Recent Discovery and Development of Inhibitors that Target CDK9 and Their Therapeutic Indications.

CDK9 is a cyclin-dependent kinase that plays pivotal roles in multiple cellular functions including gene transcription, cell cycle regulation, DNA damage repair, and cellular differentiation. Targeting CDK9 is considered an attractive strategy for antitumor therapy, especially for leukemia and lymphoma. Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials. However, many of them face challenges such as low clinical efficacy and multiple adverse reactions and may necessitate the exploration of novel strategies to lead to success in the clinic. In this perspective, we present a comprehensive overview of the structural characteristics, biological functions, and preclinical status of CDK9 inhibitors. Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

What is the impact of BIRC5 gene polymorphisms on urinary cancer susceptibility? Evidence from 9348 subjects.

As a member of apoptosis inhibition gene family, baculoviral IAP repeat containing 5 (BIRC5) protein acts as a survival factor in oncology through multiple ways. There are huge inconsistent results between urinary cancer risk and BIRC5 polymorphisms, so we searched and documented all eligible articles to clear up the mystery with the help of meta-analysis. According to the inclusion and exclusion criteria, we performed an overall search in Web of Science, PubMed, Google Scholar, Medline, CNKI and Wanfang database with pre-set search strategy up to November 2019. Z-test was performed to determine the statistical difference by Odds ratios (ORs) and 95% confidence intervals (CIs). The stability of the pooled ORs was conducted by one-way sensitivity analyses, Begg's funnel plots and Egger's test were employed to access the potential publication bias. The relationship of polymorphisms and BIRC5 expression was exposed by in-silico analysis, as well as the effects to tumorigenesis and prognosis. Finally, we enrolled 19 case-control studies to conducted this meta-analysis. An upgrade risk in rs9904341 of BIRC5 were revealed to be associated with urinary cancer in allele contrast model (OR = 1.222, P = 0.012), homozygote contrast model (OR = 1.579, P = 0.0001) and recessive contrast model (OR = 1.433, P < 0.001), as well as rs2071214 polymorphism in the subgroup analysis of BCa in allele contrast model (OR = 1.362, P = 0.011) and recessive contrast model (OR = 1.417, P = 0.015). On the other hand, rs17878467 variant plays an important role in prevent the tumorigenicity of urinary cancer in allele contrast model (OR = 0.672, P = 0.009), heterozygote contrast model (OR = 0.585, P = 0.006) and dominant contrast model (OR = 0.595, P = 0.004). In conclusion, we found that BIRC5 rs9904341, rs2071214 polymorphisms might cause the increased risk of urinary cancer, while rs17878467 reduces risk.

Analyzing 37,900 samples shows significant association between HOTAIR polymorphisms and cancer susceptibility: a meta-analysis.

BACKGROUND AND OBJECTIVE: An increasing number of investigations are drawing attention to the relationship between polymorphisms in the HOTAIR gene and the risk of cancers, but the results obtained so far have been controversial and inconclusive. We performed an up-to-date meta-analysis to obtain a more precise estimate of the possible associations. METHODS: Crude odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the associations. RESULTS: Nine publications including 26 case-control studies comprising 37,900 individuals were enrolled for the 5 polymorphisms in HOTAIR. The overall analyses identified a significant association between the rs920778 polymorphism and increased susceptibility to cancer in homozygous and recessive models. We conducted a stratification analysis by cancer type and identified a significantly increased susceptibility to esophageal squamous cell carcinoma in all the genetic models and to gastric cancer in the dominant model. For the rs7958904 polymorphism we detected a significantly decreased susceptibility to overall cancer in all 5 genetic models rather than the heterogeneous model. However, no significant association was identified between the rs874945, rs4759314 and rs1899663 polymorphisms and cancer susceptibility. CONCLUSIONS: Our results demonstrate that the HOTAIR rs920778 polymorphism may represent a risk factor for cancer, whereas the rs7958904 polymorphism may play a protective role.

Anti-Glomerular Basement Membrane Disease Combined with IgA Nephropathy Complicated with Reversible Posterior Leukoencephalopathy Syndrome: An Unusual Case.

BACKGROUND: Anti-glomerular basement membrane disease (anti-GBM disease) is an autoimmune glomerulonephritis disease that is characterized by IgG linear deposition along the non-collagen domain of a3 chains of type IV collagen on the GBM. Although anti-GBM disease accompanied with IgA linear deposition along GBMs was discussed previously in some papers, anti-GBM disease combined with IgA granular deposition in the mesangial area, especially complicated with reversible posterior leukoencephalopathy syndrome (RPLS), was rarely reported. RPLS is usually caused by hypertensive encephalopathy, renal decompensation, fluid retention, and adverse effects of immunosuppressive drugs. CASE REPORT: A male patient with the chief complaints of headache, gross hematuria, and nocturia was referred to our hospital. Based on renal biopsy, the diagnosis was finally confirmed as anti-GBM disease combined with IgA nephropathy and, the patient received comprehensive treatment, including cyclophosphamide (CTX), which led to symptom improvement. Two days after the third impulse CTX was given, he suddenly experienced headache and dizziness, which eventually developed into a tonic-clonic seizure. RPLS was identified by cranial magnetic resonance imaging (MRI) with reversible neuroimaging. After diazepam and antihypertension management, seizures were controlled. RPLS, a neurological complication, was found in anti-GBM disease with IgA nephropathy during our immunosuppressants therapy for the first time. CONCLUSIONS: It is worth paying more attention to patients with rapidly progressive glomerulonephritis (RPGN), as they might be complicated with RPLS during intravenous administration of CTX and methylprednisolone. We suggest the neuroimaging be examined as soon as the seizure happens.