Structure–conductivity correlation in ferric chloride-doped poly(3-hexylthiophene)

Poly(3-hexylthiophene) (P3HT) matrix has been chemically doped (redox doping) by ferric chloride (FeCl3) with different molar concentrations to get P3HT–FeCl3 charge-transfer complexes. The effect of redox doping on photo-physical, structural, and morphological properties and dc electrical conductivity of P3HT matrices has been examined. The dc conductivity has been measured on films of pristine P3HT and P3HT–FeCl3 charge-transfer complexes in the temperature range 6–300 K. Analysis of dc conductivity data reveals that in the temperature range 40–300 K, the dc conductivity is predominantly governed by Mott's 3-dimensional variable range hopping (3D-VRH); however, below 40 K tunnelling seems to dominate. A slight deviation from 3D-VRH to 1D-VRH is observed with an increase in doping level or precisely with an increase in the extent of P3HT–FeCl3 charge-transfer complexes. We attribute this deviation to the induced expansion in crystallographic lattices as revealed by x-ray diffraction data and formation of discrete conducting domains as observed by atomic force microscope imaging

Carbamoylphosphonates inhibit autotaxin and metastasis formation in vivo

Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC(6)H(4)SO(2)NH(CH(2))nNHCOPO(3)H(2), with increasing lengths of methylene chains, (CH(2))(n), n = 4-8. Carbamoylphosphonates having n = 6, 7, 8 inhibited autotaxin in vitro with IC(50) ≈ 1.5 µM. Using an imaging probe we demonstrated that compound n = 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n = 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination

Arylation of 2-Phenylimidazo[1,2-a]pyridine Using Silver(I) Carboxylate

Phosphine-free palladium-catalyzed direct arylation of 2-phenyl-imidazo[1,2-a]pyridine has been developed with the concept of using silver(I) carboxylate. is protocol efficiently catalyzes the C-H arylation of 2-phenyl-imidazo[1,2-a]pyridine with aryl iodides to afford the corresponding 2-phenyl-3-aryl-imidazo[1,2-a]pyridines in moderate to-good yields

Pathophysiological Role and Medicinal Chemistry of A2A Adenosine Receptor Antagonists in Alzheimer's Disease

The A(2A) adenosine receptor is a protein belonging to a family of four GPCR adenosine receptors. It is involved in the regulation of several pathophysiological conditions in both the central nervous system and periphery. In the brain, its localization at pre- and postsynaptic level in striatum, cortex, hippocampus and its effects on glutamate release, microglia and astrocyte activation account for a crucial role in neurodegenerative diseases, including Alzheimer's disease (AD). This ailment is considered the main form of dementia and is expected to exponentially increase in coming years. The pathological tracts of AD include amyloid peptide-beta extracellular accumulation and tau hyperphosphorylation, causing neuronal cell death, cognitive deficit, and memory loss. Interestingly, in vitro and in vivo studies have demonstrated that A(2A) adenosine receptor antagonists may counteract each of these clinical signs, representing an important new strategy to fight a disease for which unfortunately only symptomatic drugs are available. This review offers a brief overview of the biological effects mediated by A(2A) adenosine receptors in AD animal and human studies and reports the state of the art of A(2A) adenosine receptor antagonists currently in clinical trials. As an original approach, it focuses on the crucial role of pharmacokinetics and ability to pass the blood-brain barrier in the discovery of new agents for treating CNS disorders. Considering that A(2A) receptor antagonist istradefylline is already commercially available for Parkinson's disease treatment, if the proof of concept of these ligands in AD is confirmed and reinforced, it will be easier to offer a new hope for AD patients

Multi-Institutional experience with FOLFIRINOX in pancreatic adenocarcinoma

Combination chemotherapy with FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) was shown to be effective in a large phase III trial. The purpose of this study was to examine the tolerance and effectiveness of FOLFIRINOX as practiced outside of the confines of a clinical trial and to document any dose modifications used by practicing oncologists. Data on patients with all stages of pancreatic adenocarcinoma treated with FOLFIRINOX at three institutions was analyzed for efficacy, tolerance, and use of any dose modifications. Total of 61 patients was included in this review. Median age was 58 years (range: 37 to 72 years), 33 were male (54.1%) and majority had ECOG performance of 0 or 1 (86.9%, 53 patients). Thirty-eight (62.3%) had metastatic disease, while 23 (37.7%) were treated for locally advanced or borderline resectable disease. Patients were treated with a median number of four cycles of FOLFIRINOX, with dose modifications in 58.3% (176/302) of all cycles. Ten patients had stable disease (16.4%), four had a partial response (6.6%) while eight had progressive disease (13.1%) on best imaging following therapy. Median progression-free survival and overall survival were 7.5 months and 13.5 months, respectively. The most common grade 3-4 adverse event was neutropenia at 19.7% (12 cases), with 4.9% (3 cases) rate of febrile neutropenia. Twenty-one patients (34.4%) were hospitalized as a result of therapy but there were no therapy-related deaths. Twenty-three (37.7%) had therapy eventually discontinued as a result of adverse events. Despite substantial rates of adverse events and use of dose modifications, FOLFIRINOX was found to be clinically effective in both metastatic and non-metastatic patients. Regimen toxicity did not detract from overall response and survival

Characteristics of spectral aerosol optical depths over India during ICARB

Spectral aerosol optical depth (AOD) measurements, carried out regularly from a network of observatories spread over the Indian mainland and adjoining islands in the Bay of Bengal and Arabian Sea, are used to examine the spatio-temporal and spectral variations during the period of ICARB (March to May 2006). The AODs and the derived Angstrom parameters showed considerable variations across India during the above period. While at the southern peninsular stations the AODs decreased towards May after a peak in April, in the north Indian regions they increased continuously from March to May. The Angstrom coefficients suggested enhanced coarse mode loading in the north Indian regions, compared to southern India. Nevertheless, as months progressed from March to May, the dominance of coarse mode aerosols increased in the columnar aerosol size spectrum over the entire Indian mainland, maintaining the regional distinctiveness. Compared to the above, the island stations showed considerably low AODs, so too the northeastern station Dibrugarh, indicating the prevalence of cleaner environment. Long-range transport of aerosols from the adjoining regions leads to remarkable changes in the magnitude of the AODs and their wavelength dependencies during March to May. HYSPLIT back-trajectory analysis shows that enhanced long-range transport of aerosols, particularly from the west Asia and northwest coastal India, contributed significantly to the enhancement of AOD and in the flattening of the spectra over entire regions; if it is the peninsular regions and the island Minicoy are more impacted in April, the north Indian regions including the Indo Gangetic Plain get affected the most during May, with the AODs soaring as high as 1.0 at 500 nm. Over the islands, the Angstrom exponent (α) remained significantly lower (~1) over the Arabian Sea compared to Bay of Bengal (BoB) (~1.4) as revealed by the data respectively from Minicoy and Port Blair. Occurrences of higher values of α, showing dominance of accumulation mode aerosols, over BoB are associated well with the advection, above the boundary layer, of fine particles from the east Asian region during March and April. The change in the airmass to marine in May results in a rapid decrease in α over the BoB

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer

Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma. Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles. Results: The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials. Conclusions: In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met

Effectiveness of a scalable group-based education and monitoring program, delivered by health workers, to improve control of hypertension in rural India: A cluster randomised controlled trial

New methods are required to manage hypertension in resource-poor settings. We hypothesised that a community health worker (CHW)-led group-based education and monitoring intervention would improve control of blood pressure (BP). We conducted a baseline community-based survey followed by a cluster randomised controlled trial of people with hypertension in 3 rural regions of South India, each at differing stages of epidemiological transition. Participants with hypertension, defined as BP ≥ 140/90 mm Hg or taking antihypertensive medication, were advised to visit a doctor. In each region, villages were randomly assigned to intervention or usual care (UC) in a 1:2 ratio. In intervention clusters, trained CHWs delivered a group-based intervention to people with hypertension. The program, conducted fortnightly for 3 months, included monitoring of BP, education about hypertension, and support for healthy lifestyle change. Outcomes were assessed approximately 2 months after completion of the intervention. The primary outcome was control of BP (BP < 140/90 mm Hg), analysed using mixed effects regression, clustered by village within region and adjusted for baseline control of hypertension (using intention-to-treat principles). Of 2,382 potentially eligible people, 637 from 5 intervention clusters and 1,097 from 10 UC clusters were recruited between November 2015 and April 2016, with follow-up occurring in 459 in the intervention group and 1,012 in UC. Mean age was 56.9 years (SD 13.7). Baseline BP was similar between groups. Control of BP improved from baseline to follow-up more in the intervention group (from 227 [49.5%] to 320 [69.7%] individuals) than in the UC group (from 528 [52.2%] to 624 [61.7%] individuals) (odds ratio [OR] 1.6, 95% CI 1.2-2.1; P = 0.001). In secondary outcome analyses, there was a greater decline in systolic BP in the intervention than UC group (-5.0 mm Hg, 95% CI -7.1 to -3.0; P < 0.001) and a greater decline in diastolic BP (-2.1 mm Hg, 95% CI -3.6 to -0.6; P < 0.006), but no detectable difference in the use of BP-lowering medications between groups (OR 1.2, 95% CI 0.8-1.9; P = 0.34). Similar results were found when using imputation analyses that included those lost to follow-up. Limitations include a relatively short follow-up period and use of outcome assessors who were not blinded to the group allocation. While the durability of the effect is uncertain, this trial provides evidence that a low-cost program using CHWs to deliver an education and monitoring intervention is effective in controlling BP and is potentially scalable in resource-poor settings globally. The trial was registered with the Clinical Trials Registry-India (CTRI/2016/02/006678)

Endocrine therapy resistant ESR1 variants revealed by genomic characterization of breast cancer derived xenografts

To characterize patient-derived xenografts (PDXs) for functional studies, we made whole-genome comparisons with originating breast cancers representative of the major intrinsic subtypes. Structural and copy number aberrations were found to be retained with high fidelity. However, at the single-nucleotide level, variable numbers of PDX-specific somatic events were documented, although they were only rarely functionally significant. Variant allele frequencies were often preserved in the PDXs, demonstrating that clonal representation can be transplantable. Estrogen-receptor-positive PDXs were associated with ESR1 ligand-binding-domain mutations, gene amplification, or an ESR1/YAP1 translocation. These events produced different endocrine-therapy-response phenotypes in human, cell line, and PDX endocrine-response studies. Hence, deeply sequenced PDX models are an important resource for the search for genome-forward treatment options and capture endocrine-drug-resistance etiologies that are not observed in standard cell lines. The originating tumor genome provides a benchmark for assessing genetic drift and clonal representation after transplantation