tbuckley/cabot-search huggingface dataset:
Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease
Authors: Katherine E. Squires, Carolina Montañez-Miranda, Rushika R. Pandya, Matthew P. Torres, John R. Hepler
Journal: Pharmacological Reviews (2018)

Regulators of G protein signaling (RGS) proteins modulate the physiologic actions of many neurotransmitters, hormones, and other signaling molecules. Human RGS proteins comprise a family of 20 canonical proteins that bind directly to G protein–coupled receptors/G protein complexes to limit the lifetime of their signaling events, which regulate all aspects of cell and organ physiology. Genetic variations account for diverse human traits and individual predispositions to disease. RGS proteins contribute to many complex polygenic human traits and pathologies such as hypertension, atherosclerosis, schizophrenia, depression, addiction, cancers, and many others. Recent analysis indicates that most human diseases are due to extremely rare genetic variants. In this study, we summarize physiologic roles for RGS proteins and links to human diseases/traits and report rare variants found within each human RGS protein exome sequence derived from global population studies. Each RGS sequence is analyzed using recently described bioinformatics and proteomic tools for measures of missense tolerance ratio paired with combined annotation-dependent depletion scores, and protein post-translational modification (PTM) alignment cluster analysis. We highlight selected variants within the well-studied RGS domain that likely disrupt RGS protein functions and provide comprehensive variant and PTM data for each RGS protein for future study. We propose that rare variants in functionally sensitive regions of RGS proteins confer profound change-of-function phenotypes that may contribute, in newly appreciated ways, to complex human diseases and/or traits. This information provides investigators with a valuable database to explore variation in RGS protein function, and for targeting RGS proteins as future therapeutic targets.
Adjuvant denosumab in early breast cancer: First results from the international multicenter randomized phase III placebo controlled D-CARE study.
Authors: Robert E. Coleman, Dianne Finkelstein, Carlos H. Barrios, Miguel Martin, Hiroji Iwata, John A. Glaspy, Ying Zhou, Danielle Jandial, Arlene Chan
Journal: Journal of Clinical Oncology (2018)

501 Background: Denosumab (Dmab) is a potent RANK ligand inhibitor approved for the management of treatment induced bone loss in early breast (EBC) and prevention of skeletal morbidity associated with metastatic bone disease. Preclinical data suggested that Dmab could prevent development of bone metastases. This trial evaluated the addition of Dmab to standard (neo)adjuvant therapy for high-risk EBC patients (pts). Methods: 4509 pts with EBC (93.5% node+) from 407 centers were randomized to standard loco-regional and (neo)adjuvant therapy plus either Dmab 120mg sc or matching placebo (P) monthly x 6 then 3 monthly for up to 5 years. In addition to routine clinical follow-up, pts underwent annual CT and bone scan imaging to screen for recurrence. Primary endpoint was bone metastasis free survival (BMFS) defined as first bone metastatic event confirmed by central imaging review or death from any cause. Secondary endpoints included disease free survival (DFS), DFS in the postmenopausal (PM) subgroup, overall survival (OS) and safety. Results: Patient groups were balanced for baseline characteristics with median age 51y, 77% ER+, 20% Her2+ and use of anthracycline and/or taxane chemotherapy in 95.9%. No benefits for the addition of Dmab were seen at a time-driven analysis performed after a median follow-up of 67 months that allowed for the full 5 years of treatment in all pts. Hazard ratio (HR) for BMFS (597 events) was 0.97, 95%CI 0.82-1.14, p = 0.70 and 1.04, 95%CI 0.91-1.19, p = 0.57 for DFS (875 events). OS (412 events) was similar in both groups (HR = 1.03, 95%CI 0.85-1.25). Dmab did not improve BMFS, DFS or OS in the PM subset (n = 2149). Exploratory analysis of time to bone metastases as first recurrence suggested benefit for Dmab (HR = 0.76, 95%CI 0.59-0.97) for this endpoint. Time to on-study fracture prior to bone recurrence was reduced with Dmab (HR = 0.76, 95%CI 0.63-0.92). 122 (5.4%) pts on Dmab and 4 (0.2%) on P developed osteonecrosis of the jaw. 9 (0.4%) pts on Dmab experienced an atypical femoral fracture. Conclusions: Adjuvant Dmab does not reduce breast cancer recurrences or deaths in EBC pts receiving optimal loco-regional and standard of care systemic adjuvant therapy. Clinical trial information: NCT01077154.
From Nanowarming to Thermoregulation: New Multiscale Applications of Bioheat Transfer
Authors: John C. Bischof, Kenneth R. Diller
Journal: Annual Review of Biomedical Engineering (2018)

This review explores bioheat transfer applications at multiple scales from nanoparticle (NP) heating to whole-body thermoregulation. For instance, iron oxide nanoparticles are being used for nanowarming, which uniformly and quickly rewarms 50–80-mL (≤5-cm-diameter) vitrified systems by coupling with radio-frequency (RF) fields where standard convective warming fails. A modification of this approach can also be used to successfully rewarm cryopreserved fish embryos (∼0.8 mm diameter) by heating previously injected gold nanoparticles with millisecond pulsed laser irradiation where standard convective warming fails. Finally, laser-induced heating of gold nanoparticles can improve the sensitivity of lateral flow assays (LFAs) so that they are competitive with laboratory tests such as the enzyme-linked immunosorbent assay. This approach addresses the main weakness of LFAs, which are otherwise the cheapest, easiest, and fastest to use point-of-care diagnostic tests in the world. Body core temperature manipulation has now become possible through selective thermal stimulation (STS) approaches. For instance, simple and safe heating of selected areas of the skin surface can open arteriovenous anastomosis flow in glabrous skin when it is not already established, thereby creating a convenient and effective pathway to induce heat flow between the body core and environment. This has led to new applications of STS to increase or decrease core temperatures in humans and animals to assist in surgery (perioperative warming), to aid ischemic stress recovery (cooling), and even to enhance the quality of sleep. Together, these multiscale applications of nanoparticle heating and thermoregulation point to dramatic opportunities for translation and impact in these prophylactic, preservative, diagnostic, and therapeutic applications of bioheat transfer.
The Value of Negative Diagnosis in Thyroid Fine-Needle Aspiration: a Retrospective Study with Histologic Follow-Up
Authors: Rita Abi-Raad, Manju Prasad, Rebecca Baldassari, Kevin Schofield, Glenda G. Callender, David Chhieng, Adebowale J. Adeniran
Journal: Endocrine Pathology (2018)
Supplemental Vitamins and Minerals for CVD Prevention and Treatment
Authors: David J.A. Jenkins, J. David Spence, Edward L. Giovannucci, Young-in Kim, Robert Josse, Reinhold Vieth, Sonia Blanco Mejia, Effie Viguiliouk, Stephanie Nishi, Sandhya Sahye-Pudaruth, Melanie Paquette, Darshna Patel, Sandy Mitchell, Meaghan Kavanagh, Tom Tsirakis, Lina Bachiri, Atherai Maran, Narmada Umatheva, Taylor McKay, Gelaine Trinidad, Daniel Bernstein, Awad Chowdhury, Julieta Correa-Betanzo, Gabriella Del Principe, Anisa Hajizadeh, Rohit Jayaraman, Amy Jenkins, Wendy Jenkins, Ruben Kalaichandran, Geithayini Kirupaharan, Preveena Manisekaran, Tina Qutta, Ramsha Shahid, Alexis Silver, Cleo Villegas, Jessica White, Cyril W.C. Kendall, Sathish C. Pichika, John L. Sievenpiper
Journal: Journal of the American College of Cardiology (2018)

The authors identified individual randomized controlled trials from previous meta-analyses and additional searches, and then performed meta-analyses on cardiovascular disease outcomes and all-cause mortality. The authors assessed publications from 2012, both before and including the U.S. Preventive Service Task Force review. Their systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, β-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks.
Abstract 15716: Tristetraprolin Protects the Heart Against Iron Deficiency by Reducing Expression of Iron-requiring Proteins and Optimizing Cellular Iron Utilization
Authors: Tatsuya Sato, Marina Bayeva, Hossein Ardehali
Journal: Circulation (2015)

Background: Iron deficiency is the most common nutrient deficiency in the world, however, patients with severe iron deficiency generally have normal cardiac function. This suggests that a mechanism exists in the heart that maintains cardiac iron levels despite systemic iron deficiency, however, the mechanism for this adaptation of the heart to iron deficiency is not known. We recently discovered an mRNA-binding protein tristetraprolin (TTP) to mediate iron utilization within an iron-deprived cell independently of the canonical iron regulatory proteins (IRPs). Here, we hypothesized that TTP protects the heart against iron deficiency through intracellular conservation of iron, and that disruption of this pathway will make the heart vulnerable to low-iron states. Results: Consistent with the above hypothesis, we demonstrated that hearts of TTP knockout mice have normal baseline function, yet deteriorate when subjected to iron deficiency. On contrary, iron-deficient TTP WT mice show no decline in cardiac function in spite of significant reduction in iron levels. Since TTP is known to reduce protein expression through mRNA degradation, we hypothesized that it halts expression of iron-consuming proteins, reducing overall cardiomyocyte’s iron requirements. We identified three mitochondrial iron-requiring proteins to be negatively regulated by TTP: NDUFS1 (part of complex I), UQCRFS1 (part of complex III), and mitochondrial aconitase (part of the TCA cycle). Specifically, we showed that TTP binds to and degrades mRNAs of these targets. This is based on data that the steady state level of the mRNAs for these proteins are decreased with iron chelation, but do not change with TTP deletion. Additionally, mRNAs of these proteins are protected against after actinomycin-D treatment with TTP deletion. RNA co-immunoprecipitation studies confirmed TTP binding to the mRNAs of these proteins. Thus, in the absence of TTP, these proteins continue to be expressed and act as “iron sinks” in a cell that is already iron deficient. Conclusions: Our results, for the first time, provide the mechanism of cellular adaptation to iron deficiency, and demonstrate a major role for TTP in this process by regulating mitochondrial proteins.
The study of relationships between pKa value and siRNA delivery efficiency based on tri-block copolymers
Authors: Lili Du, Changrong Wang, Lingwei Meng, Qiang Cheng, Junhui Zhou, Xiaoxia Wang, Deyao Zhao, Jianhua Zhang, Liandong Deng, Zicai Liang, Anjie Dong, Huiqing Cao
Journal: Biomaterials (2018)

Tri-block copolymers have exhibited great potentials in small interfering RNA (siRNA) therapeutics. To reveal structure-activity relationships, we here synthesized a series of tri-block copolymers with different hydrophobic segments, PEG-PAMA-P(C6Ax-C7Ay-DPAz-DBAm) (EAAS) and PEG-PDAMAEMA-P(C6Ax-C7Ay-DPAz-DBAm) (EDAS), termed from EAASa to EAASh and EDASa to EDASh, with pKa ranging from 5.2 to 7.0. Our data showed that the better gene silencing efficiency was located in pKa of 5.8–6.2, which was contributed from higher endosomal escape observed with confocal images and hemolysis assay. EAASc, the leader polymer, showed excellent gene knockdown at w/w ratio of 14.5 on HepG2 (89.94%), MDA-MB-231 (92.45%), 293A (83.06%), and Hela cells (80.27%), all better than lipofectamine 2000. Besides, EAASc mediated effective gene silencing in tumor when performed peritumoral injection. This work found out that polymers with pKa ranging from 5.8 to 6.2 were efficient in siRNA delivery, which provided an optimization strategy for siRNA delivery systems, especially for tri-block copolymers.
Effect of Higher vs Standard Dosage of Vitamin D<sub>3</sub>Supplementation on Bone Strength and Infection in Healthy Infants
Authors: Jenni Rosendahl, Saara Valkama, Elisa Holmlund-Suila, Maria Enlund-Cerullo, Helena Hauta-alus, Otto Helve, Timo Hytinantti, Esko Levälahti, Eero Kajantie, Heli Viljakainen, Outi Mäkitie, Sture Andersson
Journal: JAMA Pediatrics (2018)

Although guidelines for vitamin D supplementation in infants have been widely implemented, they are mostly based on studies focusing on prevention of rickets. The optimal dose for bone strength and infection prevention in healthy infants remains unclear.To determine whether daily supplementation with 1200 IU of vitamin D3 increases bone strength or decreases incidence of infections in the first 2 years of life compared with a dosage of 400 IU/d.A randomized clinical trial involving a random sample of 975 healthy term infants at a maternity hospital in Helsinki, Finland. Study recruitment occurred between January 14, 2013, and June 9, 2014, and the last follow-up was May 30, 2016. Data analysis was by the intention-to-treat principle.Randomization of 489 infants to daily oral vitamin D3 supplementation of 400 IU and 486 infants to 1200 IU from age 2 weeks to 24 months.Primary outcomes were bone strength and incidence of parent-reported infections at 24 months.Of the 975 infants who were randomized, 485 (49.7%) were girls and all were of Northern European ethnicity. Eight hundred twenty-three (84.4%) completed the 24-month follow-up. We found no differences between groups in bone strength measures, including bone mineral content (mean difference, 0.4 mg/mm; 95% CI, -0.8 to 1.6), mineral density (mean difference, 2.9 mg/cm3; 95% CI, -8.3 to 14.2), cross-sectional area (mean difference, -0.9 mm2; 95% CI, -5.0 to 3.2), or polar moment of inertia (mean difference, -66.0 mm4, 95% CI, -274.3 to 142.3). Incidence rates of parent-reported infections did not differ between groups (incidence rate ratio, 1.00; 95% CI, 0.93-1.06). At birth, 914 of 955 infants (95.7%) were vitamin D sufficient (ie, 25-hydroxyvitamin D [25(OH)D] concentration ≥20.03 ng/mL). At 24 months, mean 25(OH)D concentration was higher in the 1200-IU group than in the 400-IU group (mean difference, 12.50 ng/mL; 95% CI, 11.22-13.78).A vitamin D3 supplemental dose of up to 1200 IU in infants did not lead to increased bone strength or to decreased infection incidence. Daily supplementation with 400 IU vitamin D3 seems adequate in maintaining vitamin D sufficiency in children younger than 2 years.ClinicalTrials.gov Identifier: NCT01723852.
Homeopathy: challenge to prescription ban is rejected by High Court
Authors: Clare Dyer
Journal: BMJ (2018)

A legal challenge by the British Homeopathic Association to NHS England guidance stating that GPs should not prescribe homeopathic treatments has been comprehensively rejected by the High Court.1

The association had challenged a consultation by NHS England on the use of homeopathy and a decision to issue guidance to clinical commissioning groups in November 2017. This recommended that GPs should not prescribe homeopathic remedies to new patients and that doctors should be “supported in …
Prognostic Significance of Interim 11C-Methionine PET/CT in Primary Central Nervous System Lymphoma
Authors: Seo-Yeon Ahn, Seong Young Kwon, Sung-Hoon Jung, Jae-Sook Ahn, Su Woong Yoo, Jung-Joon Min, Hee-Seung Bom, So Yeon Ki, Hyeoung-Joon Kim, Je-Jung Lee, Sang Yun Song, Deok-Hwan Yang
Journal: Clinical Nuclear Medicine (2018)

Primary central nervous system lymphoma (PCNSL) has a poor prognosis. There has been limited study evaluating the role of interim PET/CT in PCNSL. This prospective study investigated the interim response using sequential brain PET/CT with C-methionine (C-MET) to provide prognostic information during the treatment of PCNSL.A total of 26 immunocompetent patients recently diagnosed with PCNSL were evaluated. Brain MRI and C-MET PET/CT were performed at the time of diagnosis and after 4 cycles of high-dose methotrexate-based induction chemotherapy. Tumor-to-normal tissue (T/N) ratio and MTV were used to assess the interim response.All patients had diffuse large B-cell lymphoma. No differences were observed in initial tumor volume or quantitative uptake among the International Extranodal Lymphoma Study Group groups. Higher International Extranodal Lymphoma Study Group risk scores were associated with higher median values for interim MTV and T/N ratios, as well as poor outcomes. After a median follow-up of 21 months, interim C-MET PET/CT assessments based on the quantitative T/N ratio and MTV predicted progression-free survival and overall survival, respectively. A high interim T/N ratio was significantly associated with decreased progression-free survival (hazards ratio, 3.68; P = 0.044).Response assessments based on interim C-MET PET/CT could predict the therapeutic outcome of PCNSL.
Effects of land use on zoonotic host communities: a global correlative analysis
Authors: Rory Gibb, David W Redding, Kai Qing Chin, Tim M Blackburn, Tim Newbold, Kate E Jones
Journal: The Lancet Planetary Health (2018)

BackgroundEnvironmental trade-offs associated with land use—for example, between food security and biodiversity conservation—are crucial dimensions of planetary health. Land use-driven biodiversity change might predictably affect disease risk if reservoir host species are consistently more likely to persist under human disturbance (ie, if ecological communities in modified habitats generally have a higher zoonotic potential than those in unmodified habitats). Such a phenomenon has been observed in specific disease systems, but with substantial change in global land use projected for this century, assessing its global and taxonomic generality would shed light on an important hypothesised driver of environmental synergies or trade-offs between conservation and public health.MethodsWe collated data on hosts of human parasites and pathogens from the published literature, and combined these with the Projecting Responses of Ecological Diversity in Changing Terrestrial Systems (PREDICTS) global database of local ecological communities and associated land use data. We analysed the effects of land use on host richness and abundance across 7330 sites globally, controlling for disease-related research effort and differences in survey methods.FindingsEcological communities in anthropogenic land uses (managed and urban ecosystems) contained a consistently higher richness and abundance of host species than did communities in nearby primary (undisturbed) sites. However, among mammal hosts of zoonotic pathogens, we found considerable taxonomic variation in host responses to land use, with abundances of rodents and bats generally increasing and those of primates and carnivores generally declining in modified landscapes.InterpretationOur results suggest that future change in global land use has the potential to drive overall increasing contact between people and ecological communities with increased shared pathogen potential (ie, more potential hosts and possible opportunities for transmission). However, the differences in host responses to modified landscapes among mammal orders suggests that these changes are unlikely to affect all zoonotic diseases consistently. This result supports arguments that, rather than expecting a consistent relationship between biodiversity change and disease, in practice, policies aiming both to conserve biodiversity and reduce human disease (eg, through establishment of protected areas) must be disease and context specific.FundingThis research was supported by a Graduate Research Scholarship from University College London (to RG), the Natural Environment Research Council (to DWR and KEJ), and a Royal Society University Research Fellowship (to TN).
Estrogen abrogates zoledronic acid induced gene expression signature in endocrine sensitive tumor cell lines <i>in vitro</i>.
Authors: Sigrid Weingartshofer, Martin Bilban, Marie Theres Kastner, Juraj Hlavaty, Ingrid Walter, Thomas W. Grunt, Christian F. Singer
Journal: Journal of Clinical Oncology (2018)

e12570 Background: Clinical data from several trials (ABCSG-12, ZO-FAST, AZURE) suggest an improved disease-free survival after the treatment with zoledronic acid (ZO) in adjuvant breast cancer, with an improved overall survival in women after ZO treatment that were more than five years postmenopausal or older than 60 years at baseline. The chief object of the study was to identify the molecular mechanism at genomic, non-genomic and mitochondrial levels that protect hormone-sensitive breast cancer cells from ZO induced cell death. We here report the genomic level. Methods: To identify the most re-sensitive days against estradiol (1nM E2) and Insulin-like growth factor 1 (10ng/ml IGF-1), a proliferation assay was performed using MCF-7, T47D and MDA-MB-231 breast cancer cell lines. EZ4U and SRB assays were used to investigate the influence of several ZO concentrations (0µM, 6.25µM, 12.5µM, 25µM, 50µM and 100µM) and 1nM E2 and 10ng/ml IGF-1 under estrogen-free conditions. Data of a microarray (Affymetrix) were analyzed to identify target genes involved in the interaction of E2 combined with ZO treatment. Results: The proliferation assay showed that day six and day eight are the most responsive days to E2 and to IGF-1. At these days, in cell viability assays, MCF-7 and T47D cells showed significantly reduced cell death in low ZO concentrations in the presence of E2 but not in the presence of IGF-1. MDA-MB-231 cells didn’t show significantly inhibited response neither to E2 nor to IGF-1. The Venn diagram of performed microarray analysis resulted in a cluster of 113 genes which are up- and downregulated by ZO, E2 and ZO+E2. Hierarchical clustering in a heatmap then performed with the complete linkage method using the Euclidean distance measure resulted in 23 genes downregulated only by E2 which will be used for further experiments. Conclusions: Clinical findings and our preliminary results suggest that estrogen leads to an inactivation of ZO induced gene expression signatures and affect the potential anticancer activity of ZO treatment. Consequently, our study can contribute to a better understanding of the action of ZO in vitro and thus, may ultimately lead to a more accurate therapy for breast cancer.