Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain

<p>Abstract</p> <p>Background</p> <p>The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer and development, at present not much is known about the functional domains of BMI1 oncoprotein. In the present study, we carried out a deletion analysis of BMI1 to identify its negative regulatory domain.</p> <p>Results</p> <p>We report that deletion of the C-terminal domain of BMI1, which is rich in proline-serine (PS) residues and previously described as PEST-like domain, increased the stability of BMI1, and promoted its pro-oncogenic activities in human mammary epithelial cells (HMECs). Specifically, overexpression of a PS region deleted mutant of BMI1 increased proliferation of HMECs and promoted an epithelial-mesenchymal transition (EMT) phenotype in the HMECs. Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts.</p> <p>Conclusions</p> <p>In summary, our data suggest that the PS domain of BMI1 is involved in its stability and that it negatively regulates function of BMI1 oncoprotein. Our results also suggest that the PS domain of BMI1 could be targeted for the treatment of proliferative disorders such as cancer and aging.</p

Habitat use pattern and conservation status of smooth–coated otters Lutrogale perspicillata in the Upper Ganges Basin, India

Modelo de uso del hábitat y estado de conservación de las nutrias lisas Lutrogale perspicillata en la zona alta de la cuenca del Ganges, India Las nutrias lisas habitan en varios sistemas fluviales importantes del Asia meridional y sus necesidades medioambientales las vinculan con problemas de seguridad alimentaria e hídrica, debido a la elevada densidad de humanos. La falta de datos de referencia sobre su distribución y ecología es otra limitación notable que la especie está afrontando en la India. El presente estudio se vio impulsado por el rápido descenso de la población de nutrias en el país y se centra en estimar el estado de conservación, el modelo de uso del hábitat y las amenazas asociadas en la zona alta de la cuenca del río Ganges (Asia septentrional). Nuestros resultados contribuyen a comprender mejor las complejas interacciones ecológicas y a elaborar medidas de conservación eficaces. Junto con las preferencias de hábitat, en el estudio también se informa sobre nuevas ubicaciones en la distribución de la especie. Asimismo se ponen de relieve las deficiencias existentes en la conservación de la especie y se sugieren las zonas cuya ordenación debería ser prioritaria.Smooth–coated otters inhabit several major river systems in southern Asia, and their environmental requirements link them to food and water security issues as the region is so densely populated by humans. The lack of baseline data on their distribution and ecology is another major constraint that the species is facing in India. The present study was stimulated by the rapid decline in the otter’s population in the country and focuses on estimating the conservation status, habitat use pattern, and associated threats in the upper Ganges River Basin (N India). Our findings contribute towards a better understanding of the complex ecological interactions and the design of effective conservation measures. Coupled with the habitat preferences, the study also provides new locations in the species distribution. This paper highlights the gap areas in the conservation of the species and suggests areas that should be prioritized for management.Modelo de uso del hábitat y estado de conservación de las nutrias lisas Lutrogale perspicillata en la zona alta de la cuenca del Ganges, India Las nutrias lisas habitan en varios sistemas fluviales importantes del Asia meridional y sus necesidades medioambientales las vinculan con problemas de seguridad alimentaria e hídrica, debido a la elevada densidad de humanos. La falta de datos de referencia sobre su distribución y ecología es otra limitación notable que la especie está afrontando en la India. El presente estudio se vio impulsado por el rápido descenso de la población de nutrias en el país y se centra en estimar el estado de conservación, el modelo de uso del hábitat y las amenazas asociadas en la zona alta de la cuenca del río Ganges (Asia septentrional). Nuestros resultados contribuyen a comprender mejor las complejas interacciones ecológicas y a elaborar medidas de conservación eficaces. Junto con las preferencias de hábitat, en el estudio también se informa sobre nuevas ubicaciones en la distribución de la especie. Asimismo se ponen de relieve las deficiencias existentes en la conservación de la especie y se sugieren las zonas cuya ordenación debería ser prioritaria

Wavelet analysis of the seismograms for tsunami warning

The complexity in the tsunami phenomenon makes the available warning systems not much effective in the practical situations. The problem arises due to the time lapsed in the data transfer, processing and modeling. The modeling and simulation needs the input fault geometry and mechanism of the earthquake. The estimation of these parameters and other aprior information increases the utilized time for making any warning. Here, the wavelet analysis is used to identify the tsunamigenesis of an earthquake. The frequency content of the seismogram in time scale domain is examined using wavelet transform. The energy content in high frequencies is calculated and gives a threshold for tsunami warnings. Only first few minutes of the seismograms of the earthquake events are used for quick estimation. The results for the earthquake events of Andaman Sumatra region and other historic events are promising

Sectorwise assessment of glacial lake outburst flood danger in the Indian Himalayan region

Climate change and associated glacier recession have led to the formation of new glacial lakes and the expansion of existing ones across the Himalayas. Many pose a potential glacial lake outburst flood (GLOF) threat to downstream communities and infrastructure. In this paper, 4418 glacial lakes in the Indian Himalayan Region and 636 transboundary lakes are analyzed. We consider hazard, exposure, and integrated danger levels using robust geographic information system-based automated approaches. The hazard level of lakes was estimated based on the potential for avalanches to strike the lake, size of the lake and its upstream watershed, and distal slope of its dam. Exposure levels were calculated by intersecting cropland, roads, hydropower projects, and the human population with potential GLOF trajectories. Then, GLOF danger was determined as a function of hazard and exposure. The study demonstrates that Jammu and Kashmir (JK) is potentially the most threatened region in terms of total number of very high and high danger lakes (n = 556), followed by Arunachal Pradesh (AP) (n = 388) and Sikkim (SK) (n = 219). Sectorwise, JK faces the greatest GLOF threat to roads and population, whereas the threat to cropland and hydropower is greatest in AP and SK, respectively. Transboundary lakes primarily threaten AP and, to a lesser extent, Himachal Pradesh (HP). For Uttarakhand (UK), the impacts of potential future glacial lakes, expected to form during rapid ongoing glacier recession because of climate change, are explored. Finally, a comparison of current results with previous studies suggests that 13 lakes in SK, 5 in HP, 4 in JK, 2 in UK, and 1 in AP are of highest priority for local investigation and potential risk reduction measures. Current results are of vital importance to policymakers, disaster management authorities, and the scientific community

Cloudbursts in Indian Himalayas: a review

Cloudbursts in and around the southern rim of the Indian Himalayas are elusive in terms of their position and time of occurrences. Most of the reported cloudbursts are in the interior of the Himalayas and hence their observation itself is limited. Most of these events are reported once their affect in terms of loss to life and property is experienced in the downstream habitats. In addition, they are mostly associated with flash floods as an impact of the torrential precipitation. The principal understanding of the cloudburst is associated with sudden heavy deluge of precipitation in very less time interval over a very small area. Except this understanding and India Meteorology Department (IMD) definition of > 100 mm/h precipitation over a geographical region of approximately 20–30 km2, nothing much else is known about these events. There are a very few studies carried out on understanding of these events. Present paper synthesizes the available information and research on cloudburst events and tries to define it based on associated dynamics, thermodynamics and physical processes leading to a cloudburst event. Thus in the present work, characterizations and impacts of cloudburst leading from precipitation to dynamical to thermodynamical to large scale forcings to orographical forcings to followed geomorphology to impacts are intertwined to present comprehensive portray of it. Most of the cloudburst events are seen occurring in the elevation range of 1000 m to 2500 m within the valley folds of the southern rim of the Indian Himalayas. Apart from some of the large scale flow shown by few of the studies, it is found that cloudburst events are convectively triggered followed by orographically locked systems. These intertwined mechanisms lead cloudburst events to form. Amiss of any one of these mechanisms will not lead the cloudburst mechanism to form. These interactions in the present paper established the vagaries associated with the cloudburst events

Disturbance of oxidant/antioxidant balance, acute phase response and high mobility group box–1 protein in acute undifferentiated diarrhea in crossbred piglets

The objective of the present study was to investigate the status of high mobility group box–1 (HMGB1) protein, oxidative stress and acute phase proteins in natural cases of acute undifferentiated diarrhoea in piglets aged 1–15 days old. The study was conducted on 30 crossbred (Landrace × indigenous) piglets; fifteen suffering from acute enteritis (group 1) and fifteen healthy piglets as control (group 2). The diarrhoea was diagnosed on the basis of clinical symptoms. From the results of the study, it is concluded that HMGB1 protein, markers of oxidative stress and acute phase proteins might play important roles in the pathophysiology of piglet diarrhoea and that these may be targets for supportive therapy

Expression of BMI-1 and Mel-18 in breast tissue - a diagnostic marker in patients with breast cancer

<p>Abstract</p> <p>Background</p> <p>Polycomb Group (PcG) proteins are epigenetic silencers involved in maintaining cellular identity, and their deregulation can result in cancer. Expression of Mel-18 and Bmi-1 has been studied in tumor tissue, but not in adjacent non-cancerous breast epithelium. Our study compares the expression of the two genes in normal breast epithelium of cancer patients and relates it to the level of expression in the corresponding tumors as well as in breast epithelium of healthy women.</p> <p>Methods</p> <p>A total of 79 tumors, of which 71 malignant tumors of the breast, 6 fibroadenomas, and 2 DCIS were studied and compared to the reduction mammoplastic specimens of 11 healthy women. In addition there was available adjacent cancer free tissue for 23 of the malignant tumors. The tissue samples were stored in RNAlater, RNA was isolated to create expression microarray profile. These two genes were then studied more closely first on mRNA transcription level by microarrays (Agilent 44 K) and quantitative RT-PCR (TaqMan) and then on protein expression level using immunohistochemistry.</p> <p>Results</p> <p>Bmi-1 mRNA is significantly up-regulated in adjacent normal breast tissue in breast cancer patients compared to normal breast tissue from noncancerous patients. Conversely, mRNA transcription level of Mel-18 is lower in normal breast from patients operated for breast cancer compared to breast tissue from mammoplasty. When protein expression of these two genes was evaluated, we observed that most of the epithelial cells were positive for Bmi-1 in both groups of tissue samples, although the expression intensity was stronger in normal tissue from cancer patients compared to mammoplasty tissue samples. Protein expression of Mel-18 showed inversely stronger intensity in tissue samples from mammoplasty compared to normal breast tissue from patients operated for breast cancer.</p> <p>Conclusion</p> <p>Bmi-1 mRNA level is consistently increased and Mel-18 mRNA level is consistently decreased in adjacent normal breast tissue of cancer patients as compared to normal breast tissue in women having had reduction mammoplasties. Bmi-1/Mel-18 ratio can be potentially used as a tool for stratifying women at risk of developing malignancy.</p

Cellular changes in boric acid-treated DU-145 prostate cancer cells

Epidemiological, animal, and cell culture studies have identified boron as a chemopreventative agent in prostate cancer. The present objective was to identify boron-induced changes in the DU-145 human prostate cancer cell line. We show that prolonged exposure to pharmacologically-relevant levels of boric acid, the naturally occurring form of boron circulating in human plasma, induces the following morphological changes in cells: increases in granularity and intracellular vesicle content, enhanced cell spreading and decreased cell volume. Documented increases in β-galactosidase activity suggest that boric acid induces conversion to a senescent-like cellular phenotype. Boric acid also causes a dose-dependent reduction in cyclins A–E, as well as MAPK proteins, suggesting their contribution to proliferative inhibition. Furthermore, treated cells display reduced adhesion, migration and invasion potential, along with F-actin changes indicative of reduced metastatic potential. Finally, the observation of media acidosis in treated cells correlated with an accumulation of lysosome-associated membrane protein type 2 (LAMP-2)-negative acidic compartments. The challenge of future studies will be to identify the underlying mechanism responsible for the observed cellular responses to this natural blood constituent

Dehydroepiandrosterone inhibits the progression phase of mammary carcinogenesis by inducing cellular senescence via a p16-dependent but p53-independent mechanism

INTRODUCTION: Dehydroepiandrosterone (DHEA), an adrenal 17-ketosteroid, is a precursor of testosterone and 17β-estradiol. Studies have shown that DHEA inhibits carcinogenesis in mammary gland and prostate as well as other organs, a process that is not hormone dependent. Little is known about the molecular mechanisms of DHEA-mediated inhibition of the neoplastic process. Here we examine whether DHEA and its analog DHEA 8354 can suppress the progression of hyperplastic and premalignant (carcinoma in situ) lesions in mammary gland toward malignant tumors and the cellular mechanisms involved. METHODS: Rats were treated with N-nitroso-N-methylurea and allowed to develop mammary hyperplastic and premalignant lesions with a maximum frequency 6 weeks after carcinogen administration. The animals were then given DHEA or DHEA 8354 in the diet at 125 or 1,000 mg/kg diet for 6 weeks. The effect of these agents on induction of apoptosis, senescence, cell proliferation, tumor burden and various effectors of cellular signaling were determined. RESULTS: Both agents induced a dose-dependent decrease in tumor multiplicity and in tumor burden. In addition they induced a senescent phenotype in tumor cells, inhibited cell proliferation and increased the number of apoptotic cells. The DHEA-induced cellular effects were associated with increased expression of p16 and p21, but not p53 expression, implicating a p53-independent mechanism in their action. CONCLUSION: We provide evidence that DHEA and DHEA 8354 can suppress mammary carcinogenesis by altering various cellular functions, inducing cellular senescence, in tumor cells with the potential involvement of p16 and p21 in mediating these effects

Mammary epithelial cell transformation: insights from cell culture and mouse models

Normal human mammary epithelial cells (HMECs) have a finite life span and do not undergo spontaneous immortalization in culture. Critical to oncogenic transformation is the ability of cells to overcome the senescence checkpoints that define their replicative life span and to multiply indefinitely – a phenomenon referred to as immortalization. HMECs can be immortalized by exposing them to chemicals or radiation, or by causing them to overexpress certain cellular genes or viral oncogenes. However, the most efficient and reproducible model of HMEC immortalization remains expression of high-risk human papillomavirus (HPV) oncogenes E6 and E7. Cell culture models have defined the role of tumor suppressor proteins (pRb and p53), inhibitors of cyclin-dependent kinases (p16(INK4a), p21, p27 and p57), p14(ARF), telomerase, and small G proteins Rap, Rho and Ras in immortalization and transformation of HMECs. These cell culture models have also provided evidence that multiple epithelial cell subtypes with distinct patterns of susceptibility to oncogenesis exist in the normal mammary tissue. Coupled with information from distinct molecular portraits of primary breast cancers, these findings suggest that various subtypes of mammary cells may be precursors of different subtypes of breast cancers. Full oncogenic transformation of HMECs in culture requires the expression of multiple gene products, such as SV40 large T and small t, hTERT (catalytic subunit of human telomerase), Raf, phosphatidylinositol 3-kinase, and Ral-GEFs (Ral guanine nucleotide exchange factors). However, when implanted into nude mice these transformed cells typically produce poorly differentiated carcinomas and not adenocarcinomas. On the other hand, transgenic mouse models using ErbB2/neu, Ras, Myc, SV40 T or polyomavirus T develop adenocarcinomas, raising the possibility that the parental normal cell subtype may determine the pathological type of breast tumors. Availability of three-dimensional and mammosphere models has led to the identification of putative stem cells, but more studies are needed to define their biologic role and potential as precursor cells for distinct breast cancers. The combined use of transformation strategies in cell culture and mouse models together with molecular definition of human breast cancer subtypes should help to elucidate the nature of breast cancer diversity and to develop individualized therapies