Selective inhibition of CDK9 in triple negative breast cancer.

Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281-734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272-771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

Neonatal outcomes of preterm neonates and its predictors in Ethiopian public hospitals: Multicenter prospective follow-up study.

Introduction: Preterm birth remains the most significant clinical and public health encounter. Preterm infant outcomes pose key evidence for clinicians and policymakers and are extensively used to set clinical and policy verdicts to improve services. It is necessary to conduct the outcomes of neonates frequently, as it varies from place to place and even from time to time in a similar place. There is limited literature in Ethiopia about preterm neonates' outcomes and their predictors. Objective: This study aimed to assess the neonatal outcomes of preterm neonates and their predictors in South Gondar zone public hospitals, Northwest Ethiopia, 2021. Methods: A prospective observational study was employed on 462 preterm neonates in South Gondar Zone Public Hospitals. The data were entered into Epidata 4.6 and analyzed using STATA version 16/MP software. A parametric log-normal survival model was used to identify possible predictors for preterm neonate death. Statistical significance was declared at a P-value less than 0.05. Result: The overall preterm survival rate was 71.1% (95% CI: 66.7, 75.1). Thirty-six percent of preterm neonates were diagnosed with sepsis. One-fourth of the neonates had respiratory distress syndrome. Gestational age greater than 34 weeks (ß = 1.04; 95% CI: 0.53, 1.56), respiratory distress syndrome (ß = 0.85; 95% CI: 0.49, 1.22), body mass index (ß = -1.34; 95% CI: -1.87, -0.80), non-union marital status (ß = -0.71; 95% CI: -1.34, -0.09), multiple pregnancies (ß = -0.66; 95% CI: -0.99-0.32), multiparous (ß = 0.35; 95% CI: 0.01, 0.69), hypothermia (ß = -1.19; 95% CI: -1.76, -0.62), Kangaroo Mother Care (ß = -1.9; 95% CI: -2.34, -1.41) and non-cephalic presentation (ß = -1.23; 95% CI: -1.99,-0.46) were significant predictors. Conclusion: In this study, the preterm survival rate was low. Gestational age greater than 34 weeks, no respiratory distress syndrome, and multiparous mothers were positively associated with the survival of preterm neonates. Though, high pre-pregnancy maternal body mass index, non-union marital status of mothers, multiple pregnancies, hypothermia, Kangaroo mother care is not given, and non-cephalic presentation were negatively associated. A significant focus should be given to implementing WHO recommendations on preventing and caring for preterm births.

Mother-Infant Bonding and Its Associated Factors Among Mothers in the Postpartum Period, Northwest Ethiopia, 2021.

Background: The emotional bond that a mother senses to her infant is essential to their social, emotional, and cognitive development. Understanding the level of mother-infant bonding plays an imperative role in the excellence of care. However, in Ethiopia, there is a paucity of information about mother-infant bonding in the postpartum period. Objective: This study aimed to assess the level of mother-infant bonding and its associated factors among mothers in the postpartum period, Debre Tabor Town Northwest Ethiopia, 2021. Methods: A community-based cross-sectional study was conducted with 422 postpartum mothers. The postpartum Bonding Questionnaire was used to assess mother-infant bonding. The Edinburgh Postnatal Depression Scale was used to assess postnatal depression. The level of marital satisfaction was assessed by using Kansas marital satisfaction scale. Social support was assessed by Oslo social support scale. A simple random sampling technique was applied to select study participants. Simple and multiple linear regression were used to identify potential factors associated with the mother-infant bonding scale. A P-value of <0.05 was considered to declare statistical significance. Results: In this study, out of 420 postpartum mothers,53 (12.6%) had a risk for the quality of mother-infant bond difficulties between mother and an infant; 8.1% of mothers had a risk for rejection and pathological anger; 3.6% of mothers had a risk for infant-focused anxiety and 1.9% of mothers had risk for incipient abuse of an infant. Maternal depression status [adjusted ß coefficient (ß) = 2.31, 95% CI: (1.98, 2.64)], non-union marital status [ß = 15.58, 95% CI: (9.88, 21.27)], being government employee [ß = -5.68, 95% CI: (-9.71, -1.64)], having current pregnancy complication [ß = -7.28, 95% CI: (-12.27, -2.29)], being non-breastfeeding mother [ß = 7.66, 95% CI: (2.94, 12.38)], substance use history [ß = -6.55, 95% CI: (-12.80, -0.30)], and social support [ß = -2, 95% CI: (-2.49, -1.50)] were statistically significant factors for mother-infant bonding. Conclusion: Generally, a significant number of mothers had mother-infant bonding difficulties in the postpartum period. Preventing strategies for bonding difficulties focus on social support during pregnancy, screening postpartum mothers for postpartum depression, and special attention to substance users, non-union maternal status, and non-breastfeeding mothers.

An Orally Bioavailable and Highly Efficacious Inhibitor of CDK9/FLT3 for the Treatment of Acute Myeloid Leukemia.

Mutations in FMS-like tyrosine kinase 3 (FLT3) occur in approximately one-third of AML patients and are associated with a particularly poor prognosis. The most common mutation, FLT3-ITD, is a self-activating internal tandem duplication (ITD) in the FLT3 juxtamembrane domain. Many FLT3 inhibitors have shown encouraging results in clinical trials, but the rapid emergence of resistance has severely limited sustainable efficacy. Co-targeting of CDK9 and FLT3 is a promising two-pronged strategy to overcome resistance as the former plays a role in the transcription of cancer cell-survival genes. Most prominently, MCL-1 is known to be associated with AML tumorigenesis and drug resistance and can be down-regulated by CDK9 inhibition. We have developed CDDD11-8 as a potent CDK9 inhibitor co-targeting FLT3-ITD with Ki values of 8 and 13 nM, respectively. The kinome selectivity has been confirmed when the compound was tested in a panel of 369 human kinases. CDDD11-8 displayed antiproliferative activity against leukemia cell lines, and particularly potent effects were observed against MV4-11 and MOLM-13 cells, which are known to harbor the FLT3-ITD mutation and mixed lineage leukemia (MLL) fusion proteins. The mode of action was consistent with inhibition of CDK9 and FLT3-ITD. Most importantly, CDDD11-8 caused a robust tumor growth inhibition by oral administration in animal xenografts. At 125 mg/kg, CDDD11-8 induced tumor regression, and this was translated to an improved survival of animals. The study demonstrates the potential of CDDD11-8 towards the future development of a novel AML treatment.

Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations.

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action.

Determinants of acute respiratory infection (ARI) among under-five children in rural areas of Legambo District, South Wollo Zone, Ethiopia: A matched case-control study.

BACKGROUND: Acute respiratory infection (ARI) leads to morbidity and mortality among under-fivechildren in developing countries, especially in rural settings. ARI ranks among the top 10 diseases in under-five children in Legambo District, South Wollo Zone, Ethiopia. The aim of this study was to evaluate determinant factors for ARI in Legambo District in 2019. MATERIALS AND METHODS: A community-based matched case-control study was conducted, involving 139 cases and 278 controls under 5 years of age, from mid-January to mid-February 2019. Data were collected using a structured questionnaire. Bivariate and multivariable conditional logistic regression analyses were performed. From the multivariable conditional logistic regression analysis, variables with a significance level of p < 0.05 were taken as significantly associated with ARI among under-five children. RESULT: ARI among children under 5 years of age was significantly associated with age of the mother/caregiver being ≥35 years, occupation of mother/caregiver being housewife, the family being of medium wealth status, the type of stove used in the house, carrying the child while preparing food, absence of windows in the house, and nutritional status of the child. CONCLUSION: The occurrence of ARI could be reduced by improving economic status, stove use, and nutrition of children, and by increasing community awareness regarding indoor air pollution and ventilation.