bluuebunny/crossref_metadata_2025 huggingface dataset:
Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis
Authors: Mizutani Yasuyuki , Kobayashi Hiroki , Iida Tadashi , Asai Naoya , Masamune Atsushi , Hara Akitoshi , Esaki Nobutoshi , Ushida Kaori , Mii Shinji , Shiraki Yukihiro , Ando Kenju , Weng Liang , Ishihara Seiichiro , Ponik Suzanne M. , Conklin Matthew W. , Haga Hisashi , Nagasaka Arata , Miyata Takaki , Matsuyama Makoto , Kobayashi Tomoe , Fujii Tsutomu , Yamada Suguru , Yamaguchi Junpei , Wang Tongtong , Woods Susan L. , Worthley Daniel , Shimamura Teppei , Fujishiro Mitsuhiro , Hirooka Yoshiki , Enomoto Atsushi , Takahashi Masahide
Published: August 2019

Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression.

Significance:

Meflin marks and functionally contributes to a subset of cancer-associated fibroblasts that exert antitumoral effects.
POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients
Authors: Baird Richard D. , van Rossum Annelot G.J. , Oliveira Mafalda , Beelen Karin , Gao Meiling , Schrier Mariette , Mandjes Ingrid A.M. , Garcia-Corbacho Javier , Vallier Anne-Laure , Dougall Greig , van Werkhoven Erik , Linossi Constanza , Kumar Sanjeev , van Tinteren Harm , Callari Maurizio , Beddowes Emma , Perez-Garcia José-Manuel , Rosing Hilde , Platte Else , Nederlof Petra , Schot Margaret , de Vries Schultink Aurelia , Bernards René , Saura Cristina , Gallagher William , Cortès Javier , Caldas Carlos , Linn Sabine C.
Published: August 2019

Purpose:

The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor.

Patients and Methods:

30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design.

Results:

Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients.

Conclusions:

Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.
Molecular Characterization of Locally Relapsed Head and Neck Cancer after Concomitant Chemoradiotherapy
Authors: de Roest Reinout H. , Mes Steven W. , Poell Jos B. , Brink Arjen , van de Wiel Mark A. , Bloemena Elisabeth , Thai Elena , Poli Tito , Leemans C. René , Brakenhoff Ruud H.
Published: August 2019

Purpose:

To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy.

Experimental Design:

First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity. Next, this CNA-based algorithm was combined with target enrichment sequencing of genes frequently mutated in HNSCC to assess the genetic relationships of paired tumors and LRs of patients treated with chemoradiotherapy.

Results:

Genetic relationship analysis using CNAs could accurately (96%) predict tumor biopsy pairs as patient-matched or independent. However, subsequent CNA analysis of PTs and LRs after chemoradiotherapy suggested genetic relationships in only 20% of cases, and absence in 80%. Target enrichment sequencing for mutations confirmed absence of any genetic relationship in half of the paired PTs and LRs.

Conclusions:

There are minor variations in CNA profiles within different areas of HNSCC tumors and many between independent tumors, suggesting that CNA profiles could be exploited as a marker of genetic relationship. Using CNA profiling and mutational analysis of cancer driver genes, relapses after chemoradiotherapy appear to be partially genetically related to the corresponding PTs, but seem often genetically unrelated. This remarkable observation warrants further studies and will impact therapeutic innovations and prognostic modeling when using index tumor characteristics.
Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan
Authors: Reidy-Lagunes Diane , Pandit-Taskar Neeta , O'Donoghue Joseph A. , Krebs Simone , Staton Kevin D. , Lyashchenko Serge K. , Lewis Jason S. , Raj Nitya , Gönen Mithat , Lohrmann Christian , Bodei Lisa , Weber Wolfgang A.
Published: August 2019

Purpose:

Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan.

Patients and Methods:

Twenty patients with advanced SSTR2-positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.

Results:

Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6–NR).

Conclusions:

In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.
Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer
Authors: Pailler Emma , Faugeroux Vincent , Oulhen Marianne , Mezquita Laura , Laporte Mélanie , Honoré Aurélie , Lecluse Yann , Queffelec Pauline , NgoCamus Maud , Nicotra Claudio , Remon Jordi , Lacroix Ludovic , Planchard David , Friboulet Luc , Besse Benjamin , Farace Françoise
Published: August 2019

Purpose:

Patients with anaplastic lymphoma kinase (ALK)–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC.

Experimental Design:

Resistance mutations were investigated in CTCs isolated at the single-cell level from patients at disease progression on crizotinib (n = 14) or lorlatinib (n = 3). Three strategies including filter laser-capture microdissection, fluorescence activated cell sorting, and the DEPArray were used. One hundred twenty-six CTC pools and 56 single CTCs were isolated and sequenced. Hotspot regions over 48 cancer-related genes and 14 ALK mutations were examined to identify ALK-independent and ALK-dependent resistance mechanisms.

Results:

Multiple mutations in various genes in ALK-independent pathways were predominantly identified in CTCs of crizotinib-resistant patients. The RTK-KRAS (EGFR, KRAS, BRAF genes) and TP53 pathways were recurrently mutated. In one lorlatinib-resistant patient, two single CTCs out of 12 harbored ALK compound mutations. CTC-1 harbored the ALKG1202R/F1174C compound mutation virtually similar to ALKG1202R/F1174L present in the corresponding tumor biopsy. CTC-10 harbored a second ALKG1202R/T1151M compound mutation not detected in the tumor biopsy. By copy-number analysis, CTC-1 and the tumor biopsy had similar profiles, whereas CTC-10 harbored multiple copy-number alterations and whole-genome duplication.

Conclusions:

Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies.
Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC)
Authors: Chen Kezhong , Zhao Heng , Shi Yanbin , Yang Fan , Wang Lien Tu , Kang Guannan , Nie Yuntao , Wang Jun
Published: August 2019

Purpose:

No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer.

Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B–time D), and after surgery (time P1–time P3). Next-generation sequencing–based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection.

Results:

Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002).

Conclusions:

ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.
Transforming the Early Drug Development Paradigm at the National Cancer Institute: The Formation of NCI's Experimental Therapeutics Clinical Trials Network (ETCTN)
Authors: Massett Holly A. , Mishkin Grace , Moscow Jeffrey A. , Gravell Amy , Steketee Michael , Kruhm Martha , Han Sae H. , Barry Barbara , Montello Michael , Zwiebel James , Abrams Jeffrey S. , Doroshow James H. , Ivy S. Percy
Published: August 2019

Early drug development for cancer requires broad collaboration and skilled clinical investigators to enable enrollment of patients whose tumors have defined molecular profiles. To respond to these challenges, the National Cancer Institute (NCI) transformed its 60-year-old early-phase drug development program in 2014 into the Experimental Therapeutics Clinical Trials Network (ETCTN). The ETCTN is a consolidated, national network of 40+ academic institutions responsible for conducting more than 100 early-phase clinical trials. It promotes team science coordinated among basic, translational, and clinical investigators, emphasizing the inclusion of early career trialists. This perspective provides a brief overview of the ETCTN, summarizes its successes and challenges over its first grant funding cycle, and discusses the program's future directions. Measures indicated strong connectivity across the institutions, significant increases in investigator approval of the ETCTN scientific portfolio from years 1 to 4, and substantial research activity over 5 years, with 334 letters of intent submitted, 102 trials activated, and 3,570 patients accrued. The ETCTN's successful adoption relied heavily on the inclusion of senior investigators who have long-standing interactions with the NCI and a willingness to participate in a team science approach and to mentor early career investigators. In addition, NCI invested substantial resources in a centralized infrastructure to conduct trials and to support the inclusion of biomarkers in its studies. The ETCTN provides evidence that a collaborative national clinical trial network for early drug development is feasible and can address the demands of precision medicine approaches to oncologic clinical trials.
Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment
Authors: Kahraman Deniz Cansen , Kahraman Tamer , Cetin-Atalay Rengul
Published: August 2019

Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.
Sodium-Glucose Cotransporter 2 (SGLT2) Inhibition in Kidney Transplant Recipients with Diabetes Mellitus
Authors: Mahling Moritz , Schork Anja , Nadalin Silvio , Fritsche Andreas , Heyne Nils , Guthoff Martina
Published: August 2019

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibition has been shown to reduce cardiovascular mortality and preserve kidney function in patients with type 2 diabetes. Kidney transplant recipients with diabetes demonstrate increased risk and accelerated progression of micro- and macrovascular complications and may specifically benefit from SGLT2 inhibition. However, potential concerns of SGLT2 inhibition include volume depletion and urinary tract infections. Objectives: We report data on the use of SGLT2 inhibitors in a case series of ten patients with diabetes after kidney transplantation in order to analyze efficacy, safety, and the effect on renal function. Methods: Patients with a stable allograft function and no history of recurrent urinary tract infections were eligible. The SGLT2 inhibitor empagliflozin was given as add-on to preexisting antidiabetic treatment with initial dose reduction of the latter. Results: Median estimated glomerular filtration rate at baseline was 57 mL/min/1.73 m2 and remained stable throughout the follow-up of 12.0 (5.3–12.0) months. Median HbA1c decreased from 7.3 to 7.1%. The rate of urinary tract infections and other side effects was low. Conclusions: SGLT2 inhibition is feasible and well tolerated in selected kidney transplant recipients with diabetes. Whether SGLT2 inhibition is able to reduce cardiovascular mortality and improve allograft survival in these patients has to be addressed in further studies.
Psychosocial and Cultural Determinants of Interest and Uptake of Skin Cancer Genetic Testing in Diverse Primary Care
Authors: Hay Jennifer L. , Meyer White Kirsten , Sussman Andrew , Kaphingst Kim , Guest Dolores , Schofield Elizabeth , Dailey Yvonne T. , Robers Erika , Schwartz Matthew R. , Zielaskowski Kate , Li Yuelin , Buller David , Hunley Keith , Berwick Marianne
Published: August 2019

Background: Translational research in genomics has limited reach and requires efforts to broaden access and utility in diverse populations. Skin cancer is common and rates are rising, including among Hispanics. Germline variants in the melanocortin-1 receptor (MC1R) gene are common in the population and confer moderate risk for melanoma and basal cell cancers across skin types. Feedback about MC1R risk status may promote skin cancer risk awareness and risk reduction. Aims: We examined the level of interest in pursuing MC1R testing, and patterns of interest across skin cancer perceived threat and control attitudes, cultural beliefs (family influence on health, health system distrust, cancer fatalism, skin cancer misconceptions), and health literacy. Methods: We used a study website to inform primary care patients in Albuquerque, NM about the benefits and drawbacks of MC1R testing. Website logon, request of a saliva test kit, and return of the test kit (yes vs. no) were primary assessments of study interest and uptake. Results: Of 499 participants provided with a test offer, 33% requested and returned the test. Lower family influence on participants’ health was an important factor both overall and within ethnicity subgroups, and may indicate that primary care patients interested in skin cancer genetic testing see themselves as proactive health seekers, independent from family encouragement. Lower self-efficacy for skin cancer prevention was also an important characteristic of those who tested. Conclusion: As evidence for common genetic markers for skin cancer accumulates, these findings suggest characteristics of those most likely to pursue genetic testing for skin cancer risk.
МЕРЕЖЕВА ОСНОВА ФУНКЦІОНУВАННЯ БІОЛОГІЧНИХ ОСЦИЛЯТОРІВ — ТРИГЕРІВ КОЛИВАЛЬНИХ ЛАНЦЮГІВ У КЛІТИНАХ І БЕЗКЛІТИННИХ СИСТЕМАХ. АНАЛІТИЧНИЙ ОГЛЯД
Authors: Mintser O. P. , Zaliskyi V. M. , Babintseva L. Yu.
Published: August 2019

В аналітичному дослідженні розглядаються експериментальні та теоретичні дослідження в області кількісного системного аналізу ролі біологічних осциляторів — тригерів коливальних ланцюгів у клітинах і безклітинних системах. Біологічні осцилятори управляють сплесками активності нейронів, клітинними циклами, патернами сну та пробудження, а також багатьма іншими важливими процесами в живих системах. Передбачається, що кількісні дослідження функціонування біологічних осциляторів допоможуть в попередженні та лікуванні багатьох захворювань людини. За останні десятиліття розвиток методів в області системної і синтетичної біології дозволив намітити шляхи до розшифровки фундаментальних механізмів, що лежать в основі функціонування цих осциляторів. Показано, що істотне значення в подальшому визначенні механізмів функціонування біологічних осциляторів набуває системна та синтетична біологія. Хоча в дослідженнях із функціонування біологічних осциляторів і був досягнутий певний прогрес щодо виявлення особливостей роботи природних і штучних осциляторів, котрі підвищують надійність і якість управління ритмами біологічних реакцій, проте роль багатьох інших другорядних модифікацій залишається маловивченою. Для її розуміння необхідні подальші як теоретичні так і експериментальні дослідження. Вкрай важливою в просуванні системної та синтетичної біології стає роль розвитку інструментів і методів біоінформатики, а вже усталені кількісні підходи системної та синтетичної біології в трансдисциплінарному підході із залученням сучасних методик інших областей знань.
Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction
Authors: Haynes Bronson A. , Yang Li Fang , Huyck Ryan W. , Lehrer Eric J. , Turner Joshua M. , Barabutis Nektarios , Correll Vanessa L. , Mathiesen Allison , McPheat William , Semmes O. John , Dobrian Anca D.
Published: August 2019

Objective:

Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV).

Approach and Results:

We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors.

Conclusions:

We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.
Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
Authors: Verma Subodh , Mazer C. David , Yan Andrew T. , Mason Tamique , Garg Vinay , Teoh Hwee , Zuo Fei , Quan Adrian , Farkouh Michael E. , Fitchett David H. , Goodman Shaun G. , Goldenberg Ronald M. , Al-Omran Mohammed , Gilbert Richard E. , Bhatt Deepak L. , Leiter Lawrence A. , Jüni Peter , Zinman Bernard , Connelly Kim A. ,   For the EMPA-HEART CardioLink-6 Investigators
Published: August 2019

Background:

SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease.

Methods:

Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m
2
. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide).

Results:

Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m
2
, LV mass indexed to body surface area 60.7 [11.9] g/m
2
), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m
2
and 0.01 g/m
2
for those assigned empagliflozin and placebo, respectively (adjusted difference −3.35 g/m
2
; 95% CI, −5.9 to −0.81g/m
2
,
P
=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference −6.8mmHg, 95% CI −11.2 to −2.3mmHg,
P
=0.003), diastolic blood pressure (adjusted difference −3.2mmHg; 95% CI, −5.8 to −0.6mmHg,
P
=0.02) and elevation of hematocrit (
P
=0.0003).

Conclusions:

Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02998970.
The kitābī Wife’s Conversion to Islam: An Unusual Interpretation by Ibn Qayyim al-Jawziyya
Authors: Bosanquet Antonia
Published: August 2019

This essay analyzes Ibn Qayyim al-Jawziyya’s (d. 751/1350) teaching about the legal options open to a woman who converts to Islam while married to a Jewish or Christian husband. I argue that Ibn al-Qayyim’s preferred position is unusual for the eighth/fourteenth century in which he wrote, although it may derive from Ibn Taymiyya’s (d. 728/ 1328) teaching on the subject. In order to contextualize Ibn al-Qayyim’s view, I summarize the variety of approaches to single-spouse conversion that dominated in the first century AH, and the broad consensus on the topic that developed after this. Although female conversion to Islam has received some attention in historical studies, there has been less focus on the legal discourse surrounding this question. The essay seeks to contribute to this discussion.
Islamic Law on the Provincial Margins: Christian Patrons and Muslim Notaries in Upper Egypt, 2nd-5th/8th-11th Centuries
Authors: Weitz Lev
Published: August 2019

This article examines the interaction of Coptic Christians with Islamic legal institutions in provincial Egypt on the basis of a corpus of 193 Arabic legal documents, as well as relevant Coptic ones, dating to the 2nd-5th/8th-11th centuries. I argue that around the 3rd/9th century Islamic Egypt’s Christian subjects began to make routine use of Islamic legal institutions to organize their economic affairs, including especially inheritance and related matters internal to Christian families. They did so in preference to the Christian authorities and Coptic deeds that had been their standard resource in the first two centuries of Muslim rule. The changing character of the Egyptian judiciary encouraged this shift in practice, as qāḍīs who adhered to fiqh procedural rules increasingly filled judicial roles formerly held by administrative officials. By eschewing and nudging into disuse a previously vital Coptic legal tradition, Christian provincials participated in the Islamization of ʿAbbāsid and Fāṭimid Egypt.
Life as a Reflexive Project: The Logics of Ethical Veganism and Meat-Eating
Authors: Presser Lois , Schally Jennifer L. , Vossler Christine
Published: August 2019

This paper is concerned with the ways that vegans and meat-eaters talk about themselves and their dietary practices. Data from a total of 81 semi-structured interviews with ethical vegans (n = 21) and meat-eaters (n = 60) were analyzed for themes and discursive strategies, and results were compared. Vegans insisted that nonhuman animals had interests of their own and spoke of making consumption choices. Meat-eaters tended to reduce animals to human purposes and claimed powerlessness to avoid doing harm to animals while also referencing some license to eating meat. Vegans shared stories of eating meat, whereas few of the meat-eaters did so. Turning points in those (vegan) stories pertained to realizations of harming animals, and thought knowledge were prominent themes in their accounts generally. Vegans were prone to critique past selves and the movement they had aligned themselves with. This research can help promote discourses of compassion and counter discourses of harm.
The Ecosystem Approach and Environmental Justice Nexus in Natural Resource Management
Authors: Alam Shawkat , Mohammad Sheikh Noor
Published: August 2019

The ecosystem approach emerged in the international environmental realm to promote equity and justice for both people and nature. It provides a set of mechanisms, including equitable benefit sharing; conservation and sustainable use; adaptive management; and participatory practices. This article explores how the ecosystem approach that is used in natural resource management shares synergies with notions of environmental justice, including distributional justice, procedural justice and justice-as-recognition. It also explores how the ecosystem approach responds to two additional principles of environmental justice that are specific to environmental disciplines, namely, intergenerational equity and the precautionary principle. The article illustrates the complementarity between the ecosystem approach and environmental justice through practical examples and argues that environmental justice can be promoted by utilizing the ecosystem approach as a vehicle for policy-makers.
Redescription of Daphnia turbinata Sars, 1903 (Crustacea: Cladocera: Daphniidae)
Authors: ZUYKOVA ELENA I. , SHEVELEVA NATALIA G. , KOTOV ALEXEY A.
Published: August 2019

The genus Daphnia O.F. Müller (Crustacea: Cladocera: Daphniidae) has a long history of its study, it attracts maximum attention of evolutionary biologists as compared to other cladoceran taxa. But still there are many unresolved problems concerning the genus taxonomy. We redescribe forgotten Daphnia (D.) turbinata Sars, 1903 which has a relatively narrow distribution in the Altay-Sayan mountain region (southern Siberia and Mongolia). Diagnostic characters of the taxon are discussed as well as possibilities of morphological discrimination of taxa within the D. (D.) longispina species group.
Making the Black Box More Transparent: Understanding the Physical Implications of Machine Learning
Authors: McGovern Amy , Lagerquist Ryan , John Gagne David , Jergensen G. Eli , Elmore Kimberly L. , Homeyer Cameron R. , Smith Travis
Published: August 2019

This paper synthesizes multiple methods for machine learning (ML) model interpretation and visualization (MIV) focusing on meteorological applications. ML has recently exploded in popularity in many fields, including meteorology. Although ML has been successful in meteorology, it has not been as widely accepted, primarily due to the perception that ML models are “black boxes,” meaning the ML methods are thought to take inputs and provide outputs but not to yield physically interpretable information to the user. This paper introduces and demonstrates multiple MIV techniques for both traditional ML and deep learning, to enable meteorologists to understand what ML models have learned. We discuss permutation-based predictor importance, forward and backward selection, saliency maps, class-activation maps, backward optimization, and novelty detection. We apply these methods at multiple spatiotemporal scales to tornado, hail, winter precipitation type, and convective-storm mode. By analyzing such a wide variety of applications, we intend for this work to demystify the black box of ML, offer insight in applying MIV techniques, and serve as a MIV toolbox for meteorologists and other physical scientists.
Predictors of help-seeking in unemployed people with mental health problems
Authors: Wigand Moritz E , Oexle Nathalie , Waldmann Tamara , Staiger Tobias , Becker Thomas , Rüsch Nicolas
Published: August 2019

Background:

Unemployment and mental ill health often contribute to each other and lead to social exclusion with negative consequences for individuals and society. Yet, unemployed people with mental health problems often do not seek care.

Aims:

The aim of this study was to assess predictors of help-seeking among unemployed people with mental health problems.

Methods:

At baseline, 301 unemployed participants with mental health problems reported potential predictors of help-seeking in terms of mental health literacy, perceived barriers to care, self-concept as having a mental illness and current mental health service use. At 6-month follow-up, 240 participants reported whether or not they had started new mental health treatment since baseline.

Results:

Adjusted for symptoms, sociodemographic and work-related variables, help-seeking was predicted by previous mental health service use and by fewer non-stigma-related barriers, not by stigma-related barriers.

Conclusion:

Implications for interventions to increase help-seeking among this vulnerable group are discussed.
Japanese Treatment of Allied Prisoners During the Second World War: Evaluating the Death Toll
Authors: Sturma Michael
Published: August 2019

The high death rate of Allied prisoners of war in the Pacific compared with those in Europe is commonly used to signify the barbarous way in which the Japanese fought the Second World War. This study examines the extent to which ‘friendly fire’ inflated the death rate of Allied prisoners under the Japanese, and evaluates more broadly the perceived disparity between Japanese and German treatment of Allied prisoners of war (POWs). Four broad conclusions are drawn. First, that while Allied submarine and air attacks elevated the deaths rate of Allied prisoners held by the Japanese, even if these are excluded the POW death rate remains significantly higher than for those held by Germany. Second, in some respects, POW death rates under the Japanese can be more productively and favourably compared to Germany's treatment of Soviet prisoners on the Eastern front than its treatment of Western captives. Third, the death rates mask the diversity of prisoners’ experience under the Japanese. Finally, it is suggested that perhaps the single most important difference between German and Japanese treatment of Allied prisoners was the latter's failure to adequately distribute Red Cross supplies.
The Dynamics of Change Following Extreme Events: Transition, Scale, and Adaptation in Systems Under Stress
Authors: Comfort Louise K. , Haase Thomas W. , Ertan Gunes , Scheinert Steve R.
Published: August 2019

Whether and how organizations adapt to risk in changing contexts is a perennial problem in public administration. We explore this problem in a comparative analysis of four hurricanes that struck the Gulf Coast in 2005 and 2008: Hurricanes Katrina and Gustav in Louisiana and Hurricanes Rita and Ike in Texas. We use a framework of complex adaptive systems to assess what changes facilitate this transition in disaster contexts and what conditions inhibit adaptation. Methods include content and network analysis, including the calculation of E/I index scores. Findings suggest that investment in information technology and training in Louisiana following a perceived poor response to Katrina in 2005 led to adaptive performance in Gustav in 2008 in Louisiana, whereas minimal change following a perceived credible response to Rita in 2005 led to slower adaptation in response to Ike in 2008 in Texas.
Credibility and Incredulity in Milgram’s Obedience Experiments: A Reanalysis of an Unpublished Test
Authors: Perry Gina , Brannigan Augustine , Wanner Richard A. , Stam Henderikus
Published: August 2019

This article analyzes variations in subject perceptions of pain in Milgram’s obedience experiments and their behavioral consequences. Based on an unpublished study by Milgram’s assistant, Taketo Murata, we report the relationship between the subjects’ belief that the learner was actually receiving painful electric shocks and their choice of shock level. This archival material indicates that in 18 of 23 variations of the experiment, the mean levels of shock for those who fully believed that they were inflicting pain were lower than for subjects who did not fully believe they were inflicting pain. These data suggest that the perception of pain inflated subject defiance and that subject skepticism inflated their obedience. This analysis revises our perception of the classical interpretation of the experiment and its putative relevance to the explanation of state atrocities, such as the Holocaust. It also raises the issue of dramaturgical credibility in experiments based on deception. The findings are discussed in the context of methodological questions about the reliability of Milgram’s questionnaire data and their broader theoretical relevance.
Identification and evaluation of observational measures for the assessment and/or monitoring of level of consciousness in adult palliative care patients: A systematic review for I-CAN-CARE
Authors: Krooupa Anna-Maria , Vivat Bella , McKeever Stephen , Marcus Elena , Sawyer Joseph , Stone Paddy
Published: August 2019

Background:

The use of observational measures to assess palliative care patients’ level of consciousness may improve patient care and comfort. However, there is limited knowledge regarding the validity and reliability of these measures in palliative care settings.

Aim:

To identify and evaluate the psychometric performance of observational level of consciousness measures used in palliative care.

Design:

Systematic review; PROSPERO registration: CRD42017073080.

Data sources:

We searched six databases until November 2018, using search terms combining subject headings and free-text terms. Psychometric performance for each identified tool was appraised independently by two reviewers following established criteria for developing and evaluating health outcome measures.

Results:

We found 35 different levels of consciousness tools used in 65 studies. Only seven studies reported information about psychometric performance of just eight tools. All other studies used either ad hoc measures for which no formal validation had been undertaken ( n = 21) or established tools mainly developed and validated in non-palliative care settings ( n = 37). The Consciousness Scale for Palliative Care and a modified version of the Richmond Agitation–Sedation Scale received the highest ratings in our appraisal, but, since psychometric evidence was limited, no tool could be assessed for all psychometric properties.

Conclusion:

An increasing number of studies in palliative care are using observational measures of level of consciousness. However, only a few of these tools have been tested for their psychometric performance in that context. Future research in this area should validate and/or refine the existing measures, rather than developing new tools.
Gut microbiota: an overlooked factor that plays a significant role in osteoporosis
Authors: Hao Meng-lei , Wang Guang-yao , Zuo Xiao-qin , Qu Chan-juan , Yao Bo-chen , Wang Dong-lai
Published: August 2019

Gut microbes are known as the body’s second gene pool. Symbiotic intestinal bacteria play a major role in maintaining balance in humans. Bad eating habits, antibiotic abuse, diseases, and a poor living environment have a negative effect on intestinal flora. Abnormal intestinal microbes are prone to cause a variety of diseases, affecting life expectancy and long-term quality of life, especially in older people. Several recent studies have found a close association between intestinal microorganisms and osteoporosis. The potential mechanism of intestinal flora affecting bone formation or destruction by mediating nitric oxide, the immune and endocrine systems, and other factors is briefly described in this review. All of these factors may be responsible for the intestinal flora that causes osteoporosis. Studying the relationship between intestinal flora and bone health not only provides new ideas for studying the role of intestinal microorganism in osteoporosis, but also provides a new therapeutic direction for clinically refractory osteoporosis. Study of the relationship between intestinal microbiota and osteoporosis is important for maintaining bone health and minimizing osteoporosis.
‘We could be anything we wanted to be’: remembering Jimmy Rogers
Authors: Romyn Michael
Published: August 2019

Between 1967 and his death in 2018, Jimmy Rogers, a unique figure in the UK’s black self-help movement, dedicated himself to the welfare of black young people via basketball. Through Rogers’ own words and oral histories of individuals who knew him, this article traces his path from Liverpool 8, where he introduced organised basketball in 1967, to London, where he established the Brixton Topcats basketball club in response to the ‘riots’ of 1981. Rogers learnt through his own life of hardship – of being brought up ‘in care’ – the need for discipline, self-belief and self-reliance. And he used these experiences and his basketball skills to mentor generations of dispossessed young black men and later women, who found, through his clubs, an antidote to a world of institutional racism, economic hardships, and heavy-handed policing. At a time of drastic cuts in youth services, he showed the importance of alternative community-led youth provision to black working-class inner-city residents.
US Commuter Rail Renaissance: A 30-Year Progress Report
Authors: Nelson David O. , O’Neil Katherine K.
Published: August 2019

In 1989 the first new US commuter railroad in living memory opened for business in South Florida running over a 41-mile route between Miami and Boca Raton. “Tri-Rail” quickly expanded to result in a 71-mile-long service that spanned three counties. Tri-Rail soon had a long string of imitators among other Sun Belt and western cities wrestling with highway congestion and a paucity of affordable fixed guideway transit options. New commuter rail services were started in other cities with no previous history of commuter rail service. Thirty years later, commuter rail service is now offered in 14 new US jurisdictions. Most had no previous experience with commuter service. The number of US commuter railroads has more than doubled in the last 30 years and the legacy systems have enjoyed a 50% growth in ridership. This paper reviews this remarkable success story, tracing the “New Start” commuter rail phenomenon while also reporting how the nine “Legacy” systems that were operating in 1988 have fared over the last 30 years. The paper uses the most recently published (2016) federally collected data to compare the New Start services with the older, and generally larger, legacy systems. 1987 also marked the US’s first competitively procured commuter rail service in Boston, soon followed by Miami in 1988. Today, 14 US commuter railroads are operated under the auspices of a competitively tendered procurement. Eleven other railroads are “owner operated” either by employees of the public agency sponsoring the service or by the private owner (freight railway) of the subject railway under the auspices of a negotiated service contract. This paper considers how this management innovation has worked out by comparing the economic performance of the “competitive contract” services with the “owner operators.”
Decellularized equine carotid artery layers as matrix for regenerated neurites of spiral ganglion neurons
Authors: Yilmaz-Bayraktar Suheda , Schwieger Jana , Scheper Verena , Lenarz Thomas , Böer Ulrike , Kreienmeyer Michaela , Torrente Mariela , Doll Theodor
Published: August 2019

Today’s best solution in compensating for sensorineural hearing loss is the cochlear implant, which electrically stimulates the spiral ganglion neurons in the inner ear. An optimum hearing impression is not ensured due to, among other reasons, a remaining anatomical gap between the spiral ganglion neurons and the implant electrodes. The gap could be bridged via pharmacologically triggered neurite growth toward the electrodes if biomaterials for neurite guidance could be provided. For this, we investigated the suitability of decellularized tissue. We compared three different layers (tunica adventitia, tunica media, and tunica intima) of decellularized equine carotid arteries in a preliminary approach. Rat spiral ganglia explants were cultured on decellularized equine carotid artery layers and neurite sprouting was assessed quantitatively. Generally, neurite outgrowth was possible and it was most prominent on the intima (in average 83 neurites per spiral ganglia explants, followed by the adventitia (62 neurites) and the lowest growth on the media (20 neurites). Thus, decellularized equine carotid arteries showed promising effects on neurite regeneration and can be developed further as efficient biomaterials for neural implants in hearing research.