bluuebunny/crossref_metadata_2025 huggingface dataset:
DeepMILO: a deep learning approach to predict the impact of non-coding sequence variants on 3D chromatin structure
Authors: Trieu Tuan , Martinez-Fundichely Alexander , Khurana Ekta
Published: March 2020

Non-coding variants have been shown to be related to disease by alteration of 3D genome structures. We propose a deep learning method, DeepMILO, to predict the effects of variants on CTCF/cohesin-mediated insulator loops. Application of DeepMILO on variants from whole-genome sequences of 1834 patients of twelve cancer types revealed 672 insulator loops disrupted in at least 10% of patients. Our results show mutations at loop anchors are associated with upregulation of the cancer driver genesBCL2andMYCin malignant lymphoma thus pointing to a possible new mechanism for their dysregulation via alteration of insulator loops.
A comprehensive environmental scanning and strategic analysis of Iranian Public Hospitals: a prospective approach
Authors: Pourmohammadi Kimia , Bastani Peivand , Shojaei Payam , Hatam Nahid , Salehi Asiyeh
Published: March 2020

Objectives

This study was conducted to provide a strategic direction to public hospitals in Iran via environmental scanning in order to equip hospitals to plan and perform proactively and adapt with the everchanging environment.

Results

A mixed method study including in-depth interview and survey were used to determine influential environmental factors based on PESTLE (political, economic, social, technological, legal and environmental) and Douglas West framework to determine the effectiveness and feasibility of factors. Issues identified at micro environmental level were over prescription, inequality in distribution of healthcare services and high demands for luxurious health services. Issues identified at the macro environmental level were related to changes in disease patterns, inappropriate hospital budgeting, economic sanctions, government corruption and healthcare centralization. In order to tackle the issues identified, it is paramount to enhance bed distribution management, improve strategic policies for a more equitable payment system, and enhance the efficiency and effectiveness of services by implementing a strategic inventory control. Furthermore, the considerable impact of economic sanctions on financial resources of Iranian hospitals should not be ignored.
DNA methylation outlier burden, health, and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936
Authors: Seeboth Anne , McCartney Daniel L. , Wang Yunzhang , Hillary Robert F. , Stevenson Anna J. , Walker Rosie M. , Campbell Archie , Evans Kathryn L. , McIntosh Andrew M. , Hägg Sara , Deary Ian J. , Marioni Riccardo E.
Published: March 2020

Background

DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples.

Results

Here, we showed an association between age and log10-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N = 7010, β = 0.0091, p < 2 × 10−16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N = 430, β = 0.033, p = 7.9 × 10−4) and 1936 (N = 898, β = 0.0079, p = 0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, body mass index (BMI), smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log10-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases, and it was not heritable (SNP-based heritability of 4.4%, p = 0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually or in the meta-analysis after correction for multiple testing (HRmeta = 1.12; 95% CImeta = [1.02; 1.21]; pmeta = 0.021).

Conclusions

These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.
IGF-1C domain–modified hydrogel enhanced the efficacy of stem cells in the treatment of AMI
Authors: Yao Yong , Yang Liang , Feng Li-feng , Yue Zhi-wei , Zhao Nian-huan , Li Zongjin , He Zuo-xiang
Published: March 2020

Background

Due to the low survival rate of cell transplantation, stem cell has not been widely used in clinical treatment of acute myocardial infarction (AMI). In this study, we immobilized the C domain peptide of insulin-like growth factor-1 on chitosan (CS-IGF-1C) to obtain bioactive hydrogel. The purpose was to investigate whether CS-IGF-1C hydrogel incorporated with human placenta–derived mesenchymal stem cells (hP-MSCs) can boost the survival of hP-MSCs and enhance their therapeutic effects.

Methods

hP-MSCs, which continuously expressed green fluorescent protein (GFP) and firefly luciferase (Fluc), were transplanted with CS-IGF-1C hydrogel into a mouse myocardial infarction model. Cell survival was detected by bioluminescence imaging (BLI), and cardiac function was measured by echocardiogram. Real-time PCR and histological analysis were used to explore the therapeutic mechanism of CS-IGF-1C hydrogel.

Results

CS-IGF-1C hydrogel could induce the proliferation of hP-MSCs and exert anti-apoptotic effects in vitro. The Calcine-AM/PI staining results showed that hP-MSCs seeded on CS-IGF-1C hydrogel could protect neonatal mouse ventricular cardiomyocytes (NMVCs) against oxidative stress. It was observed by BLI that CS-IGF-1C hydrogel injected into ischemic myocardium could improve the survival rate of hP-MSCs. Histology analysis indicated that co-transplantation of the CS-IGF-1C hydrogel and hP-MSCs could increase angiogenesis, reduce collagen deposition, ameliorate left ventricular expanded, and further promote the recovery of cardiac function. Besides, we found that the inflammatory response was inhibited and the expression of apoptosis-related genes was downregulated by CS-IGF-1C hydrogel.

Conclusions

CS-IGF-1C hydrogel provides a conducive microenvironment for cells and significantly boosts the survival of hP-MSCs in mouse myocardial infarction model, which suggest that it may be a potential candidate for prolonging the therapeutic effect of hP-MSCs during AMI.
Loss of receptor tyrosine kinase-like orphan receptor 2 impairs the osteogenesis of mBMSCs by inhibiting signal transducer and activator of transcription 3
Authors: Lei Lizhen , Huang Zhuwei , Feng Jingyi , Huang Zijing , Tao Yiwei , Hu Xiaoli , Zhang Xiaolei
Published: March 2020

Background

Receptor tyrosine kinase-like orphan receptor 2 (Ror2) plays a key role in bone formation, but its signaling pathway is not completely understood. Signal transducer and activator of transcription 3 (Stat3) takes part in maintaining bone homeostasis. The aim of this study is to reveal the role and mechanism of Ror2 in the osteogenic differentiation from mouse bone marrow mesenchymal stem cells (mBMSCs) and to explore the effect of Stat3 on Ror2-mediated osteogenesis.

Methods

Ror2 CKO mice were generated via the Cre-loxp recombination system using Prrx1-Cre transgenic mice. Quantitative real-time PCR and western blot were performed to assess the expression of Stat3 and osteogenic markers in Ror2-knockdown mBMSCs (mBMSC-sh-Ror2). After being incubated in osteogenic induction medium for 3 weeks, Alizarin Red staining and western blot were used to examine the calcium deposit and osteogenic markers in Stat3 overexpression in mBMSC-sh-Ror2.

Results

Loss of Ror2 in mesenchymal or osteoblast progenitor cells led to a dwarfism phenotype in vivo. The mRNA expression of osteogenic markers (osteocalcin, osteopontin (OPN), and collagen I) in the ulna proximal epiphysis of Ror2 CKO mice was significantly decreased (P < 0.05). The mRNA and protein expression of Stat3 and osteogenic markers (Runx2, osterix, and OPN) decreased in mBMSC-sh-Ror2 cells (P < 0.05). The overexpression of Stat3 in mBMSC-sh-Ror2 cells rescued the calcium deposit and expression of Runx2, osterix, and OPN to a level comparable to normal mBMSCs.

Conclusions

Ror2 was essential for skeleton development by regulating mBMSCs’ osteogenesis and osteoblast differentiation. Loss of Ror2 may impair the osteogenesis of mBMSCs by inhibiting Stat3.
Mending a broken heart: current strategies and limitations of cell-based therapy
Authors: Liew Lee Chuen , Ho Beatrice Xuan , Soh Boon-Seng
Published: March 2020

The versatility of pluripotent stem cells, attributable to their unlimited self-renewal capacity and plasticity, has sparked a considerable interest for potential application in regenerative medicine. Over the past decade, the concept of replenishing the lost cardiomyocytes, the crux of the matter in ischemic heart disease, with pluripotent stem cell-derived cardiomyocytes (PSC-CM) has been validated with promising pre-clinical results. Nevertheless, clinical translation was hemmed in by limitations such as immature cardiac properties, long-term engraftment, graft-associated arrhythmias, immunogenicity, and risk of tumorigenicity. The continuous progress of stem cell-based cardiac therapy, incorporated with tissue engineering strategies and delivery of cardio-protective exosomes, provides an optimistic outlook on the development of curative treatment for heart failure. This review provides an overview and current status of stem cell-based therapy for heart regeneration, with particular focus on the use of PSC-CM. In addition, we also highlight the associated challenges in clinical application and discuss the potential strategies in developing successful cardiac-regenerative therapy.
Autophagy modulation altered differentiation capacity of CD146+ cells toward endothelial cells, pericytes, and cardiomyocytes
Authors: Hassanpour Mehdi , Rezaie Jafar , Darabi Masoud , Hiradfar Amirataollah , Rahbarghazi Reza , Nouri Mohammad
Published: March 2020

Background

To date, many attempts are employed to increase the regenerative potential of stem cells. In this study, we evaluated the hypothesis of whether an autophagy modulation could alter differentiation potency of CD146+ cells into mature pericyte, endothelial, and cardiomyocyte lineage.

Methods

In this study, CD146+cells were enriched from the human bone marrow aspirates and trans-differentiated into mature endothelial cells, pericytes, and cardiomyocytes after exposure to autophagy stimulator (50-μM Met)/inhibitor (15-μM HCQ). The protein levels of autophagy proteins were monitored by western blotting. NO content was measured using the Griess assay. Using real-time PCR assay and western blotting, we monitored the lineage protein and gene levels. Pro-inflammatory cytokine and angiocrine factors were measured by ELISA. The fatty acid change was determined by gas chromatography. We also measured exosome secretion capacity by measuring AChE activity and real-time PCR assay.

Result

Data revealed the modulation of autophagy factors, Beclin-1, P62, and LC3 II/I ratio in differentiating CD146+ cells after exposure to Met and HCQ (p < 0.05). The inhibition of autophagy increased NO content compared to the Met-treated cells (p < 0.05). Real-time PCR analysis showed that the treatment of CD146+ cells with autophagy modulators altered the expression of VE-cadherin, cTnI, and α-SMA (p < 0.05). Met increased the expression of VE-cadherin, α-SMA, and cTnI compared to the HCQ-treated cells (p < 0.05) while western blotting revealed the protein synthesis of all lineage-specific proteins under the stimulation and inhibition of autophagy. None statistically significant differences were found in the levels of Tie-1, Tie-2, VEGFR-1, and VEGFR-2 after autophagy modulation. Fatty acid profile analysis revealed the increase of unsaturated fatty acids after exposure to HCQ (p < 0.05). The treatment of cells with HCQ increased the levels of TNF-α and IL-6 compared to the Met-treated cells. Data revealed the increase of exosome biogenesis and secretion to the supernatant in cells treated with HCQ compared to the Met groups (p < 0.05).

Conclusions

In summary, autophagy modulation could alter differentiation potency of CD146+cells which is important in cardiac regeneration.
Fractional spectral differentiation matrices based on Legendre approximation
Authors: Ghorbani Asghar , Baleanu Dumitru
Published: March 2020

A simple scheme is proposed for computing $N \times N$N×N spectral differentiation matrices of fractional order α for the case of Legendre approximation. The algorithm derived here is based upon a homogeneous three-term recurrence relation and is numerically stable. The matrices are then applied to numerically differentiate.
Study on microbubble of cellulose acetate microfilm of the Republic of China (AD 1912–1949) collected in the Second Historical Archives of China
Authors: Jia Zhihui , Li Yuhu , Qi Yunpeng , Zhou Yajun , Hu Daodao , Chao Xiaolian , Xing Huiping , Li Jing
Published: March 2020

The white spots known as microbubbles that are formed in cellulose acetate film, significantly affects the texture of the image. However, the formation of microbubbles and their corresponding microstructure are poorly understood. In this paper, cellulose acetate microfilm from the Republic of China (AD 1912–1949) collected in the Second Historical Archives of China was chosen as a prototype to investigate the causes of microbubble disease for the first time. A comparative study was conducted between the film samples with and without microbubbles. Herein, the microstructural analyses including optical and SEM microscopy were conducted. The crystals in the microbubbles proved to be triphenyl phosphate as identified by NMR spectroscopy and SEM–EDX. Comparative properties of the film substrate with and without microbubbles were measured by TG, XRD and FT-IR spectroscopy. The results show that formation of microbubbles was generally accompanied with the vinegar syndrome and was produced between the protective and emulsion layers with the different types of shapes along the closed structure (the diameter of ~ 0.1–2 mm). The formed microbubble was filled with plasticizer. Based on the above-mentioned results, the possible formation process of microbubble was proposed in the present study. The results can provide support for the cause of microbubbles and basis for the conservation of photographic films.
Gap models across micro- to mega-scales of time and space: examples of Tansley’s ecosystem concept
Authors: Shugart H. H. , Foster Adrianna , Wang Bin , Druckenbrod Dan , Ma Jianyong , Lerdau Manuel , Saatchi Sassan , Yang Xi , Yan Xiaodong
Published: March 2020

Background

Gap models are individual-based models for forests. They simulate dynamic multispecies assemblages over multiple tree-generations and predict forest responses to altered environmental conditions. Their development emphases designation of the significant biological and ecological processes at appropriate time/space scales. Conceptually, they are with consistent with A.G. Tansley’s original definition of “the ecosystem”.

Results

An example microscale application inspects feedbacks among terrestrial vegetation change, air-quality changes from the vegetation’s release of volatile organic compounds (VOC), and climate change effects on ecosystem production of VOC’s. Gap models can allocate canopy photosynthate to the individual trees whose leaves form the vertical leaf-area profiles. VOC release depends strongly on leaf physiology by species of these trees. Leaf-level VOC emissions increase with climate-warming. Species composition change lowers the abundance of VOC-emitting taxa. In interactions among ecosystem functions and biosphere/atmosphere exchanges, community composition responses can outweigh physiological responses. This contradicts previous studies that emphasize the warming-induced impacts on leaf function.

As a mesoscale example, the changes in climate (warming) on forests including pest-insect dynamics demonstrates changes on the both the tree and the insect populations. This is but one of many cases that involve using a gap model to simulate changes in spatial units typical of sampling plots and scaling these to landscape and regional levels. As this is the typical application scale for gap models, other examples are identified. The insect/climate-change can be scaled to regional consequences by simulating survey plots across a continental or subcontinental zone. Forest inventories at these scales are often conducted using independent survey plots distributed across a region. Model construction that mimics this sample design avoids the difficulties in modelling spatial interactions, but we also discuss simulation at these scales with contagion effects.

Conclusions

At the global-scale, successful simulations to date have used functional types of plants, rather than tree species. In a final application, the fine-scale predictions of a gap model are compared with data from micrometeorological eddy-covariance towers and then scaled-up to produce maps of global patterns of evapotranspiration, net primary production, gross primary production and respiration. New active-remote-sensing instruments provide opportunities to test these global predictions.
QSAR, molecular docking, and design of novel 4-(N,N-diarylmethyl amines) Furan-2(5H)-one derivatives as insecticides against Aphis craccivora
Authors: Isyaku Yusuf , Uzairu Adamu , Uba Sani , Ibrahim Muhammad Tukur , Umar Abdullahi Bello
Published: March 2020

Background

Aphis craccivora has many plant hosts, though it seemingly forechoice to groups of bean family. Other plants it hosts are families of Solanaceae, Rosaceae, Malvaceae, Chenopodiaceae, Caryophyllaceae, Ranunculaceae, Cucurbitaceae, Brassicaceae, and Asteraceae.

Result

A computational study was carried out on a series of twenty compounds of novel 4-(N,N-diarylmethylamines) furan-2(5H)-one derivatives against Aphis craccivora insect. Optimization of the compounds was performed with the aid of Spartan 14 software using DFT/B3LYP/6-31G** quantum mechanical method. Using PaDel descriptor software to calculate the descriptors, Generic Function Approximation (GFA) was employed to generate the model. Model 1 found to be the optimal out of four models generated which has the following statistical parameters; R2 = 0.871489, R2adj = 0.83644, cross-validated R2 = 0.790821, and external R2 = 0.550768. Molecular docking study occurred between the compounds and the complex crystal structure of the acetylcholine (protein AChBP) (PDB CODE 2zju) in which compound 13 was identified to have the highest binding energy of − 8.4 kcalmol−1. Statistical analyses, such as variance inflation factor, mean effect, and the applicability domain, were conducted on the model. This compound has a strong affinity with the macromolecular target point of the A. craccivora (2zju) producing H-bond and as well the hydrophobic interaction at the target point of amino acid residue. Molecular docking gave an insight into the structure-based design of the new compounds with better activity against A. craccivora in which three compounds A, B, and C were designed and discovered to be of high quality and have greater binding affinity compared to the one obtained from the literature.

Conclusion

The QSAR model was generated by the employment of Genetic Function Approximation (GFA). The model was found to be robust and possessed a good statistical parameter. Furthermore, a molecular docking study was performed to get an idea for structure-based design in which three (3) compounds A, B, and C were designed and were found to be more active than the template (compound 13, i.e., the one with highest docking score). QSAR model was developed to give an insight into the ligand/template-based design of computer-aided drug design.
The Treatment of Hepatocellular Carcinoma With Portal Vein Tumor Thrombosis
Authors: Qadan Motaz , Kothary Nishita , Sangro Bruno , Palta Manisha
Published: March 2020

Hepatocellular carcinoma (HCC) is the sixth most common cancer and third leading cause of cancer-related death worldwide. HCC is also is a tumor with a distinct ability to invade and grow within the hepatic vasculature. Approximately 20% of patients with HCC have macrovascular invasion (MVI) at the time of diagnosis. MVI is associated with dismal prognosis, with median survival ranging from 2 to 5 months. Current staging systems designate MVI as advanced disease. Recent advances in multimodal approaches, including systemic therapies, radiation therapy, liver-directed therapies, and surgical approaches, in the treatment of HCC with MVI have rendered this disease process more treatable with improved outcomes and are discussed here.
Secondary Sarcomas: Biology, Presentation, and Clinical Care
Authors: Eulo Vanessa , Lesmana Harry , Doyle Leona A. , Nichols Kim E. , Hirbe Angela C.
Published: March 2020

Secondary sarcomas are a subset of sarcomas that occur in patients with prior cancer diagnoses and are associated with environmental or genetic factors. Although secondary sarcomas are rare in general, there are predisposing factors that can substantially increase this risk in certain populations. Herein, we review the environmental factors with the strongest association of sarcoma risk, including chemical exposure, certain viruses, cytotoxic and immunosuppressive agents, chronic edema, and radiation exposure. Additionally, the most common genetic disorders that carry a predisposition for sarcoma development will be discussed, including hereditary retinoblastoma (RB), Li-Fraumeni syndrome (LFS), neurofibromatosis type 1 (NF1), and DICER1 syndrome. Although treatment does not generally differ for sporadic versus secondary sarcomas, awareness of the risk factors can alter therapeutic strategies to minimize risk, aid prompt diagnosis by increasing clinical suspicion, and allow for appropriate surveillance and genetic counseling for those patients with cancer predisposition syndromes.
Optimizing Cardiovascular Health in Patients With Cancer: A Practical Review of Risk Assessment, Monitoring, and Prevention of Cancer Treatment–Related Cardiovascular Toxicity
Authors: Dent Susan F. , Kikuchi Robin , Kondapalli Lavanya , Ismail-Khan Roohi , Brezden-Masley Christine , Barac Ana , Fradley Michael
Published: March 2020

Advances in cancer screening and improved treatment approaches have led to an increase in survivorship and, consequently, recognition of an association between cancer treatments and the development of cardiovascular complications. In addition, as the population becomes proportionally older, comorbid cardiovascular risk factors are more prevalent in the population and compound the risk of developing cancer treatment–related cardiovascular toxicity. Cardio-oncology has emerged as a new subspecialty of medicine that provides a multidisciplinary approach, bringing together oncologists, cardiologists, and allied health care providers who are tasked with optimizing the cardiovascular health of patients exposed to potentially cardiotoxic cancer therapy. Using a case-based approach, practical advice on how to identify, monitor, and treat patients with cancer who are at risk for developing cancer treatment–related cardiovascular dysfunction is discussed. Cardiovascular risk factors (e.g., age, hypertension, diabetes) and cancer therapies (chemotherapy, targeted therapy, radiation) associated with cardiovascular toxicity are presented. Current cardiac monitoring strategies such as two- and three-dimensional echocardiography, cardiac MRI, and biomarkers (troponin and brain natriuretic peptide [BNP]) are discussed. Last, the current literature on pharmacologic (e.g., angiotensin-converting enzyme inhibitors, β-blockers, statins) and lifestyle (diet and exercise) strategies to mitigate cardiovascular toxicity during and following completion of cancer therapy are reviewed.
Predictors of Survival After Head and Neck Squamous Cell Carcinoma in South America: The InterCHANGE Study
Authors: Abrahão Renata , Perdomo Sandra , Pinto Luis Felipe Ribeiro , Nascimento de Carvalho Flávia , Dias Fernando Luis , de Podestá José Roberto V. , Ventorin von Zeidler Sandra , Marinho de Abreu Priscila , Vilensky Marta , Giglio Raul Eduardo , Oliveira José Carlos , Mineiro Matinair Siqueira , Kowalski Luiz P. , Ikeda Mauro K. , Cuello Mauricio , Munyo Andres , Rodríguez-Urrego Paula A. , Hakim José Antonio , Suarez-Zamora David Alfonso , Cayol Federico , Figari Marcelo Fernando , Oliver Javier , Gaborieau Valerie , Keogh Ruth H. , Brennan Paul , Curado Maria Paula ,   on behalf of the InterCHANGE Group
Published: March 2020

PURPOSE

Head and neck squamous cell carcinoma (HNSCC) incidence is high in South America, where recent data on survival are sparse. We investigated the main predictors of HNSCC survival in Brazil, Argentina, Uruguay, and Colombia.

METHODS

Sociodemographic and lifestyle information was obtained from standardized interviews, and clinicopathologic data were extracted from medical records and pathologic reports. The Kaplan-Meier method and Cox regression were used for statistical analyses.

RESULTS

Of 1,463 patients, 378 had a larynx cancer (LC), 78 hypopharynx cancer (HC), 599 oral cavity cancer (OC), and 408 oropharynx cancer (OPC). Most patients (55.5%) were diagnosed with stage IV disease, ranging from 47.6% for LC to 70.8% for OPC. Three-year survival rates were 56.0% for LC, 54.7% for OC, 48.0% for OPC, and 37.8% for HC. In multivariable models, patients with stage IV disease had approximately 7.6 (LC/HC), 11.7 (OC), and 3.5 (OPC) times higher mortality than patients with stage I disease. Current and former drinkers with LC or HC had approximately 2 times higher mortality than never-drinkers. In addition, older age at diagnosis was independently associated with worse survival for all sites. In a subset analysis of 198 patients with OPC with available human papillomavirus (HPV) type 16 data, those with HPV-unrelated OPC had a significantly worse 3-year survival compared with those with HPV-related OPC (44.6% v 75.6%, respectively), corresponding to a 3.4 times higher mortality.

CONCLUSION

Late stage at diagnosis was the strongest predictor of lower HNSCC survival. Early cancer detection and reduction of harmful alcohol use are fundamental to decrease the high burden of HNSCC in South America.
First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors
Authors: Hassan Raffit , Blumenschein George R. , Moore Kathleen N. , Santin Alessandro D. , Kindler Hedy L. , Nemunaitis John J. , Seward Shelly M. , Thomas Anish , Kim Stella K. , Rajagopalan Prabhu , Walter Annette O. , Laurent Dirk , Childs Barrett H. , Sarapa Nenad , Elbi Cem , Bendell Johanna C.
Published: March 2020

PURPOSE

This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.

PATIENTS AND METHODS

This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.

RESULTS

Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.

CONCLUSION

Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.
Initial Clinical Impressions of the Critical Care of COVID-19 Patients in Seattle, New York City, and Chicago
Authors: Sommer Phillip , Lukovic Elvedin , Fagley Eliot , Long Dustin R. , Sobol Julia B. , Heller Katherine , Moitra Vivek K. , Pauldine Ronald , O’Connor Michael F. , Shahul Sajid , Nunnally Mark E. , Tung Avery
Published: March 2020

Since the first recognition of a cluster of novel respiratory viral infections in China in late December 2019, intensivists in the United States have watched with growing concern as infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus―now named coronavirus disease of 2019 (COVID-19)―have spread to hospitals in the United States. Because COVID-19 is extremely transmissible and can progress to a severe form of respiratory failure, the potential to overwhelm available critical care resources is high and critical care management of COVID-19 patients has been thrust into the spotlight. COVID-19 arrived in the United States in January and, as anticipated, has dramatically increased the usage of critical care resources. Three of the hardest-hit cities have been Seattle, New York City, and Chicago with a combined total of over 14,000 cases as of March 23, 2020.

In this special article, we describe initial clinical impressions of critical care of COVID-19 in these areas, with attention to clinical presentation, laboratory values, organ system effects, treatment strategies, and resource management. We highlight clinical observations that align with or differ from already published reports. These impressions represent only the early empiric experience of the authors and are not intended to serve as recommendations or guidelines for practice, but rather as a starting point for intensivists preparing to address COVID-19 when it arrives in their community.
Control of translation elongation in health and disease
Authors: Knight John R. P. , Garland Gavin , Pöyry Tuija , Mead Emma , Vlahov Nikola , Sfakianos Aristeidis , Grosso Stefano , De-Lima-Hedayioglu Fabio , Mallucci Giovanna R. , von der Haar Tobias , Smales C. Mark , Sansom Owen J. , Willis Anne E.
Published: March 2020

Regulation of protein synthesis makes a major contribution to post-transcriptional control pathways. During disease, or under stress, cells initiate processes to reprogramme protein synthesis and thus orchestrate the appropriate cellular response. Recent data show that the elongation stage of protein synthesis is a key regulatory node for translational control in health and disease. There is a complex set of factors that individually affect the overall rate of elongation and, for the most part, these influence either transfer RNA (tRNA)- and eukaryotic elongation factor 1A (eEF1A)-dependent codon decoding, and/or elongation factor 2 (eEF2)-dependent ribosome translocation along the mRNA. Decoding speeds depend on the relative abundance of each tRNA, the cognate:near-cognate tRNA ratios and the degree of tRNA modification, whereas eEF2-dependent ribosome translocation is negatively regulated by phosphorylation on threonine-56 by eEF2 kinase. Additional factors that contribute to the control of the elongation rate include epigenetic modification of the mRNA, coding sequence variation and the expression of eIF5A, which stimulates peptide bond formation between proline residues. Importantly, dysregulation of elongation control is central to disease mechanisms in both tumorigenesis and neurodegeneration, making the individual key steps in this process attractive therapeutic targets. Here, we discuss the relative contribution of individual components of the translational apparatus (e.g. tRNAs, elongation factors and their modifiers) to the overall control of translation elongation and how their dysregulation contributes towards disease processes.
A murine model demonstrates capsule-independent adaptive immune protection in survivors of Klebsiella pneumoniae respiratory tract infection
Authors: Twentyman Joy , Morffy Smith Catherine , Nims Julia S. , Dahler Aubree A. , Rosen David A.
Published: March 2020

Klebsiella pneumoniae represents a growing clinical threat, given its rapid development of antibiotic resistance, necessitating new therapeutic strategies. Existing live-infection models feature high mortality rates, limiting their utility in the study of natural adaptive immune response to this pathogen. We developed a preclinical model of pneumonia with low overall mortality, in which previously exposed mice are protected from subsequent respiratory tract challenge with K. pneumoniae. Histologic analyses of infected murine lungs demonstrate lymphocytic aggregates surrounding vasculature and larger airways. Initial exposure in RAG1 knockout mice (lacking functional B and T cells) failed to confer protection against subsequent K. pneumoniae challenge. While administration of isolated K. pneumoniae capsule was sufficient to provide protection, we also found that initial inoculation with K. pneumoniae mutants lacking capsule (Δcps), O-antigen (ΔwecA) or both conferred protection from subsequent wild-type infection and elicited K. pneumoniae-specific antibody responses, indicating that non-capsular antigens may also elicit protective immunity. Experiments in this model will inform future development of multivalent vaccines to prevent invasive K. pneumoniae infections.
Redox-Active α-Diimine Complexes of Early Transition Metals: From Bonding to Catalysis
Authors: Mashima Kazushi
Published: March 2020

It is an intrinsic nature that early transition metals favorably adopt their highest oxidation state with d0 configuration. We have been interested in early transition metal complexes bearing redox active α-diimine ligands for introducing redox processes at the metal center through reversible interconversion among possible coordination modes, i.e., a neutral 1,4-diaza-1,3-diene form A, a monoanionic form B, and dianionic ene-diamido forms, σ2-enediamido form C and σ2,π-enediamido form D. In this context, we continuously investigated synthesis of a series of α-diimine complexes of group 3, 5 and 6 metals by implementing two synthetic methodologies, (1) a salt-metathesis protocol by treating ligand-supported metal precursors with the alkali metal salts of α-diimines and (2) a salt-free protocol by applying organosilicon compounds, such as 3,6-di(trimethylsilyl)-1,4-cyclohexadiene (abbrev. Si-CHD) and 1,4-di(trimethylsilyl)-2-methyl-cyclohexa-2,4-diene (abbrev. Si-Me-CHD) together with 1,4-di(trimethylsilyl)-2,5-dimethyl-1,4-dihydropyrazine (abbrev. Si-Me2-DHP) and 1,4-di(trimethylsilyl)-2,3,5,6-tetramethyl-1,4-dihydropyrazine (abbrev. Si-Me4-DHP), for reducing homoleptic chlorides and imide chlorides of early transition metals in the presence of α-diimine ligands. This account thus summarizes the author’s achievements on bonding and reactivity of various α-diimine complexes of group 3, group 5, and group 6 metals as well as their catalytic performance.
The Paper Trail of Knowledge Spillovers: Evidence from Patent Interferences
Authors: Ganguli Ina , Lin Jeffrey , Reynolds Nicholas
Published: March 2020

We show evidence of localized knowledge spillovers using a new database of US patent interferences terminated between 1998 and 2014. Interferences resulted when two or more independent parties submitted identical claims of invention nearly simultaneously. Following the idea that inventors of identical inventions share common knowledge inputs, interferences provide a new method for measuring knowledge spillovers. Interfering inventors are 1.4 to 4.0 times more likely to live in the same local area than matched control pairs of inventors. They are also more geographically concentrated than citation-linked inventors. Our results emphasize geographic distance as a barrier to tacit knowledge flows. (JEL D83, O31, O33, O34)
Charging Ahead: Prepaid Metering, Electricity Use, and Utility Revenue
Authors: Jack Kelsey , Smith Grant
Published: March 2020

Monthly bills for services such as electricity often go unpaid in developing countries. Prepaid meters offer a potential technological solution. In Cape Town, South Africa, over 4,000 residential customers on monthly billing were switched to prepaid metering, with random variation in the timing of the switch. In response, electricity use falls by 14 percent, driven at least in part by an increase in marginal price sensitivity. The decrease in revenue to the municipal electric utility is more than offset by lower revenue recovery costs. Switching poorer and more in-debt customers generates the greatest net revenue gains to the utility. (JEL L94, L98, O13, Q41, Q48)
Taken by Storm: Hurricanes, Migrant Networks, and US Immigration
Authors: Mahajan Parag , Yang Dean
Published: March 2020

Do negative shocks in origin countries encourage or inhibit international migration? What roles do networks play in modifying out-migration responses? The answers to these questions are not theoretically obvious, and past empirical findings are equivocal. We examine the impact of hurricanes on a quarter century of international migration to the United States. Hurricanes increase migration to the United States, with the effect’s magnitude increasing in the size of prior migrant stocks. We provide new insights into how networks facilitate legal, permanent US immigration in response to origin country shocks, a matter of growing importance as climate change increases natural disaster impacts. (JEL F22, J15, Q54, Z13)
The metabolic hypothesis is more likely than the epileptogenic hypothesis to explain stroke-like lesions
Authors: Finsterer Josef
Published: March 2020

Stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episode (MELAS) syndrome but occur in other mitochondrial disorders (MIDs) as well. The morphological equivalent of the SLE is the stroke-like lesion (SLL) on magnetic resonance imaging (MRI). The pathophysiology of SLLs is under debate, but several hypotheses have been raised to explain the phenomenon. Of these, the metabolic, epileptogenic, and vascular hypotheses are the most frequently discussed. There are several arguments for and against these hypotheses, but a consensus has not been reached which of them provides the correct explanation. A recent consensus statement generated by a panel of experts applying the Delphi method, favoured the epileptogenic hypothesis and recommended treatment of SLEs with antiepileptic drugs, irrespective if the patient presented with a seizure or epileptiform discharges on electroencephalography (EEG) or not. We disagree with this general procedure and provide the following arguments against the epileptogenic hypothesis: 1. not each SLE is associated with seizures. 2. epileptiform discharges may be absent on EEG during a SLE. 3. SLLs are not restricted to the cortex. 4. antiseizure-drugs (ASDs) may not prevent the progression or recurrence of a SLL. 5. ASDs may terminate seizures but no other phenotypic feature of a SLE. 6. patients already under ASDs are not immune from developing a SLL. 7. SLLs usually last longer than seizures. 8. no animal model supports the epileptogenic hypothesis. The strongest arguments for the metabolic hypothesis are that SLLs are not confined to a vascular territory, that the oxygen-extraction fraction within a SLL is reduced, and that there is hypometabolism within a SLL on FDG-PET. SLLs may respond to antioxidants, NO-precursors, steroids, or the ketogenic diet. ASDs should be applied only if there is clinical or electrophysiological evidence of seizure-activity.
Os fatores sociodemográficos moderam a associação da prática de atividade física dos pais e amigos com o nível de atividade física dos adolescentes?
Authors: Mendonça Gerfeson , Mendes Jacqueline de Oliveira , Lucena Joana Marcela Sales de , Farias Júnior José Cazuza de
Published: March 2020

O objetivo deste estudo foi analisar se os fatores sociodemográficos moderam a associação da prática de atividade física dos pais e dos amigos com o nível de atividade física dos adolescentes. Trata-se de um estudo epidemiológico transversal, realizado com 2.859 adolescentes (57,8% sexo feminino) de 14 a 19 anos de idade do município de João Pessoa, Paraíba. O nível de atividade física dos adolescentes e a prática de atividade física dos pais e dos amigos foram mensurados por questionários. A prevalência de adolescentes fisicamente ativos foi de 50,2% (IC95%: 47,3-53,1), sendo mais elevada no sexo masculino (66,3%; IC95%: 63,7-69,0) comparada ao feminino (38,4%; IC95%: 36,1-40,8). Os resultados da regressão logística binária demostraram que há associação entre a prática de atividade física dos pais e dos amigos e o nível de atividade física dos adolescentes (p < 0,001). No entanto, essa associação é moderada por fatores sociodemográficos (sexo e classe econômica). A magnitude da medida de associação entre a prática de atividade física dos amigos e a dos adolescentes foi mais elevada nos adolescentes do sexo masculino (OR = 5,02; IC95%: 2,73-9,26 vs. feminino OR = 2,21; IC95%: 1,55-3,14) e de classe econômica A/B (OR = 3,90; IC95%: 2,39-6,39 vs. classe C/D/E: OR = 2,27; IC95%: 1,53-3,37). A prática de atividade física da mãe se associou de forma significativa e positiva com o nível de atividade física nos adolescentes de classe econômica A/B (OR = 1,87; IC95%: 1,32-2,62). Conclui-se que os fatores sociodemográficos moderam a associação da prática de atividade física dos amigos e da mãe com o nível de atividade física dos adolescentes. A magnitude da associação entre essas variáveis variou com o sexo e a classe econômica dos adolescentes.
Efeito da substituição do tempo de tela e atividades físicas no lazer na percepção positiva de saúde de universitários
Authors: Sousa Thiago Ferreira , Ferreira Mariana da Silva , Barros Gerleison Ribeiro , Farias Gildeene Silva
Published: March 2020

O objetivo deste estudo foi estimar o impacto da substituição do tempo de prática de atividades físicas no lazer e comportamentos sedentários sobre a autoavaliação positiva da saúde em universitários de uma instituição de ensino superior do estado da Bahia. Foram realizados dois inquéritos repetidos com universitários de uma mesma instituição nos anos de 2012 e 2014. A autoavaliação positiva de saúde foi o desfecho deste estudo. O tempo por dia despendido em 17 modalidades e o tempo no total de atividades físicas no lazer, mais quatro comportamentos sedentários de tela e tempo de tela no total foram padronizados por uma constante de 30 minutos. O modelo de substituição isotemporal foi empregado por meio da estimativa do Odds Ratio (OR), via regressão logística binaria. O nível de significância foi de 5%. Houve a participação de 1.085 e 1.041 universitários nos anos de 2012 e 2014, respectivamente. Observou-se maiores chances de percepção positiva da saúde ao realocar o tempo de uso de computador em pesquisas para a prática de futebol, lutas, corrida em esteira e musculação. De modo geral, maiores chances de autoavaliação positiva da saúde foram mostrados ao realocar 30 minutos por dia do tempo de tela no total para o tempo de prática de atividades físicas no lazer no total (OR = 1,14; IC95%: 1,10–1,18). Conclui-se que substituir pelo menos 30 minutos por dia de uso de computador em pesquisas para a prática de atividades físicas no lazer, maximiza a autoavaliação positiva do nível de saúde em universitários.
When the Bank Comes to You: Branch Network and Customer Omnichannel Banking Behavior
Authors: Zhou Mi , Geng Dan , Abhishek Vibhanshu , Li Beibei
Published: March 2020

Banks today have been increasingly reducing their physical presence and redirecting customers to digital channels, and yet, the consequences of this strategy are not well studied. This research investigates the effects of banks’ branch network changes (i.e., branch openings and branch closures) on customer omnichannel banking behavior. Using a proprietary data set from a large commercial bank in the United States, this paper shows the asymmetric effects of branch openings and branch closures on customer omnichannel banking behavior. In particular, it finds that branch openings increase customers’ branch transactions. However, the first branch opening leads to a migration of complex transactions to the branches, which might result in a net decrease in online banking in the short term. As consumers interact more with the physical channel, there is a gradual synergistic increase in customers’ transactions via online banking as well as alternative channels due to a learning spillover effect. This learning spillover effect goes from easy online inquiries to more complex online transactions as additional branches open. On the contrary, branch closures result in a favorable migration pattern from the branch channel to online banking. This pattern, however, could be reversed once the last branch closes within the customer’s residential neighborhood.
How Economically Significant Are Unused Capacity Costs? A Large-Scale Empirical Analysis
Authors: Ederhof Merle , Nagar Venky , Rajan Madhav
Published: March 2020

This study uses a confidential Census sample of 151,900 U.S. manufacturing plant-years from 1974 to 2011 to investigate the impact of excluding the cost of unused capacity from key financial indicators, namely, product costs and gross margins. We estimate the magnitude of unused capacity cost as a percentage of sales to be about 4.8%, which for Compustat manufacturing firms in 2011 amounts to $142 billion (by comparison, the well-researched topic of research and development expenses totals to $223 billion). We find that excluding the cost of unused capacity decreases product costs by approximately 6% and increases gross margins by around 26%. These magnitudes are economically significant and pervasive across industries and over time. Excluding the cost of unused capacity also smooths the time-series variation in unitized product costs and gross margins, with the standard deviation of gross margins declining (significantly) by 5%. Additional analyses indicate the presence of congestion and other costs at high capacity utilization levels, as predicted by the operations literature.

This paper was accepted by Suraj Srinivasan, accounting.