Search

Background: Down syndrome or trisomy 21 is one of the most common chromosomal disorders with moderate intellectual disability. In addition to mental retardation, this syndrome is associated with different congenital anomalies and characteristic dysmorphic features. Affected individuals are more susceptible to congenital heart disease and digestive anomalies, pulmonary complications, immune and endocrine system disorders. While several international studies have shown association of co-morbidities with trisomy 21, there is insufficient data available in Bangladesh.The present study aimed to evaluate the associated co-morbidities in children with Down syndrome. Methods: A cross-sectional study was conducted among pediatric cases with Down syndrome who attended the endocrine outpatient department (OPD) of BIRDEM General Hospital from June 2006 to December 2016. The cases were diagnosed either by Karyotyping or by characteristic phenotypes.The clinical and laboratory data of the patients were collected from outpatient history records for analysis. Results: There were total 42 children with Down syndrome, with mean age 4.2 years at assessment and female predominance (1.47:1). Thyroid dysfunction was the most common (69%) followed by congenital heart disease (57%). Among the thyroid disorders, acquired hypothyroidism was found in 55% cases, congenital hypothyroidism in 41% cases and only one had hyperthyroidism. Isolated patent ductus arteriosus (PDA) and atrial septal defect (ASD) comprised the commonest single congenital heart disease found in 53% and combined atrioventricular septal defect was the commonest among complex congenital cardiac defect observed in our study. Both thyroid dysfunction and congenital heart disease were found more in female children with Down syndrome than their male counterpart and it was found statistically significant. Fifty percent of our Down syndrome cases were referred from other healthcare centers to address developmental delay. Conclusion: Hypothyroidism and congenital heart disease are frequently associated in Down syndrome children in Bangladesh. This calls for developing awareness among health professionals to diagnose comorbidities at an early stage and to form recommendations for long term follow up. BIRDEM Med J 2021; 11(3): 191-196

not available DS (Child) H J 2020; 36(2): 152-159

In 1997, during the 41st session of the Regional Committee for the Eastern Mediterranean, the 21 countries in the World Health Organization (WHO) Eastern Mediterranean Region* (EMR) passed a resolution to eliminate† measles (1). In 2015, this goal was included as a priority in the Eastern Mediterranean Vaccine Action Plan 2016-2020 (EMVAP) (2), endorsed at the 62nd session of the Regional Committee (3). To achieve this goal, the WHO Regional Office for the Eastern Mediterranean developed a four-pronged strategy: 1) achieve ≥95% vaccination coverage with the first dose of measles-containing vaccine (MCV1) among children in every district of each country through routine immunization services; 2) achieve ≥95% vaccination coverage with a second MCV dose (MCV2) in every district of each country either through implementation of a routine 2-dose vaccination schedule or through supplementary immunization activities§ (SIAs); 3) conduct high-quality, case-based surveillance in all countries; and 4) provide optimal measles clinical case management, including dietary supplementation with vitamin A (4). This report describes progress toward measles elimination in EMR during 2013-2019 and updates a previous report (5). Estimated MCV1 coverage increased from 79% in 2013 to 82% in 2018. MCV2 coverage increased from 59% in 2013 to 74% in 2018. In addition, during 2013-2019, approximately 326.4 million children received MCV during SIAs. Reported confirmed measles incidence increased from 33.5 per 1 million persons in 2013 to 91.2 in 2018, with large outbreaks occurring in Pakistan, Somalia, and Yemen; incidence decreased to 23.3 in 2019. In 2019, the rate of discarded nonmeasles cases¶ was 5.4 per 100,000 population. To achieve measles elimination in the EMR, increased visibility of efforts to achieve the measles elimination goal is critically needed, as are sustained and predictable investments to increase MCV1 and MCV2 coverage, conduct high-quality SIAs, and reach populations at risk for not accessing immunization services or living in areas with civil strife.

Background: Doxorubicin (DOX) is a potential chemotherapeutic agent but its use is restricted due to cardiotoxicity. Edaravone is a potent-free radical scavenging agent used in cerebral ischaemia. Benidipine is a triple calcium channel blocker.Objective: We investigated the potential cardioprotective effects of edaravone and benidipine alone and their combination against DOX-induced cardiotoxicity. Cardiotoxicity was induced by administering six equal injections of DOX (2.5 mg/kg) on alternative days for 2 weeks.Result: DOX-treated group showed significant increase level of lipid peroxide and decrease in antioxidant status along with mitochondrial enzymatic activity. Cardiotoxity effect of DOX illustrated by significantly increased the cardiac biomarkers such as Cardiac troponin-I, Brain natriuretic peptide, Creatine kinase-MB in serum. Significant increased activation of TNF-α, Caspase-3 activity and myocardial infarct size in DOX-treated group. Histopathological evaluation also confirmed the DOX-induced cardiotoxicity. Pretreated with edaravone and benidipine was significantly attenuated level of thiobarbituric acid reactive substance, endogenous enzymes, mitochondrial enzyme activities and cardiac biomarkers. Furthermore, pretreated group showed decreased activation of TNF-α, Caspase-3 activity along with reduction in the myocardial infarct size. Histopathological evaluation also strengthened the above results.Conclusion: Taken together these results suggest that the pretreated with edaravone and benidipine have potential protective effect against DOX-induced cardiotoxicity.

Sacubitril (SAC), a neprilysin inhibitor prevent degradation of neprilysin and activate cGMP signaling pathways leading to rise in blood volume concurrent to blood pressure by means of vasoactive peptides, adrenomedullin, and bradykinin.The aim of this study was to evaluate the anti-ischemic effects of SAC through inhibiting neprilysin in isoproterenol (ISO) induced myocardial infarction (MI) in Wistar albino rats. ISO (85 mg/kg) was injected subcutaneously at the end of 14 days pre-treatment with SAC and valsartan (VAL).Biochemical investigation revealed that SAC along with VAL significantly prevented the antioxidant enzymes (SOD, Catalase, GR, GPx, GST, and GSH) degradation and malondialdehyde (MDA) induced by ISO intoxication in Wistar rats. Along with this, cardiac biomarkers (LDH, CK-MB, ALT, AST, and ALP) were also significantly ameliorated by SACand VAL in ISO-treated rats. Concurrently, decreased infarction area (IA)and marked reduction in myofibril damage by SACand VAL further supported its protective benefits in MI.Taken together, the results suggest that inhibition of enzyme neprilysin alleviated the ISO induces myocardial damage mediated by its strong antioxidant potential.

Objective To evaluate the cardioprotective effect of Nigella sativa L. (N. sativa) in isoproterenol-induced myocardial infarction (MI). Methods Groups were treated with different doses of ethanol extract of N. sativa (EENS) and N. sativa oil alone and along with enalapril for 28 days. MI was induced by subcutaneous administration of isoproterenol (85 mg/kg) in two consecutive doses. Levels of cardiac biomarkers and antioxidant enzymes such as creatine kinase–N-acetyl-l-cysteine, lactate dehydrogenase, aspartate aminotransferase, malondialdehyde, superoxide dismutase, reduced glutathione and catalase were evaluated along with gross histopathological examination. Results Isoproterenol (85 mg/kg) induced MI by causing the significant (P

Background: The study aimed to evaluate the efficacy of AgNORs on FNAC smears of breast lesion.Methods: FNAC were done in 200 female patients of breast lump consecutively, Papanicolau and AgNOR staining was done in all 200 cases of FNA smears.Among them biopsy and histopathology were done in 99 cases. The findings of FNAC and AgNOR analysis were compared to histopathological findings.Results: By FNAC, 53 (26.5%) cases were non-neoplastic benign, 89(44.5%) cases were benign neoplasm, 07 (3.5%) cases were atypical ductal hyperplasia and 51(25.5%) cases were malignant (Duct cell carcinoma).Among them histopathology was done in 99 cases.Out of 40 FNAC malignant cases, histopathologically all were proved malignant. Out of 42 benign cases, 1 was found malignant. 4 atypical ductal hyperplasia were also diagnosed as malignant histopathologically. True positive cases are 40, True negative cases are 36, false positive are nil (0), and false negative is 01. The sensitivity is 97.56%, specificity is 100%, positive predictive value is 100%, Negative predictive value is 97.3%, and accuracy is 98.7%. AgNOR impression were analysed in 99 histopathologically confirmed cases. The results showed benign impression in 50 cases and malignant impression in 48 cases. 01 histopathologically malignant case was impressed as benign by AgNOR and 01 as suspicious which may be included as malignant by AgNOR impression. 2 histopathologically benign cases showed higher proliferative activities and counted as malignant. True positive cases are 46, True negative 49, false positive is 02 and false negative is 01. The sensitivity is 97.87%, Specificity 96.07%, PPV 95.83%, NPV 98%, Overall accuracy is 96.93%.Conclusion: The efficacy of FNAC and AgNOR analysis in the diagnosis of breast lesion was found more or less similar and mild over lapping.Chatt Maa Shi Hosp Med Coll J; Vol.15 (2); Jul 2016; Page 14-20

Diabetic cardiomyopathy plays a major role in morbidity and mortality among cardiovascular disorder-related complications. This study was designed to explore long-term benefits of Levosimendan (LEVO) along with Ramipril and Insulin. Diabetic cardiomyopathy was induced using streptozotocin (STZ) at the dose of 25 mg/kg/body weight/day for three consecutive days in Wistar rats. Rats were randomly divided into 10 groups and treatments were started after 2 weeks of STZ administration. A gradual but severe hyperglycemia ((§§§)p 0.001) was observed in all STZ-treated groups except those received insulin (2 U/day). LEVO alone and in combination with Ramipril and Insulin normalized (**p 0.01) mean arterial pressure and heart rate, restored catalase, superoxide dismutase, malondialdehyde, glutathione level and also attenuated (***p 0.001) the raised serum levels of creatine kinase-heart type, lactate dehydrogenase, tumor necrosis factor-alpha, C-reactive protein, and caspase-3 level in heart tissue altered after STZ treatment. Myofibril degeneration, mitochondrial fibrosis and vacuolization occurred after STZ treatment, were also reversed by LEVO in combination with Ramipril and Insulin. The combination of LEVO with Ramipril and Insulin improved hemodynamic functions, maintained cardiac enzymes and ameliorated myofibril damage in diabetic cardiomyopathy.

The effects of benidipine on oxidative stress and myocardial apoptosis were assessed in isoproterenol (ISO)-induced myocardial infarction (MI) in wistar rats.Animals were pretreated with benidipine (1, 3, 10 μg/kg/day Body weight) intravenously for a period of 28 days. After pretreatment, ISO (85 mg/kg Body weight, subcutaneous) was injected in rats at an interval of 24 h to induce MI. Myocardial oxidative stress, cardiac biomarkers, apoptosis, inflammatory mediators, and ultrastructural architecture of the cardiac tissue were assessed in ISO-induced MI in rats.Significant variation in the level of TBA, antioxidant enzymes (GSH, CAT, SOD, GPx, GRx, GST) in myocardium, cardiac biomarkers (CK-MB, LDH) in serum, Caspase-3, C-reactive protein (CRP), and alteration in ultrastructural architecture of cardiac tissue confirmed the cardiotoxicity induced by ISO. Pretreatment with benidipine preserved the lipid peroxide and antioxidant enzymes, and furthermore showed maintained levels of myocardial biomarker, CRP and caspase-3. Ultrastructure architecture of cardiac tissue was also found to be well preserved.The present study suggested cardioprotective effect of benidipine which may possibly be due to its antioxidant activity and antiapoptotic nature.

Objective : To examine the relationship between umbilical cord C-peptide and risk of hypoglycemia in infants of diabetic mothers. Method: Sixty neonates born to diabetic mothers were studied in BIRDEM hospital. Thirty infants who developed hypoglycemia at any time during the first 24 hours of age were considered as cases. Another 30 infants who did not develop hypoglycemia during the first 24 hours were considered as controls. Umbilical cord C-peptide levels were measured in both groups. All babies were screened for hypoglycemia at 4, 6, 8, 12, 18 and 24 hours of life. Blood glucose value of less than 2.6 mmol/l was considered as hypoglycemia. Results: Clinical characteristics of cases and controls and their mothers did not show any significant difference. In 73.3% of cases hypoglycemia was detected by 6 hours of age. Most babies were asymptomatic (93.3%). It was found that IDMs who developed hypoglycemia had significantly higher cord C-peptide level at birth compared to those who remained normoglycemic (4.57±2.50 vs. 2.81± 2.11 ng/ml, P= 0.005). That means, there is significant association between raised level of cord C-peptide and hypoglycemia in IDMs. Conclusion: Hypoglycemia in infants of diabetic mothers associated with raised cord blood C-peptide levels. DOI: http://dx.doi.org/10.3329/bjch.v36i2.13082 Bangladesh J Child Health 2012; Vol 36 (2): 71-75

Objectives: In the present study, we investigated whether combination therapy of low-dose benidipine with the potent free radical scavenger edaravone has a cardioprotective effect against isoproterenol (ISO)-induced myocardial infarction (MI) in Wistar rats. Methods: Rats were pretreated with concurrent doses of benidipine and edaravone (1 μg/kg/day + 1 mg/kg/day and 3 μg/kg/day + 3 mg/kg/day) by intravenous (i.v.) and intraperitoneal (i.p.) routes respectively for 28 days, followed by MI induction using ISO (85 mg/kg) by subcutaneous route for two days at 24 h intervals. After the treatment period, blood was withdrawn and the heart was preserved for biochemical estimations. Results: The activities of the cardiac biomarkers (lactate dehydrogenase and creatine kinase-MB), and the level of malondialdehyde (MDA) significantly increased, while antioxidant markers (reduced glutathione, catalase, superoxidase dismutase, glutathione peroxidase, glutathione reductase) were significantly decreased in the ISO intoxicated group compared with the control group. Moreover, the level of C-reactive protein (CRP) and Caspase-3 activity significantly increased in ISO-intoxicated group. An ultrastructure study was also carried out. Pretreatment with a combination of benidipine and edaravone significantly attenuated the activities of the cardiac biomarkers and the level of MDA, and significantly increased the antioxidant markers compared with the ISO-intoxicated group. Furthermore, pretreatment with the combination of benidipine and edaravone significantly decreased the level of CRP and Caspase-3 activity as compared to the ISO-treated group. The ultrastructure study of myocardium revealed that pretreated groups preserved the mitochondrial shape, the membrane and its internal structures. Conclusion: Taken together these results suggest that the combination of benidipine and edaravone showed significant protective effect in ISO-induced MI.

Objective: To examine the influence of maternal HbA1c level at delivery and risk of hypoglycemia in infants of diabetic mothers. Method: This case-control study was done with sixty neonates born to diabetic mothers in BIRDEM hospital. Out of sixty neonates, 30 neonates who developed hypoglycemia during the first 24 hours of age were considered as cases and another 30 neonates who did not develop hypoglycemia during the first 24 hours were considered as controls. Maternal glycemic status was examined by measurement of Glycosylated hemoglobin (HbA1c) and level of

This aim of this study was to assess the clinical utility of quantitative ST-segment depression (STD) for refining the risk stratification of non-ST elevation acute coronary syndromes in the prospective, multinational Global Registry of Acute Coronary Events (GRACE). Quantitative measurements of STD on admission electrocardiograms were evaluated independently by a core laboratory, and their predictive value for in-hospital and cumulative 6-month mortality was examined. Although more severe STD is a marker of increased short- and long-term mortality, it is also associated with higher risk clinical features and biomarkers. Thus, after adjustment for these clinically important predictors, quantitative STD does not provide incremental prognostic value beyond simple dichotomous evaluation for the presence of STD. Furthermore, adopting quantitative instead of the prognostically proven qualitative evaluation of STD does not improve risk discrimination afforded by the validated GRACE risk models. In conclusion, the findings do not support the quantification of STD in routine clinical practice beyond simple evaluation for the presence of STD as an integral part of comprehensive risk stratification using the GRACE risk score.

It is unclear whether quantitative ST-segment assessment can improve risk stratification of unselected acute coronary syndrome (ACS) patients using the validated Global Registry of Acute Cardiac Events (GRACE) risk model.In the prospective, multicenter, Canadian ACS Registry, the admission electrocardiogram was evaluated centrally at a blinded core laboratory. Patients with ST-elevation myocardial infarction and other electrocardiogram confounders were excluded. ST depression (ST down) was measured and summed in all leads except aVR. Patients with ST down were divided into 3 groups based on tertiles of cumulative ST down. A multivariable model was developed to examine the independent prognostic value of ST down severity after adjusting for other known prognosticators in the GRACE risk model.Among 2590 patients with non-ST-elevation ACS, more severe ST down was associated with advanced age, higher heart rate and Killip class, elevated creatinine, abnormal biomarkers, higher GRACE risk score, and higher 1-year mortality (all P.001). After adjusting for these confounding prognosticators, the presence of any ST down remained independently associated with higher 1-year mortality (odds ratio 1.78, 95% CI 1.21-2.63, P = .004). However, the gradient of risk with increasing magnitude of ST down was no longer evident (adjusted odds ratios 1.77, 1.77, 1.81, for ascending tertiles of cumulative ST down, respectively). Moreover, quantitative ST down did not improve the model discrimination for 1-year mortality. The results were similar when the number of leads with ST down or the maximum magnitude of ST down was analyzed, after adjusting for tertiles of GRACE risk score or inhospital revascularization, or using the composite end point of death or myocardial (re)infarction at 1 year.Greater ST down is associated with other adverse prognosticators across the broad spectrum of non-ST-elevation ACS. Although the presence of any ST down is an independent predictor of 1-year mortality, its quantitative assessment is not as important as its mere presence when studied on the background of comprehensive clinical and biomarker evaluation in a nonclinical trial-based ACS population.

There is conflicting evidence with regard to the value of electrocardiographic left ventricular hypertrophy (LVH) in myocardial infarction. Of 5,951 patients in the ASSENT-3 trial, 273 (5%) had LVH on baseline electrocardiograms and had significantly higher mortality rates at 30 days (11% vs 6%, p = 0.001) and 1 year (13% vs 8%, p = 0.007). After adjustment for differences in baseline parameters, LVH remained an independent predictor of 30-day (hazard ratio 2.3, 95% confidence interval 1.4 to 3.9) and 1-year (hazard ratio 1.8, 95% confidence interval 1.1 to 2.8) mortality rates. Thus, electrocardiographic LVH is a prognostic tool in identifying short- and long-term mortality rates in patients who have ST-elevation myocardial infarction and receive fibrinolysis.

Objective: This study was aimed to evaluate the conventional Papanicolaou (Pap) test for detection of cervical intraepithelial lesions and cancer, with histopathologic association, in a tertiary hospital of a developing country. Methods : A crosssectional hospital-based study was carried out in a total of 550 women, who underwent Pap smear examination, followed by colposcopy. Specimen adequacy and reporting was assessed according to the revised Bethesda system. 195 of these women, either Pap test positive, colposcopically positive or both, subsequently had their cervical tissue examination done with routine histopathology, as histopathology is the gold standard and Pap smear test was compared with it. Results: Among the total of 195 positive cases, histologic diagnosis of 104 (53.33%) cases were negative for cervical intraepithelial lesions or cancer, 64 (32.82%) were cervical neoplasia grade I (CIN I), 19 (9.74%) showed features of cervical intraepithelial neoplasia grade 2 and 3 (CIN II and III) and 08 (04.11%) as squamous cell carcinoma. The sensitivity and specificity of Pap test were 89.01% and 91.31%, respectively. Positive predictive value was 91.01%, while the negative predictive value was 90.56%. Conclusion: The findings of this study will be utile in supporting some useful information of Pap test, which plays a potential role in detection of cervical cancer and its precursors in a developing country like Bangladesh, where HPV-DNA test or liquid-based cytology is too expensive. DOI: http://dx.doi.org/10.11566/cmoshmcj.v12i2.31 Chatt Maa Shi Hosp Med Coll J 2013; 12(2): 1-6

Background. The aim of this study is to assess the role of multiparameter analysis of silver (Ag)-stained nucleolar organizer regions (AgNORs) technique on aspiration smears of thyroid swellings to distinguish between benign and malignant lesions.Materials and Methods. Aspiration smears from 166 cases of thyroid swellings were examined. Diagnosis was confirmed by histology in 61 cases. AgNOR staining was done on FNA smears according to silver-staining protocol proposed by the International Committee for AgNOR quantification. Multiparameter analysis of AgNORs such as mAgNOR, pAgNOR, and AgNOR size grade was done on 50–100 cells under oil immersion lens.Results. AgNOR parameter of benign and malignant thyroid lesions was compared and was found to be statistically significant. Out of 157 satisfactory AgNOR stained cases, 148 (94.3%) were benign lesions and 9 (5.7%) cases were malignant lesions. In AgNOR analysis, sensitivity was found to be 83.33%, specificity 100%, PPV 100%, NPV 98.21%, and accuracy was 98.36%.Conclusions. AgNOR analysis in the FNA smears is a simple, sensitive, and cost-effective method for differentiating benign from malignant thyroid swellings.

Aims Previous analyses suggest only modest agreement between local site and core-laboratory (core-lab) electrocardiogram (ECG) interpretation in patients with acute coronary syndromes (ACSs); however, this has not been well examined outside of clinical trial populations. Methods and results Patients ( n = 5277 from 51 hospitals; 4916 with 1 year vital status) participating in the Canadian ACS Registry who were hospitalized with an ACS and had an interpretable initial ECG were included in this study. Core-lab ECG interpretation was blinded to site interpretation and outcomes. There was moderate agreement between site and core-lab regarding the predominant ECG findings (κ = 0.49). Patients with core-lab-defined ST-elevation and cardiac marker elevation ( n = 1202) not classified as ST-elevation by the site were less likely to receive acetylsalicylic acid (ASA) (90 vs. 96%, P < 0.0001), heparin (91 vs. 95%, P = 0.04), and reperfusion therapy (14 vs. 76%, P < 0.0001) than patients for whom there was agreement that ST-elevation was present. After adjusting for other validated prognostic factors, site-unrecognized ST-elevation was independently associated with higher mortality (odds ratio = 2.21; 95% CI, 1.46–3.36; P < 0.001). Conclusions In patients with ACS, there was only moderate agreement between core-lab and site interpretation of the initial ECG. Site-unrecognized ST-elevation myocardial infarction was associated with underutilization of evidence-based therapies and increased 1-year mortality.

In the prospective, multinational Global Registry of Acute Coronary Events (GRACE), patients diagnosed with non-ST-elevation acute coronary syndromes had their admission electrocardiogram independently evaluated by a central core laboratory, and its interpretation by the core laboratory and enrolling site were compared. One in 6 of these patients had clinically important features of left-bundle branch block or ST-segment deviation diagnosed by the core laboratory that were apparently not recognized at the local sites; this subgroup of patients was less likely to undergo risk stratification and revascularization. Importantly, failure to recognize these features as confirmed by the core laboratory in routine clinical practice was independently associated with higher mortality and recurrent myocardial infarction at 6 months (adjusted odds ratio 1.41, 95% confidence interval 1.01 to 1.96, p = 0.043). In conclusion, these findings underscore an urgent need to promote more accurate interpretation of electrocardiograms in contemporary clinical practice to bridge treatment gaps and improve patient outcome.

Background: Chronic myelogenous leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL) are caused by the t(9;22)(q34;q11.2) chromosome translocation, resulting in fusion of the BCR and ABL1 genes on the Philadelphia chromosome to encode constitutively active ABL1 kinase. Despite the dramatic progress made over the past decade with tyrosine kinase inhibitors (TKIs) in the treatment of CML, allogeneic stem cell transplant is considered the only proven curative therapy. To achieve cure or benefit from treatment-free remissions with pharmacologically-based therapies, it is estimated that patients will likely need to achieve a sustained reduction in tumor burden of 4 logs (MR4) or deeper (MR4.5). Currently, only 39% and 18% of patients achieve MR4 by 24 months of treatment with single agent nilotinib or imatinib, respectively. Furthermore, for a subset of CML patients and the majority of Ph+ ALL patients, resistance develops to current TKI’s as a result of emergence of point mutations in the ATP site of the kinase domain. ABL001 is a potent, selective BCR-ABL inhibitor that maintains activity across most mutations, including T315I, with a distinct, allosteric mechanism of action which recently entered Phase I development for the treatment of patients with CML and Ph+ ALL. ABL001 was developed to be dosed in combination with nilotinib to provide greater pharmacological coverage of BCR-ABL disease and prevent the emergence of resistance. Methods: Based on X-ray crystallography, NMR and molecular modeling, ABL001 is the result of a structure-guided medicinal chemistry program targeting the myristoyl pocket of the ABL1 kinase. In vitro cell based assays were performed using the Ba/F3 isogenic cell system and a panel of over 300 cell lines. KCL-22 cells were used to develop an in vivo xenograft model to assess the efficacy of ABL001 and the PD marker, pSTAT5, was used to monitor the inhibition of BCR-ABL signaling. Results: In contrast to TKIs that bind to the ATP-site of the ABL1 kinase domain, NMR and X-Ray crystallography studies confirmed that ABL001 binds to a pocket on the BCR-ABL kinase domain that is normally occupied by the myristoylated N-terminus of ABL1. Upon fusion with BCR, this myristoylated N-terminus that serves to autoregulate ABL1 activity is lost. ABL001 functionally mimics the role of the myristoylated N-terminus by occupying its vacant binding site and restores the negative regulation of the kinase activity. Cell proliferation studies demonstrate that ABL001 selectively inhibited the growth of CML and Ph+ ALL cells with potencies ranging from 1-10nM range. In contrast, BCR-ABL-negative cell lines remained unaffected at concentrations 1000-fold higher. With resistance emerging in the clinic to current TKI’s as a result of point mutations in the ATP-site, ABL001 was tested for activity against clinically observed mutations and found to be active in the low nM range. In the KCL-22 mouse xenograft model, ABL001 displayed potent anti-tumor activity with complete tumor regression observed and a clear dose-dependent correlation with pSTAT5 inhibition. The KCL-22 xenograft model was also used to compare the dosing of ABL001 and nilotinib as single agents to dosing a combination of ABL001 and nilotinib. Single agent dosing regimens led to tumor regressions; however, despite continuous dosing, all tumors relapsed within 30-60 days with evidence of point mutations in the resistant tumors. In contrast, animals treated with the combination of ABL001 and nilotinib achieved sustained tumor regression with no evidence of disease relapse either during the 70 days of treatment or for > 150 days after treatment stopped. Conclusion: ABL001 selectively inhibited the proliferation of cells expressing the BCR-ABL fusion gene and was active against clinically important mutations that arise with current TKI therapy in CML. In an in vivo model of CML, the combination of ABL001 and nilotinib resulted in complete and sustained tumor regression with no evidence of disease relapse. These results provide proof-of-principle that simultaneous targeting of the myristoyl pocket and ATP-pocket by ABL001 and nilotinib, respectively, promotes a more sustained overall efficacy and prevents the emergence of resistance via acquisition of point mutations in the respective binding sites. ABL001 is currently being evaluated in a Phase 1 study in patients with CML and Ph+ ALL. Disclosures Wylie: Novartis Institutes for Biomedical Research, Inc: Employment. Schoepfer:Novartis Institutes for Biomedical Research: Employment. Berellini:Novartis Institutes for Biomedical Research: Employment. Cai:Novartis Institutes for Biomedical Research: Employment. Caravatti:Novartis Institutes for Biomedical Research: Employment. Cotesta:Novartis Institues for Biomedical Research: Employment. Dodd:Novartis Institutes for Biomedical Research: Employment. Donovan:Novartis Institutes for Biomedical Research: Employment. Erb:Novartis Institutes for Biomedical Research: Employment. Furet:Novartis Institutes for Biomedical Research: Employment. Gangal:Novartis Institutes for Biomedical Research: Employment. Grotzfeld:Novartis Institutes for Biomedical Research: Employment. Hassan:Novartis Institutes for Biomedical Research: Employment. Hood:Novartis Institutes for Biomedical Research: Employment. Iyer:Novartis Institutes for Biomedical Research: Employment. Jacob:Novartis Institutes for Biomedical Research: Employment. Jahnke:Novartis Institutes for Biomedical Research: Employment. Lombardo:Novartis Institutes for Biomedical Research: Employment. Loo:Novartis Institutes for Biomedical Research: Employment. Manley:Novartis Institutes for Biomedical Research: Employment. Marzinzik:Novartis Institutes for Biomedical Research: Employment. Palmer:Novartis Institutes for Biomedical Research: Employment. Pelle:Novartis Institutes for Biomedical Research: Employment. Salem:Novartis Institutes for Biomedical Research: Employment. Sharma:Novartis Institutes for Biomedical Research: Employment. Thohan:Novartis Institutes for Biomedical Research: Employment. Zhu:Novartis Institutes for Biomedical Research: Employment. Keen:Novartis Institutes for Biomedical Research: Employment. Petruzzelli:Novartis Institutes for Biomedical Research: Employment. Vanasse:Novartis: Employment, Equity Ownership. Sellers:Novartis: Employment.