ObjectiveTo explore the mechanism of Huoxue Rongluo prescription （HXRLP） in repairing the blood-brain barrier （BBB） after ischemic stroke （IS）. MethodsMale C57BL/6 mice were randomly divided into sham operation （Sham） group， cerebral infarction model （MCAO） group， environmental circadian disruption with cerebral infarction model （ECD-MCAO） group， low-， medium-， and high-dose HXRLP （HXRLP-L， M， and H） groups （8.5， 17， 34 g·kg^-1·d^-1， respectively）， and positive drug butylphthalide （NBP） group （0.23 mL·d^-1）. In the Sham group， only the exposed blood vessels were isolated without suture insertion. In the other groups， the middle cerebral artery occlusion （MCAO） model of mice was prepared. In the ECD-MCAO group， HXRLP groups， and NBP group， the environmental circadian disruption （ECD） model was prepared. The mice in the Sham group， MCAO group， and ECD-MCAO group were given the same volume of soybean oil by gavage， while those in the other groups were given the corresponding drugs by gavage. Samples were collected after 7 consecutive days of administration. The mNSS score was used to evaluate the repair effect of HXRLP on neurological deficits after IS. Hematoxylin-eosin （HE） staining was used to assess the impact of HXRLP on the pathological damage of brain tissue after IS. 2，3，5-Triphenyltetrazolium chloride （TTC） staining and cerebral blood perfusion status were used to evaluate the repair effect of HXRLP on brain tissue damage after IS. Evans blue staining and transmission electron microscopy were used to evaluate the improvement effect of HXRLP on the permeability injury of BBB after IS. Immunofluorescence （IF） staining was used to observe the expression of von Willebrand Factor （vWF）， brain and muscle Arnt-like 1 （Bmal1）， and Occludin in brain tissue. Western blot was used to detect the protein expression of Bmal1， Occludin， tight junction protein （Claudin-5）， vascular endothelial growth factor （VEGF）， and angiopoietins（Ang）， and related analysis was conducted. ResultsCompared with the Sham group， the MCAO group exhibited significantly aggravated neurological deficits， cerebral infarction volume， brain pathological damage， and BBB leakage （P0.01） and significantly reduced cerebral blood perfusion （P0.01）. The expression of Bmal1， vWF， vascular endothelial growth factor A （VEGFA）， and Ang in brain tissue was significantly enhanced （P0.01）， while the expression of Occludin and Claudin-5 was significantly weakened （P0.01）. Compared with the MCAO group， the ECD-MCAO group showed significantly aggravated neurological deficits， cerebral infarction volume， and BBB leakage （P0.01）， obviously worsened brain pathological damage （P0.05）， significantly reduced cerebral blood perfusion （P0.01）， and significantly decreased expression of Bmal1， vWF， VEGFA， Ang， Occludin， and Claudin-5 in brain tissue （P0.01）. Compared with the ECD-MCAO group， the HXRLP groups of all doses presented significantly improved neurological deficits， cerebral infarction volume， brain pathological damage， and BBB leakage （P0.01）， significantly increased cerebral blood perfusion （P0.01）， and enhanced expression levels of Bmal1， vWF， VEGFA， Ang， Occludin， and Claudin-5 in brain tissue （P0.01）. ConclusionHXRLP can regulate the clock protein Bmal1 and promote the expression of VEGFA， Ang， Occludin， and Claudin-5， thereby improving BBB damage after IS.

Objective To construct a nomogram to predict the prognosis of patients with gallbladder cancer(GBC).Methods The clinicopathological data of GBC patients were extracted from the SEER database,and the independent prognostic factors of GBC patients were analyzed by Cox regression,and a nomogram was constructed.Finally,the column diagrams in the training queue and validation queue are verified.Results Age,T stage,M stage,histological grade,radiotherapy,surgery and tumor size were independent prognostic factors in GBC patients,and the differences were statistically significant(P＜0.05).In the training cohort,the C index was 0.735(95％CI=0.721～0.749),and the AUC values at 1,3 and 5 years were 0.821,0.820 and 0.833,respectively.In the verification group,the C index was 0.733(95％CI=0.711～0.755),and the AUC values for 1,3 and 5 years were 0.816,0.807 and 0.827,respectively.The calibration curve shows that the predicted values of the nomogram are in good agreement with the observed values.The decision curve shows that the nomogram model has better prediction ability than TNM staging system.Conclusion The constructed dynamic prognosis nomogram of GBC patients has high accuracy and reliability.

Objective To investigate the effect of solasonine,an active component of Solanum nigrum,on proliferation and apoptosis of non-small cell lung cancer PC9 cells.Methods PC9 cells were treated with 2,5,10,15,20,or 25 μmol/L solasonine,and the changes in cell proliferation were examined using CCK-8 assay.Tetramethyl rhodamine ethyl ester(TMRE)was used to detect the changes in mitochondrial membrane potential,and caspase-3/7 detection kit and GreenNuc? caspase-3/Annexin V-mCherry kit for live cell were used to analyze the changes in caspase-3 of the cells.Annexin V-FITC/PI double staining was employed to analyze the apoptosis rate of the cells.The effect of PTEN inhibitors on solasonine-induced cell apoptosis was examined by detecting apoptosis-related protein expressions using Western blotting.Results Solasonine treatment for 24,48,and 72 h significantly lowered the viability of PC9 cells.The cells treated with solasonine for 24 h showed significantly decreased mitochondrial membrane potential and increased cell apoptosis with enhanced caspase-3/7 and caspase-3 activities and expression of cleaved caspase-3.Solasonine treatment significantly decreased phosphorylation levels of PI3K and Akt,increased the protein expressions of PTEN and Bax,and lowered the expression of Bcl-2 protein in the cells.Conclusion Solasonine inhibits proliferation and induces apoptosis of PC9 cells by regulating the Bcl-2/Bax/caspase-3 pathway and its upstream proteins.

Objective To investigate the relationship between Kirsten rat sarcoma viral oncogene homolog(KRAS),neuroblastoma viral oncogene RAS homolog(NRAS),V-raf murine sarcoma viral oncogene homo-log B(BRAF),human epidermal growth factor receptor 2(HER2)gene mutations and microsatellite instabili-ty(MSI)status and clinicopathological features in patients with colorectal cancer.Methods The clinical data of 226 patients with colorectal cancer treated in the hospital from October 2019 to March 2022 were collected.Next-generation sequencing technology was used to detect KRAS,NRAS,BRAF,HER2 gene mutations and MSI status.Immunohistochemistry was used to evaluate the mismatch repair system(MMR)status.Multiva-riate Logistic regression analysis was used to analyze the relationship between KRAS,NRAS,BRAF,HER2 gene mutations and clinicopathological features.Results Among 226 colorectal cancer patients,the mutation frequencies of KRAS,NRAS,BRAF and HER2 were 54.89％,5.3％,8.4％and 1.8％,respectively.The fre-quency of KRAS mutation in mucinous adenocarcinoma was higher than that in common adenocarcinoma(P＜0.05).The risk of KRAS mutation in right colon cancer was increased(OR=2.145,P=0.012).NR AS gene mutation was more frequent in left colon and rectal cancer(P＜0.05).The frequency of BRAF gene mu-tation was higher in poorly differentiated and microsatellite instability-high(MSI-H)colorectal cancer(P＜0.05),and the risk of BRAF gene mutation in the right colon was increased(OR=2.844,P=0.042).HER2 gene amplification mutation showed distant metastasis(P＜0.05).KRAS mutations were mutually exclusive with NRAS,BRAF and HER2 amplification mutations(P＜0.05).MSI-H was more frequent in the right co-lon(P＜0.05).Of the 226 cases,10 cases were defective mismatch repair(dMMR)/MSI-H,8 cases were dM-MR/microsatellite stable,and 5 cases were proficient mismatch repair/MSI-H.There was a moderate agree-ment between dMMR and MSI-H(Kappa=0.575).Conclusion KRAS,NRAS,BRAF,HER2 and MSI sta-tus are associated with clinicopathological features in patients with colorectal cancer.Combined detection of KRAS,NRAS,BRAF,HER2 and MSI can provide more accurate and effective data to guide the treatment and prognosis of patients.

Objective To investigate the effect of solasonine,an active component of Solanum nigrum,on proliferation and apoptosis of non-small cell lung cancer PC9 cells.Methods PC9 cells were treated with 2,5,10,15,20,or 25 μmol/L solasonine,and the changes in cell proliferation were examined using CCK-8 assay.Tetramethyl rhodamine ethyl ester(TMRE)was used to detect the changes in mitochondrial membrane potential,and caspase-3/7 detection kit and GreenNuc? caspase-3/Annexin V-mCherry kit for live cell were used to analyze the changes in caspase-3 of the cells.Annexin V-FITC/PI double staining was employed to analyze the apoptosis rate of the cells.The effect of PTEN inhibitors on solasonine-induced cell apoptosis was examined by detecting apoptosis-related protein expressions using Western blotting.Results Solasonine treatment for 24,48,and 72 h significantly lowered the viability of PC9 cells.The cells treated with solasonine for 24 h showed significantly decreased mitochondrial membrane potential and increased cell apoptosis with enhanced caspase-3/7 and caspase-3 activities and expression of cleaved caspase-3.Solasonine treatment significantly decreased phosphorylation levels of PI3K and Akt,increased the protein expressions of PTEN and Bax,and lowered the expression of Bcl-2 protein in the cells.Conclusion Solasonine inhibits proliferation and induces apoptosis of PC9 cells by regulating the Bcl-2/Bax/caspase-3 pathway and its upstream proteins.

Patients with severe trauma require an extremely timely treatment and transfusion plays an irreplaceable role in the emergency treatment of such patients. An increasing number of evidence-based medicinal evidences and clinical practices suggest that patients with severe traumatic bleeding benefit from early transfusion of low-titer group O whole blood or hemostatic resuscitation with red blood cells, plasma and platelet of a balanced ratio. However, the current domestic mode of blood supply cannot fully meet the requirements of timely and effective blood transfusion for emergency treatment of patients with severe trauma in clinical practice. In order to solve the key problems in blood supply and blood transfusion strategies for emergency treatment of severe trauma, Branch of Clinical Transfusion Medicine of Chinese Medical Association, Group for Trauma Emergency Care and Multiple Injuries of Trauma Branch of Chinese Medical Association, Young Scholar Group of Disaster Medicine Branch of Chinese Medical Association organized domestic experts of blood transfusion medicine and trauma treatment to jointly formulate Chinese expert consensus on blood support mode and blood transfusion strategies for emergency treatment of severe trauma patients ( version 2024). Based on the evidence-based medical evidence and Delphi method of expert consultation and voting, 10 recommendations were put forward from two aspects of blood support mode and transfusion strategies, aiming to provide a reference for transfusion resuscitation in the emergency treatment of severe trauma and further improve the success rate of treatment of patients with severe trauma.

Objective　To analyze the causes of death of one case of imported falciparum malaria in Guangxi Zhuang Autonomous Region in January 2023, to provide a reference for the prevention of fatal malaria cases. Methods Interviews were conducted with the doctors who received and consulted the patient, as well as the family members of the patient. Clinical data from the patient's diagnosis and treatment process were collected, and the patient's clinical records and epidemiological investigation data were analyzed. Results The patient, Mr. He, a 53-year-old male from Pingnan County, Guigang City, Guangxi Zhuang Autonomous Region, returned from working in Côte d'Ivoire, Africa, and entered Guangxi on December 26, 2022. He returned home after his centralized quarantine was lifted on January 3, 2023. On January 4th, 2023, the patient developed dizziness and vomiting, considering himself to a possible COVID-19 infection, he did not seek treatment. On the morning of January 6, the patient developed a fever (peak body temperature of 40 ℃), accompanied by fatigue and sore throat, and the preemptive symptoms were aggravated. The patient was admitted to the Guancheng Town Health Center with "Pneumonia" and treated with ribavirin, dexamethasone, ceftriaxone sodium, etc. On January 7, the patient again experienced a high fever (40 ℃) and was discharged to the Emergency Department of the First Affiliated Hospital of Guangxi Medical University. Upon admission, the patient's blood pressure was measured at 78/53mmHg, further comprehensive examination showed a decrease in platelets and abnormalities in liver and renal function, procalcitonin levels at 49.9 ng/mL. Chest CT showed pneumonia, and fluid supplements and antibiotics were given. On January 8, malaria parasites were found in the patient's blood smear, and the patient was diagnosed with malaria (not classified, confirmed as falciparum malaria on January 9th). The patient was recommended to transfer to the provincial malaria-designated hospital, but his family refused. On January 8 at 13:27, the patient excreted approximately 700 g of dark red bloody stools accompanied by blurred consciousness and received hemostasis treatment. After coordinating with multiple parties, four doses of "artemisinin injection " (60 mg/dose) were taken for treatment. At 18:59 on January 8, intravenous administration of 60 mg injectable Artesunate was given, accompanied by symptomatic treatment for fever reduction and rehydration. At 19:40, the patient developed severe hypoglycemia, and severe metabolic acidosis, and blood pressure continued to decrease despite the use of vasopressors. After comprehensive treatment at 3:00 am on January 9, the patient's condition continued to deteriorate, the patient's shock could not be corrected, he lapsed into a coma, and the family requested to be discharged from the hospital. The patient returned home at 7:00 am and died of multiple organ failure at 7:30 am. Conclusions For imported malaria, early and precise diagnosis based on epidemiological history, clinical symptoms, laboratory test results, early antimalarial treatment, and management of organ dysfunction are the keys to avoiding fatal outcomes.

Objective: Progressive supranuclear palsy (PSP) involves a variety of visual symptoms that are thought to be partially caused by structural abnormalities of the retina. However, the relationship between retinal structural changes, disease severity, and intracranial alterations remains unknown. We investigated distinct retinal thinning patterns and their relationship with clinical severity and intracranial alterations in a PSP cohort. Methods: We enrolled 19 patients with PSP (38 eyes) and 20 age-matched healthy controls (40 eyes). All of the participants underwent peripapillary and macular optical coherence tomography. Brain 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography imaging were also performed in patients with PSP. We investigated the association between retinal thickness changes and clinical features, striatal dopamine transporter availability, and cerebral glucose metabolism. Results: The peripapillary retinal nerve fiber layer (pRNFL) and macula were significantly thinner in patients with PSP than in controls. The thickness of the superior sector of the pRNFL demonstrated a significant negative relationship with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III and Hoehn and Yahr staging scale scores. A significant negative correlation was found between outer inferior macular thickness and disease duration. Outer temporal macular thickness was positively correlated with Montreal Cognitive Assessment scores. In PSP, lower outer temporal macular thickness was also positively correlated with decreased dopamine transporter binding in the caudate. Conclusion The pRNFL and macular thinning may be candidate markers for monitoring disease severity. Additionally, macular thinning may be an in vivo indicator of nigrostriatal dopaminergic cell degeneration in PSP patients.

BACKGROUND: LY01005 (Goserelin acetate sustained-release microsphere injection) is a modified gonadotropin-releasing hormone (GnRH) agonist injected monthly. This phase III trial study aimed to evaluated the efficacy and safety of LY01005 in Chinese patients with prostate cancer. METHODS: We conducted a randomized controlled, open-label, non-inferiority trial across 49 sites in China. This study included 290 patients with prostate cancer who received either LY01005 or goserelin implants every 28 days for three injections. The primary efficacy endpoints were the percentage of patients with testosterone suppression ≤50 ng/dL at day 29 and the cumulative probability of testosterone ≤50 ng/dL from day 29 to 85. Non-inferiority was prespecified at a margin of -10%. Secondary endpoints included significant castration (≤20 ng/dL), testosterone surge within 72 h following repeated dosing, and changes in luteinizing hormone, follicle-stimulating hormone, and prostate specific antigen levels. RESULTS: On day 29, in the LY01005 and goserelin implant groups, testosterone concentrations fell below medical-castration levels in 99.3% (142/143) and 100% (140/140) of patients, respectively, with a difference of -0.7% (95% confidence interval [CI], -3.9% to 2.0%) between the two groups. The cumulative probabilities of maintaining castration from days 29 to 85 were 99.3% and 97.8%, respectively, with a between-group difference of 1.5% (95% CI, -1.3% to 4.4%). Both results met the criterion for non-inferiority. Secondary endpoints were similar between groups. Both treatments were well-tolerated. LY01005 was associated with fewer injection-site reactions than the goserelin implant (0% vs . 1.4% [2/145]). CONCLUSION: LY01005 is as effective as goserelin implants in reducing testosterone to castration levels, with a similar safety profile. TRIAL REGISTRATION ClinicalTrials.gov, NCT04563936.
Humans ; Male ; Antineoplastic Agents, Hormonal/therapeutic use* ; East Asian People ; Gonadotropin-Releasing Hormone/agonists* ; Goserelin/therapeutic use* ; Prostate-Specific Antigen ; Prostatic Neoplasms/drug therapy* ; Testosterone

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.
Humans ; Antibodies, Monoclonal/pharmacology* ; B7-H1 Antigen/antagonists & inhibitors* ; CTLA-4 Antigen/antagonists & inhibitors* ; Immune Checkpoint Inhibitors/pharmacology* ; Neoplasms/drug therapy* ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment