N1-methyladenosine(m1A)RNA methylation is critical for regulating mRNA translation;however,its role in the development,progression,and immunotherapy response of head and neck squamous cell carcinoma(HNSCC)remains largely unknown.Using Tgfbr1 and Pten conditional knockout(2cKO)mice,we found the neoplastic transformation of oral mucosa was accompanied by increased m1A modification levels.Analysis of m1A-associated genes identified TRMT61A as a key m1A writer linked to cancer progression and poor prognosis.Mechanistically,TRMT61A-mediated tRNA-m1A modification promotes MYC protein synthesis,upregulating programmed death-ligand 1(PD-L1)expression.Moreover,m1A modification levels were also elevated in tumors treated with oncolytic herpes simplex virus(oHSV),contributing to reactive PD-L1 upregulation.Therapeutic m1A inhibition sustained oHSV-induced antitumor immunity and reduced tumor growth,representing a promising strategy to alleviate resistance.These findings indicate that m1A inhibition can prevent immune escape after oHSV therapy by reducing PD-L1 expression,providing a mutually reinforcing combination immunotherapy approach.

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

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.

Background: Gut microbiota is closely related to the occurrence and development of diabetes and affects the prognosis of diabetic complications, and the underlying mechanisms are only partially understood. We aimed to explore the possible link between the gut microbiota and vascular inflammation of diabetic mice. Methods: The db/db diabetic and wild-type (WT) mice were used in this study. We profiled gut microbiota and examined the and vascular function in both db/db group and WT group. Gut microbiota was analyzed by 16s rRNA sequencing. Vascular function was examined by ultrasonographic hemodynamics and histological staining. Clostridium butyricum (CB) was orally administered to diabetic mice by intragastric gavage every 2 days for 2 consecutive months. Reactive oxygen species (ROS) and expression of nuclear factor erythroid-derived 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by fluorescence microscopy. The mRNA expression of inflammatory cytokines was tested by quantitative polymerase chain reaction. Results: Compared with WT mice, CB abundance was significantly decreased in the gut of db/db mice, together with compromised vascular function and activated inflammation in the arterial tissue. Meanwhile, ROS in the vascular tissue of db/db mice was also significantly increased. Oral administration of CB restored the protective microbiota, and protected the vascular function in the db/db mice via activating the Nrf2/HO-1 pathway. Conclusion This study identified the potential link between decreased CB abundance in gut microbiota and vascular inflammation in diabetes. Therapeutic delivery of CB by gut transplantation alleviates the vascular lesions of diabetes mellitus by activating the Nrf2/HO-1 pathway.

Esophageal cancer is a digestive tract malignancy with high morbidity and mortality and mainly occurs in males. The 5-year survival rate is lower than 20%. In China， the morbidity and mortality of esophageal cancer rank the first in the world， seriously threatening national health. The pathogenesis of esophageal cancer is diverse， which is generally considered as the consequence of environmental-genetic-gene interaction. In addition to genetic factors and regional characteristics， gene mutation， RNA interference， DNA damage repair， tumor microenvironment， dietary habit， chronic adverse stimulation， and inflammatory reaction are all involved in the occurrence and development of esophageal cancer. However， there is no unified and accurate conclusion. Clarifying the exact pathogenesis of esophageal cancer is of great significance for its early screening， diagnosis， prevention， treatment， and prognosis. Surgery， radiotherapy， and chemotherapy are the three effective methods for the treatment of esophageal cancer. However， due to the atypical early symptoms， most patients have missed the best operation period when diagnosed， resulting in poor clinical prognosis. Moreover， radiotherapy and chemotherapy will cause side effects such as loss of appetite， low immune function， esophagitis， pneumonia， and malnutrition， which is not conducive to the prognosis and treatment maintenance of patients. With definite efficacies on esophageal cancer， traditional Chinese medicine （TCM）， which is flexible and diverse in the treatment， can primarily or alternatively be involved in the treatment of esophageal cancer. TCM can eliminate postoperative complications and postoperative infections and relieve adverse gastrointestinal reactions， weakened immune function， and organ damage caused by radiotherapy and chemotherapy. It can enhance clinical efficacy and improve the quality of life of patients. Therefore， it is necessary to systematically summarize the clear pathogenesis or risk factors of esophageal cancer and review the clinical characteristics of TCM in the prevention and treatment of esophageal cancer to facilitate the early screening， diagnosis， and treatment of esophageal cancer and promote the application of TCM in the prevention and treatment of esophageal cancer and related adverse reactions.

The "triple combination" review system provides an opportunity for the transformation of human use experience into new Chinese drugs. However, there are some methodological and technical limitations in the assessment of human experience. Hence, the efficacy and safety evaluation methods should be established in accordance with the characteristics of Chinese herbs. This study summarized some evidence-based methodology to promote the transformation of human use experience to new Chinese drugs, mainly including the individualized pragmatic randomized controlled trial(RCT), cluster RCT, single-case RCT, single arm RCT with objective performance criteria, and partially nested RCT. As the real world data can be used to support the transformation of human experience, attention should be paid to convenient and efficient collection of data, prudent selection of design types, and adoption of appropriate ana-lysis methods to deal with confounding bias, including multi-factor regression model and propensity score. The newly proposed mixed research method can also be utilized to assess the human use experience, which is suitable for mining the theory of traditional Chinese medicine(TCM) and expert experience from different aspects. Meanwhile, considering the study design requirements and TCM cha-racteristics, this study put forward the common problems and solutions in the development of new Chinese drugs based on human use experience, including how to select the feasible outcome indicators, how to collect prescription data in the case of herb and dosage adjustment, and how to evaluate the comprehensive effectiveness of TCM from the perspective of "combination of disease and syndrome".
China ; Drug Development ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Medicine, Chinese Traditional ; Research Design

Objective: To investigate the localization methods of supratrochlear artery (STA) and supraorbital artery (SOA), and to explore the clinical benefit of locating nerve via accompanying vascular localization in combined transfrontal and intranasal endoscopic approaches. Methods: From June 2019 to May 2021, 14 patients, including 11 males and 3 females, aging from 18 to 69 years old, were underwent frontal sinus surgery through the combined transfrontal and intranasal endoscopic approaches in the Department of Otorhinolaryngology Head and Neck Surgery of the Third Affiliated Hospital of Sun Yat-sen University. Before the surgery, localization of STA and SOA was determined by color doppler flow imaging (CDFI), computerized topographic angiography (CTA) and contrast enhanced magnetic resonance angiography (CE-MRA) respectively, and the distances between STA and SOA from facial midline were measured on 28 eyebrows. The position of external incision was determined according to the preoperative localization of STA and SOA. The examination time, cost and postoperative complications of the three methods were recorded. The accuracy of localization at 14 sides was verified by the surgery. GraphPad Prism 8.3 software was used for statistical analysis. Results: STA and SOA could be located by CDFI, CTA and CE-MRA. There was no significant difference in the measurement of the distance between STA and SOA from the facial midline among 3 methods (all P>0.05). Determining the position of external incision according to the localization of STA and SOA could protect both the blood vessels and accompanying nerves. No postoperative complications such as numbness of the forehead skin occurred. The measurement time of CDFI, CTA and CE-MRA was 22.50 (15.75, 30.00), 30.00 (28.00, 34.25) and 48.00 (44.00, 52.75) min (M (Q₁, Q₃)), respectively (all P<0.05). CDFI incurred the lowest costs and took the shortest time. Conclusions: CDFI is an efficient and economic localization method. The localization of STA and SOA facilitates the precise selection of the position of external incision, protects the accompanying nerve and reduces postoperative complications.
Adolescent ; Adult ; Aged ; Angiography ; Arteries ; Endoscopy ; Female ; Humans ; Male ; Middle Aged ; Postoperative Complications ; Young Adult

BACKGROUND: Anterior thalamic nuclei (ATN) deep brain stimulation (DBS) is an effective method of controlling epilepsy, especially temporal lobe epilepsy. Mossy fiber sprouting (MFS) plays an indispensable role in the pathogenesis and progression of epilepsy, but the effect of ATN-DBS on MFS in the chronic stage of epilepsy and the potential underlying mechanisms are unknown. This study aimed to investigate the effect of ATN-DBS on MFS, as well as potential signaling pathways by a kainic acid (KA)-induced epileptic model. METHODS: Twenty-four rhesus monkeys were randomly assigned to control, epilepsy (EP), EP-sham-DBS, and EP-DBS groups. KA was injected to establish the chronic epileptic model. The left ATN was implanted with a DBS lead and stimulated for 8 weeks. Enzyme-linked immunosorbent assay, Western blotting, and immunofluorescence staining were used to evaluate MFS and levels of potential molecular mediators in the hippocampus. One-way analysis of variance, followed by the Tukey post hoc correction, was used to analyze the statistical significance of differences among multiple groups. RESULTS: ATN-DBS is found to significantly reduce seizure frequency in the chronic stage of epilepsy. The number of ectopic granule cells was reduced in monkeys that received ATN stimulation (P < 0.0001). Levels of 3',5'-cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) in the hippocampus, together with Akt phosphorylation, were noticeably reduced in monkeys that received ATN stimulation (P = 0.0030 and P = 0.0001, respectively). ATN-DBS also significantly reduced MFS scores in the hippocampal dentate gyrus and CA3 sub-regions (all P < 0.0001). CONCLUSION ATN-DBS is shown to down-regulate the cAMP/PKA signaling pathway and Akt phosphorylation and to reduce the number of ectopic granule cells, which may be associated with the reduced MFS in chronic epilepsy. The study provides further insights into the mechanism by which ATN-DBS reduces epileptic seizures.
Adenosine Monophosphate ; Anterior Thalamic Nuclei ; Cyclic AMP-Dependent Protein Kinases ; Deep Brain Stimulation ; Epilepsy/therapy* ; Epilepsy, Temporal Lobe/therapy* ; Hippocampus ; Humans ; Mossy Fibers, Hippocampal ; Signal Transduction

Purpose: Diabetes mellitus (DM) is associated with elevated cancer risk and poor survival outcome in malignancies. The objective of this study was to evaluate the prognostic value of preexisting DM in chronic lymphocytic leukemia (CLL). Materials and Methods: Six hundred and thirty-three subjects with newly-diagnosed CLL between 2007 and 2016 were recruited. Propensity score-matched method was performed to balance baseline characteristics and eliminate possible bias. Univariate and multivariate Cox regression analyses screened the independent risk indicators for time-to-first-treatment (TTFT) and cancer-specific survival (CSS) of CLL. Receiver operator characteristic curves and the corresponding areas under the curve assessed the predictive accuracy of CLL–International Prognostic Index (IPI) together with DM. Results: The results showed that 111 patients had pre-existing DM. In the propensity-matched cohort, DM was correlated with inferior TTFT and CSS in CLL patients, and it was an independent prognostic factor for both CSS and TTFT. Pre-diabetics also shared undesirable prognostic outcome compared with patients with no diabetic tendency, and a positive association between longer diabetic duration and poorer prognosis of CLL was identified. DM as one additional point to CLL-IPI had larger area under the curve compared with CLL-IPI alone in CSS prediction and could improve the prognostic capacity of CLL-IPI. Conclusion Pre-existing DM was found to be a valuable prognostic predictor and could help predict life expectancy and build refined prognostication models for CLL.

OBJECTIVETo explore clinical outcome of locked fibular nail in treating lateral malleolus fractures in elderly patients with diabetes.

METHODSFrom July 2012 to July 2014, clinical data of 22 diabetic patients with lateral malleolus fractures were respectively analyzed, including 15 females and 7 males, aged from 62 to 84 years old with an average of (69.3±13.7) years old. According to Danis-Weber classification, 2 cases were type A, 13 cases were type B, 5 cases were type C, and 2 cases were other type. All patients were reduced and fixed with Acumed locked fibular nail through a minimally invasive approach. Complication and fracture healing was recorded after operation. Clinical function was evaluated according to AOFAS.

RESULTSAll patients were followed up from 12 to 24 months with an average of (17.3±5.9) months. All incisions were healed at stage I. No wound complication, neurovascular or tendon injuries occurred. No fixation loss or discomfort of nail was reported. All patients achieved primary bone union, and healing time ranged from 8 to 14 weeks with an average of (10.3±3.9) weeks. AOFAS score was 87.4±5.2 at 1 year after operation 9 cases got excellent results and 12 cases good.

CONCLUSIONSFor elderly diabetic patients with lateral malleolus fractures, locked fibular nail has advantages of effective and stable fixation, high rate of bone healing, short healing time, less complication, and could obtain satisfied clinical effect.

Aged ; Aged, 80 and over ; Ankle Fractures ; surgery ; Bone Nails ; Diabetes Mellitus ; Female ; Fibula ; surgery ; Fracture Fixation, Internal ; Humans ; Male ; Middle Aged ; Treatment Outcome