ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease (AD), but the neurobiological mechanisms linking synaptic pathology, neural oscillatory dynamics, and brain network reorganization remain unclear. This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments, molecular profiling, and neurophysiological monitoring. MethodsIn this prospective double-blind trial, 12 AD patients underwent a 14-day protocol of 20 Hz rTMS, with comprehensive multimodal assessments performed pre- and post-intervention. Cognitive functioning was quantified using the mini-mental state examination (MMSE) and Montreal cognitive assessment (MOCA), while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living (ADL) scale and combined neuropsychiatric inventory (NPI)-Hamilton depression rating scale (HAMD). Peripheral blood biomarkers, specifically Aβ1-40 and phosphorylated tau (p-tau181), were analyzed to investigate the effects of rTMS on molecular metabolism. Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients, while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization. Furthermore, systematic assessment of correlations between cognitive scale scores, blood biomarkers, and network characteristics was performed to elucidate cross-modal therapeutic associations. ResultsClinically, MMSE and MOCA scores improved significantly (P<0.05). Biomarker showed that Aβ1-40 level increased (P<0.05), contrasting with p-tau181 reduction. Moreover, the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores. Post-intervention analyses revealed significant modulations in oscillatory power, characterized by pronounced reductions in delta (P<0.05) and theta bands (P<0.05), while concurrent enhancements were observed in alpha, beta, and gamma band activities (all P<0.05). Network analysis revealed frequency-specific reorganization: clustering coefficients were significantly decreased in delta, theta, and alpha bands (P<0.05), while global efficiency improvement was exclusively detected in the delta band (P<0.05). The alpha band demonstrated concurrent increases in average nodal degree (P<0.05) and characteristic path length reduction (P<0.05). Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181. Additionally, the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band. However, the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands. Conclusion20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) significantly improves cognitive function and enhances the metabolic clearance of β-amyloid and tau proteins in AD patients. This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation, which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks. These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales, blood biomarkers, and EEG——in understanding and monitoring the progression of AD. This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

The implementation of amplicon sequencing and metagenomic sequencing methods in the whole-genome sequen-cing for MPXV testing was compared,to provide a technical reference for sequencing,tracing,and epidemic prevention and control of MPXV.For amplicon sequencing,targeted amplification of the viral whole genome was performed on MPXV DNA,and was followed by next-generation sequencing of the amplification products.For metagenomic sequencing,next-generation sequencing was performed directly on MPXV DNA.After the sequences were obtained,software such as CLC and IGV were used to analyze the effective data percentage,sequencing depth,and whole-genome sequencing coverage under different sequen-cing depths for both sequencing methods,to evaluate sequencing quality.Nextclade was used to analyze virus typing,muta-tions,and deletions.Subsequently,the similarity and completeness of sequences obtained through both sequencing methods were further compared.On the basis of mapping to the refer-ence sequence of strain MPXV-M5312_HM12_Rivers(Gen-Bank number NC_063383.1),the percentage effective data obtained from amplicon sequencing and metagenomic sequen-cing was 99.72％and 7.54％,respectively,with a sequencing depth range of 0× to 334 839 ×,and 44 × to 1 000 ×.On the basis of a sequencing depth of 10 ×,the site coverage of the above was 90.3％and 100％,respectively.IGV was used to validate the whole-genome coverage under different sequencing depths.The depth coverage of whole-genome sites for metagenomic sequencing was uniform,whereas that of the whole-genome sites for amplicon sequencing was uneven and significantly differed.Virus typing and sequence similarity analysis indicated that the viral sequences obtained with the two sequencing methods all belonged to the Ⅱb B.1 lineage of MPXV.Comparison with the reference sequence indicated that metagenomic sequencing identified 73 nucleotide mutation sites,whereas amplicon sequen-cing identified 68 mutation sites.Further analysis demonstrated that seven common mutation sites of Ⅱb B.1 were not detected in the amplicon sequencing,and two false positive private mutation sites were identified.Amplicon or metagenomic sequencing methods thus can be flexibly used in MPXV virus whole-genome sequencing.Amplicon sequencing yields more effective data,whereas metagenomic sequencing provides better uniformity of coverage and sequence accuracy.This study provides a prelimi-nary understanding of the efficacy of each method and may serve as a technical reference for improving the success rate of whole-genome sequencing of MPXV.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Objective: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m 2 ) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this phase I trial, a time-to-event Bayesian optimal interval design was used.Docetaxel was given at a starting dose of 60 mg/m2 and was increased in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The doselimiting toxicity (DLT) rate was set at 25%, with a total sample size of 30 patients. HIPEC was delivered immediately following debulking surgery at a target temperature of 43°C for 90 minutes. Results: From August 2022 to November 2022, 30 patients were enrolled. Among the patients who received a dose of docetaxel ≤65 mg/m2 , no DLT was reported. DLTs were observed in one patient who received 70 mg/m2 docetaxel (grade 3 anaemia) and in three patients who received 75 mg/m2 docetaxel (one case of grade 3 anaemia, one case of grade 3 hepatic impairment and one case of grade 4 thrombocytopenia). Patients treated with docetaxel 75 mg/m2 in combination with cisplatin 75 mg/m2 had an estimated DLT rate of 25%, which was the closest to the target DLT rate and was therefore chosen as the MTD. Conclusion Docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be used safely at intraperitoneal doses of 75 mg/m2 in ovarian cancer patients who received HIPEC (43°C, 90 minutes) following debulking surgery.

Digital guided therapy (DGT) has been advocated as a contemporary computer-aided technique for treating endodontic diseases in recent decades. The concept of DGT for endodontic diseases is categorized into static guided endodontics (SGE), necessitating a meticulously designed template, and dynamic guided endodontics (DGE), which utilizes an optical triangulation tracking system. Based on cone-beam computed tomography (CBCT) images superimposed with or without oral scan (OS) data, a virtual template is crafted through software and subsequently translated into a 3-dimensional (3D) printing for SGE, while the system guides the drilling path with a real-time navigation in DGE. DGT was reported to resolve a series of challenging endodontic cases, including teeth with pulp obliteration, teeth with anatomical abnormalities, teeth requiring retreatment, posterior teeth needing endodontic microsurgery, and tooth autotransplantation. Case reports and basic researches all demonstrate that DGT stand as a precise, time-saving, and minimally invasive approach in contrast to conventional freehand method. This expert consensus mainly introduces the case selection, general workflow, evaluation, and impact factor of DGT, which could provide an alternative working strategy in endodontic treatment.
Humans ; Consensus ; Endodontics/methods* ; Tooth ; Printing, Three-Dimensional ; Dental Care ; Cone-Beam Computed Tomography ; Root Canal Therapy

Objective: To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. Methods: The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Results: Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% vs 63.8% ; P=0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (P<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Conclusion: Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Male ; Humans ; Middle Aged ; Asparaginase/therapeutic use* ; Prognosis ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Etoposide ; Cyclophosphamide ; Methotrexate/therapeutic use* ; DNA/therapeutic use* ; Treatment Outcome

Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/β-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knock-down.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/β-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alle-viated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.