Epstein-Barr virus protein BKRF4 restricts nucleosome assembly to suppress host antiviral responses.

Inhibition of host DNA damage response (DDR) is a common mechanism used by viruses to manipulate host cellular machinery and orchestrate viral life cycles. Epstein-Barr virus tegument protein BKRF4 associates with cellular chromatin to suppress host DDR signaling, but the underlying mechanism remains elusive. Here, we identify a BKRF4 histone binding domain (residues 15-102, termed BKRF4-HBD) that can accumulate at the DNA damage sites to disrupt 53BP1 foci formation. The high-resolution structure of the BKRF4-HBD in complex with a human H2A-H2B dimer shows that BKRF4-HBD interacts with the H2A-H2B dimer via the N-terminal region (NTR), the DWP motif (residues 80-86 containing D81, W84, P86), and the C-terminal region (CTR). The "triple-anchor" binding mode confers BKRF4-HBD the ability to associate with the partially unfolded nucleosomes, promoting the nucleosome disassembly. Importantly, disrupting the BKRF4-H2A-H2B interaction impairs the binding between BKRF4-HBD and nucleosome in vitro and inhibits the recruitment of BKRF4-HBD to DNA breaks in vivo. Together, our study reveals the structural basis of BKRF4 bindings to the partially unfolded nucleosome and elucidates an unconventional mechanism of host DDR signal attenuation.

GSK-3ß/ß-catenin pathway plays crucial roles in the regulation of NK cell cytotoxicity against myeloma cells.

The plasma cell malignancy, multiple myeloma (MM), has significantly improved by the application of new drugs and autologous hematopoietic stem cell transplantation. However, MM remains incurable. A number of studies have revealed an anti-MM effect of natural killer (NK) cells; however, their clinical efficacy is limited. Furthermore, glycogen synthase kinase (GSK)-3ß inhibitors show an antitumor function. In this study, we aimed to evaluate the potential roles of a GSK-3ß inhibitor (TWS119) in the regulation of NK cell cytotoxicity against MM. Our results showed that, in the presence of TWS119, the NK cell line, NK-92, and in vitro-expanded primary NK cells exhibited a significantly higher degranulation activity, expression of activating receptors, cellular cytotoxicity, and cytokine secretion when they were exposed to MM cells. Mechanistic studies indicated that TWS119 treatment markedly upregulated RAB27A expression, a key molecule for NK cell degranulation, and induced the colocalization of ß-catenin with NF-κB in the nucleus of NK cells. More importantly, GSK-3ß inhibition combined with the adoptive transfer of TWS119-treated NK-92 cells significantly reduced tumor volume and prolonged the survival time of myeloma-bearing mice. In summary, our novel findings suggest that targeting GSK-3ß through the activation of ß-catenin/NF-κB pathway may be an important approach to improve therapeutic efficacy of NK cell transfusion for MM.

Clinical significance and predictive risk factors for event-free survival at 24 months in patients with PTCL, NOS.

Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), is a heterogeneous and aggressive type of non-Hodgkin's lymphoma with a bleak prognosis. This study was designed to assess the value of EFS24 as an alternative clinical endpoint and identify prognosis-related factors in PTCL, NOS. Patients diagnosed with PTCL, NOS were retrospectively collected and slides were reviewed by two hematopathologists. EFS was defined as the time from diagnosis to the occurrence of disease progression after initial treatment, retreatment, or death. Subsequent overall survival (OS) was defined from EFS24 or time of progression, if it occurred within 24 months, to the last follow-up or death. 97 cases with complete follow-up were selected. Approximately 66 patients (68.04%) failed to achieve ES24, with the median OS of 12.17 months, and 5-year OS rate of 15.17%. While patients who reached EFS24 had a median OS of 60.57 months and a 5-year OS rate of 68.77%. Multivariate Cox analysis indicated that bone marrow involvement and elevated ß2 Microglobulin (ß2-MG) were associated with a poor prognosis. B symptoms, extranodal involvement more than one site, and a high Ki67 index were significant factors in predicting the failure of EFS24. EFS24 can help stratify the subsequent outcomes of PTCL, NOS. Patients who achieve EFS24 have a favorable prognosis, although it does not reach that of the general population. On the other hand, patients who do not achieve EFS24 have an extremely poor prognosis. Therefore, EFS24 can be used for patient risk stratification, patient counseling, and study design.

Outcomes following KRASG12C inhibitor treatment in patients with KRASG12C-mutated solid tumors: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy and safety of FDA-approved KRASG12C inhibitors in patients with KRASG12C-mutated solid tumors. METHODS: We searched PubMed, EMBASE, Cochrane Library, and major international conferences for clinical trials published in English up to March 6, 2023. Clinical trials investigating sotorasib or adagrasib and reporting the clinical outcomes of the objective response rate (ORR), disease control rate (DCR), or incidence rate of grade ≥ 3 adverse events (AEs) were eligible. The primary endpoint was the ORR. Secondary endpoints included the DCR, incidence rate of grade ≥ 3 AEs, and odds ratio (OR) of the ORR between patients with or without co-mutation. The Random-effects model was applied for the outcomes of interest. RESULTS: 18 studies with 1224 patients were included in this meta-analysis. The pooled ORR, DCR, and incidence rate of grade ≥ 3 AEs were 31 % (95 % CI, 25-37 %), 86 % (95 % CI, 82-89 %), and 29 % (95 % CI, 23-36 %), respectively. KRASG12C-mutated NSCLC patients with a co-mutation of KEAP1 exhibited a worse ORR than those with wild-type KEAP1 (OR: 0.35, 95 % CI: 0.16-0.77). CONCLUSIONS: This study provided a comprehensive understanding of the efficacy and safety of KRASG12C inhibitors in treating solid tumors and identified KEAP1 mutation as a potential predictive biomarker of inferior response in patients treated with KRASG12C inhibitors. These findings may assist in the design of future clinical trials for identifying populations that may benefit from KRASG12C inhibitor treatment.

Tislelizumab and radiation therapy in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type: a phase II study protocol.

Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).

Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).

αO-Conotoxin GeXIVA[1,2] Suppresses In Vivo Tumor Growth of Triple-Negative Breast Cancer by Inhibiting AKT-mTOR, STAT3 and NF-κB Signaling Mediated Proliferation and Inducing Apoptosis.

Breast cancer is one of the leading causes of cancer mortality worldwide, and triple-negative breast cancer (TNBC) is the most problematic subtype. There is an urgent need to develop novel drug candidates for TNBC. Marine toxins are a valuable source for drug discovery. We previously identified αO-conotoxin GeXIVA[1,2] from Conus generalis, which is a selective antagonist of α9 nicotinic acetylcholine receptors (nAChRs). Recent studies indicated that α9 nAChR expression is positively correlated with breast cancer development; thus, α9 nAChR could serve as a therapeutic target for breast cancer. In this study, we aimed to investigate the in vivo antitumor effects of GeXIVA[1,2] on TNBC and to elucidate its underlying anticancer mechanism. Our data showed that GeXIVA[1,2] effectively suppressed 4T1 tumor growth in vivo at a very low dose of 0.1 nmol per mouse. Our results uncovered that the antitumor mechanism of GeXIVA[1,2] simultaneously induced apoptosis and blocked proliferation. Further investigations revealed that GeXIVA[1,2]-induced Caspase-3-dependent apoptosis was achieved through regulating Bax/Bcl-2 balance, and GeXIVA[1,2]-inhibited proliferation was mediated by the downregulation of the AKT-mTOR, STAT3 and NF-κB signaling pathways. Our study provides valuable arguments to demonstrate the potential of GeXIVA[1,2] as a novel marine-derived anticancer drug candidate for the treatment of TNBC.

Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism.

Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.

A culture-free method for rapidly and accurately quantifying active SARS-CoV-2.

Determining the quantity of active virus is the most important basis to judge the risk of virus infection, which usually relies on the virus median tissue culture infectious dose (TCID50) assay performed in a biosafety level 3 laboratory within 5-7 days. We have developed a culture-free method for rapid and accurate quantification of active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by targeting subgenomic RNA (sgRNA) based on reverse transcription digital PCR (RT-dPCR). The dynamic range of quantitative assays for sgRNA-N and sgRNA-E by RT-dPCR was investigated, and the result showed that the limits of detection (LoD) and quantification (LoQ) were 2 copies/reaction and 10 copies/reaction, respectively. The delta strain (NMDC60042793) of SARS-CoV-2 was cultured at an average titer of 106.13 TCID50/mL and used to evaluate the developed quantification method. Copy number concentrations of the cultured SARS-CoV-2 sgRNA and genomic RNA (gRNA) gave excellent linearity (R2 = 0.9999) with SARS-CoV-2 titers in the range from 500 to 105 TCID50/mL. Validation of 63 positive clinical samples further proves that the quantification of sgRNA-N by RT-dPCR is more sensitive for active virus quantitative detection. It is notable that we can infer the active virus titer through quantification of SARS-CoV-2 sgRNA based on the linear relationship in a biosafety level 2 laboratory within 3 h. It can be used to timely and effectively identify infectious patients and reduce unnecessary isolation especially when a large number of COVID-19 infected people impose a burden on medical resources.

Peptidase inhibitor (PI16) impairs bladder cancer metastasis by inhibiting NF-κB activation via disrupting multiple-site ubiquitination of NEMO.

BACKGROUND: Bladder cancer (BLCA) is a malignancy that frequently metastasizes and leads to poor patient prognosis. It is essential to understand the molecular mechanisms underlying the progression and metastasis of BLCA and identify potential biomarkers. METHODS: The expression of peptidase inhibitor 16 (PI16) was analysed using quantitative PCR, immunoblotting and immunohistochemistry assays. The functional roles of PI16 were evaluated using wound healing, transwell, and human umbilical vein endothelial cell tube formation assays, as well as in vivo tumour models. The effects of PI16 on nuclear factor κB (NF-κB) signalling activation were examined using luciferase reporter gene systems, immunoblotting and immunofluorescence assays. Co-immunoprecipitation was used to investigate the interaction of PI16 with annexin-A1 (ANXA1) and NEMO. RESULTS: PI16 expression was downregulated in bladder cancer tissues, and lower PI16 levels correlated with disease progression and poor survival in patients with BLCA. Overexpressing PI16 inhibited BLCA cell growth, motility, invasion and angiogenesis in vitro and in vivo, while silencing PI16 had the opposite effects. Mechanistically, PI16 inhibited the activation of the NF-κB pathway by interacting with ANXA1, which inhibited K63 and M1 ubiquitination of NEMO. CONCLUSIONS: These results indicate that PI16 functions as a tumour suppressor in BLCA by inhibiting tumour growth and metastasis. Additionally, PI16 may serve as a potential biomarker for metastatic BLCA.

Systematic analysis of IL-6 as a predictive biomarker and desensitizer of immunotherapy responses in patients with non-small cell lung cancer.

BACKGROUND: Cytokines have been reported to alter the response to immune checkpoint inhibitors (ICIs) in patients with the tumor in accordance with their plasma concentrations. Here, we aimed to identify the key cytokines which influenced the responses and stimulated resistance to ICIs and tried to improve immunological response and develop novel clinical treatments in non-small cell lung cancer (NSCLC). METHODS: The promising predictive cytokines were analyzed via the multi-analyte flow assay. Next, we explored the correlation baseline level of plasma cytokines and clinical outcomes in 45 NSCLC patients treated with ICIs. The mechanism of the potential candidate cytokine in predicting response and inducing resistance to ICIs was then investigated. RESULTS: We found NSCLC with a low baseline concentration of IL-6 in plasma specimens or tumor tissues could derive more benefit from ICIs based on the patient cohort. Further analyses revealed that a favorable relationship between PD-L1 and IL-6 expression was seen in NSCLC specimens. Results in vitro showed that PD-L1 expression in the tumor was enhanced by IL-6 via the JAK1/Stat3 pathway, which induced immune evasion. Notably, an adverse correlation was found between IL-6 levels and CD8+ T cells. And a positive association between IL-6 levels and myeloid-derived suppressor cells, M2 macrophages and regulator T cells was also seen in tumor samples, which may result in an inferior response to ICIs. Results of murine models of NSCLC suggested that the dual blockade of IL-6 and PD-L1 attenuated tumor growth. Further analyses detected that the inhibitor of IL-6 stimulated the infiltration of CD8+ T cells and yielded the inflammatory phenotype. CONCLUSIONS: This study elucidated the role of baseline IL-6 levels in predicting the responses and promoting resistance to immunotherapy in patients with NSCLC. Our results indicated that the treatment targeting IL-6 may be beneficial for ICIs in NSCLC.

Characterization of molecular genetics and clinicopathology in thymic MALT lymphoma.

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is a type of low-grade malignant B-cell lymphoma. The aim of this study was to investigate the clinicopathological characteristics of thymic MALT lymphoma. We analyzed the clinical, morphological, immunophenotypical, cytogenetic, and molecular characteristics of 11 cases of thymic MALT lymphoma. The relevant literature was also reviewed. The median age of the 11 patients was 50 (range: 33-60). There was a female predominance with a female-to-male ratio of 10:1. Three patients presented with Sjögren syndrome, autoimmune thrombocytopenia purpura, and type B1 thymoma, respectively. Microscopically, thymic MALT lymphoma was characterized by epithelium-lined cysts that were surrounded by small lymphocytes, centrocyte-like cells, and monocytoid B-cells. Plasmacytic differentiation was observed in two cases. The tumor cells expressed CD20, CD79α, and BCL2. Clonal immunoglobulin genes were detected in all 8 examined cases. Fluorescence in situ hybridization (FISH) for 18q21 was performed in 7 cases, and no translocations involving 18q21 were found. Targeted gene sequencing was performed in five cases with available DNA samples, and TNFAIP3, CARD11, IGLL5, and CCND3 mutations were identified. Thymic MALT lymphoma is a rare type of B cell malignancy with a female predominance and excellent clinical outcomes. Molecular aberrations involving the NF-κB pathway are frequent in thymic MALT lymphoma, suggesting that dysregulation of the NF-κB pathway is an important mechanism underlying the pathogenesis of thymic MALT lymphoma.

Comparison analysis of first-line asparaginase- versus non-asparaginase-based regimens for early-stage extranodal NK/T-cell lymphoma.

The present study investigated the efficacy and toxicity profile of first-line asparaginase (ASP)-based versus non-ASP-based regimens in treating early-stage extranodal NK/T-cell lymphoma (ENKTCL) in non-anthracycline therapy era. This multi-center, real-world retrospective study consisted 305 newly diagnosed localized ENKTCL patients who were treated with sequential chemoradiation between 2010 and 2020 in China: 190 cases received ASP-based regimens and 115 cases received non-ASP-based regimens. Propensity score matching and multivariable analyses were used to compare survivals and toxicities between the two treatment groups. Non-ASP-based regimens achieved comparable survivals compared with ASP-based regimens in the entire cohort. The 5-year overall survival (OS), progression-free survival (PFS) rates were 84.7% and 73.5% for non-ASP-based regimens, and 87.7% (P=0.464) and 74.6% (P=0.702) for ASP-based regimens. The non-inferior survivals of non-ASP-based regimens were consistent after adjustment using PSM and multivariable analyses. However, survival benefits of ASP varied in different treatment modalities. Among patients receiving sequential chemotherapy and radiation (CT+RT±CT), ASP-based regimens achieved higher complete remission rate (54.3 vs. 34.5%, P=0.047) and more favorable survivals compared with non-ASP-based regimens (5-year OS, 87.0 vs. 69.0%, P=0.028). However, for patients receiving sequential radiation and chemotherapy (RT+CT), non-ASP-based regimens achieved comparable favorable survivals as ASP-based regimens. Besides, liver injury, malnutrition, and coagulative dysfunction were significantly more commonly documented in ASP-based regimens. These findings suggested that ASP was an effective agent in treating ENKTCL, especially among those receiving induction CT and RT. For patients who received upfront RT, non-ASP-based regimens might be a comparably effective and more tolerable treatment option.

Chlorogenic acid exerts neuroprotective effect against hypoxia-ischemia brain injury in neonatal rats by activating Sirt1 to regulate the Nrf2-NF-κB signaling pathway.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIE) is caused by perinatal asphyxia, which is associated with various confounding factors. Although studies on the pathogenesis and treatment of HIE have matured, sub-hypothermia is the only clinical treatment available for HIE. Previous evidence indicates that chlorogenic acid (CGA) exerts a potential neuroprotective effect on brain injury. However, the role of CGA on neonatal HI brain damage and the exact mechanism remains elusive. Here, we investigate the effects of CGA on HI models in vivo and in vitro and explore the underlying mechanism. METHODS: In the in vivo experiment, we ligated the left common carotid artery of 7-day-old rats and placed the rats in a hypoxic box for 2 h. We did not ligate the common carotid artery of the pups in the sham group since they did not have hypoxia. Brain atrophy and infarct size were evaluated by Nissl staining, HE staining and 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining. Morris Water Maze test (MWM) was used to evaluate neurobehavioral disorders. Western-blotting and immunofluorescence were used to detect the cell signaling pathway. Malondialdehyde (MDA) content test, catalase (CAT) activity detection and Elisa Assay was used to detect levels of inflammation and oxidative stress. in vitro experiments were performed on isolated primary neurons. RESULT: In our study, pretreatment with CGA significantly decreased the infarct volume of neonatal rats after HI, alleviated brain edema, and improved tissue structure in vivo. Moreover, we used the Morris water maze to verify CGA's effects on enhancing the learning and cognitive ability and helping to maintain the long-term spatial memory after HI injury. However, Sirt1 inhibitor EX-527 partially reversed these therapeutic effects. CGA pretreatment inhibited neuronal apoptosis induced by HI by reducing inflammation and oxidative stress. The findings suggest that CGA potentially activates Sirt1 to regulate the Nrf2-NF-κB signaling pathway by forming complexes thereby protecting primary neurons from oxygen-glucose deprivation (OGD) damage. Also, CGA treatment significantly suppresses HI-induced proliferation of glial. CONCLUSION: Collectively, this study uncovered the underlying mechanism of CGA on neonatal HI brain damage. CGA holds promise as an effective neuroprotective agent to promote neonatal brain recovery from HI-induced injury. Video Abstract.

Rain Classroom assisted by WeChat for preliminary online physiology teaching during the COVID-19 pandemic.

Due to the COVID-19 pandemic during spring semester 2020, teachers and students were forced to engage in online instruction. However, there is little evidence on the feasibility of online physiology teaching. This study demonstrated a 3-wk preliminary online physiology course based on Rain Classroom assisted by the mobile application WeChat. Eighty-seven nursing undergraduate students attended an online physiology course during the spring semester of the 2019-2020 academic year from March 9 to March 29. We determined the effects of the online physiology learning based on in-class tests, preclass preparation, and review rates for the course materials. We also measured the students' perceptions and attitudes about online learning with a questionnaire survey. Posttest scores from the first week to the third week in online physiology course (7.22 ± 1.83, 7.68 ± 2.09, and 6.21 ± 2.92, respectively) exceeded the pretest scores (5.32 ± 2.14, 6.26 ± 2.49, and 3.72 ± 2.22, respectively), and this finding was statistically significant (all P < 0.001). Moreover, the pretest scores were significant positive predictors of final grade (all P < 0.01). In addition, the percentage of preclass preparation increased in 3 wk, from 43.68% to 57.47% to 68.97%. From the first week to the third week, the review rate increased from 86.21% to 91.95%; however, the second week was the lowest of all (72.41%). Finally, students' perceptions about their online physiology learning experiences were favorable. In conclusion, online physiology instruction based on Rain Classroom assisted by WeChat was an effective strategy during the COVID-19 pandemic.

Status of traditional Chinese medicine healthcare services in nursing homes across China.

This study aimed to elucidate the status of traditional Chinese medicine (TCM) healthcare services provided in nursing homes across China. We investigated 484 nursing homes using self-compiled questionnaires with a convenient sampling method. Chi-squared and Wilcoxon rank-sum tests were used for univariate analysis and binary logistic regression for multi-factor analysis. Of the 443 nursing homes finally included, 215 (48.5%) provided TCM healthcare services. Nursing home leaders majored in integrated TCM and Western medicine, leaders with a better understanding of TCM and government policies, nursing homes charging over 5,000 CNY/month, and those with ≥500 beds were more likely to provide improved TCM healthcare services. Massage, moxibustion, cupping or scraping, plaster therapy, decocting pieces, and acupuncture were the most prevalent and popular TCM services. Lack of professionals, financial investment, and policy support were the most common factors limiting the provision of TCM healthcare services in Chinese nursing homes.

Identification and validation of cellular senescence patterns to predict clinical outcomes and immunotherapeutic responses in lung adenocarcinoma.

BACKGROUND: Aging and senescence can alter immune cell fitness and influence the efficacy of lung cancer treatments, especially immunotherapy. However, the correlations between cellular senescence and tumor microenvironment are still not clearly clarified and the value of cellular senescence-related genes in evaluating the immune infiltration and clinical outcomes of lung adenocarcinoma (LUAD) need further investigated. METHODS: We identified three cellular senescence clusters by NMF algorithm and correlated the cellular senescence clusters with the immune landscape in LUAD patients. A prognostic scoring system was established using random survival forest algorithm and validated in 4 external cohorts. Multivariate Cox regression analysis was performed to evaluate the prognostic value of the scoring system. Expression of LYPD3 was evaluated by immunohistochemistry in LUAD samples. RESULTS: Based on the mRNA expression profiles of 278 cellular senescence-related genes, three cellular senescence clusters with distinct prognosis were identified. We characterized three cellular senescence clusters by differences in biological processes, EMT score, expression of immunomodulatory genes, extent of intratumor heterogeneity and response to immunotherapy. Meanwhile, a cellular senescence-related scoring system (CSS) was established and validated as an independent prognostic factor and immunotherapy predictor of LUAD. Patients with low CSS was characterized by prolonged survival time. In response to anti-cancer drugs, patients with low CSS exhibited higher sensitivities to molecular drugs, such as Roscovitine (CDKs inhibitor), Lenaidornide (TNF-α inhibitor), MK2206 (Akt 1/2/3 inhibitor), and especially increased response to anti-PD-1/L1 immunotherapy. CONCLUSIONS: This study demonstrated the correlations between cellular senescence patterns and tumor immune landscape in LUAD, which enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the outcome of immunotherapy for LUAD patients.

Association between Dietary Zinc and Selenium Intake, Oxidative Stress-Related Gene Polymorphism, and Colorectal Cancer Risk in Chinese Population - A Case-Control Study.

Zinc and selenium may protect against colorectal cancer (CRC) progression through their anti-oxidative effects. This study examined the independent and combined effect of dietary zinc and selenium intake, and polymorphisms of the oxidative stress-related genes (superoxide dismutase 1, superoxide dismutase 2, glutathione peroxidase, and catalase) on CRC risk in a Chinese case-control study. A total of 493 cases and 498 sex and age-matched controls were randomly selected from an ongoing case-control study. Dietary information was assessed through face-to-face interviews using a validated food frequency questionnaire. Multiplex PCR-ligase detection reaction was used for genotyping the target SNPs. Multivariable logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI). Intake of selenium was found to be inversely associated with CRC risk, while zinc was not associated with CRC risk. The ORs (95% CI) for the highest vs. the lowest quartile were 0.42 (95% CI 0.28, 0.64, Ptrend < 0.001) for selenium and 0.96 (95% CI 0.63, 1.47, Ptrend = 0.505) for zinc. Combined effect was observed between zinc and SOD1 rs4998557 on CRC risk (Pinteraction < 0.05). This study identified a novel diet-gene interaction in the oxidative stress pathway on CRC risk in Chinese population.

Melatonin synthesis genes N-acetylserotonin methyltransferases evolved into caffeic acid O-methyltransferases and both assisted in plant terrestrialization.

Terrestrialization is one of the most momentous events in the history of plant life, which leads to the subsequent evolution of plant diversity. The transition species, in this process, had to acquire a range of adaptive mechanisms to cope with the harsh features of terrestrial environments compared to that of aquatic habitat. As an ancient antioxidant, a leading regulator of ROS signaling or homeostasis, and a presumed plant master regulator, melatonin likely assisted plants transition to land and their adaption to terrestrial ecosystems. N-acetylserotonin methyltransferases (ASMT) and caffeic acid O-methyltransferases (COMT), both in the O-methyltransferase (OMT) family, catalyze the core O-methylation reaction in melatonin biosynthesis. How these two enzymes with close relevance evolved in plant evolutionary history and whether they participated in plant terrestrialization remains unknown. Using combined phylogenetic evidence and protein structure analysis, it is revealed that COMT likely evolved from ASMT by gene duplication and subsequent divergence. Newly emergent COMT gained a significantly higher ASMT activity to produce greater amounts of melatonin for immobile plants to acclimate to the stressful land environments after evolving from the more environmentally-stable aquatic conditions. The COMT genes possess more conserved substrate-binding sites at the amino acid level and more open protein conformation compared to ASMT, and getting a new function to catalyze the lignin biosynthesis. This development directly contributed to the dominance of vascular plants among the Earth's flora and prompted plant colonization of land. Thus, ASMT, together with its descendant COMT, might play key roles in plant transition to land. The current study provides new insights into plant terrestrialization with gene duplication contributing to this process along with well-known horizontal gene transfer.

Associations between serum concentration of flavonoids and breast cancer risk among Chinese women.

PURPOSE: In vitro and in vivo studies suggested that flavonols, flavones, flavanones and flavan-3-ols have preventive effects on breast carcinogenesis. Epidemiological evidence about the associations between these flavonoid biomarkers and breast cancer risk is limited. This study aimed to investigate the association between serum concentration of these flavonoids and breast cancer risk among Chinese women. METHODS: This hospital-based case-control study recruited 792 breast cancer cases and 813 age frequency-matched (5-year interval) controls who provided eligible blood samples in Guangdong Province, China. Ultra-high-performance liquid chromatography-tandem mass spectrometry was used to measure flavonoids. Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence internal (CI). RESULTS: Higher concentrations of serum flavonols, isorhamnetin, kaempferol, flavanones and naringenin were significantly associated with lower breast cancer risk, with adjusted ORs (95% CIs) for the highest versus the lowest group of 0.66 (0.49-0.89) for flavonols, 0.52 (0.38-0.70) for isorhamnetin, 0.60 (0.45-0.80) for kaempferol, 0.65 (0.49-0.87) for flavanones and 0.45 (0.34-0.60) for naringenin, respectively. Significant positive associations were observed between serum flavan-3-ols, epigallocatechin, epigallocatechin-3-gallate and breast cancer risk. No significant associations were observed for serum quercetin, flavones, apigenin, luteolin, hesperetin, catechin, epicatechin and epicatechin-3-gallate with overall breast cancer risk. CONCLUSIONS: This study suggested that serum flavonols and flavanones were inversely associated with breast cancer risk and serum flavan-3-ols were positively associated with breast cancer risk. Serum flavones were not associated with overall breast cancer risk. These findings warrant further confirmation in prospective studies.