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 conduct a literature review of one case of follicular lymphoma complicated with iliac bone Cryptococcus neoformans infection so as to raise the understanding of such pathogen in the field of HIV-negative Hodgkin's/non-Hodgkin's lymphoma.METHODS The clinical data were collected from one case of follicular lymphoma patient complicated with C.neoformans infection who was treated in Xinrui Hospital of Xin-wu District,Wuxi City on Feb.24,2023 and retrospectively analyzed.All of relevant literatures regarding to the subject were retrieved in Pubmed,CNKI,Wanfang and VIP databases,and the clinical data of the patients with HIV-negative Hodgkin's/non-Hodgkin's lymphoma with C.neoformans infection were screened out and summa-rized.RESULTS The case was a 28-year-old male and had the underlying disease of follicular lymphoma.The C.neoformans was detected by iliac bone histopathology and metagenome next generation sequencing(mNGS).The condition of the patient improved after the treatment with amphotericin B cholesterol sulphate com-pound and fluconazole.A total of 28 patients,with this case included,were involved in the literature review,23 of whom were male,and 5 were female,and the age ranged between 16 and 79 years old.With respect to major in-fection sites,there were 15(53.57％)cases of cerebral infection,9(32.14％)cases of blood infections,7(25.00％)cases of pulmonary infection,4(14.285％)cases of skin infections,2(7.14％)cases of muscle tis-sue infections,2(7.14％)cases of pleural effusion infections,2(7.14％)cases of bone infections and 1(3.57％)case of bone marrow infection.Totally 11 patients had disseminated Cryptococcus infection,accounting for 39.28％.CONCLUSIONS The C.neoformans infection is seldom detected in the patients with HIV-negative Hodgkin's/non-Hodgkin's lymphoma.The brain is the major infection site with the high probability of dissemina-ted infection.It is necessary for the hospital to deepen the understanding of the pathogen in the field of HIV-negative Hodgkin's/non-Hodgkin's lymphoma.

Objective:To explore the changes in carcinoembryonic antigen(CEA)during the immune process of programmed death-1(PD-1)inhibitor Sintilimab in human epithelial growth factor receptor 2(HER2)negative advanced gastric cancer patients and its relationship with prognosis.Methods:HER2 negative late stage gastric cancer patients(88 cases)who were treated in North Anhui Coal Power Group General Hospital from May 2020 to April 2022 were selected as study subjects,all of whom received PD-1 inhibitor Sintilimab treatment;according to the prognosis,they were divided into death group(36 cases)and survival group(52 cases).Followed up was conducted every 6 months to collect tumor marker levels before and after treatment.Analyzed relationship between tumor markers(CEA,CA199,CA125)levels and clinical staging,lymph node metastasis and prognosis.Kaplan-Meier sur-vival curve was used to analyze survival time of patients with negative and positive tumor markers.Multivariate Cox regression model and stepwise regression analysis were used to identify risk factors affecting prognosis.Spearman was used for correlation analysis.Results:After two cycles of treatment,72 cases(81.82%)had disease control and 16 cases(18.18%)had progression.Compared with patients before treatment,positive rate of serum tumor markers in patients after treatment was significantly reduced(P<0.05).Positive rates of CEA and CA199 were significantly correlated with clinical staging(P<0.05).When predicting patient death,sensitivity of CEA level was the highest(48.57%),while CA125 had the highest specificity(95.62%)and the lowest sensitivity(25.71%).Kaplan-Meier sur-vival curve analysis showed that the survival time of patients with positive tumor markers were significantly shorter than that of negative patients(P<0.05).Clinical staging,serum CEA and CA199 levels were independent factors for predicting prognosis(P<0.05).Spear-man correlation analysis results showed that the multiple increases in CEA(r=-0.512,P=0.005)and CA199(r=-0.467,P=0.011)were negatively correlated with patient survival time.Conclusion:After treatment with PD-1 inhibitor Sintilimab,serum tumor markers levels in HER2 negative advanced gastric cancer patients have been significantly reduced on average.High serum levels of CEA,CA199 and CA125 can all predict poor prognosis,and clinical staging,serum CEA and CA199 levels are independent factors in pre-dicting prognosis.The higher the increase in CEA and CA199,the shorter the patient's survival time.

OBJECTIVE To conduct a literature review of one case of follicular lymphoma complicated with iliac bone Cryptococcus neoformans infection so as to raise the understanding of such pathogen in the field of HIV-negative Hodgkin's/non-Hodgkin's lymphoma.METHODS The clinical data were collected from one case of follicular lymphoma patient complicated with C.neoformans infection who was treated in Xinrui Hospital of Xin-wu District,Wuxi City on Feb.24,2023 and retrospectively analyzed.All of relevant literatures regarding to the subject were retrieved in Pubmed,CNKI,Wanfang and VIP databases,and the clinical data of the patients with HIV-negative Hodgkin's/non-Hodgkin's lymphoma with C.neoformans infection were screened out and summa-rized.RESULTS The case was a 28-year-old male and had the underlying disease of follicular lymphoma.The C.neoformans was detected by iliac bone histopathology and metagenome next generation sequencing(mNGS).The condition of the patient improved after the treatment with amphotericin B cholesterol sulphate com-pound and fluconazole.A total of 28 patients,with this case included,were involved in the literature review,23 of whom were male,and 5 were female,and the age ranged between 16 and 79 years old.With respect to major in-fection sites,there were 15(53.57％)cases of cerebral infection,9(32.14％)cases of blood infections,7(25.00％)cases of pulmonary infection,4(14.285％)cases of skin infections,2(7.14％)cases of muscle tis-sue infections,2(7.14％)cases of pleural effusion infections,2(7.14％)cases of bone infections and 1(3.57％)case of bone marrow infection.Totally 11 patients had disseminated Cryptococcus infection,accounting for 39.28％.CONCLUSIONS The C.neoformans infection is seldom detected in the patients with HIV-negative Hodgkin's/non-Hodgkin's lymphoma.The brain is the major infection site with the high probability of dissemina-ted infection.It is necessary for the hospital to deepen the understanding of the pathogen in the field of HIV-negative Hodgkin's/non-Hodgkin's lymphoma.

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 : To analyze the epidemiological characteristics of tuberculosis in Urumqi and assess the im⁃pact of the national health examination policy , as well as COVID⁃19 prevention and control measures , on tuberculo⁃sis incidence in Xinjiang. Methods: The seasonal patterns of pulmonary tuberculosis were examined using the seasonal index method and circular distribution analysis. An Interrupted Time Series (ITS , Interrupted Time Series) model was employed to investigate how the national health examination policy and COVID_19 interventions influenced trends in tuberculosis incidence in Urumqi. Results: From 2013 to 2021 , a total of 19 ,049 cases of tuberculosis were reported in Urumqi. The peak incidence day occurred on May 25th , indicating a consistently high rate throughout the year, particularly during spring and summer months. The results of the interrupted time series model indicated that the initial monthly incidence rate of pulmonary tuberculosis in Urumqi was 5. 05 per 100 ,000. From January 2013 to September 2016 , the incidence rate of pulmonary tuberculosis showed a slow upward trend , and the upward trend was significant (β1 = 0. 039 ,P < 0. 05) . After the implementation of the universal health checkup policy , the incidence rate of pulmonary tuberculosis showed a slow downward trend , and the downward trend was significant(β3 = - 0. 109 ,P < 0. 05) . After the outbreak of the COVID_19 epidemic in January 2020 , the incidence rate of pulmonary tuberculosis in Urumqi first dropped rapidly and then entered a slow upward stage , and the upward trend was significant(β5 = 0. 082 , P < 0. 05) . Conclusion It is recommended that public health authorities prioritize timely identification of potential TB patients during periods with elevated incidence rates observed in spring and summer months. While significant progress has been made through implementing national health examinations policies , attention must be directed towards understanding how ongoing epidemics affect TB patient detection. Thus , enhancing surveillance efforts and intervention strategies are essential in adapting to this new normal. Key words tuberculosis ; seasonal index method ; circular distribution method ; national health examination ; COVID_19 ; interruption time series

Objective:To evaluate the short-and medium-term therapeutic efficacy of shockwave balloon therapy for TASCⅡ C/D femoropopliteal artery atherosclerosis obliteration.Methods:This retrospective cohort study included 25 patients who received shockwave balloon therapy in five vascular centers from August 2022 to June 2023. All patients were diagnosed with TASC Ⅱ C/D femoropopliteal arteriosclerosis obliterans (13 cases of type C and 12 cases of type D), and underwent intravascular shock wave lithotripsy (IVL) to treat calcified lesions. The immediate effectiveness (residual stenosis<30% and no flow-limiting dissection), safety (whether there were adverse vascular events during the operation) and the rate of salvage stent implantation were recorded. The observation indexes of patients before operation, early postoperative period (immediately after operation or before discharge) and postoperative follow-up period (3, 6, 12 months after operation) were collected. The observation indexes included ankle-brachial index (ABI), Rutherford classification, and minimum lumen diameter (MLD). Repeated measures ANOVA was used to evaluate the changes of observation indexes in the early postoperative and follow-up stages compared with those before operation; Kaplan-Meier survival analysis was used to evaluate the one-stage patency rate at follow-up and the target lesion revascularization rate free from clinical drive.Results:The immediate effectiveness of surgery was 100% in all patients, with no vascular related adverse events occurred, and no remedial stent implantation was performed. The ABI, Rutherford grade and MLD of the patients in the early postoperative period and each follow-up stage were improved compared with those before operation, with statistically significant differences ( P<0.05). Kaplan-Meier survival analysis showed that the primary patency rate at 12 months after surgery was 0.78 (95% CI 0.64-0.84), and the revascularization rate of target lesions free from clinical drive was 0.87 (95% CI 0.85-0.95). Conclusion:Shockwave balloon therapy for complex calcified femoropopliteal artery lesions is safe and reliable, with satisfactory short-and medium-term efficacy.