Search

Aim: To study the prevalence of various histomorphological spectrum of endometrium in cases of abnormal uterine bleeding (AUB). Background: Endometrium being a dynamic, hormonally sensitive and active organ undergoes structural and functional changes throughout the lifetime of females. Due to such dynamic nature of endometrium, it is prone to spectra of functional derangements. Abnormal Uterine Bleeding (AUB) and Dysfunctional Uterine Bleeding (DUB) are most commonly reported derangements in uterine function/endometrium with significant morbidity and mortality associated with them. Endometrial Biopsy is a gold standard diagnostic modality for diagnosis of AUB and DUB. Methods: A Cross-sectional study was conducted over a period of 2 years in patients from age groups 18-75 years at Tertiary care hospital in a tribal area of Northern Maharashtra. Samples collected by either endometrial biopsy or endometrial curettage, from 176 patients were studied and reviewed systematically. Results: The results of this study show most common age group of abnormal uterine bleeding was 41-50 years (perimenopausal) i.e. 61.01%. Most common histomorphological pattern observed was proliferative phase 47.72% of endometrium followed by secretory phase 9.09%. Amongst all the cases most common group of symptoms reported were menorrhagia, polymenorrhagia and abdominal pain. Disordered proliferative endometrium were reported in 10 cases i.e. 5.70%. Conclusions: Abnormal uterine bleeding (AUB) poses a significant challenge for gynecologists and pathologists. Study of histomorphological spectrum of endometrium along with further collaborative research related to cases of AUB and DUB can provide an essential data pertaining to conditions such as premalignant changes, hormonal imbalance, physiological changes, pathological lesions, etc. which can significantly guide gynecologists, clinicians and pathologists to establish a definitive diagnosis and plan an early, effective and appropriate intervention strategy accordingly. [ABSTRACT FROM AUTHOR]

Autophagy is the principal catabolic response to nutrient starvation and is necessary to clear dysfunctional or damaged organelles, but excessive autophagy can be cytotoxic or cytostatic and contributes to cell death. Depending on the abundance of enzymes involved in molecule biosynthesis, cells can be dependent on uptake of exogenous nutrients to provide these molecules. Argininosuccinate synthetase 1 (ASS1) is a key enzyme in arginine biosynthesis, and its abundance is reduced in many solid tumors, making them sensitive to external arginine depletion. We demonstrated that prolonged arginine starvation by exposure to ADI-PEG20 (pegylated arginine deiminase) induced autophagy-dependent death of ASS1-deficient breast cancer cells, because these cells are arginine auxotrophs (dependent on uptake of extracellular arginine). Indeed, these breast cancer cells died in culture when exposed to ADI-PEG20 or cultured in the absence of arginine. Arginine starvation induced mitochondrial oxidative stress, which impaired mitochondrial bioenergetics and integrity. Furthermore, arginine starvation killed breast cancer cells in vivo and in vitro only if they were autophagy-competent. Thus, a key mechanism underlying the lethality induced by prolonged arginine starvation was the cytotoxic autophagy that occurred in response to mitochondrial damage. Last, ASS1 was either low in abundance or absent in more than 60% of 149 random breast cancer biosamples, suggesting that patients with such tumors could be candidates for arginine starvation therapy.

Research was conducted to examine the hypothesis that growth hormone (GH) maintains the abundance of functional L-type Ca2+ channels in adipocyte plasma membranes. Immunoassay or dihydropyridine binding was used to measure L-type Ca2+ channels in purified plasma membranes which suggested a two- to fourfold decrease after 3 h of incubation without GH. During unfractionated adipocyte membrane preparations, no such decrease was observed. Results indicate that GH may regulate the abundance of Ca2+ channels in the adipocyte plasma membrane.

Rat adipocytes showed a two-fold increase in cytosolic free calcium (Ca2+) concentration after treatment with growth hormone due to Ca2+ influx. Ca2+ concentration also increased following membrane depolarization but influx was blocked by nimodipine, a Ca2+ channel blocker, suggesting that GH increased Ca2+ concentration by stimulating L-type Ca2+ channels. However, the effects of GH were blocked by inhibitors of protein kinase C (PKC) such as calphostin C and chelerythrine. This suggests that GH-stimulated Ca2+ influx is also dependent on PKC.

The role of growth hormones (GH) in the regulation of cytosolic free calcium (Ca2+) concentration in rat adipocytes was investigated by measuring Ca2+ concentration of untreated and GH-treated adipocytes. GH-treated fat cells showed a higher rate of Ca2+ influx than untreated cells. Ca2+ influx was blocked by nimodipine to a higher degree in GH-treated than in untreated cells. Ca2+ agonists also had a stronger effect on GH-treated cells, suggesting that growth hormones mediate Ca2+ concentration through L-type Ca2+ channels.

Abstract Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cell adhesion molecule expressed in a variety of cell types is a putative tumor suppressor gene. Alternative splicing of CEACAM1 generates 11 different splice variants, which include 1–4 ectodomains with either short or long cytoplasmic domain generated by the exclusion (CEACAM1-S) or inclusion (CEACAM1-L) of exon 7. Studies in rodents indicate that optimal ratios of CEACAM1 splice variants are required to inhibit colonic tumor cell growth. Results We show that CEACAM1 is expressed in a tissue specific manner with significant differences in the ratios of its short (CEACAM1-S) and long (CEACAM1-L) cytoplasmic domain splice variants. Importantly, we find dramatic differences between the ratios of S:L isoforms in normal breast tissues versus breast cancer specimens, suggesting that altered splicing of CEACAM1 may play an important role in tumorogenesis. Furthermore, we have identified two regulatory cis-acting elements required for the alternative splicing of CEACAM1. Replacement of these regulatory elements by human β-globin exon sequences resulted in exon 7-skipped mRNA as the predominant product. Interestingly, while insertion of exon 7 in a β-globin reporter gene resulted in its skipping, exon 7 along with the flanking intron sequences recapitulated the alternative splicing of CEACAM1. Conclusion Our results indicate that a network of regulatory elements control the alternative splicing of CEACAM1. These findings may have important implications in therapeutic modalities of CEACAM1 linked human diseases.

Reports that growth hormone regulates cytosolic free calcium in rat fat cells by maintaining l-type calcium channels. Permeability of growth hormone treated adipocytes to calcium; Effect of the blockade of calcium channels with nimodipine.

Background: Bortezomib demonstrates synergism with gemcitabine via a fixed-dose rate (FDR). The aim of this phase I trial in solid tumors was to establish the maximum tolerated dose (MTD) and safety data for this combination., Patients and Methods: Twenty-nine patients with a median age of 63 (range 36-84) years and median Karnofsky Performance Status of 90 (range 60-100) were enrolled and treated with bortezomib (1.0 or 1.3 mg/m(2)) on days 1, 4, 8 and 11 and FDR gemcitabine (750, 1,000, or 1,250 mg/m(2)) on days 1 and 8 of each 21-day cycle. Response was evaluated every two cycles., Results: Dose-limiting toxicities were grade 4 thrombocytopenia and neutropenia and grade 3 liver function test abnormalities. The MTD was bortezomib 1 mg/m2 and FDR gemcitabine 1,250 mg/m(2). The median number of cycles delivered was 3 (range 1-28). There was one partial response and six cases of stable disease. The median duration of response was 8.5 (range 3-20) months., Conclusion: FDR gemcitabine and bortezomib combination can be delivered effectively with acceptable toxicity.

The majority of eukaryotic genes undergo alternative splicing, an evolutionarily conserved phenomenon, to generate functionally diverse protein isoforms from a single transcript. The fact that defective pre-mRNA splicing can generate non-functional and often toxic proteins with catastrophic effects, accurate removal of introns and joining of exons is vital for cell homeostasis. Thus, molecular tools that could either silence a disease-causing gene or regulate its expression in trans will find many therapeutic applications. Here we present two RNA-based approaches, namely RNAi and theophylline-responsive riboswitch that can regulate gene expression by loss-of-function and modulation of splicing, respectively. These strategies are likely to continue to play an integral role in studying gene function and drug discovery.