ASXL1 mutations are associated with distinct epigenomic alterations that lead to sensitivity to venetoclax and azacytidine

The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1^G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.Subject terms: Myelodysplastic syndrome, Acute myeloid leukaemia     

Magnetization transfer MR imaging in CNS tuberculosis.

BACKGROUND AND PURPOSE: CNS tuberculosis may simulate other granulomas and meningitis on MR images. The purpose of this study was to improve the characterization of lesions in CNS tuberculosis and to assess the disease load using magnetization transfer (MT) imaging. METHODS: A total of 107 tuberculomas in seven patients with or without meningitis and 15 patients with tuberculosis meningitis alone were studied. Fifteen patients with cysticercus granulomas with T2 hypointensity, five patients each with viral and pyogenic meningitis, and two patients with cryptococcal meningitis were also studied. The MT ratios were calculated from tuberculomas, cysticercus granulomas, and thickened meninges in tuberculous, viral, pyogenic, and cryptococcal meningitis and were compared within each pathologic group and with the MT ratio of different regions of normal brain parenchyma. Detectability of lesions on T1-weighted MT spin-echo (SE) images was compared with that on conventional SE and postcontrast MT-SE images. RESULTS: Thickened meninges appeared hyperintense relative to surrounding brain parenchyma in the basal and supratentorial cisterns on precontrast MT-SE images in all 18 patients with tuberculosis meningitis. These meninges were not seen or were barely visible on conventional SE images, and enhanced on postcontrast MT-SE images. The MT ratio from the thickened meninges of tuberculous meningitis was significantly lower than that from the meninges in cryptococcal and pyogenic disease and significantly higher than the meninges in viral meningoencephalitis. The MT ratio from T2 visible and invisible tuberculomas appeared to be significantly lower than that of normal white matter. The MT ratio of T2 hypointense cysticercus granuloma was significantly higher than that of T2 hypointense tuberculoma. CONCLUSION: Precontrast MT-SE imaging helps to better assess the disease load in CNS tuberculosis by improving the detectability of the lesions. With the use of MT ratios, it may be possible to differentiate tuberculosis from similar-appearing infective lesions on MR images.     

A study on anti-mannose binding lectin (anti-MBL) antibodies and serum MBL levels in Indian systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by systemic inflammation and autoantibody production. Anti-MBL autoantibodies have been studied in SLE for their possible effect on MBL levels and functional activity. This study aimed at detection of anti-MBL autoantibodies in Indian SLE patients and evaluates their relationship with related immunological parameters. Two hundred diagnosed SLE patients from Western India were included in the study where 87 patients were lupus nephritis (LN) (43.5 %) and remaining (56.5 %) were non-LN. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Anti-MBL autoantibodies to IgG and IgM isotypes, anti-C1q autoantibodies, MBL levels and circulating immune complex levels were detected by ELISA. C3, C4 and CRP levels were detected by nephelometer. Anti-MBL autoantibodies were detected in 52 % SLE patients, where 55 % had IgG-anti-MBL, 33.8 % had IgM-anti-MBL and 11.3 % had both subclasses. Low MBL levels were present in 64.4 % anti-MBL positives as compared with 61.5 % in anti-MBL negatives. Among anti-MBL positives, 74 % had anti-C1q antibodies, whereas 41.7 % of anti-MBL negatives had anti-C1q autoantibodies (p = 3.45E06). An inverse correlation was observed between serum MBL and CIC levels. A statistically significant difference was noted between anti-MBL positives and anti-MBL negative patients with hsCRP levels (p = 0.002). Occurrence of infections was higher among anti-MBL positives (65 %) as compared with anti-MBL negatives (35 %). The difference between SLEDAI scores among anti-MBL positive and negative groups was statistically insignificant. Anti-MBL autoantibodies in SLE patients can influence functional activity of MBL and have a significant role in SLE disease pathogenesis.     

Atypical metatarsal fracture in a patient on long term bisphosphonate therapy

A 24 years old female of cushing disease had undergone adrenelectomy. She was put on alendronate and steroid. After six and a half years she developed pathological fracture subtrochanteric femur. The patient was treated with proximal femoral nailing and the fracture united. 2 years later she developed pain right foot. She was diagnosed as transverse fracture of fifth metatarsal. We report this rare case of atypical metatarsal fracture in a patient on long term bisphosphonate therapy.     

An unusual case of myocardial noncompaction involving both ventricles—Case report

Noncompaction of ventricular myocardium (NCVM) is a rare congenital cardiomyopathy characterized by numerous excessively prominent trabeculations and intertrabecular recesses in the myocardium without any other cardiac structural abnormality. Transthoracic echocardiography is the imaging modality of choice for diagnosing NCVM. Although this disease commonly affects the left ventricle, the right ventricle or both ventricles can rarely be affected. We report the case of an 18‐year‐old male patient with NCVM involving both ventricles. © 2012 Wiley Periodicals, Inc. J Clin Ultrasound 41 :389–391, 2013     

Aseptic loosening of total hip replacement presenting as an anterior thigh mass

Aseptic loosening is one of the commonest complications of total hip replacement that can cause pain and instability. The chronic inflammatory response to the wear debris from the polyethylene or metal can cause osteolysis and implant failure. We report a case of aseptic loosening of the hip, presented with a swelling over the anterior thigh without any pain or instability in the joint. This mass was a foreign body granuloma formed secondary to the polyethylene wear debris due to the instability of the polyethylene in the metal shell. The patient underwent successful revision hip arthroplasty after the removal of the foreign body granuloma.     

WriteSim TCExam - An open source text simulation environment for training novice researchers in scientific writing

Background  

The ability to write clearly and effectively is of central importance to the scientific enterprise. Encouraged by the success of simulation environments in other biomedical sciences, we developed WriteSim TCExam, an open-source, Web-based, textual simulation environment for teaching effective writing techniques to novice researchers. We shortlisted and modified an existing open source application - TCExam to serve as a textual simulation environment. After testing usability internally in our team, we conducted formal field usability studies with novice researchers. These were followed by formal surveys with researchers fitting the role of administrators and users (novice researchers)     

Infanticide and reproductive restraint in a polygynous social mammal

Alpha male chacma baboons experience uncontested access to individual estrus females. Consequently, alpha male paternity certainty is high and underpins significant levels of infanticide by immigrant males that, in turn, has selected for male defense of infants. There is also, however, a high probability that alpha males will be absent during the period when their own offspring are vulnerable, suggesting selection for additional countermeasures. We use data from a long-term study to test the prediction that alpha male chacma baboons cede reproductive opportunities to subordinate males and that this leads to the presence of other fathers that can serve as a buffer against infanticidal attack. We found that subordinate males obtained significantly more conceptive opportunities than predicted by priority of access alone, and that this occurred because alpha males did not consort all receptive periods. There was no evidence that this was due to energetic constraint, large male cohorts, alpha male inexperience, or the competitive strength of queuing subordinates. The number of males who benefited from concession and the length of time that they were resident relative to those who did not benefit in this way greatly reduced the probability that infants of alpha males would face immigrant males without a surrogate father whose own offspring were vulnerable. The absence of such males was associated with observed infanticide as well as, unexpectedly, an increased likelihood of takeover when alpha males with vulnerable infants were present.