Radiotherapy of intrathoracic and chest wall tumors may lead to exposure of the heart to ionizing radiation, resulting in radiation-induced heart diseases (RIHD). The main manifestations of RIHD become apparent many years after treatment and include cardiomyopathy and accelerated atherosclerosis. This study examines the role of the kallikrein-kinin system (KKS) in RIHD by investigating the cardiac radiation response in a kininogen-deficient Brown Norway Katholiek (BN/Ka) rat model. BN/Ka rats and wild-type Brown Norway (BN) rats were exposed to local heart irradiation with a single dose of 18 Gy or 24 Gy and were observed for 3-6 months. Examinations included in vivo and ex vivo cardiac function, histopathology, gene and protein expression measurements, and mitochondrial swelling assays. Upon local heart irradiation, changes in in vivo cardiac function were significantly less in BN/Ka rats. For instance, a single dose of 24 Gy caused a 35% increase in fractional shortening in BN rats compared to a 16% increase in BN/Ka rats. BN rats, but not BN/Ka rats, showed a 56% reduction in cardiac numbers of CD2-positive cells, and a 57% increase in CD68-positive cells, together with a 52% increase in phosphorylation of Erk1/2. Local heart irradiation had similar effects on histopathology, mitochondrial changes, and left ventricular mRNA levels of NADPH oxidases in the two genotypes. These results suggest that the KKS plays a role in the effects of radiation on cardiac function and recruitment of inflammatory cells. The KKS may have these effects at least in part by altering Erk1/2 signaling.
Radiation-induced heart disease; Kallikrein-kinin system; Bradykinin
Synovial sarcoma is a deadly malignancy with limited sensitivity to traditional cytotoxic chemotherapy. SS18-SSX fusion oncogene expression characterizes human synovial sarcomas and drives oncogenesis in a mouse model. Elevated expression of BCL2 is considered a consistent feature of the synovial sarcoma expression profile. Our objective was to evaluate the expression of apoptotic pathway members in synovial sarcomas and interrogate the impact of modulating SS18-SSX expression on this pathway. We show in human and murine synovial sarcoma cells that SS18-SSX increases BCL2 expression, but represses other anti-apoptotic genes, including MCL1 and BCL2A1. This repression is achieved by directly suppressing expression via binding through ATF2 to the cyclic AMP response element in the promoters of these genes and recruiting TLE1/Groucho. The suppression of these two anti-apoptotic pathways silences the typical routes by which other tumors evade BH3-domain peptidomimetic pharmacotherapy. We show that mouse and human synovial sarcoma cells are sensitive in vitro to ABT-263, a BH3-peptidomimetic, much more so than are other tested cancer cell lines. ABT-263 also enhances the sensitivity of these cells to doxorubicin, a traditional cytotoxic chemotherapy used for synovial sarcoma. We also demonstrate the capacity of ABT-263 to stunt synovial sarcomagenesis in vivo in a genetic mouse model. These data recommend pursuit of BH3-peptidomimetic pharmacotherapy in human synovial sarcomas.
synovial sarcoma; apoptosis; chemotherapy; targeted therapy; mouse model
Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.
Radiation-induced bystander effects have been extensively studied at low doses, since evidence of bystander induced cell killing and other effects on unirradiated cells were found to be predominant at doses up to 0.5 Gy. Therefore, few studies have examined bystander effects induced by exposure to higher doses of radiation, such as spatially fractionated radiation (GRID) treatment. In the present study, we evaluate the ability of GRID treatment to induce changes in GRID adjacent (bystander) regions, in two different murine carcinoma cell lines following exposure to a single irradiation dose of 10 Gy. Murine SCK mammary carcinoma cells and SCCVII squamous carcinoma cells were irradiated using a brass collimator to create a GRID pattern of nine circular fields 12 mm in diameter with a center-to-center distance of 18 mm. Similar to the typical clinical implementation of GRID, this is approximately a 50:50 ratio of direct and bystander exposure. We also performed experiments by irradiating separate cultures and transferring the medium to unirradiated bystander cultures. Clonogenic survival was evaluated in both cell lines to determine the occurrence of radiation-induced bystander effects. For the purpose of our study, we have defined bystander cells as GRID adjacent cells that received approximately 1 Gy scatter dose or unirradiated cells receiving conditioned medium from irradiated cells. We observed significant bystander killing of cells adjacent to the GRID irradiated regions compared to sham treated controls. We also observed bystander killing of SCK and SCCVII cells cultured in conditioned medium obtained from cells irradiated with 10 Gy. Therefore, our results confirm the occurrence of bystander effects following exposure to a high-dose of radiation and suggest that cell-to-cell contact is not required for these effects. In addition, the gene expression profile for DNA damage and cellular stress response signaling in SCCVII cells after GRID exposure was studied. The occurrence of GRID-induced bystander gene expression changes in significant numbers of DNA damage and cellular stress response signaling genes, providing molecular evidence for possible mechanisms of bystander cell killing.
We report a patient with a mass in the right atrium which led to pulmonary embolism. Postoperatively the mass was identified as a tuberculoma and it was culture-positive for Mycobacterium tuberculosis. Patient responded to modified antitubercular treatment and discharged from hospital in satisfactory condition.
Antemortem diagnosis; Mycobacterium tuberculosis; Myocardial tuberculosis; Right atrial tuberculoma
The receptor tyrosine kinase AXL has emerged in recent years as an potential oncology target due to its over expression in several types of cancers coupled with its ability to promote tumor growth and metastasis. In order to identify small molecule inhibitors of AXL, we built a homology model of its catalytic domain to virtually screen and identify scaffolds displaying an affinity for AXL. Further computational and structure-based design resulted in the synthesis of a series of 2,4,5-trisubstitued pyrimidines which demonstrated potent inhibition of AXL in vitro (IC50 19 nM) and strongly inhibited the growth of several pancreatic cell lines.
AXL kinase inhibitors; anticancer; structure-activity relationship
Aim of the study
This study was made to investigate the antidiabetic, antioxidant and hypolipidemic potential of Cinnamomum tamala, (Buch.-Ham.) Nees & Eberm (Tejpat) oil (CTO) in streptozotocin (STZ) induced diabetes in rats along with evaluation of chemical constituents.
Materials and methods
The GC-MS (Gas chromatography–mass spectrometry) analysis of the oil showed 31 constituents of which cinnamaldehyde was found the major component (44.898%). CTO and cinnamaldehyde was orally administered to diabetic rats to study its effect in both acute and chronic antihyperglycemic models. The body weight, oral glucose tolerance test and biochemical parameters viz. glucose level, insulin level, liver glycogen content, glycosylated hemoglobin, total plasma cholesterol, triglyceride and antioxidant parameters were estimated for all treated groups and compared against diabetic control group.
CTO (100 mg/kg and 200 mg/kg), cinnamaldehyde (20 mg/kg) and glibenclamide (0.6 mg/kg) in respective groups of diabetic animals administered for 28 days reduced the blood glucose level in streptozotocin induced diabetic rats. There was significant increase in body weight, liver glycogen content, plasma insulin level and decrease in the blood glucose, glycosylated hemoglobin and total plasma cholesterol in test groups as compared to control group. The results of CTO and cinnamaldehyde were found comparable with standard drug glibenclamide. In vitro antioxidant studies on CTO using various models showed significant antioxidant activity. In vivo antioxidant studies on STZ induced diabetic rats revealed decreased malondialdehyde (MDA) and increased reduced glutathione (GSH).
Thus the investigation results that CTO has significant antidiabetic, antioxidant and hypolipidemic activity.
Cinnamomum tamala; Cinnamaldehyde; Glibenclamide; Hyperglycaemia; Streptozotocin
This study was undergone to evaluate the in-vivo anti-hyperglycemic and antioxidant potential of ethanolic extract of leaves of Tecomella undulata Seem. on streptozotocin-nicotinamide induced type 2 diabetic rats. Type 2 diabetes was induced by single intraperitoneal injection (i.p.) of 60 mg/kg streptozotocin, 15 minutes after the i.p administration of 110 mg/kg body weight of nicotinamide. The extract has shown significant blood glucose lowering effect in the oral glucose tolerance test (OGTT). The blood glucose level, cholesterol, glycogen contents, glycosylated hemoglobin, and antioxidant parameters (Malondialdehyde and Glutathione level) were estimated from the blood plasma by using standard kits to demonstrate the hypoglycemic and antioxidant effect in treated animals. The data showed that the extract have significant influence on the above biochemical parameters. Thus ethanolic fraction of the plant Tecomella undulata can be used as new candidate for antihyperglycemic and antioxidant.
Tecomella undulata; Streptozotocin; Diabetic rats; Malondialdehyde; Glycosylated hemoglobin
Nrf2-mediated activation of antioxidant response element is a central part of molecular mechanisms governing the protective function of phase II detoxification and antioxidant enzymes against carcinogenesis, oxidative stress and inflammation. Nrf2 is sequestered in the cytoplasm by its repressor, Keap1. We have designed and synthesized novel chalcone derivatives as Nrf2 activators. The potency of these compounds was measured by the expression of Nrf2 dependent antioxidant genes, GCLM, NQO1 and HO1, in human lung epithelial cells; while the cytotoxicity was analyzed using MTT assay. In vivo potency of identified lead compounds to activate Nrf2 was evaluated using mouse model. Our studies showed 2-trifluoromethyl-2’-methoxychalone (2b) to be a potent activator of Nrf2, both, in vitro and in mice. Additional experiments showed that the activation of Nrf2 by this compound is independent of reactive oxygen species or redox changes. We have discussed a quantitative structure-activity relationship and proposed a possible mechanism of Nrf2 activation.
Diabetes mellitus is a potentially morbid condition with high prevalence worldwide thus being a major medical concern. Experimental induction of diabetes mellitus in animal models is essential for the advancement of our knowledge and understanding of the various aspects of its pathogenesis and ultimately finding new therapies and cure. Experimental diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic (immunological) manipulations. Most of the experiments in diabetes are carried out in rodents, although some studies are still performed in larger animals. The present review highlights the various methods of inducing diabetes in experimental animals in order to test the newer drugs for their anti-diabetic potential.
Streptozotocin; alloxan; diabetic rats; animal models; diabetes
Kodak MinR-2000 mammography film is widely used for mammography imaging. The sensitometric indices like base plus fog level (B + F), maximum optical density (ODmax), average gradient (AG) and speed of this film at varying development temperatures and times were evaluated using a light sensitometer. Totally 33 film strips were cut from a single Kodak MinR-2000 mammography film box and exposed in a light sensitometer operated in the green light spectrum to produce a 21-step sensitometric strip. These exposed film strips were processed at temperatures in the range of 32°C–37°C in the step of 1°C and at processing times in the range of 1–6 minutes in the step of 1 minute. The results of the present study show that the measured base plus fog level of the mammography film was not affected much, whereas significant changes were seen in the ODmax, AG and speed with varying development temperatures and times. The ODmax values of the film were found in the range of 3.67–3.76, AG values were in the range of 2.48–3.4 and speed values were in the range of 0.015–0.0236 when the processing temperature was varied from 32°C to 37°C. With processing time variation from 1 to 6 minutes, the observed changes in ODmax values were in the range of 3.54-3.71, changes in AG were in the range of 2.66–3.27 and changes in speed were in the range of 0.011–0.025. Based on these observations, recommendations for optimum processing parameters to be used for this film are made.
Average gradient; base plus fog; mammography; optical density; speed; sensitometry
Classic cancer research for several decades has focused on understanding the biology of tumor cells in vitro. However, extending these findings to in vivo settings has been impeded owing to limited insights on the impact of microenvironment on tumor cells. We hypothesized that tumor cell biology and treatment response would be more informative when done in the presence of stromal components, like endothelial cells, which exist in the tumor microenvironment. To that end, we have developed a system to grow three-dimensional cultures of GFP-4T1 mouse mammary tumor and 2H11 murine endothelial cells in hanging drops of medium in vitro. The presence of 2H11 endothelial cells in these three-dimensional cocultures was found to sensitize 4T1-GFP tumor cells to chemotherapy (Taxol) and, at the same time, protect cells from ionizing radiation. These spheroidal cultures can also be implanted into the dorsal skinfold window chamber of mice for fluorescence imaging of vascularization and disease progression/treatment response. We observed rapid neovascularization of the tumor-endothelial spheroids in comparison to tumor spheroids grown in nude mice. Molecular analysis revealed pronounced up-regulation of several proangiogenic factors in the tumor tissue derived from the tumor-endothelial spheroids compared with tumor-only spheroids. Furthermore, the rate of tumor growth from tumor-endothelial spheroids in mice was faster than the tumor cell-only spheroids, resulting in greater metastasis to the lung. This three-dimensional coculture model presents an improved way to investigate more pertinent aspects of the therapeutic potential for radiation and/or chemotherapy alone and in combination with antiangiogenic agents.
Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.
sarcoma; immunotherapy; immunosurveillance; vaccine
Telecobalt machines are still prominently used for the treatment of a variety of cancer cases in developing countries. The human body is a heterogeneous composition of variety of tissues and cavities which vary widely in their physical and radiological properties. The presence of heterogeneities in the path of telecobalt beam presents an altered dose distribution in the region of clinical interests. A computerized treatment planning system (TPS) is generally used for calculating the dose distribution in the patient. Experimental measurements were carried out in a telecobalt beam with the objectives to study the effects of low-density heterogeneities and to verify the ability of the ASHA radiotherapy TPS in predicting the altered dose distribution along the central axis and off-axis of the beam. Locally available kailwood was tested for its lung equivalence and measurements were carried out in a polymethyl methacrylate phantom by introducing lung equivalent and air gap heterogeneities. A comparison of experimentally measured and TPS calculated dose values indicates that the TPS overestimates the dose by 11.6% in lung equivalent (kailwood) heterogeneity along the central axis. Similarly, it was found that the TPS overestimates the dose by 3.9% and 5.9%, respectively, with air heterogeneity of 1.0 and 2.0 cm. While testing the adequacy of TPS in off-axis region, it was found that the TPS calculation does not indicate the widening of the beam profile in the low-density heterogeneity region. This study suggests that the effective path length based algorithm of the ASHA radiotherapy TPS is unable to achieve the recommended 3% accuracy of clinical dose calculation in heterogeneous media.
Dosimetry; heterogeneity; telecobalt; therapy; treatment planning; validation
Panobinostat is partly metabolized by CYP3A4 in vitro. This study evaluated the effect of a potent CYP3A inhibitor, ketoconazole, on the pharmacokinetics and safety of panobinostat.
Patients received a single panobinostat oral dose on day 1, followed by 4 days wash-out period. On days 5–9, ketoconazole was administered. On day 8, a single panobinostat dose was co-administered with ketoconazole. Panobinostat was administered as single agent three times a week on day 15 and onward.
In the presence of ketoconazole, there was 1.6- and 1.8-fold increase in Cmax and AUC of panobinostat, respectively. No substantial change in Tmax or half-life was observed. No difference in panobinostat-pharmacokinetics between patients carrying CYP3A5*1/*3 and CYP3A5*3/*3 alleles was observed. Most frequently reported adverse events were gastrointestinal related. Patients had asymptomatic hypophosphatemia (64%), and urine analysis suggested renal phosphate wasting.
Co-administration of panobinostat with CYP3A inhibitors is feasible as the observed increase in panobinostat PK parameters was not considered clinically relevant. Considering the variability in exposure following enzyme inhibition and the fact that chronic dosing of panobinostat was not studied with CYP3A inhibitors, close monitoring of panobinostat-related adverse events is necessary.
Panobinostat; LBH589; Histone deacetylase inhibitor; CYP3A
Peptic ulcer is a global health problem of the gastrointestinal tract characterized by mucosal damage secondary to pepsin and gastric acid secretion which occurs due to due to an imbalance between offensive and defensive factors.
The present study was carried out with methanolic extract of the seed coat of Tamarindus indica Linn. to evaluate its antiulcer potential on ibuprofen, alcohol and pyloric ligation induced gastric lesions.
Materials and Methods:
Doses of 100 mg/kg & 200 mg/kg of methanolic extract wre administered orally to rats of different groups. Ranitidine at a dose of 50 mg/kg was used as a standard drug for these gastric ulcer models. The gastric content was collected and the volume was measured. The ulceration index was determined by examining the inner lining of each stomach. Furthermore, the effect was assessed by free acidity, pepsin activity, total carbohydrate (TC), protein content (PK).
The result showed that the methanolic extract of seed coats of Tamarindus indica significantly reduce the total volume of gastric juice, free and total acidity of gastric secretion (P < 0.01) in pylorus ligation induced ulcer model as is comparable with the standard drug ranitidine. There was also a significant reduction in ulcer index (P < 0.01) as compared to control group.
The methanolic extracts of seed coat of Tamarindus indica can be used as a new source of antiulcer agent in animals.
Peptic ulcer; ranitidine; Tamarindus indica; ulcer index
To investigate the effect of ethanolic extract of fruit pulp of Tamarindus indica Linn. (Family: Caesalpiniaceae) on obesity in rats using cafeteria diet-induced obesity and antipsychotic drug (sulpiride)-induced obesity.
Materials and Methods:
Cafeteria dietwas administered for 40 successive days to male Wistar rats and sulpiride (20 mg/kg, i.p.) was administered for 28 successive days to female Wistar rats. In separate groups of animals, the ethanolic extract (50 and 100 mg/kg p.o.) of Tamarindus indica fruit was administered along with cafeteria diet for 40 successive days to Wistar male rats and along with sulpiride for 28 successive days to Wistar female rats.
Cafeteria diet alone significantly increased body weight, serum total cholesterol, triglycerides, and glucose levels and decreased HDL cholesterol in male rats as compared to control. Sulpiride per se significantly increased the levels of glucose, triglycerides, cholesterol and there was no significant effect on HDL-cholesterol in female rats as compared to control. Ethanolic extract showed a significant decrease in body weight, serum cholesterol, and triglycerides and a significant increase in HDL-cholesterol in cafeteria diet- and sulpiride-induced obese rats as compared to their respective control groups.
Thus, the ethanolic extract of Tamarindus indica fruit pulp showed a significant weight-reducing and hypolipidemic activity in cafeteria diet- and sulpiride-induced obese rats.
Cafeteria diet; hyperlipidemia; obesity; sulpiride; Tamarindus indica
Sternal osteomyelitis with bacteremia due to Mycobacterium abscessus is rarely seen in immunocompetent hosts. Routine pyogenic cultures in these cases are often negative causing a delay in diagnosis and treatment. Clinicians and microbiologists should rule out the possibility of infection due to nontuberculous mycobacteria while managing cases of nonhealing culture-negative wounds with conventional antibiotic therapy. We report a case of bacteremia secondary to a nonhealing sternal wound due to M. abscessus. A combination of radical debridement and prolonged antimicrobial therapy helped in the complete eradication of the infection.
Bacteremia; Mycobacterium abscessus; nontuberculous mycobacteria; sternal osteomyelitis
Given the current status of HIV infection in youth in India, developing and implementing HIV education and prevention interventions is critical. The goal for School-based Teenage Education Program (STEP) was to demonstrate that a HIV/AIDS and alcohol abuse educational program built with specific cultural, linguistic, and community-specific characteristics could be effective. Utilizing the Train-the-Trainer model, the instructors (17–21 years) were trained to present the 10 session manualized program to primarily rural and tribal youth aged 13–16 years in 23 schools (N = 1,421) in the northern state of Himachal Pradesh in India. The intervention had a greater impact on girls; girls evidenced greater communication skills and a trend towards greater self efficacy and reduced risk taking behavior. The STEP has been successfully adapted by the community organizations that were involved in coordinating the program at the local level. Their intention to continue STEP beyond extra funding shows that utilizing the local community in designing, implementing and evaluating programs promotes ownership and sustainability.
School-based intervention; Youth; HIV infection; Prevention education
Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders may be altering human metabolism.