Induction of MNK Kinase-dependent eIF4E Phosphorylation by Inhibitors Targeting BET Proteins Limits Efficacy of BET Inhibitors.

BET inhibitors (BETi), which target transcription of key oncogenic genes, are currently being evaluated in early-phase clinical trials. However, because BETis show limited single-agent activity, there is increasing interest in identifying signaling pathways to enhance the efficacy of BETis. Here, we demonstrate increased MNK kinase-dependent eIF4E phosphorylation following treatment with BETis, indicating activation of a prosurvival feedback mechanism in response to BETis. BET PROTACs, which promote degradation of BET proteins, also induced eIF4E phosphorylation in cancer cells. Mechanistically, we show that the effect of BETis on MNK-eIF4E phosphorylation was mediated by p38 MAPKs. We also show that BETis suppressed RacGAP1 to induce Rac signaling-mediated eIF4E phosphorylation. Significantly, MNK inhibitors and MNK1/2 knockdown enhanced the efficacy of BETis in suppressing proliferation of cancer cells in vitro and in a syngeneic mouse model. Together, these results demonstrate a novel prosurvival feedback signaling induced by BETis, providing a mechanistic rationale for combination therapy with BET and MNK inhibitors for synergistic inhibition of cancer cells.

Alarming rates of attrition among tuberculosis patients in public-private facilities in Lahore, Pakistan.

Setting: All public-private mix (PPM) facilities caring for tuberculosis (TB) patients in Lahore city, Pakistan, under four models: PPM1 (general practitioners), PPM2 (non-governmental organisations), PPM3 (private hospitals) and PPM4 (others). Objective: To assess the pre-treatment loss to follow-up (LTFU), defined as patients documented in the laboratory registers but not in the treatment registers of any PPM facility, among sputum smear-positive TB patients diagnosed during January-March 2015, and unfavourable treatment outcomes among patients registered for treatment and associated factors. Design: This was a retrospective cohort study reviewing existing programme records. Poisson regression was used to identify factors associated with outcomes. Results: Of 2473 patients diagnosed, 1590 (64%) were lost to follow-up before treatment. This was higher among males (68%) and the elderly (79%), and lower among 'high positives' (smear grading 2+ or 3+, 53%) and in the PPM1 model (34%). Of 883 patients started on treatment, 165 (19%) had unfavourable outcomes: 8% LTFU, 5% treatment failure, 3% died and 3% not evaluated. Previously treated patients (34%) and children (44%) had the worst outcomes. Conclusion: Pre-treatment LTFU was alarmingly high and requires urgent attention, including the development and institution of mechanisms for patient tracking using information and mobile phone technology, and making TB notification mandatory in the private sector.

Contexte: Toutes les structures mixtes public-privé (PPM) prenant en charge les patients tuberculeux (TB) à Lahore, Pakistan, dans quatre modalités : PPM1 (médecins généralistes), PPM2 (organisations non gouvernementales), PPM3 (hôpitaux privés), PPM4 (autres).Objectif: Evaluer les pertes de vue avant traitement (LTFU), définies comme des patients figurant dans le registre du laboratoire mais pas dans le registre de l'une quelconque des PPM pour leur traitement, parmi les patients ayant eu un diagnostic de TB à frottis positif de janvier à mars 2015 et un résultat défavorable du traitement parmi les patients enregistrés pour leur traitement, ainsi que les facteurs associés.Schéma: Une étude rétrospective de cohorte par revue des dossiers de programme existants. La régression de Poisson a été utilisée pour identifier les facteurs associés aux résultats.Résultats: Sur 2473 patients diagnostiqués, 1590 (64%) ont été perdus de vue avant le traitement. Ce résultat a été plus élevé parmi les hommes (68%) et les patients plus âgés (79%), et plus faible parmi les patients « hautement positifs ¼ (frottis grade 2+ ou 3+, 5%) et dans le modèle de PPM1 (34%). Sur 883 patients ayant mis en route leur traitement, 165 (19%) ont eu un résultat défavorable (8% LTFU, 5% d'échecs du traitement, 3% décédés, 3% non évalués). Les patients déjà traités (34%) et les enfants (44%) ont eu des résultats plus mauvais.Conclusion: Les LTFU avant le traitement ont été élevées de manière alarmante et demandent une attention urgente. Ceci inclut le développement et la mise en œuvre de mécanismes de recherche des patients grâce aux techniques d'information et de téléphonie mobile, et l'obligation de notification de la TB par le secteur privé.

Marco de referencia: Todos los establecimientos de la colaboración público privada (PPM, por public-private mix) que atienden pacientes con tuberculosis (TB) en la ciudad de Lahore, en Pakistán, según cuatro modelos, a saber: PPM1 (médicos generalistas), PPM2 (organizaciones no gubernamentales), PPM3 (hospitales privados) y PPM4 (otros).Objetivo: Examinar las pérdidas durante el seguimiento antes del tratamiento (LTFU), definidas como los pacientes que aparecen en los registros de laboratorio, pero no se encuentran en los registros de tratamiento en ningún establecimiento PPM, de los pacientes con baciloscopia positiva del esputo, diagnosticados de enero a marzo del 2015, evaluar los desenlaces terapéuticos desfavorables en los pacientes registrados en tratamiento y determinar los factores asociados con estos desenlaces.Método: Un estudio retrospectivo de cohortes con análisis de los registros del programa. Mediante una regresión de Poisson se definieron los factores asociados con los criterios de valoración.Resultados: De los 2473 pacientes diagnosticados, 1590 se perdieron durante el seguimiento antes de comenzar el tratamiento (64%). Esta proporción fue más alta en los hombres (68%) y los ancianos (79%) y más baja en los casos con baciloscopia de alta positividad (53%, frotis calificado como 2+ o 3+) y en el modelo PPM1 (34%). De los 883 pacientes que iniciaron tratamiento, 165 (19%) presentaron desenlaces desfavorables (8% LTFU, 5% fracaso terapéutico, 3% fallecieron, 3% no se evaluaron). Los desenlaces más desfavorables se observaron en los pacientes con antecedente de tratamiento antituberculoso (3%) y en los niños (44%).Conclusión: La proporción de LTFU durante el seguimiento antes de iniciar el tratamiento antituberculoso fue muy alarmante y exige una atención urgente. La respuesta puede consistir en la elaboración y aplicación de mecanismos de localización de los pacientes mediante las tecnologías de la información y los teléfonos celulares y la introducción de la notificación obligatoria de la TB en el sector privado.

A new subspecies identification and population study of the Asian small-clawed otter (Aonyx cinereus) in Malay Peninsula and southern Thailand based on fecal DNA method.

Three species of otter can be found throughout Malay Peninsula: Aonyx cinereus, Lutra sumatrana, and Lutrogale perspicillata. In this study, we focused on the A. cinereus population that ranges from the southern and the east coast to the northern regions of Malay Peninsula up to southern Thailand to review the relationships between the populations based on the mitochondrial D-loop region. Forty-eight samples from six populations were recognized as Johor, Perak, Terengganu, Kelantan, Ranong, and Thale Noi. Among the 48 samples, 33 were identified as A. cinereus, seven as L. sumatrana, and eight as L. perspicillata. Phylogenetically, two subclades formed for A. cinereus. The first subclade grouped all Malay Peninsula samples except for samples from Kelantan, and the second subclade grouped Kelantan samples with Thai sample. Genetic distance analysis supported the close relationships between Thai and Kelantan samples compared to the samples from Terengganu and the other Malaysian states. A minimum-spanning network showed that Kelantan and Thailand formed a haplogroup distinct from the other populations. Our results show that Thai subspecies A. cinereus may have migrated to Kelantan from Thai mainland. We also suggest the classification of a new subspecies from Malay Peninsula, the small-clawed otter named A. cinereus kecilensis.

Echocardiographic risk stratification for early surgery with endocarditis: a cost-effectiveness analysis.

BACKGROUND: Despite widespread acceptance of echocardiography for diagnosis of infective endocarditis, few investigators have evaluated its utility as a risk-stratification tool to aid therapeutic decision-making. METHODS: A decision tree and Markov analysis model were constructed using published and institutional data to estimate the cost-effectiveness of an echocardiographic risk-stratification strategy for infective endocarditis. The models compared surgery for high-risk patients based on clinical factors ("standard care") and surgery for high-risk patients based on echocardiographic findings ("echocardiography-guided"). RESULTS: The cost per patient for standard care and echocardiography-guided strategies was $47,766 and $53,669, respectively. The expected quality-adjusted life years (QALY) for standard care and echocardiography-guided strategies were 5.86 years and 6.10 years, respectively. Compared with standard care, the echocardiography-guided strategy cost an additional $23,867 per QALY saved. In one-way sensitivity analyses, the incremental cost of this strategy remained <$50,000/QALY across a broad range of scenarios. Baseline stroke risk had the greatest effect on cost-effectiveness. For populations with stroke risk less than 3.65%, the echocardiography-guided strategy was not cost-attractive (ICER >$50,000/QALY). At stroke risk between 3.65% and 14%, the ICER for the echocardiography-guided strategy was attractive (<$50,000 /QALY). The echocardiography-guided strategy became economically dominant at any baseline stroke risk greater than 18.3%. CONCLUSION: Echo-guided risk stratification for early surgery in patients with large vegetations is a cost-attractive treatment strategy for IE, as it improves outcome for an incremental cost <$50,000/QALY.

Acute myocardial infarction: profile and management at a tertiary care hospital in Karachi.

OBJECTIVE: Acute Myocardial Infarction (AMI) is a rising epidemic in developing countries. While studies in the West have established the characteristics and management of AMI patients, comprehensive data reflecting these issues in the Pakistani subjects is scarce. This study examined the profile and management of AMI in patients hospitalized at a tertiary care hospital in Karachi, Pakistan. METHODS: Three hundred forty four patients admitted in 1998 with the diagnosis of AMI met our inclusion criteria. Data on presentation, investigations, monitoring and therapy was obtained. Chi-square and t tests were used to analyze the data. RESULTS: Out of 344 patients with AMI, 71% were males; 58% had a Q wave MI. Majority of the patients who presented within 2 hours of symptom onset (36%), had chest pain. Patients with dyspnea and no chest pain were more likely to present after 12 hours of the onset of symptoms. In-house mortality was found to be 10.8%. Low HDL and diabetes was associated with in-hospital complications. Twenty nine percent of patients were given thrombolytic therapy with a mean door-to-needle time of 1 hour 36 minutes; 33% of patients who were eligible of Streptokinase did not receive it. Cardiac catheterization was performed in 28% patients. Echocardiography and Exercise Tolerance Test, both under utilized, were performed in 67% and 16% of patients, respectively. Two hundred sixteen (70%) patients discharged from hospital were contacted via telephone and the 1-year mortality rate among them was 28%. CONCLUSION: The profile and management of AMI was in coherence with earlier, Western studies. Chest pain units need to be established in the Emergency Room. Patients should be risk stratified prior to discharge. Public awareness regarding primary and secondary prevention and symptoms of AMI needs to be increased.

Hormone replacement therapy menopause with a better future--a survey of views on hormone replacement therapy (HRT).

OBJECTIVE: To assess the views and prescribing practices of doctors regarding hormone replacement therapy (HRT). METHODS: In April 1999, 103 doctors from a teaching hospital participated in a survey. Using a self-administered questionnaire, subjects were contacted at the departments of Internal Medicine, Family Medicine, Obstetrics and Gynaecology, and Orthopaedics. RESULTS: Seventy-two percent were below 40 years of age and 67% of the respondents were male. Most doctors believed that HRT decreases the risk of subsequent osteoporosis (97%), ischaemic heart disease (77%) and depression associated with menopause (64%). Doctors generally considered menopausal symptoms (90%), premature menopause (87%), surgical menopause (85%) and osteoporotic fracture (77%) as clear indications for hormone replacement therapy. Absolute contraindications to the therapy were stated as recent breast cancer (82%) and recent endometrial cancer (84%). Among the specialities covered, there were differing views on proposed duration of HRT. It was generally believed that a pelvic examination, cervical smear and mammography were pre-requisites when initiating and monitoring HRT. Majority (69%) felt that HRT should be offered to all menopausal women, assuming no contraindications and most (73%) did discuss HRT with their patients. However, less than 10% of the menopausal patients under their care were using HRT. Those doctors not in favor of universal offering of HRT (31%) considered unreliable patient follow up to be the main reason. Females were two times more likely to discuss HRT with their patients (p = .08). Doctors who discussed HRT with their patients were four times more likely to consider HRT for themselves or their spouses (p = .13). Gynecologists were eight times more likely to prescribe HRT than non-gynecologists (p = .001). CONCLUSION: Doctors are positively disposed to the universal offering, and use of HRT. Further studies are needed to understand a possible gap between perceived and actual prescribing practice.