Recent studies have shown that the physiological homeostasis of oral mucosal cells is regulated by the circadian clock.Dis-ruption or dysfunction of the circadian clock is closely associated with the development of oral squamous cell carcinoma(OSCC).Research based on the circadian clock offers a novel perspective on the pathogenesis and therapeutic strategies for OSCC.However,there is current-ly limited research on this topic,and people generally have insufficient understanding and recognition of the circadian clock.Given the complexity and challenges of circadian clock which is the fourth dimension of medical research,we organize relevant experts based on summarizing the current research results of circadian clock in the pathogenesis and precision diagnosis and treatment of OSCC,combining the scientific principles of the circadian clock's role and their long-term research experience,then summarizes and recommends the con-sensus opinions for the research of circadian clock in the pathogenesis mechanism and precision diagnosis and treatment of human OSCC,with the hope of providing guidance for the basic research and clinical application of circadian clock or circadian rhythm in the pathogene-sis mechanism and precision diagnosis and treatment of oral and maxillofacial squamous cell carcinoma.

Establishing hematology care units (HCU) is essential for strengthening hematology-specific critical care capacity. This article outlines two HCU operational models in China—the ICU model and the pre-ICU model—and discusses practical insights from their implementation. It recommends establishing HCU within hematology wards, equipped for respiratory and hemodynamic monitoring and blood purification, and led by hematologists trained in critical care or by teams collaborating efficiently with general ICU through standardized workflows. For units not yet meeting these standards, establishing a resuscitation room and strengthening critical care training are advised. HCU primarily admit patients with severe or life-threatening bleeding due to hematologic diseases, severe infections or septic shock, early complications of newly diagnosed acute myeloid leukemia or acute promyelocytic leukemia (AML/APL), treatment-related complications, rapidly progressive or highly lethal conditions, and those requiring organ support or blood purification. Emphasis is placed on quantitative assessment of disease severity and timely transfer to the HCU, using tools such as the National Early Warning Score, quick Sequential Organ Failure Assessment (qSOFA), SOFA/ΔSOFA, and the Multinational Association of Supportive Care in Cancer risk index for patient stratification. Early implementation of sepsis bundles is emphasized. For organ support, high-flow nasal cannula oxygen therapy is prioritized to improve oxygenation. Continuous renal replacement therapy is performed when there are indications such as renal failure with oliguria or anuria, congestive heart failure, or drug overdose, etc. Treatment of the underlying hematologic disease follows a "three-tier stratification" and "watch-and-adjust" strategy, while respecting patient preferences. We encourage eligible hematology centers to actively establish HCU, explore new care models, and strengthen hematology-specific critical care capacity.

OBJECTIVES: To investigate the expression levels of marginal zone B and B1-cell-specific protein (MZB1) in pan-cancer and its association with patient prognosis and tumor microenvironment (TME). METHODS: MZB1 expression data, clinicopathological parameters, and survival data from 33 cancer types were extracted from the UCSC database for analyzing the correlations of MZB1 with clinical stage, patient prognosis, immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI). MZB1 gene mutations in pan-cancer were assessed using cBioPortal online database, and the value of MZB1 for cancer diagnosis was evaluated using ROC curve analysis. MZB1 expression levels in myeloid leukemia and renal carcinoma cells were detected using RT-qPCR and Western blotting, and the effect of MZB1 knockdown on cell proliferation was examined using EdU assay. RESULTS: MZB1 was significantly overexpressed in 20 cancer types, including kidney renal clear cell carcinoma (KIRC), breast invasive carcinoma, and acute myeloid leukemia. Its expression was associated with TNM stage, clinical stage, overall survival, and progression-free survival in multiple cancers. In most tumors, MZB1 expression was correlated significantly with immunomodulatory genes, immune checkpoint genes, tumor stemness, immune cell infiltration, TMB, and microsatellite instability. Gene amplification was the predominant mutation type of MZB1 in pan-cancer, and MZB1 showed high diagnostic value for skin cutaneous melanoma, KIRC, and head and neck squamous cell carcinoma. MZB1 was highly expressed in different myeloid leukemia cell lines and renal carcinoma cell lines, and MZB1 knockdown significantly suppressed the proliferation of HL60 and 769-P cells. CONCLUSIONS MZB1 is highly expressed in a variety of tumors, and its aberrant expression affects the occurrence and prognosis of many tumors, suggesting its potential as a novel tumor biomarker and immunomodulatory target.
Humans ; Prognosis ; Tumor Microenvironment ; Neoplasms/pathology* ; Cell Line, Tumor ; Mutation ; Kidney Neoplasms ; Microsatellite Instability ; Cell Proliferation ; Carcinoma, Renal Cell

Recent studies have shown that the physiological homeostasis of oral mucosal cells is regulated by the circadian clock.Dis-ruption or dysfunction of the circadian clock is closely associated with the development of oral squamous cell carcinoma(OSCC).Research based on the circadian clock offers a novel perspective on the pathogenesis and therapeutic strategies for OSCC.However,there is current-ly limited research on this topic,and people generally have insufficient understanding and recognition of the circadian clock.Given the complexity and challenges of circadian clock which is the fourth dimension of medical research,we organize relevant experts based on summarizing the current research results of circadian clock in the pathogenesis and precision diagnosis and treatment of OSCC,combining the scientific principles of the circadian clock's role and their long-term research experience,then summarizes and recommends the con-sensus opinions for the research of circadian clock in the pathogenesis mechanism and precision diagnosis and treatment of human OSCC,with the hope of providing guidance for the basic research and clinical application of circadian clock or circadian rhythm in the pathogene-sis mechanism and precision diagnosis and treatment of oral and maxillofacial squamous cell carcinoma.

Establishing hematology care units (HCU) is essential for strengthening hematology-specific critical care capacity. This article outlines two HCU operational models in China—the ICU model and the pre-ICU model—and discusses practical insights from their implementation. It recommends establishing HCU within hematology wards, equipped for respiratory and hemodynamic monitoring and blood purification, and led by hematologists trained in critical care or by teams collaborating efficiently with general ICU through standardized workflows. For units not yet meeting these standards, establishing a resuscitation room and strengthening critical care training are advised. HCU primarily admit patients with severe or life-threatening bleeding due to hematologic diseases, severe infections or septic shock, early complications of newly diagnosed acute myeloid leukemia or acute promyelocytic leukemia (AML/APL), treatment-related complications, rapidly progressive or highly lethal conditions, and those requiring organ support or blood purification. Emphasis is placed on quantitative assessment of disease severity and timely transfer to the HCU, using tools such as the National Early Warning Score, quick Sequential Organ Failure Assessment (qSOFA), SOFA/ΔSOFA, and the Multinational Association of Supportive Care in Cancer risk index for patient stratification. Early implementation of sepsis bundles is emphasized. For organ support, high-flow nasal cannula oxygen therapy is prioritized to improve oxygenation. Continuous renal replacement therapy is performed when there are indications such as renal failure with oliguria or anuria, congestive heart failure, or drug overdose, etc. Treatment of the underlying hematologic disease follows a "three-tier stratification" and "watch-and-adjust" strategy, while respecting patient preferences. We encourage eligible hematology centers to actively establish HCU, explore new care models, and strengthen hematology-specific critical care capacity.

The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1β/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Animals ; Monkeypox/drug therapy* ; Antiviral Agents/therapeutic use* ; Phosphoric Monoester Hydrolases/therapeutic use* ; Macaca fascicularis

The application of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) can be limited due to a lack of compatible protospacer adjacent motif (PAM) sequences in the DNA regions of interest. Recently, SpRY, a variant of Streptococcus pyogenes Cas9 (SpCas9), was reported, which nearly completely fulfils the PAM requirement. Meanwhile, PAMs for SpRY have not been well addressed. In our previous study, we developed the PAM Definition by Observable Sequence Excision (PAM-DOSE) and green fluorescent protein (GFP)‍-reporter systems to study PAMs in human cells. Herein, we endeavored to identify the PAMs of SpRY with these two methods. The results indicated that 5'-NRN-3', 5'-NTA-3', and 5'-NCK-3' could be considered as canonical PAMs. 5'-NCA-3' and 5'-NTK-3' may serve as non-priority PAMs. At the same time, PAM of 5'-NYC-3' is not recommended for human cells. These findings provide further insights into the application of SpRY for human genome editing.
CRISPR-Associated Protein 9/metabolism* ; CRISPR-Cas Systems ; DNA ; Gene Editing/methods* ; Humans ; Streptococcus pyogenes/metabolism*

Objective:To compare the assisted-reproduction outcomes of two long-acting gonadotropin-releasing hormone agonists (GnRH-a) in patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) during the long-term early follicular phase. Methods:A retrospective cohort study was conducted in the Reproductive Center of the Second Affiliated Hospital of Wenzhou Medical University from March 1, 2019 to July 31, 2019. A total of 802 patients were divided into leuprorelin acetate group (group A) and triptorelin group (group B) according to the difference of long-acting GnRH-a in the long-term early follicular phase, and the clinical and laboratory outcomes between the two groups were compared.Results:There were no significant differences in age, infertility duration, body mass index (BMI), basic hormone levels, infertility type, sex hormone level on the day of initiation of injection of gonadotropin (Gn), total duration and dosage of Gn used, duration of down-regulation, estradiol level and endometrial thickness on hCG injection day, the number of embryos transferred, clinical outcomes, total treatment cost, and owing to the uneven inner membrane, elevated progesterone, embryo quality problems, individual factors resulting in cancelling the transplant, between the two groups ( P>0.05). However, antral follicle count (AFC) (19.59±7.93), the number of retrieved oocytes (15.39±7.59), fertilized oocytes (11.20±6.53), cleaved oocytes (10.85±6.42), good-quality embryos on Day 3 (3.01±2.66), and blastocysts (5.27±4.02) in group B was larger than that in group A (17.68±7.23, 13.70±6.94, 9.50±5.43, 9.26±5.34, 2.57±2.33, 4.49±3.40) ( P=0.001, P=0.002, P<0.001, P=0.001, P=0.017, P=0.007). The levels of luteinizing hormone (LH) [(0.78±0.64) IU/L] and progesterone [(0.72±0.39) μg/L] on hCG injection day in group A were higher than those in group B [(0.55±0.30) IU/L, (0.64±0.36) μg/L] ( P<0.001, P=0.005). The rate of preventing the occurrence of ovarian hyperstimulation syndrome (OHSS) in group A [28.52% (75/263)] was higher than that in group B [14.95% (16/107), P=0.006]. Conclusion:Two long-acting GnRH-a drugs can achieve satisfactory down-regulation effect, laboratory and clinical outcomes in the long-term early follicular phase. Compared with the triptorelin, leuprolide acetate is relatively mild to pituitary inhibition, with an increasing trend of the clinical pregnancy rate.