Luminous, relativistic, directional electron bunches from an intense laser driven grating plasma.

Bright, energetic, and directional electron bunches are generated through efficient energy transfer of relativistic intense (~ 1019 W/cm2), 30 femtosecond, 800 nm high contrast laser pulses to grating targets (500 lines/mm and 1000 lines/mm), under surface plasmon resonance (SPR) conditions. Bi-directional relativistic electron bunches (at 40° and 150°) are observed exiting from the 500 lines/mm grating target at the SPR conditions. The surface plasmon excited grating target enhances the electron flux and temperature by factor of 6.0 and 3.6, respectively, compared to that of the plane substrate. Particle-in-Cell simulations indicate that fast electrons are emitted in different directions at different stages of the laser interaction, which are related to the resultant surface magnetic field evolution. This study suggests that the SPR mechanism can be used to generate multiple, bright, ultrafast relativistic electron bunches for a variety of applications.

Association of TYRP1 with hypoxia and its correlation with patient outcome in uveal melanoma

Purpose Molecular mechanisms of uveal melanoma development in association with high pigmentation are unclear. Tyrosinase Related Protein (TYRP1) is not only one of the important melanogenesis marker that contributes to melanin synthesis, but can also prevents the melanocyte death. The induction of melanogenesis leads to induction of HIF-1α which can affect the behavior of melanoma cells and its surrounding environment. The aim of our study was to determine the expression of TYRP1 and HIF-1α at the protein and RNA level and determine its prognostic significance. Methods In the present study, the expression of TYRP1 and HIF-1α was investigated on 61 formalin-fixed paraffin-embedded choroidal melanoma samples by immunohistochemistry. Fresh 50 samples were validated by real-time PCR. Results were correlated with clinicopathological parameters and Kaplan–Meier was performed to determine the prognostic significance. Results High immunoexpression of TYRP1 and HIF-1α was present in 61 and 54% of patients, respectively. Both TYRP1 and HIF-1α correlated well with high pigmentation and BAP1 (BRCA1 Associated Protein-1) loss (p < 0.05) at IHC level as well as transcriptional level. There was reduced metastatic free survival in patients with necrosis and this was statistically significant (p = 0.010). Conclusion Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field (AU)

Association of TYRP1 with hypoxia and its correlation with patient outcome in uveal melanoma.

PURPOSE: Molecular mechanisms of uveal melanoma development in association with high pigmentation are unclear. Tyrosinase Related Protein (TYRP1) is not only one of the important melanogenesis marker that contributes to melanin synthesis, but can also prevents the melanocyte death. The induction of melanogenesis leads to induction of HIF-1α which can affect the behavior of melanoma cells and its surrounding environment. The aim of our study was to determine the expression of TYRP1 and HIF-1α at the protein and RNA level and determine its prognostic significance. METHODS: In the present study, the expression of TYRP1 and HIF-1α was investigated on 61 formalin-fixed paraffin-embedded choroidal melanoma samples by immunohistochemistry. Fresh 50 samples were validated by real-time PCR. Results were correlated with clinicopathological parameters and Kaplan-Meier was performed to determine the prognostic significance. RESULTS: High immunoexpression of TYRP1 and HIF-1α was present in 61 and 54% of patients, respectively. Both TYRP1 and HIF-1α correlated well with high pigmentation and BAP1 (BRCA1 Associated Protein-1) loss (p < 0.05) at IHC level as well as transcriptional level. There was reduced metastatic free survival in patients with necrosis and this was statistically significant (p = 0.010). CONCLUSION: Our findings indicate that TYRP1 can be used as a potential biomarker in the development of targeted therapy in UM. Further studies on melanogenesis markers associated with TYRP1 could provide us a better understanding in this field.

DNA damage response proteins and its role in tumor progression of uveal melanoma with patient outcome.

BACKGROUND: The role of DNA damage response (DDR) proteins is poorly understood in uveal melanoma. ATR belongs to one of those proteins that induce DDR by arresting the cell cycle which leads to DNA repair. ATR is localized at position 23 on the same chromosome 3 where BAP1 is located at position 21.1 which is a known poor prognostic marker of UM. The aim of our study is to detect the expression of ATR at the protein and RNA levels and determine its prognostic significance. METHODS: Expression of nuclear ATR was investigated on sixty-nine UM patients. Formalin-fixed paraffin-embedded choroidal melanoma samples were taken to evaluate the expression of ATR. Fifty samples were also validated by real-time PCR. Results of both protein and mRNA were then correlated with clinicopathological parameters. To determine the prognostic significance, Kaplan-Meier and multivariate analyses were performed. RESULTS: Loss of ATR protein was seen in 72% cases which was statistically significant with epithelioid cell type (p = 0.005), tumor thickness (p = 0.016), mitotic figures (p = 0.001) and BAP1 loss (p < 0.001). At the transcriptional level loss of ATR was seen in 76% cases which were statistically significant with metastasis (p = 0.046), staging (0.044) and loss of BAP1 (p = 0.022). On multivariate analysis loss of ATR and tumor staging came out to be independent prognostic parameters. CONCLUSION: Our data suggest that ATR might serve as a potential prognostic marker in UM patients and could serve as a potential therapeutic target.

Transition from Coherent to Stochastic electron heating in ultrashort relativistic laser interaction with structured targets.

Relativistic laser interaction with micro- and nano-scale surface structures enhances energy transfer to solid targets and yields matter in extreme conditions. We report on the comparative study of laser-target interaction mechanisms with wire-structures of different size, revealing a transition from a coherent particle heating to a stochastic plasma heating regime which occurs when migrating from micro-scale to nano-scale wires. Experiments and kinetic simulations show that large gaps between the wires favour the generation of high-energy electrons via laser acceleration into the channels while gaps smaller than the amplitude of electron quivering in the laser field lead to less energetic electrons and multi-keV plasma generation, in agreement with previously published experiments. Plasma filling of nano-sized gaps due to picosecond pedestal typical of ultrashort pulses strongly affects the interaction with this class of targets reducing the laser penetration depth to approximately one hundred nanometers. The two heating regimes appear potentially suitable for laser-driven ion/electron acceleration schemes and warm dense matter investigation respectively.

Preferential enhancement of laser-driven carbon ion acceleration from optimized nanostructured surfaces.

High-intensity ultrashort laser pulses focused on metal targets readily generate hot dense plasmas which accelerate ions efficiently and can pave way to compact table-top accelerators. Laser-driven ion acceleration studies predominantly focus on protons, which experience the maximum acceleration owing to their highest charge-to-mass ratio. The possibility of tailoring such schemes for the preferential acceleration of a particular ion species is very much desired but has hardly been explored. Here, we present an experimental demonstration of how the nanostructuring of a copper target can be optimized for enhanced carbon ion acceleration over protons or Cu-ions. Specifically, a thin (≈ 0.25 µm) layer of 25-30 nm diameter Cu nanoparticles, sputter-deposited on a polished Cu-substrate, enhances the carbon ion energy by about 10-fold at a laser intensity of 1.2 × 10(18) W/cm(2). However, particles smaller than 20 nm have an adverse effect on the ion acceleration. Particle-in-cell simulations provide definite pointers regarding the size of nanoparticles necessary for maximizing the ion acceleration. The inherent contrast of the laser pulse is found to play an important role in the species selective ion acceleration.

Photoionization of clusters in intense few-cycle near infrared femtosecond pulses.

In this article we present a perspective on the current state of the art in the photoionization of atomic clusters in few-cycle near-infrared laser pulses. Recently, several studies have reported intriguing phenomena associated with the photoionization of clusters by pulses as short as ~10 fs which approach the natural timescales of collective electronic motion in such nanoscale aggregates. In contrast to the dynamics occurring on few- and sub-picosecond timescales where ionic motion sets in and plays a key role marked by resonant plasmon oscillations, the few-cycle limit precludes cluster expansion due to the nuclear motion of ionic constituents. Thus, pulses lasting just a few optical cycles explore a new "impulsive" regime for the first time in cluster nanoplasmas wherein ions essentially remain "frozen". Along with the perspective on this new regime, we present first measurements of photoelectron distributions and temperatures.

Anomalous ion charge distribution from cluster nanoplasmas.

In nearly all the intense laser experiments with nanoclusters, the key observation has been that immense ionization drives highly charged ions to highest energies while low charge ions, if any, have lower kinetic energies. We show experimental measurements that are contrary to this established notion. The active role of outer-ionized electrons in a multicluster interaction is shown to effectively reduce high charge ions to low charge states with no loss of momentum. The role of Rydberg excited clusters, intrinsic in dense cluster ensembles, is identified and a quantitative analysis is shown to comprehensively explain the anomalous charge distribution and ion energies observed in experiments.

Dopant-induced ignition of helium nanodroplets in intense few-cycle laser pulses.

We demonstrate ultrafast resonant energy absorption of rare-gas doped He nanodroplets from intense few-cycle (~10 fs) laser pulses. We find that less than 10 dopant atoms "ignite" the droplet to generate a nonspherical electronic nanoplasma resulting ultimately in complete ionization and disintegration of all atoms, although the pristine He droplet is transparent for the laser intensities applied. Our calculations at those intensities reveal that the minimal pulse length required for ignition is about 9 fs.

Neoadjuvant and adjuvant therapy with imatinib for locally advanced gastrointestinal stromal tumors in eastern Indian patients.

BACKGROUND: Imatinib mesylate is able to at least modify the course of gastrointestinal stromal tumours (GISTs). Neoadjuvant use for locally advanced lesions is evolving as a new treatment paradigm in this hitherto universally fatal disease. METHODS AND RESULTS: The study patients with locally advanced GIST received neoadjuvant and adjuvant imatinib mesylate. Response was noted as per the RECIST protocol and overall progression free survival was reported. Of 19 patients (mean age 38.5 years, range 26 yrs to 64 yrs) studied, 13 achieved partial response (PR) and 6 a stationary disease (SD) on preoperative imatinib. Histopathological evaluation and grading of responses revealed only moderate and low grade pathological response after imatinib. R0 resection was possible in 13/19 and R1 in 6/19. Imatinib was well tolerated and adverse reactions were minimal. Post operative complications of surgery were not out of the ordinary for a surgical series featuring extensive abdominal surgery. CONCLUSION: Preoperative imatinib in locally advanced GIST seems to be a reasonable option for locally advanced GIST patients and enough downstaging to allow a resection with microscopically negative margins can be expected in a fairly good proportion of patients.

BRCA1 protein expression and its correlation with ER/PR status in sporadic and familial breast cancer in Eastern Indian patients--a hospital based study.

BRCA1 gene expression in familial breast cancer is mainly focused on mutational analysis. However in sporadic cancers BRCA1 protein expression is the main area of interest because somatic inactivation of one allele of the gene is likely to occur during the oestrogen mediated proliferation at puberty and subsequent tumourigenic events take place in the same cell. Standard immunohistochemical analysis was used to assess BRCA1 and oestrogen/progesterone receptor (ER/PR) status in familial and sporadic breast cancer patients and correlation of BRCA1 protein expression with histopathological features ER/PR status was studied in these tumours. One hundred and seventy-seven sporadic tumours (group A) and 28 familial tumours (patients with history of breast cancer in first or second degree relative ie, group B) were studied. In group A, 61 tumours had absent/reduced BRCA 1 protein expression; 30 (49%) out of these were negative for ER/PR receptors. In group B, 18 patients had absent/reduced BRCA1 protein expression, and 10 (55.6%) out of these, were ER/PR negative. Overall in 2 groups, 82 tumours were of grade 1, 61 tumours of grade 2 and 62 tumours were of grade 3 differentiation. Test of proportion showed that percentage of ER/PR negativity is significantly higher than ER/PR positivity in sporadic as well as in familial tumours with absent/ reduced BRCA 1 protein expression (p < 0.05). Sporadic tumours with deranged BRCA1 protein expression like familial tumours have more unfavourable histopathological characteristics and are likely to be of higher grade and oestrogen receptor negative

Pattern of breast cancer in a tertiary care center.

INTRODUCTION: Breast Cancer is the second commonest cause of cancer death in women. Almost all women survive breast cancer if it is detected before it starts to spread. The aim of the study is to analyze the demographical profile, stage of presentation, histological type, and treatment modalities of breast cancer in a tertiary care setting. METHODS: Total 1141 cases of breast cancer had been followed retrospectively from 1999 to 2006 A.D. in a tertiary care center and their patterns were analyzed. RESULTS: The mean age of presentation of breast cancer was 47.30 +/- 11.57 years in female and 59.03 +/- 14.63 in male, 31 (2.1%) cases of breast cancer were male. There were 123 (10.78%) stage I, 281 (24.62%) stage II, 466 (40.84%) stage III, and 271 (23.75%) stage IV patients. Infiltrating ductal carcinoma was the commonest variety 610 (53.5%). Chemotherapy was the mainstay for treatment of breast cancer 341 (29.9%) followed by surgery 287 (25.2%). CONCLUSIONS: Breast cancer trend is rising with more in late and advanced stages, mostly due to lack of awareness. Infiltrating ductal carcinoma is the commonest variety. Chemotherapy is the most commonly used modality of treatment. Male breast cancer present late and is not so uncommon.

A scenario of cervical carcinoma in a cancer hospital.

INTRODUCTION: Cervical carcinoma is an important women's health problem throughout the world. There are very few published data on this disease in Nepal. We wanted to study the pattern of cervical carcinoma based on hospital data. METHODS: A 10 years retrospective study of scenario of cervical carcinoma was conducted. The data have been analyzed according to age, occurrence of other cancers, histological type, religion, risk factors and district wise. RESULTS: The number of cervical carcinoma showed a rising pattern over the 10 year period. The median age of the patients was 45 years and maximum frequency (33%) of cases were found in the age group 40 to 49 years. Squamous cell carcinoma comprised 40% of cases, Adenocarcinoma 4% and 1.1% cases were of mixed variety. 92% of cases were Hindu by religion. 43% of patients were smoker in our study, 5% had positive family history. Chitwan with 7.35% had the maximum number of cases followed by Rupandehi with 6.40% and Nawalparasi with 5.41%. CONCLUSIONS: The cancer pattern revealed by the present study provides valuable leads to cervical cancer epidemiology in Nepal. Routine cytological screening of the population for cervical cancer is highly necessary for its early detection and treatment.

Clinical relevance of HBV DNA load in patients with chronic hepatitis B infection.

BACKGROUND: Hepatitis B virus (HBV) DNA detection and quantification are now playing an increasing role in the assessment of disease activity and response to therapy. However, viraemia levels which define various stages of HBV infection have not yet been established. AIM: To define viraemia levels which describe various stages of chronic hepatitis B virus infection. METHODS: In a retrospective study, stored sera samples of chronic hepatitis B virus (CHB) infected patients registered at AIIMS liver clinic, from January 1996 to June 2005 were subjected to competitive, quantitative PCR analysis. RESULTS: The median HBV DNA load was lowest among carriers and highest among patients with chronic hepatitis B [0 (0-8) vs. 7 (0-12) log10 copies/ml, respectively; p<0.05]. As compared to chronic hepatitis patients the DNA load was also lower among cirrhotics [7 (0-12) vs. 4.5 (0-8) log10 copies/ml, respectively; p<0.05] and hepatocellular cancer patients [ 7(0-12) vs. 0 (0-8) log10 copies/ml, respectively; p<0.05]. Patients with carriers had a DNA load which was significantly lower than e antigen negative CHB [0 (0-8) vs. 6 (0-10) log10 copies/ml; p<0.05] or e antigen positive CHB [0 (0-8) vs 8 (0-12) log10 copies/ml; p<0.05]. A threshold of 3.5 log10 copies/ml had sensitivity and specificity of 83% and 58% respectively in differentiating carriers from e antigen negative CHB. There was a strong positive correlation of HBV DNA load with inflammatory grade (R=0.334; p=0.0001), fibrosis stage (R=0.276; p=0.001) and ALT levels (R=0.378; p=0.0001). 82% (9/11) of those who lost e antigen had a decline in HBV DNA levels to <5 log10 copies/ml, whereas only 12.5% (1/8) of those who did not lose e antigen had a decline in DNA load below this level. CONCLUSIONS: HBV DNA viraemia levels correlate positively with the inflammatory grade, fibrosis stage and ALT levels. Most patients who loose e antigen have a decline in DNA load to below 5 log10 copies/ml. Further prospective studies employing repeated measurements are required to define a threshold to differentiate between HBV carriers and e antigen negative CHB.

Oxidative stress, antioxidant status and lipid profile in ischemic heart disease patients from western region of Nepal.

Disturbed lipid profile is one of the most important and potent risk factors in ischemic heart disease (IHD). In recent years, it has been demonstrated that raised oxidative stress promotes several undesirable pathways including the formation of oxidised LDL (O-LDL) and oxidized cholesterol which encourages cholesterol accumulation in arterial tissues. We, therefore, aimed to ascertain the redox balance by measuring oxidative stress (OS) and total antioxidant activity (TAA) along with lipid profile to determine their possible association with IHD. Our study group comprised of 28 confirmed cases of IHD. The inclusion criterion was history of chest pain, ischemic changes in the ECG and good left ventricular (LV) function. Patients with diabetes mellitus, poor LV function, previous infarct and valvular heart disease were excluded. Lipid profile, plasma thiobarbituric acid reactive substances (TBARS), plasma total antioxidant activity (TAA) and urinary TBARS were estimated in these patients by standard procedures and the values were compared with 30 age, sex and socioeconomically matched normal healthy control subjects. Body mass index (BMI) and waist/hip ratio (W/H ratio) was also noted in both the groups. Lipid profile and OS (TBARS levels) were significantly raised in IHD patients. Though statistically not significant but TAA tended to be lower and urinary TBARS levels tended to be higher in patients. BMI, W/H ratio, smoking and alcohol did not show discernible association with lipid profile, OS or TAA. OS is significantly raised in majority of IHD patients. The non association of BMI, W/H ratio, smoking and alcohol with lipid profile, OS and TAA suggest that there are other risk factors which primarily contribute to the initiation and progression of IHD.

A study of oxidative stress, antioxidant status and lipid profile in diabetic patient in the western region of Nepal.

AIMS AND OBJECTIVES: Diabetes mellitus (DM) is often termed as a disease of premature aging. Several studies have indicated lopsided redox balance due to pro oxidant environment as one of the important etiological factors. Some recent researches also indicate a causal relationship with oxidative stress (OS). So far, no study has been undertaken on this aspect in Nepali populations. We, therefore, aimed this maiden study in Nepali population to examine redox balance by measuring OS and antioxidant status along with lipid profile in 37 patients of DM type- 2 and 30 matched normal subjects. METHODOLOGY: Thirty seven patients of DM type-2 without any complications (mean age= 57.6+/- 10.6 years) and 30 normal subjects (mean age= 55.8 +/- 14.8 years) were included in this study. Body Mass Index (BMI) and Waist/Hip (W/H) ratio were measured. Fasting blood sample was collected for the analysis of total antioxidant activity (TAA), plasma and urinary thiobarbituric acid reactive substances (TBARS) and lipid profile by standard procedures in both the groups. The statistical analysis was done with SPSS 10 version. RESULTS: Total cholesterol, triglyceride, VLDL-cholesterol, LDL-cholesterol, plasma and urinary TBARS were significantly raised whereas, plasma TAA was significantly reduced in DM type-2 patients as compared to controls. The comparison of old and fresh cases revealed that though TAA was lower and PTBARS and UTBARS were higher in patients but did not attain the level of significance. W/H ratio is significantly higher in patients compared to normal subjects. But, no significant correlation of BMI and W/H with lipid profile is observed in both control and patients. CONCLUSION: Oxidative stress is raised in type 2 DM patients. This along with deranged lipid profile and decreased antioxidant status could be the risk factors in the development of complications associated with DM.

Cigarette smoke induced oxidative insult in local population of Pokhara.

OBJECTIVES: To assess the effect of cigarette smoking on lipid peroxidation induced oxidative stress, antioxidants, uric acid and blood sugar in normal subjects. METHODS: The study included 61 normal subjects with regular smoking habit and 57 never-smokers normal subjects matched in respect to socio-economic status, age and BMI. Information regarding smoking habit and other personal details were collected by oral questionnaire. Total antioxidant activity (TAA), reduced glutathione (GSH), alpha-tocopherol (alpha-T), ascorbic acid (AA), uric acid (UA), plasma and urinary thiobarbituric acid reactive substances (TBARS), fasting blood sugar (FBS) and urinary creatinine (Cr) were estimated by standard procedures in both the groups. Ferric Reducing Antioxidant Power (FRAP) procedure is used to estimate TAA which measures total dietary antioxidants. Statistical analysis was done with SPSS version 10. RESULTS: The mean pack years smoked by smokers was 14.4 +/- 15.8. The plasma TBARS level in smokers and never-smokers was 2.6 +/- 0.8 and 2.5 +/- 0.6 micromol/L respectively. The respective figure for urinary TBARS level was 4.6 +/- 2.7 and 3.7 +/- 1.4 micromol/gmCr. Smokers did not show any significant difference from never-smokers with respect to GSH, alpha-T, AA, plasma TBARS and FBS. However, the smokers had significantly lower levels of TAA (p<0.05) and raised level of urinary TBARS (p<0.05) and uric acid (p<0.01) as compared to never-smokers. CONCLUSION: Our study suggests that smoking induces mild lipid peroxidation but the body is able to compensate for it by removing its adducts. Importantly it also indicates enhanced oxidation of purines which are essential components of both DNA and RNA. Dietary antioxidants are consumed to scavenge free radicals (FR) and other reactive species (RS) in smoke. Female smokers are more prone to oxidative insult than male smokers. In summary RS present in smoke induce mild lipid peroxidation but are not the major contributors of redox imbalance in smoke induced toxicity in the selected subjects.

Cloning and functional expression of an acyl-ACP thioesterase FatB type from Diploknema (Madhuca) butyracea seeds in Escherichia coli.

A cDNA of fatty acyl-acyl carrier protein (ACP) thioesterase (Fat) from developing seed of Madhuca butyracea has been cloned. The deduced amino acid sequence of the cDNA corresponding to the mature polypeptide showed 30-40% and 60-75% identity to the reported FatA and FatB class of plant thioesterases, respectively. This gene, MbFatB, is present as a single copy in M. butyracea genome and the MbFatB protein was detected clearly in seed tissues of this plant but not in that of Indian mustard (Brassica juncea). Heterologous expression of the MbFatB gene driven by different promoters in E. coli wild type and fatty acid beta-oxidation mutant (fadD88) strains resulted production of the recombinant protein with various fusion tags either as biologically inactive (insoluble) or functionally active forms. Expression of functionally active recombinant MbFatB in E. coli affected bacterial growth and cell morphology as well as changed the fatty acid profiles of the membrane lipid and the culture supernatant. Alteration of the fatty acid composition was directed predominantly towards palmitate and to a lesser extent myristate and oleate due to acyl chain termination activity of plant thioesterase in bacteria. Thus, this new MbFatB gene isolated from a non-traditional oil-seed tree can be used in future for transgenic development of oil-seed Brassica, a widely cultivated crop that expresses predominantly oleoyl-ACP thioesterase (FatA) in its seed tissue and has high amount of unwanted erucic acid in edible oil in order to alter the fatty acid profile in a desirable way.

Energy pooling in multiple ionization and Coulomb explosion of clusters by nanosecond-long, megawatt laser pulses.

We report the results of experiments that establish the possibility of bringing about multiple ionization and Coulomb explosion of molecular clusters with nanosecond laser pulses at intensities as small as 10(9) W cm(-2). We demonstrate several new facets of the laser-cluster interaction in the low-intensity, long-pulse domain: (i) The choice of laser wavelength for a given cluster species is very crucial. (ii) Excited electronic states play a very important role in the ionization dynamics. (iii) When field ionization is insignificant and ponderomotive energies are very small, it is energy pooling rather than inverse bremsstrahlung that determines how clusters absorb energy from the optical field.