Targeting the Ubiquitin System in Glioblastoma

Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered “undruggable” ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma

HLA-DR2 subtypes & immune responses in pulmonary tuberculosis

Background & objectives: HLA-DR2 has been shown to be associated with the susceptibility to pulmonary tuberculosis and altered antibody and lymphocyte response in pulmonary tuberculosis. In the present study, the influence of DR2 subtypes on antibody titre and lymphocyte response ,to Mycobacterium tuberculosis culture filtrate antigens (10 μg/ml) was studied in 22 patients with active pulmonary TB (ATB), 50 inactive (cured) TB (ITB) patients and 36 healthy control subjects. Methods. HLA-DR2 gene was amplified by polymerase chain reaction (PCR) and dot-blotted. Genotyping of DRBl*1501, *1502, *1503, *1601 and *1602 was carried out using sequence specific oligonucleotide probes (SSOPs) and detected by chemiluminescence method. Antibody titre as well as lymphocyte response to M.tuberculosis antigens were measured by enzyme linked immunosorbent assay (ELISA) and lymphocyte transformation test (LTT) respectively. Results: The allele frequency of DRB1*15Ol was significantly increased in pulmonary tuberculosis patients as compared to controls (P<0.05). No marked difference in the antibody titre and lymphocyte response to M. tuberculosis antigens was observed between the DRBl *1501, *1502 and *1503 positive or negative controls, ATB and ITB patients. DRBl *1501 and *1502 positive as well as negative ATB patients showed a higher antibody titre as compared to controls and ITB patients. ITB patients with *1502 showed a higher lymphocyte response as compared to *1502 positive controls (P<0.001) and ATB patients (P<0.05). Similarly, an increased lymphocyte response was observed in *1501, and *I503 negative ITB patients compared to *1501 and *1503 negative controls and ATB patients. Interpretation & conclusion: The present study revealed that DRBl *1501 may be associated either alone or with other DR2 alleles, with the susceptibility to pulmonary tuberculosis. None of the DR2 alleles influenced the antibody and lymphocyte response to M tuberculosis culture filtrate antigens. This suggested that HLA-DR2 gene/gene products as a whole may influence the immune response in pulmonary tuberculosis

Vitamin D receptor and interleukin-1 receptor antagonist gene polymorphism in spinal tuberculosis

Our earlier studies revealed that both MHC (Major Histocomptibility Complex) and non-MHC genes are associated with the susceptibility to pulmonary tuberculosis (TB). To find out whether non-MHC genes such as vitamin D receptor (VDR) and interleukin-1 receptor antagonist (IL-1RA) genes are associated with the susceptibility to spinal TB (extrapulmonary form of TB), the present study was carried out in spinal TB patients (n=66) and spouses of TB patients (spinal-TB and pulmonary-TB) ( n = 80) (family contacts). A trend towards an increased per cent genotype frequency of IL-1RA genotype variant 22 (12.1%) was seen in spinal TB patients when compared to the controls (3.8%) (spouses of the patients) (P=0.057; odds ratio 3.5). No difference was observed in the frequency of VDR genotypes between the overall spinal TB patients and the family contacts. However, the VDR mutant genotype tt was seen at a higher frequency in female patients with TB spine (TBS) (12.8%) than female contacts (4.2%) ( P >0.05 not significant; odds ratio 3.5). Among the contacts, a significantly increased frequency of wild type genotype TT (wild homozygotes) was seen in female contacts (55.1%) than male contacts (16.1%) (P =0.0012). Similarly a significant decrease in tt genotype was seen in female contacts (4.1%) than male contacts (25.8%) (P=0.012). The present study suggests that IL-1RA genotype 22 may be associated with the susceptibility to spinal TB. Moreover, vitamin D receptor tt genotype may be associated with the susceptibility to spinal TB in female patients. The study reveals that multicandidate genes may be associated with the susceptibility to spinal TB

Influence of non-MHC genes on lymphocyte response to Mycobacterium tuberculosis antigens and tuberculin status in Pulmonary tuberculosis

Background & objectives : Major histocompatibility complex (MHC) genes are known to influence the immune functions. In the present study, the influence of non-MHC genes such as mannose binding protein (MBP), vitamin D receptor (VDR) and interleukin-1 receptor antagonist (IL-IRA) gene polymorphisms on lymphocyte response to Mycobacterium tuberculosis culture filtrate antigen (10 μg/ml) was studied in 44 patients with active pulmonary TB and the family contacts (35) and in 32 normal healthy subjects. The influence of these gene polymorphisms on tuberculin (1TU of PPD of M. tuberculosis) reactivity status in 146 pulmonary TB patients was also studied. Methods : The MBP and VDR genes were amplified using polymerase chain reaction (PCR) and genotyping was carried out using sequence specific oligonucleotide probes by dot blot and IL-1RA by agarose gel electrophoresis. Results : A significantly decreased lymphocyte response to M. tuberculosis antigen was seen in pulmonary TB patients positive for functional mutant homozygotes of MBP (00) compared to heterozygote carriers (AO; P<0.02) and wild homozygotes (AA; P<0.01). The variant mutant genotype (tt) of VDR gene was associated with an increased lymphocyte response in control subjects compared to active TB patients with tt genotype (P<0.05). Heterozygote carriers of MBP (AO) were associated with a significantly (P<0.001) decreased tuberculin reactivity compared to wild homozygotes (AA). The VDR genotype Tt (heterozygote carrier) was associated with an increased tuberculin reactivity in female TB patients as compared to male patients (P<0.001). Interpretation & conclusions : The present study suggested that MBP and VDR genes influence the cell mediated immune response in pulmonary TB patients. Non-MHC genes along with HLA-Class II genes/gene products may be playing an immunoregulatory role in the mechanism of susceptibility/resistance to tuberculosis

Effect of Organic Nutrition Practices on Papaya (cv. Surya) Fruit Yield, Quality and Soil Health

A field experiment was conducted during 2005-07 at Indian Institute of Horticultural Research, Bangalore, on papaya cv. Surya with six organic treatments along with recommended dose of fertilizers and no manure/fertilizer application. Results indicated that crop growth and fruit yield were higher in inorganic fertilizer treatment (55 t ha1) compared to organic treatments (26.9 to 38 t ha-1). There was no significant variation in average fruit weight and TSS, but shelf life of the fruit was significantly higher in organic treatments (6.2 to 7.9 days) as compared to inorganic fertilizer treatment (5.1days). Among the treatments, application of 7 kg urban compost plant-1 or 10 kg FYM plant-1 was found to be ideal for improving soil health in terms of microbial population, and biochemical reaction compared to other treatments

Clinical profile and management of outpatients with non-ischemic and non-hypertensive systolic heart failure: Analysis of the Polish DATA-HELP registry

Background: Although coronary artery disease and arterial hypertension are the most common etiologies underlying heart failure (HF), there are still many patients present with non-ischemic and non-hypertensive HF whose management remains very challenging. In this research study the clinical profile and applied treatment of patients with HF without coronary artery disease or hypertension versus patients with known etiology of HF (ischemic/hypertensive) were compared. Methods: Clinical data about 5563 patients with stable systolic HF were obtained from prospective multicenter DATA-HELP registry performed between October and December 2009 in ambulatory clinics in Poland, in which 500 cardiologists and 290 general practitioners participated. Results: Heart failure of non-ischemic and non-hypertensive etiology which affected 10% of all patients and was particularly frequent in younger patients, both in women: &lt; 50 years old 42%; 50–65 years old 12%; &gt; 65 years old 7%; and men: &lt; 50 years old 47%; 50–65 years old 10%; &gt; 65 years old 5%; p &lt; 0.0001. Patients with non-ischemic and non-hypertensive HF were characterized by younger age, fewer co-morbidities, shorter duration of HF and, surprisingly, more advanced HF. Patients in this group were less likely to have received life-prolonging treatment in HF recommended by European Society of Cardiology (ESC) and more often required symptomatic management. Similarly, they were more likely to have implanted CRT-D and ICD. Conclusions: Heart failure of non-ischemic and non-hypertensive origin affects particularly young patients. These patients, despite suffering from more advanced HF are not optimally managed according to ESC guidelines

Fully Enclosed Microfluidic Paper-Based Analytical Devices

This article introduces fully enclosed microfluidic paper-based analytical devices (microPADs) fabricated by printing toner on the top and bottom of the devices using a laser printer. Enclosing paper-based microfluidic channels protects the channels from contamination, contains and protects reagents stored on the device, contains fluids within the channels so that microPADs can be handled and operated more easily, and reduces evaporation of solutions from the channels. These benefits extend the capabilities of microPADs for applications as low-cost point-of-care diagnostic devices

Correction to Fully Enclosed Microfluidic Paper-Based Analytical Devices

There is an error in the units of the concentrations of potassium iodide and trehalose described in the experimental details on page 1581. The correct concentrations are 0.6 M potassium iodide and 0.3 M trehalose

Yield attributes and yield in somaclones of ginger (Zingiber officinale Rosc.)

Twenty five somaclones derived from two induced polyploids (Z-0-78 and Z-0-86) and diploid cultivar ‘Himachal Pradesh’ were field evaluated and subjected to yield and yield attribute analyses. Somaclones were highly variable in the yield and yield attributes. Extent of variation was more in somaclones when compared to check varieties (Karthika and IISR-Varada) rather than parent cultivars (Z-0-78, Z-0-86 and HP). Somaclones derived from Z-0-86 recorded superiority in rhizome characters over those derived from ‘Himachal Pradesh’ and Z-0-78. About 92% of somaclones showed higher yield over parent cultivars while 84% of somaclones showed higher rhizome yield over check varieties. Somaclones derived from Z-0-86 alone recorded higher driage and dry yield. &nbsp

HLA-DR phenotypes and lymphocyte response to M. tuberculosis antigens and in cured spinal tuberculosis patients and their contacts

Background: Our earlier studies on Human Leucocyte Antigens (HLA) in pulmonary tuberculosis patients revealed the association of HLA-DR2 antigen with susceptibility to pulmonary TB and DR2 antigen has been shown to influence the immunity to tuberculosis. Objectives: The present study was carried out to find out whether HLA-DR antigens are associated with susceptibility to spinal tuberculosis. Moreover, the role of HLA-DR antigens on lymphoproliferative response to Mycobacterium tuberculosis culture filtrate antigens was studied using Lymphocyte Transformation Test (LTT). Material and Methods: HLA-DR genotyping and lymphoproliferative response was carried out in 63 cured spinal TB patients and 63 control subjects (spouses of pulmonary and spinal TB patients). Results: A trend towards an increased frequency of HLA-DR9 antigen was observed in spinal TB patients compared to controls. A significantly decreased lymphocyte response to M. tuberculosis antigens was observed in HLA-DR9 antigen positive control subjects compared to HLA- DR9 antigen negative subjects (P=0.0009) whereas increased response was observed with DR9 positive cured spinal TB patients compared to HLA-DR9 antigen negative patients. Further, HLADR3 antigen positive patients showed a decreased lymphocyte response compared to HLA-DR3 antigen negative patients (P<0.05). Conclusion: The study suggests that HLA-DR9 antigen either alone or in combination with other HLA antigen as lhplotype and non-HLA genes may be associated with susceptibility to spinal TB and play a regulatory role on the immune response to M. tuberculosis in spinal tuberculosis patients