Disulfiram is a promising repurposed drug that, combining with radiation and chemotherapy, exhibits effective anticancer activities in several preclinical models. The cellular metabolites of ...disulfiram have been established, however, the intracellular targets of disulfiram remain largely unexplored. We have previously reported that disulfiram suppresses the coronaviral papain-like proteases through attacking their zinc-finger domains, suggesting an inhibitory function potentially on other proteases with similar catalytic structures. Ubiquitin-specific proteases (USPs) share a highly-conserved zinc-finger subdomain that structurally similar to the papain-like proteases and are attractive anticancer targets as upregulated USPs levels are found in a variety of tumors. Here, we report that disulfiram functions as a competitive inhibitor for both USP2 and USP21, two tumor-related deubiquitinases. In addition, we also observed a synergistic inhibition of USP2 and USP21 by disulfiram and 6-Thioguanine (6TG), a clinical drug for acute myeloid leukemia. Kinetic analyses revealed that both drugs exhibited a slow-binding mechanism, moderate inhibitory parameters, and a synergistically inhibitory effect on USP2 and USP21, suggesting the potential combinatory use of these two drugs for USPs-related tumors. Taken together, our study provides biochemical evidence for repurposing disulfiram and 6TG as a combinatory treatment in clinical applications.
Early detection would improve upper gastrointestinal cancer prognosis. We aimed to identify serum protein biomarker for the detection of early-stage upper gastrointestinal cancer.
We performed a ...three-tiered study including 2028 participants from three medical centres. First, we applied two different antibody arrays to screen candidate serum proteins that increased in 20 patients with oesophageal squamous cell carcinoma (ESCC) compared with 20 normal controls. We then evaluated the selected protein by enzyme-linked immunosorbent assay in 1064 participants including 731 upper gastrointestinal cancer patients (287 ESCCs, 237 oesophagogastric junction adenocarcinomas (EJAs), and 207 stomach cancers) and 333 normal controls. The diagnostic value of the selected protein was finally validated in two independent cohorts of ESCC patients and controls (n=472 and 452, respectively). The receiver operating characteristic was used to calculate diagnostic accuracy.
Serum insulin-like growth factor binding protein-1 (IGFBP-1) identified in both antibody arrays showed significantly elevated levels in upper gastrointestinal cancers, compared with normal controls. Serum IGFBP-1 provided high diagnostic accuracy of early-stage ESCC, EJA, stomach and cancer (areas under the curve: 0·898, 0·936 and 0·864, respectively). This protein maintained diagnostic performance for early-stage ESCC in independent cohorts 1 and 2 (0·849 and 0·911, respectively). Additionally, serum levels of IGFBP-1 dropped significantly after surgical resection of primary tumours, compared with the corresponding pre-operative ESCC samples (p < 0·05).
Serum IGFBP-1 represents a promising diagnostic biomarker to detect early-stage upper gastrointestinal cancer.
Irritable bowel syndrome (IBS) and functional constipation (FC) are highly prevalent in the general population and have significant symptom overlap, while the clinical associations and psychological ...links between IBS and FC remains poorly understood. We aimed to compare the clinical, metabolic and psychological factors between patients with FC patients and constipation predominated IBS.
We consecutively enrolled 360 patients from the outpatient clinics of Hualien Tzu Chi medical center. Constipation-predominant IBS (IBS-C) and FC were diagnosed based on Rome III criteria. All participants completed the Pittsburg Sleep Quality Index (PSQI) score, the State Trait Anxiety Inventory (STAI) score and the Taiwanese Depression Questionnaire (TDQ) score.
Fifty-four patients had FC and twenty-three patients had IBS-C. Compared to asymptomatic controls, FC/IBS-C groups had female predominance (p < 0.001), FC as well as more GI discomforts and inferior psychosocial characteristics (p < 0.05). Compared to FC, IBS-C had higher severity scores of abdominal distention (4.52 ± 1.90 vs. 3.07 ± 1.88) and heartburn (2.17 ± 1.50 vs. 1.46 ± 1.14). However, FC was independently associated with poor sleep quality adjusted OR: 1.19 (1.08–1.31), p < 0.001 and IBS-C with depression adjusted OR: 1.07 (1.02–1.12), p = 0.005.
Patients with FC and IBS-C shared many similar GI complaints and psychosocial characteristics, however IBS-C had more severe bloating, heartburn and depression and FC had worse sleeping quality.
The purpose of this study was to explore the histopathological staging and differential diagnosis of marginal zone lymphoma in gastric mucosa-associated lymphoid tissue (MALT lymphoma). We performed ...detailed histomorphology and immunohistochemistry investigations as well as genetic testing on endoscopic biopsy and endoscopic mucosal resection specimens from 18 patients with gastric MALT lymphoma. We found that gastric MALT lymphoma typically begins as a small, isolated area outside the lymphoid follicular mantle zone or proliferates in a multifocal, patchy manner, gradually spreads to the interfollicular zone, forming diffuse proliferation, invades the gastric mucosal glands, and infiltrates or proliferates into the center of peripheral reactive lymphoid follicles. Abnormally proliferating lymphocytes invade the surrounding lymphoid follicles, resulting in damage, atrophy, and disappearance of their normal follicles as well as of the gastric mucosa glands, forming diffuse proliferation. Redifferentiation and proliferation lead to the transformation of lymphocytes; that is, MALT transitions into highly invasive lymphoma. Based on our findings in this study, we propose the following five stages in the process of development and progression of gastric MALT lymphoma: the stage of cell proliferation outside the lymphoid follicular mantle zone; the stage of heterogeneous proliferative lymphoepithelial lesion; the stage of reactive lymphoid follicular implantation; the stage of lymphoid follicular clonal proliferation; and the stage of MALT transforming into highly invasive lymphoma. We examined the differential diagnosis of histopathological features at each stage. The clinicopathological staging of gastric MALT lymphoma can help clinicians provide accurate treatment and track malignant cell transformation, thus playing a significant role in controlling its development and progression.
The action of DNA topoisomerase II (Top2) creates transient DNA breaks that are normally concealed inside Top2-DNA covalent complexes. Top2 poisons, including ubiquitously present natural compounds ...and clinically used anti-cancer drugs, trap Top2-DNA complexes. Here, we show that cells actively prevent Top2 degradation to avoid the exposure of concealed DNA breaks. A genome-wide screen revealed that fission yeast cells lacking Rrp2, an Snf2-family DNA translocase, are strongly sensitive to Top2 poisons. Loss of Rrp2 enhances SUMOylation-dependent ubiquitination and degradation of Top2, which in turn increases DNA damage at sites where Top2-DNA complexes are trapped. Rrp2 possesses SUMO-binding ability and prevents excessive Top2 degradation by competing against the SUMO-targeted ubiquitin ligase (STUbL) for SUMO chain binding and by displacing SUMOylated Top2 from DNA. The budding yeast homolog of Rrp2, Uls1, plays a similar role, indicating that this genome protection mechanism is widely employed, a finding with implications for cancer treatment.
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•Fission yeast Rrp2 is critical for normal cellular resistance to Top2 poisons•Rrp2 binds SUMOylated Top2 and prevents it from being ubiquitinated and degraded•Rrp2 uses its ATPase activity to displace SUMOylated Top2 from DNA•Rrp2 competes with the STUbL (SUMO-targeted ubiquitin ligase) for SUMO chain binding
Wei et al. show that the fission yeast protein Rrp2 safeguards the genome from damage induced by chemicals poisoning DNA topoisomerase II (Top2), such as the anti-cancer drug etoposide. Rrp2 binds the SUMO-modified form of Top2 and prevents it from being ubiquitinated by the SUMO-targeted ubiquitin ligase (STUbL).
Non-suicidal self-injury (NSSI) is a common psychological and behavioral problem among adolescents. The COVID-19 pandemic has had a significant impact on people's mental health. To date, few studies ...have documented the temporal changes in adolescents' psychological status during the pandemic, as well as the impact of large-scale public health intervention strategies. This study contributes to the existing evidence on the subject.
Participants were 6,023 adolescents aged 10 years and older, with data from two waves of longitudinal surveys, including data for a 7-month interval before and during the pandemic. A cross-lagged model was used to test the bidirectional relationship between NSSI and depressive symptoms in adolescents; logistic regression analysis was used to explore the predictors of NSSI implementation in adolescents with depressive symptoms.
In this study, 32.69% participants reported depressive symptoms at baseline and 34.27% at follow-up; 44.34% participants with depressive symptoms reported NSSI at baseline and 53.44% at follow-up. The duration of the online class, depressed affect, and somatic and related activity were the risk factors for NSSI; sleep duration and positive mood were the protective factors. The lag effect of depression symptoms on NSSI is significant, and so is NSSI on depressive symptoms.
During the COVID-19 pandemic, adolescents' mental health has worsened, resulting in an increase in the prevalence of NSSI among those with depressive symptoms compared to pre-pandemic levels. Early screening for depression is crucial in preventing or decreasing NSSI in adolescents.
The cutaneous microbiota responses to skin health as well as atopic dermatitis. To reveal the microbiota effect in atopic dermatitis children under therapy with topical corticosteroids and ...antibiotics. 59 atopic dermatitis patients were randomized to two treatment groups (by corticosteroids or combination therapy) in Beijing Children's Hospital. The lesion microbial samples were collected for 16S rDNA sequencing and bioinformatics analysis. After treatment, 57 patients recovered significantly. Though topical antibiotics application blocked the restoration of commensal Streptococcus, no remarkable differences of cutaneous microbiota were identified between the two groups along the treatment. In subject 1081, who received the combination therapy, the Streptococcus and Pseudomonas as well as Chryseobacterium increased dramatically. On the contrary, the Staphylococcus aureus decreased sharply in subject 1107 with topical corticosteroids treatment Our preliminary study suggested the necessity to consider cutaneous microbiota profile when prescribing antibiotics.
ABSTRACT Photometric and spectroscopic observations of a slowly declining, luminous Type Ia supernova (SN Ia) SN 2011hr in the starburst galaxy NGC 2691 are presented. SN 2011hr is found to peak at , ...with a postmaximum decline rate Δm15(B) = 0.92 0.03 mag. From the maximum-light bolometric luminosity, , we estimate the mass of synthesized 56Ni in SN 2011hr to be . SN 2011hr appears more luminous than SN 1991T at around maximum light, and the absorption features from its intermediate-mass elements (IMEs) are noticeably weaker than those of the latter at similar phases. Spectral modeling suggests that SN 2011hr has IMEs of ∼0.07 in the outer ejecta, which is much lower than the typical value of normal SNe Ia (i.e., 0.3-0.4 ) and is also lower than the value of SN 1991T (i.e., ∼0.18 ). These results indicate that SN 2011hr may arise from a Chandrasekhar-mass white dwarf progenitor that experienced a more efficient burning process in the explosion. Nevertheless, it is still possible that SN 2011hr may serve as a transitional object connecting the SN 1991T-like SNe Ia with a superluminous subclass like SN 2007if given that the latter also shows very weak IMEs at all phases.
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