THE ECOLOGY OF DISTURBANCES AND GLOBAL CHANGE IN THE MONTANE GRASSLANDS OF THE NILGIRIS, SOUTH INDIA

Biodiversity rich regions worldwide face threats from various global change agents. This research quantifies environmental influences on vegetation, and the impacts of exotic woody plant invasion and anthropogenic nitrogen (N) deposition in a global biodiversity hotspot. The study was conducted in the montane grasslands of the Nilgiris, Western Ghats, and outlines potential management options for this region. Specifically, I examined (1) the role of environmental factors in influencing native plant distribution and ecosystem properties, (2) the status and impact of exotic shrub (Scotch broom, henceforth broom) invasion, (3) the role of disturbances in the success of broom, (4) the role of fire in restoring invaded grasslands, and (5) the impacts of terrestrial N loading on the grassland ecosystem. I used experiments and surveys to assess these. Distributions of several key species were explained by a few complex environmental gradients. In invaded-grasslands, broom populations consisted mainly of intermediate size and age classes, with no clear indication of population decline. Invasion negatively impacted plant community structure and drastically changed composition, favoring shade-tolerant and weedy species. However, invasion did not greatly alter ecosystem function. Fire successfully eliminated mature broom stands, but resulted in a short-term increase in broom seedling recruitment. At the end of 18 months, the fire effects on uninvaded-grasslands were not apparent, but there was no conclusive evidence of the formerly invaded patches attaining the composition of uninvaded-grasslands following burning. N fertilization strongly influenced soil N dynamics, and shoot N concentrations, but effects on aboveground production were weak. Surprisingly, N enrichment had positive effects on diversity in the short-term. It is clear that these grasslands need immediate management intervention to forestall degradation from invasion. Fire could be used to eliminate mature broom stands and deplete persistent seedbanks, which will facilitate colonization by shade-intolerant grassland plants. Active restoration should be mindful of environmental preferences of framework species. Long-term studies of the impacts of N deposition in the context of disturbances will help determine realistic critical thresholds and utilize disturbances to buffer the potential adverse effects of increasing N loading

DNA repair in cancer: emerging targets for personalized therapy

Genomic deoxyribonucleic acid (DNA) is under constant threat from endogenous and exogenous DNA damaging agents. Mammalian cells have evolved highly conserved DNA repair machinery to process DNA damage and maintain genomic integrity. Impaired DNA repair is a major driver for carcinogenesis and could promote aggressive cancer biology. Interestingly, in established tumors, DNA repair activity is required to counteract oxidative DNA damage that is prevalent in the tumor microenvironment. Emerging clinical data provide compelling evidence that overexpression of DNA repair factors may have prognostic and predictive significance in patients. More recently, DNA repair inhibition has emerged as a promising target for anticancer therapy. Synthetic lethality exploits intergene relationships where the loss of function of either of two related genes is nonlethal, but loss of both causes cell death. Exploiting this approach by targeting DNA repair has emerged as a promising strategy for personalized cancer therapy. In the current review, we focus on recent advances with a particular focus on synthetic lethality targeting in cancer

Dilated cardiomyopathy in a child with abdominal neuroblastoma and normal serum catecholamine levels: anaesthetic management and review of literature

Neuroblastoma is the most common extracranial solid tumour of childhood. Dilated cardiomyopathy as an initial presentation of neuroblastoma is rare. We report the case of a three-year-old child with giant abdominal neuroblastoma encasing the abdominal aorta who presented with dilated cardiomyopathy in heart failure without hypertension or elevated serum catecholamine levels. The probable pathophysiological mechanism for such an occurrence and review of similar cases along with perioperative management is presented.Keywords: anaesthesia, catecholamines, child, dilated cardiomyopathy, neuroblastom

Upper GI biopsies for adenocarcinoma: how many biopsies should endoscopists take?

Aims: There is evidence that 4 or 5 gastric cancer biopsies are required for accurate HER2 interpretation. However, the number of biopsies that need to be taken to reach this number of viable cancer biopsies is without evidence. This study aimed to address this gap by assessing the number of biopsies required to get at least 4 viable biopsies containing cancerMethods and results: 105 consecutive biopsy cases of gastric and oesophageal adenocarcinoma were retrieved from file. Only definite cancer diagnoses were included; missed cancers or unproven cases were not considered. The cases were reviewed and the number of biopsies taken, and the number containing viable tumour was recorded. In total, 667 biopsies were taken of which 471 had viable tumour (70.6%) 70/105 cases (67%) had 4 viable tumour biopsies but only 47/105 (45%) had 5 viable tumour biopsies. In order to have a >90% chance of having 4 viable tumour biopsies, 7 biopsies needed to be taken, while 10 or more biopsies were required for a >90% chance of 5 viable tumour biopsies. Mathematically, using a 0.7 probability for a single biopsy, 8 biopsies would be required for a 94% chance of at least 4 viable tumour biopsies.Conclusion: In our large upper GI cancer centre, many biopsy cases do not contain sufficient material for adequate HER2 assessment. In order to meet the 4 biopsy requirement for adequate HER2 assessment in >90% of cases, at least 8 biopsies need to be taken, while 10 biopsies would be required for the 5 cancer biopsy threshold

Clinicopathological significance of ataxia-telangiectasia-mutated (ATM) kinase and ataxia telangiectasia-mutated and Rad3 related (ATR) kinase in MYC overexpressed breast cancers

Purpose: MYC transcription factor has critical roles in cell growth, proliferation, metabolism, differentiation, transformation and angiogenesis. MYC overexpression is seen in about 15% of breast cancers and linked to aggressive phenotypes. MYC overexpression also induces oxidative stress and replication stress in cells. ATM and ATR- mediated signalling is critical for MYC induced DNA damage response. Whether ATM and ATR expression influence clinical outcomes in MYC overexpressed breast cancers is unknown.Methods: We investigated ATM, ATR and MYC at the transcriptional level [Molecular Taxonomy of Breast Cancer International Consortium cohort (n=1950)] and at the protein level in the Nottingham series comprising 1650 breast tumours. We correlated ATM, ATR and MYC expression to clinicopathological features and survival outcomes.Results: In MYC over expressed tumours, high ATR or low ATM levels were associated with aggressive breast cancer features such as higher tumour grade, de-differentiation, pleomorphism, high mitotic index, high risk Nottingham Prognostic Index, triple negative and basal-like breast cancers (all adjusted p values [less than] 0.05). Tumours with low ATM or high ATR levels in conjunction with MYC overexpression also have worse overall breast cancer-specific survival (BCSS) (p value [less than] 0.05).Conclusions: We conclude that ATR/ATM directed stratification and personalisation of therapy may be feasible in MYC overexpressed breast cancer

Intrahepatic Sarcomatoid Cholangiocarcinoma

Intrahepatic sarcomatoid cholangiocarcinoma is a rare but an aggressive variant of cholangiocarcinoma with a very poor prognosis. We report the first caucasian patient who presented with a rapidly enlarging liver mass requiring hepatic resection. Detailed histopathological analyses including immunohistochemistry and electron microscopy confirmed sarcomatoid cholangiocarcinoma. The patient had early onset disease recurrence within 5 weeks of surgery. Here we demonstrate that combination chemotherapy with gemcitabine and cisplatin is a potential treatment option in patients with advanced sarcomatous cholangiocarcinoma. The patient achieved sustained partial remission with combination chemotherapy and remains alive and well more than 29 months since initial surgery

Targeting ataxia telangiectasia mutated and Rad3 related kinase (ATR) in PTEN deficient breast cancers for personalized therapy

Purpose: PTEN, a negative regulator of PI3K signaling, is involved in DNA repair. ATR is a key sensor of DNA damage and replication stress. We evaluated whether ATR signaling has clinical significance and could be targeted by synthetic lethality in PTEN deficient triple negative breast cancer (TNBC). Methods: PTEN, ATR and pCHK1Ser345 protein level was evaluated in 1650 human breast cancers. ATR blockade by VE-821 was investigated in PTEN-proficient (MDAMB-231) and PTEN-deficient (BT-549, MDA-MB-468) TNBC cell lines. Functional studies included DNA repair expression profiling, MTS cell-proliferation assay, FACS (cell cycle progression & γH2AX accumulation) and FITC-annexin V flow cytometry analysis. Results: Low nuclear PTEN was associated with higher grade, pleomorphism, dedifferentiation, higher mitotic index, larger tumour size, ER negativity, and shorter survival (p values <0.05). In tumours with low nuclear PTEN, high ATR and/or high pCHK1ser345 level was also linked to higher grade, larger tumour size and poor survival (all p values <0.05). VE-821 was selectively toxic in PTEN deficient TNBC cells and resulted in accumulation of double strand DNA breaks, cell cycle arrest, and increased apoptosis. Conclusion: ATR signalling adversely impact survival in PTEN deficient breast cancers. ATR inhibition is synthetically lethal in PTEN deficient TNBC cells