Safe Step Act: does it undermine step therapy?

Drug expenditure in the United States has continued to increase unsustainably; the specialty of dermatology has been particularly affected. Resources are limited - someone has to make decisions about what treatments will be covered and how they will be reimbursed. Step therapy is a cost-control method used by insurers to encourage the use of the most cost-effective treatments before more expensive options are attempted. However, a rigid step therapy policy can be problematic when protocols are out of date, or delay necessary treatment leading to unnecessary suffering, increased morbidity, and overall cost. To address some of these concerns, the proposed Safe Step Act (S. 2546 and H.R. 2279) attempts to create a requirement that insurers provide a transparent, expeditious exceptions process for step therapy protocols. Increased flexibility in this process will allow for the unique circumstances of individual patients and improve access to expensive drugs for special cases. However, this bill may be exploited, further weakening insurers' ability to negotiate on cost. We should be cautious about measures that reduce the effectiveness of this tool, particularly if we, as a society, aim to expand access to basic care to all Americans

Co3O4 Nanocrystals on Graphene as a Synergistic Catalyst for Oxygen Reduction Reaction

Catalysts for oxygen reduction and evolution reactions are at the heart of key renewable energy technologies including fuel cells and water splitting. Despite tremendous efforts, developing oxygen electrode catalysts with high activity at low costs remains a grand challenge. Here, we report a hybrid material of Co3O4 nanocrystals grown on reduced graphene oxide (GO) as a high-performance bi-functional catalyst for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). While Co3O4 or graphene oxide alone has little catalytic activity, their hybrid exhibits an unexpected, surprisingly high ORR activity that is further enhanced by nitrogen-doping of graphene. The Co3O4/N-doped graphene hybrid exhibits similar catalytic activity but superior stability to Pt in alkaline solutions. The same hybrid is also highly active for OER, making it a high performance non-precious metal based bi-catalyst for both ORR and OER. The unusual catalytic activity arises from synergetic chemical coupling effects between Co3O4 and graphene.Comment: published in Nature Material

Antimony-doped graphene nanoplatelets

Heteroatom doping into the graphitic frameworks have been intensively studied for the development of metal-free electrocatalysts. However, the choice of heteroatoms is limited to non-metallic elements and heteroatom-doped graphitic materials do not satisfy commercial demands in terms of cost and stability. Here we realize doping semimetal antimony (Sb) at the edges of graphene nanoplatelets (GnPs) via a simple mechanochemical reaction between pristine graphite and solid Sb. The covalent bonding of the metalloid Sb with the graphitic carbon is visualized using atomic-resolution transmission electron microscopy. The Sb-doped GnPs display zero loss of electrocatalytic activity for oxygen reduction reaction even after 100,000 cycles. Density functional theory calculations indicate that the multiple oxidation states (Sb3+ and Sb5+) of Sb are responsible for the unusual electrochemical stability. Sb-doped GnPs may provide new insights and practical methods for designing stable carbon-based electrocatalystsclose0

SMURF1 Amplification Promotes Invasiveness in Pancreatic Cancer

Pancreatic cancer is a deadly disease, and new therapeutic targets are urgently needed. We previously identified DNA amplification at 7q21-q22 in pancreatic cancer cell lines. Now, by high-resolution genomic profiling of human pancreatic cancer cell lines and human tumors (engrafted in immunodeficient mice to enrich the cancer epithelial fraction), we define a 325 Kb minimal amplicon spanning SMURF1, an E3 ubiquitin ligase and known negative regulator of transforming growth factor β (TGFβ) growth inhibitory signaling. SMURF1 amplification was confirmed in primary human pancreatic cancers by fluorescence in situ hybridization (FISH), where 4 of 95 cases (4.2%) exhibited amplification. By RNA interference (RNAi), knockdown of SMURF1 in a human pancreatic cancer line with focal amplification (AsPC-1) did not alter cell growth, but led to reduced cell invasion and anchorage-independent growth. Interestingly, this effect was not mediated through altered TGFβ signaling, assayed by transcriptional reporter. Finally, overexpression of SMURF1 (but not a catalytic mutant) led to loss of contact inhibition in NIH-3T3 mouse embryo fibroblast cells. Together, these findings identify SMURF1 as an amplified oncogene driving multiple tumorigenic phenotypes in pancreatic cancer, and provide a new druggable target for molecularly directed therapy

Simple, Rapid and Cost-Effective Method for High Quality Nucleic Acids Extraction from Different Strains of Botryococcus braunii

This study deals with an effective nucleic acids extraction method from various strains of Botryococcus braunii which possesses an extensive extracellular matrix. A method combining freeze/thaw and bead-beating with heterogeneous diameter of silica/zirconia beads was optimized to isolate DNA and RNA from microalgae, especially from B. braunii. Eukaryotic Microalgal Nucleic Acids Extraction (EMNE) method developed in this study showed at least 300 times higher DNA yield in all strains of B. braunii with high integrity and 50 times reduced working volume compared to commercially available DNA extraction kits. High quality RNA was also extracted using this method and more than two times the yield compared to existing methods. Real-time experiments confirmed the quality and quantity of the input DNA and RNA extracted using EMNE method. The method was also applied to other eukaryotic microalgae, such as diatoms, Chlamydomonas sp., Chlorella sp., and Scenedesmus sp. resulting in higher efficiencies. Cost-effectiveness analysis of DNA extraction by various methods revealed that EMNE method was superior to commercial kits and other reported methods by >15%. This method would immensely contribute to area of microalgal genomics

Genomic Profiling Identifies GATA6 as a Candidate Oncogene Amplified in Pancreatobiliary Cancer

Pancreatobiliary cancers have among the highest mortality rates of any cancer type. Discovering the full spectrum of molecular genetic alterations may suggest new avenues for therapy. To catalogue genomic alterations, we carried out array-based genomic profiling of 31 exocrine pancreatic cancers and 6 distal bile duct cancers, expanded as xenografts to enrich the tumor cell fraction. We identified numerous focal DNA amplifications and deletions, including in 19% of pancreatobiliary cases gain at cytoband 18q11.2, a locus uncommonly amplified in other tumor types. The smallest shared amplification at 18q11.2 included GATA6, a transcriptional regulator previously linked to normal pancreas development. When amplified, GATA6 was overexpressed at both the mRNA and protein levels, and strong immunostaining was observed in 25 of 54 (46%) primary pancreatic cancers compared to 0 of 33 normal pancreas specimens surveyed. GATA6 expression in xenografts was associated with specific microarray gene-expression patterns, enriched for GATA binding sites and mitochondrial oxidative phosphorylation activity. siRNA mediated knockdown of GATA6 in pancreatic cancer cell lines with amplification led to reduced cell proliferation, cell cycle progression, and colony formation. Our findings indicate that GATA6 amplification and overexpression contribute to the oncogenic phenotypes of pancreatic cancer cells, and identify GATA6 as a candidate lineage-specific oncogene in pancreatobiliary cancer, with implications for novel treatment strategies

Коррекция двигательных и поведенческих функций в лечении и реабилитации больных шизотипическим расстройством

На основании особенностей невербального поведения больных шизотипическим расстройством разработаны поведенческие методы, применение которых в их комплексной терапии позволяет добиться более полной редукции психопатологической симптоматики.Behavioral methods were worked out basing of the peculiarities of non−verbal behavior of the patients with schizotypical disorders. The use of the methods in complex therapy allows to achieve more complete reduction in psychopathological signs

Identification of genetic alterations in pancreatic cancer by the combined use of tissue microdissection and array-based comparative genomic hybridisation

Pancreatic ductal adenocarcinoma (PDAC) is characterised pathologically by a marked desmoplastic stromal reaction that significantly reduces the sensitivity and specificity of cytogenetic analysis. To identify genetic alterations that reflect the characteristics of the tumour in vivo, we screened a total of 23 microdissected PDAC tissue samples using array-based comparative genomic hybridisation (array CGH) with 1 Mb resolution. Highly stringent statistical analysis enabled us to define the regions of nonrandom genomic changes. We detected a total of 41 contiguous regions (>3.0 Mb) of copy number changes, such as a genetic gain at 7p22.2–p15.1 (26.0 Mb) and losses at 17p13.3–p11.2 (13.6 Mb), 18q21.2–q22.1 (12.0 Mb), 18q22.3–q23 (7.1 Mb) and 18q12.3–q21.2 (6.9 Mb). To validate our array CGH results, fluorescence in situ hybridisation was performed using four probes from those regions, showing that these genetic alterations were observed in 37–68% of a separate sample set of 19 PDAC cases. In particular, deletion of the SEC11L3 gene (18q21.32) was detected at a very high frequency (13 out of 19 cases; 68%) and in situ RNA hybridisation for this gene demonstrated a significant correlation between deletion and expression levels. It was further confirmed by reverse transcription–PCR that SEC11L3 mRNA was downregulated in 16 out of 16 PDAC tissues (100%). In conclusion, the combination of tissue microdissection and array CGH provided a valid data set that represents in vivo genetic changes in PDAC. Our results raise the possibility that the SEC11L3 gene may play a role as a tumour suppressor in this disease

rs4919510 in hsa-mir-608 Is Associated with Outcome but Not Risk of Colorectal Cancer

Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer.A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GG genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal cancer risk (African American: OR(GG vs. CC) 0.89 [95% CI, 0.41-1.80]) (Caucasian: OR(GG vs. CC) 1.76, ([95% CI, 0.48-6.39]). However, we did observe an association with survival. The GG genotype was associated with an increased risk of death in Caucasians (HR(GG vs. CC) 3.54 ([95% CI, 1.38-9.12]) and with a reduced risk of death in African Americans (HR(GG vs. CC) 0.36 ([95% CI 0.12-1.07).These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner that is dependent on race

The Promoter of Rv0560c Is Induced by Salicylate and Structurally-Related Compounds in Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major global health threat. During infection, bacteria are believed to encounter adverse conditions such as iron depletion. Mycobacteria synthesize iron-sequestering mycobactins, which are essential for survival in the host, via the intermediate salicylate. Salicylate is a ubiquitous compound which is known to induce a mild antibiotic resistance phenotype. In M. tuberculosis salicylate highly induces the expression of Rv0560c, a putative methyltransferase. We identified and characterized the promoter and regulatory elements of Rv0560c. PRv0560c activity was highly inducible by salicylate in a dose-dependent manner. The induction kinetics of PRv0560c were slow, taking several days to reach maximal activity, which was sustained over several weeks. Promoter activity could also be induced by compounds structurally related to salicylate, such as aspirin or para-aminosalicylic acid, but not by benzoate, indicating that induction is specific to a structural motif. The −10 and −35 promoter elements were identified and residues involved in regulation of promoter activity were identified in close proximity to an inverted repeat spanning the −35 promoter element. We conclude that Rv0560c expression is controlled by a yet unknown repressor via a highly-inducible promoter