Outcomes and toxicity of oral Fosfestrol in metastatic castration-resistant prostate cancer-a real-world experience.

Introduction: Although there are multiple drugs approved for the treatment of metastatic castration-resistant prostate cancer (CRPC), the cost can be a limiting factor in using them in a resource-limited setting. Therefore, less expensive alternatives are the need of the hour. We have been using Fosfestrol which is a cheap and orally administered oestrogen analogue in metastatic CRPC. We carried out a retrospective study to analyse its efficacy and toxicity. Results: A total of 65 patients received Fosfestrol during 2015-2020. The median age was 65 years (range 50-83 years). Thirty-four patients (53%) had other medical comorbidities. Skeletal-only metastasis was the commonest pattern of metastasis (n = 41, 64%) followed by skeletal with nodal metastasis (n = 15, 23%). The majority of the patients had undergone upfront surgical castration (n = 60, 93%). All the patients had adenocarcinoma and 38 patients (58%) had a high Gleason's score. Forty-one patients (63%) had a prostate-specific antigen (PSA) response (decrease of ≥50% in the PSA concentration from the pre-treatment baseline PSA value) and 54 patients (83%) had a symptomatic response. At the end of a median follow-up of 16 months, the median progression-free survival (PFS) was 8.3 months (CI 4.7-11.8) and the median overall survival (OS) was 27.5 months (CI 25.4-29.5). PSA response and prior treatment with abiraterone acetate were found to have a significant association with survival outcomes. Patients with PSA response had better median PFS and OS; while patients who have received prior abiraterone acetate therapy had worse survival outcomes. Twenty-nine patients (45%) received some form of subsequent treatment after stopping Fosfestrol. The most common oxicity observed was thrombosis (n = 9, 13%) followed by gynecomastia (n = 4, 6%). Conclusion: We conclude that oral Fosfestrol is a cheap and effective agent in the armamentarium against metastatic CRPC and warrants further studies in a clinical trial setting.

Oral metronomic chemotherapy as a feasible preoperative therapy in advanced resectable oral cavity squamous cell carcinomas- a preliminary experience.

Introduction: Surgery is an important component of multimodality treatment in advanced oral cavity cancers. But in low-middle-income countries like India, with limited centres offering complex head and neck surgeries, prolonged waiting times for surgery is a major problem. An increase in waiting times for treatment has been shown to be a negative prognosticator in head and neck cancer and many patients can develop interim progression making them ineligible for radical treatment. We share our preliminary experience of using oral metronomic chemotherapy as a preoperative treatment in patients expecting delay in surgery. Methods: This was a retrospective analysis of case records of patients with resectable Stage III and Stage IV (IVA & IVB) oral cavity cancers who had received preoperative oral metronomic chemotherapy (POMT). The POMT schedule consisted of oral Methotrexate 15 mg/m2 weekly, Celecoxib 200 mg twice daily and Erlotinib 100 mg daily. Clinico-radiological assessments were done prior to surgery using standard response assessment criteria. Results: A total of 68 patients received POMT with a median age of 55 years (range: 34-73 years). Forty-eight (70%) were males, 29 (42%) had carcinoma tongue and majority (N = 52, 76%) had Stage IVA cancer. Mean duration of POMT administration was 30.45 days (standard deviation: 8.22). Thirty-seven (54%) patients had partial responses and another 23 (34%) had stable disease. Two (3%) had disease progression on POMT. Fifty-eight (85%) underwent surgery after POMT. Margin positive resection was seen in two patients. Half of the patients who received POMT did not experience any toxicity. Grade 3/4 toxicities were seen in four (6%) patients. Conclusions: POMT is a feasible strategy worth considering in cases where there are prolonged waiting times to surgery.

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy.

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5'-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

Association of UGT1A6 gene polymorphism with clinical outcome in pediatric epileptic patients on sodium valproate monotherapy

Pediatric epilepsy comprises chronic neurological disorders characterized by recurrent seizures. Sodium valproate is one of the common antiseizure medications used for treatment. Glucuronide conjugation is the major metabolic pathway of sodium valproate, carried out by the enzyme uridine 5′-diphosphate (UDP) glucuronosyl transferase (UGT) whose gene polymorphisms may alter the clinical outcome. The objective of this study was to assess the association between UGT1A6 genetic polymorphism and clinical outcome in terms of efficacy and tolerability in pediatric epileptic patients on sodium valproate monotherapy. Pediatric epileptic patients (n=65) aged 2-18 years receiving sodium valproate monotherapy for the past one month were included. Genetic polymorphism patterns of UGT1A6 (T19G, A541G, A552C) were evaluated by PCR-RFLP. Clinical outcome was seizure control during the 6 months observation period. Tolerability was measured by estimating the hepatic, renal, and other lab parameters. Out of 65 patients, TT (40%), TG (57%), and GG (3%) patterns were observed in UGT1A6 (T19G) gene, AA (51%), AG (40%), and GG (9%) in (A541G) gene, and AA (43%), AC (43%), and CC (14%) in (A552C) gene. No statistical difference in clinical outcome was found for different UGT1A6 genetic polymorphism patterns. We concluded that different patterns of UGT1A6 genetic polymorphism were not associated with the clinical outcome of sodium valproate in terms of efficacy and tolerability. Sodium valproate was well-tolerated among pediatric patients with epilepsy and can be used as an effective antiseizure medication.

Rigidity controls human desmoplastic matrix anisotropy to enable pancreatic cancer cell spread via extracellular signal-regulated kinase 2.

It is predicted that pancreatic ductal adenocarcinoma (PDAC) will become the second most lethal cancer in the US by 2030. PDAC includes a fibrous-like stroma, desmoplasia, encompassing most of the tumor mass, which is produced by cancer-associated fibroblasts (CAFs) and includes their cell-derived extracellular matrices (CDMs). Since elimination of desmoplasia has proven detrimental to patients, CDM reprogramming, as opposed to stromal ablation, is therapeutically desirable. Hence, efforts are being made to harness desmoplasia's anti-tumor functions. We conducted biomechanical manipulations, using variations of pathological and physiological substrates in vitro, to culture patient-harvested CAFs and generate CDMs that restrict PDAC growth and spread. We posited that extrinsic modulation of the environment, via substrate rigidity, influences CAF's cell-intrinsic forces affecting CDM production. Substrates used were polyacrylamide gels of physiological (~1.5 kPa) or pathological (~7 kPa) stiffnesses. Results showed that physiological substrates influenced CAFs to generate CDMs similar to normal/control fibroblasts. We found CDMs to be softer than the corresponding underlying substrates, and CDM fiber anisotropy (i.e., alignment) to be biphasic and informed via substrate-imparted morphological CAF aspect ratios. The biphasic nature of CDM fiber anisotropy was mathematically modeled and proposed a correlation between CAF aspect ratios and CDM alignment; regulated by extrinsic and intrinsic forces to conserve minimal free energy. Biomechanical manipulation of CDMs, generated on physiologically soft substrates, leads to reduction in nuclear translocation of pERK1/2 in KRAS mutated pancreatic cells. ERK2 was found essential for CDM-regulated tumor cell spread. In vitro findings correlated with in vivo observations; nuclear pERK1/2 is significantly high in human PDAC samples. The study suggests that altering underlying substrates enable CAFs to remodel CDMs and restrict pancreatic cancer cell spread in an ERK2 dependent manner.

Strain diversity and relative transmission of Mycobacterium tuberculosis in south coastal Karnataka, India.

BACKGROUND: There are no published reports on the strain diversity and relative transmission of Mycobacterium tuberculosis isolates circulating in Karnataka State, India. OBJECTIVE: To explore the strain diversity of M. tuberculosis isolates and their relative transmission in south coastal Karnataka using spoligotyping and mycobacterial interspersed repetitive unit-variable number of tandem repeats (MIRU-VNTR) typing. DESIGN: A total of 108 clinical isolates of M. tuberculosis were processed for spoligotyping, and 12-locus MIRU-VNTR typing and cluster analysis was performed. RESULTS: Spoligotyping data of 108 isolates revealed 63 spoligotype patterns: 36 (80 isolates, 74.1%) patterns corresponded to spoligotype international types (SITs), whereas 27 (28 isolates, 25.9%) patterns were orphans. A further 57 (52.8%) isolates were clustered into 12 clusters; 51 (47.2%) isolates were unique. The largest spoligotype cluster comprised SIT 48 (L1.2.2), followed by SIT 1942 (L3) and SIT 11 (L1.1.2). Combined MIRU-VNTR typing and spoligotyping analysis further differentiated these 108 isolates into five clusters of two isolates each and 98 individual patterns. CONCLUSIONS: Combined use of spoligotyping and MIRU-VNTR typing is best suited for genotyping studies in this region. Very high genetic diversity was observed among the clinical isolates. Further elaborate studies are required for a better understanding of the genetic diversity and transmission dynamics of the strains circulating in this region.

Response of biopolymer networks governed by the physical properties of cross-linking molecules.

In this study, we examine how the physical properties of cross-linking molecules affect the bulk response of bio-filament networks, an outstanding question in the study of biological gels and the cytoskeleton. We show that the stress-strain relationship of such networks typically undergoes linear increase - strain hardening - stress serration - total fracture transitions due to the interplay between the bending and stretching of individual filaments and the deformation and breakage of cross-linkers. Interestingly, the apparent network modulus is found to scale with the linear and rotational stiffness of the crosslinks to a power exponent of 0.78 and 0.13, respectively. In addition, the network fracture energy will reach its minimum at intermediate rotational compliance values, reflecting the fact that most of the strain energy will be stored in the distorted filaments with rigid cross-linkers while the imposed deformation will be "evenly" distributed among significantly more crosslinking molecules with high rotational compliance.

Selective activation of angiotensin AT2 receptors attenuates progression of pulmonary hypertension and inhibits cardiopulmonary fibrosis.

BACKGROUND AND PURPOSE: Pulmonary hypertension (PH) is a devastating disease characterized by increased pulmonary arterial pressure, which progressively leads to right-heart failure and death. A dys-regulated renin angiotensin system (RAS) has been implicated in the development and progression of PH. However, the role of the angiotensin AT2 receptor in PH has not been fully elucidated. We have taken advantage of a recently identified non-peptide AT2 receptor agonist, Compound 21 (C21), to investigate its effects on the well-established monocrotaline (MCT) rat model of PH. EXPERIMENTAL APPROACH: A single s.c. injection of MCT (50 mg·kg(-1) ) was used to induce PH in 8-week-old male Sprague Dawley rats. After 2 weeks of MCT administration, a subset of animals began receiving either 0.03 mg·kg(-1) C21, 3 mg·kg(-1) PD-123319 or 0.5 mg·kg(-1) A779 for an additional 2 weeks, after which right ventricular haemodynamic parameters were measured and tissues were collected for gene expression and histological analyses. KEY RESULTS: Initiation of C21 treatment significantly attenuated much of the pathophysiology associated with MCT-induced PH. Most notably, C21 reversed pulmonary fibrosis and prevented right ventricular fibrosis. These beneficial effects were associated with improvement in right heart function, decreased pulmonary vessel wall thickness, reduced pro-inflammatory cytokines and favourable modulation of the lung RAS. Conversely, co-administration of the AT2 receptor antagonist, PD-123319, or the Mas antagonist, A779, abolished the protective actions of C21. CONCLUSIONS AND IMPLICATIONS: Taken together, our results suggest that the AT2 receptor agonist, C21, may hold promise for patients with PH.

On the failure load and mechanism of polycrystalline graphene by nanoindentation.

Nanoindentation has been recently used to measure the mechanical properties of polycrystalline graphene. However, the measured failure loads are found to be scattered widely and vary from lab to lab. We perform molecular dynamics simulations of nanoindentation on polycrystalline graphene at different sites including grain center, grain boundary (GB), GB triple junction, and holes. Depending on the relative position between the indenter tip and defects, significant scattering in failure load is observed. This scattering is found to arise from a combination of the non-uniform stress state, varied and weakened strengths of different defects, and the relative location between the indenter tip and the defects in polycrystalline graphene. Consequently, the failure behavior of polycrystalline graphene by nanoindentation is critically dependent on the indentation site, and is thus distinct from uniaxial tensile loading. Our work highlights the importance of the interaction between the indentation tip and defects, and the need to explicitly consider the defect characteristics at and near the indentation site in polycrystalline graphene during nanoindentation.

Inverse pseudo Hall-Petch relation in polycrystalline graphene.

Understanding the grain size-dependent failure behavior of polycrystalline graphene is important for its applications both structurally and functionally. Here we perform molecular dynamics simulations to study the failure behavior of polycrystalline graphene by varying both grain size and distribution. We show that polycrystalline graphene fails in a brittle mode and grain boundary junctions serve as the crack nucleation sites. We also show that its breaking strength and average grain size follow an inverse pseudo Hall-Petch relation, in agreement with experimental measurements. Further, we find that this inverse pseudo Hall-Petch relation can be naturally rationalized by the weakest-link model, which describes the failure behavior of brittle materials. Our present work reveals insights into controlling the mechanical properties of polycrystalline graphene and provides guidelines for the applications of polycrystalline graphene in flexible electronics and nano-electronic-mechanical devices.

Patterned graphone--a novel template for molecular packing.

Precise positioning and packing of nanoscale building blocks is essential for the fabrication of many nanoelectro-mechanical devices. Carrying out such manipulations at the nanoscale still remains a challenge. Here we propose the use of graphone domain arrays embedded in a graphene sheet as a template to precisely position and pack molecules. Our atomistic simulations show that a graphone domain is able to adopt well-defined three-dimensional geometries, which in turn create 'energy wells' to trap molecules by means of physisorption. Using the C60 molecule as a model block, the stable trapping conditions are identified. The present work presents a novel route to position and pack molecules for nanoengineering applications.

A microscopic formulation for the actin-driven motion of listeria in curved paths.

Using a generalized Brownian ratchet model that accounts for the interactions of actin filaments with the surface of Listeria mediated by proteins like ActA and Arp2/3, we have developed a microscopic model for the movement of Listeria. Specifically, we show that a net torque can be generated within the comet tail, causing the bacteria to spin about its long axis, which in conjunction with spatially varying polymerization at the surface leads to motions of bacteria in curved paths that include circles, sinusoidal-like curves, translating figure eights, and serpentine shapes, as observed in recent experiments. A key ingredient in our formulation is the coupling between the motion of Listeria and the force-dependent rate of filament growth. For this reason, a numerical scheme was developed to determine the kinematic parameters of motion and stress distribution among filaments in a self-consistent manner. We find that a 5-15% variation in polymerization rates can lead to radii of curvatures of the order of 4-20 microm, measured in experiments. In a similar way, our results also show that most of the observed trajectories can be produced by a very low degree of correlation, <10%, among filament orientations. Since small fluctuations in polymerization rate, as well as filament orientation, can easily be induced by various factors, our findings here provide a reasonable explanation for why Listeria can travel along totally different paths under seemingly identical experimental conditions. Besides trajectories, stress distributions corresponding to different polymerization profiles are also presented. We have found that although some actin filaments generate propelling forces that push the bacteria forward, others can exert forces opposing the movement of Listeria, consistent with recent experimental observations.

Enhanced quantum confinement due to nonuniform composition in alloy quantum dots.

Strain and nanoscale variations in composition can significantly alter the electronic and optical properties of self-assembled alloy quantum systems. Using a combination of finite element and first-principles methods, we have developed an efficient and accurate technique to study the influence of strain and composition on the quantum confinement behavior in alloy quantum dots. Interestingly, we find that a nonuniform distribution of alloy components can lead to an enhanced confinement potential that allows a large quantum dot to behave electronically in a manner similar to a much smaller dot. The approach presented here provides a general means to quantitatively predict the influence of strain and composition variations on the performance characteristics of various small-scale alloy systems.

17beta-Estradiol modulates local cardiac renin-angiotensin system to prevent cardiac remodeling in the DOCA-salt model of hypertension in rats.

Ventricular remodeling can play a detrimental role in the progression of cardiovascular diseases, leading to heart failure. The current study was designed to investigate the effects of 17beta-estradiol (E2) on cardiac remodeling. Cardiac fibrosis and hypertrophy were examined in deoxycorticosterone acetate (DOCA)-salt treated rats with chronic, six-week administration of two different doses of E2. Bilaterally ovariectomized (Ovex) female Sprague-Dawley rats were randomly assigned to one of the following groups: Ovex-control; Ovex-DOCA; Ovex-DOCA+low-dose E2 (1.66 microg/day); or Ovex-DOCA+high-dose E2 (2.38 microg/day). All DOCA-treated rats were uninephrectomized and drinking water was replaced by 0.15M NaCl solution for the remainder of the study period. DOCA-salt treatment resulted in a significant increase in blood pressure, which was not altered by estrogen replacement. Histological examinations revealed marked cardiac remodeling (both ventricular hypertrophy and interstitial fibrosis) with DOCA treatment, which was attenuated in animals receiving estrogen therapy. Western blot analysis demonstrated increased cardiac levels of angiotensin converting enzyme (ACE) with DOCA treatment, which was attenuated by E2 replacement. Furthermore, increased levels of cardiac angiotensin converting enzyme 2 (ACE2) protein were observed in animals receiving high-dose E2 replacement. These findings suggest that physiologically relevant estrogen replacement therapy has blood pressure-independent cardioprotective effects, which are possibly mediated through modulation of the cardiac renin-angiotensin system.

Substrate-induced magnetism in epitaxial graphene buffer layers.

Magnetism in graphene is of fundamental as well as technological interest, with potential applications in molecular magnets and spintronic devices. While defects and/or adsorbates in freestanding graphene nanoribbons and graphene sheets have been shown to cause itinerant magnetism, controlling the density and distribution of defects and adsorbates is in general difficult. We show from first principles calculations that graphene buffer layers on SiC(0001) can also show intrinsic magnetism. The formation of graphene-substrate chemical bonds disrupts the graphene pi-bonds and causes localization of graphene states near the Fermi level. Exchange interactions between these states lead to itinerant magnetism in the graphene buffer layer. We demonstrate the occurrence of magnetism in graphene buffer layers on both bulk-terminated as well as more realistic adatom-terminated SiC(0001) surfaces. Our calculations show that adatom density has a profound effect on the spin distribution in the graphene buffer layer, thereby providing a means of engineering magnetism in epitaxial graphene.

Melioidosis and tuberculosis: dual pathogens in a neck abscess.

INTRODUCTION: Melioidosis is an infectious disease caused by a saprophytic bacterium, Burkholderia pseudomallei. It is endemic to Southeast Asia and Northern Australia. It may manifest as a pulmonary lesion, osteomyelitis, abscesses in soft tissue and various organs, or as septicaemia. CASE REPORT: We report a case of a 40-year-old, diabetic man who presented with a neck lump resulting from super-infection of a tuberculosis cavity with B pseudomallei. The patient was successfully managed by drainage along with meticulous excision of the capsule and prolonged antibiotic and anti-tubercular treatment. DISCUSSION: Melioidosis may be confused diagnostically with tuberculosis, as both diseases are endemic in the same regions. Our patient was unfortunate to suffer from both endemic diseases simultaneously, perhaps representing the first such case in the world literature. CONCLUSION: Increased awareness of melioidosis is important as, although the organism is easy to culture, it may be dismissed as a contaminant.

Stress-enhanced pattern formation on surfaces during low energy ion bombardment.

Ion-induced surface patterns (sputter ripples) are observed to grow more rapidly than predicted by current models, suggesting that additional sources of roughening may be involved. Using a linear stability analysis, we consider the contribution of ion-induced stress in the near surface region to the formation rate of ripples. This leads to a simple model that combines the effects of stress-induced roughening with the curvature-dependent erosion model of Bradley and Harper. The enhanced growth rate observed on Cu surfaces appears to be consistent with the magnitude of stress measured from wafer curvature measurements.

Spontaneous formation and growth of a new polytype on SiC(0001).

Using in situ electron microscopy, we have measured the structure of SiC(0001)-4H during annealing in vacuum. Above 1000 degrees C, an additional SiC bilayer forms on the surface that changes the polytype from hexagonal (4H) to cubic (3C). The interaction with surface steps prevents the cubic layer from growing thicker: the new phase does not wet the steps of the underlying 4H substrate. Instead, the cubic layer expands laterally, accelerating step bunching in the surrounding hexagonal regions. During SiC homoepitaxy, this lack of step edge wetting leads to the growth of 3C twins separated by deep grooves.