bluuebunny/crossref_metadata_2025_split huggingface dataset:
5-Azacitidine Induces NOXA to Prime AML Cells for Venetoclax-Mediated Apoptosis
Authors: Jin Sha , Cojocari Dan , Purkal Julie J. , Popovic Relja , Talaty Nari N. , Xiao Yu , Solomon Larry R. , Boghaert Erwin R. , Leverson Joel D. , Phillips Darren C. 
Published: February 2020

Abstract

Purpose:
Patients with acute myeloid leukemia (AML) frequently do not respond to conventional therapies. Leukemic cell survival and treatment resistance have been attributed to the overexpression of B-cell lymphoma 2 (BCL-2) and aberrant DNA hypermethylation. In a phase Ib study in elderly patients with AML, combining the BCL-2 selective inhibitor venetoclax with hypomethylating agents 5-azacitidine (5-Aza) or decitabine resulted in 67% overall response rate; however, the underlying mechanism for this activity is unknown.

Experimental Design:
We studied the consequences of combining two therapeutic agents, venetoclax and 5-Aza, in AML preclinical models and primary patient samples. We measured expression changes in the integrated stress response (ISR) and the BCL-2 family by Western blot and qPCR. Subsequently, we engineered PMAIP1 (NOXA)- and BBC3 (PUMA)-deficient AML cell lines using CRISPR-Cas9 methods to understand their respective roles in driving the venetoclax/5-Aza combinatorial activity.

Results:
In this study, we demonstrate that venetoclax and 5-Aza act synergistically to kill AML cells in vitro and display combinatorial antitumor activity in vivo. We uncover a novel nonepigenetic mechanism for 5-Aza–induced apoptosis in AML cells through transcriptional induction of the proapoptotic BH3-only protein NOXA. This induction occurred within hours of treatment and was mediated by the ISR pathway. NOXA was detected in complex with antiapoptotic proteins, suggesting that 5-Aza may be “priming” the AML cells for venetoclax-induced apoptosis. PMAIP1 knockout confirmed its major role in driving venetoclax and 5-Aza synergy.

Conclusions:
These data provide a novel nonepigenetic mechanism of action for 5-Aza and its combinatorial activity with venetoclax through the ISR-mediated induction of PMAIP1.
A Phase II Trial of 5-Day Neoadjuvant Radiotherapy for Patients with High-Risk Primary Soft Tissue Sarcoma
Authors: Kalbasi Anusha , Kamrava Mitchell , Chu Fang-I , Telesca Donatello , Van Dams Ritchell , Yang Yingli , Ruan Dan , Nelson Scott D. , Dry Sarah M. , Hernandez Jackie , Chmielowski Bartosz , Singh Arun S. , Bukata Susan V. , Bernthal Nicholas M. , Steinberg Michael L. , Weidhaas Joanne B. , Eilber Fritz C. 
Published: February 2020

AbstractPurpose:In a single-institution phase II study, we evaluated the safety of a 5-day dose-equivalent neoadjuvant radiotherapy (RT) regimen for high-risk primary soft tissue sarcoma.Patients and Methods:Patients received neoadjuvant RT alone (30 Gy in five fractions) to the primary tumor with standard margins. The primary endpoint was grade ≥2 late-radiation toxicity. Major wound complications, local recurrences, and distant metastases were also examined. In exploratory analysis, we evaluated germline biomarkers for wound toxicity and the effects of the study on treatment utilization.Results:Over 2 years, 52 patients were enrolled with median follow-up of 29 months. Seven of 44 evaluable patients (16%) developed grade ≥2 late toxicity. Major wound complications occurred in 16 of 50 patients (32%); a signature defined by 19 germline SNPs in miRNA-binding sites of immune and DNA damage response genes, in addition to lower extremity tumor location, demonstrated strong predictive performance for major wound complications. Compared with the preceding 2-year period, the number of patients treated with neoadjuvant RT alone at our institution increased 3-fold, with a concomitant increase in the catchment area.Conclusions:A shorter 5-day neoadjuvant RT regimen results in favorable rates of wound complications and grade ≥2 toxicity after 2-year follow-up. Five-day RT significantly increased utilization of neoadjuvant RT at our high-volume sarcoma center. With further validation, a putative germline biomarker for wound complications may guide safer RT utilization.
Doppler-Derived Arterial Load Indices Better Reflect Left Ventricular Afterload Than Systolic Blood Pressure in Coarctation of Aorta
Authors: Egbe Alexander C. , Reddy Yogesh N.V. , Obokata Masaru , Borlaug Barry A. 
Published: February 2020

Background:
Patients with vascular stiffening may display increased arterial afterload that is out of proportion to systolic blood pressure (SBP). Since vascular and endothelial dysfunction develop in patients with coarctation of aorta (COA), we hypothesized that for any SBP, patients with mild COA (COA peak velocity <2 m/s) will have a higher arterial afterload and increased left ventricular mass index (LVMI) compared with controls, and that Doppler-derived arterial load indices would be a better predictor of LVMI compared with SBP alone.

Methods:
We studied 204 COA patients (age 35±12 y) and 204 matched controls. Doppler-derived arterial afterload was assessed using effective arterial elastance index and total arterial compliance index.

Results:

Despite similar SBP, the mild COA group displayed higher arterial afterload as evidenced by a higher elastance index (3.3±0.9 versus 2.9±0.7 mm Hg/mL·m
2
;
P
<0.001) and lower total arterial compliance index (0.8±0.3 versus 1.2±0.5 mL/mm Hg·m
2
;
P
<0.001). This was associated with higher LVMI in COA (109±35 versus 93±32, g/m
2
;
P
<0.001). Compared with SBP (β=0.24 [95% CI, 0.02–0.45]), elastance index (β=20.2 [95% CI, 15.8–44.1]) and total arterial compliance index (β=−32.5 [95% CI, −43.8 to −123.6]) were better predictors of LVMI. Elastance index (but not SBP) was predictive of longitudinal increases in LVMI (
r
=0.43,
P
<0.001).

Conclusions:
COA patients had higher arterial afterload compared with controls with similar SBP. In comparison to SBP, Doppler-derived arterial load indices correlate more strongly with LV hypertrophy. These data suggest that SBP may underestimate LV afterload in this population. This has important clinical implications since titration of antihypertensive therapy is currently based on SBP.
Trends in Hospitalization, Management, and Clinical Outcomes Among Veterans With Critical Limb Ischemia
Authors: Mentias Amgad , Qazi Abdul , McCoy Kimberly , Wallace Robert , Vaughan-Sarrazin Mary , Girotra Saket 
Published: February 2020

Background:
Contemporary patterns in management and outcomes of critical limb ischemia among United States veterans are unknown.

Methods:
We used Veterans Health Administration data to identify patients admitted for critical limb ischemia between 2005 and 2014. We examined temporal trends in incidence, management, and outcomes.

Results:

A total of 20 938 veterans with critical limb ischemia were hospitalized between 2005 and 2014. Mean age was 67.8 years. Incidence decreased from 0.3 to 0.24 per 1000 persons from 2005 to 2013,
P
<0.01. During the study period, there was a temporal increase in use of revascularization within 90 days of hospitalization—endovascular (11.2% in 2005 to 18.4% in 2014), surgical (23.8% in 2005 to 26.4% in 2014), and hybrid (6.2% in 2005 to 13.1% in 2014,
P
value for trend <0.01). Statin prescriptions increased from 47.4% in 2005 to 60.9% in 2014 (
P
value for trend <0.01). There was a significant decline in risk-adjusted mortality (11.8% in 2005 to 9.7% in 2014) and major amputation (19.8% in 2005 to 12.9% in 2014;
P
value for trend <0.01 for both) at 90 days. In adjusted analyses, revascularization was associated with a lower risk of mortality (RR, 0.45 [95% CI, 0.41–0.50];
P
<0.001) and major amputation at 90 days (RR, 0.23 [95% CI, 0.21–0.26];
P
<0.001). Nearly half of the patients who underwent amputation did not receive an invasive vascular procedure within the preceding 90 days. There was large site-level variation in the use of revascularization (median rate, 41.7% [interquartile range, 12.5%–53.2%]). Differences in patient case-mix explained only 8% of site-level variation in receipt of revascularization.

Conclusions:
Over the past decade, use of revascularization increased among veterans with critical limb ischemia, which was accompanied by a reduction in mortality and major amputation. However, opportunities to further improve care in this high-risk population still remain.
Noninvasive Imaging Estimation of Myocardial Iron Repletion Following Administration of Intravenous Iron: The Myocardial‐IRON Trial
Authors: Núñez Julio , Miñana Gema , Cardells Ingrid , Palau Patricia , Llàcer Pau , Fácila Lorenzo , Almenar Luis , López‐Lereu Maria P. , Monmeneu Jose V. , Amiguet Martina , González Jessika , Serrano Alicia , Montagud Vicente , López‐Vilella Raquel , Valero Ernesto , García‐Blas Sergio , Bodí Vicent , de la Espriella‐Juan Rafael , Lupón Josep , Navarro Jorge , Górriz José Luis , Sanchis Juan , Chorro Francisco J. , Comín‐Colet Josep , Bayés‐Genís Antoni , Soler Meritxell , Villaescusa Amparo , Civera Jose , Mollar Anna , del Carmen Moreno Maria , Vidal Veronica 
Published: February 2020

Background

Intravenous ferric carboxymaltose (
FCM
) improves symptoms, functional capacity, and quality of life in heart failure and iron deficiency. The mechanisms underlying these effects are not fully understood. The aim of this study was to examine changes in myocardial iron content after
FCM
administration in patients with heart failure and iron deficiency using cardiac magnetic resonance.

Methods and Results

Fifty‐three stable heart failure and iron deficiency patients were randomly assigned 1:1 to receive intravenous
FCM
or placebo in a multicenter, double‐blind study. T2* and T1 mapping cardiac magnetic resonance sequences, noninvasive surrogates of intramyocardial iron, were evaluated before and 7 and 30 days after randomization using linear mixed regression analysis. Results are presented as least‐square means with 95% CI. The primary end point was the change in T2* and T1 mapping at 7 and 30 days. Median age was 73 (65–78) years, with N‐terminal pro‐B‐type natriuretic peptide, ferritin, and transferrin saturation medians of 1690 pg/mL (1010–2828), 63 ng/mL (22–114), and 15.7% (11.0–19.2), respectively. Baseline T2* and T1 mapping values did not significantly differ across treatment arms. On day 7, both T2* and T1 mapping (ms) were significantly lower in the
FCM
arm (36.6 [34.6–38.7] versus 40 [38–42.1],
P
=0.025; 1061 [1051–1072] versus 1085 [1074–1095],
P
=0.001, respectively). A similar reduction was found at 30 days for T2* (36.3 [34.1–38.5] versus 41.1 [38.9–43.4],
P
=0.003), but not for T1 mapping (1075 [1065–1085] versus 1079 [1069–1089],
P
=0.577).

Conclusions

In patients with heart failure and iron deficiency,
FCM
administration was associated with changes in the T2* and T1 mapping cardiac magnetic resonance sequences, indicative of myocardial iron repletion.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
03398681.
New species of Ilanga (Gastropoda: Trochoidea: Solariellidae) from the Indo-West Pacific
Authors: VILVENS CLAUDE , WILLIAMS SUZANNE T. 
Published: February 2020

In this study we list and figure a total of 22 species assigned to the genus Ilanga Herbert, 1987 that were collected during recent Paris Museum expeditions, of which 16 are new and described here (listed in the order they appear in the text): Ilanga herberti n. sp., I. euryomphalos n. sp., I. polygramma n. sp., I. stephanophora n. sp., I. harrytaylori n. sp., I. eurystoma n. sp., I. oxeia n. sp., I. cosmia n. sp., I. corrineae n. sp., I. comes n. sp., I. dongshaensis n. sp., I. philia n. sp., I. helicoides n. sp., I. lauensis n. sp., I. mesembrine n. sp. and I. boreia n. sp.. These species occur throughout the Indo-West Pacific, extending the known range of this genus beyond the south west Indian Ocean. We also synonymise Microgaza fulgens Dall, 1907 and Microgaza konos Vilvens, 2009 (syn. nov.) (as I. fulgens). New combinations include Ilanga fulgens and I. navakaensis.
Impacts of Irrigation on Summertime Temperatures in the Pacific Northwest
Authors: Lawston Patricia M. , Santanello Joseph A. , Hanson Brian , Arsensault Kristi 
Published: February 2020

AbstractIrrigation has the potential to modify local weather and regional climate through a repartitioning of water among the surface, soil, and atmosphere with the potential to drastically change the terrestrial energy budget in agricultural areas. This study uses local observations, satellite remote sensing, and numerical modeling to 1) explore whether irrigation has historically impacted summer maximum temperatures in the Columbia Plateau, 2) characterize the current extent of irrigation impacts to soil moisture (SM) and land surface temperature (LST), and 3) better understand the downstream extent of irrigation’s influence on near-surface temperature, humidity, and boundary layer development. Analysis of historical daily maximum temperature (TMAX) observations showed that the three Global Historical Climate Network (GHCN) sites downwind of Columbia Basin Project (CBP) irrigation experienced statistically significant cooling of the mean summer TMAX by 0.8°–1.6°C in the post-CBP (1968–98) as compared to pre-CBP expansion (1908–38) period, opposite the background climate signal. Remote sensing observations of soil moisture and land surface temperatures in more recent years show wetter soil (~18%–25%) and cooler land surface temperatures over the irrigated areas. Simulations using NASA’s Land Information System (LIS) coupled to the Weather Research and Forecasting (WRF) Model support the historical analysis, confirming that under the most common summer wind flow regime, irrigation cooling can extend as far downwind as the locations of these stations. Taken together, these results suggest that irrigation expansion may have contributed to a reduction in summertime temperatures and heat extremes within and downwind of the CBP area. This supports a regional impact of irrigation across the study area.
Diurnal Cycles of Precipitation and Lightning in the Tropics Observed by TRMM3G68, GSMaP, LIS, and WWLLN
Authors: Minobe Shoshiro , Park Jun Hyock , Virts Katrina S. 
Published: February 2020

AbstractDiurnal cycles of precipitation and lightning are investigated by analyzing rain rates of the TRMM3G68 dataset, consisting of Precipitation Radar and Microwave Imager data only; rain rates of Global Satellite Mapping of Precipitation (GSMaP), for which infrared (IR) data are also used; lightning flash rates observed by TRMM Lightning Imaging Sensor (LIS); and lightning stroke rates of World Wide Lightning Location Network (WWLLN) over the tropics. Diurnal amplitudes relative to averages are generally larger for lightning than for precipitation. Over ocean, relative amplitudes are stronger in the stratocumulus deck region in the southeast Pacific than those over typical ocean regions. The phase of GSMaP is substantially delayed to TRMM3G68 due to the phase-delay problem of IR-based estimation. The diurnal peaks tend to occur between 1400 and 1800 LST over the continent after spatial averaging with a phase leading order of TRMM3G68, LIS, and WWLLN, and between 0000 and 0700 LST over oceanic regions where diurnal cycles are prominent in all datasets. Off-equatorward phase propagations are found in the precipitation in the Pacific and Indian Oceans. Over selected coastal regions, all data exhibit consistent oceanward phase propagation with the longest, medium, and shortest phase propagation distances for TRMM3G68 precipitation, WWLLN lightning, and LIS lightning, respectively, with a phase leading order of LIS, WWLLN, and TRMM3G68. The summertime diurnal cycle over the Gulf Stream also exhibits oceanward phase propagation, but with strong amplitude enhancement over the Gulf Stream. Diurnal cycle amplitude is also enhanced over the Kuroshio in the East China Sea in the baiu–mei-yu rainy season.
Bifurcation and Upwelling of the Equatorial Undercurrent West of the Galápagos Archipelago
Authors: Jakoboski Julie , Todd Robert E. , Owens W. Brechner , Karnauskas Kristopher B. , Rudnick Daniel L. 
Published: February 2020

AbstractThe Equatorial Undercurrent (EUC) encounters the Galápagos Archipelago on the equator as it flows eastward across the Pacific. The impact of the Galápagos Archipelago on the EUC in the eastern equatorial Pacific remains largely unknown. In this study, the path of the EUC as it reaches the Galápagos Archipelago is measured directly using high-resolution observations obtained by autonomous underwater gliders. Gliders were deployed along three lines that define a closed region with the Galápagos Archipelago as the eastern boundary and 93°W from 2°S to 2°N as the western boundary. Twelve transects were simultaneously occupied along the three lines during 52 days in April–May 2016. Analysis of individual glider transects and average sections along each line show that the EUC splits around the Galápagos Archipelago. Velocity normal to the transects is used to estimate net horizontal volume transport into the volume. Downward integration of the net horizontal transport profile provides an estimate of the time- and areal-averaged vertical velocity profile over the 52-day time period. Local maxima in vertical velocity occur at depths of 25 and 280 m with magnitudes of (1.7 ± 0.6) × 10−5 m s−1 and (8.0 ± 1.6) × 10−5 m s−1, respectively. Volume transport as a function of salinity indicates that water crossing 93°W south (north) of 0.4°S tends to flow around the south (north) side of the Galápagos Archipelago. Comparisons are made between previous observational and modeling studies with differences attributed to effects of the strong 2015/16 El Niño event, the annual cycle of local winds, and varying longitudes between studies of the equatorial Pacific.
Are all automation-resistant skills rewarded? Linguistic skills in the US labour market
Authors: Ubalde Josep , Alarcón Amado 
Published: February 2020

Skills that are difficult to automate are expected to increase in demand and reward according to skill-biased technological change advocates, who have identified high rewards for cognitive and social skills. However, such broad skill categories involve numerous essential competencies that can be differentially rewarded or go simply unrewarded. Using US data, this article analyses the demand for and payment of linguistic competency, a cross-cutting kind of skill that is basic for both cognitive and social work in the new economy and is one of the human capacities that is most difficult to automate. While human capital theory predicts an increase in wages as the demand for linguistic skills rises, from cultural/institutional perspectives, it can be theorised that communicative abilities and foreign-language knowledge are socially undervalued because of their association with feminised activities, ethnicity, and low-status service jobs. We analyse the demand and reward for linguistic skills through a two-step analysis of occupational and individual data derived from two sources: the Occupational Information Network and the Current Population Survey. Results show that while ‘hard’ verbal-reasoning skills are associated with high average salaries, as is predicted by neoclassical theory, the potentially undervalued linguistic skills – interactive and multilingual skills – are unrewarded and even penalised. This evidence requires further political attention, given its implications for large number of workers, especially in feminised, low-status service jobs. JEL Codes: J01, J23, J24, J31, J38
Effectiveness of Parenting Program for Macau Shift Work Parents: Randomized Controlled Trial
Authors: Leung Cynthia , Chan Stanley , Ip H. L. , Szeto Heidi , Lee Miki , Chan Kama , Chan Marco 
Published: February 2020

Purpose: This study aimed to evaluate the effectiveness of the Happy Parenting: Round-the-Clock Parenting (HPRCP) program for Macau parents on shift work, using randomized controlled trial design. Methods: The participants included 154 parents on shift work who were randomized into the intervention ( n = 78) and waitlist control ( n = 76) groups. Participants were requested to complete a set of questionnaires on their children’s behavior, their own parenting stress, parenting practices, and emotion-focused parenting style both before and after the completion of the program by the intervention group. Results: Analysis was by intention-to-treat. The results indicated significant reduction in child behavior problems, parenting stress, and dysfunctional parenting practices in the intervention group after intervention. Conclusions: The results provided promising evidence on the effectiveness of the HPRCP program for parents on shift work.
Metastasis suppressor 1 acts as a tumor suppressor by inhibiting epithelial-to-mesenchymal transition in triple-negative breast cancer
Authors: Yu Jinling , Shen Weida , Gao Beimin , Xu Jinping , Gong Bo 
Published: February 2020

Objective: This study aimed to analyze the function of metastasis suppressor 1 ( MTSS1) in triple negative breast cancer (TNBC). Methods: MTSS1 expression in 30 TNBC and paracancerous tissues was measured by quantitative reverse transcriptase polymerase chain reaction. The prognostic value of MTSS1 was assessed by Kaplan–Meier analysis followed by the log-rank test. MCF7 cells were transfected with si- MTSS1, while MDA-MB-231 cells were transfected with pcDNA3.1- MTSS1. Cell proliferation assay and transwell assay were performed to investigate the effects of MTSS1 on the biological behavior of breast cancer cells. Immunofluorescence and western blot were used to detect the influence of MTSS1 on epithelial–mesenchymal transition (EMT) markers. Results: MTSS1 expression was significantly lower in TNBC tissues compared with that in paracancerous tissues (0.012 vs. 0.370; P = 0.006). A lower MTSS1 expression level was also found in tumor tissues of patients with lymph node metastasis ( P = 0.002) or tumor node metastasis stage ( P = 0.010). Patients with low expression of MTSS1 (⩽ 0.009) had shorter disease-free survival (47.4 vs. 56.0 months; P = 0.012). The knockdown of MTSS1 in MCF7 cells inhibited cell proliferation, enhanced cell migration and invasion capacities, decreased the E-cadherin level, and increased the vimentin level, whereas overexpression of MTSS1 in MDA-MB-231 cells had the opposite effects ( P < 0.05). Conclusions: Our findings demonstrated that MTSS1 regulates proliferation, invasion, migration, and EMT in TNBC, and that decreased MTSS1 is associated with shorter disease-free survival.