Discovery of Imidazopyridines as Potent Inhibitors of Indoleamine 2,3-Dioxygenase 1 for Cancer Immunotherapy

Indoleamine 2,3-dioxygenase 1 (IDO1) has been identified as a target for small-molecule immunotherapy for the treatment of a variety of cancers including renal cell carcinoma and metastatic melanoma. This work focuses on the identification of IDO1 inhibitors containing replacements or isosteres for the amide found in BMS-986205, an amide-containing, IDO1-selective inhibitor currently in phase III clinical trials. Detailed subsequently are efforts to identify a structurally differentiated IDO1 inhibitor via the pursuit of a variety of heterocyclic isosteres, leading to the discovery of highly potent, imidazopyridine-containing IDO1 inhibitors.     

High fat diet containing cholesterol induce aortic aneurysm through recruitment and proliferation of circulating agranulocytes in apoE knock out mice model

We studied and compared the efficiency of induction aneurysm in apo E mice by using high fat diet and Ang II. Aneurysm induced in 6 week old male apo E −/− mice by subcutaneous release of Ang II injection for 45 days. Also, aneurysm was induced in three month old male apo E by administration of high fat diet for a period of three months. No difference in body weight in Ang II treated mice. But, increase in body weight and mean arterial blood pressure observed in high fat diet group animals. Highly significant increase in total cholesterol, TG, LDL and significant decrease in HDL level were observed in Ang II treated animals. Significant increase in total cholesterol, but no changes in TG, LDL, HDL levels were observed in high fat diet group. Higher percentage of circulating monocytes was observed in ang II treated group but more number of circulating lymphocytes were observed in high fat diet group in FACS analysis. In histopathology, intimal layer of abdominal aorta was completely replaced by chronic inflammatory cells particularly macrophages (80%) which appeared as foam cells and lymphocytes (20%) in ang II treated animals. Degradation of elastin, infiltration of lymphocytes, chondrocytes and cellular migration towards media were observed in the abdominal aorta of high fat diet group. Real time analysis and immunofluorescence assay supports over expression of Vcam 1 Icam1, MCP 1and MMP2 genes were observed in Ang II treated animals. In immunofluorescence assay, over expression of Mac 3 protein specific for macrophages was observed in abdominal aorta of ang II treated animals, but over expression of CD45.1 & 45.2 proteins specific to lymphocytes were observed in high fat diet group. Based on our observations, Ang II induced aortic aneurysm by recruiting/ proliferating circulating monocytes by up regulating Icam-1, Vcam -1 and MCP-1. Also, ang II involved in degradation of elastin in the abdominal aorta by up regulation of MMP2 to promote agranulocytes migration in the intimal layers. Epithelial cell hyperplasia with accumulation of fatty fluids (cyst) was observed in seminal vesicle and ventral prostate of high fat treated animals. Fatty degeneration, germ cell apoptosis and infiltration giant cells were observed in the testes of high fat diet group. As per available literature these observations were not reported with high fat diet treatments with apo E models. High fat diet induced aneurysm prominently in abdominal, thoracic aorta and extensive plaque formation was observed in femoral and renal arteries. Administration of high fat diet containing cholesterol induced aneurysm in apo E mice model also efficient method to rule out the pathogenesis of aortic aneurysm when compared with angiotensin.     

Adult Acute Lymphoblastic Leukemia: Results of an Aggressive Regimen in India

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.     

Endolaser around macular hole in the management of associated retinal detachment in highly myopic eyes

PURPOSE: To analyze the role of endolaser around macular hole in managing associated retinal detachment in patients with high myopia. METHODS: Review of medical records of 25 consecutive eyes of 25 patients with at least 5.00 diopters of myopia who underwent primary pars plana vitrectomy and fluid-gas exchange. In the first half of the study period, one row of contiguous argon green endolaser was routinely applied over the retinal edge of the macular hole (EL group). In the second half of the study period, endolaser was not applied around any macular hole (NEL group). Demographic information, intraoperative and postoperative complications, and final visual acuities and retinal reattachment rates were studied. RESULTS: The mean (+/-SD) refractive error was -11.8 +/- -3.5 diopters (D) for the EL group and -11.6 +/- -5.4 D for the NEL group. The mean axial length was 29.0 +/- 1.8 mm for the EL group and 28.3 +/- 1.7 mm for the NEL group. The primary anatomic success was 62.5% (10/16) and 77.8% (7/9) in the EL and NEL groups, respectively. No statistically significant difference was found in preoperative, postoperative, or change in best-corrected visual acuities between the two groups. CONCLUSION: Endolaser around the macular hole after pars plana vitrectomy and internal gas tamponade may not affect the anatomic or visual outcome in primary retinal detachment secondary to a highly myopic macular hole.     

Conjunctival rhinosporidiosis associated with scleral melting and staphyloma formation: diagnosis and management

PURPOSE: Although conjunctival rhinosporidiosis is endemic in India, associated scleral melting and staphyloma formation are quite rare. We report clinical features and management in three patients with this unusual presentation. METHODS: Retrospective review of case records of three patients with conjunctival rhinosporidiosis. RESULTS: Infection occurred in young, healthy adults and was localized to the forniceal conjunctiva in all patients. The affected conjunctiva had numerous grey-white spherules, but a polyp-like lesion was not present in any patient. Diagnosis was based on clinical features and examination of scrapings from the involved conjunctiva. Treatment was surgical, with excision of infected conjunctival tissues and staphyloma repair with homologous sclera or autogenous periosteum. Failure to recognize the conjunctival pathology in one patient resulted in recurrence of the staphyloma. CONCLUSION: Conjunctival rhinosporidiosis can be associated with scleral staphyloma in young, healthy, adults. Differentiating this entity from idiopathic scleral ectasia requires knowledge of the clinical features of conjunctival rhinosporidiosis and a high index of clinical suspicion.     

Survival of Childhood Acute Lymphoblastic Leukemia: Results of Therapy at Tata Memorial Hospital, Bombay, India

The purpose of this study was to analyze the outcome of patients who completed therapy for acute lymphoblastic leukemia (ALL) and to study the role of an aggressive induction regimen in preventing post therapy relapses. Four hundred and twenty-two patients with ALL who completed therapy during the period 1975-1991 were followed. Two hundred and sixty patients received the aggressive MCP 841 protocol and 162 patients received various other less aggressive treatment regimens. Patients were followed with periodic examination and complete blood counts. The incidence of post therapy relapse was 27% in the less aggressive protocols and 15% in the MCP 841 protocol (p = 0.001). An higher percentage of relapses was seen in males (p = 0.05) and 89% relapses occurred within two years of stopping therapy. The relapse rate after 5 years of cessation of therapy was 0.59%. In conclusion, aggressive induction therapy is the most crucial factor in predicting relapses following cessation of therapy in ALL patients. However, relapses are unlikely to occur five years post therapy.     

Postoperative endophthalmitis caused by sequestered Acinetobacter calcoaceticus

PURPOSE:To describe postoperative endophthalmitis caused by sequestered Acinetobacter calcoaceticus.METHOD:Case report. A 40-year-old woman developed recurrence of inflammation after extracapsular cataract extraction with intraocular lens (IOL) implantation. At last recurrence, the capsular bag was studded with white deposits. Intraocular lens was removed along with capsular bag during pars plana vitrectomy.RESULTS:The capsular bag, when cultured, grew A calcoaceticus. The media remained clear with no evidence of recurrence of infection over a 3-month follow-up. CONCLUSION:Postoperative endophthalmitis similar to that caused by sequestered Propionibacterium acnes can be caused by A calcoaceticus.     

Eales disease--an update

Eales disease, first described by Henry Eales in 1880, remains an enigma. The disease, observed more commonly in the Indian subcontinent than in the rest of the world, occurs in young healthy adult males, initially presenting as retinal periphlebitis and later as retinal ischemia that may lead to vascular alterations and neovascularization. Recurrent vitreous hemorrhage with or without retinal detachment is the common sequelae. In recent years, immunological, molecular biological, and biochemical studies have indicated the role of human leukocyte antigen, retinal autoimmunity, mycobacterium tuberculosis genome, and free radical mediated damage in the etiopathogenesis of this disease. However, its etiology appears to be multifactorial. The management depends on the stage of the disease and consists of medical treatment with oral corticosteroids in the active inflammatory stage and laser photocoagulation in the advanced retinal ischemia and neovascularization stages. The results of vitreoretinal surgery have been found to be satisfactory in case of vitreous hemorrhage with or without retinal detachment.     

Refractive error in children in a rural population in India

PURPOSE: To assess the prevalence of refractive error and related visual impairment in school-aged children in the rural population of the Mahabubnagar district in the southern Indian state of Andhra Pradesh. METHODS: Random selection of village-based clusters was used to identify a sample of children 7 to 15 years of age. From April 2000 through February 2001, children in the 25 selected clusters were enumerated in a door-to-door survey and examined at a rural eye center in the district. The examination included visual acuity measurements, ocular motility evaluation, retinoscopy and autorefraction under cycloplegia, and examination of the anterior segment, media, and fundus. Myopia was defined as spherical equivalent refractive error of at least -0.50 D and hyperopia as +2.00 D or more. Children with reduced vision and a sample of those with normal vision underwent independent replicate examinations for quality assurance in seven clusters. RESULTS: A total of 4414 children from 4876 households was enumerated, and 4074 (92.3%) were examined. The prevalence of uncorrected, baseline (presenting), and best corrected visual acuity of 20/40 or worse in the better eye was 2.7%, 2.6%, and 0.78%, respectively. Refractive error was the cause in 61% of eyes with vision impairment, amblyopia in 12%, other causes in 15%, and unexplained causes in the remaining 13%. A gradual shift toward less-positive values of refractive error occurred with increasing age in both boys and girls. Myopia in one or both eyes was present in 4.1% of the children. Myopia risk was associated with female gender and having a father with a higher level of schooling. Higher risk of myopia in children of older age was of borderline statistical significance (P = 0.069). Hyperopia in at least one eye was present in 0.8% of children, with no significant predictors. CONCLUSIONS: Refractive error was the main cause of visual impairment in children aged between 7 and 15 years in rural India. There was a benefit of spectacles in 70% of those who had visual acuity of 20/40 or worse in the better eye at baseline examination. Because visual impairment can have a significant impact on a child's life in terms of education and development, it is important that effective strategies be developed to eliminate this easily treated cause of visual impairment.