DNA polymerase theta (Polθ), also known as DNA polymerase θ, is the member of the DNA polymerase A family and plays a crucial role in the repair of DNA double-strand breaks (DSB). Polθ has 3 distinct structural domains: the N-terminal helicase-like domain with a conserved sequence, the C-terminal polymerase domain, and the central domain, which is a disordered sequence connecting these two regions. Notably, Polθ is the only known polymerase in eukaryotes that possesses helicase activity. However, it is also an error-prone polymerase. When DNA DSBs occur, a specialized network consisting of at least 4 pathways, including classical-non homologous end joining (C-NHEJ), homologous recombination (HR), single-strand annealing (SSA), and alternative-end joining (Alt-EJ), is responsible for repairing DNA damage caused by DSBs. In the absence of major DNA repair pathways like HR, cells rely on Alt-EJ pathway mediated by Polθ to repair damaged DNA and maintain genomic stability. Nevertheless, due to the low fidelity of Polθ, Alt-EJ repair often leads to errors. Depletion of Polθ has shown to increases DSB formation and compromise genomic stability. Conversely, overexpression of Polθ has been associated with increases DNA damage markers and impairs cell cycle progression. As a result, the impact of Polθ on genome stability remains controversial. Furthermore, overexpression of Polθ is frequently observed in cancer and is associated with a characteristic mutational signature and poor prognosis. Depleting Polθ in an HR-deficient background has been shown to impair cell viability, suggesting a synthetic lethal (SL) relationship between Polθ and HR factors. In recent years, targeted chemotherapy drugs that inhibit tumor growth have gained significant attention. However, off-target effects and drug resistance pose challenges for clinical application, particularly with poly-ADP-ribose polymerase inhibitor (PARPi). Blocking Polθ activity in HR-deficient tumor cells has been found to reverse PARPi resistance, making Polθ a very promising therapeutic target in cancer treatment. The availability of crystal structures for both helicase and polymerase domain has facilitated the design of potent inhibitors of Polθ. Currently, several highly specific and effective small molecule inhibitors targeting Polθ, such as Novobiocin, RP-6685, and ART558, have been reported to effectively block various cancers with HR deficiency. The initial success of these inhibitors points to new directions for treating BRCA1/2-mutated tumors. Additionally, reducing the Alt-EJ repair pathway mediated by Polθ can improve HR repair efficiency and increase the chance of exogenous gene target integration (TI), suggesting potential new applications for Polθ inhibitors. This article reviews the recent research progress on the molecular function of Polθ and its involvement in the Alt-EJ pathway modification mechanism, providing insights for a deeper understanding of this field.

Objective To investigate the effects of dynamic lung compliance(Cdyn)-guided indi-vidual positive end-expiratory pressure(PEEP)titration on pulmonary function in elderly patients undergoing laparoscopic colorectal cancer surgery.Methods Sixty-eight elderly patients were selected for laparoscopic radical resection of colorectal cancer,37 males and 31 females,aged 65-79 years,BMI<30 kg/m2,ASA physical status Ⅱ or Ⅲ.The patients were divided into two groups using the random number table method:individualized PEEP group(group P)and control group(group C),34 patients in each group.In group P,the patients received recruitment maneuvers and PEEP titration test at immediately after intubation,immediately after establishing pneumoperitoneum-Trendelenburg position and immediately after pneumoperitoneum.The patients in group C received PEEP 5 cmH2 O during procedure.The three best titra-tion PEEP and the actual tidal volume(VT)in group P were also recorded.PaO2,PaCO2,PETCO2 10 mi-nutes after the tracheal intubation(T1),10 minutes(T2)and 1 hour(T3)after establishing pneumoperito-neum-Trendelenburg position,at the end of the surgery but before extubation(T4)were recorded,and the oxygenation index(OI),physiological dead space to tidal volume(Vd/VT),alveolar arterial oxygen differ-ence(A-aDO2),driving pressure,and Cdyn were calculated.Concentrations of interleukin-8(IL-8),tumor necrosis factor-α(TNF-α),Clara cell secretoyr protein(CC16)and lung alveolar surface active sub-stances-D(SP-D)in the serum samples were determined by ELISA before anesthesia induction(T0)and 10 minutes after extubation(T5).Postoperative pulmonary complications(PPCs)were also recordrd.Results The individualized PEEP of Cdyn?guided PEEP titration was 4 cmH2O. Compared with group C, the PaO2 and OI in group C were significantly increased at T4, the Cdyn was significantly increased at T1,T3, and T4, the driving pressure was significantly decreased at T1 -T4, the serum concentration of CC16 was significantly decreased at T5 ( P < 0. 05). There were no significant differences in PaCO2, PET CO2,A?aDO2, and Vd/ VT between the two groups. There was no severe PPCs in the two groups. Conclusion Pressure?controlled ventilation modes combined with Cdyn?guide PEEP titration can increase the Cdyn, reduce thedriving pressure, and improve OI at the end of the operation, reduce the concentrations of CC16 at postop?eration, improve pulmonary function in elderly patients undergoing laparoscopic colorectal cancer surgery.

AIM To investigate the consistency of chemical constituents between formula granules and standard decoction of Coptidis Rhizoma.METHODS Eighteen batches of standard decoctions were prepared,after which the extraction rate and contents,transfer rates of magnolflorine,jatrorrhizine,columbamine,epiberberine,coptisine,palmatine,berberin were determined,HPLC characteristic chromatograms were established.RESULTS There were 11 common peaks in the characteristic chromatograms of 18 batches of standard decoctions and 24 batches of formula granules with the similarities of 0.861-1.000,which were clusterd into two categories.The formula granules and standard decoction demonstrated approximated extraction rate and contents,transfer rates of index constituents.CONCLUSION The chemical constituents between formula granules and standard decoction of Coptidis Rhizoma display good consistency,which can provide references for the quality control,process research and clinical application of the former.

Objective To investigate the diagnostic value of combining carotid intima-media thickness (cIMT) with serum Galectin-3 (Gal-3) and Pentraxin 3 (PTX3) in patients with psoriasis complicated with cardiovascular disease (CVD). Methods Thirty-eight patients with psoriasis complicated with CVD were included in CVD group, 51 patients with psoriasis alone were included in psoriasis group, and 60 healthy subjects were selected as control group. Clinical data were collected from each group. The cIMT was measured using carotid ultrasound, and serum Gal-3, PTX3, and inflammatory markers[high sensitivity C-reactive protein (hs-CRP), procalcitonin (PCT), tumor necrosis factor-α (TNF-α)]were detected using enzyme-linked immunosorbent assay. Multivariate Logistic regression analysis was used to identify the influencing factors of CVD in patients with psoriasis. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of serum Gal-3, PTX3, and cIMT for CVD. Results The cIMT was greater in the CVD group and the psoriasis group than in the control group, and the CVD group was greater than the psoriasis group (P < 0.05). The serum levels of Gal-3, PTX3, hs-CRP, PCT, and TNF-α were higher in the CVD group and the psoriasis group than in the control group, and their levels were higher in the CVD group than in the psoriasis group (P < 0.05). The psoriasis area and severity index (PASI) score was higher in the CVD group than in the psoriasis group (P < 0.05). Pearson's correlation analysis showed that cIMT, Gal-3, and PTX3 were separately positively correlated with hs-CRP, PCT, and TNF-α (P < 0.05). Multivariate Logistic regression analysis showed that PASI score, cIMT, Gal-3, PTX3, hs-CRP, and TNF-α were independent influencing factors for CVD in patients with psoriasis (OR=1.250, 1.451, 1.432, 1.365, 1.413, 1.465; P < 0.05). The diagnostic model based on cIMT combined with serum Gal-3 and PTX3 had higher diagnostic value for CVD in patients with psoriasis than single diagnosis. The area under the curve was 0.922, with sensitivity and specificity of 0.91 and 0.85, respectively. Conclusion The cIMT, serum Gal-3, and serum PTX3 are independent influencing factors for CVD in patients with psoriasis. The combination of the three indicators has higher diagnostic value for CVD in patients with psoriasis.

Objective: To examine the association between smoking status and related mortality among elderly people aged 60 and above in urban and rural areas of Beijing City. Methods: Based on Beijing City Elderly Comprehensive Health Cohort Study from 2009 to 2014, a total of 4 499 eligible older adults included in the baseline survey were followed up and investigated to collect information on survival and death. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), and the dose-response relationship was estimated between the smoking index, the years of quitting and mortality. Results: The median (IQR) age of 4 499 subjects was 70.00 (10.00) years old, including 1 814 (40.32%) males. The proportion of non-smokers, former smokers and current smokers was 69.50% (3 127/4 499), 13.20% (594/4 499) and 17.30% (778/4 499), respectively. After adjusting for confounding factors such as demographic and sociological characteristics, lifestyle, etc., the results of multivariate Cox regression analysis showed that, compared to non-smokers, former smokers had a 30.6% increased risk of all-cause mortality [HR (95%CI): 1.306 (1.043-1.636)] and the HR (95%CI) of all-cause, malignant tumor and lung cancer mortality among current smokers has increased by 50.0% [HR (95%CI): 1.500 (1.199-1.877)], 80.3% [HR (95%CI): 1.803 (1.226-2.652)] and 212.6% [HR (95%CI): 3.126 (1.626-6.012)], respectively. The smoking index was positively associated with the increased risk of all-cause, malignant tumor and lung cancer mortality, while the years of smoking cessation were negatively associated with that risk (P<0.05). Conclusion: Smoking is associated with tobacco-related mortality among elderly people in Beijing City.
Aged ; Male ; Humans ; Child ; Female ; Beijing ; Cohort Studies ; Lung Neoplasms ; Smoking ; Tobacco Smoking

OBJECTIVE: To retrospectively analyze the efficacy and complications of our institution's modified nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) in treating intermediate-risk acute myeloid leukemia (AML) - first complete remission (CR1) and prognostic factors. METHODS: Clinical data of 50 intermediate-risk AML-CR1 patients who underwent matched related NST at the Fifth Medical Center of Chinese People's Liberation Army General Hospital from August 2004 to April 2021 were collected, the hematopoietic recovery, donor engraftment and complications were observed, and overall survival (OS) rate, leukemia-free survival (LFS) rate, treatment-related mortality (TRM), and cumulative relapse rate were calculated. Statistical analysis of factors affecting prognosis was also preformed. RESULTS: The median times for neutrophil and platelet recovery after transplantation were 10 (6-16) and 13 (6-33) days, respectively. One month after transplantation, 22 patients (44%) achieved full donor chimerism (FDC), and 22 patients (44%) achieved mixed chimerism (MC), among whom 18 cases gradually transited to FDC during 1-11 months, 4 cases maintained MC status. The overall incidence of acute graft-versus-host disease (aGVHD) was 36%, with a rate of 18% for grade II-IV aGVHD and a median onset time of 45 (20-70) days after transplantation. The overall incidence of chronic GVHD (cGVHD) was 34%, with 20% and 14% of patients having limited or extensive cGVHD, respectively. The incidence rates of infections, interstitial pneumonia, and hemorrhagic cystitis were 30%, 10%, and 16%, respectively. The 5-year OS rate, LFS rate, TRM, and cumulative relapse rate were 68%, 64%, 16%, and 20%, respectively. The increase of the number of CD34⁺ cells infused had shortened the recovery time for neutrophils and platelets (r =0.563, r =0.350). The number of CD34⁺ cells infused significantly influenced the occurrence of extensive cGVHD (OR =1.36, 95%CI : 1.06-1.84, P =0.024). CONCLUSION Modified NST is effective in treating intermediate-risk AML-CR1 patients, however, further expansion of sample size is needed to study prognostic factors.
Humans ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Leukemia, Myeloid, Acute/complications* ; Prognosis ; Recurrence ; Retrospective Studies

The regulation of spermatogonial proliferation and apoptosis is of great significance for maintaining spermatogenesis. The single-cell RNA sequencing (scRNA-seq) analysis of the testis was performed to identify genes upregulated in spermatogonia. Using scRNA-seq analysis, we identified the spermatogonia upregulated gene origin recognition complex subunit 6 (Orc6), which is involved in DNA replication and cell cycle regulation; its protein expression in the human and mouse testis was detected by western blot and immunofluorescence. To explore the potential function of Orc6 in spermatogonia, the C18-4 cell line was transfected with control or Orc6 siRNA. Subsequently, 5-ethynyl-2-deoxyuridine (EdU) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, flow cytometry, and western blot were used to evaluate its effects on proliferation and apoptosis. It was revealed that ORC6 could promote proliferation and inhibit apoptosis of C18-4 cells. Bulk RNA sequencing and bioinformatics analysis indicated that Orc6 was involved in the activation of wingless/integrated (Wnt)/ β-catenin signaling. Western blot revealed that the expression of β-catenin protein and its phosphorylation (Ser675) were significantly decreased when silencing the expression of ORC6. Our findings indicated that Orc6 was upregulated in spermatogonia, whereby it regulated proliferation and apoptosis by activating Wnt/β-catenin signaling.

OBJECTIVES: To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). METHODS: A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. RESULTS: Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. CONCLUSIONS Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.
Male ; Humans ; Child ; Disorders of Sex Development/pathology* ; Hypospadias/complications* ; Cryptorchidism/complications* ; Retrospective Studies ; Adrenal Hyperplasia, Congenital ; Steroid 21-Hydroxylase

Objective: To examine the association between smoking status and related mortality among elderly people aged 60 and above in urban and rural areas of Beijing City. Methods: Based on Beijing City Elderly Comprehensive Health Cohort Study from 2009 to 2014, a total of 4 499 eligible older adults included in the baseline survey were followed up and investigated to collect information on survival and death. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), and the dose-response relationship was estimated between the smoking index, the years of quitting and mortality. Results: The median (IQR) age of 4 499 subjects was 70.00 (10.00) years old, including 1 814 (40.32%) males. The proportion of non-smokers, former smokers and current smokers was 69.50% (3 127/4 499), 13.20% (594/4 499) and 17.30% (778/4 499), respectively. After adjusting for confounding factors such as demographic and sociological characteristics, lifestyle, etc., the results of multivariate Cox regression analysis showed that, compared to non-smokers, former smokers had a 30.6% increased risk of all-cause mortality [HR (95%CI): 1.306 (1.043-1.636)] and the HR (95%CI) of all-cause, malignant tumor and lung cancer mortality among current smokers has increased by 50.0% [HR (95%CI): 1.500 (1.199-1.877)], 80.3% [HR (95%CI): 1.803 (1.226-2.652)] and 212.6% [HR (95%CI): 3.126 (1.626-6.012)], respectively. The smoking index was positively associated with the increased risk of all-cause, malignant tumor and lung cancer mortality, while the years of smoking cessation were negatively associated with that risk (P<0.05). Conclusion: Smoking is associated with tobacco-related mortality among elderly people in Beijing City.
Aged ; Male ; Humans ; Child ; Female ; Beijing ; Cohort Studies ; Lung Neoplasms ; Smoking ; Tobacco Smoking

Ajania belonging to the subtribe Artemisiinae of Anthemideae(Asteraceae) is a genus of semi-shrubs closely related to Chrysanthemum. There are 24 species of Ajania in northwestern China, most of which are folk herbal medicines with strong stress tolerance. Modern medical studies have demonstrated that the chemical constituents of Ajania mainly include terpenoids, flavonoids, phenylpropanoids, alkynes, and essential oils. These compounds endow the plants with antimicrobial, anti-inflammatory, antitumor, antimalarial, antioxidant, and insecticide effects. In this study, we reviewed the research progress in the chemical constituents and pharmacological activities of Ajania, aiming to provide reference for the further research and development of Ajania.
Asteraceae ; Chrysanthemum ; Alkynes ; Antimalarials ; Antioxidants/pharmacology*