Cholangiocarcinoma (CCA) is a fatal malignancy with steadily increasing incidence and poor prognosis. Since most CCA cases are diagnosed at an advanced stage, systemic therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, play a crucial role in the management of unresectable CCA. The recent advances in targeted therapies and immunotherapies brought more options in the clinical management of unresectable CCA. This review depicts the advances of targeted therapies and immunotherapies for unresectable CCA, summarizes crucial clinical trials, and describes the efficacy and safety of different drugs, which may help further develop precision and individualization in the clinical treatment of unresectable CCA.
Humans ; Cholangiocarcinoma/drug therapy* ; Immunotherapy/methods* ; Bile Duct Neoplasms/drug therapy* ; Molecular Targeted Therapy/methods*

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Lysosomes represent a promising target for cancer therapy and reducing drug resistance. However, the short treatment time and low efficiency of lysosomal targeting have limited the application in lysosome-targeting anticancer drugs. In this study, we proposed an adhesive-bandage approach and synthesized a new lysosomal targeting drug, namely long-term lysosome-targeting anticancer drug (LLAD). It contains a SLC38A9-targeting covalently bound moiety and an alkaline component both to prolong the inhibition of SLC38A9 in lysosomes and alkalinize lysosomes. Upon short term and low-dose treatment of HeLa cells, at passage 0, with LLAD, it rapidly alkalinized lysosomes and also can be detected in lysosomes even at passage 15. LLAD induced apoptosis in HeLa cells through long-term lysosomal damage, and showed better long-term anticancer effect than cisplatin in vivo. Overall, our study paves the way for developing long-term lysosomal targeting drugs to treat cancer and overcome the drug resistance of cancer cells, and also provides a candidate drug, LLAD, for treating cancer.

Schizophrenia (SZ) stands as a severe psychiatric disorder. This study applied diffusion tensor imaging (DTI) data in conjunction with graph neural networks to distinguish SZ patients from normal controls (NCs) and showcases the superior performance of a graph neural network integrating combined fractional anisotropy and fiber number brain network features, achieving an accuracy of 73.79% in distinguishing SZ patients from NCs. Beyond mere discrimination, our study delved deeper into the advantages of utilizing white matter brain network features for identifying SZ patients through interpretable model analysis and gene expression analysis. These analyses uncovered intricate interrelationships between brain imaging markers and genetic biomarkers, providing novel insights into the neuropathological basis of SZ. In summary, our findings underscore the potential of graph neural networks applied to multimodal DTI data for enhancing SZ detection through an integrated analysis of neuroimaging and genetic features.
Humans ; Schizophrenia/pathology* ; Diffusion Tensor Imaging/methods* ; Male ; Female ; Adult ; Brain/metabolism* ; Young Adult ; Middle Aged ; White Matter/pathology* ; Gene Expression ; Nerve Net/diagnostic imaging* ; Graph Neural Networks

Objective To observe the clinical efficacy of scalp acupuncture combined with repetitive transcranial magnetic stimulation in the treatment of patients with mild to moderate vascular dementia and to explore its potential mechanism of action.Methods A total of 102 patients diagnosed with mild to moderate vascular dementia who were treated in the outpatient and inpatient departments of Cangzhou Hospital of Integrated Traditional Chinese and Western Medicine from July 2021 to May 2023 were selected as the study subjects.The patients were randomly divided into an observation group and a control group using a random number table,with 51 patients in each group.The control group received repetitive transcranial magnetic stimulation treatment,while the observation group received scalp acupuncture therapy in addition to the treatment given to the control group.The treatment lasted for 16 weeks.After treatment,the clinical efficacy of the two groups was evaluated.Changes in the Mini-Mental State Examination(MMSE)scores,Montreal Cognitive Assessment(MoCA)scores,and traditional Chinese medicine(TCM)syndrome scores were observed before and after treatment.Additionally,serum levels of brain-derived neurotrophic factor(BDNF),vascular endothelial growth factor(VEGF),and homocysteine(Hcy)were measured.The cerebral blood flow velocities in the anterior,middle,and posterior arteries,as well as the levels of lipid peroxide(LPO),malondialdehyde(MDA),and superoxide dismutase(SOD),were compared between the two groups before and after treatment.The safety and incidence of adverse reactions in both groups were also evaluated.Results(1)After treatment,the MMSE and MoCA scores of both groups were significantly improved(P＜0.05),and the observation group showed significantly better improvement in MMSE and MoCA scores compared to the control group,with a statistically significant difference(P＜0.05).(2)After treatment,the serum levels of BDNF,VEGF,and Hcy in both groups were significantly improved(P＜0.05),and the observation group showed significantly better improvement in these levels compared to the control group,with a statistically significant difference(P＜0.05).(3)After treatment,the cerebral blood flow velocities in the posterior,middle,and anterior arteries were significantly improved in both groups(P＜0.05),and the observation group showed significantly better improvement in these velocities compared to the control group,with a statistically significant difference(P＜0.05).(4)After treatment,the levels of LPO,MDA,and SOD were significantly improved in both groups(P＜0.05),and the observation group showed significantly better improvement in these levels compared to the control group,with a statistically significant difference(P＜0.05).(5)After treatment,the TCM syndrome scores improved significantly in both groups(P＜0.05),and the observation group showed significantly better improvement in these scores compared to the control group,with a statistically significant difference(P＜0.05).(6)The total effective rate in the observation group was 88.24%(45/51),while it was 70.59%(36/51)in the control group.The efficacy of the observation group was superior to that of the control group,with a statistically significant difference(P＜0.05).(7)The incidence of adverse reactions in the observation group was 3.92%(2/51),while it was 1.96%(1/51)in the control group.There was no statistically significant difference in the incidence of adverse reactions between the two groups(P＞0.05).Conclusion Scalp acupuncture combined with repetitive transcranial magnetic stimulation in the treatment of mild to moderate vascular dementia helps regulate cerebral hemodynamics and neurotrophic factor expression,improves cognitive function,and demonstrates significant efficacy with good safety.

Objective During the rapid expansion of postgraduate education,it is meeting more and more conflicts between enroll-ment scale and cultivation quality.The construction of a cultivation quality assurance system for postgraduates becomes an urgent task in the new situation.Methods The data was analyzed with SPSS 24.0,based on the anonymous review results of postgraduates'disserta-tions by a three-A stomatological hospital during 2022-2023.Results The results showed that the overall evaluation of anonymous dis-sertation opinions in 2022 was better than that in 2023,and the passing rate of anonymous dissertation evaluation of doctoral students was higher than that of master students.Irregular forms of composition,low research workload,and insufficient innovation were found in failed postgraduates'dissertations.Conclusion Strengthening the management of study style education and training process,and ex-ploring cultivating mode of overlapping subjects,are necessary to improve the construction of cultivation quality assurance system of postgraduates.

Objective:To investigate the changes of mitochondria in the substantia nigra pars reticulata(SNr)in a mouse model of acute hepatic encephalopathy(AHE),and the effects of mitochondrial division inhibitor Mdivi-1 on the motor function and mitochondrial function of SNr in AHE mice.Methods:The mouse model of AHE was established by intraperitoneal injection of thioacetamide(TAA)and treated with Mdivi-1.The changes of serum aspartate aminotrans-ferase(AST),alanine aminotransferase(ALT),and blood ammonia were detected by biochemical detection kits.Open field test,rotor-rod fatigue test and elevated plus maze test were performed to observe the motor function of AHE mice.Mitochondrial membrane potential(MMP),cellular reactive oxygen species(ROS)and ATP of SNr were detected by commercial kits.Results:Compared with the control group,the levels of AST,ALT and blood ammonia in AHE mice were increased.The total movement distance of the mice in the open field was reduced,and the movement time of the rotor-rod fatigue test and the elevated plus maze test were shortened.In SNr,mitochondria became smaller and rounder,mitochondrial fission increased,MMP decreased,cellular ROS increased,and ATP production decreased.After treat-ment with Mdivi-1,the levels of AST,ALT and blood ammonia in AHE mice were decreased.In the open field,the total movement distance of mice increased,the movement time of rotorrod fatigue test and elevated plus maze test increased,the mitochondria of SNr were larger,with decreased roundness,decreased mitochondrial division,increased MMP,decreased cellular ROS,and increased ATP production.Conclusion:Mdivi-1 can improve movement disorders in AHE mice by repairing mitochondrial in the SNr.

Objective:To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency.Methods:This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively.Results:The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders.Conclusions:Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Objective:To investigate the clinical features and outcomes of adolescence-onset methylmalonic acidemia (MMA) and explore preventive strategies.Methods:This was a retrospective case analysis of the phenotypes, genotypes and prognoses of adolescence-onset MMA patients. There were 55 patients diagnosed in Peking University First Hospital from January 2002 to June 2023, the data of symptoms, signs, laboratory results, gene variations, and outcomes was collected. The follow-ups were done through WeChat, telephone, or clinic visits every 3 to 6 months.Results:Among the 55 patients, 31 were males and 24 were females. The age of onset was 12 years old (range 10-18 years old). They visited clinics at Tanner stages 2 to 5 with typical secondary sexual characteristics. Nine cases (16%) were trigged by infection and 5 cases (9%) were triggered by insidious exercises. The period from onset to diagnosis was between 2 months and 6 years. Forty-five cases (82%) had neuropsychiatric symptoms as the main symptoms, followed by cardiovascular symptoms in 12 cases (22%), kidney damage in 7 cases (13%), and eye disease in 12 cases (22%). Fifty-four cases (98%) had the biochemical characteristics of methylmalonic acidemia combined with homocysteinemia, and 1 case (2%) had the isolated methylmalonic acidemia. Genetic diagnosis was obtained in 54 cases, with 20 variants identified in MMACHC gene and 2 in MMUT gene. In 53 children with MMACHC gene mutation,1 case had dual gene variants of PRDX1 and MMACHC, with 105 alleles. The top 5 frequent variants in MMACHC were c.482G>A in 39 alleles (37%), c.609G>A in 17 alleles (16%), c.658_660delAAG in 11 alleles (10%), c.80A>G in 10 alleles (10%), c.567dupT and c.394C>T both are 4 alleles (4%). All patients recovered using cobalamin, L-carnitine, betaine, and symptomatic therapy, and 54 patients (98%) returned to school or work.Conclusions:Patients with adolescence-onset MMA may triggered by fatigue or infection. The diagnosis is often delayed due to non-specific symptoms. Metabolic and genetic tests are crucial for a definite diagnosis. Treatment with cobalamin, L-carnitine, and betaine can effectively reverse the prognosis of MMA in adolescence-onset patients.

Objective: To analyze the spatio-temporal distribution characteristics of pulmonary tuberculosis incidence in Xinjiang, and to provide reference for the prevention and control of pulmonary tuberculosis. Methods: The reported incidence numbers of tuberculosis and population data from various counties, cities(prefectures), and districts in Xinjiang from 2010 to 2022 were collected. Based on spatial-temporal scan statistics, standard deviational ellipse analysis, and centroid migration models, the clustering and migration trends of tuberculosis incidence were evaluated. Utilizing Kriging interpolation techniques, an interpolation analysis of the 2022 incidence rate was conducted on an annual scale, with the reported incidence rate in 2018 serving as a temporal control, to identify hotspots of the spatio-temporal distribution. ArcGIS software was employed to visualize the continuous spatial trends of incidence rate changes. Results: The annual reported incidence rate of tuberculosis in Xinjiang from 2010 to 2022 varied year by year, with fluctuations and increases prior to 2018, peaking in 2018, and then declining annually thereafter. The spatial distribution of the incidence rate exhibited a trend of initial clustering followed by diffusion, with the centroid of incidence shifting towards the northeast, yet the epicenter of the epidemic remained in Aksu Prefecture. The results of spatiotemporal scan statistics analysis revealed that the three-level aggregated areas of the epidemic encompassed a total of 41 prefectures, counties, and cities, with the tuberculosis incidence risk in the primary and secondary aggregated areas being significantly higher than that in other regions(P<0.01). The Kriging interpolation prediction map suggested that the four prefectures in southern Xinjiang continued to be high-risk regions for tuberculosis(incidence rate>300/100 000). The overall incidence rate in the northern region was relatively low, with the lowest rate observed in Urumqi, radiating outwards. Conclusion The incidence rate of tuberculosis in Xinjiang shows an upward trend before 2018, followed by a year-on-year decrease. The centroid of the incidence rate shifts towards the northeast. From 2010 to 2022, the tuberculosis epidemic in Xinjiang exhibits a notable spatiotemporal clustering, particularly prominent in the southwestern region, where the four prefectures constitute high-risk areas for tuberculosis. The prevention and control efforts of tuberculosis in Xinjiang should prioritize the regions with high tuberculosis incidence, intensifying prevention and control measures as well as policy support.