Evaluation of toxicity after one-months treatment with Bauhinia forficata decoction in streptozotocin-induced diabetic rats

BACKGROUND: Previous experiments have shown that a decoction of Bauhinia forficata leaves reduces the changes in carbohydrate and protein metabolism that occur in rats with streptozotocin-induced diabetes. In the present investigation, the serum activities of enzymes known to be reliable toxicity markers were monitored in normal and streptozotocin-diabetic rats to discover whether the use of B. forficata decoction has toxic effects on liver, muscle or pancreas tissue or on renal microcirculation. METHODS: An experimental group of normal and streptozotocin-diabetic rats received an aqueous decoction of fresh B. forficata leaves (150 g/L) by mouth for 33 days while a control group of normal and diabetic rats received water for the same length of time. The serum activity of the toxicity markers lactate dehydrogenase, creatine kinase, amylase, angiotensin-converting enzyme and bilirubin were assayed before receiving B. forficata decoction and on day 19 and 33 of treatment. RESULTS: The toxicity markers in normal and diabetic rats were not altered by the diabetes itself nor by treatment with decoction. Whether or not they received B. forficata decoction the normal rats showed a significant increase in serum amylase activity during the experimental period while there was a tendency for the diabetic rats, both treated and untreated with decoction, to have lower serum amylase activities than the normal rats. CONCLUSIONS: Administration of an aqueous decoction of B. forficata is a potential treatment for diabetes and does not produce toxic effects measurable with the enzyme markers used in our study

Genetic Evidence for the Association between the Early Growth Response 3 (EGR3) Gene and Schizophrenia

Recently, two genome scan meta-analysis studies have found strong evidence for the association of loci on chromosome 8p with schizophrenia. The early growth response 3 (EGR3) gene located in chromosome 8p21.3 was also found to be involved in the etiology of schizophrenia. However, subsequent studies failed to replicate this finding. To investigate the genetic role of EGR3 in Chinese patients, we genotyped four SNPs (average interval ∼2.3 kb) in the chromosome region of EGR3 in 470 Chinese schizophrenia patients and 480 healthy control subjects. The SNP rs35201266 (located in intron 1 of EGR3) showed significant differences between cases and controls in both genotype frequency distribution (P = 0.016) and allele frequency distribution (P = 0.009). Analysis of the haplotype rs35201266-rs3750192 provided significant evidence for association with schizophrenia (P = 0.0012); a significant difference was found for the common haplotype AG (P = 0.0005). Furthermore, significant associations were also found in several other two-, and three-SNP tests of haplotype analyses. The meta-analysis revealed a statistically significant association between rs35201266 and schizophrenia (P = 0.0001). In summary, our study supports the association of EGR3 with schizophrenia in our Han Chinese sample, and further functional exploration of the EGR3 gene will contribute to the molecular basis for the complex network underlying schizophrenia pathogenesis

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL

Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well

The genetic epidemiology of joint shape and the development of osteoarthritis

Congruent, low-friction relative movement between the articulating elements of a synovial joint is an essential pre-requisite for sustained, efficient, function. Where disorders of joint formation or maintenance exist, mechanical overloading and osteoarthritis (OA) follow. The heritable component of OA accounts for ~ 50% of susceptible risk. Although almost 100 genetic risk loci for OA have now been identified, and the epidemiological relationship between joint development, joint shape and osteoarthritis is well established, we still have only a limited understanding of the contribution that genetic variation makes to joint shape and how this modulates OA risk. In this article, a brief overview of synovial joint development and its genetic regulation is followed by a review of current knowledge on the genetic epidemiology of established joint shape disorders and common shape variation. A summary of current genetic epidemiology of OA is also given, together with current evidence on the genetic overlap between shape variation and OA. Finally, the established genetic risk loci for both joint shape and osteoarthritis are discussed

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Women in business leadership

This scholarly study is the first to compare business leadership in the Arab Gulf states in terms of the presence of female managers in various positions. It documents the status of women leaders—senior executives and managers—through a quantitative gender analysis of 2805 private and publicly listed companies in the Kingdom of Bahrain, the State of Kuwait, the Kingdom of Saudi Arabia, the Sultanate of Oman, the State of Qatar, and the United Arab Emirates. The study details the positions women hold within organizations and analyzes and compares these by country, business classification, company size, and ownership. The contribution to cross-cultural management is that these data on gender composition in the workforce highlight the low participation of women in business leadership as an issue. Furthermore, the study provides knowledge for cross-cultural managers about cultural attitudes toward women’s economic participation in this geographical area. The research offers helpful insights and important implications for government leaders in these countries as well as for educators, practitioners, and scholars who work to help prepare and advance women to leadership within this region

Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen