Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix (ECM)-cytoskeletal linkers and transducers in biochemical and mechanical ...signals between cells and their environment in a wide range of states in health and diseases. Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms, including protein-protein interactions, conformational changes, and trafficking. Due to their exposure on the cell surface and sensitivity to the molecular blockade, integrins have been investigated as pharmacological targets for nearly 40 years, but given the complexity of integrins and sometimes opposite characteristics, targeting integrin therapeutics has been a challenge. To date, only seven drugs targeting integrins have been successfully marketed, including abciximab, eptifibatide, tirofiban, natalizumab, vedolizumab, lifitegrast, and carotegrast. Currently, there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies, including small molecules, antibodies, synthetic mimic peptides, antibody-drug conjugates (ADCs), chimeric antigen receptor (CAR) T-cell therapy, imaging agents, etc. A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs. Herein, we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic. In addition, we further discuss the trend of drug development, how to improve the success rate of clinical trials targeting integrin therapies, and the key points for clinical research, basic research, and translational research.
Introduction Antibiotics frequently induce abnormal liver function. Omadacycline is a novel aminomethylcycline antibiotic, which shows potent activity against Gram-positive and Gram-negative aerobic, ...anaerobic, and atypical (including Legionella pneumophila ) bacteria. Of note, omadacycline is tolerable in most patients with liver impairment. However, evidence regarding the application of omadacycline in patients with Legionella pneumophila pneumonia after experiencing liver dysfunction is scarce. Methods The current study reported 6 cases of patients with Legionella pneumophila pneumonia receiving omadacycline as subsequent antibiotics after experiencing liver dysfunction. Results These 6 cases were admitted to the hospital for pneumonia and received antibiotic therapy, including piperacillin-tazobactam, imipenem, meropenem, and moxifloxacin. After receiving these antibiotics, increased liver enzymes were noted. Although hepatoprotective therapy (such as magnesium isoglycyrrhizinate and glutathione) was given, the liver function was still abnormal. According to metagenomic next-generation sequencing, these patients were diagnosed with Legionella pneumophila pneumonia. Considering the abnormal liver function, the antibiotic therapy was switched to omadacycline-containing antibiotic therapy. After that, liver function was improved, and the infection was ameliorated. Ultimately, all patients discharged from the hospital, including 2 patients who achieved complete clinical symptomatic improvement and 4 patients who achieved partial clinical symptomatic improvement. Discussion This study emphasizes the successful treatment of switching to omadacycline after experiencing abnormal liver function in patients with Legionella pneumophila pneumonia. This study suggests that omadacycline may serve as an optional antibiotic for patients with Legionella pneumophila pneumonia, especially when occurring liver dysfunction. However, more clinical studies are required to validate our findings.
Abstract
The tumor ecosystem of papillary thyroid carcinoma (PTC) is poorly characterized. Using single-cell RNA sequencing, we profile transcriptomes of 158,577 cells from 11 patients’ paratumors, ...localized/advanced tumors, initially-treated/recurrent lymph nodes and radioactive iodine (RAI)-refractory distant metastases, covering comprehensive clinical courses of PTC. Our data identifies a “cancer-primed” premalignant thyrocyte population with normal morphology but altered transcriptomes. Along the developmental trajectory, we also discover three phenotypes of malignant thyrocytes (follicular-like, partial-epithelial-mesenchymal-transition-like, dedifferentiation-like), whose composition shapes bulk molecular subtypes, tumor characteristics and RAI responses. Furthermore, we uncover a distinct
BRAF
-like-B subtype with predominant dedifferentiation-like thyrocytes, enriched cancer-associated fibroblasts, worse prognosis and promising prospect of immunotherapy. Moreover, potential vascular-immune crosstalk in PTC provides theoretical basis for combined anti-angiogenic and immunotherapy. Together, our findings provide insight into the PTC ecosystem that suggests potential prognostic and therapeutic implications.
Decabromodiphenyl ether (BDE209), an essential industrial flame retardant that is widely used, has recently been reported to be increasing in human serum. Due to the structural similarity between ...BDE209 and thyroid hormones, its toxic effects on the thyroid are of particular concern.
Original articles in the PubMed database were collected using the terms "BDE209", "decabromodiphenyl ether", "endocrine disrupting", "thyroid", "carcinogenesis", "polybrominated diphenyl ethers", "PBDEs," and their synonyms from inception up to October of 2022.
Of the 748 studies initially identified, 45 were selected, which emphasized the adverse effects of BDE209 on endocrine system. BDE209 may have a toxic effect not only on thyroid function but also on thyroid cancer tumorigenesis at multiple levels, such as by directly interfering with the TR, hypothalamic-pituitary-thyroid (HPT) axis, enzyme activity, and methylation. However, it is impossible to draw a definitive conclusion on the exact pathway of thyroid toxicity from BDE209.
Although the toxic effects of BDE209 on the thyroid have been well investigated, its tumorigenic effects remain unclear and further research is necessary.
Subjective well-being (SWB) is an important part of positive psychology research. Compared with other countries and regions, Chinese adolescents’ well-being level is relatively lower. Under the ...guidance of ecological systems theory, this study is based on the survey data of PISA 2018, with 10,805 middle school students from four provinces and cities in China (Beijing, Shanghai, Jiangsu, and Zhejiang) as the research samples, and examines the theoretical model of the influence of family capital on adolescents’ subjective well-being by means of structural equation modeling, in which the effects of family capital, school climate and academic achievement on adolescents’ subjective well-being are discussed. The empirical results show that family capital directly and indirectly negatively influences adolescents’ subjective well-being through academic achievements, and indirectly positively influences adolescents’ subjective well-being through school climate. School climate directly positively affects adolescents’ subjective well-being and indirectly negatively influences adolescents’ subjective well-being through their academic achievement. Academic achievement negatively affects adolescents’ subjective well-being. The research results strongly support the correctness of the theoretical framework, indicating the complexity of the formation of adolescents’ subjective well-being.
Abstract
PARP1 is a DNA-dependent ADP-Ribose transferase with ADP-ribosylation activity that is triggered by DNA breaks and non-B DNA structures to mediate their resolution. PARP1 was also recently ...identified as a component of the R-loop-associated protein-protein interaction network, suggesting a potential role for PARP1 in resolving this structure. R-loops are three-stranded nucleic acid structures that consist of a RNA–DNA hybrid and a displaced non-template DNA strand. R-loops are involved in crucial physiological processes but can also be a source of genome instability if persistently unresolved. In this study, we demonstrate that PARP1 binds R-loops in vitro and associates with R-loop formation sites in cells which activates its ADP-ribosylation activity. Conversely, PARP1 inhibition or genetic depletion causes an accumulation of unresolved R-loops which promotes genomic instability. Our study reveals that PARP1 is a novel sensor for R-loops and highlights that PARP1 is a suppressor of R-loop-associated genomic instability.
Graphical Abstract
Graphical Abstract
PARP1 association with R-loop structures induces its Poly(ADP-ribosyl)ation activity. PARP1 genetic depletion or inhibition leads to R-loop persistence and triggers genome instability.
Background The impact of smokeless tobacco (SLT) use on the risk of oral cavity cancer (OCC) has been confirmed; however, the sex-based difference in this association remains inconclusive. Therefore, ...this study aimed to estimate the association between SLT use and OCC risk in women and compared it to that in men. Methods PubMed, Embase, and Cochrane Library databases were systematically searched for eligible studies from their inception up to August 2020. Studies reporting the effect estimates of SLT use on OCC risk in men and women, were eligible for inclusion. The relative risk ratio (RRR) was applied to calculate the sex-based difference in the relationship between SLT use and OCC risk, and pooled analysis was conducted using a random-effects model with inverse variance weighting. Results Nineteen studies reporting a total of 6593 OCC cases were included in the final meta-analysis. The pooled relative risk (RR) suggested that SLT use was associated with an increased risk of OCC in both men (RR, 2.94; 95% confidence interval CI, 2.05-4.20; P < 0.001) and women (RR, 6.39; 95%CI, 3.16-12.93; P < 0.001). Moreover, the SLT-use-related risk of OCC was higher in women than that in men (RRR,1.79; 95%C, 1.21-2.64; P = 0.003). The risk of OCC related to SLT use in women was still significantly higher than that in men (RRR, 1.75; 95%CI, 1.15-2.66; P = 0.008) after excluding indirect comparison results. Finally, a subgroup analysis suggested significant sex-based differences only in individuals who received chewed smokeless products, regardless of the control definition. Pooled analysis of studies with high design quality confirmed the notably higher risk of OCC in women than in men. Conclusions This study found that SLT use was associated with a higher risk of OCC in women than in men. Further large-scale prospective cohort studies should be conducted to verify sex-based differences in the association between use of specific smokeless products and OCC risk. Keywords: Smokeless tobacco, Oral cavity cancer, Sex-based difference, Meta-analysis
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a continuous debate regarding the classification of thyroid follicular lesions and the term “well‐differentiated tumor of uncertain malignant potential (WDT‐UMP)” was recently introduced to ...cover this problematic spectrum of tumors. The objective of this study was to reappraise WDT‐UMP using morphological, immunochemical, and molecular analysis and to shed more light on encapsulated thyroid follicular‐patterned tumors. A total of 30 cases of WDT‐UMP with equivocal papillary thyroid carcinoma‐type nuclear changes (PTC‐N) or focal unequivocal PTC‐N were examined. As a control, follicular adenoma (n = 29), follicular carcinoma (n = 8), hyalinizing trabecular adenoma (n = 5), and PTC (n = 48) were included. HBME‐1, cytokeratin 19, and galectin‐3 were positive in 12 (40.0%), 10 (33.3%) and 11 (36.7%) cases of WDT‐UMP, respectively. According to the positivity of those markers, significant differences were obtained between WDT‐UMP and PTC encapsulated common type (P = 0.028, 0.010, and 0.004, respectively), infiltrative follicular variant (P = 0.020, 0.026, and 0.008, respectively), and infiltrative common type (P = 0.004, 0.001, and 0.005, respectively), but not between WDT‐UMP and follicular adenoma or follicular carcinoma. BRAFV600E mutation was absent but RET/PTC1 rearrangement was found in only two (6.7%) cases of WDT‐UMP. None of the 20 patients with WDT‐UMP developed recurrence, with an average follow‐up of 80 months. These findings indicate that WDT‐UMP has a favorable outcome and is distinct from PTC in morphological, immunohistochemical, and molecular characteristics. We propose that WDT‐UMP should be classified as “well‐differentiated tumor with uncertain behavior”. (Cancer Sci 2011; 102: 288–294)
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