bluuebunny/crossref_metadata_2025 huggingface dataset:
Pade Method for Construction of Numerical Algorithms for Fractional Initial Value Problem
Authors: Gao Feng , Chi Chunmei
Published: July 2020

In this paper, we propose an efficient method for constructing numerical algorithms for solving the fractional initial value problem by using the Pade approximation of fractional derivative operators. We regard the Grunwald–Letnikov fractional derivative as a kind of Taylor series and get the approximation equation of the Taylor series by Pade approximation. Based on the approximation equation, we construct the corresponding numerical algorithms for the fractional initial value problem. Finally, we use some examples to illustrate the applicability and efficiency of the proposed technique.
Distribution Features of the Minimum Rock Cover Thickness of the Surrounding Rock Self‐Stability of the Metro Tunnel in the Soil‐Rock Dualistic Stratum
Authors: Zhang Ziguang , Xu Tao , Cao Guangyong , Liu Xiaofeng
Published: July 2020

Based on the maximum value of the self‐stability of surrounding rock, the key issues affecting the distribution of the minimum mock cover thickness of the surrounding rock self‐stability (MRCT‐SRS) of the metro tunnel in the soil‐rock dualistic stratum are discussed. The MRCT‐SRS was studied for different soft stratum thicknesses Hs and excavation spans D based on cusp catastrophe theory. Moreover, the 3D spatial distribution was determined, and the fitted curves were constructed according to the MRCT‐SRS, Hs, and D. This facilitated the assessment of the stability of the surrounding rock in the excavation of a metro tunnel. Combined with the construction practices used for the Qingdao metro project, the validity of the obtained MRCT‐SRS has been verified by the inverse analysis of the monitored data from the metro tunnel. Furthermore, the application of the MRCT‐SRS in determining the reasonable buried depth of a metro line has been explored. The research results have provided theoretical support and scientific basis for the preparation, revision, and improvement of the relevant codes, standards, and guidelines for metro tunnel planning and design.
Exosomal Noncoding RNAs and Tumor Drug Resistance
Authors: Guo Chengyao , Liu Jinbo , Zhou Quanbo , Song Junmin , Zhang Zhiyong , Li Zhen , Wang Guixian , Yuan Weitang , Sun Zhenqiang
Published: July 2020

Tumor drug resistance is a major challenge in the treatment of cancer. Noncoding RNAs (ncRNA) play a role in the progression of drug resistance. Recent studies have indicated that exosomes, with their in vitro and in vivo compatibility, are the best natural carrier of ncRNA, and their transport of ncRNA into cells could regulate drug resistance. Exosomal ncRNA impact drug resistance through participation in drug efflux, regulation of signaling pathways, and modification of the tumor microenvironment. In this review, we evaluate the mechanism of exosomal ncRNA related to tumor drug resistance, their role in different tumors, and potential clinical applications.
The Pathognomonic FOXL2 C134W Mutation Alters DNA-Binding Specificity
Authors: Carles Annaïck , Trigo-Gonzalez Genny , Cao Qi , Cheng S.-W. Grace , Moksa Michelle , Bilenky Misha , Huntsman David G. , Morin Gregg B. , Hirst Martin
Published: July 2020

The somatic missense point mutation c.402C>G (p.C134W) in the FOXL2 transcription factor is pathognomonic for adult-type granulosa cell tumors (AGCT) and a diagnostic marker for this tumor type. However, the molecular consequences of this mutation and its contribution to the mechanisms of AGCT pathogenesis remain unclear. To explore these mechanisms, we engineered V5-FOXL2WT- and V5-FOXL2C134W–inducible isogenic cell lines and performed chromatin immunoprecipitation sequencing and transcriptome profiling. FOXL2C134W associated with the majority of the FOXL2 wild-type DNA elements as well as a large collection of unique elements genome wide. This model enabled confirmation of altered DNA-binding specificity for FOXL2C134W and identification of unique targets of FOXL2C134W including SLC35F2, whose expression increased sensitivity to YM155. Our results suggest FOXL2C134W drives AGCT by altering the binding affinity of FOXL2-containing complexes to engage an oncogenic transcriptional program.

Significance:

A mechanistic understanding of FOXL2C134W-induced regulatory state alterations drives discovery of a rationally designed therapeutic strategy.
Cellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Authors: Alimirah Fatouma , Pulido Tanya , Valdovinos Alexis , Alptekin Sena , Chang Emily , Jones Elijah , Diaz Diego A. , Flores Jose , Velarde Michael C. , Demaria Marco , Davalos Albert R. , Wiley Christopher D. , Limbad Chandani , Desprez Pierre-Yves , Campisi Judith
Published: July 2020

Cellular senescence entails an irreversible growth arrest that evolved in part to prevent cancer. Paradoxically, senescent cells secrete proinflammatory and growth-stimulatory molecules, termed the senescence-associated secretory phenotype (SASP), which is correlated with cancer cell proliferation in culture and xenograft models. However, at what tumor stage and how senescence and the SASP act on endogenous tumor growth in vivo is unknown. To understand the role of senescence in cancer etiology, we subjected p16-3MR transgenic mice, which permit the identification and selective elimination of senescent cells in vivo, to the well-established two-step protocol of squamous cell skin carcinoma, in which tumorigenesis is initiated by a carcinogen 7,12-dimethylbenz[α]anthracene, and then promoted by 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We show that TPA promotes skin carcinogenesis by inducing senescence and a SASP. Systemic induction of senescence in nontumor-bearing p16-3MR mice using a chemotherapy followed by the two-step carcinogenesis protocol potentiated the conversion of benign papillomas to carcinomas by elevating p38MAPK and MAPK/ERK signaling. Ablation of senescent cells reduced p38MAPK and MAPK/ERK signaling, thereby preventing the progression of benign papillomas to carcinomas. Thus, we show for the first time that senescent cells are tumor promoters, not tumor initiators, and that they stimulate skin carcinogenesis by elevating p38MAPK and MAPK/ERK signaling. These findings pave the way for developing novel therapeutics against senescence-fueled cancers.

Significance:

These findings identify chemotherapy-induced senescence as a culprit behind tumor promotion, suggesting that elimination of senescent cells after chemotherapy may reduce occurrence of second cancers decades later.
Brain Metastasis Cell Lines Panel: A Public Resource of Organotropic Cell Lines
Authors: Valiente Manuel , Van Swearingen Amanda E.D. , Anders Carey K. , Bairoch Amos , Boire Adrienne , Bos Paula D. , Cittelly Diana M. , Erez Neta , Ferraro Gino B. , Fukumura Dai , Gril Brunilde , Herlyn Meenhard , Holmen Sheri L. , Jain Rakesh K. , Joyce Johanna A. , Lorger Mihaela , Massague Joan , Neman Josh , Sibson Nicola R. , Steeg Patricia S. , Thorsen Frits , Young Leonie S. , Varešlija Damir , Vultur Adina , Weis-Garcia Frances , Winkler Frank
Published: July 2020

Spread of cancer to the brain remains an unmet clinical need in spite of the increasing number of cases among patients with lung, breast cancer, and melanoma most notably. Although research on brain metastasis was considered a minor aspect in the past due to its untreatable nature and invariable lethality, nowadays, limited but encouraging examples have questioned this statement, making it more attractive for basic and clinical researchers. Evidences of its own biological identity (i.e., specific microenvironment) and particular therapeutic requirements (i.e., presence of blood–brain barrier, blood–tumor barrier, molecular differences with the primary tumor) are thought to be critical aspects that must be functionally exploited using preclinical models. We present the coordinated effort of 19 laboratories to compile comprehensive information related to brain metastasis experimental models. Each laboratory has provided details on the cancer cell lines they have generated or characterized as being capable of forming metastatic colonies in the brain, as well as principle methodologies of brain metastasis research. The Brain Metastasis Cell Lines Panel (BrMPanel) represents the first of its class and includes information about the cell line, how tropism to the brain was established, and the behavior of each model in vivo. These and other aspects described are intended to assist investigators in choosing the most suitable cell line for research on brain metastasis. The main goal of this effort is to facilitate research on this unmet clinical need, to improve models through a collaborative environment, and to promote the exchange of information on these valuable resources.
A Complex Systems Model of Breast Cancer Etiology: The Paradigm II Conceptual Model
Authors: Hiatt Robert A. , Engmann Natalie J. , Balke Kaya , Rehkopf David H.
Published: July 2020

Background:

The etiology of breast cancer is a complex system of interacting factors from multiple domains. New knowledge about breast cancer etiology continues to be produced by the research community, and the communication of this knowledge to other researchers, practitioners, decision makers, and the public is a challenge.

Methods:

We updated the previously published Paradigm model (PMID: 25017248) to create a framework that describes breast cancer etiology in four overlapping domains of biologic, behavioral, environmental, and social determinants. This new Paradigm II conceptual model was part of a larger modeling effort that included input from multiple experts in fields from genetics to sociology, taking a team and transdisciplinary approach to the common problem of describing breast cancer etiology for the population of California women in 2010. Recent literature was reviewed with an emphasis on systematic reviews when available and larger epidemiologic studies when they were not. Environmental chemicals with strong animal data on etiology were also included.

Results:

The resulting model illustrates factors with their strength of association and the quality of the available data. The published evidence supporting each relationship is made available herein, and also in an online dynamic model that allows for manipulation of individual factors leading to breast cancer (https://cbcrp.org/causes/).

Conclusions:

The Paradigm II model illustrates known etiologic factors in breast cancer, as well as gaps in knowledge and areas where better quality data are needed.

Impact:

The Paradigm II model can be a stimulus for further research and for better understanding of breast cancer etiology.
Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome
Authors: Shah Manish A. , Enzinger Peter , Ko Andrew H. , Ocean Allyson J. , Philip Philip Agop , Thakkar Prashant V. , Cleveland Kyle , Lu Yao , Kortmansky Jeremy , Christos Paul J. , Zhang Chao , Kaur Navjot , Elmonshed Dina , Galletti Giuseppe , Sarkar Sandipto , Bhinder Bhavneet , Pittman Meredith E. , Plotnikova Olga Mikhaylovna , Kotlov Nikita , Frenkel Felix , Bagaev Aleksander , Elemento Olivier , Betel Doron , Giannakakou Paraskevi , Lenz Heinz-Josef
Published: July 2020

Purpose:

We examined cabazitaxel, a novel next-generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study.

Patients and Methods:

Patients who have progressed on one or more prior therapies for locally advanced, unresectable, or metastatic disease were eligible, and prior taxane therapy was allowed. Taxane-naïve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon's two-stage design (10% significance and 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing.

Results:

Fifty-three patients enrolled in the taxane-naïve cohort (Arm A) and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013, to April 8, 2015: median age 61.7 years (range, 35.5–91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A and 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% [95% confidence interval (CI), 17%–42%] and did not meet the prespecified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI, 16%–57%) and surpassed its efficacy target. HER2 amplification or overexpression was associated with improved disease control (P = 0.003), PFS (P = 0.04), and overall survival (P = 0.002). An M2 macrophage signature was also associated with improved survival (P = 0.031).

Conclusions:

Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation.
Molecular Study on the Potential Protective Effects of Bee Venom against Fructose-Induced Nonalcoholic Steatohepatitis in Rats
Authors: Abd El-Haleim Enas Ahmed
Published: July 2020

Background: There is a causative relation between the increased hepatic steatohepatitis prevalence and sweeteners intake, fructose in particular. Despite an increasing understanding of the mechanisms of nonalcoholic steatohepatitis (NASH) pathogenesis, there are no drugs approved for it. Objectives: Evaluate the effect of bee venom (BV) treatment on the fructose-induced NASH in rats and demonstrate its possible molecular mechanisms. Methods: NASH was induced in rats by 10% fructose in drinking water for 8 weeks. BV was administered (0.1 mg/kg, i.p.) 3 times per week during the last 2 weeks of the experiment. Sera were used for the determination of lipids, cholesterol, glucose, insulin, and liver enzymes. Hepatic gene expressions of farnesoid X receptor (FXR)α and the liver X receptor (LXR) were determined. Hepatic sterol regulatory element-binding protein (SREBP)1/2, oxidative stress, and inflammation parameters were measured. Liver parts were used for histopathological examination. Small intestine was removed for the determination of tight junction proteins. Results: Fructose caused overt histological damage in the liver, and this was associated with parallel changes in all parameters measured. BV effectively prevented these changes, presumably through amelioration of hepatic SREBP1/2, LXR, and FXRα expression as well as intestinal tight junction proteins. Conclusion: These findings support the therapeutic usefulness of BV, a remedy with a favorable safety profile, in the prevention of fructose-induced NASH.
Frailty Prevalence in Younger End-Stage Kidney Disease Patients Undergoing Dialysis and Transplantation
Authors: Chu Nadia M. , Chen Xiaomeng , Norman Silas P. , Fitzpatrick Jessica , Sozio Stephen M. , Jaar Bernard G. , Frey Alena , Estrella Michelle M. , Xue Qian-Li , Parekh Rulan S. , Segev Dorry L. , McAdams-DeMarco Mara A.
Published: July 2020

Background: Frailty, originally characterized in community-dwelling older adults, is increasingly being studied and implemented for adult patients with end-stage kidney disease (ESKD) of all ages (>18 years). Frailty prevalence and manifestation are unclear in younger adults (18–64 years) with ESKD; differences likely exist based on whether the patients are treated with hemodialysis (HD) or kidney transplantation (KT). Methods: We leveraged 3 cohorts: 378 adults initiating HD (2008–2012), 4,304 adult KT candidates (2009–2019), and 1,396 KT recipients (2008–2019). The frailty phenotype was measured within 6 months of dialysis initiation, at KT evaluation, and KT admission. Prevalence of frailty and its components was estimated by age (≥65 vs. <65 years). A Wald test for interactions was used to test whether risk factors for frailty differed by age. Results: In all 3 cohorts, frailty prevalence was higher among older than younger adults (HD: 71.4 vs. 47.3%; candidates: 25.4 vs. 18.8%; recipients: 20.8 vs. 14.3%). In all cohorts, older patients were more likely to have slowness and weakness but less likely to report exhaustion. Among candidates, older age (odds ratio [OR] = 1.79, 95% CI: 1.47–2.17), non-Hispanic black race (OR = 1.30, 95% CI: 1.08–1.57), and dialysis type (HD vs. no dialysis: OR = 2.06, 95% CI: 1.61–2.64; peritoneal dialysis vs. no dialysis: OR = 1.78, 95% CI: 1.28–2.48) were associated with frailty prevalence, but sex and Hispanic ethnicity were not. These associations did not differ by age (pinteractions > 0.1). Similar results were observed for recipients and HD patients. Conclusions: Although frailty prevalence increases with age, younger patients have a high burden. Clinicians caring for this vulnerable population should recognize that younger patients may experience frailty and screen all age groups.
Venous Thromboembolism Research Priorities: A Scientific Statement From the American Heart Association and the International Society on Thrombosis and Haemostasis
Authors: Cushman Mary , Barnes Geoffrey D. , Creager Mark A. , Diaz Jose A. , Henke Peter K. , Machlus Kellie R. , Nieman Marvin T. , Wolberg Alisa S. ,   On behalf of the American Heart Association Council on Peripheral Vascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Epidemiology and Prevention; and the International Society on Thrombosis and Haemostasis
Published: July 2020

Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General’s
The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism
in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism.
Better Document-Level Machine Translation with Bayes’ Rule
Authors: Yu Lei , Sartran Laurent , Stokowiec Wojciech , Ling Wang , Kong Lingpeng , Blunsom Phil , Dyer Chris
Published: July 2020

We show that Bayes’ rule provides an effective mechanism for creating document translation models that can be learned from only parallel sentences and monolingual documents a compelling benefit because parallel documents are not always available. In our formulation, the posterior probability of a candidate translation is the product of the unconditional (prior) probability of the candidate output document and the “reverse translation probability” of translating the candidate output back into the source language. Our proposed model uses a powerful autoregressive language model as the prior on target language documents, but it assumes that each sentence is translated independently from the target to the source language. Crucially, at test time, when a source document is observed, the document language model prior induces dependencies between the translations of the source sentences in the posterior. The model’s independence assumption not only enables efficient use of available data, but it additionally admits a practical left-to-right beam-search algorithm for carrying out inference. Experiments show that our model benefits from using cross-sentence context in the language model, and it outperforms existing document translation approaches.
Four new species of Splendid Ghost Moths (Lepidoptera: Hepialidae: Aenetus) from Australia and Papua New Guinea
Authors: BEAVER ETHAN P. , MOORE MICHAEL D. , GREHAN JOHN R. , VELASCO-CASTRILLÓN ALEJANDRO , STEVENS MARK I.
Published: July 2020

Four new Aenetus Herrich-Schäffer species are described from northern Australasia; Aenetus simonseni sp. nov. from the top-end of the Northern Territory, Australia, A. maiasinus sp. nov. from the Kimberley region of Western Australia, A. trigonogrammus sp. nov. from south-eastern Queensland, Australia, and A. albadamanteum sp. nov. from eastern Papua New Guinea. Aenetus simonseni sp. nov. and A. maiasinus sp. nov. appear to belong to the tegulatus-group of species (sensu Grehan et al. 2018), A. trigonogrammus sp. nov. is part of the splendens-group of species (sensu Simonsen 2018), while A. albadamanteum sp. nov. shares morphological similarities with A. hampsoni (Joicey & Noakes, 1914), A. crameri Viette, 1956, and A. toxopeusi Viette, 1956, from New Guinea, and A. cohici Viette, 1961 from New Caledonia. The four new species are illustrated and compared with superficially similar species in morphology and, for two species, molecular (mtDNA COI gene) sequences.
New records of brittle stars (Echinodermata: Ophiuroidea) from the Lakshadweep atolls, northern Indian Ocean, with notes on Indophioderma ganapatii Sastry, Marimuthu & Rajan, 2019
Authors: PARAMESWARAN USHA V. , MOHAMMED NOWSHAD B. , DIXIT SUDHANSHU , MANJEBRAYAKATH HASHIM , IDREESBABU K.K. , SARAVANANE N.
Published: July 2020

The paper presents three new records of brittle stars for Indian waters, collected from the Lakshadweep atolls (northern Indian Ocean)—Ophiarachnella septemspinosa (Müller & Troschel, 1842), Ophiocoma cynthiae Benavides-Serrato & O’Hara, 2008 & Ophiomoeris obstricta (Lyman, 1878). Further, this paper also discusses the validity of two recently described taxa from this archipelago, the genus Indophioderma with the species Indophioderma ganapatii Sastry, Marimuthu & Rajan, 2019. A checklist of brittle stars reported so far from the Lakshadweep Islands is provided, which includes 40 valid species—32 from shallow (reef) areas and 8 deep-sea (>200m) species.
A hybrid dual-mode trust management scheme for vehicular networks
Authors: Rai Ibrahim Abdo , Shaikh Riaz Ahmed , Hassan Syed Raheel
Published: July 2020

Vehicular ad-hoc networks allow vehicles to exchange messages pertaining to safety and road efficiency. Building trust between nodes can, therefore, protect vehicular ad-hoc networks from malicious nodes and eliminate fake messages. Although there are several trust models already exist, many schemes suffer from varied limitations. For example, many schemes rely on information provided by other peers or central authorities, for example, roadside units and reputation management centers to ensure message reliability and build nodes’ reputation. Also, none of the proposed schemes operate in different environments, for example, urban and rural. To overcome these limitations, we propose a novel trust management scheme for self-organized vehicular ad-hoc networks. The scheme is based on a crediting technique and does not rely on other peers or central authorities which distinguishes it as an economical solution. Moreover, it is hybrid, in the sense it is data-based and entity-based which makes it capable of revoking malicious nodes and discarding fake messages. Furthermore, it operates in a dual-mode (urban and rural). The simulation has been performed utilizing Veins, an open-source framework along with OMNeT++, a network simulator, and SUMO, a traffic simulator. The scheme has been tested with two trust models (urban and rural). The simulation results prove the performance and security efficacy of the proposed scheme.
Nebuliser hygiene in cystic fibrosis: evidence-based recommendations
Authors: Bell Jane , Alexander Lauren , Carson Jane , Crossan Amanda , McCaughan John , Mills Hazel , O'Neill Damian , Moore John E. , Millar B. Cherie
Published: July 2020

Nebulised therapies are extensively used in the daily therapeutic management of cystic fibrosis both for mucociliary clearance and for the management of chronic infections. Extensive developments have been made in relation to nebulised drug delivery mechanisms and drug formulations, and guidelines have been prepared that have addressed the appropriate use of such therapies. However, due to these developments, a plethora of nebuliser devices and drug chambers exist, and frequently, the limited guidance provided in relation to nebuliser hygiene is to follow manufacturers' instructions. Such instructions are inconsistent and at times confusing, translating to an increase in the burden associated with nebuliser maintenance. An evidence-based universal guideline relating to nebuliser care and hygiene is urgently required that is applicable to both at-home use and inpatient use. This article reviews the scientific literature in order to propose an evidence-based approach to nebuliser hygiene to ensure optimum drug delivery, and infection prevention and control.

Educational aims

To understand the reasons why nebuliser hygiene is important.

To give an overview of the current nebuliser care instructions that have been described by manufacturers, societies and the scientific literature.

To outline the current nebuliser hygiene practices used by persons with cystic fibrosis in the home and hospital settings.

To highlight areas that need further evaluation to promote optimum nebuliser care.

To establish an evidence-based guideline for nebuliser hygiene in relation to cystic fibrosis.
The Establishment and Application Studies on Precise Lysosome pH Indicator Based on Self-Decomposable Nanoparticles
Authors: Pang Cui , Song Chaojun , Li Yize , Wang Qiaofeng , Zhu Xiaosheng , Wu Jianwei , Tian Yi , Fan Hao , Hu Jinwei , Li Chen , Wang Baolong , Li Xiaoye , Liu Wenchao , Fan Li
Published: July 2020

Acidic pH of lysosomes is closely related to autophagy; thus, well known of the precise lysosomes, pH changes will give more information on the autophagy process and status. So far, however, only pH changes in a relatively broad range could be indicated, the exact lysosomes pH detection has never arrived. In our study, we established an endo/lysosome pH indicator based on the self-decomposable SiO2 nanoparticle system with specific synthesis parameters. The central concentrated methylene blue (MB) in the central-hollow structural nanoparticles presented sensitive release as a function of pH values from pH 4.0–4.8, which is exactly the pH range of lysosomes. The linear correlation of the optical density (OD) values and the pH values has been built up, which has been used for the detection of lysosomes pH in 6 different cell lines. Moreover, by this system, we succeeded in precisely detecting the pH average changes of lysosomes before and after black mesoporous silicon (BPSi) NP endocytosis, clarifying the mechanism of the autophagy termination after BPSi endocytosis. So, the self-decomposable nanoparticle-based luminal pH indicator may provide a new methodology and strategy to know better of the lysosome pH, then indicate more details on the autophagy process or other important signaling about metabolisms.
HEnRY: a DZIF LIMS tool for the collection and documentation of biomaterials in multicentre studies
Authors: Heinen Stephanie , Schulze Nick , Franke Bernd , Klein Florian , Lehmann Clara , Vehreschild Maria J. G. T. , Gloistein Claas , Stecher Melanie , Vehreschild Jörg Janne
Published: July 2020

Background

Well-characterized biomaterials of high quality have great potential for acceleration and quality improvement in translational biomedical research. To improve accessibility of local sample collections, efforts have been made to create central biomaterial banks and catalogues. Available technical solutions for creating professional local sample catalogues and connecting them to central systems are cost intensive and/or technically complex to implement. Therefore, the Translational Thematic Unit HIV of the German Center for Infection Research (DZIF) developed a Laboratory Information and Management System (LIMS) called HIV Engaged Research Technology (HEnRY) for implementation into the Translational Platform HIV (TP-HIV) at the DZIF and other research networks.

Results

HEnRY is developed at the University Hospital of Cologne. It is an advanced LIMS to manage processing and storage of samples and aliquots of different sample types. Features include:

monitoring of stored samples and associated information

data selection via query tools or Structured Query Language (SQL)

preparation of summary documents, including scannable search lists

centralized management of the practical laboratory part of multicentre studies (e.g. import of drawing schemes and sample processing steps),

preparation of aliquot shipments, including associated documents to be added to shipments

unique and secure identification of aliquots through use of customizable Quick Response (QR) code labels directly from HEnRY

support of aliquot data transmission to central registries.

In summary, HEnRY offers all features necessary for a LIMS software. In addition, the structure of HEnRY provides sufficient flexibility to allow the implementation in other research areas.

Conclusion

HEnRY is a free biobanking tool published under the MIT license. While it was developed to support HIV research in Germany, the feature set and language options, allow much broader applications and make this a powerful free research tool.
Critique of the pairwise method for estimating qPCR amplification efficiency: beware of correlated data!
Authors: Tellinghuisen Joel
Published: July 2020

Background

A recently proposed method for estimating qPCR amplification efficiency E analyzes fluorescence intensity ratios from pairs of points deemed to lie in the exponential growth region on the amplification curves for all reactions in a dilution series. This method suffers from a serious problem: The resulting ratios are highly correlated, as they involve multiple use of the raw data, for example, yielding ~ 250 E estimates from ~ 25 intensity readings. The resulting statistics for such estimates are falsely optimistic in their assessment of the estimation precision.

Results

Monte Carlo simulations confirm that the correlated pairs method yields precision estimates that are better than actual by a factor of two or more. This result is further supported by estimating E by both pairwise and Cq calibration methods for the 16 replicate datasets from the critiqued work, and then comparing the ensemble statistics for these methods.

Conclusion

Contrary to assertions in the proposing work, the pairwise method does not yield E estimates a factor of 2 more precise than estimates from Cq calibration fitting (the standard curve method). On the other hand, the statistically correct direct fit of the data to the model behind the pairwise method can yield E estimates of comparable precision. Ways in which the approach might be improved are discussed briefly.
Molecular docking and machine learning analysis of Abemaciclib in colon cancer
Authors: Liñares-Blanco Jose , Munteanu Cristian R. , Pazos Alejandro , Fernandez-Lozano Carlos
Published: July 2020

Background

The main challenge in cancer research is the identification of different omic variables that present a prognostic value and personalised diagnosis for each tumour. The fact that the diagnosis is personalised opens the doors to the design and discovery of new specific treatments for each patient. In this context, this work offers new ways to reuse existing databases and work to create added value in research. Three published signatures with significante prognostic value in Colon Adenocarcinoma (COAD) were indentified. These signatures were combined in a new meta-signature and validated with main Machine Learning (ML) and conventional statistical techniques. In addition, a drug repurposing experiment was carried out through Molecular Docking (MD) methodology in order to identify new potential treatments in COAD.

Results

The prognostic potential of the signature was validated by means of ML algorithms and differential gene expression analysis. The results obtained supported the possibility that this meta-signature could harbor genes of interest for the prognosis and treatment of COAD. We studied drug repurposing following a molecular docking (MD) analysis, where the different protein data bank (PDB) structures of the genes of the meta-signature (in total 155) were confronted with 81 anti-cancer drugs approved by the FDA. We observed four interactions of interest: GLTP - Nilotinib, PTPRN - Venetoclax, VEGFA - Venetoclax and FABP6 - Abemaciclib. The FABP6 gene and its role within different metabolic pathways were studied in tumour and normal tissue and we observed the capability of the FABP6 gene to be a therapeutic target. Our in silico results showed a significant specificity of the union of the protein products of the FABP6 gene as well as the known action of Abemaciclib as an inhibitor of the CDK4/6 protein and therefore, of the cell cycle.

Conclusions

The results of our ML and differential expression experiments have first shown the FABP6 gene as a possible new cancer biomarker due to its specificity in colonic tumour tissue and no expression in healthy adjacent tissue. Next, the MD analysis showed that the drug Abemaciclib characteristic affinity for the different protein structures of the FABP6 gene. Therefore, in silico experiments have shown a new opportunity that should be validated experimentally, thus helping to reduce the cost and speed of drug screening. For these reasons, we propose the validation of the drug Abemaciclib for the treatment of colon cancer.
Unveiling the genetic basis of Sclerotinia head rot resistance in sunflower
Authors: Filippi C. V. , Zubrzycki J. E. , Di Rienzo J. A. , Quiroz F. J. , Puebla A. F. , Alvarez D. , Maringolo C. A. , Escande A. R. , Hopp H. E. , Heinz R. A. , Paniego N. B. , Lia V. V.
Published: July 2020

Background

Sclerotinia sclerotiorum is a necrotrophic fungus that causes Sclerotinia head rot (SHR) in sunflower, with epidemics leading to severe yield losses. In this work, we present an association mapping (AM) approach to investigate the genetic basis of natural resistance to SHR in cultivated sunflower, the fourth most widely grown oilseed crop in the world.

Results

Our association mapping population (AMP), which comprises 135 inbred breeding lines (ILs), was genotyped using 27 candidate genes, a panel of 9 Simple Sequence Repeat (SSR) markers previously associated with SHR resistance via bi-parental mapping, and a set of 384 SNPs located in genes with molecular functions related to stress responses. Moreover, given the complexity of the trait, we evaluated four disease descriptors (i.e, disease incidence, disease severity, area under the disease progress curve for disease incidence, and incubation period). As a result, this work constitutes the most exhaustive AM study of disease resistance in sunflower performed to date.

Mixed linear models accounting for population structure and kinship relatedness were used for the statistical analysis of phenotype-genotype associations, allowing the identification of 13 markers associated with disease reduction. The number of favourable alleles was negatively correlated to disease incidence, disease severity and area under the disease progress curve for disease incidence, whereas it was positevily correlated to the incubation period.

Conclusions

Four of the markers identified here as associated with SHR resistance (HA1848, HaCOI_1, G33 and G34) validate previous research, while other four novel markers (SNP117, SNP136, SNP44, SNP128) were consistently associated with SHR resistance, emerging as promising candidates for marker-assisted breeding. From the germplasm point of view, the five ILs carrying the largest combination of resistance alleles provide a valuable resource for sunflower breeding programs worldwide.
Social and behavioural risk factors in the prevention and management of cardiovascular disease in Kerala, India: a catchment area population survey
Authors: Madavanakadu Devassy Saju , Webber Martin , Scaria Lorane , Amuthavalli Thiyagarajan Jotheeswaran , Fendt-Newlin Meredith , Joubert Jacques , Benny Anuja Maria , Nannatt Anjana , Joubert Lynette
Published: July 2020

Background

Cardiovascular disease (CVD) is the leading cause of mortality in India. Social and behavioural factors are strongly interrelated in the prevention and control of CVD. The ability to make lifestyle changes to control hypertension and diabetes (major risk factors for CVD) is determined by factors such as education, gender, caste, poverty, and urbanicity. This study aimed to improve our understanding of the inter-relationship of social and behavioural factors in the management of elevated serum glucose and high blood pressure and co-morbid mental health conditions.

Methods

A population-based catchment area cross sectional survey was conducted in Kerala, India. Data were collected from residents aged over 30 years (n = 997) using standardized tools and clinical measures. We performed latent class analysis incrementally to extract homogeneous latent classes of individuals based on their responses to social and behavioural risk factors in the survey. Using structural equation models, we assessed the mediating effect of depression and anxiety, and social or behavioural risk factors, on management of high blood pressure and raised serum glucose levels.

Results

The prevalence of high blood pressure and blood glucose in the sample was 33 and 26% respectively. Latent class analysis found three clusters of risk factors. One had a predominance of behavioural characteristics, another of social risk factors and the third was a low risk group. Age, female sex, and marital status had an effect on high blood pressure and high glucose, though were mediated by mental health, social and behavioural risk factors.

Conclusions

Interventions to improve the management of risk factors for CVD need to address social risk factors and be sensitive to the needs of population sub-groups that may require additional support to access health services. An integration of social and health services may be required to achieve this.
Open necrosectomy combined with continuous positive drainage and prophylactic diverting loop ileostomy for late infected pancreatic necrosis: a retrospective cohort study
Authors: Niu Dong-Guang , Li Wei-Qin , Huang Qian , Yang Fan , Tian Wei-Liang , Li Chen , Ding Lian-An , Fang Hong-Chun , Zhao Yun-Zhao
Published: July 2020

Background

To evaluate an innovative open necrosectomy strategy with continuous positive drainage and prophylactic diverting loop ileostomy for the management of late infected pancreatic necrosis (LIPN).

Methods

Consecutive patients were divided into open necrosectomy (ON) group (n = 23), open necrosectomy with colonic segment resection (ON+CSR) group (n = 8) and open necrosectomy with prophylactic diverting loop ileostomy (ON+PDLI) group (n = 11). Continuous positive drainage (CPD) via double-lumen irrigation–suction tube (DLIST) was performed in ON+PDLI group. The primary endpoints were duration of organ failure after surgery, postoperative complication, the rate of re-surgery and mortality. The secondary endpoints were duration of hospitalization, cost, time interval between open surgery and total enteral nutrition (TEN).

Results

The recovery time of organ function in ON+PDLI group was shorter than that in other two groups. Colonic complications occurred in 13 patients (56.5%) in the ON group and 3 patients (27.3%) in the ON+PDLI group (p = 0.11). The length of stay in the ON+PDLI group was shorter than the ON group (p = 0.001). The hospitalization cost in the ON+PDLI group was less than the ON group (p = 0.0052).

Conclusion

ON+PDLI can avoid the intestinal dysfunction, re-ileostomy, the resection of innocent colon and reduce the intraoperative trauma. Despite being of colonic complications before or during operation, CPD + PDLI may show superior effectiveness, safety, and convenience in LIPN.
Measuring vaccine effectiveness against persistent HPV infections: a comparison of different statistical approaches
Authors: Donken R. , Hoes J. , Knol M. J. , Ogilvie G. S. , Dobson S. , King A. J. , Singer J. , Woestenberg P. J. , Bogaards J. A. , Meijer C. J. L. M. , de Melker H. E.
Published: July 2020

Background

Persistent high-risk human papillomavirus (HPV) infection is endorsed by the World Health Organization as an intermediate endpoint for evaluating HPV vaccine effectiveness/efficacy. There are different approaches to estimate the vaccine effectiveness/efficacy against persistent HPV infections.

Methods

We performed a systematic literature search in Pubmed to identify statistical approaches that have been used to estimate the vaccine effectiveness/efficacy against persistent HPV infections. We applied these methods to data of a longitudinal observational study to assess their performance and compare the obtained vaccine effectiveness (VE) estimates.

Results

Our literature search identified four approaches: the conditional exact test for comparing two independent Poisson rates using a binomial distribution, Generalized Estimating Equations for Poisson regression, Prentice Williams and Peterson total time (PWP-TT) and Cox proportional hazards regression. These approaches differ regarding underlying assumptions and provide different effect measures. However, they provided similar effectiveness estimates against HPV16/18 and HPV31/33/45 persistent infections in a cohort of young women eligible for routine HPV vaccination (range VE 93.7–95.1% and 60.4–67.7%, respectively) and seemed robust to violations of underlying assumptions.

Conclusions

As the rate of subsequent infections increased in our observational cohort, we recommend PWP-TT as the optimal approach to estimate the vaccine effectiveness against persistent HPV infections in young women. Confirmation of our findings should be undertaken by applying these methods after longer follow-up in our study, as well as in different populations.
Epidemiological characteristics of pulmonary tuberculosis among health-care workers in Henan, China from 2010 to 2017
Authors: Wang Guojie , Xu Jiying , Huang Bin , Gao Sanyou , Zhuang Yan , Wang Kan , Zhang Yanqiu , Jiang Jianguo
Published: July 2020

Background

Health-care workers (HCWs) are an epidemiological group with increased exposure to tuberculosis (TB), especially at health-care facilities (HCFs) with poor TB infection control in high-TB-burden settings. China is a high-TB-burden country, and the comprehensive measures for stopping TB transmission at some HCFs were not implemented well owing to limited resources and other factors. The purpose of this study was to review risk of occupational exposure to TB among HCWs and its change trend, and identify epidemiological characteristics of pulmonary tuberculosis (PTB) among HCWs in Henan, central part of China.

Methods

A retrospective cohort study was conducted from 2010 to 2017. All HCWs and teachers in Henan were enrolled to the study as exposed group and non-exposed control group, respectively. Relative risk (RR), attributable risk (AR) and AR percent (AR%) were used to measure the association between the occupational exposure and PTB, and estimated with Poisson regression.

Results

The study results showed a total of 1663 cases of PTB were reported among the HCWs in Henan, accounting for 3.2‰ of all PTB cases reported in the whole population, and annual incidence rate of PTB among HCWs declined by 34% from 2010 to 2017. Over the eight years, the incidence rate of PTB among HCWs was 43.7 cases per 100,000 person-years (PYs), significantly higher than that among teachers (18.8 cases/100,000 PYs), and RR, AR and AR% were estimated to 2.3, 24.9 cases per 100,000 PYs and 57%, respectively. Among HCWs, males were more likely to suffer from PTB than females (adjusted RR: 1.3; 95%CI: 1.2–1.4), and HCWs aged under 25 years had the highest relative risk over all age groups with adjusted RR equaling to 8.3 (95%CI: 6.9-9.9) calculated with those aged 45–54 years as the reference.

Conclusions

Although overall incidence rate of PTB among HCWs showed decreasing temporal trends over the period of 2010–2017, attributable risk of occupational exposure to TB among HCWs did not decrease in Henan, and TB infection at HCFs for males, young or senior HCWs, especially for young HCWs is of much concern.
Prevalence of HBV and HCV infections, Bhutan, 2017: Progress and next steps
Authors: Tshering N. , Dhakal G. P. , Wangchuk U. , Wangdi S. , Khandu L. , Pelden S. , Nogareda F. , Patel M. K. , Hutin Y. J. F. , Wannemuehler K. , Rewari B. B. , Wangchuk S.
Published: July 2020

Background

Bhutan is committed to eliminating hepatitis B and hepatitis C, though recent baseline estimates of disease burden in the general population are unknown. In 2017, we carried out a biomarker survey in the general population to estimate the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) biomarkers to evaluate the impact of immunization and guide further efforts.

Methods

In 2017, a cross-sectional, population-based, three-stage cluster survey was undertaken of the general population (1–17 and 20+ years of age). We visited households, collected blood specimens and administered a standard questionnaire. Specimens were collected for hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) testing. We calculated prevalence of infection and selected characteristics, along with confidence intervals (CIs).

Results

Of 1372 individuals approached, 1358 (99%) participated. Of those, 1321 (97%) had a specimen tested for HBsAg, and among 1173 enrolled individuals 5 years of age or older, 1150 (98%) individuals were tested for anti-HCV. The prevalence of HBsAg was 2.0% in 775 persons 20 years of age or older (95% CI: 1.0–4.0) and 0.5% in 546 persons 1–17 years of age (95% CI: 0.1–1.8). The prevalence of anti-HCV was 0.3% (95% CI: 0.1–0.8) among persons ≥5 years.

Conclusions

Universal hepatitis B immunization of infants has resulted in a low prevalence of chronic HBV infection in persons 1–17 years of age and the prevalence of anti-HCV is low among persons aged ≥5 years. Efforts should continue to reach high coverage of the timely birth dose along with completion of the hepatitis B vaccine series. To reduce the chronic liver disease burden among adults, HBV and HCV testing and treatment as indicated might be restricted to pregnant women, blood donors, individuals with chronic liver diseases, and other groups with history of high-risk exposures.