The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.

Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-4(-pyridin-2-yl)-1H-imidazole (CDDO-2P-Im or '2P-Im'), exhibits enhanced activity and improved pharmacokinetics over CDDO-Im, a previous generation SOT. However, the mechanisms leading to these properties are not defined. Here, we show the synergy of 2P-Im and the proteasome inhibitor ixazomib in human multiple myeloma (MM) cells and 2P-Im activity in a murine model of plasmacytoma. RNA sequencing and quantitative reverse transcription PCR revealed the upregulation of the unfolded protein response (UPR) in MM cells upon 2P-lm treatment, implicating the activation of the UPR as a key step in 2P-Im-induced apoptosis. Supporting this hypothesis, the deletion of genes encoding either protein kinase R-like endoplasmic reticulum kinase (PERK) or DNA damage-inducible transcript 3 protein (DDIT3; also known as CHOP) impaired the MM response to 2P-Im, as did treatment with ISRIB, integrated stress response inhibitor, which inhibits UPR signaling downstream of PERK. Finally, both drug affinity responsive target stability and thermal shift assays demonstrated direct binding of 2P-Im to endoplasmic reticulum chaperone BiP (GRP78/BiP), a stress-inducible key signaling molecule of the UPR. These data reveal GRP78/BiP as a novel target of SOTs, and specifically of 2P-Im, and suggest the potential broader utility of this class of small molecules as modulators of the UPR.

A Rare Malignant Transformation of an Ovarian Cystic Teratoma: A Case Report.

Mature cystic teratoma (MCT) is the commonest germ cell neoplasm of the ovary but malignant transformation is a rare occurrence (1-2%). Of these malignancies documented in literature the commonest are squamous cell carcinoma and adenocarcinoma. Urothelial carcinomas arising in an MCT are a rare occurrence and only 7 cases have been reported in literature. We report a case of an MCT which was complicated by the presence of urothelial carcinoma confirmed on histopathological examination.

Skull metastasis in papillary carcinoma of thyroid: A case report.

Papillary thyroid carcinoma with metastasis to the skull is extremely rare. We report a case of unsuspected papillary thyroid carcinoma with skull metastasis. A 48-year-old female patient presenting with painless, pulsatile, progressively increasing swelling in the occipitoparietal region of the scalp approached for an X-ray of the skull. Ultrasound of palpable swelling in the neck revealed a heteroechoic lesion with increased vascularity. Foci of calcification were seen involving both lobes of the thyroid. Ultrasound of scalp showed a destructive mass in the skull with increased vascularity. Biopsy of thyroid lesions revealed branching papillae having a dense fibrovascular core covered by cuboidal epithelial cells with nuclei having a clear ground glass appearance. This case illustrates how isolated extensive skull metastasis can be found in papillary carcinoma patients without causing significant morbidity. Therefore, in the clinical course of thyroid papillary carcinoma, skull metastasis should be considered, and the patients should be meticulously investigated and followed up.

Study of changes in antioxidant enzymes status in diabetic post menopausal group of women suffering from cardiovascular complications.

BACKGROUND: In type 2 diabetic patients, persistence of hyperglycemia has been reported as a cause of increased production of oxygen free radicals (FR), which leads to oxidative stress (OS) and becomes the main factor for predisposition to the cardiovascular complications in diabetes. Diabetic postmenopausal women are prone to cardiovascular disease due to reduced production of estrogen which is a potent antioxidant and prevents oxidative stress (OS) in body. The study is being aimed to find out the status of antioxidant enzymes (AOEs) and malondialdehyde (MDA) in post-menopausal diabetic women. METHODS: The study was conducted with a total of 70 cases, which included 35 Type 2 diabetic post-menopausal females (45 - 60 years) with diabetic CVD complication as the study group and 35 age matched type 2 diabetic postmenopausal females without CVD complication. RESULTS: All diabetic post menopausal females with CVD had significantly higher levels of fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), catalase (CAT), and malondialdehyde (MDA) and significantly lower levels of HDL-C, reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), and superoxide dismutase (SOD) as compared to the levels of control subjects. CONCLUSIONS: During menopause, reduced production of estrogen causes hypertriglyceridemia, hypercholesterolemia, and hyperlipoproteinemia whose oxidation causes the accumulation of FR in the cell, which precipitates OS. Also, type 2 diabetic subjects with CVD poor glycemic control and impaired AOEs result in increased oxidative injury by failure of protective mechanisms, which further leads to oxidative stress.

Wild type p53-dependent transcriptional upregulation of cathepsin L expression is mediated by C/EBPα in human glioblastoma cells.

Mutations in the tumor suppressor gene p53 are frequent in human glioblastomas. Similarly cathepsin L, a lysosomal cysteine protease, is overexpressed and secreted by most human tumors including glioblastomas. However, hitherto there is no information on whether or not the mutation(s) in the p53 gene affect(s) expression of this protease. Using human glioblastoma cell lines harboring wild type and mutant p53, we demonstrate here for the first time that only the wild type but not the mutant p53 upregulates cathepsin L expression. By transfection of promoter reporter constructs, site-directed mutagenesis and chip assays we have established that wild type p53 elevates the levels of cathepsin L in these cells. It does so directly by binding to the cathepsin L promoter and also indirectly by inducing the expression of C/EBPα, which is crucial for the transcription of this protease. In view of its role in tumorigenesis, angiogenesis and tumor cell invasion, increased expression of cathepsin L in glioblastoma cells harboring wild type p53 might confer invasive ability and growth advantage to these cells. Therefore, use of cathepsin L inhibitors could prove useful in the management of these tumors.

Outcome of sixty four cases of ethylene dibromide ingestion treated in tertiary care hospital.

BACKGROUND AND AIMS: In view of high incidence and mortality due to ethylene dibromide poisoning, a prospective study was planned to assess demographic, toxicological, clinical profile and outcome. MATERIAL AND METHODS: Prospectively collected data of sixty four patients with ethylene dibromide poisoning were reviewed. All the patients were from Gwalior and neighbouring districts. RESULTS: Majority were males in the age group 21-30 years. Out of sixty-four cases 26 patients (40.6%) survived and 38 patients (59.4%) expired. Nausea vomiting and pain abdomen were most common symptoms at presentation. Diarrhoea, drowsiness, palpitations and oliguria were other features. Pulse rate was normal (< 100) in 22 (84.6%) survived patients whereas it was > 100 in 24 (63.1%) of expired patients at the time of admission (p value = 0.0004199). Half ampoule (1.5ml.) of ethylene dibromide was sufficient as fatal dose. Mortality was 20% and 46.15% with half and one ampoule respectively. Best outcome was when the patient presented to the hospital within six hours. Death occurred anywhere between twelve hours and five days. Gastrointestinal toxicity was predominant at presentation. Nausea, vomiting and abdominal pain was present in all the patients. Nephrotoxicity 32 (50%), hepatotoxicity 28 (43.8%), cardiotoxicity 28 (43.8%), central nervous system 8 (12.5%) toxicity and hypoglycemia 24 (37.5%) were also observed. CONCLUSION: Ethylene dibromide is highly toxic. Patients who consumed half to one ampoule usually survived with supportive care provided they presented to the hospital within six hours. Pulse rate more than 100 at presentation was a poor prognostic factor. Patients with normal pulse and blood pressure at admission had better prognosis.

Tumor necrosis factor alpha (TNF-α) and estrogen hormone in osteoarthritic female patients.

Osteoarthritis of knee joints is a disease of old age in both sex. It is very common after the age of 40 years in elderly females or in postmenopausal phase of females. It is characterized by narrowing of space in joints due to inflammation. The exact mechanism of inflammation in this disease is not yet clear. Tumor necrosis factor alpha (TNF-α) may involve in onset of disease. The present study is being carried out in 130 female subject of age group 40-60 years suffering from osteoarthritis of knee joints and 50 normal healthy control female subjects. A correlation is made between TNF-α and estrogen and found significant inverse correlation (r<0.001), between TNF-α and estrogen hormone in osteoarthritic female patients as compared to normal healthy control female group.