tbuckley/cabot-search huggingface dataset:
Activation of Endoplasmic Reticulum-Specific Stress Responses Associated with the Liver Disorder Hereditary Haemochromatosis
Authors: MW Lawless, S Norris
Journal: Endoscopy (2006)

Aims: The aim of this study was to characterise the intracellular events involved in the molecular pathogenesis of HH induced liver disease, in particular the unfolded protein response (UPR) indicated by increased GRP78/BiP and GRP94 protein production.
The difference between ice cream and Nazis: Moral externalization and the evolution of human cooperation
Authors: P. Kyle Stanford
Journal: Behavioral and Brain Sciences (2017)

Abstract A range of empirical findings is first used to more precisely characterize our distinctive tendency to objectify or externalize moral demands and obligations, and it is then argued that this salient feature of our moral cognition represents a profound puzzle for evolutionary approaches to human moral psychology that existing proposals do not help resolve. It is then proposed that such externalization facilitated a broader shift to a vastly more cooperative form of social life by establishing and maintaining a connection between the extent to which an agent is herself motivated by a given moral norm and the extent to which she uses conformity to that same norm as a criterion in evaluating candidate partners in social interaction generally. This connection ensures the correlated interaction necessary to protect those prepared to adopt increasingly cooperative, altruistic, and other prosocial norms of interaction from exploitation, especially as such norms were applied in novel ways and/or to novel circumstances and as the rapid establishment of new norms allowed us to reap still greater rewards from hypercooperation. A wide range of empirical findings is then used to support this hypothesis, showing why the status we ascribe to moral demands and considerations exhibits the otherwise puzzling combination of objective and subjective elements that it does, as well as showing how the need to effectively advertise our externalization of particular moral commitments generates features of our social interaction so familiar that they rarely strike us as standing in need of any explanation in the first place.
Cancer-Associated Fibroblasts Share Characteristics and Protumorigenic Activity with Mesenchymal Stromal Cells
Authors: Lucia Borriello, Rie Nakata, Michael A. Sheard, G. Esteban Fernandez, Richard Sposto, Jemily Malvar, Laurence Blavier, Hiroyuki Shimada, Shahab Asgharzadeh, Robert C. Seeger, Yves A. DeClerck
Journal: Cancer Research (2017)

Cancer-associated fibroblasts (CAF) have been suggested to originate from mesenchymal stromal cells (MSC), but their relationship with MSCs is not clear. Here, we have isolated from primary human neuroblastoma tumors a population of αFAP- and FSP-1-expressing CAFs that share phenotypic and functional characteristics with bone marrow-derived MSCs (BM-MSC). Analysis of human neuroblastoma tumors also confirmed the presence of αFAP- and FSP-1-positive cells in the tumor stroma, and their presence correlated with that of M2 tumor-associated macrophages. These cells (designated CAF-MSCs) enhanced in vitro neuroblastoma cell proliferation, survival, and resistance to chemotherapy and stimulated neuroblastoma tumor engraftment and growth in immunodeficient mice, indicating an effect independent of the immune system. The protumorigenic activity of MSCs in vitro and in xenografted mice was dependent on the coactivation of JAK2/STAT3 and MEK/ERK1/2 in neuroblastoma cells. In a mouse model of orthotopically implanted neuroblastoma cells, inhibition of JAK2/STAT3 and MEK/ERK/1/2 by ruxolitinib and trametinib potentiated tumor response to etoposide and increased overall survival. These data point to a new type of protumorigenic CAF in the tumor microenvironment of neuroblastoma and to STAT3 and ERK1/2 as mediators of their activity. Cancer Res; 77(18); 5142-57. ©2017 AACR.
EFFECTS OF REDUCED PLANTAR CUTANEOUS SENSATION ON GAIT KINEMATICS IN INDIVIDUALS WITH OR WITHOUT CHRONIC ANKLE INSTABILITY
Authors: Mi Hyang Chang, Tae Kyu Kang, Sae Yong Lee
Journal: British Journal of Sports Medicine (2017)

Background Chronic ankle instability (CAI) is associated with repetitive lateral ankle sprains, exhibiting postural-control deficits and altered gait biomechanics. Plantar cutaneous receptors have been theorized to affect postural control, but their contribution to postural-control deficits shown in CAI group during walking is unclear. Objective To examine the effect of diminished plantar cutaneous sensation induced by cooling on gait kinematics in participants with or without CAI. Design Case-control study. Setting Laboratory. Patients (or Participants) Seven individuals with CAI (age: 23.57±2.72 years; height: 166.14±7.74 cm; weight: 67.84±12.60 kg) and 10 healthy controls (age: 23.4±2.15 years; height: 164.29±5.88 cm; weight: 59.16±9.66 kg). Interventions (or Assessment of Risk Factors) The plantar aspect of the participants' foot was submersed in ice water (0°C) for 10 minutes to induce hypoesthesia. Before and after the cooling procedure, plantar cutaneous sensation thresholds and walking trials were measured. Main Outcome Measurements 3-dimensional lower extremity joint kinematics were recorded throughout the gait cycle. Group means and 95% confidence intervals were compared for percentages of the gait cycle where the confidence intervals did not overlap. Results With plantar hypoesthesia, CAI participants indicated less hip adduction from 5% to 70% (mean difference=3.44±1.66°) and more knee internal rotation from 32% to 54%(mean difference=11.78±0.74°), and from 88% to 100%(mean difference=8.65±0.91°) of the gait cycle compared to healthy controls. No significant interactions were found between sensation and groups for lower extremity gait kinematics during walking. Conclusions There was no significant effect of reduced plantar cutaneous sensation on gait kinematics in individual with or without CAI. The alterations in proximal joint kinematics can be a preservation strategy for individuals with CAI to complete normal ambulation. Our findings may explain that there are other factors contributing to altered proximal joint kinematics in CAI group during gait than plantar cutaneous sensation.
Abstract 121: Hyperglycemia-induced Prorenin Receptor Abundance on Plasma Membrane of Kidney Collecting Duct Cells: is a Novel Mechanism to Explain Diabetic Nephropathy?
Authors: Venkateswara R Gogulamudi, Danielle Y Arita, Camille RT Bourgeois, Ryosuke Satou, Minolfa C Prieto
Journal: Circulation Research (2015)

Activation of the renin-angiotensin system (RAS) leads to nephropathy during Diabetes Mellitus (DM). Prorenin levels are increased in the circulation of DM patients and predict microvascular damage. In streptozotocin (STZ)-induced type 1 DM rats, the collecting duct is the major source of prorenin in the kidney. The prorenin receptor (PRR), a new RAS component, elicits intracellular signals linked to fibrosis upon binding of prorenin at the cell plasma membrane (PM). We propose that PRR may contribute to the development of tubulointerstitial fibrosis by being locally activated by prorenin. To support this concept, we tested the hypothesis that hyperglycemia increases membrane bound PRR to collecting duct cells. To address this hypothesis, we used T1DM rats (N=10) induced with a single STZ injection (ip; 200ng/kg x 7 d) as well as mouse collecting duct M-1 cells, treated at different time intervals 0, 5 min, 1, 12, and 24 h with normal glucose (NG; 5mM glucose+20mM mannitol) and high glucose (HG; 25mM) to assess PRR trafficking alterations induced by glucose. After 7-days induction, STZ-rats showed plasma glucose as 428±13 vs.138±9 gr/dl and plasma insulin as 0.07±0.02 vs 2.42 ng/ml; compared to controls. By immunofluorescence (IF) in rat kidney sections, PRR was mainly localized on the apical aspect of collecting duct cells in STZ-rats, while in controls most of PRR signal was observed intracellularly. Although PRR mRNA levels did not differ in the collecting ducts between groups; its protein levels were augmented in STZ-rats. Importantly, compared with NG-treated cells, PRR protein levels (membrane bound) were significantly higher in PM extracts from M-1 cells treated with HG, and a maximum peak was observed at 1 h. Interestingly, in de-convoluted IF images of M-1 cells, PRR was localized mainly in the perinuclear areas during NG conditions; however, in HG-treated cells, PRR was found toward the cell surface. These data suggest that hyperglycemia induces PRR trafficking alterations of PRR. The present results suggest that hyperglycemia-induced PRR abundance on the PM in the collecting duct might be a novel mechanism underlying the development of diabetic nephropathy, particularly tissue fibrosis in DM. Grant support by the NIH-NIDDK (DK104375-01)
A case of Alagille syndrome presenting with chronic cholestasis in an adult
Authors: Jihye Kim, Bumhee Yang, Namyoung Paik, Yon Ho Choe, Yong-Han Paik
Journal: Clinical and Molecular Hepatology (2017)

Alagille syndrome (AGS) is a complex multisystem disorder that involves mainly the liver, heart, eyes, face, and skeleton. The main associated clinical features are chronic cholestasis due to a paucity of intrahepatic bile ducts, congenital heart disease primarily affecting pulmonary arteries, vertebral abnormalities, ocular embryotoxon, and peculiar facies. The manifestations generally become evident at a pediatric age. AGS is caused by defects in the Notch signaling pathway due to mutations in JAG1 or NOTCH2. It is inherited in an autosomal dominant pattern with a high degree of penetrance, but variable expressivity results in a wide range of clinical features. Here we report on a 31-year-old male patient who presented with elevated serum alkaline phosphatase and gamma-glutamyl transpeptidase, and was diagnosed with AGS associated with the JAG1 mutation after a comprehensive workup.
Docetaxel, oxaliplatin, and fluorouracil/leucovorin (FLOT) versus epirubicin, cisplatin, and fluorouracil or capecitabine (ECF/ECX) as perioperative treatment of resectable gastric or gastro-esophageal junction adenocarcinoma: The multicenter, randomized phase 3 FLOT4 trial (German Gastric Group at AIO)
Authors: Salah-Eddin Al-Batran, Claudia Pauligk, Nils Homann, Harald Schmalenberg, Hans-Georg Kopp, Georg Martin Haag, Barbara Luley Kim, H. Schmiegel Wolff, Gunnar Folprecht, Stephan Probst, Nicole Prasnikar, C. Thuss-Patience Peter, Jorg Trojan, Thorsten Oliver Goetze, Johannes Meiler, H. Schuler Martin, Elke Jäger, Ralf-Dieter Hofheinz
Journal: Annals of Oncology (2017)
Air pollution link to premature death is supported by US study
Authors: Jacqui Wise
Journal: BMJ (2017)

Long term exposure to airborne fine particulate matter (PM2.5) and ozone increases the risk of premature death even at levels below current air quality standards, a US study of 60 million people suggests.1

Researchers writing in the New England Journal of Medicine said that lowering PM2.5 by just 1 microgram per cubic metre (μg/m3) throughout the United States could save 12 000 lives every year. Similarly, if the level of ozone could be lowered by just one part per billion (ppb) nationwide, another 1900 lives a year could be saved.

The …
Supporting patients who are bereaved
Authors: M Katherine Shear, Stephanie Muldberg, Vyjeyanthi Periyakoil
Journal: BMJ (2017)

#### What you need to know

A doctor consults with a 69 year old patient and notes that she seems distant and sad. It is three months since her partner died. When the doctor asks how she is managing she says the house feels empty without him and she feels low. She no longer sees any reason to cook and struggles to clean. She longs for companionship but refuses invitations from her friends because being with them makes her miss her partner. Her grandchildren are a pleasure but they ask about grandpa, so she doesn’t want to see them. Tearfully, she talks of dreading her future.

A woman presents with sleep disturbance and severe headaches a month after her son died by suicide. She believes that a good mother would have saved him and she is plagued by guilty self-recrimination. She seems irritable and has been fighting with her husband. She has been finding it very hard to care for her two living children.

Loss of a loved one can be very painful. When seeking support, some people turn to their doctor. Because of their pivotal role in the community, physicians can provide excellent support for bereaved people and can often direct them to additional resources.1 Medical professionals who see bereaved patients …
Tissue-Specific MicroRNA Expression Patterns in Four Types of Kidney Disease
Authors: Maria Angeles Baker, Seth J. Davis, Pengyuan Liu, Xiaoqing Pan, Anna Marie Williams, Kenneth A. Iczkowski, Sean T. Gallagher, Kaylee Bishop, Kevin R. Regner, Yong Liu, Mingyu Liang
Journal: Journal of the American Society of Nephrology (2017)

MicroRNAs contribute to the development of kidney disease. Previous analyses of microRNA expression in human kidneys, however, were limited by tissue heterogeneity or the inclusion of only one pathologic type. In this study, we used laser-capture microdissection to obtain glomeruli and proximal tubules from 98 human needle kidney biopsy specimens for microRNA expression analysis using deep sequencing. We analyzed specimens from patients with diabetic nephropathy (DN), FSGS, IgA nephropathy (IgAN), membranoproliferative GN (MPGN) (n=19-23 for each disease), and a control group (n=14). Compared with control glomeruli, DN, FSGS, IgAN, and MPGN glomeruli exhibited differential expression of 18, 12, two, and 17 known microRNAs, respectively. The expression of several microRNAs also differed between disease conditions. Specifically, compared with control or FSGS glomeruli, IgAN glomeruli exhibited downregulated expression of hsa-miR-3182. Furthermore, in combination, the expression levels of hsa-miR-146a-5p and hsa-miR-30a-5p distinguished DN from all other conditions except IgAN. Compared with control proximal tubules, DN, FSGS, IgAN, and MPGN proximal tubules had differential expression of 13, 14, eight, and eight microRNAs, respectively, but expression of microRNAs did not differ significantly between the disease conditions. The abundance of several microRNAs correlated with indexes of renal function. Finally, we validated the differential glomerular expression of select microRNAs in a second cohort of patients with DN (n=19) and FSGS (n=21). In conclusion, we identified tissue-specific microRNA expression patterns associated with several kidney pathologies. The identified microRNAs could be developed as biomarkers of kidney diseases and might be involved in disease mechanisms.
Bowel Damage in Patients With Long-term Crohn’s Disease, Assessed by Magnetic Resonance Enterography and the Lémann Index
Authors: Aida Kapic Lunder, Jørgen Jahnsen, Linda Tøften Bakstad, Arne Borthne, Johannes Roksund Hov, Morten Vatn, Anne Negård, Bjørn Moum, Inger Camilla Solberg, Tomm Bernklev, Ole Høie, Magne Henriksen, Marte Lie Høivik, Øistein Hovde, Gert Huppertz-Hauss, Iril Monstad
Journal: Clinical Gastroenterology and Hepatology (2017)
Abstract 16853: Dietary Improvements and the Preventable Cost of Cardiovascular Disease: Evidence From the Literature
Authors: Donglan Zhang, Mary E Cogswell, Guijing Wang
Journal: Circulation (2015)

Introduction: Cardiovascular diseases (CVD) risk has been linked to dietary components in many studies, but the associated reduction in CVD healthcare costs with dietary improvements has not been systematically evaluated. Hypothesis: CVD healthcare cost savings associated with an improvement in dietary metrics are substantial. Methods: We searched PubMed, Embase, CINAHL and ABI/Inform to identify population-based studies published between January 1990 and December 2014 on CVD healthcare costs related to a dietary component. The selected dietary components, in accordance with those identified by the American Heart Association in their 2010 Strategic Impact goals, included salt/sodium, sugar-sweetened beverages, fruits and vegetables, fish/omega-3 fatty acids, whole grains/fiber. Other selected dietary components, based on AHA’s secondary dietary metrics, were nuts, processed meat and saturated fat. For each dietary component, we evaluated the CVD healthcare cost savings if the current consumption level were to be changed. Results: In 329 articles obtained, 15 studies evaluated the healthcare costs associated with one or more of dietary components: salt/sodium (n=12); fruit and vegetables (n=1); meat (n=1); saturated fat (n=3). The majority of studies (n=11) used an incidence-based approach, and the remaining were prevalence-based analyses. Adjusting the costs to 2013 US dollar values using consumer price index and purchasing power parity exchange rate, reducing average sodium intake by 1.2 g/day could save $1794 per person per year in the United Kingdom. Reducing individual sodium intake to 2.3 g/day could save $1955 per person in the United States. Increasing consumption of fruits and vegetables from &lt;0.5 cup / day to more than 1.5 cups / day could save $1481 per person in the United States. Conclusions: In conclusion, reducing sodium intake and increasing consumption of fruits and vegetables could substantially reduce CVD costs. Few studies were available on the cost savings associated with dietary components for cardiovascular health. These results suggest a need for economic studies using high-quality cost information and the most recent evidence to predict long-term cost savings.
Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia
Authors: Kerstin Knies, Shojiro Inano, María J. Ramírez, Masamichi Ishiai, Jordi Surrallés, Minoru Takata, Detlev Schindler
Journal: Journal of Clinical Investigation (2017)

The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.
Abstract DDT02-02: SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms
Authors: Stephen C. Alley, Megan O'Meara, Shyra J. Gardai, Nicole M. Okeley
Journal: Cancer Research (2017)

Abstract Increased fucosylation is associated with tumor progression and metastasis, and targeting fucosylation is a novel strategy in cancer therapy. 2-Fluorofucose (SGN-2FF) has been shown to inhibit cellular fucosylation by depletion of the fucosylation substrate GDP-fucose, as well as by direct inhibition of fucosyltransferases, leading to the production of afucosylated glycoproteins including antibodies. SGN-2FF has antitumor activity in multiple mouse tumor models, showing substantial tumor growth delay. SGN-2FF also enhanced the protective effect of a lymphoma vaccine in a syngeneic mouse model (1). This protection was determined to be immune dependent since depletion of CD4 and CD8 T cells reduced the SGN-2FF/vaccine activity. In vitro, SGN-2FF has been shown to activate human T cells in an antigen-dependent manner. Therefore, by inhibiting fucosylation SGN-2FF can potentially work through multiple mechanisms, including but not limited to effects on immune cells, tumor cells, and the tumor microenvironment. A first-in-human, phase 1, multicenter dose-escalation study of SGN-2FF is ongoing to investigate the safety, pharmacokinetics, and antitumor activity of SGN-2FF given orally to patients with advanced solid tumors (NCT# 02952989). Pharmacodynamic effects, including markers of fucosylation status, will also be evaluated to help determine the optimal biologic dose. This presentation reviews the preclinical activity data of SGN-2FF and describes the design of the phase 1 study, showing how demonstrated preclinical pharmacodynamic effects on fucosylation status informed how activity and pharmacodynamics will be monitored and evaluated in the phase 1 study. Reference &amp;lt;BIBL&amp;gt; 1. Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ, Emmerton KM, et al. Development of orally active inhibitors of protein and cellular fucosylation. Proc Natl Acad Sci U S A 2013;110:5404-9. Citation Format: Stephen C. Alley, Megan O'Meara, Shyra J. Gardai, Nicole M. Okeley. SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2017-DDT02-02
MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer
Authors: Veronica Tisato, Rebecca Voltan, Arianna Gonelli, Paola Secchiero, Giorgio Zauli
Journal: Journal of Hematology & Oncology (2017)

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers.