bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma
Authors: Curti Brendan , Crittenden Marka , Seung Steven K , Fountain Christopher B , Payne Roxanne , Chang ShuChing , Fleser Jessica , Phillips Kimberly , Malkasian Ian , Dobrunick Lyn B , Urba Walter J 
Published: May 2020

BackgroundA pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) showed a higher than anticipated objective response rate (ORR) among patients with metastatic melanoma (MM). We performed a prospective randomized study to determine if the ORR of SBRT + IL-2 was greater than IL-2 monotherapy in patients with advanced melanoma.MethodsPatients with MM who had adequate physiological reserve for IL-2 and at least one site suitable for SBRT were eligible. There was a 1:1 randomization to SBRT + IL-2 or IL-2 monotherapy. Patients received one or two doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting the first cycle of IL-2. IL-2 (600,000 IU per kg via intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Responding patients received up to six IL-2 cycles. Patients assigned to IL-2 monotherapy who exhibited progression of melanoma after cycle 2 were allowed to crossover and receive SBRT and additional IL-2. Response Evaluation Criteria in Solid Tumors 1.1 criteria were applied to non-irradiated lesions for response assessment.Results44 patients were included in the analysis. The ORR in the SBRT + IL-2 group was 54%: 21% complete response (CR), 33% partial response (PR), 21% stable disease (SD) and 25% progressive disease (PD). The ORR in patients receiving IL-2 monotherapy was 35%: 15% CR, 20% PR, 25% SD and 40% PD. Seven patients assigned to IL-2 subsequently received SBRT + IL-2. One CR and two PRs were observed in the crossover group. There was no difference in progression-free or overall survival (OS). At 5 years the OS was 26% in the SBRT + IL-2 group and 25% in the IL-2 monotherapy group. The disease control rate (DCR) was higher in the SBRT + IL-2 group (75% vs 60%, p=0.34).ConclusionsSBRT + IL-2 induced more objective responses with a higher DCR compared to IL-2 monotherapy in MM. IL-2 monotherapy resulted in a significantly higher ORR than anticipated. Some patients in the crossover group also achieved objective responses.Trial registration numberNCT01416831.
Differences between women and men in the relationship between psychosocial stressors at work and work absence due to mental health problem
Authors: Gilbert-Ouimet Mahée , Trudel Xavier , Aubé Karine , Ndjaboue Ruth , Duchaine Caroline , Blanchette Caty , Mâsse Benoît , Vézina Michel , Milot Alain , Brisson Chantal 
Published: May 2020

ObjectivesWomen have a higher incidence of mental health problems compared with men. Psychosocial stressors at work are associated with mental health problems. However, few prospective studies have examined the association between these stressors and objectively measured outcomes of mental health. Moreover, evidence regarding potential differences between women and men in this association is scarce and inconsistent. This study investigates whether psychosocial stressors at work are associated with the 7.5-year incidence of medically certified work absence due to a mental health problem, separately for women and men.MethodsData from a prospective cohort of white-collar workers in Canada (n=7138; 47.3% women) were used. We performed Cox regression models to examine the prospective association between self-reported psychosocial stressors at work (job strain model) at baseline and the 7.5-year HR of medically certified work absence of ≥5 days due to a mental health problem.ResultsDuring follow-up, 11.9% of participants had a certified work absence, with a twofold higher incidence among women. Women (HR 1.40, 95% CI 1.01 to 1.93) and men (HR 1.41, 95% CI 0.97 to 2.05) exposed to high strain (high demands and low control) had a higher incidence of work absence compared with those unexposed. Among women only, those exposed to an active job situation (high demands and high control) also had a higher risk (HR 1.82, 95% CI 1.29 to 2.56).ConclusionsPrevention efforts aimed at reducing psychosocial stressors at work could help lower the risk of work absence for both women and men. However, important differences between women and men need to be further studied in order to orient these efforts.
Advances in the management of diabetes: therapies for type 2 diabetes
Authors: Tsoutsouki Jovanna , Wunna Wunna , Chowdhury Aisha , Chowdhury Tahseen Ahmad 
Published: May 2020

AbstractThe incidence of type 2 diabetes is rapidly rising worldwide leading to an increasing burden of cardiovascular and microvascular complications. The aim of treatment of the condition is to improve quality of life and reduce such complications. To this end, improvement in glucose control remains an important consideration. In recent years, important therapeutic advances have occurred in the management of hyperglycaemia in people with type 2 diabetes. These include the use of dipeptidylpeptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium glucose transporter-2 inhibitors. The latter two classes appear to have some specific beneficial effects on cardiovascular and renal outcomes, independent of their antihyperglycaemic effects. This review aims to outline the current state of diagnosis and management of diabetes for the general physician, with a particular focus on new therapeutic agents for management of glucose in patients with type 2 diabetes.
E-HeaRT BPA: electronic health record telemetry BPA
Authors: Chin Kuo-Kai , Svec David , Leung Benjamin , Sharp Christopher , Shieh Lisa 
Published: May 2020

AbstractIntroductionContinuous cardiac monitoring in non-critical care settings is expensive and overutilised. As such, it is an important target of hospital interventions to establish cost-effective, high-quality care. Since inappropriate telemetry use was persistently elevated at our institution, we devised an electronic best practice alert (BPA) and tested it in a randomised controlled fashion.MethodsBetween 4 March 2018 and 5 July 2018 at our 600-bed academic hospital, all non-critical care patients who had at least one telemetry order were randomised to the control or intervention group. The intervention group received daily BPAs if telemetry was active.Results275 and 283 patients were randomised to the intervention and control groups, respectively. The intervention group triggered 1042 alerts and trended toward fewer telemetry days (3.8 vs 5.0, p=0.017). The intervention group stopped telemetry 31.7% of the alerted patient-days compared with 23.3% for the control group (OR 1.53, 95% CI 1.24 to 1.88, p&lt;0.001). There were no significant differences in length of stay, rapid responses, code blues, or mortality between the two groups.ConclusionsUsing a randomised controlled design, we show that BPAs significantly reduce telemetry without negatively affecting patient outcomes. They should have a role in promoting high-value telemetry use.
Five-dimensional charged rotating minimally gauged supergravity black hole cannot be over-spun and/or over-charged in non-linear accretion
Authors: Shaymatov Sanjar , Dadhich Naresh , Ahmedov Bobomurat , Jamil Mubasher 
Published: May 2020

AbstractGenerally a black hole could be over-charged/spun, violating the weak cosmic censorship conjecture (WCCC) for linear order accretion while the same is always restored for non-linear accretion. The only exception, however, is that of a five-dimensional rotating black hole with single rotation, which cannot be overspun even at linear order. In this paper we investigate this question for a five-dimensional charged rotating minimally gauged supergravity black hole and show that it could not be overspun under non-linear accretion, thereby respecting WCCC. However, in the case of single rotation WCCC is also respected for linear accretion when the angular momentum of the accreting particle is greater than its charge irrespective of the relative dominance of the charge and rotation parameters of the black hole.
Insulin-Like Growth Factor-1 Receptor Expression and Disease Recurrence and Survival in Patients with Resected Pancreatic Ductal Adenocarcinoma
Authors: Du Chunxia , da Silva Annacarolina , Morales-Oyarvide Vicente , Dias Costa Andressa , Kozak Margaret M. , Dunne Richard F. , Rubinson Douglas A. , Perez Kimberly , Masugi Yohei , Hamada Tsuyoshi , Brais Lauren K. , Yuan Chen , Babic Ana , Ducar Matthew D. , Thorner Aaron R. , Aguirre Andrew , Kulke Matthew H. , Ng Kimmie , Clancy Thomas E. , Findeis-Hosey Jennifer J. , Chang Daniel T. , Hornick Jason L. , Fuchs Charles S. , Ogino Shuji , Koong Albert C. , Hezel Aram F. , Wolpin Brian M. , Nowak Jonathan A. 
Published: May 2020

Abstract

Background:
Insulin-like growth factor-1 receptor (IGF1R) signaling is important in pancreatic ductal adenocarcinoma (PDAC) biology, but little is known regarding IGF1R expression and patient characteristics and outcomes.

Methods:
In 365 patients with resected PDAC, we evaluated IGF1R protein expression using IHC on whole-slide sections and IGF1R genomic status using next-generation sequencing. Associations of IGF1R expression, measured by H-scores incorporating staining intensity and proportion of positive tumor cells, with disease-free survival (DFS) and overall survival (OS) were evaluated in 317 and 321 patients, respectively, using Cox regression adjusting for known prognostic factors.

Results:
Higher IGF1R expression in tumor cells was associated with worse DFS comparing highest versus lowest expression tertiles [median DFS, 10.8 vs. 16.1 months; adjusted hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.24–2.44; Ptrend = 0.002] and worse OS (median OS, 17.4 vs. 25.8 months; HR, 1.39; 95% CI, 1.00–1.92; Ptrend = 0.046). The association between high IGF1R expression and reduced DFS was identified primarily among patients with a preoperative body mass index ≥25 kg/m2 (HR, 4.27; 95% CI, 2.03–8.96, comparing extreme tertiles; Pinteraction = 0.032). KRAS-mutant tumors had greater IGF1R expression, and IGF1R expression in tumor epithelium was inversely correlated with that in stromal cells. Mutations in IGF1R were infrequent, and no overt loss-of-function alterations were identified. Higher IGF1R expression was modestly associated with higher gene copy number (Pearson correlation coefficient = 0.26, P &lt; 0.001).

Conclusions:
Higher IGF1R protein expression was associated with worse patient outcomes in resected PDAC.

Impact:
IGF1R expression in PDAC represents a potential biomarker to guide patient selection for more aggressive, multidrug regimens in the adjuvant setting.
Metabolic Syndrome, Physical Activity, and Inflammation: A Cross-Sectional Analysis of 110 Circulating Biomarkers in Japanese Adults
Authors: Van Alsten Sarah C. , Rabkin Charles S. , Sawada Norie , Shimazu Taichi , Charvat Hadrien , Yamaji Taiki , Inoue Manami , Kemp Troy J. , Pinto Ligia A. , Camargo M. Constanza , Tsugane Shoichiro , Song Minkyo 
Published: May 2020

Abstract

Background:
Metabolic syndrome (MetS) is a systemic inflammatory state. Low physical activity (PA) could modify this patho-physiology or act as an independent contributor to inflammation. Previous studies of both conditions have identified altered levels of inflammation- and immune-related proteins based on limited sets of candidate markers.

Methods:
We investigated associations of MetS and low PA with circulating inflammation markers in a stratified random sample of Japanese adults (N = 774, mean age 60.7 years) within the Japan Public Health Center-based Prospective Study (JPHC) Cohort II. AHA/NHLBI criteria were used to define MetS (19%) and the bottom quartile of PA was considered low. 110 circulating biomarkers, including cytokines, chemokines, and soluble receptors were measured by multiplex bead-based and proximity-extension assays. Associations of MetS and low PA with marker quantiles were adjusted for each other and for age, sex, study site, cigarette smoking, alcohol consumption, and blood sample fasting state by ordinal logistic regression. P values were corrected for FDR.

Results:
MetS was significantly associated with levels of six markers: IL18R1 [odds ratio 2.37; 95% confidence interval (CI), 1.45–3.87], CRP (2.07; 95% CI, 1.48–2.90), SAP (2.08; 95% CI, 1.47–2.95), CCL19/MIP3β (2.06; 95% CI, 1.48–2.88), CXCL12/SDF1α+β (0.48; 95% CI, 0.32–0.65), and CCL28 (0.44; 95% CI, 0.27–0.71). Low PA had no significant marker associations.

Conclusions:
Positively associated markers with MetS are mostly Th1 immune response–related and acute phase proteins, whereas negatively associated markers are generally Th2-related.

Impact:
MetS is associated with a broad range of alterations in immune and inflammatory biomarkers that may contribute to risks of various chronic diseases, independent of low PA.
A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer
Authors: Rotunno Melissa , Barajas Rolando , Clyne Mindy , Hoover Elise , Simonds Naoko I. , Lam Tram Kim , Mechanic Leah E. , Goldstein Alisa M. , Gillanders Elizabeth M. 
Published: May 2020

Abstract
The application of next-generation sequencing (NGS) technologies in cancer research has accelerated the discovery of somatic mutations; however, progress in the identification of germline variation associated with cancer risk is less clear. We conducted a systematic literature review of cancer genetic susceptibility studies that used NGS technologies at an exome/genome-wide scale to obtain a fuller understanding of the research landscape to date and to inform future studies. The variability across studies on methodologies and reporting was considerable. Most studies sequenced few high-risk (mainly European) families, used a candidate analysis approach, and identified potential cancer-related germline variants or genes in a small fraction of the sequenced cancer cases. This review highlights the importance of establishing consensus on standards for the application and reporting of variants filtering strategies. It also describes the progress in the identification of cancer-related germline variation to date. These findings point to the untapped potential in conducting studies with appropriately sized and racially diverse families and populations, combining results across studies and expanding beyond a candidate analysis approach to advance the discovery of genetic variation that accounts for the unexplained cancer heritability.
Comparison of Tissue-Based Molecular Markers in Younger versus Older Patients with Colorectal Neoplasia
Authors: Limburg Paul J. , Mahoney Douglas W. , Ahlquist David A. , Allawi Hatim T. , Johnson Scott C. , Kaiser Michael , Katerov Viatcheslav E. , Statz Sandra , Graham Rondell P. , Foote Patrick H. , Doering Karen A. , Burger Kelli N. , Lidgard Graham P. , Kisiel John B. 
Published: May 2020

Abstract

Background:
Emerging colorectal cancer trends demonstrate increased incidence and mortality in younger populations, prompting consideration of average-risk colorectal cancer screening initiation at age 45 versus 50 years. However, screening test performance characteristics in adults 45–49 years have been minimally described. To inform the biologic rationale for multi-target stool DNA (mt-sDNA) screening in younger patients, we analyzed and compared tissue levels of methylation (BMP3, NDRG4) and mutation (KRAS) markers included in the FDA-approved, mt-sDNA assay (Cologuard; Exact Sciences Corporation).

Methods:
Within 40–44, 45–49, and 50–64 year age groups, archived colorectal tissue specimens were identified for 211 sporadic colorectal cancer cases, 123 advanced precancerous lesions (APLs; adenomas &gt;1 cm, high-grade dysplasia, ≥25% villous morphology, or sessile serrated polyp; 45–49 and 50–64 age groups only), and 204 histologically normal controls. Following DNA extraction, KRAS, BMP3, and NDRG4 were quantified using QuARTS assays, relative to ACTB (reference gene).

Results:
None of the molecular marker concentrations were significantly associated with age (P &gt; 0.05 for all comparisons), with the exception of NDRG4 concentration in APL samples (higher in older vs. younger cases; P = 0.008). However, NDRG4 levels were also statistically higher in APL case versus normal control samples in both the 45–49 (P &lt; 0.0001) and 50–64 (P &lt; 0.0001) year age groups.

Conclusions:
Overall, these findings support the potential for earlier onset of average-risk colorectal cancer screening with the mt-sDNA assay.

Impact:
These novel data address an identified knowledge gap and strengthen the biologic basis for earlier-onset, average-risk screening with the mt-sDNA assay.
Menstrual Factors, Reproductive History, Hormone Use, and Urothelial Carcinoma Risk: A Prospective Study in the EPIC Cohort
Authors: Lujan-Barroso Leila , Botteri Edoardo , Caini Saverio , Ljungberg Börje , Roswall Nina , Tjønneland Anne , Bueno-de-Mesquita Bas , Gram Inger T. , Tumino Rosario , Kiemeney Lambertus A. , Liedberg Fredrik , Stocks Tanja , Gunter Marc J. , Murphy Neil , Cervenka Iris , Fournier Agnès , Kvaskoff Marina , Häggström Christel , Overvad Kim , Lund Eiliv , Waaseth Marit , Fortner Renée Turzanski , Kühn Tilman , Menéndez Virginia , Sánchez Maria-Jose , Santiuste Carmen , Perez-Cornago Aurora , Zamora-Ros Raul , Cross Amanda J. , Trichopoulou Antonia , Karakatsani Anna , Peppa Eleni , Palli Domenico , Krogh Vittorio , Sciannameo Veronica , Mattiello Amalia , Panico Salvatore , van Gils Carla H. , Onland-Moret N. Charlotte , Barricarte Aurelio , Amiano Pilar , Khaw Kay-Tee , Boeing Heiner , Weiderpass Elisabete , Duell Eric J. 
Published: May 2020

Abstract

Background:
Urothelial carcinoma is the predominant (95%) bladder cancer subtype in industrialized nations. Animal and epidemiologic human studies suggest that hormonal factors may influence urothelial carcinoma risk.

Methods:
We used an analytic cohort of 333,919 women from the European Prospective Investigation into Cancer and Nutrition Cohort. Associations between hormonal factors and incident urothelial carcinoma (overall and by tumor grade, tumor aggressiveness, and non–muscle-invasive urothelial carcinoma) risk were evaluated using Cox proportional hazards models.

Results:
During a mean of 15 years of follow-up, 529 women developed urothelial carcinoma. In a model including number of full-term pregnancies (FTP), menopausal status, and menopausal hormone therapy (MHT), number of FTP was inversely associated with urothelial carcinoma risk (HR≥5vs1 = 0.48; 0.25–0.90; Ptrend in parous women = 0.010) and MHT use (compared with nonuse) was positively associated with urothelial carcinoma risk (HR = 1.27; 1.03–1.57), but no dose response by years of MHT use was observed. No modification of HRs by smoking status was observed. Finally, sensitivity analyses in never smokers showed similar HR patterns for the number of FTP, while no association between MHT use and urothelial carcinoma risk was observed. Association between MHT use and urothelial carcinoma risk remained significant only in current smokers. No heterogeneity of the risk estimations in the final model was observed by tumor aggressiveness or by tumor grade. A positive association between MTH use and non–muscle-invasive urothelial carcinoma risk was observed.

Conclusions:
Our results support that increasing the number of FTP may reduce urothelial carcinoma risk.

Impact:
More detailed studies on parity are needed to understand the possible effects of perinatal hormone changes in urothelial cells.
Methodologic Considerations in Calculating and Analyzing Proportion of Time Covered as a Measure of Longitudinal Cancer Screening Adherence
Authors: Chubak Jessica , Anderson Melissa L. , Cook Andrea J. , Murphy Caitlin C. , Jackson Michael L. , Green Beverly B. 
Published: May 2020

Abstract

Background:
Proportion of time covered (PTC, or “covered time”) is a longitudinal measure of adherence to preventive health services, the use of which has increased in recent years. This measure is helpful for evaluating the success of delivering screening interventions over time. However, there are challenges and nuances in computing and interpreting PTC.

Methods:
In this manuscript, we describe some desired properties of PTC measures, challenges in achieving those, and potential solutions using hypothetical examples.

Results:
We propose a modified PTC measure (mPTC) to complement the standard, existing PTC measure. The mPTC measure focuses on screening completion rather than initiation when a screening modality requires more than one step; is affected less by loss to follow-up, death, or cancer during covered time than the standard PTC measure; and is not sensitive to screening episode results. We propose weighting strategies to ensure that the average PTC and mPTC are more heavily influenced by individuals who were observed for longer and are thus more informative. We further describe how PTC and mPTC measures can incorporate test indication to focus specifically on screening.

Conclusions:
We recommend that studies of covered time present ample descriptive information, calculate both PTC and mPTC, describe how symptoms and indication are handled, and present multiple complementary measures, such as the proportion never screened and the proportion in need of screening.

Impact:
Common approaches, terminology, and reporting practices for covered time measures have the potential to improve the study of longitudinal cancer screening adherence.
PRAS40 Phosphorylation Correlates with Insulin-Like Growth Factor-1 Receptor-Induced Resistance to Epidermal Growth Factor Receptor Inhibition in Head and Neck Cancer Cells
Authors: Dougherty Michael I. , Lehman Christine E. , Spencer Adam , Mendez Rolando E. , David Abel P. , Taniguchi Linnea E. , Wulfkuhle Julie , Petricoin Emanuel F. , Gioeli Daniel , Jameson Mark J. 
Published: May 2020

AbstractEGFR inhibitors have shown poor efficacy in head and neck squamous cell carcinoma (HNSCC) with demonstrated involvement of the insulin-like growth factor-1 receptor (IGF1R) in resistance to EGFR inhibition. IGF1R activates the PI3K–Akt pathway, which phosphorylates proline-rich Akt substrate of 40 kDa (PRAS40) to cease mTOR inhibition resulting in increased mTOR signaling. Proliferation assays separated six HNSCC cell lines into two groups: sensitive to EGFR inhibition or resistant; all sensitive cell lines demonstrated reduced sensitivity to EGFR inhibition upon IGF1R activation. Reverse phase protein microarray analysis and immunoblot identified a correlation between increased PRAS40 phosphorylation and IGFR-mediated resistance to EGFR inhibition. In sensitive cell lines, PRAS40 phosphorylation decreased 44%–80% with EGFR inhibition and was restored to 98%–196% of control by IGF1R activation, while phosphorylation was unaffected in resistant cell lines. Possible involvement of mTOR in this resistance mechanism was demonstrated through a similar pattern of p70S6K phosphorylation. However, addition of temsirolimus, an mTORC1 inhibitor, was insufficient to overcome IGF1R-mediated resistance and suggested an alternative mechanism. Forkhead box O3a (FOXO3a), which has been reported to complex with PRAS40 in the cytoplasm, demonstrated a 6-fold increase in nuclear to cytoplasmic ratio upon EGFR inhibition that was eliminated with concurrent IGF1R activation. Transcription of FOXO3a-regulated TRAIL and PTEN-induced putative kinase-1 (PINK1) was increased with EGFR inhibition in sensitive cell lines; this effect was diminished with IGF1R stimulation.Implications:These data suggest PRAS40 may play an important role in IGF1R-based therapeutic resistance to EGFR inhibition, and this likely occurs via inhibition of FOXO3a-mediated proapoptotic gene transcription.