JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors.
Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Since bromodomain (BRD) and extra terminal domain (BET) proteins are ‘readers’ of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18 and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18 and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer.
Gram-negative endocarditis due to HACEK bacteria (Haemophilus species, Actinobacillus, Cardiobacterium, Eikenella and Kingella species) and non-HACEK organisms is an infrequent occurrence but is associated with significant morbidity and mortality. Traditionally, non-HACEK Gram-negative endocarditis has been associated with injection drug use. However, emerging data from more contemporary cohorts suggest changing epidemiology and risk factors for Gram-negative endocarditis, necessitating an updated review of this subject. Moreover, optimal management, including the need for surgical intervention, and strategies for the prevention of Gram-negative endocarditis need to be revisited.
The BCR-ABL1-negative myeloproliferative neoplasms (MPN) share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhage are less well defined than those for thrombosis. Because patients with CALR mutations have higher platelet counts compared to JAK2 V617F-mutated patients, bleeding rates may be increased in this group. Our aim was to retrospectively evaluate whether acquired von Willebrand disease (AvWD), thrombocytosis, mutational status, or treatment history are associated with bleeding in a cohort of MPN patients. Using an electronic database, MPN patients seen between 2005 and 2013 were retrospectively identified using ICD-9 codes and billing records. A bleeding event was defined as one that was identified in the medical record and graded based on the Common Terminology Criteria for Adverse Event (CTCAE) version 4.0. Among 351 MPN patients, 15.6 % experienced 64 bleeding event types. There was no association of bleeding with mutational status, gender, MPN subtype, aspirin use, prior thrombosis, or platelet count at presentation. There was an association between bleeding and older age at diagnosis. aVWD was identified in six patients. In this single-center retrospective study, bleeding events were identified in 15 % of patients, and associated with older age at diagnosis. aVWD was rarely tested for in this cohort.
Among 6,565 consecutive abnormal cytogenetic reports at our institution, 3,192 (49%) constituted sole abnormalities, of which 230 (7%) involved chromosome 7: monosomy 7 (n = 98), 7q‐ (n = 51), der(1;7)(q10;p10) (n = 44), balanced translocations (n = 15), ring 7 (n = 13), and 7p‐ (n = 9). The most frequent histopathologic correlates were myelodysplastic syndromes (MDS; 28%), acute myeloid leukemia (AML; 17%), secondary or therapy‐related MDS/AML (13%), primary myelofibrosis (PMF; 7%), and chronic myelomonocytic leukemia (6%). Monosomy 7 was the most frequent in each one of these disease categories except PMF where 7q‐ was more frequent. In primary MDS, patients with der(1;7)(q10;p10) (n = 13), compared to those with monosomy 7 (n = 30) or 7q‐ (n = 15), were less likely (P = 0.04) to display excess blasts or multilineage dysplasia but overall and leukemia‐free survival adjusted for these variables revealed no significant difference between the three groups (P = 0.57 and 0.81, respectively). The current study does not prognostically distinguish monosomy 7 from 7q‐ or der(1;7), in MDS. Am. J. Hematol. 87:684–686, 2012. © 2012 Wiley Periodicals, Inc.
Background Urinary tract infections (UTIs) are the common cause of bacterial infection. Recently UTI become more complicated and difficult to treat because of appearance of pathogen with increasing resistance to antimicrobial agents. Objective To determine the etiology of the urinary tract infections and their susceptibility to antimicrobial agents. Methods This study was carried out in Kathmandu Medical College, at department of microbiology. Total 3,460 urine samples were tested microbiologically by standard procedure. Antibiotic susceptibility test was performed for all the isolates by Kirby Bauer disc diffusion method and result was interpreted according to National Committee for Clinical Laboratory Standards (NCCLS) guide line. Results Out of 3,460 urine samples 680 (19.7%) showed the significant bacteriuria. The most common pathogens isolated were Escherichia coli 75.7% followed by Klebsiella pneumoniae 10.7%, Acinetobacter spp 5.5%, Proteus spp 3.5% and Pseudomonas aeruginosa 1.2%. Most susceptible antibiotic was Amikacin, Ceftriaxone and Ciprofloxacin for most of the isolates. E. coli which was the main isolate was found to be most susceptible to Amikacin 96.1%, Nitrofurantoin 91.3% and Gentamicin 77.7% followed by Ceftriaxone 65.8% and Ciprofloxacin 64.1%. ConclusionRegular surveillance of the resistance rate among uro-pathogens is needed to ensure the appropriate therapy of UTI.DOI: http://dx.doi.org/10.3126/kumj.v9i4.6348 Kathmandu Univ Med J 2011;9(4):295-7
Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced fibro-inflammatory stromal reaction that contributes to tumor progression. A critical step in invasion and metastasis is the epithelial to mesenchymal transition (EMT), which can be regulated by the Snail family of transcription factors. Overexpression of Snail (Snai1) and mutant KrasG12D in the pancreas of transgenic mice, using an elastase (EL) promoter, resulted in fibrosis. To identify how Snail modulates inflammation in the pancreas, we examined the effect of expressing Snail in ELKrasG12D mice (KrasG12D/Snail) on mast cell infiltration, which has been linked to PDAC progression. Using this animal model system, it was demonstrated that there are increased numbers of mast cells in the pancreas of KrasG12D/Snail mice compared to control KrasG12D mice. In addition, it was revealed that human primary PDAC tumors with increased Snail expression are associated with increased mast cell infiltration and that Snail expression in these clinical specimens positively correlated with the expression of stem cell factor (SCF/KITLG), a cytokine known to regulate mast cell migration. Concomitantly, SCF levels are increased in the KrasG12D/Snail mice compared to control mice. Moreover, overexpression of Snail in PDAC cells increased SCF levels and that the media conditioned by Snail-expressing PDAC cells promoted mast cell migration. Finally, inhibition of SCF using a neutralizing antibody significantly attenuated Snail-induced migration of mast cells. Implications Together, these results elucidate how the EMT regulator Snail contributes to inflammation associated with PDAC tumors.
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