284553-A allele and rs4263839-A allele were lower in CD patients compared with controls (P < 0.05). While the rs4263839-A allele was more prevalent in ileocolonic CD patients than in those with isolated small intestinal or colonic disease (P = 0.035). Gene-environment interactions revealed associations between rs2284553 and breastfeeding, sunshine exposure, and fridge-stored food, affecting age at diagnosis, intestinal involvement, and intestinal stricture. Interaction of rs4263839 and breastfeeding influenced small intestinal lesions and intestinal stricture in CD. CONCLUSIONS: This study provided information on the genetic background in Chinese CD patients. Incorporating these SNPs into predictive models may improve risk assessment and outcome prediction. Gene-environment interaction contributes to the understanding of CD pathogenesis.

Measurable residual disease testing by next generation sequencing is more accurate compared with multiparameter flow cytometry in adults with B-cell acute lymphoblastic leukemia.

Results of measurable residual disease (MRD)-testing by next-generation sequencing (NGS) correlate with relapse risk in adults with B-cell acute lymphoblastic leukemia (ALL) receiving chemotherapy or an allotransplant from a human leukocyte antigen (HLA)-identical relative or HLA-matched unrelated donor. We studied cumulative incidence of relapse (CIR) and survival prediction accuracy using a NGS-based MRD-assay targeting immunoglobulin genes after 2 courses of consolidation chemotherapy cycles in 93 adults with B-cell ALL most receiving HLA-haplotype-matched related transplants. Prediction accuracy was compared with MRD-testing using multi-parameter flow cytometry (MPFC). NGS-based MRD-testing detected residual leukemia in 28 of 65 subjects with a negative MPFC-based MRD-test. In Cox regression multi-variable analyses subjects with a positive NGS-based MRD-test had a higher 3-year CIR (Hazard Ratio [HR] = 3.37; 95 % Confidence Interval [CI], 1.34-8.5; P = 0.01) and worse survival (HR = 4.87 [1.53-15.53]; P = 0.007). Some data suggest a lower CIR and better survival in NGS-MRD-test-positive transplant recipients but allocation to transplant was not random. Our data indicate MRD-testing by NGS is more accurate compared with testing by MPFC in adults with B-cell ALL in predicting CIR and survival. (Registered in the Beijing Municipal Health Bureau Registration N 2007-1007 and in the Chinese Clinical Trial Registry [ChiCTR-OCH-10000940 and ChiCTROPC-14005546]).

Dietary ellagic acid therapy for CNS autoimmunity: Targeting on Alloprevotella rava and propionate metabolism.

BACKGROUND: Mediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS. RESULTS: We found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells. CONCLUSIONS: Our study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis. Video Abstract.

Vividness of visual imagery is associated with the effect of relaxation response meditation training in elderly people with nonorganic insomnia: A randomized, double-blind, multi-center clinical trial.

BACKGROUND: This study aims to explore the efficacy of Relaxation Response Meditation Training (RRMT) on elderly individuals with different levels of vividness of visual imagery. METHODS: In this randomized controlled, double-blind, multi-center clinical trial, we recruited a total of 136 elderly individuals who were over 60 years with nonorganic sleep disorders to participate in a 4-week RRMT intervention from October 2020 to October 2022. The intervention occurred twice a week, totaling eight times. These individuals were divided into high and low groups based on the vividness of visual imagery, and then randomly assigned to either the control or intervention groups, as follows: low-visualizers intervention group (LI group); low-visualizers control group (LC group); high-visualizers intervention group (HI group); high-visualizers control group (HC group). Their social and psychological parameters were assessed before and after the intervention by the Pittsburgh Sleep Quality Index (PSQI), the Revised Piper's fatigue scale (RPFS), General well-being scale (GWB), and Satisfaction rating. The alpha waves of patients were also collected through electroencephalogram to assess their level of relaxation. RESULTS: Compared to the LI group, the HI group had a greater reduction rate in the PSQI score [25.2 % (18.8 % to 31.7 %), P < 0∙001], shorter sleep latency (P = 0.001), lower frequency of sleep medication (P < 0.001), lower PSQI scores (P < 0.001), and higher GWB scores (P < 0.001). There were significant differences in all indicators in the HI group vs. HC group and in the LI group vs. LC group. In the first five relaxation training sessions, there was no statistically significant difference in the proportion of α waves between the LI group and the LC group; however, from the sixth session onward, we observed a statistically significant difference (t = 2.86, P = 0.019)，while The HI group and HC group showing significant differences in the first relaxation training session (t = 4.464, P < 0.001). There was a statistically significant difference in subjective satisfaction between the intervention group and the control group (x2 = 49.605, P < 0.001). CONCLUSION: In this study, we found that most elderly people benefitted from RRMT regardless of their vividness of visual imagery. However, low-visualizers experienced slower and less effective results, so these patients may benefit more from alternative approaches.

SRSF9 promotes cell proliferation and migration of glioblastoma through enhancing CDK1 expression.

BACKGROUND: Glioblastoma (GBM) is a highly aggressive and prevalent brain tumor that poses significant challenges in treatment. SRSF9, an RNA-binding protein, is essential for cellular processes and implicated in cancer progression. Yet, its function and mechanism in GBM need clarification. METHODS: Bioinformatics analysis was performed to explore differential expression of SRSF9 in GBM and its prognostic relevance to glioma patients. SRSF9 and CDK1 expression in GBM cell lines and patients' tissues were quantified by RT-qPCR, Western blot or immunofluorescence assay. The role of SRSF9 in GBM cell proliferation and migration was assessed by MTT, Transwell and colony formation assays. Additionally, transcriptional regulation of CDK1 by SRSF9 was investigated using ChIP-PCR and dual-luciferase assays. RESULTS: The elevated SRSF9 expression correlates to GBM stages and poor survival of glioma patients. Through gain-of-function and loss-of-function strategies, SRSF9 was demonstrated to promote proliferation and migration of GBM cells. Bioinformatics analysis showed that SRSF9 has an impact on cell growth pathways including cell cycle checkpoints and E2F targets. Mechanistically, SRSF9 appears to bind to the promoter of CDK1 gene and increase its transcription level, thus promoting GBM cell proliferation. CONCLUSIONS: These findings uncover the cellular function of SRSF9 in GBM and highlight its therapeutic potential for GBM.

Identification and Validation of PKR as a Direct Target for the Novel Sulfonamide-Substituted Tetrahydroquinoline Nonselective Inhibitor of the NLRP3 Inflammasome.

The NLRP3 inflammasome is a critical component of the innate immune system. The persistent abnormal activation of the NLRP3 inflammasome is implicated in numerous human diseases. Herein, sulfonamide-substituted tetrahydroquinoline derivative S-9 was identified as the most promising NLRP3 inhibitor, without obvious cytotoxicity. In vitro, S-9 inhibited the priming and activation stages of the NLRP3 inflammasome. Incidentally, we also observed that S-9 had inhibitory effects on the NLRC4 and AIM2 inflammasomes. To elucidate the multiple anti-inflammatory activities of S-9, photoaffinity probe P-2, which contained a photoaffinity label and a functional handle, was developed for target identification by chemical proteomics. We identified PKR as a novel target of S-9 in addition to NLRP3 by target fishing. Furthermore, S-9 exhibited a significant anti-neuroinflammatory effect in vivo. In summary, our findings show that S-9 is a promising lead compound targeting both PKR and NLRP3 that could emerge as a molecular tool for treating inflammasome-related diseases.

Discovery of Novel Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) Inhibitors for Cancer Treatment.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncogenic membrane protein in several malignancies and has been considered an attractive target for the treatment of human cancers. In this study, structure-based virtual screening and structure optimization were conducted to identify novel ROR1 inhibitors. Based on hit compound 2, 45 novel ROR1 inhibitors were designed and synthesized, and the detailed structure-activity relationship was investigated. Representative compound 19h potently binds ROR1 with a KD value of 0.10 µM, exhibiting antitumor activity in lung cancer and breast cancer cell lines (IC50: 0.36-1.37 µM). Additionally, a mechanism investigation demonstrated that compound 19h induces the apoptosis of tumor cells. Importantly, compound 19h significantly suppressed tumor growth in a mouse model without obvious toxicity. Overall, this work identified compound 19h as a new ROR1 inhibitor, providing a novel lead compound for the treatment of lung cancer and breast cancer.

Immunotherapy combined with antiangiogenic therapy as third- or further-line therapy for stage IV non-small cell lung cancer patients with ECOG performance status 2: A retrospective study.

BACKGROUND: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 2 probably cannot tolerate chemotherapy or other antitumor therapies. Some studies have reported that immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity. However, the efficacy of this combination as a later-line therapy in patients with ECOG PS 2 is unclear. This study evaluated the effectiveness and safety of this combination strategy as third- or further-line therapy in stage IV non-small cell lung cancer (NSCLC) patients with ECOG PS 2. METHODS: In this retrospective study, patients treated with camrelizumab plus antiangiogenic therapy (bevacizumab, anlotinib, or recombinant human endostatin) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed by ECOG PS, and safety were analyzed. RESULTS: Between January 10, 2019, and February 28, 2024, a total of 59 patients were included. The ORR was 35.6% (21/59) and the DCR was 86.4%. With a median follow-up of 10.5 months (range: 0.7-23.7), the median PFS was 5.5 months (95% confidence interval [CI]: 3.8-7.3) and the median OS was 10.5 months (95% CI: 11.2-13.6). QOL was improved (≥1 reduction in ECOG PS) in 39 patients (66.1%). The most common Grade 3-4 treatment-related adverse events were hepatic dysfunction (6 [10%]), hypertension (5 [8%]), and hypothyroidism (3 [5%]). There were no treatment-related deaths. CONCLUSIONS: Third- or further-line immunotherapy combined with antiangiogenic therapy is well-tolerated and shows good antitumor activity in stage IV NSCLC patients with ECOG PS 2. Future large-scale prospective studies are required to confirm the clinical benefits of this combination therapy.

Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes.

Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.