bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Targeted Therapies Elicit Concurrent Apoptotic and GSDME-Dependent Pyroptotic Tumor Cell Death
Authors: Lu Haijiao , Zhang Shengzhe , Wu Jie , Chen Minjiang , Cai Mei-Chun , Fu Yujie , Li Wenfeng , Wang Jing , Zhao Xiaojing , Yu Zhuang , Ma Pengfei , Zhuang Guanglei 
Published: July 2018

Abstract

Purpose:
The induced death signals following oncogene inhibition underlie clinical efficacy of molecular targeted therapies against human cancer, and defects of intact cell apoptosis machinery often lead to therapeutic failure. Despite potential importance, other forms of regulated cell death triggered by pharmacologic intervention have not been systematically characterized.

Experimental Design:
Pyroptotic cell death was assessed by immunoblot analysis, phase-contrast imaging, scanning electron microscopy, and flow cytometry. Tumor tissues of patients with lung cancer were analyzed using IHC. Functional impact of pyroptosis on drug response was investigated in cell lines and xenograft models.

Results:
We showed that diverse small-molecule inhibitors specifically targeting KRAS-, EGFR-, or ALK-driven lung cancer uniformly elicited robust pyroptotic cell death, in addition to simultaneously invoking cellular apoptosis. Upon drug treatment, the mitochondrial intrinsic apoptotic pathway was engaged and the mobilized caspase-3 protease cleaved and activated gasdermin E (GSDME, encoded by DFNA5), which permeabilized cytoplasmic membrane and executed cell-lytic pyroptosis. GSDME displayed ubiquitous expression in various lung cancer cell lines and clinical specimens, including KRAS-mutant, EGFR-altered, and ALK-rearranged adenocarcinomas. As a result, cooccurrence and interplay of apoptosis and pyroptosis were widespread in lung cancer cells, succumbing to genotype-matched regimens. We further demonstrated that pyroptotic cell death partially contributed to the drug response in a subset of cancer models.

Conclusions:
These results pinpoint GSDME-dependent pyroptosis as a previously unrecognized mechanism of action for molecular targeted agents to eradicate oncogene-addicted neoplastic cells, which may have important implications for the clinical development and optimal application of anticancer therapeutics.
NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors in Naturally Occurring Canine Lymphoma
Authors: Burton Jenna H. , Mazcko Christina , LeBlanc Amy , Covey Joseph M. , Ji Jiuping , Kinders Robert J. , Parchment Ralph E. , Khanna Chand , Paoloni Melissa , Lana Sue , Weishaar Kristen , London Cheryl , Kisseberth William , Krick Erika , Vail David , Childress Michael , Bryan Jeffrey N. , Barber Lisa , Ehrhart E.J. , Kent Michael , Fan Timothy , Kow Kelvin , Northup Nicole , Wilson-Robles Heather , Tomaszewski Joseph , Holleran Julianne L. , Muzzio Miguel , Eiseman Julie , Beumer Jan H. , Doroshow James H. , Pommier Yves 
Published: July 2018

Abstract

Purpose:
Only one chemical class of topoisomerase I (TOP1) inhibitors is FDA approved, the camptothecins with irinotecan and topotecan widely used. Because of their limitations (chemical instability, drug efflux-mediated resistance, and diarrhea), novel TOP1 inhibitors are warranted. Indenoisoquinoline non-camptothecin topoisomerase I (TOP1) inhibitors overcome chemical instability and drug resistance that limit camptothecin use. Three indenoisoquinolines, LMP400 (indotecan), LMP776 (indimitecan), and LMP744, were examined in a phase I study for lymphoma-bearing dogs to evaluate differential efficacy, pharmacodynamics, toxicology, and pharmacokinetics.

Experimental Design:
Eighty-four client-owned dogs with lymphomas were enrolled in dose-escalation cohorts for each indenoisoquinoline, with an expansion phase for LMP744. Efficacy, tolerability, pharmacokinetics, and target engagement were determined.

Results:
The MTDs were 17.5 mg/m2 for LMP 776 and 100 mg/m2 for LMP744; bone marrow toxicity was dose-limiting; up to 65 mg/m2 LMP400 was well-tolerated and MTD was not reached. None of the drugs induced notable diarrhea. Sustained tumor accumulation was observed for LMP744; γH2AX induction was demonstrated in tumors 2 and 6 hours after treatment; a decrease in TOP1 protein was observed in most lymphoma samples across all compounds and dose levels, which is consistent with the fact that tumor response was also observed at low doses LMP744. Objective responses were documented for all indenoisoquinolines; efficacy (13/19 dogs) was greatest for LMP744.

Conclusions:
These results demonstrate proof-of-mechanism for indenoisoquinoline TOP1 inhibitors supporting their further clinical development. They also highlight the value of the NCI Comparative Oncology Program (https://ccr.cancer.gov/Comparative-Oncology-Program) for evaluating novel therapies in immunocompetent pets with cancers.
Optimal Ranking Regime Analysis of U.S. Summer Temperature and Degree-Days: 1895–2015
Authors: Mauget Steven A. 
Published: July 2018

AbstractThe optimal ranking regime (ORR) method was applied to mean summer maximum (TMXS) and mean summer minimum (TMNS) temperature and to cumulative summer cooling degree-days (CDDS) calculated from U.S. climate-division data during 1895–2015. CDDS is proposed as a proxy for growing degree-days for summer corn given their high rank correlation in station data during 1950–2014. The TMXS and CDDS ORR analyses show similar climate-regime patterns. Western and northeastern divisions experienced multidecadal cool periods before 1930 and warm periods after 1990. The 1930s drought appears as decadal warm regimes over the Midwest and Great Plains. Multidecadal TMXS and CDDS temperature cycles are evident over the Southeast, but TMXS and CDDS variation over the Midwest’s Corn Belt agricultural region has been regime free since the early 1940s. By contrast, TMNS regimes consistent with centennial-scale warming trends are found over most divisions outside the Southeast. From the multidecadal regime patterns detected by the ORR analyses, the TMXS, TMNS, and CDDS series of each climate division were tested for significant linear trends during 1910–2015 and 1970–2015. Significant positive TMNS trends during 1910–2015 are found in 48 of the 102 divisions, with some western trend magnitudes being greater than 15% of the twentieth-century climatological mean. During 1970–2015, positive TMXS trends are detected over 39 western and northeastern divisions, but warming TMNS trends are evident nationally. In some cooler western divisions, positive 1970–2015 CDDS trend magnitudes exceed 90% of the climatological mean. Consistent with the ORR analyses, Corn Belt TMXS and CDDS trends are insignificant during 1970–2015.
A Stochastic Lagrangian Basis for a Probabilistic Parameterization of Moisture Condensation in Eulerian Models
Authors: Tsang Yue-Kin , Vallis Geoffrey K. 
Published: July 2018

Abstract
In this paper, we describe the construction of an efficient probabilistic parameterization that could be used in a coarse-resolution numerical model in which the variation of moisture is not properly resolved. An Eulerian model using a coarse-grained field on a grid cannot properly resolve regions of saturation—in which condensation occurs—that are smaller than the grid boxes. Thus, in the absence of a parameterization scheme, either the grid box must become saturated or condensation will be underestimated. On the other hand, in a stochastic Lagrangian model of moisture transport, trajectories of parcels tagged with humidity variables are tracked, and small-scale moisture variability can be retained; however, explicitly implementing such a scheme in a global model would be computationally prohibitive. One way to introduce subgrid-scale saturation into an Eulerian model is to assume the humidity within a grid box has a probability distribution. To close the problem, this distribution is conventionally determined by relating the required subgrid-scale properties of the flow to the grid-scale properties using a turbulence closure. Here, instead, we determine an assumed probability distribution by using the statistical moments from a stochastic Lagrangian version of the system. The stochastic system is governed by a Fokker–Planck equation, and we use that, rather than explicitly following the moisture parcels, to determine the parameters of the assumed distribution. We are thus able to parameterize subgrid-scale condensation in an Eulerian model in a computationally efficient and theoretically well-founded way. In two idealized advection–condensation problems, we show that a coarse Eulerian model with the subgrid parameterization is well able to mimic its Lagrangian counterpart.
Effects of vitamin C on the outcome of in vitro fertilization–embryo transfer in endometriosis: A randomized controlled study
Authors: Lu Xiang , Wu Zhengmu , Wang Min , Cheng Weiwei 
Published: July 2018

Objective This study was performed to investigate the effect of vitamin C (VitC) supplementation on the outcomes of in vitro fertilization–embryo transfer (IVF-ET) in patients with endometriosis (EMs). Methods A total of 280 patients with EMs underwent IVF-ET (VitC treatment group, n=160; VitC non-treatment group, n=120). An additional 150 patients who did not have EMs but underwent IVF-ET (control group) were also enrolled in this study. Superoxide dismutase (SOD), total antioxidant capacity (TAC), malondialdehyde (MDA) and reactive oxygen species (ROS) were measured to determine the role of VitC on oxidative stress markers in serum and follicular fluid (FF). Results In total, 245 patients with EMs and 132 patients without EMs underwent successful IVF-ET and follow-up. The serum or FF levels of VitC, SOD, and TAC were lower in the EMs than control group; however, the MDA and ROS levels in serum or FF were higher in the EMs than control group. After 2 months of VitC treatment, the serum VitC levels in serum and FF were significantly increased, while oxidative stress markers were unaffected. Conclusion Treatment with VitC oral formulation improved the serum and FF levels of VitC but did not affect oxidative stress markers in patients with EMs.
Individualized Anterior Cruciate Ligament Graft Matching: In Vivo Comparison of Cross-sectional Areas of Hamstring, Patellar, and Quadriceps Tendon Grafts and ACL Insertion Area
Authors: Offerhaus Christoph , Albers Márcio , Nagai Kanto , Arner Justin W. , Höher Jürgen , Musahl Volker , Fu Freddie H. 
Published: July 2018

Background: Recent literature correlated anterior cruciate ligament (ACL) reconstruction failure to smaller diameter of the harvested hamstring (HS) autograft. However, this approach may be a simplification, as relation of graft size to native ACL size is not typically assessed and oversized grafts may impart their own complications. Purpose: To evaluate in vivo data to determine if the commonly used autografts reliably restore native ACL size. Study Design: Descriptive laboratory study. Methods: Intraoperative data of the tibial insertion area and HS graft diameter were collected and retrospectively evaluated for 46 patients who underwent ACL reconstruction with HS autografts. Magnetic resonance imaging measurements of the cross-sectional area (CSA) of the possible patellar tendon (PT) and quadriceps tendon (QT) autografts were also done for each patient. The percentages of tibial insertion site area restored by the 3 possible grafts were then calculated and compared for each individual. Results: The mean ACL tibial insertion area was 107.2 mm2 (60.5-155.5 mm2). The mean CSAs of PT, HS, and QT were 33.2, 55.3, and 71.4 mm2, respectively. When all grafts were evaluated, the percentage reconstruction of the insertion area varied from 16.2% to 123.1% on the tibial site and from 25.5% to 176.7% on the femoral site, differing significantly for each graft type ( P < .05). On average, 32.8% of the tibial insertion area would have been filled with PT, 53.6% by HS, and 69.5% by QT. Based on previous cadaveric studies indicating that graft size goal should be 50.2% ± 15% of the tibial insertion area, 82.7% of patients in the HS group were within this range (36.9%, QT; 30.5%, PT), while 65.2% in the PT group were below it and 60.9% in the QT group were above it. Conclusion: ACL insertion size and the CSAs of 3 commonly used grafts vary greatly for each patient and are not correlated with one another. Thus, if the reconstructed ACL size is determined by the harvested autograft size alone, native ACL size may not be adequately restored. PT grafts tended to undersize the native ACL, while QT might oversize it. Clinical Relevance: These results may help surgeons in preoperative planning, as magnetic resonance imaging measurements can be helpful in determining individualized graft choice to adequately restore the native ACL.
A comparison of the reported use of involuntary treatment orders within Australian jurisdictions
Authors: Clugston Bobbie , Young Amy , Heffernan Edward B 
Published: July 2018

Objective: This paper identifies publicly available data about the use of involuntary treatment orders within Australia and considers whether this reporting is sufficient given the gravity of the intervention. Method: A search of mental health tribunal, health department and justice department annual reports was conducted to determine the use of involuntary treatment orders in Australia. Results: Reporting of involuntary treatment orders varied significantly across jurisdictions; for example, South Australia reported 11,570 distinct orders made during a 12-month period while the Australian Capital Territory reported 627 for the same period. Conclusion: The publicly available data for involuntary treatment orders in Australia is inadequate for jurisdictional comparisons. This concern should be addressed to enable transparent public reporting and facilitate benchmarking.
Role of Amputation in Improving Mobility, Pain Outcomes, and Emotional and Psychological Well-Being in Children With Metastatic Osteosarcoma
Authors: Gil Sebastian , Fernandez-Pineda Israel , Rao Bhaskar , Neel Michael D. , Baker Justin N. , Wu Huiyun , Wu Jianrong , Anghelescu Doralina L. 
Published: July 2018

Background: Few studies have analyzed the benefit of limb amputations in children with metastatic osteosarcoma and limited life span. Objective: We studied outcomes of limb amputations in children with metastatic osteosarcoma. Design: We performed a retrospective review of patients who underwent limb amputations (January 1995-June 2015) and died within 1 year of surgery. Setting/Participants: We studied 12 patients with osteosarcoma at a single institution. Measurements: Data on mobility, pain, and emotional and psychological well-being were retrieved from medical records from 1 month before surgery to 6 months after surgery. Results: Of the 12 patients (7 females and 5 males; median age at surgery 13 years [range, 7-20 years]) meeting study criteria, 3 patients and 9 patients had primary osteosarcoma in upper and lower limbs, respectively. Mobility improved postamputation in 8 bedridden/wheelchair-bound patients. Postamputation, emotional, and psychological well-being improved for 9 patients, 3 patients had persistent psychological and/or emotional symptoms, and no patient experienced signs of regret. Daily mean pain scores were significantly lower at 1 week (median 3 [range, 0-6]; P = .03) and 3 months (median 0 [range, 0-8]; P = .02) postsurgery than at 1 week presurgery (median 5.5 [range, 0-10]). Morphine consumption (mg/kg/d) showed a trend toward higher values at 1 week (median 0.2 [range, 0-7.6]; P = .6) and 3 months (median 0.2 [range, 0-0.5]; P = .3) postsurgery than at 1 week presurgery (median 0.1 [range, 0-0.5]). Conclusions: Patients undergoing limb amputations had reduced pain and improved mobility and emotional and psychological well-being. Amputations are likely to benefit children with limited life expectancy.
Length of efficacy and effect of implant location in adult tom cats treated with a 9.4 mg deslorelin subcutaneous implant
Authors: Romagnoli Stefano , Baldan Anna , Ferro Silvia , Righetti Camilla , Scenna Ludovico , Gabai Gianfranco , Badon Tamara , Fontaine Christelle , Mollo Antonio , Stelletta Calogero , Milani Chiara 
Published: July 2018

Objectives The objective of this study was to assess duration of efficacy, side effects and return to fertility following use of the 9.4 mg deslorelin implant (Suprelorin 12; Virbac) in cats, and test whether efficacy and duration of action are influenced by implantation site (interscapular vs periumbilical). Methods Sixteen healthy adult tom cats were checked with (1) reproductive examination, (2) gonadotropin-releasing hormone stimulation test and (3) semen collection until achievement of sterility, then with (1) and (2) only at 2, 4, 6 and 12 months, and every 6 months thereafter until treatment effect disappeared. Results Serum testosterone reached basal levels by 7 days post-treatment. Semen quality improved initially then started to worsen by 1 month post-treatment and after 70 days post-treatment all cats were sterile. Early in the third month post-treatment there was a significant decrease in testicular volume and penile spikes. Testicular histology was normal upon neutering performed after resumption of fertility. No injection site lesions or treatment-related side effects were observed. There was no difference between periumbilical and interscapular placement for all criteria, but there was a trend for the decrease in testicular volume to last longer and for the regression of penile spikes to start sooner after interscapular administration. One of 16 cats did not respond to treatment. Six cats were lost at variable times during the study while fully responding to treatment. In the cats that completed the study, normal fertility was regained after 805 days, on average, but with a variable duration of effect from 750–850 days. Conclusions and relevance Treatment with a 9.4 mg deslorelin implant in male cats was effective for a period of 750–850 days, which is 1.5–2 times longer than the effect of the 4.7 mg deslorelin implant. Fertility (based on serum testosterone production and the presence of penile spikes) was regained at the end of the study. Placing implants in the intrascapular vs periumbilical location did not affect duration of suppression of testosterone production. The interscapular location may be characterised by a better efficacy, although further studies are needed to clarify this issue.
The influence of alcohol abuse on agitation, delirium and sedative requirements of patients admitted to a general intensive care unit
Authors: Stewart Donald , Kinsella John , McPeake Joanne , Quasim Tara , Puxty Alex 
Published: July 2018

Purpose Patients with alcohol-related disease constitute an increasing proportion of those admitted to intensive care unit. There is currently limited evidence regarding the impact of alcohol use on levels of agitation, delirium and sedative requirements in intensive care unit. This study aimed to determine whether intensive care unit-admitted alcohol-abuse patients have different sedative requirements, agitation and delirium levels compared to patients with no alcohol issues. Methods This retrospective analysis of a prospectively acquired database (June 2012–May 2013) included 257 patients. Subjects were stratified into three risk categories: alcohol dependency (n = 69), at risk (n = 60) and low risk (n = 128) according to Fast Alcohol Screening Test scores and World Health Organisation criteria for alcohol-related disease. Data on agitation and delirium were collected using validated retrospective chart-screening methods and sedation data were extracted and then log-transformed to fit the regression model. Results Incidence of agitation (p = 0.034) and delirium (p = 0.041) was significantly higher amongst alcohol-dependent patients compared to low-risk patients as was likelihood of adverse events (p = 0.007). In contrast, at-risk patients were at no higher risk of these outcomes compared to the low-risk group. Alcohol-dependent patients experienced suboptimal sedation levels more frequently and received a wider range of sedatives (p = 0.019) but did not receive higher daily doses of any sedatives. Conclusions Our analysis demonstrates that when admitted to intensive care unit, it is those who abuse alcohol most severely, alcohol-dependent patients, rather than at-risk drinkers who have a significantly increased risk of agitation, delirium and suboptimal sedation. These patients may require closer assessment and monitoring for these outcomes whilst admitted.
Clinicopathological parameters influencing inhibitor development in patients with hemophilia A receiving on-demand therapy
Authors: Arshad Sanya , Singh Anshima , Awasthi Namrata Punit , Kumari Swati , Husain Nuzhat 
Published: July 2018

Background: Development of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive ‘on-demand’ rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving ‘on-demand’ therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors. Methods: The study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities. Results: In the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% ( n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%). Conclusions: Factor VIII inhibitor prevalence in PWHA receiving ‘on-demand’ therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.