Showing papers by "Rajesh Kumar published in 2005"

Optimizing drug delivery systems using systematic "design of experiments." Part I: fundamental aspects.

Abstract: Design of an impeccable drug delivery product normally encompasses multiple objectives. For decades, this task has been attempted through trial and error, supplemented with the previous experience, knowledge, and wisdom of the formulator. Optimization of a pharmaceutical formulation or process using this traditional approach involves changing one variable at a time. Using this methodology, the solution of a specific problematic formulation characteristic can certainly be achieved, but attainment of the true optimal composition is never guaranteed. And for improvement in one characteristic, one has to trade off for degeneration in another. This customary approach of developing a drug product or process has been proved to be not only uneconomical in terms of time, money, and effort, but also unfavorable to fix errors, unpredictable, and at times even unsuccessful. On the other hand, the modern formulation optimization approaches, employing systematic Design of Experiments (DoE), are extensively practiced in the development of diverse kinds of drug delivery devices to improve such irregularities. Such systematic approaches are far more advantageous, because they require fewer experiments to achieve an optimum formulation, make problem tracing and rectification quite easier, reveal drug/polymer interactions, simulate the product performance, and comprehend the process to assist in better formulation development and subsequent scale-up. Optimization techniques using DoE represent effective and cost-effective analytical tools to yield the "best solution" to a particular "problem." Through quantification of drug delivery systems, these approaches provide a depth of understanding as well as an ability to explore and defend ranges for formulation factors, where experimentation is completed before optimization is attempted. The key elements of a DoE optimization methodology encompass planning the study objectives, screening of influential variables, experimental designs, postulation of mathematical models for various chosen response characteristics, fitting experimental data into these model(s), mapping and generating graphic outcomes, and design validation using model-based response surface methodology. The broad topic of DoE optimization methodology is covered in two parts. Part I of the review attempts to provide thought-through and thorough information on diverse DoE aspects organized in a seven-step sequence. Besides dealing with basic DoE terminology for the novice, the article covers the niceties of several important experimental designs, mathematical models, and optimum search techniques using numeric and graphical methods, with special emphasis on computer-based approaches, artificial neural networks, and judicious selection of designs and models.

Prospective Study of One Million Deaths in India: Rationale, Design, and Validation Results

Abstract: Background Over 75% of the annual estimated 9.5 million deaths in India occur in the home, and the large majority of these do not have a certified cause. India and other developing countries urgently need reliable quantification of the causes of death. They also need better epidemiological evidence about the relevance of physical (such as blood pressure and obesity), behavioral (such as smoking, alcohol, HIV-1 risk taking, and immunization history), and biological (such as blood lipids and gene polymorphisms) measurements to the development of disease in individuals or disease rates in populations. We report here on the rationale, design, and implementation of the world's largest prospective study of the causes and correlates of mortality.

Scaling, power, and the future of CMOS

Abstract: This paper briefly reviews the forces that caused the power problem, the solutions that were applied, and what the solutions tell us about the problem As systems became more power constrained, optimizing the power became more critical; viewing power reduction from an optimization perspective provides valuable insights Section III describes these insights in more detail, including why Vdd and Vth have stopped scaling Section IV describes some of the low power techniques that have been used in the past in the context of the optimization framework This framework also makes it easy to see the impact of variability, which is discussed in more detail in section V along with the adaptive mechanisms that have been proposed and deployed to minimize the energy cost Section VI describes possible strategies for dealing with the slowdown in gate energy scaling, and the final section concludes by discussing the implications of these strategies for device designers

Lecithin organogels as a potential phospholipid-structured system for topical drug delivery: A review

Abstract: The purpose of this review is to give an insight into the considerable potential of lecithin organogels (LOs) in the applications meant for topical drug delivery. LOs are clear, thermodynamically stable, viscoelastic, and biocompatible jelly-like phases, chiefly composed of hydrated phospholipids and appropriate organic liquid. These systems are currently of interest to the pharmaceutical scientist because of their structural and functional benefits. Several therapeutic agents have been formulated as LOs for their facilitated transport through topical route (for dermal or transdermal effect), with some very encouraging results. The improved topical drug delivery has mainly been attributed to the biphasic drug solubility, the desired drug partitioning, and the modification of skin barrier function by the organogel components. Being thermodynamically stable, LOs are prepared by spontaneous emulsification and therefore posses prolonged shelf life. The utility of this novel matrix as a topical vehicle has further increased owing to its very low skin irritancy potential. Varied aspects of LOs viz formation, composition, phase behavior, and characterization have been elaborated, including a general discussion on the developmental background. Besides a comprehensive update on the topical applications of lecithin organogels, the review also includes a detailed account on the mechanistics of organogelling.

“Phosphatonins” and the regulation of phosphorus homeostasis

Abstract: Phosphate ions are critical for normal bone mineralization, and phosphate plays a vital role in a number of other biological processes such as signal transduction, nucleotide metabolism, and enzyme regulation. The study of rare disorders associated with renal phosphate wasting has resulted in the discovery of a number of proteins [fibroblast growth factor 23 (FGF-23), secreted frizzled related protein 4 (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF 7 (FGF-7)] that decrease renal sodium-dependent phosphate transport in vivo and in vitro. The "phosphatonins," FGF-23 and sFRP-4, also inhibit the synthesis of 1alpha,25-dihydroxyvitamin D, leading to decreased intestinal phosphate absorption and further reduction in phosphate retention by the organism. In this review, we discuss the biological properties of these proteins, alterations in their concentrations in various clinical disorders, and their possible physiological role.

DaVinci canvas: a telerobotic surgical system with integrated, robot-assisted, laparoscopic ultrasound capability

Abstract: We present daVinci Canvas: a telerobotic surgical system with integrated robot-assisted laparoscopic ultrasound capability. DaVinci Canvas consists of the integration of a rigid laparoscopic ultrasound probe with the daVinci robot, video tracking of ultrasound probe motions, endoscope and ultrasound calibration and registration, autonomous robot motions, and the display of registered 2D and 3D ultrasound images. Although we used laparoscopic liver cancer surgery as a focusing application, our broader aim was the development of a versatile system that would be useful for many procedures.

Effect of common B-RAF and N-RAS mutations on global gene expression in melanoma cell lines.

Abstract: We studied global gene expression in three melanoma cell lines with the most common and potent V600E mutation in the B-RAF gene-four cell lines with a common Q61R mutation in the N-RAS gene and three cell lines with no mutations using human HG-U133A 2.0 micro-arrays with 22 277 transcripts. Data analysis using stringent criteria revealed several upregulated and downregulated genes in cell lines with B-RAF and N-RAS mutations compared with cell lines without mutations. We found 29 genes specifically upregulated and 32 genes downregulated in cell lines with B-RAF mutations, whereas 70 genes were upregulated and 39 downregulated in cell lines with N-RAS mutations; 11 genes showed overlapping upregulation and 45 downregulation. The micro-array data for nine selected genes were validated by the real-time PCR technique. Expression of a large number of genes, that encode members or regulators of the RAS/RAF/MEK/ERK pathways or are involved in metastasis or invasion, was affected in cell lines with mutations in B-RAF and N-RAS. Upregulated genes in cell lines with mutations included dual-specificity phosphatase 6 (DUSP6), sprouty 2 (SPRY2), v-akt murine thymoma viral oncogene homolog 3 (AKT3) and matrix metalloproteinase 14 (MMP14); downregulated genes included interleukin 18 (IL18), Kruppel-like factor 5 (KLF5) and inhibitor of DNA binding 2 (ID2). Our results, though carried on cell lines, provide a novel insight into the effect of mutations in the B-RAF and N-RAS genes on global gene expression in melanoma and highlight the complexity of mechanisms involved in tumour initiation and maintenance.

Micronuclei in humans induced by exposure to low level of ionizing radiation: influence of polymorphisms in DNA repair genes

Abstract: Understanding the risks deriving from protracted exposure to low doses of ionizing radiation has remarkable societal importance in view of the large number of work settings in which sources of IR are encountered. To address this question, we studied the frequency of micronuclei (MN), which is an indicator of DNA damage, in a population exposed to low levels of ionizing radiation and in matched controls. In both exposed population and controls, the possible influence of single nucleotide polymorphisms in XRCC1 , XRCC3 and XPD genes on the frequency of micronuclei was also evaluated. We also considered the effects of confounding factors, like smoking status, age and gender. The results indicated that MN frequency was significantly higher in the exposed workers than in the controls [8.62 ± 2.80 versus 6.86 ± 2.65; P = 0.019]. Radiological workers with variant alleles for XRCC1 or XRCC3 polymorphisms or wild-type alleles for XPD exon 23 or 10 polymorphisms showed a significantly higher MN frequency than controls with the same genotypes. Smoking status did not affect micronuclei frequency either in exposed workers or controls, while age was associated with increased MN frequency in the exposed only. In the combined population, gender but not age exerted an influence on the yield of MN, being higher in females than in males. Even though there is a limitation in this study due to the small number of subjects, these results suggest that even exposures to low level of ionizing radiation could have genotoxic effects and that XRCC3 , XRCC1 and XPD polymorphisms might contribute to the increased genetic damage in susceptible individuals occupationally exposed to chronic low levels of ionizing radiation. For a clear conclusion on the induction of DNA damage caused by protracted exposure to low doses of ionizing radiation and the possible influence of genetic polymorphism in DNA repair genes larger studies are needed.

Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter.

Abstract: The NF-κB component RelB is essential for dendritic cell (DC) differentiation and maturation. The vitamin D receptor (VDR) is a nuclear receptor that mediates inhibition of DC maturation and transcriptional repression of relB after engagement of its ligand, 1α,25-dihydroxyvitamin D3, or related analogs (D3 analogs). Ligand-dependent relB suppression was abolished by a histone deacetylase (HDAC) inhibitor. Constitutive association of VDR with the relB promoter was demonstrated in DCs by chromatin immunoprecipitation. Promoter binding by VDR was enhanced by ligand and reduced by LPS. Association of HDAC3 and HDAC1 with the relB VDR-binding site was observed, but only HDAC3 was reciprocally modulated by D3 analog and LPS. Overexpression of HDAC3 caused relB promoter suppression, increased sensitivity to D3 analog, and resistance to LPS. Depletion of HDAC3 attenuated relB suppression by D3 analog. In vivo, D3 analog resulted in reduced RelB in DCs from VDR WT mice but not VDR knockout mice. Other NF-lation of RelB and c-Rel in control animals. We conclude that vitamin D-regulated relB transcription in DCs is controlled by chromatin remodeling by means of recruitment of complexes including HDAC3.

Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin.

Abstract: In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.

Method and System for Performing Video Flashlight

Abstract: In an immersive surveillance system, videos or other data from a large number of cameras and other sensors is managed and displayed by a video processing system overlaying the data within a rendered 2D or 3D model of a scene. The system has a viewpoint selector configured to allow a user to selectively identify a viewpoint from which to view the site. A video control system receives data identifying the viewpoint and based on the viewpoint automatically selects a subset of the plurality of cameras that is generating video relevant to the view from the viewpoint, and causes video from the subset of cameras to be transmitted to the video processing system. As the viewpoint changes, the cameras communicating with the video processor are changed to hand off to cameras generating relevant video to the new position. Playback in the immersive environment is provided by synchronization of time stamped recordings of video. Navigation of the viewpoint on constrained paths in the model or map-based navigation is also provided.

Neuroanatomic deficits in congenital central hypoventilation syndrome.

Abstract: Congenital Central Hypoventilation Syndrome (CCHS) patients exhibit compromised autonomic regulation, reduced breathing drive during sleep, diminished ventilatory responses to chemoreceptor stimulation, and diminished air hunger perception. The syndrome provides an opportunity to partition neural processes regulating breathing and cardiovascular action. No obvious lesions appear with conventional magnetic resonance imaging; however, T2 relaxometry procedures can detect reduced cell or fiber density or diminished myelination not found with routine evaluation. High-resolution T1, proton density, and T2-weighted brain images were collected from 12 patients and 28 age- and gender-matched controls. Voxel-by-voxel T2 maps were generated from the proton density and T2-weighted images and evaluated by voxel-based-relaxometry procedures. Normalized and smoothed T2 maps were compared between groups using analysis of covariance at each voxel, with age and ventricle size included as covariates. Patients showed damaged or maldeveloped tissue, principally right-sided, including white matter from the level of the anterior cingulate cortex caudally to the level of the posterior cingulate and laterally to the posterior superior temporal cortex. Portions of the posterior, mid, and anterior cingulate, as well as the internal capsule, putamen, and globus pallidus and basal forebrain extending to the anterior and medial thalamus were affected. Deficits in the cingulum bundle and mid-hippocampus and ventral prefrontal cortex appeared, as well as the right cerebellar cortex and deep nuclei. Neuroanatomic deficiencies in limbic structures suggest a structural basis for reduced air hunger perception, thermoregulatory and autonomic deficiencies in the syndrome, while cerebellar deficits may also contribute to breathing and cardiovascular dysregulation.

High Diversity of Group A Streptococcal emm Types in an Indian Community: The Need to Tailor Multivalent Vaccines

Abstract: Background. Concern about the emergence of antibiotic-resistant strains and about morbidity and/ormortality related to rheumatic fever and rheumatic heart disease has been a continuous impetus for the development of a safe, effective vaccine against group A Streptococcus (GAS). To date, 1120 GAS M types are known, as identified by serological typing. In general, serum immunoglobulin G directed to the hypervariable NH2 terminal portion of M protein leads to complement fixation and opsonophagocytosis of the homologous streptococcal serotype by polymorphonuclear leukocytes, and the protection is type specific. The sequence variation at the N terminus ultimately affects the binding of opsonic antibodies. Because of hypervariability in these opsonic sequences from different M types, it was relevant to use epitopes derived from these multiple sequences in a "multivalent vaccine" design for evaluation of protection against these M types of GAS. Thus, any attempts to design vaccines for a given community will require information on N terminal-sequence typing and variation. Methods. In the present study, we performed molecular characterization of isolates recovered from patients in northern India-to our knowledge, for the first time-in an attempt to study the circulating M types and their N terminal sequence variability. Results. We report tremendous diversity in GAS strains recovered from symptomatic patients, with implications on the design of appropriate vaccines. Fifty-nine isolates represented 33 different sequence types. Very few novel types and no predominant clones were found. Conclusions. The high diversity of emm types encountered in a single year suggests that any M protein-based multivalent vaccine would have to be specifically tailored for this region.

Design, Development and Optimization of Nimesulide-Loaded Liposomal Systems for Topical Application

Abstract: Nimesulide, a non-steroidal anti-inflammatory drug, was incorporated into multilamellar liposomes to improve its performance on topical administration. The drug was loaded onto liposomes employing thin film hydration technique. Various process and formulation variables were investigated to obtain the liposomal products of desired quality. Liposomes were monitored for percent drug entrapment, after separating the unentrapped drug by mini column centrifugation, for vesicular properties (such as size distribution profile, morphological attributes and agglomeration tendency), drug diffused through synthetic semipermeable membrane, and drug leakage. Systematic optimization studies were carried out using 32 factorial design to select the optimized liposomal composition with reference to percent drug entrapment, drug diffusion and leakage. The optimized batch of liposomes was subjected to drug permeation and drug retention studies employing rat skin and human cadaver skin. In comparison to methanolic solution of pure nimesulide, liposomal formulations were found to retain higher amounts of nimesulide in the skin. Anti-inflammatory studies, using carragenan-induced rat paw edema model, indicated significantly better performance of liposomally entrapped nimesulide in comparison to the marketed gel formulation and the Carbopol gel containing nimesulide.

Basal cell carcinoma and variants in genes coding for immune response, DNA repair, folate and iron metabolism

Abstract: Basal cell carcinoma (BCC) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years. BCCs are caused by an interplay between genetic and environment factors. We conducted a case-control association study in BCC patients and controls from Sweden and Finland. Fifteen single nucleotide polymorphisms (SNPs), IL-6 -174G/C, -634G/C, and -597G/A; IL-10 -1082G/A and -592C/A; IL-1β -511C/T; NBS1 exon 5 Glu185Gln; XPC exon 15 Lys939Gln; XPD exon 23 Lys751Gln; XRCC1 exon 10 Arg399Gln; XRCC3 exon 7 Thr241Met; cyclin D1 exon 4 G870A; MTHFR exon 4 Ala222Val and exon 7 Glu429Ala; HFE exon 4 C282Y were performed by Pyrosequencing and RFLP techniques. Most of the genotype distributions were in accordance with the Hardy–Weinberg equilibrium (HWE), except for IL-10 -1082G/A, where cases with BCC showed a significant deviation from HWE ( P = 0.04). Linkage disequilibrium was observed between the −174 and −597 alleles in the IL-6 gene in the present populations. No difference between BCC and controls appeared in any of the SNPs analyzed. Only the combined distributions of TT/AA genotypes in MTHFR exon 4 (C/T) and exon 7 (A/C) showed slight increase in BCC compared to controls ( P

Sarcoidosis demonstrated by FDG PET imaging with negative findings on gallium scintigraphy.

Abstract: The manifestations of sarcoidosis are protean and have been well described. Conventionally, gallium-67 scan is used to evaluate sarcoidosis in nuclear medicine. Fluorodeoxyglucose positron emission tomography (FDG PET) has been successfully used in the evaluation of cancers. However, FDG is not a tumor-specific radiotracer and can also accumulate in the sarcoid lesions. We present a case of sarcoidosis, which demonstrated an unremarkable gallium-67 scintigraphy but showed extensive FDG uptake in the chest and the brain on PET imaging.

Differential regulation of voltage-gated K+ channels by oxidized and reduced pyridine nucleotide coenzymes.

Abstract: The activity of the voltage-sensitive K+ (Kv) channels varies as a function of the intracellular redox state and metabolism, and several Kv channels act as oxygen sensors. However, the mechanisms u...

Dynamical cluster-decay model for hot and rotating light-mass nuclear systems applied to the low-energy S 32 + Mg 24 → Ni 56 ∗ reaction

Abstract: The dynamical cluster-decay model (DCM) is developed further for the decay of hot and rotating compound nuclei (CN) formed in light heavy-ion reactions. The model is worked out in terms of only one parameter, namely the neck-length parameter, which is related to the total kinetic energy TKE($T$) or effective $Q$ value ${\mathit{Q}}_{\mathrm{eff}}(T)$ at temperature $T$ of the hot CN and is defined in terms of the CN binding energy and ground-state binding energies of the emitted fragments. The emission of both the light particles (LP), with $A\ensuremath{\le}4,Z\ensuremath{\le}2$, as well as the complex intermediate mass fragments (IMF), with $4lAl20,Zg2$, is considered as the dynamical collective mass motion of preformed clusters through the barrier. Within the same dynamical model treatment, the LPs are shown to have different characteristics compared to those of the IMFs. The systematic variations of the LP emission cross section ${\ensuremath{\sigma}}_{\mathrm{LP}}$ and IMF emission cross section ${\ensuremath{\sigma}}_{\text{IMF}}$ calculated from the present DCM match exactly the statistical fission model predictions. A nonstatistical dynamical description is developed for the first time for emission of light particles from hot and rotating CN. The model is applied to the decay of ${^{56}\mathrm{Ni}}^{\ensuremath{\ast}}$ formed in the $^{32}\mathrm{S}+^{24}\mathrm{Mg}$ reaction at two incident energies ${E}_{\mathrm{c}\mathrm{.}\mathrm{m}\mathrm{.}}=51.6$ and 60.5 MeV. Both the IMFs and average $\stackrel{\underline{}}{\mathit{TKE}}$ spectra are found to compare resonably well with the experimental data, favoring asymmetric mass distributions. The LPs' emission cross section is shown to depend strongly on the type of emitted particles and their multiplicities.

Reproductive health education intervention trial.

Abstract: Objective: To measure the effectiveness of a reproductive health education package in improving the knowledge of adolescent girls aged 15–19 years in Chandigarh (India).Methods: A reproductive health education package, developed in consultation with parents, teachers and adolescents, was delivered to randomly sampled classes of two senior secondary schools and one school was selected as control. In one school, a nurse conducted 15 sessions for 94 students in three batches using conventional education approach. In another school she conducted sessions for a selected group of 20 adolescents who later disseminated the messages informally to their 84 classmates (peer education). Using a 70-item structured questionnaire the knowledge of 95 adolescents from conventional, 84 from peer, and 94 from control school were assessed before and one month after the last session. Change in the score in intervention and control groups was tested by ANOVA taking age and socio-economic status as covariates.Results: Teachers, parents and students overwhelmingly (88%, 95.5% and 93% respectively) favoured reproductive health education program. Five percent of the respondents reported that someone in their class is having sexual relations, and 13% of the girls approved of pre-marital sexual relations. Reproductive health knowledge scores improved significantly after intervention in conventional education (27.28) and peer education group (20.77) in comparison to the controls (3.64). Post-test scores were not significantly different between peer education group and conventional education group (43.65 and 40.52 respectively) though the time consumed in delivering the peer education intervention was almost one third of the time taken to implement conventional education.Conclusion: Peer education and conventional education strategies were effective in improving the reproductive health knowledge of adolescent girls but peer strategy was less time consuming

The phosphatonins and the regulation of phosphorus homeostasis

Abstract: Phosphate ions are critical for normal bone mineralization, and phosphate plays a vital role in a number of other biological processes such as signal transduction, nucleotide metabolism, and enzyme regulation. The study of rare disorders associated with renal phosphate wasting has resulted in the discovery of a number of proteins [fibroblast growth factor 23 (FGF-23), secreted frizzled related protein 4 (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF 7 (FGF-7)] that decrease renal sodium-dependent phosphate transport in vivo and in vitro. The \"phosphatonins,\" FGF-23 and sFRP-4, also inhibit the synthesis of 1alpha,25-dihydroxyvitamin D, leading to decreased intestinal phosphate absorption and further reduction in phosphate retention by the organism. In this review, we discuss the biological properties of these proteins, alterations in their concentrations in various clinical disorders, and their possible physiological role.

High prevalence of bacteriuria in pregnancy and its screening methods in north India.

Abstract: Urinary tract infections (UTI) are the most common bacterial infections encountered among pregnant patients Despite the fact that most women with bacteriuria of pregnancy have a benign course it has been clearly established that untreated bacteriuria can have serious implications for both mother and foetus Approximately one-third to one-half of women with untreated infections progresses to pyelonephritis Besides it has also been implicated as a risk factor for adverse perinatal outcomes like premature birth low birth weight and perinatal deaths In addition associations have been documented between antepartum UTI and a variety of maternal complications of pregnancy including hypertension pre-eclampsia anaemia amnionitis and endometritis Prevalence of asymptomatic bacteriuria in the obstetric population ranges from 3-10% It is generally accepted that 11-40% of women who have bacteriuria in early pregnancy and 1-3% of those who do not will develop overt infection before delivery Studies have also shown that only 30-50% of women with clinical symptoms have infected urine Observations suggest but do not prove that a proportion of patients with asymptomatic bacteriuria go on to develop symptomatic infection It is also conceivable that the development of symptomatic disease may ultimately protect the patients from complications since symptomatic disease leads to treatment Although these observations offer an attempt to delineate those at risk at present it seems safest to make a sweeping recommendation to screen all pregnant women and to treat bacteriuria when detected regardless of symptomatology of the patient (excerpt)

Low frequency of BRAF and CDKN2A mutations in endometrial cancer.

Abstract: Several pathways have been implicated in the pathogenesis of endometrial carcinoma. Based on recent reports, BRAF mutations provide an alternative route for activation of the RAS signalling pathway. The CDKN2A (p16) tumour suppressor gene is also altered in several tumour types. We therefore wanted to assess the pattern and prognostic impact of BRAF mutations and p16 alterations in endometrial carcinomas. Only 1 of 48 tumours (2%) was found to have a BRAF mutation in exon 15, whereas 8 of 45 tumours (18%) had a K-ras mutation. Homozygous deletion, amplification, promoter region methylation or mutation of the p16 gene was seen in 6 cases (13%), and 18 cases (38%) carried polymorphisms in the p16 gene. All tumours with presence of p16 methylation, non-sense mutation, deletion or amplification exhibited loss of p16 expression as evaluated by immunohistochemistry. Presence of a p16 hit was significantly correlated with high FIGO stage (p = 0.04), high histologic grade (p = 0.02), estrogen receptor negativity (p = 0.05), pathologic expression of p53 (p = 0.02), pathologic expression of p16 (p = 0.05) and poor survival (p = 0.02). There was also a significant correlation between loss of p16 expression and K-ras mutations, pathologic p53 expression and serous papillary/clear cell histologic types (p = 0.05/p = 0.001/p = 0.002). In conclusion, BRAF mutation is an infrequent finding in endometrial carcinomas. Loss of p16 expression is seen in all cases with alterations of the p16 gene. The presence of a p16 hit might be important in a subset of endometrial carcinomas with aggressive clinical behaviour. However, the mechanism of p16 inactivation remains unclear for the majority of cases exhibiting loss of expression, but the interactions with K-ras and p53 should be further studied.

Method and system for customizations in a dynamic environment

Abstract: Systems and methods for applying both profile and user customizations to an application user interface are provided. Profile customizations, created for a specialized use or field, are adapted to an application user interface, which has command-menu-toolbar contributions from various add-in modules. The user has access to the customizations through a user interface. Then, as a user is customizing the application, through commands, toolbars, and menus, the user customizations are tagged. A priority and group is assigned to each customization to allow for relative positioning of each customization. The difference between the user's final desired state and a reset state is computed. This difference computation is used to track the changes made to the application and to assist in resets of the customizations.

Mutations in the BRAF and N-ras genes in childhood acute lymphoblastic leukaemia

Abstract: selected cell line models, suppression of Ras signaling or the farnesylated Rho-B proteins promotes heterotypic adhesion through activation of beta-1 and/or beta-2 integrin binding avidity or increased sensitivity to the inhibitory effects of TGFb, suggesting that promotion of heterotypic adhesion may arise as a class effect of Ras protein signal inhibition. Additional investigations are necessary to discern the relevant cellular target(s) of lonafarnib and possibly other FTIs that may promote transient expansion of leukemia mass and possibly predispose to endovascular complications.

Positron emission tomography: clinical applications in oncology. Part 1.

Abstract: Positron emission tomography is a functional diagnostic imaging technique, which can accurately measure in vivo distribution of a radiopharmaceutical with high resolution. The ability of positron emission tomography to study various biologic processes opens up new possibilities for both research and day-to-day clinical use. Positron emission tomography has progressed rapidly from being a research technique in laboratories to a routine clinical imaging modality becoming part of armamentarium for the medical profession. The most widely used radiotracer in positron emission tomography is 18F-fluoro-2-deoxy-d-glucose (FDG), which is an analog of glucose. FDG uptake in cells is directly proportional to glucose metabolism of cells. Since glucose metabolism is increased many fold in malignant tumors, positron emission tomography has a high sensitivity and high negative predictive value. Positron emission tomography with FDG is now the standard of care in initial staging, monitoring the response to therapy and ma...