bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulating the effect of school closure during COVID-19 outbreaks in Ontario, Canada
Authors: Abdollahi Elaheh , Haworth-Brockman Margaret , Keynan Yoav , Langley Joanne M. , Moghadas Seyed M.
Published: July 2020

Background

The province of Ontario, Canada, has instituted indefinite school closures (SC) as well as other social distancing measures to mitigate the impact of the novel coronavirus disease 2019 (COVID-19) pandemic. We sought to evaluate the effect of SC on reducing attack rate and the need for critical care during COVID-19 outbreaks, while considering scenarios with concurrent implementation of self-isolation (SI) of symptomatic cases.

Methods

We developed an age-structured agent-based simulation model and parameterized it with the demographics of Ontario stratified by age and the latest estimates of COVID-19 epidemiologic characteristics. Disease transmission was simulated within and between different age groups by considering inter- and intra-group contact patterns. The effect of SC of varying durations on the overall attack rate, magnitude and peak time of the outbreak, and requirement for intensive care unit (ICU) admission in the population was estimated. Secondly, the effect of concurrent community-based voluntary SI of symptomatic COVID-19 cases was assessed.

Results

SC reduced attack rates in the range of 7.2–12.7% when the duration of SC increased from 3 to 16 weeks, when contacts among school children were restricted by 60–80%, and in the absence of SI by mildly symptomatic persons. Depending on the scenario, the overall reduction in ICU admissions attributed to SC throughout the outbreak ranged from 3.3 to 6.7%. When SI of mildly symptomatic persons was included and practiced by 20%, the reduction of attack rate and ICU admissions exceeded 6.3% and 9.1% (on average), respectively, in the corresponding scenarios.

Conclusion

Our results indicate that SC may have limited impact on reducing the burden of COVID-19 without measures to interrupt the chain of transmission during both pre-symptomatic and symptomatic stages. While highlighting the importance of SI, our findings indicate the need for better understanding of the epidemiologic characteristics of emerging diseases on the effectiveness of social distancing measures.
Retrospective evaluation of labetalol as antihypertensive agent in dogs
Authors: Zublena Francesco , De Gennaro Chiara , Corletto Federico
Published: July 2020

Background

To evaluate the effect on arterial blood pressure (ABP) of labetalol infusion as treatment for perioperative non nociceptive acute hypertension in dogs. The clinical records of dogs receiving intra or postoperative labetalol infusion were retrospectively reviewed. Invasive systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressure and heart rate (HR) before labetalol infusion (T0) and 15, 30, 45 and 60 min (T1, T2, T3 and T4 respectively) after infusion were retrieved. The dose rate of labetalol infusion and use of concurrently administered drugs that could have potentially affected ABP and/or HR were also recorded. ANOVA for repeated measures and Dunnett’s multiple comparison test were used to determine the effect of labetalol on ABP and HR. Differences were considered significant whenp < 0.05.

Results

A total of 20 dogs met the inclusion criteria, and hypertension was documented after craniotomy (12/20), adrenalectomy (4/20) and other procedures (4/20). Five dogs received labetalol intraoperatively, 14 postoperatively, and 1 during the surgical procedure and recovery. Median infusion duration and rate were 463 (60-2120) minutes and 1.1 (0.2–3.4) mg/kg/h respectively. Median loading dose was 0.2 (0.2–0.4) mg/kg. Labetalol produced a significant decrease in SAP and DAP at all time points compared to T0 (p < 0.05), while the effect was not significant at T1 for MAP (p = 0.0519). Median maximum MAP decrease was 31 (20–90) mmHg. Heart rate did not increase significantly during treatment (p = 0.2454). Acepromazine given before or during labetalol treatment did not reduce significantly ABP (p = 0.735).

Conclusions

Labetalol produced a reliable and titratable decrease in ABP with non significant increase in HR.
Overexpressed GATA3 enhances the sensitivity of colorectal cancer cells to oxaliplatin through regulating MiR-29b
Authors: Wang Wei , Wang Mei , Xu Jing , Long Fei , Zhan Xianbao
Published: July 2020

Background

GATA binding protein 3 (GATA3) and miR-29b are related to colorectal cancer (CRC). The current study explored the regulatory relationship between GATA3 and miR-29b, and the mechanism of the two in the drug resistance of CRC cells to oxaliplatin.

Method

Apoptosis of CRC cells induced by oxaliplatin at various doses was detected by flow cytometry. CRC cells were separately transfected with overexpression and knockdown of GATA3, miR-29b agomir and antagomir, and treated by oxaliplatin to detect the cell viability and apoptosis by performing Cell Couting Kit-8 (CCK-8) and flow cytometry. The expression levels of GATA3, caspase3 and cleaved caspase3 were determined by Western blot, and the expression of miR-29b was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Animal experiments were performed to examine the changes of transplanted tumors in nude mouse xenograft studies and observed by in vivo imaging. TUNEL staining was performed to detect tumor cell apoptosis.

Result

Both GATA3 and miR-29b agomir inhibited the activity of the CRC cells, promoted apoptosis and Cleaved caspase3 expression, and reduced the resistance of the cells to chemotherapy drug oxaliplatin. Although GATA3 could up-regulate miR-29b expression, the tumor-suppressive effect of GATA3 was partially reversed by miR-29b antagomir. In vivo experiments showed that down-regulating the expression of GATA3 promoted the growth rate and volume of transplanted tumors, while overexpressing GATA3 had no significant effect on tumor growth. TUNEL staining results showed that knocking down or overexpression of GATA3 did not cause significant changes to apoptotic bodies of CRC cells, while oxaliplatin treatment increased the number of apoptotic bodies.

Conclusion

GATA3 inhibits the cell viability of CRC cells, promotes apoptosis, and reduces oxaliplatin resistance of CRC cells through regulating miR-29b.
Long non-coding RNA KCNQ1OT1 up-regulates CTNND1 by sponging miR-329-3p to induce the proliferation, migration, invasion, and inhibit apoptosis of colorectal cancer cells
Authors: Liu Xing , Zhang Yexiang , Wang Yan , Bian Chao , Wang Fengji
Published: July 2020

Background

Long non-coding RNAs (lncRNAs) have been certified to be involved in the occurrence and growth of diverse cancers, including CRC. The purpose of the research was to explore the effects of lncRNA KCNQ1 overlapping transcript 1 (KCNQ1OT1) on proliferation, migration, invasion, and apoptosis in CRC cells and its mechanism.

Methods

The levels of KCNQ1OT1 and miR-329-3p were examined by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC tissues and cells. The mRNA and protein levels of catenin delta-1 (CTNND1) were measured by qRT-PCR and western blot analysis, respectively. The targets of KCNQ1OT1 and miR-329-3p were predicted by online software and confirmed by luciferase reporter assay. The cell proliferation, migration, invasion, and apoptosis were examined using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), transwell, and apoptosis assay. The expression levels of CyclinD1, Bcl-2, MMP9, Cleaved-casp-3, and E-cadherin in SW480 and LS1034 cells were gauged by western blot analysis. Xenograft tumor model was structured to prove the biological role of KCNQ1OT1 of CRC in vivo.

Results

The levels of KCNQ1OT1 and CTNND1 were significantly increased in CRC tissues and cells. Knockdown of KCNQ1OT1 suppressed proliferation, migration, invasion, and induced apoptosis in CRC cells. Conversely, CTNND1 overexpression reversed the impact of KCNQ1OT1 knockdown on CRC cells. Moreover, CTNND1 was verified as a direct target of miR-329-3p, and miR-329-3p could specially bind to KCNQ1OT1. Also, the down-regulation of KCNQ1OT1 triggered the CRC progress by up-regulating CTNND1 expression in CRC cells. Besides, KCNQ1OT1 knockdown inhibited CRC tumor growth through the miR-329-3p/CTNND1 axis in vivo.

Conclusion

Our results indicated that KCNQ1OT1 could positively regulate CTNND1 expression by sponging miR-329-3p, thereby boosting the progression of CRC. Our findings provided the underlying therapy targets for CRC.
Kinematics and temporospatial parameters during gait from inertial motion capture in adults with and without HIV: a validity and reliability study
Authors: Berner Karina , Cockcroft John , Louw Quinette
Published: July 2020

Background

Inertial measurement unit (IMU)-based motion capture systems are gaining popularity for gait analysis outside laboratories. It is important to determine the performance of such systems in specific patient populations. We aimed to validate and determine within-day reliability of an IMU system for measuring lower limb gait kinematics and temporal–spatial parameters (TSP) in people with and without HIV.

Methods

Gait was recorded in eight adults with HIV (PLHIV) and eight HIV-seronegative participants (SNP), using IMUs and optical motion capture (OMC) simultaneously. Participants performed six gait trials. Fifteen TSP and 28 kinematic angles were extracted. Intraclass correlations (ICC), root-mean-square error (RMSE), mean absolute percentage error and Bland–Altman analyses were used to assess concurrent validity of the IMU system (relative to OMC) separately in PLHIV and SNP. IMU reliability was assessed during within-session retest of trials. ICCs were used to assess relative reliability. Standard error of measurement (SEM) and percentage SEM were used to assess absolute reliability.

Results

Between-system TSP differences demonstrated acceptable-to-excellent ICCs (0.71–0.99), except for double support time and temporophasic parameters (< 0.60). All TSP demonstrated good mean absolute percentage errors (≤7.40%). For kinematics, ICCs were acceptable to excellent (0.75–1.00) for all but three range of motion (ROM) and four discrete angles. RMSE and bias were 0.0°–4.7° for all but two ROM and 10 discrete angles. In both groups, TSP reliability was acceptable to excellent for relative (ICC 0.75–0.99) (except for one temporal and two temporophasic parameters) and absolute (%SEM 1.58–15.23) values. Reliability trends of IMU-measured kinematics were similar between groups and demonstrated acceptable-to-excellent relative reliability (ICC 0.76–0.99) and clinically acceptable absolute reliability (SEM 0.7°–4.4°) for all but two and three discrete angles, respectively. Both systems demonstrated similar magnitude and directional trends for differences when comparing the gait of PLHIV with that of SNP.

Conclusions

IMU-based gait analysis is valid and reliable when applied in PLHIV; demonstrating a sufficiently low precision error to be used for clinical interpretation (< 5° for most kinematics; < 20% for TSP). IMU-based gait analysis is sensitive to subtle gait deviations that may occur in PLHIV.
Measuring the well-being of people with dementia: a conceptual scoping review
Authors: Clarke Chris , Woods Bob , Moniz-Cook Esme , Mountain Gail , Øksnebjerg Laila , Chattat Rabih , Diaz Ana , Gove Dianne , Vernooij-Dassen Myrra , Wolverson Emma
Published: July 2020

Background

Enabling people with dementia to ‘live well’ is a policy and research priority in many countries. However, instruments for measuring outcomes of psychosocial interventions designed to promote well-being in dementia are often derived from a symptom-focused, loss/deficit approach, or from broad quality of life concepts. A pan-European dementia working group called for research on the development of an alternative asset/strengths-based conceptual framework of well-being in dementia. This paper takes forward this recommendation by developing such a framework and using this to map relevant self-report outcome measures.

Methods

Three scoping reviews of published studies were conducted iteratively. First, we examined the literature on lived experiences of well-being and quality of life in people with dementia and then the wider dementia literature for application of well-being constructs. The synthesised findings generated conceptual domains of well-being in people with dementia. Corresponding self-report instruments used in dementia research were scoped, categorised within the conceptual framework and their potential value in measuring outcomes for people with dementia was examined.

Findings

Six conceptual domains for the measurement of well-being and 35 self-report instruments that have been used with people with dementia were identified. Six instruments were developed specifically for people with dementia, five were derived from the gerontological literature and 24 from the well-being literature. Fifteen instruments and one sub-scale have been examined for psychometric properties amongst people with dementia. To date, 20 have been used as outcome measures, with seven measuring change over time. A number of identified instruments utilise traditional retrospective Likert-scaling response formats, limiting their potential for use with some groups of people with dementia.

Conclusion

An assets/strengths-based framework is presented, outlining structural domains for selecting self-report measures of well-being in people with dementia. It provides a foundation for enhancing research into processes and outcomes of psychosocial interventions, including instrument development, more precise matching of intervention aims with outcome measurement, and newer technology-based ‘in-the-moment’ measurement.
Acute kidney injury following on-pump or off-pump coronary artery bypass grafting in elderly patients: a retrospective propensity score matching analysis
Authors: Wang Rui , Wang Xian , Zhu Yifan , Chen Wen , Li Liangpeng , Chen Xin
Published: July 2020

Objectives

This single-centre, retrospective propensity score matching (PSM) study designed to study the impact of cardiopulmonary bypass (CPB) on postoperative acute kidney injury (AKI) and the relationship between AKI and long-term outcomes in elderly patients undergoing coronary artery bypass grafting (CABG).

Methods

After PSM, 466 pairs of patients (A group, on-pump; B group, off-pump) who were aged≥70 years undergoing first isolated CABG surgery from January 2012 to December 2016 entered the study. AKI was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. The incidence and severity of in-hospital AKI were compared. The impacts of AKI on the long-term outcomes including new onset of dialysis and mortality were analyzed.

Results

The two PSM groups had similar baseline and procedure except whether the CPB was used or not. In hospital and 30-day mortality was of no difference(χ2 = 0.051, p = 0.821). AKI of any severity occurred in 40.3% of all patients, with stage 1 accounting for most cases. No difference regarding the incidence and severity of AKI could be found: AKIN stage 1: 139 (29.8%) vs 131 (28.1%); AKIN stage 2: 40 (8.6%) vs 35 (7.5%); AKIN stage 3: 18 (3.9%) vs 13 (2.8%), (u = 0.543, p = 0.532). No difference was observed in the in-hospital new onset of dialysis (χ2 = 0.312, P = 0.576). The use of CPB was not found to influence long-term new onset of dialysis (χ2 = 0.14, p = 0.708) and mortality (χ2 = 0.099, p = 0.753). Comparing with non-AKI patients, AKI patients were associated with an increased rates of new onset of dialysis (χ2 = 8.153, p = 0.004) and mortality (χ2 = 6.277, p = 0.012) during the follow-up. Multivariable logistic regression manifested that the HR for long-term new onset of dialysis and mortality in AKI patients vs. non-AKI patients was 1.83 and 1.31 respectively (95%CI 1.12–2.86, p = 0.007; 95%CI 1.17–2.58, p = 0.015). The HR for long-term new onset of dialysis and mortality in on-pump group vs. off-pump group was 1.07 and 1.11 respectively (95%CI 1.03–1.23, p = 0.661; 95%CI 1.09–1.64, p = 0.702).

Conclusions

For elderly CABG patients, AKI was common, but deterioration of dialysis was a seldom incidence. Comparing with on-pump, off-pump did not decrease the rates or severity of AKI, long-term new onset of dialysis or mortality. AKI was associated with an increased long-term new onset of dialysis and decreased long-term survival.
Microbial involvement in Alzheimer disease development and progression
Authors: Bulgart Hannah R. , Neczypor Evan W. , Wold Loren E. , Mackos Amy R.
Published: July 2020

Alzheimer disease (AD) is the most prominent form of dementia and the 5th leading cause of death in individuals over 65. AD is a complex disease stemming from genetic, environmental, and lifestyle factors. It is known that AD patients have increased levels of senile plaques, neurofibrillary tangles, and neuroinflammation; however, the mechanism(s) by which the plaques, tangles, and neuroinflammation manifest remain elusive. A recent hypothesis has emerged that resident bacterial populations contribute to the development and progression of AD by contributing to neuroinflammation, senile plaque formation, and potentially neurofibrillary tangle accumulation (Fig. 1). This review will highlight recent studies involved in elucidating microbial involvement in AD development and progression.
Pediatric obesity: prevention is better than care
Authors: Romanelli Roberta , Cecchi Nicola , Carbone Maria Grazia , Dinardo Michele , Gaudino Giuseppina , Miraglia del Giudice Emanuele , Umano Giuseppina Rosaria
Published: July 2020

Pediatric obesity is one of the most relevant health issues of the last century. Obesity-related short and long-term consequences are responsible of a large amount of economic cost. In addition, the different therapeutic strategies, such as lifestyle correction, drug, and bariatric surgery have displayed low effectiveness. Considering this evidence, prevention appears to be more promising than treatment in contrasting obesity epidemic. In this review, we summarize obesity pathogenesis with the aim of highlight the main obesity risk factors that can be addressed as target of preventive interventions. Moreover, we report the evidence about effectiveness of different interventions targeting family, school, and community. A multiple-component intervention, addressing different targets and settings, might be desirable, however more studies are needed to confirm long-term efficacy and to direct policy interventions.
Rationale and design of individualized quality improvement based on the Computer Analysing system to improve Stroke management quality Evaluation (CASE): a multicenter historically controlled study
Authors: Chen Yi , Zhong Wansi , Gong Xiaoxian , Hu Haitao , Yan Shenqiang , Zhang Xuting , Chen Zhicai , Zhou Ying , Lou Min
Published: July 2020

Background

Guideline-based medical care has been identified to improve outcomes in stroke. However, data acquisition and medical quality management during hospital stay still need to be improved in China. We have developed a computer-based medical data collecting system, together with automated calculation of key performance indicators (KPIs) and regular individualized education, and thus aim to explore whether it can improve the medical care quality of acute ischemic stroke (AIS) during hospital stay in stroke centers.

Methods

The individualized quality improvement based on the Computer Analysing system to improve Stroke management quality Evaluation (CASE) trial is a prospective, multicenter, historical control study among 30 stroke centers in China. In this trial, the data is directly extracted from the saved original medical record of each AIS patient during hospital stay, regardless of different Electronic Medical Record System (EMRS) in each center. Then, the automated calculation of KPIs and the regular education via teleconference per month allow the clinicians to examine the causes of non-compliance of guideline-based care and develop programs to decrease their frequency.

Discussion

We compare KPIs between pre-intervention stage and post-intervention stage (without or with education) among stroke centers. If proved effective, this approach might be generalized around China and even worldwide, where a unified EMRS is difficult to be applied and in-patient care needs to be improved.

Trial registration

ClinicalTrials.gov NCT03684629. Registered on 9 December 2018. Retrospectively registered.
Interpretation of vintage 2D seismic reflection data along the Austrian-Hungarian border: Subsurface expression of the Rechnitz metamorphic core complex
Authors: Tari Gabor C. , Gjerazi Ingrid , Grasemann Bernhard
Published: July 2020

In the border zone between Austria and Hungary, the Miocene extension of the Pannonian Basin was characterized by extreme, large-magnitude upper crustal extension accommodated along low-angle detachment faults. Although some of these prominent normal faults have already been described using 2D seismic data sets and well data on the Hungarian side, we offer the first systematic interpretation using the Austrian and Hungarian vintage seismic data sets acquired in the 1970s and 1980s. The refinement of the previously proposed metamorphic core complex (MCC) style, east-northeast–west-southwest-trending very high-strain extension provides a modern understanding of back-arc extension in this part of the Pannonian Basin system as the result of the collapse of the Alpine orogen. Although previous interpretations could not achieve the subsurface correlation of major structural elements across the border, we did systematically map these for the first time. Numerous exploration wells, drilled on both sides of the border, were integrated with reflection seismic data to differentiate between the lower versus upper plates of the major low-angle detachment faults, including the largest one responsible for the formation of the Rechnitz MCC. Based on our new interpretation, the regionally mapped Rechnitz detachment fault has an unexpectedly large subsurface extent, on the order of 1000 km2. Moreover, the unusually large number of industry 2D seismic profiles (approximately 50) used to map this and other prominent faults, in the Austrian and Hungarian sides, makes the Rechnitz MCC possibly the best constrained one in the world in terms of subsurface definition by reflection seismic data.
Reduced Morbidity and Mortality in Survivors of Childhood Acute Lymphoblastic Leukemia: A Report From the Childhood Cancer Survivor Study
Authors: Dixon Stephanie B. , Chen Yan , Yasui Yutaka , Pui Ching-Hon , Hunger Stephen P. , Silverman Lewis B. , Ness Kirsten K. , Green Daniel M. , Howell Rebecca M. , Leisenring Wendy M. , Kadan-Lottick Nina S. , Krull Kevin R. , Oeffinger Kevin C. , Neglia Joseph P. , Mertens Ann C. , Hudson Melissa M. , Robison Leslie L. , Armstrong Gregory T. , Nathan Paul C.
Published: July 2020

PURPOSE

Risk-stratified therapy, which modifies treatment on the basis of clinical and biologic features, has improved 5-year overall survival of childhood acute lymphoblastic leukemia (ALL) to 90%, but its impact on long-term toxicity remains unknown.

METHODS

We assessed all-cause and health-related late mortality (including late effects of cancer therapy), subsequent malignant neoplasms (SMNs), chronic health conditions, and neurocognitive outcomes among 6,148 survivors of childhood ALL (median age, 27.9 years; range, 5.9-61.9 years) diagnosed between 1970 and 1999. Therapy combinations and treatment intensity defined 6 groups: 1970s-like (70s), standard- or high-risk 1980s-like (80sSR, 80sHR) and 1990s-like (90sSR, 90sHR), and relapse/transplantation (R/BMT). Cumulative incidence, standardized mortality ratios, and standardized incidence ratios were compared between treatment groups and with the US population.

RESULTS

Overall, 20-year all-cause late mortality was 6.6% (95% CI, 6.0 to 7.1). Compared with 70s, 90sSR and 90sHR experienced lower health-related late mortality (rate ratio [95% CI]: 90sSR, 0.2 [0.1 to 0.4]; 90sHR, 0.3 [0.1 to 0.7]), comparable to the US population (standardized mortality ratio [95% CI]: 90sSR, 1.3 [0.8 to 2.0]; 90sHR, 1.7 [0.7 to 3.5]). Compared with 70s, 90sSR had a lower rate of SMN (rate ratio [95% CI], 0.3 [0.1 to 0.6]) that was not different from that of the US population (standardized incidence ratio [95% CI], 1.0 [0.6 to 1.6]). The 90sSR group had fewer severe chronic health conditions than the 70s (20-year cumulative incidence [95% CI], 11.0% [9.7% to 12.3%] v 22.5% [19.4% to 25.5%]) and a lower prevalence of impaired memory (prevalence ratio [95% CI], 0.7 [0.6 to 0.9]) and task efficiency (0.5 [0.4 to 0.7]).

CONCLUSION

Risk-stratified therapy has reduced late morbidity and mortality among contemporary survivors of standard-risk ALL, represented by 90sSR. Health-related late mortality and SMN risks among 5-year survivors of contemporary, standard-risk childhood ALL are comparable to the general population.
Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma
Authors: Van Cutsem Eric , Tempero Margaret A. , Sigal Darren , Oh Do-Youn , Fazio Nicola , Macarulla Teresa , Hitre Erika , Hammel Pascal , Hendifar Andrew E. , Bates Susan E. , Li Chung-Pin , Hingorani Sunil R. , de la Fouchardiere Christelle , Kasi Anup , Heinemann Volker , Maraveyas Anthony , Bahary Nathan , Layos Laura , Sahai Vaibhav , Zheng Lei , Lacy Jill , Park Joon Oh , Portales Fabienne , Oberstein Paul , Wu Wilson , Chondros Dimitrios , Bullock Andrea J. ,   on behalf of the HALO 109-301 Investigators
Published: July 2020

PURPOSE

To evaluate the efficacy and safety of pegvorhyaluronidase alfa (PEGPH20) plus nab-paclitaxel/gemcitabine (AG) in patients with hyaluronan-high metastatic pancreatic ductal adenocarcinoma (PDA).

PATIENTS AND METHODS

HALO 109-301 was a phase III, randomized, double-blind, placebo-controlled study. Patients ≥ 18 years of age with untreated, metastatic, hyaluronan-high PDA were randomly assigned 2:1 to PEGPH20 plus AG or placebo plus AG. Treatment was administered intravenously in 4-week cycles (3 weeks on, 1 week off) until progression or intolerable adverse events: PEGPH20 3.0 µg/kg twice per week for cycle 1 and once per week thereafter; nab-paclitaxel 125 mg/m2 once per week; and gemcitabine 1,000 mg/m2 once per week. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Response was independently assessed per RECIST v1.1.

RESULTS

At data cutoff, 494 patients were randomly assigned, with 492 (327 for PEGPH20 and 165 for placebo) included in intention-to-treat analyses. Baseline characteristics were balanced for PEGPH20 plus AG versus placebo plus AG. There were 330 deaths, with a median OS of 11.2 months for PEGPH20 plus AG versus 11.5 months for placebo plus AG (hazard ratio [HR], 1.00; 95% CI, 0.80 to 1.27; P = .97); median PFS was 7.1 months versus 7.1 months (HR, 0.97 [95% CI, 0.75 to 1.26]); ORR was 47% versus 36% (ORR ratio, 1.29 [95% CI, 1.03 to 1.63]). Grade ≥ 3 adverse events with a ≥ 2% higher rate with PEGPH20 plus AG than with placebo plus AG included fatigue (16.0% v 9.6%), muscle spasms (6.5% v 0.6%), and hyponatremia (8.0% v 3.8%).

CONCLUSION

The addition of PEGPH20 to AG increased the ORR but did not improve OS or PFS. The safety profile of PEGPH20 plus AG was consistent with that found in previous studies. These results do not support additional development of PEGPH20 in metastatic PDA.
Frequent Molecular Subtype Switching and Gene Expression Alterations in Lung and Pleural Metastasis From Luminal A–Type Breast Cancer
Authors: Klebe Max , Fremd Carlo , Kriegsmann Mark , Kriegsmann Katharina , Albrecht Thomas , Thewes Verena , Kirchner Martina , Charoentong Pornpimol , Volk Nadine , Haag Johannes , Wirtz Ralph , Oskarsson Thordur , Schulz Alexandra , Heil Jörg , Schneeweiss Andreas , Winter Hauke , Sinn Peter
Published: July 2020

PURPOSE

Conversion of tumor subtype frequently occurs in the course of metastatic breast cancer but is a poorly understood phenomenon. This study aims to compare molecular subtypes with subsequent lung or pleural metastasis.

PATIENTS AND METHODS

In a cohort of 57 patients with breast cancer and lung or pleural metastasis (BCLPM), we investigated paired primary and metastatic tissues for differential gene expression of 269 breast cancer genes. The PAM50 classifier was applied to identify intrinsic subtypes, and differential gene expression and cluster analysis were used to further characterize subtypes and tumors with subtype conversion.

RESULTS

In primary breast cancer, the most frequent molecular subtype was luminal A (lumA; 49.1%); it was luminal B (lumB) in BCLPM (38.6%). Subtype conversion occurred predominantly in lumA breast cancers compared with other molecular subtypes (57.1% v 27.6%). In lumA cancers, 62 genes were identified with differential expression in metastatic versus primary disease, compared with only 10 differentially expressed genes in lumB, human epidermal growth factor receptor 2 (HER2)–enriched, and basal subtypes combined. Gene expression changes in lumA cancers affected not only the repression of the estrogen receptor pathway and cell cycle–related genes but also the WNT pathway, proteinases ( MME, MMP11), and motility-associated cytoskeletal proteins (CK5, CK14, CK17). Subtype-switched lumA cancers were further characterized by cell proliferation and cell cycle checkpoint gene upregulation and dysregulation of the p53 pathway. This involved 83 notable gene expression changes.

CONCLUSION

Our results indicate that gene expression changes and subsequent subtype conversion occur on a large scale in metastatic luminal A–type breast cancer compared with other molecular subtypes. This underlines the significance of molecular changes in metastatic disease, especially in tumors of initially low aggressive potential.
Distinct DNA Methylation Signatures in Neuroendocrine Tumors Specific for Primary Site and Inherited Predisposition
Authors: Tirosh Amit , Killian Jonathan Keith , Petersen David , Zhu Yuelin Jack , Walker Robert L , Blau Jenny E , Nilubol Naris , Patel Dhaval , Agarwal Sunita K , Weinstein Lee Scott , Meltzer Paul , Kebebew Electron
Published: July 2020

Purpose

To compare the deoxyribonucleic acid (DNA) methylation signature of neuroendocrine tumors (NETs) by primary tumor site and inherited predisposition syndromes von Hippel–Lindau disease (VHL) and multiple endocrine neoplasia type 1 (MEN1).

Methods

Genome-wide DNA methylation (835 424 CpGs) of 96 NET samples. Principal components analysis (PCA) and unsupervised hierarchical clustering analyses were used to determine DNA methylome signatures.

Results

Hypomethylated CpGs were significantly more common in VHL-related versus sporadic and MEN1-related NETs (P < .001 for both comparisons). Small-intestinal NETs (SINETs) had the most differentially methylated CpGs, either hyper- or hypomethylated, followed by duodenal NETs (DNETs) and pancreatic NETs (PNETs, P < .001 for all comparisons). There was complete separation of SINETs on PCA, and 3 NETs of unknown origin clustered with the SINET samples. Sporadic, VHL-related, and MEN1-related PNETs formed distinct groups on PCA, and VHL clustered separately, showing pronounced DNA hypomethylation, while sporadic and MEN1-related NETs clustered together. MEN1-related PNETs, DNETs, and gastric NETs each had a distinct DNA methylome signature, with complete separation by PCA and unsupervised clustering. Finally, we identified 12 hypermethylated CpGs in the 1A promoter of the APC (adenomatous polyposis coli) gene, with higher methylation levels in MEN1-related NETs versus VHL-related and sporadic NETs (P < .001 for both comparisons).

Conclusions

DNA CpG methylation profiles are unique in different primary NET types even when occurring in MEN1-related NETs. This tumor DNA methylome signature may be utilized for noninvasive molecular characterization of NETs, through DNA methylation profiling of biopsy samples or even circulating tumor DNA in the near future.
How Do We Repair?
Authors: Manning Erin
Published: July 2020

Erin Manning, a participant in goat island archive—we have discovered the performance by making it, suggests the concept of “anarchive” as a new approach to understanding the archive. She argues that the anarchival “follow[s] the logic not of originality or wholeness, but of emergent process,” focusing on the archive’s futuristic value rather than its quality as a collection of past documents. In this allusive, poetic meditation on an ethos of “repair” as it relates to performance, archival processes, and the work of performance collective Goat Island, Manning illuminates how drawing, sculpting, and architecting can be methodologies of anarchiving, which performatively re-creates the emergent process of the original work.
Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model
Authors: Mallya Kavita , Haridas Dhanya , Seshacharyulu Parthasarathy , Pothuraju Ramesh , Junker Wade M. , Krishn Shiv Ram , Muniyan Sakthivel , Vengoji Raghupathy , Batra Surinder K. , Rachagani Satyanarayana
Published: July 2020

Pancreatic cancer (PC) is acquired postnatally; to mimic this scenario, we developed an inducible KC (iKC) mouse model (KrasG12D;Ptf1a-CreERTM), in which Kras is activated at postnatally at week 16 upon tamoxifen administration. Upon TAM treatment, iKC mice develop PanIN lesions and PC with metastasis at 4 and 40th week, respectively, and exhibited acinar-to-ductal metaplasia (ADM) and transdifferentiation. Kras activation up-regulated the transcriptional factors Ncoa3, p-cJun, and FoxM, which in turn upregulated expression of transmembrane mucins (Muc1, Muc4, and Muc16) and secretory mucin (Muc5Ac). Interestingly, knock-down of KrasG12D in multiple PC cell lines resulted in down-regulation of MUC1, MUC4, MUC5AC, and MUC16. In addition, iKC mice exhibited ADM and transdifferentiation. Our results show the iKC mouse more closely mimics human PC development and can be used to investigate studies related to PDAC biomarkers, early onset of PDAC, and ADM. iKC model can also be used for pre-clinical strategies targeting mucin axis alone/in combination with neo-adjuvant, immunotherapeutic approaches and to monitor chemotherapy response.
FGF2 modulates simultaneously the mode, the rate of division and the growth fraction in cultures of radial glia
Authors: Ledesma-Terrón Mario , Peralta-Cañadas Nuria , Míguez David G.
Published: July 2020

Radial glial progenitors in the mammalian developing neocortex have been shown to follow a deterministic differentiation program restricted to an asymmetric-only mode of division. This feature seems incompatible with their well-known ability to increase in number when cultured in vitro, driven by fibroblast growth factor 2 and other mitogenic signals. The changes in their differentiation dynamics that allow this transition from in vivo asymmetric-only division mode to an in vitro self-renewing culture have not been fully characterized. Here, we combine experiments of radial glia cultures with numerical models and a branching process theoretical formalism to show that fibroblast growth factor 2 has a triple effect by simultaneously increasing the growth fraction, promoting symmetric divisions and shortening the length of the cell cycle. These combined effects partner to establish and sustain a pool of rapidly proliferating radial glial progenitors in vitro. We also show that, in conditions of variable proliferation dynamics, the branching process tool outperforms other commonly used methods based on thymidine analogs, such as BrdU and EdU, in terms of accuracy and reliability.
In vivo x-ray diffraction and simultaneous EMG reveal the time course of myofilament lattice dilation and filament stretch
Authors: Malingen S. A. , Asencio A. M. , Cass J. A. , Ma W. , Irving T. C. , Daniel T. L.
Published: July 2020

Muscle's function within an organism depends on the feedback between molecular to meter-scale processes. While the motions of muscle's contractile machinery are well described in isolated preparations, only a handful of experiments have documented the kinematics of the lattice occurring when multi-scale interactions are fully intact. We used time-resolved x-ray diffraction to record the kinematics of the myofilament lattice within a normal operating context: the tethered flight of Manduca sexta. Since the primary flight muscles of Manduca sexta are synchronous, we used these results to reveal the timing of in vivo cross-bridge recruitment, which occurred 24 (s.d. 26) ms following activation. In addition, the thick filaments stretched an average of 0.75 (s.d. 0.32)% and thin filaments stretched 1.11 (s.d. 0.65)%. In contrast to other in vivo preparations, lattice spacing changed an average of 2.72 (s.d. 1.47)%. Lattice dilation of this magnitude significantly impacts shortening velocity and force generation, and filament stretching tunes force generation. While kinematics were consistent within individual trials, there was extensive variation between trials. Using a mechanism-free machine learning model we searched for patterns within and across trials. While lattice kinematics were predictable within trials, the model could not create predictions across trials. This indicates that the variability we see across trials may be explained by latent variables occurring in this naturally functioning system. The diverse kinematic combinations we documented mirror muscle's adaptability and may facilitate its robust function in unpredictable conditions.
Conspecific chemical cues drive density-dependent metabolic suppression independently of resource intake
Authors: Lovass Melanie K. , Marshall Dustin J. , Ghedini Giulia
Published: July 2020

Within species, individuals of the same size can vary substantially in their metabolic rate. One source of variation in metabolism is conspecific density – individuals in denser populations may have lower metabolism than those in sparser populations. However, the mechanisms through which conspecifics drive metabolic suppression remain unclear. While food competition is a potential driver, other density-mediated factors could act independently or in combination to drive metabolic suppression but these drivers have rarely been investigated. We used sessile marine invertebrates to test how food availability interacts with oxygen availability, water flow and chemical cues to affect metabolism. We show that conspecific chemical cues induce metabolic suppression independently of food and this metabolic reduction is associated with the downregulation of physiological processes rather than feeding activity. Conspecific cues should be considered when predicting metabolic variation and competitive outcomes as they are an important, but underexplored, source of variation in metabolic traits.
History and current perspectives on the biological effects of high-dose spatial fractionation and high dose-rate approaches: GRID, Microbeam & FLASH radiotherapy
Authors: Griffin Robert J , Prise Kevin M , McMahon Stephen J , Zhang Xin , Penagaricano Jose , Butterworth Karl T
Published: July 2020

The effects of various forms of ionising radiation are known to be mediated by interactions with cellular and molecular targets in irradiated and in some cases non-targeted tissue volumes. Despite major advances in advanced conformal delivery techniques, the probability of normal tissue complication (NTCP) remains the major dose-limiting factor in escalating total dose delivered during treatment. Potential strategies that have shown promise as novel delivery methods in achieving effective tumour control whilst sparing organs at risk involve the modulation of critical dose delivery parameters. This has led to the development of techniques using high dose spatial fractionation (GRID) and ultra-high dose rate (FLASH) which have translated to the clinic. The current review discusses the historical development and biological basis of GRID, microbeam and FLASH radiotherapy as advanced delivery modalities that have major potential for widespread implementation in the clinic in future years.
MRI of placenta accreta: diagnostic accuracy and impact of interventional radiology on foetal–maternal delivery outcomes in high-risk women
Authors: Fiocchi Federica , Monelli Filippo , Besutti Giulia , Casari Federico , Petrella Elisabetta , Pecchi Annarita , Caporali Cristian , Bertucci Emma , Busani Stefano , Botticelli Laura , Facchinetti Fabio , Torricelli Pietro
Published: July 2020

Objective:

To assess accuracy and reproducibility of MRI diagnosis of invasive placentation (IP) in high-risk patients and to evaluate reliability of MRI features. Secondary aim was to evaluate impact of interventional radiology (IR) on delivery outcomes in patients with IP at MRI.

Methods:

26 patients (mean age 36.24 y/o,SD 6.16) with clinical risk-factors and echographic suspicion of IP underwent 1.5 T-MRI. Two readers reviewed images. Gold-standard was histology in hysterectomised patients and obstetric evaluation at delivery for patients with preserved uterus. Accuracy and reproducibility of MRI findings were calculated.

Results:

Incidence of IP was 50% (13/26) and of PP was 11.54% (3/26). MRI showed 100% sensitivity (95% CI = 75.3–100%) and 92.3% specificity (95% CI = 64.0–100%) in the diagnosis of IP. Gold-standard was histology in 10 cases and obstetric evaluation in 16. MRI findings with higher sensitivity were placental heterogeneity, uterine bulging and black intraplacental bands. Uterine scarring, placental heterogeneity, myometrial interruption and tenting of the bladder showed better specificity. MRI inter-rater agreement with Cohen’s K was 1. 11 patients among 14 with MRI diagnosis of IP received IR assistance with positive impact on delivery outcomes in terms of blood loss, red cells count, intense care unit length of stay, days of hospitalisation and risk of being transfused.

Conclusion:

MRI is an accurate and reproducible technique in prenatal diagnosis of IP. MRI helps planning a safe and appropriate delivery eventually assisted by IR, which positively affects foetal and maternal outcomes.

Advances in knowledge:

The adoption of MRI evaluation in patients with high risk of invasive placentation allows a more accurate diagnosis in terms of both presence of the disease and its extension to or through or even beyond the myometrium. This led to a better dedicated delivery management with eventual adoption of interventional radiology with a global positive effect on foetal and maternal outcomes.
Comparison of gross tumor volumes of pulmonary metastasis defined by CT and MRI in 0.345 T MRI-guided radiotherapy
Authors: Hama Yukihiro , Tate Etsuko
Published: July 2020

Objective:

To assess the difference in gross tumor volumes (GTVs) defined by CT (GTV-CT) and by low magnetic field strength (0.345 T) MRI (GTV-MRI) in patients simulated for MRI-guided radiotherapy forlung metastasis.

Methods:

28 patients (148 lesions) who underwent CT and MRI simulation with the tri-60Co MRI-guided radiotherapy system (MRIdian, ViewRay) were included in this study. GTV-CT and GTV-MRI were compared using the paired t-test. The equivalence of variance between GTV-CT and GTV-MRI of small lesions (GTV-CT <1 ml) and large ones (GTV-CT >= 1 ml) was evaluated using F-test. The correlation between GTV-CT and GTV-MRI was evaluated by the correlation coefficient.

Results:

GTV-MRI was 120% larger than GTV-CT (p < 0.001) for small lesions, whereas GTV-MRI was 40% larger than GTV-CT (p < 0.001) for large lesions. In small lesions, the variation in GTV-MRI was significantly larger than that of GTV-CT (p < 0.001). There was no significant difference in the variation of GTV-MRI and GTV-CT in large lesions (p = 0.121). The correlation coefficient for small lesions was 0.93, whereas that for large lesions was 0.99, with large lesions having better correlation.

Conclusions:

GTV-MRI was larger than GTV-CT and the correlation between GTV-MRI and GTV-CT was better in large lesions. If the tumor volume is 1 ml or larger, the lesion can be accurately monitored even with a low magnetic field strength MRI.

Advances in knowledge:

This study is the first clinical report to evaluate the tolerability of MRI images in 0.345 T MRI-guided radiotherapy for lung metastasis. GTV contoured by MRI was larger than GTV by CT, and this tendency was more pronounced in small tumors of less than 1 ml.
TURISMO AMBIENTAL - CONHECENDO A REALIDADE DA UNIDADE DE CONSERVAÇÃO PARQUE ESTADUAL DA PEDRA BRANCA, SEDE PAU DA FOME – RJ
Authors: Passos Fábio Vinicius De Araujo , Leal Maria Amelia Da Silva , Oliveira Sérgio Domingos , Gomes Debora Neves
Published: July 2020

O artigo busca interpretar e pesquisar o desenvolvimento do turismo em uma unidade de conservação, tendo como objeto de estudo o Parque Estadual da Pedra Branca - PEPB, que está localizado no bairro da Taquara no Município do Rio de Janeiro - RJ. No trabalho, destaca-se a importância das Unidades de Conservação (UCs) para o lazer da sociedade, em que é apresentada uma leitura das principais carências e dificuldades enfrentadas para a gestão dessas áreas. Para essa proposição, utilizou-se como metodologia a revisão de literatura, associada à pesquisa exploratória, tendo a participação ativa dos autores nas reuniões da câmara de uso público. Os resultados obtidos, após o trabalho de registro com fotografia e caminhadas, demonstraram o quanto a visitação ainda é bastante incipiente, se comparada ao grande potencial do PEPB. Para tal, discutiu-se sobre formas de turismo, o qual possibilita contato junto à natureza, ressaltando ainda a importância do ecoturismo e do planejamento da atividade para a obtenção da sustentabilidade.
OS DESAFIOS DO PLANEJAMENTO DE PESSOAL EM NÍVEL GOVERNAMENTAL E O PORQUÊ DE O DFT NÃO SER A SOLUÇÃO MÁGICA
Authors: Santos Aleksandra Pereira
Published: July 2020

Este ensaio tem como objetivo apresentar questões relevantes a respeito do Dimensionamento da Força de Trabalho (DFT) na Administração Pública Federal (APF). Para tanto, foi estruturado em três seções. A primeira expõe os conceitos sobre o tema e suas perspectivas de análise, destacando a relevância do Planejamento da Força de Trabalho (PFT) como estratégia ou diretriz governamental previamente à oferta e difusão dos modelos de DFT aos órgãos e às entidades da APF. Na segunda seção, apresenta-se uma síntese dos métodos de DFT sob ponto de vista estritamente organizacional, as recentes recomendações e diretrizes provenientes do Ministério da Economia (ME) e as indicações resultantes da convergência em literatura. Enfatiza-se que os modelos existentes possuem características prescritivas, oferecem variáveis relacionadas à mensuração de produtos ou entregas individuais e desconsideram características cognitivas do trabalho realizado em boa parte do setor público, tais como as atividades relativas à formulação e à implementação de políticas públicas. Por fim, propõe-se que os modelos prescritivos ou lineares sejam substituídos por modelos autóctones e previamente validados que considerem as características da organização – incluindo políticas, produtos ou serviços prestados à sociedade – e o nível de maturidade institucional para a adoção de novas técnicas e ferramentas de gestão. Afinal, são ferramentas e precisam conferir respostas mais rápidas aos anseios governamentais.