Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor.

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

Chronic kidney disease risk prediction scores assessment and development in Mexican adult population.

Background: Chronic kidney disease (CKD) is a major public health problem, with considerable growth in prevalence and mortality in recent years. Screening of CKD at primary care is crucial for the implementation of prevention strategies. The aims of this study are to assess CKD risk prediction scores and to develop a risk prediction score for the Mexican adult population. Methods: Data from the Mexican National Health and Nutrition Survey 2016 was utilized and 3463 participants ≥ 20 years old were included. Reduced renal function with Glomerular filtration rate and/or the presence of albuminuria was defined as CKD. Multiple logistic regression models were performed for the creation of a training and validation model. Additionally, several models were validated in our Mexican population. Results: The developed training model included sex, age, body mass index, fast plasma glucose, systolic blood pressure, and triglycerides, as did the validation model. The area under the curve (AUC) was 0.78 (95% CI: 0.72, 0.79) for training model, and 0.76 (95% CI: 0.71, 0.80) in validation model for Mexican adult population. Age, female gender, presence of diabetes and hypertension, elevated systolic and diastolic blood pressure, serum and urinary creatinine, and higher HbA1c were significantly associated with the prevalent chronic kidney disease. Previous CKD risk predictive models were evaluated with a representative sample of the Mexican adult population, their AUC was between 0.61 and 0.78. Conclusion: The designed CKD risk predictive model satisfactorily predicts using simple and common variables in primary medical care. This model could have multiple benefits; such as, the identification of the population at risk, and prevention of CKD.

Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells.

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC.

Prevalencia de factores de riesgo y sintomatología prostática en indígenas de Tabasco / Prevalence of Prostate Cancer Risk Factors and Symptoms in Indigenous People in Tabasco, Mexico

Introducción: El cáncer de próstata, es un problema de salud pública, la neoplasia que se diagnostica con mayor frecuencia y segunda causa de muerte en los hombres. Poco se sabe de este problema en población indígena, por lo cual, los conocimientos actuales son demandantes en la prevención primaria. Objetivo: analizar la prevalencia de sintomatología prostática y factores de riesgo entre varones indígenas, Centro, Tabasco. Material y Métodos: estudio descriptivo correlacional, diseño transversal, muestra de 281 hombres de la etnia chontal de 40 y más años de las comunidades; Tamulté de las Sabanas, Aniceto y Tocoalt. Se utilizó el cuestionario de síntomas prostáticos y entrevista de factores de riesgo. Resultados: 52.7% sin escolaridad, 47.7% son campesinos, edad media 55 años, 16.7% con sintomatología prostática de moderada a severa. Factores de riesgo; 44.5% mediano y 55.5% alto riesgo. La prueba de Chi cuadrada de Pearson entre la variable edad y sintomatología prostática tuvo una asociación de p=.000. Un valor de p=.166 entre la edad y los factores de riesgo; hombres de menor edad presentaron más factores de riesgo. Ninguno se ha realizado los exámenes de detección integral. Discusión y conclusiones: coincide con otros estudios la prevalencia de síntomas prostáticos en adultos mayores, es preocupante la prevalencia de factores de riesgo en todos los participantes, mismos que se han observado en hombres con diagnóstico de cáncer de próstata, es importante crear estrategias de prevención con miras en los estilos de vida saludable.

Introduction: Prostate cancer is a public health problem being the most frequently diagnosed neoplasm and the second leading cause of cancer death in men. However, there is little information about this disease in indigenous people and therefore, current knowledge calls for urgent primary prevention. Objective: To analyze the prevalence of prostate cancer risk factors and symptoms in indigenous men in Centro, Tabasco. Materials and Methods: A cross-sectional descriptive correlational study was conducted with 281 Chontal men aged 40 years and older from the communities of Tamulté de las Sabanas, Aniceto and Tocoalt. The Prostate Symptom Score questionnaire and interviews for assessing risk factors were both implemented. Results: 52.7% had no formal schooling at all, 47.7% were peasants at an average age of 55 years, 16.7% had moderate to severe prostatic symptoms. As for risk factors, 44.5% were classified to be at medium risk and 55.5% at high risk. Pearson's chi-squared test between variables age and prostatic symptoms showed an association of p=.000 and a value of p=.166 between age and risk factors. Younger men showed to have more risk factors associated. None had undergone comprehensive screening. Discussion and Conclusions: Prevalence of prostatic symptoms found in older adults is consistent with other studies. Prevalence of risk factors in all participants is a matter of concern as these are the same risk factors observed in men diagnosed with prostate cancer. It is important to develop prevention strategies based on healthy lifestyles.

Introdução: O câncer de próstata é um problema de saúde pública, a neoplasia mais comumente diagnosticada e segunda causa de morte nos homens. Pouco se sabe sobre este problema na população indígena, portanto, os conhecimentos atuais são exigentes na prevenção primária. Objetivo: analisar a prevalência de sintomas de próstata e fatores de risco em varões indígenas, Centro, Tabasco. Material e Métodos: estudo descritivo correlacionado, desenho transversal, amostra de 281 homens da etnia chontal com 40 anos ou mais das comunidades; Tamulté de las Sabanas, Aniceto e Tocoalt. Foram utilizados o questionário de sintomas da próstata e a entrevista de fatores de risco. Resultados: 52.7% sem escolaridade, 47.7% são camponeses, idade média de 55 anos, 16.7% com sintomas de próstata moderados a graves. Fatores de risco; 44.5% médio y 55.5% alto risco. O teste qui-quadrado de Pearson entre a variável idade e sintomas de próstata teve uma associação de p=.000. Um valor de p=.166 entre idade e os fatores de risco; homens menores de idade apresentaram mais fatores de risco. Nenhum realizou os exames de detecção abrangente. Discussão e conclusões: coincide com outros estudos a prevalência de sintomas de próstata em idosos, é preocupante a prevalência de fatores de risco em todos os participantes, o mesmo que foi observado em homens com diagnóstico de câncer de próstata, é importante criar estratégias de prevenção com vistas a estilos de vida saudáveis.

Prevalencia de factores de riesgo y sintomatología prostática en indígenas de Tabasco / Prevalence of Prostate Cancer Risk Factors and Symptoms in Indigenous People in Tabasco, Mexico / Prevalência de fatores de risco e sintomas de próstata em indígenas de Tabasco

Resumen Introducción El cáncer de próstata, es un problema de salud pública, la neoplasia que se diagnostica con mayor frecuencia y segunda causa de muerte en los hombres. Poco se sabe de este problema en población indígena, por lo cual, los conocimientos actuales son demandantes en la prevención primaria. Objetivo analizar la prevalencia de sintomatología prostática y factores de riesgo entre varones indígenas, Centro, Tabasco. Material y Métodos estudio descriptivo correlacional, diseño transversal, muestra de 281 hombres de la etnia chontal de 40 y más años de las comunidades; Tamulté de las Sabanas, Aniceto y Tocoalt. Se utilizó el cuestionario de síntomas prostáticos y entrevista de factores de riesgo. Resultados 52.7% sin escolaridad, 47.7% son campesinos, edad media 55 años, 16.7% con sintomatología prostática de moderada a severa. Factores de riesgo; 44.5% mediano y 55.5% alto riesgo. La prueba de Chi cuadrada de Pearson entre la variable edad y sintomatología prostática tuvo una asociación de p=.000. Un valor de p=.166 entre la edad y los factores de riesgo; hombres de menor edad presentaron más factores de riesgo. Ninguno se ha realizado los exámenes de detección integral. Discusión y conclusiones coincide con otros estudios la prevalencia de síntomas prostáticos en adultos mayores, es preocupante la prevalencia de factores de riesgo en todos los participantes, mismos que se han observado en hombres con diagnóstico de cáncer de próstata, es importante crear estrategias de prevención con miras en los estilos de vida saludable.

Abstract Introduction Prostate cancer is a public health problem being the most frequently diagnosed neoplasm and the second leading cause of cancer death in men. However, there is little information about this disease in indigenous people and therefore, current knowledge calls for urgent primary prevention. Objective To analyze the prevalence of prostate cancer risk factors and symptoms in indigenous men in Centro, Tabasco. Materials and Methods A cross-sectional descriptive correlational study was conducted with 281 Chontal men aged 40 years and older from the communities of Tamulté de las Sabanas, Aniceto and Tocoalt. The Prostate Symptom Score questionnaire and interviews for assessing risk factors were both implemented. Results 52.7% had no formal schooling at all, 47.7% were peasants at an average age of 55 years, 16.7% had moderate to severe prostatic symptoms. As for risk factors, 44.5% were classified to be at medium risk and 55.5% at high risk. Pearson's chi-squared test between variables age and prostatic symptoms showed an association of p=.000 and a value of p=.166 between age and risk factors. Younger men showed to have more risk factors associated. None had undergone comprehensive screening. Discussion and Conclusions Prevalence of prostatic symptoms found in older adults is consistent with other studies. Prevalence of risk factors in all participants is a matter of concern as these are the same risk factors observed in men diagnosed with prostate cancer. It is important to develop prevention strategies based on healthy lifestyles.

Resumo Introdução O câncer de próstata é um problema de saúde pública, a neoplasia mais comumente diagnosticada e segunda causa de morte nos homens. Pouco se sabe sobre este problema na população indígena, portanto, os conhecimentos atuais são exigentes na prevenção primária. Objetivo analisar a prevalência de sintomas de próstata e fatores de risco em varões indígenas, Centro, Tabasco. Material e Métodos estudo descritivo correlacionado, desenho transversal, amostra de 281 homens da etnia chontal com 40 anos ou mais das comunidades; Tamulté de las Sabanas, Aniceto e Tocoalt. Foram utilizados o questionário de sintomas da próstata e a entrevista de fatores de risco. Resultados 52.7% sem escolaridade, 47.7% são camponeses, idade média de 55 anos, 16.7% com sintomas de próstata moderados a graves. Fatores de risco; 44.5% médio y 55.5% alto risco. O teste qui-quadrado de Pearson entre a variável idade e sintomas de próstata teve uma associação de p=.000. Um valor de p=.166 entre idade e os fatores de risco; homens menores de idade apresentaram mais fatores de risco. Nenhum realizou os exames de detecção abrangente. Discussão e conclusões coincide com outros estudos a prevalência de sintomas de próstata em idosos, é preocupante a prevalência de fatores de risco em todos os participantes, o mesmo que foi observado em homens com diagnóstico de câncer de próstata, é importante criar estratégias de prevenção com vistas a estilos de vida saudáveis.

Synergy between the NAMPT inhibitor GMX1777(8) and pemetrexed in non-small cell lung cancer cells is mediated by PARP activation and enhanced NAD consumption.

GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Oxygen limitation favors the production of protein with antimicrobial activity in Pseudoalteromonas sp

This study examined the effect of dissolved oxygen concentration on the production of biomass and metabolites with antimicrobial activity of Pseudoalteromonas sp cultured at 0, 150, 250, or 450 revolutions per minute (rev. min-1). Dissolved oxygen (D.O) was monitored during the fermentation process, biomass was quantified by dry weight, and antimicrobial activity was assessed using the disk diffusion method. The bacterium Pseudoalteromonas reached similar concentration of biomass under all experimental agitation conditions, whereas antimicrobial activity was detected at 0 and 150 rev. min-1 registering 0% and 12% of D.O respectively corresponding to microaerophilic conditions. Antibiotic activity was severely diminished when D.O was above 20% of saturation; this corresponded to 250 or 450 rev. min-1. SDS-PAGE electrophoresis revealed a protein with a molecular weight of approximately 80 kilodaltons (kDa) with antimicrobial activity. Pseudoalteromonas is capable of growing under oxic and microaerophilic conditions but the metabolites with antimicrobial activity are induced under microaerophilic conditions. The current opinion is that Pseudoalteromonas are aerobic organisms; we provide additional information on the amount of dissolved oxygen during the fermentation process and its effect on antimicrobial activity.

Oxygen limitation favors the production of protein with antimicrobial activity in Pseudoalteromonas sp.

This study examined the effect of dissolved oxygen concentration on the production of biomass and metabolites with antimicrobial activity of Pseudoalteromonas sp cultured at 0, 150, 250, or 450 revolutions per minute (rev. min(-1)). Dissolved oxygen (D.O) was monitored during the fermentation process, biomass was quantified by dry weight, and antimicrobial activity was assessed using the disk diffusion method. The bacterium Pseudoalteromonas reached similar concentration of biomass under all experimental agitation conditions, whereas antimicrobial activity was detected at 0 and 150 rev. min(-1) registering 0% and 12% of D.O respectively corresponding to microaerophilic conditions. Antibiotic activity was severely diminished when D.O was above 20% of saturation; this corresponded to 250 or 450 rev. min(-1). SDS-PAGE electrophoresis revealed a protein with a molecular weight of approximately 80 kilodaltons (kDa) with antimicrobial activity. Pseudoalteromonas is capable of growing under oxic and microaerophilic conditions but the metabolites with antimicrobial activity are induced under microaerophilic conditions. The current opinion is that Pseudoalteromonas are aerobic organisms; we provide additional information on the amount of dissolved oxygen during the fermentation process and its effect on antimicrobial activity.

Design, synthesis, and evaluation of novel 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective CXCR2 chemokine receptor antagonists.

We describe herein a novel series of 3-amino-4-hydrazine-cyclobut-3-ene-1,2-diones as potent and selective inhibitors against the CXCR2 chemokine receptor and IL-8-mediated chemotaxis of a CXCR2-expressing cell line. Furthermore, these alkyl-hydrazine series inhibitors such as 5b demonstrated acceptable metabolic stability when incubated in human and rat microsomes.

Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms.

Methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the major carbon donor in the remethylation of homocysteine to methionine. Mild MTHFR deficiency, due to a common variant at nucleotide 677, has been reported to alter risk for several disorders including cardiovascular disease, neural tube defects, pregnancy complications, and certain cancers. Little is known about MTHFR regulation, since the complete cDNA and gene sequences have not been determined. In earlier work, we isolated and expressed a 2.2-kb human cDNA comprised of 11 coding exons, and we demonstrated that it encoded an active 70-kDa isoform. However, transcript sizes of approximately 7.5 kb and 9.5 kb and the presence of a second isoform of 77 kDa on Western blots suggested that cDNA sequences were incomplete. In this report, we characterized the complete cDNA and gene structure in human and mouse. Variable 5? and 3? UTR regions were identified, resulting in transcript heterogeneity. The 5? and 3? termini of the MTHFR cDNA were found to overlap with the 5? terminus of a chloride ion channel gene (CLCN-6) and the 3? terminus of an unidentified gene, respectively; this finding has resulted in finer mapping of MTHFR on Chromosome (Chr) 1p36.3. Ribonuclease protection assays identified clusters of transcriptional start sites, suggesting the existence of multiple promoters. MTHFR has several polyadenylation sites creating 3?UTR lengths of 0.2 kb-5.0 kb or 0.6 kb-4.0 kb in human and mouse, respectively. In both species, the previously reported exon 1 was redefined to approximately 3.0 kb in length and shown to be alternatively spliced. An important splice variant contains novel coding sequences; this cDNA was expressed and shown to encode the isozyme of 77 kDa. Our results, which suggest intricate regulation of MTHFR, will facilitate additional regulatory and functional studies of the different isoforms.