Oral squamous cell carcinoma (OSCC) is a common head and neck malignancy. Approximately 50% to 60% of patients with OSCC are diagnosed at a locally advanced stage (clinical staging III-IVa). Even with comprehensive and sequential treatment primarily based on surgery, the 5-year overall survival rate remains below 50%, and patients often suffer from postoperative functional impairments such as difficulties with speaking and swallowing. Programmed death receptor-1 (PD-1) inhibitors are increasingly used in the neoadjuvant treatment of locally advanced OSCC and have shown encouraging efficacy. However, clinical practice still faces key challenges, including the definition of indications, optimization of combination regimens, and standards for efficacy evaluation. Based on the latest research advances worldwide and the clinical experience of the expert group, this expert consensus systematically evaluates the application of PD-1 inhibitors in the neoadjuvant treatment of locally advanced OSCC, covering combination strategies, treatment cycles and surgical timing, efficacy assessment, use of biomarkers, management of special populations and immune related adverse events, principles for immunotherapy rechallenge, and function preservation strategies. After multiple rounds of panel discussion and through anonymous voting using the Delphi method, the following consensus statements have been formulated: 1) Neoadjuvant therapy with PD-1 inhibitors can be used preoperatively in patients with locally advanced OSCC. The preferred regimen is a PD-1 inhibitor combined with platinum based chemotherapy, administered for 2-3 cycles. 2) During the efficacy evaluation of neoadjuvant therapy, radiographic assessment should follow the dual criteria of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune RECIST (iRECIST). After surgery, systematic pathological evaluation of both the primary lesion and regional lymph nodes is required. For combination chemotherapy regimens, PD-L1 expression and combined positive score need not be used as mandatory inclusion or exclusion criteria. 3) For special populations such as the elderly (≥ 70 years), individuals with stable HIV viral load, and carriers of chronic HBV/HCV, PD-1 inhibitors may be used cautiously under the guidance of a multidisciplinary team (MDT), with close monitoring for adverse events. 4) For patients with a poor response to neoadjuvant therapy, continuation of the original treatment regimen is not recommended; the subsequent treatment plan should be adjusted promptly after MDT assessment. Organ transplant recipients and patients with active autoimmune diseases are not recommended to receive neoadjuvant PD-1 inhibitor therapy due to the high risk of immune related activation. Rechallenge is generally not advised for patients who have experienced high risk immune related adverse events such as immune mediated myocarditis, neurotoxicity, or pneumonitis. 5) For patients with a good pathological response, individualized de escalation surgery and function preservation strategies can be explored. This consensus aims to promote the standardized, safe, and precise application of neoadjuvant PD-1 inhibitor strategies in the management of locally advanced OSCC patients.

Objective:To investigate the stability and feasibility of using absorbable screws during Bernese periacetabular osteotomy.Methods:A retrospective analysis was conducted on a 36 year-old woman diagnosed with developmental dysplasia of the hip, who had undergone Bernese periacetabular osteotomy. Finite element analysis was used to simulate the stability of the acetabulum under loads of 10%, 20%, 50%, and 100% of the patient's weight. The structural stiffness of the pelvis and the maximum equivalent stress on the absorbable screws were observed under different conditions, including whether the acetabular bone block and the ilium were in contact, whether 3 or 4 screws were used, and whether a graft (including fibular cortical bone and PEEK grafts) was used.Results:The structural stiffness of the pelvis fixed with four screws increased by 67%-94% compared to that with three screws. After using a graft, the structural stiffness of the pelvis increased by 50%-83%. As the load increased, the maximum equivalent stress on the screws also increased. When the acetabular bone block and the ilium had no contact, no graft was used, and only three screws were used for fixation, the maximum equivalent stress could reach 518.9 MPa, while this value dropped to 61% when four screws were used (318.7 MPa). When the acetabular bone block and the ilium were in contact, the maximum equivalent stress was about 12% of that when there was no contact, regardless of the number of screws used. When a cortical bone graft or a PEEK graft was used, the maximum equivalent stress could drop to 21%-26% of that without a graft. When the screw strength was 130 MPa, a load of 20% of body weight was applied, and only three screws were used without a graft, the equivalent stress could exceed the strength of the screw; if four screws were used, the equivalent stress was slightly higher than the strength of the screw when a load of 50% of body weight was applied. However, when a graft was used (either cortical bone or PEEK), even when a load of 100% of body weight was applied, the equivalent stress was slightly lower than the strength of the screw.Conclusion:Absorbable screws can provide sufficient stability for Bernese periacetabular osteotomy. The contact between the acetabular bone block and the ilium, an increase in the number of screws, and the use of grafts (cortical bone and PEEK grafts) can further improve stability. Therefore, absorbable screws have broad application prospects in Bernese periacetabular osteotomy.

The accumulation of pathological α-synuclein (α-syn) in the central nervous system and the progressive loss of dopaminergic neurons in the substantia nigra pars compacta are the neuropathological features of Parkinson's disease (PD). Recently, the findings of prion-like transmission of α-syn pathology have expanded our understanding of the region-specific distribution of α-syn in PD patients. Accumulating evidence suggests that α-syn aggregates are released from neurons and endocytosed by glial cells, which contributes to the clearance of α-syn. However, the activation of glial cells by α-syn species produces pro-inflammatory factors that decrease the uptake of α-syn aggregates by glial cells and promote the transmission of α-syn between neurons, which promotes the spread of α-syn pathology. In this article, we provide an overview of current knowledge on the role of glia and α-syn pathology in PD pathogenesis, highlighting the relationships between glial responses and the spread of α-syn pathology.
Humans ; Parkinson Disease/pathology* ; alpha-Synuclein/metabolism* ; Dopaminergic Neurons/metabolism* ; Pars Compacta/metabolism*

Since the discovery of the C9ORF72 gene in 2011, great advances have been achieved in its genetics and in identifying its role in disease models and pathological mechanisms; it is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS patients with C9ORF72 expansion show heterogeneous symptoms. Those who are C9ORF72 expansion carriers have shorter survival after disease onset than non-C9ORF72 expansion patients. Pathological and clinical features of C9ORF72 patients have been well mimicked via several models, including induced pluripotent stem cell-derived neurons and transgenic mice that were embedded with bacterial artificial chromosome construct and that overexpressing dipeptide repeat proteins. The mechanisms implicated in C9ORF72 pathology include DNA damage, changes of RNA metabolism, alteration of phase separation, and impairment of nucleocytoplasmic transport, which may underlie C9ORF72 expansion-related ALS/FTD and provide insight into non-C9ORF72 expansion-related ALS, FTD, and other neurodegenerative diseases.

GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9ORF72 produce five dipeptide repeat (DPR) proteins by an unconventional repeat-associated non-ATG (RAN) translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs (poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase (JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PR-induced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependent endocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.

Autophagy is an evolutionarily-conserved self-degradative process that maintains cellular homeostasis by eliminating protein aggregates and damaged organelles. Recently, vesicle-associated membrane protein-associated protein B (VAPB), which is associated with the familial form of amyotrophic lateral sclerosis, has been shown to regulate autophagy. In the present study, we demonstrated that knockdown of VAPB induced the up-regulation of beclin 1 expression, which promoted LC3 (microtubule-associated protein light chain 3) conversion and the formation of LC3 puncta, whereas overexpression of VAPB inhibited these processes. The regulation of beclin 1 by VAPB was at the transcriptional level. Moreover, knockdown of VAPB increased autophagic flux, which promoted the degradation of the autophagy substrate p62 and neurodegenerative disease proteins. Our study provides evidence that the regulation of autophagy by VAPB is associated with the autophagy-initiating factor beclin 1.
Autophagy ; drug effects ; physiology ; Beclin-1 ; genetics ; metabolism ; Cell Line, Transformed ; Gene Expression Regulation ; genetics ; Green Fluorescent Proteins ; genetics ; metabolism ; Humans ; Microtubule-Associated Proteins ; genetics ; metabolism ; R-SNARE Proteins ; genetics ; metabolism ; RNA, Messenger ; metabolism ; RNA, Small Interfering ; genetics ; metabolism ; RNA-Binding Proteins ; genetics ; metabolism ; Transfection

Objective To investigate the effect of isoflurane preconditioning on Toll-like receptor 4 (TLR4)-myeloid differentiation factor 88 (MyD88) signaling pathway in ischemic penumbra following focal cerebral ischemia-reperfusion (I/R) in rats.Methods Fifty-four healthy male SD rats,aged 3 months,weighing 250-280 g,were randomly divided into 3 groups (n =18 each):sham operation group (group S),I/R group and isoflurane preconditioning group (group IP).Focal cerebral I/R was induced by middle cerebral artery occlusion.In groups I/R and IP,a nylon thread with rounded tip was inserted into the right internal jugular vein and threaded cranially until resistance was met.The middle cerebral artery was occluded for 2 h,followed by 24 h reperfusion.In group IP,the animals inhaled 2.0％ isoflurane for 2 h,and middle cerebral artery occlusion was performed at 24 h after the end of preconditioning.Neurological deficit was scored at 24 h of reperfusion and then the rats were sacrificed.Five rats in each group were chosen and the brains removed for measurement of the cerebral infarct volume.The right cerebral ischemic penumbra was removed for detection of the expression of HSP60,TLR4,MyD88 protein and mRNA by Western blot analysis and real time-PCR.Apoptosis was detected in the ischemic penumbra in the left 3 rats in each group using TUNEL.Apoptosis index (AI) was calculated.Results Neurological deficit scores and AI were significantly increased,the cerebral infarct volume was significantly enlarged,and the expression of HSP60,TLR4,MyD88 protein and mRNA was up-regulated in groups I/R and IP as compared with group S ( P ＜ 0.05).Isoflurane preconditioning significantly reduced the cerebral infarct volume and decreased neurological deficit scores and AI,and down-regulated the expression of HSP60,TLR4,MyD88 protein and mRNA (P ＜ 0.05).Conclusion The mechanisn by which isoflurane preconditioning protects ischenic penumbra following focal cerebral I/R may be related to inhibition of TLR4-MyD88 signaling pathway.

Objective To investigate the effect of isoflurane preconditioning on the expression of 5-lipoxy-genase (5-LOX) during focal cerebral ischemia-reperfusion (I/R) in rats.Methods Thirty-nine male adult Sprague-Dawley rats weighing 250-300 g were randomly divided into 3 groups (n =13 each):sham operation group (group S); focal cerebral I/R group (group I/R); isoflurane preconditioning group (group Ⅰ).Focal cerebral I/R was produced by mid-cerebral artery occlusion in anesthetized rats.The rats inhaled 2 h of 2％ isoflurane and focal cerebral I/R was produced 24 h later in group I.The neurological deficits were scored at 24 h of reperfusion.The animals were then sacrificed.The brains were immediately removed for determination of the infarct size.The expression of 5-LOX,myeloid differentiation factor88 (MyD88) and nuclear factor kappa B (NF-κB) protein and mRNA was detected using Western blot and RT-PCR respectively.Results Compared with group S,the neurological deficit score was significantly increased,the infarct size was enlarged in groups I/R and I,the expression of 5-LOX,MyD88 and NF-κB protein and mRNA was up-regulated in group I/R,and the expression of 5-LOX mRNA and MyD88 protein and mRNA was up-regulated in group I (P ＜ 0.05).Compared with group I/R,the neurological deficit score was significantly lower,the infarct size was smaller,and the expression of 5-LOX,MyD88 and NF-κB protein and mRNA was lower in group I (P ＜ 0.05).Conclusion Isoflurane preconditioning can reduce focal cerebral I/R injury by down-regulating the expression of 5-LOX and inhibiting MyD88/NF-κB signaling pathway in rats.

BACKGROUND: Acellular bladder submucosa is a natural extracellular matrix, which is mainly composed of collagen Ⅰ and Ⅲ. It is regarded as an ideal biological scaffold material. OBJECTIVE: To evaluate the biocompatibility of acellular bladder submucosa as a tissue engineered scaffold material. METHODS: Pig urinary bladder was immersed in the solution of PBS and sodium azide for a night, and the mucosa was removed. Acellular bladder submucosa was prepared using continuous hypotension, freeze-thawed treatment and NaOH spallation. The biocompatibility of acellular bladder submucosa was evaluated through histologic structure, DNA residual, cytotoxicity, cell adhesion, as well as subcutaneous inflammatory reactions. RESULTS AND CONCLUSION: The cell components were completely eliminated after deoellularization treatment, while the extracellular matrix was remained intact as normal bladder:According to MTT results, cytotoxicity of acellular bladder matrix was assigned to be the first grade. No DNA signal was observed after extraction, and the matrix also supported porcine smooth muscle cell attachment and proliferation. Subcutaneous implantation of the matrix indicated that the acellular bladder submucosa trigger no immunologic rejection reaction obviously. The results demonstrated that: the acellular bladder submucosa prepared here exhibits excellent biocompatibility, which can be used as substitution in tissue-engineering field.

0.05). Phenylephrine induced contractile responses in a concentration-dependent manner in the dorsal detrusor strips, but not in the ventral detrusor strips. S-doxazosin, R-doxazosin and rac-doxazosin at 1 ?mol?L-1 antagonized the phenylephrine-induced contractile responses competitively in the dorsal detrusor strips, and their pKB values were 7.44?0.19, 7.39?0.14 and 7.38?0.30, respectively. Three pKB values of doxazosin and its enantiomers were not significantly different from each other. Electric field stimulation produced a steady contractile response that was completely inhibited by tetrodotoxin at 0.3 ?mol?L-1. S-doxazosin, R-doxazosin and rac-doxazosin significantly inhibited the contractile responses to electric field stimulation in the dorsal detrusor strips of the rabbit urinary bladder(P0.05). However, S-doxazosin, R-doxazosin and rac-doxazosin did not affect the responses to electric field stimulation in the ventral detrusor strips. Conclusion The pKB value of S-doxazosin against phenylephrine-induced contraction via-adrenoceptors is same to R-doxazosin and rac-doxazosin, and the three agents are able to inhibit the adrenergic contraction induced by electric field stimulation in dorsal detrusor strips of the rabbit urinary bladder.