bluuebunny/crossref_metadata_2025 huggingface dataset:
Drugging the “Undruggable” MYCN Oncogenic Transcription Factor: Overcoming Previous Obstacles to Impact Childhood Cancers
Authors: Wolpaw Adam J. , Bayliss Richard , Büchel Gabriele , Dang Chi V. , Eilers Martin , Gustafson W. Clay , Hansen Gwenn H. , Jura Natalia , Knapp Stefan , Lemmon Mark A. , Levens David , Maris John M. , Marmorstein Ronen , Metallo Steven J. , Park Julie R. , Penn Linda Z. , Rape Michael , Roussel Martine F. , Shokat Kevan M. , Tansey William P. , Verba Kliment A. , Vos Seychelle M. , Weiss William A. , Wolf Elmar , Mossé Yaël P.
Published: January 2021

Effective treatment of pediatric solid tumors has been hampered by the predominance of currently “undruggable” driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein–protein or protein–DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this “undruggable” transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.
A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer
Authors: Nounu Aayah , Greenhough Alexander , Heesom Kate J. , Richmond Rebecca C. , Zheng Jie , Weinstein Stephanie J. , Albanes Demetrius , Baron John A. , Hopper John L. , Figueiredo Jane C. , Newcomb Polly A. , Lindor Noralane M. , Casey Graham , Platz Elizabeth A. , Le Marchand Loïc , Ulrich Cornelia M. , Li Christopher I. , van Duijnhoven Fränzel J.B. , Gsur Andrea , Campbell Peter T. , Moreno Víctor , Vodicka Pavel , Vodickova Ludmila , Brenner Hermann , Chang-Claude Jenny , Hoffmeister Michael , Sakoda Lori C. , Slattery Martha L. , Schoen Robert E. , Gunter Marc J. , Castellví-Bel Sergi , Kim Hyeong Rok , Kweon Sun-Seog , Chan Andrew T. , Li Li , Zheng Wei , Bishop D. Timothy , Buchanan Daniel D. , Giles Graham G. , Gruber Stephen B. , Rennert Gad , Stadler Zsofia K. , Harrison Tabitha A. , Lin Yi , Keku Temitope O. , Woods Michael O. , Schafmayer Clemens , Van Guelpen Bethany , Gallinger Steven , Hampel Heather , Berndt Sonja I. , Pharoah Paul D.P. , Lindblom Annika , Wolk Alicja , Wu Anna H. , White Emily , Peters Ulrike , Drew David A. , Scherer Dominique , Bermejo Justo Lorenzo , Williams Ann C. , Relton Caroline L.
Published: January 2021

Background:

Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods:

Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL (N = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium (N = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results:

Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03–1.13; OR: 3.33, 95% CI, 2.46–4.50; and OR: 1.15, 95% CI, 1.02–1.29, respectively).

Conclusions:

MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact:

Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
Hysterectomy, Oophorectomy, and Risk of Renal Cell Carcinoma
Authors: Luo Juhua , Rohan Thomas E. , Neuhouser Marian L. , Liu Nianjun , Saquib Nazmus , Li Yueyao , Shadyab Aladdin H. , Qi Lihong , Wallace Robert B. , Hendryx Michael
Published: January 2021

Background:

Female hormones may play roles during renal cell carcinoma (RCC) carcinogenesis. The aims of this study were to investigate associations between hysterectomy, oophorectomy, and risk of RCC and to assess whether the associations were modified by exogenous estrogen, commonly used among women who have undergone hysterectomy.

Methods:

Postmenopausal women (n = 144,599) ages 50–79 years at enrollment (1993–1998) in the Women's Health Initiative were followed for a mean of 15.9 years. Hysterectomy and oophorectomy were self-reported. Incident RCC cases were confirmed by physician review of medical records and pathology reports. Multivariable Cox proportional hazards modeling was used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for potential confounders.

Results:

A total of 583 women developed RCC during follow-up. We observed that hysterectomy, regardless of oophorectomy status, was significantly associated with an increased risk of RCC (HR, 1.28; 95% CI, 1.03–1.60). The association appeared to be more pronounced in women with age at hysterectomy younger than 40 years (HR, 1.34; 95% CI, 1.01–1.80) or older than 55 years (HR, 1.52; 95% CI, 1.01–2.29). Oophorectomy was not significantly associated with risk of RCC. There was no evidence that exogenous estrogen use modified the association between hysterectomy and risk of RCC.

Conclusions:

In this large prospective study, we showed that women with a history of hysterectomy had 28% increased risk of RCC, and this finding was not modified by exogenous hormone use.

Impact:

If our findings are confirmed, women should be made aware of increased risk of RCC when considering hysterectomy.
Therapeutic Implications of Detecting MAPK-Activating Alterations in Cutaneous and Unknown Primary Melanomas
Authors: Shoushtari Alexander N. , Chatila Walid K. , Arora Arshi , Sanchez-Vega Francisco , Kantheti Havish S. , Rojas Zamalloa Jorge A. , Krieger Penina , Callahan Margaret K. , Betof Warner Allison , Postow Michael A. , Momtaz Parisa , Nair Suresh , Ariyan Charlotte E. , Barker Christopher A. , Brady Mary Susan , Coit Daniel G. , Rosen Neal , Chapman Paul B. , Busam Klaus J. , Solit David B. , Panageas Katherine S. , Wolchok Jedd D. , Schultz Nikolaus
Published: January 2021

Purpose:

Cutaneous and unknown primary melanomas frequently harbor alterations that activate the MAPK pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown.

Experimental Design:

Patients with melanoma were prospectively offered tumor sequencing of 341–468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure (TTF) was determined for patients who received first-line programmed cell death protein 1 (PD-1) monotherapy, nivolumab plus ipilimumab, or subsequent genomically matched targeted therapies. A Cox proportional hazards model was constructed for TTF using driver group and clinical variables.

Results:

A total of 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had ≥1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N = 181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22, and not reached; P < 0.0001). Driver group remained significant, independent of tumor mutational burden and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N = 141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and eight (30%) derived clinical benefit lasting ≥6 months.

Conclusions:

Targeted capture multigene sequencing can detect oncogenic RTK-RAS-MAPK pathway alterations in almost all cutaneous and unknown primary melanomas. TTF of PD-1 monotherapy varies by mechanism of ERK activation. Oncogenic kinase fusions can be successfully targeted in immune checkpoint inhibitor–refractory melanoma.
Targeting BET Proteins BRD2 and BRD3 in Combination with PI3K-AKT Inhibition as a Therapeutic Strategy for Ovarian Clear Cell Carcinoma
Authors: Shigeta Shogo , Lui Goldie Y.L. , Shaw Reid , Moser Russell , Gurley Kay E. , Durenberger Grace , Rosati Rachele , Diaz Robert L. , Ince Tan A. , Swisher Elizabeth M. , Grandori Carla , Kemp Christopher J.
Published: January 2021

Ovarian clear cell carcinoma (OCCC) is a rare, chemo-resistant subtype of ovarian cancer. To identify novel therapeutic targets and combination therapies for OCCC, we subjected a set of patient-derived ovarian cancer cell lines to arrayed high-throughput siRNA and drug screening. The results indicated OCCC cells are vulnerable to knockdown of epigenetic gene targets such as bromodomain and extra-terminal domain (BET) proteins BRD2 and BRD3. Subsequent RNA interference assays, as well as BET inhibitor treatments, validated these BET proteins as potential therapeutic targets. Because development of resistance to single targeted agents is common, we next performed sensitizer drug screens to identify potential combination therapies with the BET inhibitor CPI0610. Several PI3K or AKT inhibitors were among the top drug combinations identified and subsequent work showed CPI0610 synergized with alpelisib or MK2206 by inducing p53-independent apoptosis. We further verified synergy between CPI0610 and PI3K–AKT pathway inhibitors alpelisib, MK2206, or ipatasertib in tumor organoids obtained directly from patients with OCCC. These findings indicate further preclinical evaluation of BET inhibitors, alone or in combination with PI3K-AKT inhibitors for OCCC, is warranted.
The Role of Forkhead Box Q1 Transcription Factor in Anticancer Effects of Withaferin A in Breast Cancer
Authors: Kim Su-Hyeong , Singh Krishna B. , Hahm Eun-Ryeong , Singh Shivendra V.
Published: January 2021

Elimination of both rapidly dividing epithelial mammary cancer cells as well as breast cancer stem-like cells (bCSC) is essential for maximizing antitumor response. Withaferin A (WA), a small molecule derived from a medicinal plant (Withania somnifera), is highly effective in reducing burden and/or incidence of breast cancer in vivo in various preclinical models. We have shown previously that suppression of breast cancer incidence by WA administration in a rat model is associated with a decrease in self-renewal of bCSC but the underlying mechanism is still elusive. This study investigated the role of forkhead box Q1 (FoxQ1) transcription factor in antitumor responses to WA. Exposure of MDA-MB-231 and SUM159 cells to WA resulted in downregulation of protein and mRNA levels of FoxQ1 as well as inhibition of its transcriptional activity. FoxQ1 overexpression in SUM159 and MCF-7 cells resulted in a marked protection against WA-mediated inhibition of bCSC as judged by flow cytometric analysis of CD49fhigh population and mammosphere assay. RNA-sequencing analysis revealed upregulation of many bCSC-associated genes by FoxQ1 overexpression in SUM159 cells, including IL8 whose expression was decreased by WA treatment in SUM159 and MCF-7 cells. FoxQ1 was recruited to the promoter of IL8 that was inhibited significantly by WA treatment. On the other hand, WA-mediated inhibition of cell proliferation or migration was not affected by FoxQ1 overexpression. The FoxQ1 overexpression partially attenuated WA-mediated G2–M phase cell cycle arrest in SUM159 cells only. These results indicate that FoxQ1 is a target of WA for inhibition of bCSC fraction.

Prevention Relevance:

Withaferin A (WA) is highly effective in reducing burden and/or incidence of breast cancer in various preclinical models. However, the mechanism underlying breast cancer prevention by WA is not fully understood. This study shows a role for FoxQ1 in antitumor response to WA.
Acute Generalized Exanthematous Pustulosis with Multiple Organ Failure
Authors: Syed Tausif , Abdullah Abdullah Sayied , Mubasher Mahmood , Yousaf Zohaib , Mohamed Mouhand F.H. , Alweis Richard
Published: January 2021

Acute generalized exanthematous pustulosis (AGEP) is a rare, self-limiting condition. It presents with sterile skin pustules. We present a middle-aged lady with fluid nonresponsive circulatory shock and multiple organ dysfunction secondary to AGEP.
Local Regulation of Adrenal Steroidogenesis: Subtle in vitro Effects of IL-1β on the Human Cell Line NCI-H295R Steroid Production along with Changes in MicroRNA Profile and Orphan Nuclear Receptors NR4As
Authors: Santucci Natalia , Stampone Rocío , Brandão Ferreira da Silva Eduardo , Villar Silvina , Spinelli Silvana , Linhares-Lacerda Leandra , Ribeiro-Alves Marcelo , Bay María Luisa , Bottasso Oscar
Published: January 2021

Introduction: IL-1β, a cytokine from the innate immune response, is well known for its proinflammatory effects and stimulating activity on the hypothalamus-pituitary-adrenal axis, leading to the pituitary synthesis of adrenocorticotropic hormone followed by cortisol (and dehydroepiandrosterone – DHEA) release by the adrenal gland. While IL-1β modulates the adrenal steroidogenesis at the central level, it is unclear whether it also exerts an effect on the adrenal gland. Method: We studied the effect of IL-1β on adrenal steroid production and steroidogenic enzyme RNA expression in the human cell line NCI-H295R. We also explored eventual changes in the microRNA (miRNA) profile from IL-1β-treated NCI-H295R cells. Results: Transcripts encoding IL-1β receptors 1 and 2 were noticeable in the cell line, with cortisol and DHEA production showing a subtle increase after cytokine treatment. Transcripts from key enzymes in the steroidogenic pathway were analyzed, with no noticeable changes on them. The miRNA profile was modified by IL-1β treatment to an extent which bears some relationship with the regulatory mechanisms underlying adrenal steroid production. Since orphan nuclear receptors NR4As have emerged as potential key factors for coordinating inflammatory and metabolic responses, cell expression studies were also carried out to show an NR4As transcript augmentation following IL-1β treatment. Discussion/Conclusions: The subtle increase in adrenal steroid production in response to IL-1β stimulation without any modification in the transcription of the steroidogenic enzymes analyzed suggests an additional inflammatory/anti-inflammatory loop, wherein NR4As receptors may participate. Besides its physiological role, this process might be implied in pathological states accompanied by an unbalanced immune-endocrine relationship.
Predialytic versus Intradialytic Nutrition: A Study to Assess Effects on Intradialytic Blood Pressure, Dialysis Adequacy, and Urea Removal
Authors: Rao Namrata S. , Chandra Abhilash , Saran Sai , Kulshreshta Manish Raj , Mishra Prabhakar , Tiwari Poonam
Published: January 2021

Background: Provision of oral protein in hemodialysis (HD) is desirable due to improved compliance to protein requirements and better nutritional status, but the risks of hypotension and underdialysis need to be considered. This study compared 2 different timings for administering oral nutritional supplements (ONS), predialysis and mid-dialysis, with respect to hemodynamics, dialysis adequacy, urea removal, and tolerability. Methods: This single-center, prospective crossover study analyzed 72 stable patients with ESRD on twice a week maintenance HD with a mean age of 38.7 (±11.2) years and a dialysis vintage of 28.2 (±13.1) months. In the first week, all the patients received ONS (450 kcal energy, 20 g protein) 1 h prior to start of dialysis (group 1) and in the next week, the supplement was administered after 2 h of start of dialysis (group 2), with a predialysis fasting period of at least 3 h in both groups. Blood pressures, serum, and spent dialysate samples were collected and nausea occurrence was noted by severity. Results: Predialytic intake (group 1) was associated with higher predialysis and 1st hour blood urea, dialysis adequacy, and urea removal than group 2. Both groups achieved mean Kt/V > 1.2, and the occurrence of symptomatic hypotensive episodes and nausea was not significantly different between the groups. On repeated measures ANOVA, changes in blood urea over time showed significant group effect. Conclusions: Predialytic supplementation was associated with better dialysis adequacy and urea removal than intradialytic supplementation. However, both timings were equally tolerated and not associated with underdialysis.
Medullary Blood Oxygen Level-Dependent MRI Index (R2*) is Associated with Annual Loss of Kidney Function in Moderate CKD
Authors: Li Lu-Ping , Thacker Jon M. , Li Wei , Hack Bradley , Wang Chi , Kohn Orly , Sprague Stuart M. , Prasad Pottumarthi V.
Published: January 2021

Background: The estimated glomerular filtration rate (eGFR) is frequently used to monitor progression of kidney disease. Multiple values have to be obtained, sometimes over years to determine the rate of decline in kidney function. Recent data suggest that functional MRI (fMRI) methods may be able to predict loss of eGFR. In a prior study, baseline data with multi-parametric MRI in individuals with diabetes and moderate CKD was reported. This report extends our prior observations in order to evaluate the temporal variability of the fMRI measurements over 36 months and their association with annual change in eGFR. Methods: Twenty-four subjects with moderate CKD completed 3 sets of MRI scans over a 36-month period. Blood oxygenation level-dependent (BOLD), arterial spin labeling perfusion, and diffusion MRI images were acquired using a 3 T scanner. Coefficients of variation was used to evaluate variability between subjects at each time point and temporal variability within each subject. We have conducted mixed effects models to examine the trajectory change in GFR over time using time and MRI variables as fixed effects and baseline intercept as random effect. Associations of MRI image markers with annual change in eGFR were evaluated. Results: Multi-parametric functional renal MRI techniques in individuals with moderate CKD showed higher temporal variability in R2* of medulla compared to healthy individuals. This was consistent with the significant lower R2* in medulla observed at 36 months compared to baseline values. The results of linear mixed model showing that R2*_Medulla was the only predictor associated with change in eGFR over time. Furthermore, a significant association of medullary R2* with annual loss of eGFR was observed at all the 3 time points. Conclusions: The lower R2* values and the higher temporal variability in the renal medulla over time suggest the ability to monitor progressive CKD. These were confirmed by the fact that reduced medullary R2* was associated with higher annual loss in eGFR. These data collectively emphasize the need for inclusion of medulla in the analysis of renal BOLD MRI studies.
The Challenges in the Follow-Up and Treatment of Brazilian Children with Hereditary Angioedema
Authors: Araújo-Simões Joanna , Boanova Aline Gisele Pena , Constantino-Silva Rosemeire Navickas , Fragnan Nyla Thyara Melo Lobão , Pinto Jorge Andrade , Minafra Fernanda G. , Gonçalves Rozana Fátima , Valle Solange Rodrigues do , Alonso Maria Luiza Oliva , Dortas Sergio Duarte , Goudouris Ekaterine Simões , Rêgo-Silva Almerinda Maria , Marques Mayara Madruga , Serpa Faradiba S. , Chong-Neto Herberto Jose , Nelson Rosario Filho , Mansour Eli , Moreira Iramirton Figuerêdo , Moreno Adriana S. , Arruda Luisa Karla , Roxo Junior Pérsio , Ferriani Mariana Paes Leme , Silva Jane , Ferreira Janaira Fernandes Severo , Giavina-Bianchi Pedro , Takejima Priscila M. , Ensina Luis Felipe , Campos Regis de Albuquerque , Toledo Eliana , Pesquero João Bosco , Palma Sandra Mitie Ueda , Veronez Camila Lopes , Grumach Anete Sevciovic
Published: January 2021

Introduction: Hereditary angioedema (HAE) with C1 inhibitor (C1-INH) deficiency is a rare autosomal dominant disease. Although the first symptoms can appear in childhood, the diagnosis’s delay has a strong impact on the patient’s quality of life. We analyzed clinical and laboratory characteristics and the drug therapy of pediatric patients with HAE in Brazil. Methods: Medical records from 18 reference centers of HAE patients under 18 years of age were evaluated after confirmed diagnosis was performed by quantitative and/or functional C1-INH. Results: A total of 95 participants (51 M:44 F; mean age: 7 years old) out of 17 centers were included; 15 asymptomatic cases were identified through family history and genetic screening. Angioedema attacks affected the extremities (73.5%), gastrointestinal tract (57%), face (50%), lips (42.5%), eyelids (23.7%), genitals (23.7%), upper airways (10%), and tongue (6.3%). Family history was present in 84% of patients, and the mean delay in the diagnosis was 3.9 years. Long-term prophylaxis (51/80) was performed with tranexamic acid (39/80) and androgens (13/80); and short-term prophylaxis (9/80) was performed with tranexamic acid (6/80) and danazol (3/80). On-demand therapy (35/80) was prescribed: icatibant in 7/35, fresh frozen plasma in 16/35, C1-INH plasma-derived in 11/35, and tranexamic acid in 12/35 patients. Conclusions: This is the first study on HAE pediatric patients in Latin America. Clinical manifestations were similar to adults. Drugs such as androgens and tranexamic acid were indicated off-label, probably due to restricted access to specific drugs. Educational programs should address pediatricians to reduce late diagnosis and tailored child therapy.
Arterial Intimal Fibrosis in Reperfusion Biopsy Correlates with Graft Function after Kidney Transplant
Authors: Perez-Gutierrez Angelica , Danz David , Chang Anthony , Sekar Preethi , Cummings Richard , Bachul Piotr J. , Becker Yolanda , Fung John
Published: January 2021

Introduction: Alterations to the procurement biopsy are one of the main reasons that kidneys are not suitable for transplant and are discarded. The literature on procurement and reperfusion biopsy is inconsistent and heterogeneous. The objective of this study is to describe the correlation of the different histological characteristics detected by the procurement and reperfusion biopsies in relation to graft function. Methods: This is a retrospective cohort study of deceased donor kidney transplants performed from 2013 to 2017. All of the different histological components of procurement and reperfusion biopsies were analyzed with nonparametric tests and multivariate regressions. Graft function was expressed as glomerular filtration rate (GFR) at 1, 3, 6, and 12 months after transplant. All tests were based on a level of significance of α = 0.05. Results: A comparison of procurement and reperfusion biopsies revealed that 60.4% of the grafts exhibited more arterial intimal fibrosis and 55.6% more arteriolar hyalinosis in the reperfusion biopsy than in the procurement biopsy. Arterial intimal fibrosis in reperfusion biopsy correlated with GFR at all time points, and it was the only histological characteristic of the reperfusion biopsy that remained significant in multivariate analysis. Glomerulosclerosis in the procurement biopsy correlated with graft function and remained significant in multivariate analysis, but only at 6 months. Arterial intimal fibrosis in the reperfusion biopsy is significantly associated with graft function independently of clinical characteristics. Conclusion: Our study highlights the importance of arterial intimal fibrosis in predicting kidney function after transplant. Because arterial intimal fibrosis is a chronic change not related to ischemia-reperfusion injury, the differences between the 2 biopsies may be due to the biopsy technique. In order to increase the prognostic accuracy of the procurement biopsy, the technique should be improved to better evaluate the vasculature.
Efficiency of Double Plasma Molecular Absorption System on the Acute Severe Cholestatic Hepatitis
Authors: Wu Meimei , Zhang Huafeng , Huang Yandi , Wu Wei , Huang Jianrong , Yan Dong
Published: January 2021

Background: Cholestasis may lead to hepatic cirrhosis and a longer hospital stay. A part of the patients with cholestasis requires liver transplantation. However, most of the treatment efficiency of cholestatic hepatitis (CH) is not satisfactory. For the patients with severe CH after artificial liver support, there was a lack of systemic evaluation on the treatment efficiency of double plasma molecular absorption system (DPMAS) for acute severe CH. Objective: We aim to investigate the treatment efficiency of DPMAS on acute severe CH. Methods: This retrospective study involved 309 cases diagnosed with acute severe CH admitted to the First Affiliated Hospital, Zhejiang University. We compared the prognosis of patients received standard medical therapy (SMT) and SMT + DPMAS. Besides, the effects of DPMAS on total bilirubin (TBIL) and prothrombin time (PT) were investigated. Results: DPMAS could significantly reduce the requirements for liver transplantation in the CH patients. After DPMAS therapy, significant decline was noticed in the TBIL, direct bilirubin (DBIL), total bile acid, and cholesterol. The baseline ratio of neutrophil showed significant elevation in the patients received 4 or more DPMAS compared with those received less DPMAS. Conclusions: DPMAS could significantly eliminate the necessity of liver transplantation. The artificial liver support system should be conducted to bring down the bilirubin level and the ratio of cases with severe conditions. In general, DPMAS should be preferred as an artificial liver support therapy for the patients with acute severe CH.
Why Clinicians Choose Their Language Intervention Approach: An International Perspective on Intervention for Children with Developmental Language Disorder
Authors: Forsythe Rachel , Murphy Carol-Anne , Tulip Josie , Law James
Published: January 2021

Purpose: Considerable progress has been made in recent years in generating external evidence underpinning interventions for children with developmental language disorder (DLD), but less is known about the practitioner decision-making process underpinning such interventions and whether such decisions are context specific or are internationally generalizable. Methods: An online survey about clinical practice was developed by members of COST Action IS1406, an EU-funded research network, which included representation from 39 countries. The participants were 2,408 practitioners who answered questions in relation to their decision making for a specific child of their choosing with DLD. Analysis of open-ended questions was undertaken, and data were converted into codes for the purpose of quantitative analysis. Results: Although a wide range of intervention approaches and rationales were reported, the majority of responses referenced a client-centred approach. Level of functioning was used as a rationale only if a child had severe DLD. Practitioners with university level education or above were less likely to report basing intervention on client-centred factors. A number of differently named interventions with variable theoretical and empirical underpinnings were used in different countries. Conclusions: Specific client and practitioner characteristics have an impact on the intervention approaches and rationales adopted across countries. A limited number of practitioners reported use of external scientific evidence, which suggests that there should be more initiatives in basic training of practitioners and continuing professional development to encourage the uptake of scientific evidence-based practice.
Clinical Implementation of In-House Developed MR-Based Patient-Specific 3D Models of Liver Anatomy
Authors: Ivashchenko Oleksandra V. , Smit Jasper N. , Nijkamp Jasper , ter Beek Leon C. , Rijkhorst Erik-Jan , Kok Niels F.M. , Ruers Theo J.M. , Kuhlmann Koert F.D.
Published: January 2021

Knowledge of patient-specific liver anatomy is key to patient safety during major hepatobiliary surgery. Three-dimensional (3D) models of patient-specific liver anatomy based on diagnostic MRI images can provide essential vascular and biliary anatomical insight during surgery. However, a method for generating these is not yet publicly available. This paper describes how these 3D models of the liver can be generated using open source software, and then subsequently integrated into a sterile surgical environment. The most common image quality aspects that degrade the quality of the 3D models as well possible ways of eliminating these are also discussed. Per patient, a single diagnostic multiphase MRI scan with hepatospecific contrast agent was used for automated segmentation of liver contour, arterial, portal, and venous anatomy, and the biliary tree. Subsequently, lesions were delineated manually. The resulting interactive 3D model could be accessed during surgery on a sterile covered tablet. Up to now, such models have been used in 335 surgical procedures. Their use simplified the surgical treatment of patients with a high number of liver metastases and contributed to the localization of vanished lesions in cases of a radiological complete response to neoadjuvant treatment. They facilitated perioperative verification of the relationship of tumors and the surrounding vascular and biliary anatomy, and eased decision-making before and during surgery.
The Efficacy of Acupuncture Treatment for Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis
Authors: Chen Yi-Chen , Wu Li-Kung , Lee Ming-Shinn , Kung Yen-Lun
Published: January 2021

Background: This study aimed to assess the efficacy of acupuncture for treating attention deficit hyperactivity disorder (ADHD) in children and adolescents. Patients and Methods: Systematic review and meta-analysis including randomized controlled trials that compared the effects of acupuncture treatment (AT) with pharmacotherapy (methylphenidate hydrochloride, MPH) among patients with ADHD. A total of 12 electronic databases were searched from inception until February 3, 2020. The main outcomes were the effective rate and post-treatment hyperactivity scores. We also assessed the incidence of adverse events and follow-up course. Results: A total of 10 studies involving 876 patients were included in this study. The meta-analysis revealed that AT yielded a significantly higher effective rate than MPH (odds ratio 2.239, 95% CI 1.438–3.487, p < 0.001, 8 studies), and that AT can reduce the hyperactivity scores to a lesser degree than MPH (standardized mean difference = –0.882, 95% CI –1.295 to –0.469, p < 0.001, 3 studies). Two studies reported no adverse events in the AT group, while one study suggested that AT can reduce adverse drug reactions. Furthermore, 3 studies concluded that the effects of AT were maintained, even after completion of treatment. Conclusion: This study suggests that AT may be more beneficial than MPH therapy for ADHD patients. However, the evidence may be highly limited, especially considering the outcome of hyperactivity scores with the high risk of bias, very low GRADE, and small number of studies. Thus, further studies of rigorous design and high quality are needed to confirm and strengthen the results, especially in the Western part of the world. Additionally, well-designed randomized controlled trials that evaluate adverse events and include a long-term follow-up should be conducted to determine the efficacy, safety, and side effects of AT for ADHD in children and adolescents.
Complement Component 3 Is Required for Tissue Damage, Neutrophil Infiltration, and Ensuring NET Formation in Acute Pancreatitis
Authors: Linders Johan , Madhi Raed , Mörgelin Matthias , King Ben C. , Blom Anna M. , Rahman Milladur
Published: January 2021

Background: Neutrophil extracellular traps (NETs) are known to play an important role in the pathophysiology of acute pancreatitis (AP). Activation of the complement cascade has been shown to occur in AP. The aim of this study was to examine whether complement component 3 is involved in the generation of NETs in AP. Methods: AP was induced in wild-type and C3-deficient mice by retrograde infusion of taurocholate into the pancreatic duct. Blood, lung, and pancreas tissue were collected and MPO activity was determined in lung and pancreas tissue. Histological examination of the inflamed pancreas was performed. Plasma levels of CXCL2, MMP-9, IL-6, and DNA-histone complexes as well as pancreatic levels of CXCL1 and CXCL2 were determined by use of enzyme-linked immunosorbent assay. NETs were detected in the pancreas by electron microscopy. The amount of MPO and citrullinated histone 3 in neutrophils isolated from bone marrow was examined using flow cytometry. Results: In C3-deficient mice, challenge with taurocholate yielded much fewer NETs in the pancreatic tissue compared with wild-type controls. Taurocholate-induced blood levels of amylase, tissue injury, and neutrophil recruitment in the pancreas were markedly reduced in the mice lacking C3. Furthermore, MPO levels in the lung, and plasma levels of IL-6, MMP-9, and CXCL2 were significantly lower in the C3-deficient mice compared to wild-type mice after the induction of AP. In vitro studies revealed that neutrophils from C3-deficient mice had normal NET-forming ability and recombinant C3a was not capable of directly inducing NETs formation in the wild-type neutrophils. Conclusion: C3 plays an important role in the pathophysiology of AP as it is necessary for the recruitment of neutrophils into the pancreas and ensuring NETs formation. Targeting C3 could hence be a potential strategy to ameliorate local damage as well as remote organ dysfunction in AP.
Besondere Hygienemaßnahmen in der ophthalmologischen Praxis
Authors: Rohrschneider Klaus
Published: January 2021

This review focuses on best practices and recommendations for hygiene and disinfection to limit exposure and transmission of infection in outpatient glaucoma clinics during the current CO­VID-19 pandemic.
Teleology and Biology: a defense of teleological thinking in biology
Authors: Santis Marcelo Domingos de
Published: January 2021

Teleological language refers to a forward-looking discourse, and various biologists are troubled with this issue. In this paper, I will discuss the misunderstandings that both philosophers of science and biologists have made against teleology. Among these misunderstandings, I can mention its relationship to anthropomorphism (i.e., a planning agent external to the world reference) and reference to a force immanent to the organisms (“vitalism”) beyond the reach of empirical investigation. I will argue that they are misconceptions and that teleology has shifted its meaning and focus from its pre-evolutionary form. Now it is in the position that it can be used and maintained without violating the principles of modern science. Using an example of the adaptation and function debate, I will discuss how the teleological language is the best interpretation of these issues.
O anímico mecânico e o visível orgânico: a moderna abordagem do ser vivo no mecanicismo e na história natural
Authors: Perin Adriano , Benincá Erica Mastella , Teixeira Mariana Nunes
Published: January 2021

Este artigo aborda a consideração dos seres vivos pelos teóricos do mecanicismo e da história natural, com o objetivo de esclarecer os precedentes da autonomia científica posteriormente concedida à biologia. A primeira seção pondera sobre a abordagem mecanicista, quanto à sua substituição moderna da teoria animista e às suas especificações no pensamento de René Descartes (1596-1650) e Robert Boyle (1627-1691). A segunda seção toma em apreço a metodologia de observação do visível levada a cabo pelos teóricos da História natural, quanto aos elementos que possibilitaram o seu surgimento, à sua estru-tura, ao seu caráter observacional assistemático e ao seu método específico. A conclusão apresentada é a de que as abordagens de mecânica e observacional dos seres vivos nos séculos XVII e XVIII contribuíram para a posterior constituição da biologia como campo de estudo.
Clements e o conceito de clímax
Authors: Martins Tatiane Barbosa , Martins Lilian Al-Chueyr Pereira
Published: January 2021

Frederic Edward Clements (1874-1945), botânico norte-americano, deixou contribuições para a ecologia durante as quatro primeiras décadas do século XX. A ele é atribuída a proposta de conceitos como sucessão ecológica e clímax. O objetivo deste artigo é discutir sobre o percurso que levou Clements ao conceito de clímax no período compreendido entre 1904 e 1936. Além disso, esclarecer como esta contribuição foi recebida pela comunidade científica na época.  Esta pesquisa levou à conclusão de que o termo clímax, ou mesmo sua conotação, não surgiram de imediato nas publicações de Clements (1904; 1905). Eles só apareceram a partir de 1916 (Clements, 1916) e estão intimamente relacionados com outras concepções suas como associação e organismo complexo, presentes em trabalhos anteriores (Clementes, 1904; Clements, 1905).  Clements se baseou em estudos de campo e laboratório e em contribuições de outros autores. Não detectamos mudanças significativas em relação ao conceito de clímax entre 1916 e 1936. Ocorreu apenas a adição de mais detalhes e um refinamento das explicações anteriores. Quanto à recepção por parte da comunidade científica da época, pode-se dizer que as críticas foram dirigidas principalmente à restrição do clímax a aspectos climáticos e sua relação com a ideia de organismo complexo.
Editorial
Authors: Martins Lilian Al-Chueyr Pereira , Prestes Maria Elice de Brzezinski
Published: January 2021

Editorial da revista
Aulas on-line de instrumentos musicais: novo paradigma em tempos de pandemia
Authors: Gohn Daniel Marcondes
Published: January 2021

Este texto lança um olhar sobre o cenário da pandemia de Covid-19 no início de 2020, período que ocasionou profundas transformações na sociedade e reconfigurações no campo da educação musical. É apontada uma diferenciação entre ações de ensino remoto realizadas de forma emergencial e a educação a distância (EAD), quando aplicada com planejamento, pedagogias específicas e condições tecnológicas favoráveis. Na Universidade Federal de São Carlos (UFSCar), instituição que serve como base para as reflexões aqui apresentadas, há um processo bem elaborado e estruturado na Licenciatura em Educação Musical, oferecido na modalidade a distância em parceria com o projeto Universidade Aberta do Brasil (UAB). Em contrapartida, diversas instâncias da instituição discutiram ações emergenciais para lidar com a necessidade de distanciamento social, utilizando recursos tecnológicos como apoio. A partir do contexto pandêmico, emergiram também debates em vários âmbitos na internet, promovendo discussões no sentido de lapidar aulas on-line de instrumentos musicais. Percebe-se nesse contexto o surgimento de um novo paradigma, no qual a comunicação síncrona, por meio de softwares de videoconferência, poderá ter um papel mais relevante do que tinha em modelos de trabalho anteriores, como no exemplo do curso UAB. O presente trabalho oferece elementos específicos para aulas on-line de bateria, buscando a superação de adversidades não somente no período de enfrentamento do Covid-19, mas também para desafios que permanecerão no pós-pandemia.
Mensagem à USP Filarmônica
Authors: Mascaro Alysson Leandro
Published: January 2021

São dois os campos de reflexão necessários para um pensamento material, radical e consequente sobre a relação entre música e sociedade. O primeiro deles, o da determinação social da música. O segundo deles, o do papel político da música e também do músico. Aponto aqui, filosoficamente, para estas duas problemáticas, suas bases estruturais e suas consequências políticas.
Telomerase as a Therapeutic Target in Cardiovascular Disease
Authors: Hoffmann Jedrzej , Richardson Gavin , Haendeler Judith , Altschmied Joachim , Andrés Vicente , Spyridopoulos Ioakim
Published: January 2021

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials.

Graphic Abstract:

A graphic abstract is available for this article.
Conventional and Novel Lipid Measures and Risk of Peripheral Artery Disease
Authors: Kou Minghao , Ding Ning , Ballew Shoshana H. , Salameh Maya J. , Martin Seth S. , Selvin Elizabeth , Heiss Gerardo , Ballantyne Christie M. , Matsushita Kunihiro , Hoogeveen Ron C.
Published: January 2021

Objective:

The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD).

Approach and Results:

We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent
International Classification of Diseases, Ninth Revision, Clinical Modification
(
ICD-9-CM
) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996–1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08–1.36); RLP-C, 1.18 (1.08–1.29); LDL-TG, 1.18 (1.05–1.33); HDL-C, 1.39 (1.16–1.67); and Apo-E-HDL, 1.27 (1.07–1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD.

Conclusions:

Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones.

Graphic Abstract:

A graphic abstract is available for this article.
Taking a Stand Against Air Pollution—The Impact on Cardiovascular Disease
Authors: Brauer Michael , Casadei Barbara , Harrington Robert A. , Kovacs Richard , Sliwa Karen ,   the WHF Air Pollution Expert Group
Published: January 2021

Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to comorbidities that are known to worsen outcomes among those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.
Characteristics and Outcomes of Elderly Patients With Hypertrophic Cardiomyopathy
Authors: Alashi Alaa , Smedira Nicholas G. , Popovic Zoran B. , Fava Agostina , Thamilarasan Maran , Kapadia Samir R. , Wierup Per , Lever Harry M. , Desai Milind Y.
Published: January 2021

Background

We report characteristics and outcomes of elderly patients with hypertrophic cardiomyopathy (HCM) with basal septal hypertrophy and dynamic left ventricular outflow tract obstruction.

Methods and Results

We studied 1110 consecutive elderly patients with HCM (excluding moderate or greater aortic stenosis or subaortic membrane, age 80±5 years [range, 75–92 years], 66% women), evaluated at our center between June 2002 and December 2018. Clinical and echocardiographic data, including maximal left ventricular outflow tract gradient, were recorded. The primary outcome was death and appropriate internal defibrillator discharge. Hypertension was observed in 72%, with a Society of Thoracic Surgeons (STS) score (8.6±6); while 80% had no HCM‐related sudden cardiac death risk factors. Left ventricular mass index, basal septal thickness, and maximal left ventricular outflow tract gradient were 127±43 g/m
2
, 1.7±0.4 cm, and 49±31 mm Hg, respectively. A total of 597 (54%) had a left ventricular outflow tract gradient >30 mm Hg, of which 195 (33%) underwent septal reduction therapy (SRT; 79% myectomy and 21% alcohol ablation). At 5.1±4 years, 556 (50%) had composite events (273 [53%] in nonobstructive, 220 [55%] in obstructive without SRT, and 63 [32%] in obstructive subgroup with SRT). One‐ and 5‐year survival, respectively were 93% and 63% in nonobstructive, 90% and 63% in obstructive subgroup without SRT, and 94% and 84% in the obstructive subgroup with SRT. Following SRT, there were 5 (2.5%) in‐hospital deaths (versus an expected Society of Thoracic Surgeons mortality of 9.2%).

Conclusions

Elderly patients with HCM have a high prevalence of traditional cardiovascular rather than HCM risk factors. Longer‐term outcomes of the obstructive SRT subgroup were similar to a normal age‐sex matched US population.