on day 1 of a 21-day cycle. The primary end point is the percentage of patients who experience doselimiting toxicity (DLT) between administration of the first dose of SASP (day 1) and day 21. Results: From April 2015 to January 2016, 15 patients were enrolled in the study (mean age, 64 years; age range, 42e74 years; male/female ratio, 10/5; ECOG performance status 0/1 ratio, 6/9). Immunohistochemical staining of tumor biopsy specimens revealed that the proportion of CD44v-positive cells was >10% in 9 patients before SASP treatment. No DLT was observed in the first three patients treated at SASP dose level 1 (500 mg TID) or those treated at dose level 2 (1000 mg TID). At dose level 3 (1500 mg TID), two of three patients experienced a DLT (anorexia of grade 3). We enrolled additional patients at dose level 2 and two of the total of five patients treated at this dose level experienced DLTs (hypotension or pneumonitis, each of grade 3). To confirm the safety of dose level 1, we enrolled additional patients at this dose level and one of the total of six patients treated at this dose level experienced DLTs (AST and ALT elevation, each of grade 3). Exposure of SASP following oral administration varied markedly among individuals according to ABCG2 and NAT2 genotypes as previously reported. Conclusion: SASP 500 mg TID was the recommended dose when administered with CDDP plus PEM.
IntroductionHIV-Associated Dementia (HAD) is a significant neurological complication which occurs years after the acute viral sero-conversion reaction responsible for progressive Immuno-suppression and high viral loads. Many patients infected with HIV-1 suffer cognitive impairment ranging from mild to severe HAD. With Present available treatment system, there is no satisfactory treatment for HAD available.MethodsIn this study, nifedipine loaded solid lipid nanoparticles (SLN) were developed for targeting drug into CNS, to block the apoptosis by HIV-1 virus. This would decrease the process of neurodegeneration and increase survival time of neuronal cells. Also, this targeted delivery to brain will minimise the systemic effect of nifedipine, avoiding its delivery peripherally.The uncoated SLN were prepared by Solvent Injection Method and coated with tween 80 and Lyophylized. Shape and surface morphological studies were done by Scanning and Transmission Electron Microscopy (TEM). The in-vitro release profile of entrapped drug was studied using dialysis membrane. Ex-vivo studies consisted of DNA fragmentation followed by in-vivo studies.ResultsThe SEM and TEM images show smooth and spherical surface of SLN. In-vitro release profile of drug shows more than 90% of drug release in 48 hours. DNA fragmentation was determined in presence and in absence of gp120 mimicking agent which shows no DNA fragmentation thus developed carrier system works properly in releasing drug and blocking apoptosis in cortical cells. Fluorescence microscopy shows qualitative uptake and localization pattern of coated SLNs in brain.Conclusion: In-vitro and in-vivo studies results shows more specific delivery of Nifedipine to Brain. DNA Fragmentation and Cell Viability studies shows dementia blocking activity on brain cells. Brain specific delivery of Nifedipine could reduce the dose and potential systemic side effects, thus providing site specific delivery to brain. Thus, CNS delivery of these Nifedipine loaded SLNs via Intra-venous delivery will also open new opportunities for other Anti-Retroviral drug delivery to brain.
Thalassemia is associated with low antioxidant enzyme deficiency especially glutathione peroxidase. GPX exists in 6 isomeric forms out of which GPX1 Single Nucleotide Polymorphism is found to be associated with Thalassemia major. In our study, the determination of the allelic frequency and phenotype of a common polymorphism in Se-dependent glutathione peroxidase 1 (GPX1) was observed in Thalassemic populations. A proline/leucine variant occurs at position 197 close to the C-terminus of the protein. The genotypes encoding Pro/Pro, Pro/Leu, and Leu/ Leu are distributed according to the Hardy-Weinberg relationship. The study has been carried out in 40 Thalassemic cases and 40 control subjects. No significant association between allele frequency and risk to get fatal was evident. Erythrocyte GPX activity was determined and no significant differences were obtained between the genotypes. It can be concluded that the Pro/Leu genetic variation does not appear to compromise the defense against oxidative stress in red blood cells or to be associated with significant pathology.
Accurate estimation of skew on I/O Clocks is extremely critical when the part is expected to operate at a fixed frequency and any failure results in yield loss. Also, factors such as slow Silicon, power saving modes, thermal throttling modes makes the data-path running on I/O clocks more critical as no timing relaxation is possible. The circuits on core clocks, on the other hand, can be binned to a lower frequency using bus ratios for slower Silicon and benefit from frequency reduction during power saving modes. Further, since the I/O clock distribution typically utilizes a balanced tree structure due to its sparse usage, it suffers from higher skew compared to global clock with a tiled topology. This makes it imperative that the I/O clock performance methodology take into account all the various factors that can impact clock skew as well as slowdown in the associated datapath circuits. This paper presents a systematic skew estimation and a scientific method for performance analysis of I/O clock network. A case study on how this was adopted for Pentium-D (65 nm process) I/O clocks is presented. Key components considered are clock topology, device & interconnect in-die variation, temperature and voltage supply variation.
Crohn's Disease and Ulcerative colitis collectively known as inflammatory bowel disease IBD is chronic uncontrolled inflammation characterized by intense mucosal recruitment of activated leukocytes. Here we have developed an in vitro model for IBD using colon cancer cell line HCT-116. Colon Cancer cell line HCT-116 expressed elevated IL-23 levels when induced with LPS isolated from various bacterial strains. In this in-vitro model of IBD, IL-23 was playing a key role in inflammation cascade. Action of anti-inflammatory drug Sulfasalizine was studied and was found to block the up regulation of IL-23.
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