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Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2–7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3′ untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses.Significance:These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.

Three suppl. tables

Supplementary Table 3 from Identification of Let-7–Regulated Oncofetal Genes

Supplementary Methods, Figures 1-3, Table 1 from Identification of Let-7–Regulated Oncofetal Genes

Resume Les maladies multisystemiques, dont la plupart sont en France prises en charge en medecine interne, touchent par definition plusieurs organes ou tissus. Si les atteintes cutanees ou articulaires sont frequentes, les atteintes neurologiques sont souvent synonymes de gravite. Parmi ces dernieres, les atteintes du systeme nerveux peripherique (par exemple : neuropathies) ou du systeme nerveux central (par exemple : myelites) sont generalement de diagnostic aise, a l’aide de l’expertise clinique et d’examens complementaires adaptes. Les atteintes neuropsychologiques, c’est-a-dire touchant le fonctionnement cognitif, et notamment la memoire, l’attention, les fonctions executives ou les capacites de raisonnement, sont de diagnostic plus difficile, parfois banalisees par les cliniciens. Leurs causes sont souvent multiples et intriquees. Pourtant, ces manifestations cognitives sont cruciales dans le retentissement fonctionnel et le ressenti des patients, et sont etroitement liees a leur qualite de vie. Elles affectent ainsi l’insertion sociale, familiale et professionnelle des patients, et peuvent avoir des retentissements sur le suivi medical ou l’observance medicamenteuse. L’objectif de cette mise au point, sur les troubles cognitifs associes au lupus systemique, de leur physiopathologie a leur prise en charge, est de sensibiliser les medecins internistes aux manifestations cognitives des maladies multisystemiques, a leur prise en charge diagnostique et therapeutique, ainsi que de catalyser les futurs efforts de recherche et de mise en place de parcours de soins pour les patients suivis en medecine interne presentant des difficultes cognitives.

Background Collaborative pharmacy practice agreements (CPPAs) grant patient care authorities to pharmacists (PharmDs) under a scope of practice without direct physician supervision. Objectives The aim of this study was to discuss steps for developing and implementing a CPPA in an outpatient renal transplant clinic and assess changes in physician and nurse burden, integrated pharmacy growth, and patient safety. Practice description A CPPA was developed between physicians and pharmacists and implemented into a renal transplant clinic and the integrated pharmacy over the course of several years. Practice innovation CPPA execution in a post-transplant clinic has not been previously described and is needed to help advance patient care delivery models. Evaluation methods This single center, retrospective study compared immunosuppressant prescriptions generated by each authorizer type (nurse, physician, pharmacist) across 3 time periods: before pharmacist integration, during CPPA development, and after CPPA implementation. Pharmacy manpower and patient safety concerns post-CPPA implementation were also reviewed. Results Results show that prescription authorization migrated from either a nurse or physician (57% and 43% respectively) in pre-PharmD period, to mostly by physicians (72%) in PharmD pre-CPPA period, and largely by pharmacists (85%) in PharmD post-CPPA period. Quarterly prescription volume increased (6019 in quarter 3 of 2015 vs. 14,806 in quarter 4 of 2018) and integrated pharmacy staff grew from 8 employees (Pre-PharmD period) to 20 in PharmD post-CPPA period. No safety concerns were reported in any time period. Conclusion CPPAs have the advantage of reducing physician and nurse workload related to prescribing and advancing the role of the pharmacist by utilizing their expertise to take over certain tasks. Lessons learned during the CPPA implementation process include identifying needs, promoting maximal utility of pharmacists, and maintaining optimal communication between the healthcare team.

International audience; In this report, a catalytic enhanced-conventional process production background was employed to determine the most cost-effective and environmentally friendly techniques to improve the catalytic production of toluene and other aromatic compounds from propane aromatization. 2 wt% of zinc was co-impregnated with 1–3 wt% of cobalt on HZSM-5. Characterizations and analysis showed that catalysts are crystalline and microporous. Propane conversion was carried out at 540 °C, 1200 ml/g-h gas hourly space velocity and atmospheric pressure over Zn–Co/ZSM-5 bimetallic catalysts. Toluene selectivity in the aromatic products was greatly improved and sustained significantly together with other aromatic products. Catalytic conversion of propane and aromatic yield over Zn–Co/ZSM-5 was improved and stabilized due to metallic collaboration on HZSM-5. Aromatic yield averaged 46, 32, and 36%, respectively, for 1–3 wt% Co in Zn–Co/ZSM-5 bimetallic catalyst. Average toluene selectivity in the aromatic products for 12 h time on stream from 60, 50 and 51% for 1–3 wt% Co loading. The threshold loading of cobalt with zinc was 2% above which the general aromatic selectivity declined. A decrease in conversion from 73 to 15% was observed for flowrate increase from 6 to 35 ml min−1 and an increase in aromatic selectivity from 80 to 87%. An increase in temperature of 500–560 °C increased catalytic performance, 32–47% for propane conversion, and 79–86% aromatic selectivity.

Objective: University is a vulnerable period for discontinuing regular physical activity that can 2 have implications for students’ physical and psychological health. Accordingly, it is imperative 3 to find and implement cost and time-effective interventions to mitigate the consequences of this 4 transition. Intervention research has shown mental contrasting is an effective means of 5 promoting various health-enhancing behaviors including physical activity (Oettingen, 2012). 6 However, the efficacy of this intervention approach may be bolstered by targeting affective 7 judgements (e.g., enjoyable-unenjoyable), which exert greater influence on physical activity 8 behaviors compared to health-related instrumental judgements (e.g., useful-useless; Rhodes, 9 Fiala, & Conner, 2009). The purpose of this study was to compare the relative efficacy of a 10 mental contrasting intervention that targeted affective judgements associated with physical 11 activity, in relation to a mental contrasting intervention that targeted instrumental judgements, 12 and a ‘standard’ mental contrasting intervention (with no modifications). Method: Using a three-13 arm parallel randomized controlled trial design (ClinicalTrials.gov #: NCT02615821) 110 14 inactive, female, university students were randomly assigned to an affective, instrumental, or 15 standard mental contrasting intervention following simple randomization procedures. 16 Assessments were conducted at baseline and 4-weeks post intervention. Results: Participants in 17 the affective mental contrasting condition displayed higher levels of moderate-to-vigorous 18 physical activity (MVPA) than those in the instrumental or standard comparison conditions, F(2, 19 90) = 3.14, p < .05, ηp2 = 0.065. Conclusion: Overall, affective mental contrasting has the 20 potential to represent a low-cost and time-efficient intervention that may help inactive, female 21 students increase activity or attenuate declining levels of MVPA that occurs during university.

CD95/Fas ligand induces apoptosis through binding of the protein to the CD95 receptor. However, CD95L mRNA also induces toxicity in the absence of CD95. Dying cells exhibit features of DISE (Death Induced by Survival Gene Elimination), a form of cell death mediated by RNA interference (RNAi). DISE relies on targeting mediated by six nucleotides of complementarity between positions 2-7, the 6mer seed sequence of a RISC-bound (R-sRNA), and the 3’UTR of an mRNA, a feature that allows to predict the effect of 6mer seed sequences on cell viability. We now report that CD95L mRNA processing generates an sRNA nearly identical to shL3, a commercial CD95L-targeting shRNA that led to the discovery of DISE. Neither of the miRNA biogenesis proteins Drosha or Dicer are required for CD95L mRNA processing. Interestingly, CD95L toxicity depends on the core component of the RISC, Ago 2, in some cell lines, but not in others. In the HCT116 colon cancer cell line, Ago 1-4 appear to function redundantly in RNAi. In fact, Ago 1/2/3 knockout cells retained sensitivity to CD95L mRNA toxicity. Toxicity was only blocked by mutation of all in-frame start codons in the CD95L ORF. Expression of a toxic CD95L mRNA caused an enrichment for R-sRNAs with toxic 6mer seed sequences, while expression of the nontoxic CD95L mutant enriched for loading of R-sRNAs with nontoxic 6mer seeds. However, CD95L was not the only source of these R-sRNAs. We found that CD95L mRNA may induce DISE directly and indirectly, and that alternate mechanisms may underlie CD95L mRNA processing and toxicity.

HIV-1 (HIV) infects CD4 positive T cells, the gradual depletion of which can lead to the onset of Acquired Immunodeficiency Syndrome (AIDS) in the absence of antiretroviral therapy (ART). Several forms of cell death have been shown to be involved in HIV-mediated killing of either directly infected or bystander cells. It is still unknown, however, why some cells survive HIV infection and persist as part of the latently infected reservoir that reliably causes recurrent viremia upon ART cessation. Improved understanding of the mechanisms of HIV-mediated cell death could inform innovations designed to clear the latent reservoir. “Death Induced by Survival gene Elimination” (DISE) is an RNA interference (RNAi)-based mechanism that kills cells through short (s)RNAs with toxic 6mer seeds (pos. 2-7 of sRNA). These toxic seeds target reverse complementary seed matches in the 3’UTR of mRNA transcripts to decrease expression of hundreds of genes that are critical for cell survival. In most cells under normal conditions, highly expressed cell-encoded non-toxic microRNAs (miRNAs) block access of toxic sRNAs to the RNA-induced silencing complex (RISC) that mediates RNAi, promoting cell survival. We now report that infection of cells with HIV results in RISC-loading of an HIV-encoded miRNA, v-miRNA HIV-miR-TAR-3p, which kills cells by DISE through a noncanonical (pos. 3-8) 6mer seed. In addition, cellular RISC bound sRNAs shift to lower seed viability. Both these effects also occur with latent HIV provirus reactivation in J-Lat cells, a well-established cell model of HIV latency. Cells lacking expression of miRNA biogenesis genes Drosha, Dicer and Exportin 5 cannot produce protective miRNAs and therefore do not block RISC loading of the v-miRNA HIV-miR-TAR-3p. These mutant cells, as well as cells lacking expression of the RISC component Ago2, are hypersensitive to cell death via DISE induced by HIV infection. More precise targeting of the balance between protective and cytotoxic sRNAs could specifically and transiently increase silencing of cell survival genes to increase DISE. This could be a new addition to a “shock and kill” strategy to enhance depletion of the provirus reservoir during suppressive ART.

We aim to carry out a study on thephotometric and spectroscopic variabilitiesof four stars monitored in the Nainital-Cape survey. We analysed the photometric variability of the target stars, HD 73135,BD +19° 2045, BD +19° 2046, and TYC 1395-855-1, using ground-based differential photometric and K2 data. Spectrophotometricand high-resolution spectroscopic data areused to determine the fundamental parameters and chemical abundances. Althoughall the target are found to be non-variablebased on ground-based differential photometry, the analysis of high-precision K2 photometric time-series reveals that HD 73135,BD +19° 2045, and BD +19° 2046 are variable. We do not detect photometric variability in TYC 1395-855-1. Our analyses showthat the three stars, HD 73135, BD +19° 2045,BD +19° 2046, which are non-variable basedon ground- basedobservationsexhibitrotationalvariability in Kepler K2 data whileTYC 1395-855-1 remains constant in both datasets.Based on the chemical abundanceanalysis, HD 73135 is an Am star, whileBD +19° 2045 is non-Am.

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a recently discovered powerful cell death mechanism mediated by short (s) RNAs including micro (mi) RNAs acting through the RNA induced silencing complex (RISC). G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich seed matches in genes essential for cell survival resulting in the simultaneous activation of multiple cell death pathways. Using Argonaute precipitation and RNAseq (Ago-RP-Seq) we analyzed RISC bound sRNAs (R-sRNAs) inin vitrocell line models and in the brains of twoin vivoAD mouse models and aged mice. In cell line studies we find evidence for a contribution of RNAi to the cell death and DNA damage induced by toxic Aβ42 oligomers. In addition, in AD mouse models and in the aging brain R-sRNAs RISC bound sRNAs show a shift to more toxic seeds. In contrast, in cells of "SuperAgers", individuals over age 80 who have superior memory performance, R-sRNAs are shifted to more nontoxic seeds, supporting a protective function of miRNAs. Cell death induced by Aβ42 oligomers can be rescued by adding back protective miRNAs. Our data provide first evidence of a contribution of RNAi to the neurotoxicity and DNA damage seen in AD suggesting that increasing the levels of protective miRNAs in the brain or blocking the activity of toxic R-sRNAs could lead to a novel way of treating the disease.

In this article, we propose a slice-based interactive segmentation of spectral CT datasets using a bag of features method. The data are acquired from a MARS scanner that divides up the X-ray spectrum into multiple energy bins for imaging. In literature, most existing segmentation methods are limited to performing a specific task or tied to a particular imaging modality. Therefore, when applying generalized methods to MARS datasets, the additional energy information acquired from the scanner cannot be sufficiently utilized. We describe a new approach that circumvents this problem by effectively aggregating the data from multiple channels. Our method solves a classification problem to get the solution for segmentation. Starting with a set of labeled pixels, we partition the data using superpixels. Then, a set of local descriptors, extracted from each superpixel, are encoded into a codebook and pooled together to create a global superpixel-level descriptor (bag of features representation). We propose to use the vector of locally aggregated descriptors as our encoding/pooling strategy, as it is efficient to compute and leads to good results with simple linear classifiers. A linear support vector machine is then used to classify the superpixels into different labels. The proposed method was evaluated on multiple MARS datasets. Experimental results show that our method achieved an average of more than 10% increase in the accuracy over other state-of-the-art methods.

BACKGROUND: Disease-modifying anti-rheumatic drugs (DMARDs) improve symptoms and delay progression of rheumatoid arthritis (RA), but adherence is often sub-optimal and many patients change medication (either "switching" to a medication with a different mechanism of action or "cycling" to a medication with the same mechanism of action) during the first year of therapy. Some integrated health-system specialty pharmacies embed pharmacists in clinics to help patients access and adhere to specialty medication. OBJECTIVE: This study assessed DMARD switching, cycling, adherence, and persistence at an outpatient rheumatology clinic with an integrated health-system specialty pharmacy. METHODS: We conducted a retrospective cohort study of adults with RA, naive to biologic or targeted synthetic DMARDs, who filled ≥ 2 biologic or targeted synthetic DMARD prescriptions within 12 months. Adherence was measured using proportion of days covered (PDC); persistence was computed at 12 months. Univariate analyses compared adherence and persistence between patients with and without a medication change. Ordinal logistic regression examined whether PDC was associated with patient age, gender, race, insurance type, and medication change. RESULTS: We included 772 patients: 79% female/21% male, 89% White/11% non-White, median age 56 years (interquartile range = 48-63). Most patients (84%) did not change medication during the study period, 5% cycled medication one or more times (but did not switch), 9% switched medication one or more times (but did not cycle), and 2% of patients both switched and cycled during the study period. Median PDC of the sample was 0.94 and 73% of patients were persistent. Patients with a medication change had lower PDC than those without (0.89 vs 0.95, P = 0.004), but rate of persistence did not significantly differ between groups (77 vs 72%, P = 0.300). Odds of higher PDC was more likely for men (Odds ratio [OR] = 1.82, 95% confidence interval [CI]: 1.34-2.48, P < 0.001) and less likely for patients who changed medication (OR = 0.65, CI: 0.47-0.91, P = 0.011); age, race, and insurance type were not significant. CONCLUSIONS: Patients with RA demonstrated high medication adherence and persistence, and low rates of switching and cycling. Findings support evidence that integrated health-system specialty pharmacies with clinical pharmacists embedded in outpatient clinics help patients overcome barriers to medication adherence to persist on therapy. DISCLOSURES: This study was funded by Sanofi, Inc. James and J. Choi were employed by Sanofi, Inc., at the time of this study. Peter, Zuckerman, DeClercq, L. Choi, and Tanner, received research funding from Sanofi, Inc., for work on this study. Tanner has also received advisory board/speaker bureau fees from Pfizer, Regeneron, and Sanofi-Aventis. This study was presented as a poster at AMCP Nexus in October 2019 at National Harbor, MD.

Ovarian cancer remains one of the deadliest gynecologic malignancies affecting women, and development of resistance to platinum remains a major barrier to achieving a cure. Multiple mechanisms have been identified to confer platinum resistance. Numerous miRNAs have been linked to platinum sensitivity and resistance in ovarian cancer. miRNA activity occurs mainly when the guide strand of the miRNA, with its seed sequence at position 2–7/8, is loaded into the RNA-induced silencing complex (RISC) and targets complementary short seed matches in the 3′ untranslated region of mRNAs. Toxic 6mer seeds, which target genes critical for cancer cell survival, have been found in tumor-suppressive miRNAs. Many siRNAs and short hairpin RNAs (shRNA) can also kill cancer cells via toxic seeds, the most toxic of which carry G-rich 6mer seed sequences. We showed here that treatment of ovarian cancer cells with platinum led to increased RISC-bound miRNAs carrying toxic 6mer seeds and decreased miRNAs with nontoxic seeds. Platinum-tolerant cells did not exhibit this toxicity shift but retained sensitivity to cell death mediated by siRNAs carrying toxic 6mer seeds. Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. Significance: These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.

n/a Funding Agencies|Knut and Alice Wallenberg Foundation (KAW) through a Wallenberg Scholar grant

This paper examined the problem of kidnapping and its consequences in Nigeria. Kidnapping has the potential of creating social tension, psychological trauma (mental and emotional problems), insecurity, untimely death and others in the society. It has been observed and identified that kidnapping is not a new crime in Nigeria and other countries of the world. But the apparent problem of kidnapping is the current growth rate in all parts of the country and the benefits the perpetrators are deriving from this criminal activity. In this study, some challenges were identified. They include: poverty, unemployment, politics and religion. The mode of kidnappers' operations have been identified and its prevalence, apart from the causes attributed to the laxity in the implementation process to prosecute the offenders. As a result of these findings, it is suggested that the issue of ransom payment by the families/relatives of the victims to kidnappers should be seriously condemned. Government on their part, should endeavour to create employment for the teeming population of youths as this will help to reduce the proliferation of kidnappers. Security agents should be well equipped with sophisticated guns to wage war against kidnappers. This will no doubt help to restore peace and security in the country.

Purpose Health-system specialty pharmacies (HSSPs) provide high-quality, efficient, and collaborative care to patients receiving specialty therapy. Despite proven benefits of the integrated model, manufacturer and payer restrictions challenge the viability and utility of HSSPs. Vanderbilt Specialty Pharmacy developed a health outcomes and research program to measure and communicate the value of this model, drive improvement in patient care delivery, and advocate for recognition of HSSP pharmacists’ role in patient care. The purpose of this descriptive report is to describe the development and results of this program. Summary The health outcomes and research program began as an initiative for pharmacists to evaluate and convey the benefits they provide to patients, providers, and the health system. Early outcomes data proved useful in communicating the value of an integrated model to key stakeholders and highlighted the need to further develop research efforts. The department leadership invested resources to build a research program with dedicated personnel, engaged research experts to train pharmacists, and fostered internal and external collaborations to facilitate research efforts. As of March 2021, the health outcomes and research program team has published 33 peer-reviewed manuscripts, presented 88 posters and 7 podium presentations at national conferences, and received 4 monetary research awards. Further, the program team engages other HSSP teams to initiate and expand their own health outcomes research in an effort to empower all HSSPs in demonstrating their value. Conclusions The health outcomes and research program described has pioneered outcomes research among HSSPs nationwide and has proven valuable to specialty pharmacists, the health system, and key specialty pharmacy stakeholders.

Intracellular pathogens are mainly eliminated by cell-mediated immunity offered by phagocytic cells like neutrophils, macrophages and monocytes. Two tannin glycosides, 1-O-galloyl-6-O-luteoyl-α-D-glucopyranoside (1) and 3-O-methylellagic acid 3'-O-α-rhamnopyranoside (2) were isolated from the ethyl acetate fraction (EF) of the methanol leaf extract of Phyllanthus muellerianus. The structures of the isolated compounds were elucidated by 1H-NMR and by mass spectroscopy. The effects of the isolated compounds on phagocytic competence of macrophages and neutrophils using in vitro models were evaluated. Compounds 1 and 2 significantly (p

The invention of computing devices has brought higher attainment in professional and personal lives. Cybersecurity techniques is of growing importance due to increasing reliance on devices such as computer systems, smart phones, etc. which attempts to safeguard the cyber environment of users or organization . Cyber criminals aim at getting the information between a client and a server which are mostly in plain text formats through various means such as spreading malware inorder to gain unauthorized access. There is a need for users/organization to be aware of the various cyberattacks and in order to prevent such attacks. This paper provides the various open source cybersecurity tools inorder to mitigate the different cyber-attacks.

IntroductionData examining rates of postoperative complications among SARS-CoV-2 positive children are limited. The purpose of this study was to evaluate the impact of symptomatic and asymptomatic SARS-CoV-2 positive status on postoperative respiratory outcomes for children.MethodsThis retrospective cohort study included SARS-CoV-2 positive pediatric patients across 20 hospitals who underwent general anesthesia from March to October 2020. The primary outcome was frequency of postoperative respiratory complications, including: high-flow nasal cannula/non invasive ventilation, reintubation, pneumonia, Extracorporeal Membrane Oxygenation (ECMO), and 30-day respiratory-related readmissions or emergency department (ED) visits. Univariate analyses were used to evaluate associations between patient and procedure characteristics and stratified analyses by symptoms were performed examining incidence of complications.ResultsOf 266 SARS-CoV-2 positive patients, 163 (61.7%) were male, and the median age was 10 years (interquartile range 4-14). The majority of procedures were emergent or urgent (n=214, 80.5%). The most common procedures were appendectomies (n=78, 29.3%) and fracture repairs (n=40,15.0%). 13 patients (4.9%) had preoperative symptoms including cough or dyspnea. 26 patients (9.8%) had postoperative respiratory complications, including 15 requiring high-flow oxygen, 8 with pneumonia, 4 requiring non invasive ventilation, 3 respiratory ED visits, and 2 respiratory readmissions. Respiratory complications were more common among symptomatic patients than asymptomatic patients (30.8% vs. 8.7%, p=0.01). Higher ASA class and comorbidities were also associated with postoperative respiratory complications.ConclusionsPostoperative respiratory complications are less common in asymptomatic versus symptomatic SARS-COV-2 positive children. Relaxation of COVID-19-related restrictions for time-sensitive, non urgent procedures in selected asymptomatic patients may be reasonably considered. Additionally, further research is needed to evaluate the costs and benefits of routine testing for asymptomatic patients.Level of evidenceIii, Respiratory complications.