bluuebunny/crossref_metadata_2025 huggingface dataset:
Production of Poly(3-Hydroxybutyrate) by Haloarcula, Halorubrum, and Natrinema Haloarchaeal Genera Using Starch as a Carbon Source
Authors: Karray Fatma , Ben Abdallah Manel , Baccar Nidhal , Zaghden Hatem , Sayadi Sami
Published: January 2021

Microbial production of bioplastics, derived from poly(3-hydroxybutyrate) (PHB), have provided a promising alternative towards plastic pollution. Compared to other extremophiles, halophilic archaea are considered as cell factories for PHB production by using renewable, inexpensive carbon sources, thus decreasing the fermentation cost. This study is aimed at screening 33 halophilic archaea isolated from three enrichment cultures from Tunisian hypersaline lake, Chott El Jerid, using starch as the sole carbon source by Nile Red/Sudan Black staining and further confirmed by PCR amplification of phaC and phaE polymerase genes. 14 isolates have been recognized as positive candidates for PHA production and detected during both seasons. The identification of these strains through 16S rRNA gene analyses showed their affiliation to Halorubrum, Natrinema, and Haloarcula genera. Among them, three PHB-producing strains, CEJ34-14, CEJ5-14, and CEJ48-10, related to Halorubrum chaoviator, Natrinema pallidum, and Haloarcula tradensis were found to be the best ones reaching values of 9.25, 7.11, and 1.42% of cell dry weight (CDW), respectively. Our findings highlighted that Halorubrum, Natrinema, and Haloarcula genera were promising candidates for PHB production using soluble starch as a carbon source under high salinity (250 g L-1 NaCl).
Development of New Models for the Estimation of Hourly Components of Solar Radiation: Tests, Comparisons, and Application for the Generation of a Solar Database in Morocco
Authors: Benchrifa Mohammed , Tadili Rachid , Idrissi Ahmed , Essalhi Hajar , Mechaqrane Abdellah
Published: January 2021

All studies of solar systems need the hourly values of solar fluxes related to the different components of solar radiation. However, for most sites, measurements are not available. The goal of this paper is to establish an hourly solar radiation data bank for the entirety of Morocco. This data bank will contain the energetic components (global, diffuse, direct, and inclined solar radiation) and the spectral components (ultraviolet

I

UV

, infrared

I

IR

, and photosynthetically active radiation

I

PAR

). To create this database, in the beginning, we build up models for predicting the various components of the hourly solar radiation, from measurements provided by the different stations owned by the Laboratory of Solar Energy and Environment (LESE). Then, these equations will be verified by using statistical tests. Moreover, we compared our results with those obtained by similar studies. Finally, based on the daily database of global radiation provided by the Laboratory of Solar Energy and Environment, we created an hourly database that unites the various components of solar radiation over 10 years for the entirety of Morocco. Regarding the validity study, the statistical indicators showed that the used models have minimal errors that do not exceed, for the global radiation, -2.93% in Rabat, -3.9% in Tangier,-3.28% in Marrakech, and -0.85% in Fez, and for diffuse radiation, -1.09% in Rabat, -0.68% in Fez,-3.08% in Tangier, and -2.49% in Marrakech. These results show the good quality of the used estimation models. Thus, the data bank that we have realized will fill the gap of the hourly solar data and will meet the needs of engineers, installers of solar systems, and researchers who often need an extensive database.
Marked Changes in Serum Amyloid A Distribution and High‐Density Lipoprotein Structure during Acute Inflammation
Authors: Shimano Shitsuko , Ohkawa Ryunosuke , Nambu Mayu , Sasaoka Mai , Yamazaki Azusa , Fujii Yuki , Horiuchi Yuna , Lai Shao-Jui , Kameda Takahiro , Ichimura Naoya , Fujita Koji , Tohda Shuji , Tozuka Minoru
Published: January 2021

High‐density lipoprotein‐ (HDL‐) cholesterol measurements are generally used in the diagnosis of cardiovascular diseases. However, HDL is a complicated heterogeneous lipoprotein, and furthermore, it can be converted into dysfunctional forms during pathological conditions including inflammation. Therefore, qualitative analysis of pathophysiologically diversified HDL forms is important. A recent study demonstrated that serum amyloid A (SAA) can remodel HDL and induce atherosclerosis not only over long periods of time, such as during chronic inflammation, but also over shorter periods. However, few studies have investigated rapid HDL remodeling. In this study, we analyzed HDL samples from patients undergoing orthopedic surgery inducing acute inflammation. We enrolled 13 otherwise healthy patients who underwent orthopedic surgery. Plasma samples were obtained on preoperative day and postoperative days (POD) 1‐7. SAA, apolipoprotein A‐I (apoA‐I), and apolipoprotein A‐II (apoA‐II) levels in the isolated HDL were determined. HDL particle size, surface charge, and SAA and apoA‐I distributions were also analyzed. In every patient, plasma SAA levels peaked on POD3. Consistently, the HDL apoA‐I : apoA‐II ratio markedly decreased at this timepoint. Native‐polyacrylamide gel electrophoresis and high‐performance liquid chromatography revealed the loss of small HDL particles during acute inflammation. Furthermore, HDL had a decreased negative surface charge on POD3 compared to the other timepoints. All changes observed were SAA‐dependent. SAA‐dependent rapid changes in HDL size and surface charge were observed after orthopedic surgery. These changes might affect the atheroprotective functions of HDL, and its analysis can be available for the qualitative HDL assessment.
Therapy-Induced Transdifferentiation Promotes Glioma Growth Independent of EGFR Signaling
Authors: Oh Hwanhee , Hwang Inah , Jang Ja-Young , Wu Lingxiang , Cao Dongqing , Yao Jun , Ying Haoqiang , Li Jian Yi , Yao Yu , Hu Baoli , Wang Qianghu , Zheng Hongwu , Paik Jihye
Published: January 2021

EGFR is frequently amplified, mutated, and overexpressed in malignant gliomas. Yet the EGFR-targeted therapies have thus far produced only marginal clinical responses, and the underlying mechanism remains poorly understood. Using an inducible oncogenic EGFR-driven glioma mouse model system, our current study reveals that a small population of glioma cells can evade therapy-initiated apoptosis and potentiate relapse development by adopting a mesenchymal-like phenotypic state that no longer depends on oncogenic EGFR signaling. Transcriptome analyses of proximal and distal treatment responses identified TGFβ/YAP/Slug signaling cascade activation as a major regulatory mechanism that promotes therapy-induced glioma mesenchymal lineage transdifferentiation. Following anti-EGFR treatment, TGFβ secreted from stressed glioma cells acted to promote YAP nuclear translocation that stimulated upregulation of the pro-mesenchymal transcriptional factor SLUG and subsequent glioma lineage transdifferentiation toward a stable therapy-refractory state. Blockade of this adaptive response through suppression of TGFβ-mediated YAP activation significantly delayed anti-EGFR relapse and prolonged animal survival. Together, our findings shed new insight into EGFR-targeted therapy resistance and suggest that combinatorial therapies of targeting both EGFR and mechanisms underlying glioma lineage transdifferentiation could ultimately lead to deeper and more durable responses.

Significance:

This study demonstrates that molecular reprogramming and lineage transdifferentiation underlie anti-EGFR therapy resistance and are clinically relevant to the development of new combinatorial targeting strategies against malignant gliomas with aberrant EGFR signaling.
Targeting IGF Perturbs Global Replication through Ribonucleotide Reductase Dysfunction
Authors: Rieunier Guillaume , Wu Xiaoning , Harris Letitia E. , Mills Jack V. , Nandakumar Ashwin , Colling Laura , Seraia Elena , Hatch Stephanie B. , Ebner Daniel V. , Folkes Lisa K. , Weyer-Czernilofsky Ulrike , Bogenrieder Thomas , Ryan Anderson J. , Macaulay Valentine M.
Published: January 2021

Inhibition of IGF receptor (IGF1R) delays repair of radiation-induced DNA double-strand breaks (DSB), prompting us to investigate whether IGF1R influences endogenous DNA damage. Here we demonstrate that IGF1R inhibition generates endogenous DNA lesions protected by 53BP1 bodies, indicating under-replicated DNA. In cancer cells, inhibition or depletion of IGF1R delayed replication fork progression accompanied by activation of ATR–CHK1 signaling and the intra-S-phase checkpoint. This phenotype reflected unanticipated regulation of global replication by IGF1 mediated via AKT, MEK/ERK, and JUN to influence expression of ribonucleotide reductase (RNR) subunit RRM2. Consequently, inhibition or depletion of IGF1R downregulated RRM2, compromising RNR function and perturbing dNTP supply. The resulting delay in fork progression and hallmarks of replication stress were rescued by RRM2 overexpression, confirming RRM2 as the critical factor through which IGF1 regulates replication. Suspecting existence of a backup pathway protecting from toxic sequelae of replication stress, targeted compound screens in breast cancer cells identified synergy between IGF inhibition and ATM loss. Reciprocal screens of ATM-proficient/deficient fibroblasts identified an IGF1R inhibitor as the top hit. IGF inhibition selectively compromised growth of ATM-null cells and spheroids and caused regression of ATM-null xenografts. This synthetic-lethal effect reflected conversion of single-stranded lesions in IGF-inhibited cells into toxic DSBs upon ATM inhibition. Overall, these data implicate IGF1R in alleviating replication stress, and the reciprocal IGF:ATM codependence we identify provides an approach to exploit this effect in ATM-deficient cancers.

Significance:

This study identifies regulation of ribonucleotide reductase function and dNTP supply by IGFs and demonstrates that IGF axis blockade induces replication stress and reciprocal codependence on ATM.
CanRisk Tool—A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants
Authors: Carver Tim , Hartley Simon , Lee Andrew , Cunningham Alex P. , Archer Stephanie , Babb de Villiers Chantal , Roberts Jonathan , Ruston Rod , Walter Fiona M. , Tischkowitz Marc , Easton Douglas F. , Antoniou Antonis C.
Published: January 2021

Background:

The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model.

Methods:

The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation.

Results:

This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations.

Conclusions:

The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking.

Impact:

There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.
Neutrophil to Lymphocyte Ratio as a Predictor of Long-Term Outcome in Peritoneal Dialysis Patients: A 5-Year Cohort Study
Authors: Zhang Lin , Nie Yuxin , Guo Man , Wang Li , Shi Yiqin , Jiang Xiaotian , Ding Xiaoqiang , Xu Xialian , Ji Jun
Published: January 2021

Introduction: The mortality of peritoneal dialysis (PD) patients remains high. The neutrophil to lymphocyte ratio (NLR), as an indicator of systemic inflammation, has been considered to be a predictor of cardiovascular and all-cause mortality in hemodialysis patients. The present study aims to investigate the relationship between NLR and long-term outcome in PD patients. Materials and Methods: The study included patients who initiated PD for at least 3 months between January 1, 2013, and December 31, 2015. All the patients were followed up until death, cessation of PD, or to the end of the study (June 31, 2018). NLR was calculated as the ratio of neutrophils to lymphocytes. Results: A total of 140 patients were included in this study. The median NLR reported was 2.87. Patients with lower NLR showed a higher survival rate than patients with higher NLR (log rank 6.886, p = 0.009). Furthermore, patients with higher NLR had a significantly higher cardiovascular mortality (log rank 5.221, p = 0.022). Multivariate Cox proportional hazards model showed that older age (HR 1.054, 95% CI 1.017–1.092, p = 0.004), higher Ca × P (HR 1.689, 95% CI 1.131–2.523, p = 0.010), and higher NLR (HR 2.603, 95% CI 1.037–6.535, p = 0.042) were independent predictors of increased all-cause mortality. NLR was also independently associated with cardiovascular mortality (HR 2.886, 95% CI 1.005–8.283, p = 0.039). Higher NLR (HR 2.667, 95% CI 1.333–5.337, p = 0.006), older age (HR 1.028, 95% CI 1.005–1.052, p = 0.016), and history of cardiovascular disease (HR 1.426, 95% CI 1.195–3.927, p = 0.031) were significantly independently associated with poor peritonitis-free survival in this study. Conclusions: NLR could be a strong predictor of long-term outcome in PD patients.
ALS-Like Disorder in Three HIV-Positive Patients: Case Series
Authors: Satin Zachary Aaron , Bayat Elham
Published: January 2021

There appears to be a relationship between retroviruses such as HIV and the development of an ALS-like syndrome. Few cases have been reported; however, there exists evidence of a higher frequency of motor neuron disease in HIV-infected patients, as well as potential slowing and reversibility of disease course with combination antiretroviral therapy. We conducted a retrospective chart review of patients presenting to the George Washington University ALS Clinic from September 2006 to June 2018 to identify patients with HIV receiving HAART who were subsequently diagnosed with ALS or an ALS-like disorder. Our goals were to describe our patients’ disease course and compare them to general characteristics of ALS. We report three cases of HIV-positive individuals, all male, who were subsequently diagnosed with ALS. Each presented with symptoms of limb onset ALS with involvement of upper and lower motor neurons and whose disease originated at the cervical level. All three had been diagnosed with HIV prior to presentation and were presumably compliant with antiretroviral therapy throughout. Our patients demonstrated effective control of their HIV infection. Each experienced relatively slow progression of motor impairment compared to general ALS characteristics. Our study offers a distinct profile of HIV-positive patients compliant with HAART subsequently diagnosed with an ALS-like disorder. Further study should aim to uncover pathophysiological similarities between motor neuron disease both in the presence and absence of retroviral infection and to develop effective medical therapy for each.
Improving Culture Conditions, Proliferation, and Migration of Porcine Mesenchymal Stem Cells on Spinal Cord Contusion Injury Model in vitro
Authors: Mukhamedshina Yana , Zhuravleva Margarita , Sergeev Mikhail , Zakirova Elena , Gracheva Olga , Mukhutdinova Dina , Rizvanov Albert
Published: January 2021

Adipose tissue-derived mesenchymal stem cells (AD-MSCs) are promising for cell therapy in spinal cord injury (SCI). The pig is one of the most approximate models of many human diseases, including SCI. In our study, we selected the optimal conditions for the culture of porcine AD-MSCs and developed an in vitro SCI model based on the culture of cells in injured spinal cord extracts (SCE) 3 days and 6 weeks after SCI. We show that Dulbecco’s Modified Eagle Medium (DMEM) with 20% serum content, supplemented with a combination of 5 mM L-ascorbate-2-phosphate and nonessential amino acids, stimulated a typical fibroblast-like morphology and high proliferation of porcine AD-MSCs. SCE caused a higher proliferation of porcine AD-MSCs compared with extracts from an intact spinal cord. The optimal proliferating effect was achieved using rostral 3 days SCE, and proliferation was lower in caudal and central SCE. Porcine AD-MSCs migration to the 3 days and 6 weeks SCE was higher than to an intact one and preferred the rostral SCE, avoiding central and caudal SCE. We also studied 13 cytokines contained in SCE but did not observe any definite relationship between some analyte concentrations and a change in the behavior of AD-MSCs.
Validation of a Bench-Top Training Model for Retrograde Intrarenal Surgery
Authors: Hussain Sana , Rana Roshan-e Shahid , Ather M. Hammad
Published: January 2021

Objective: To validate the in-house built Styrofoam box bench-top training model for retrograde intrarenal surgery (RIRS). Materials and Methods: This study was performed in the setting of a half-day RIRS course. During the course, participants performed RIRS on a locally built bench-top model. We recruited 26 participants, comprising 20 trainees and 6 experts. Trainees and experts were asked to fill a self-administered questionnaire assessing various components of RIRS to assess the face and content validity. For construct validity, experts using Objective Structured Assessment of Technical Skills (OSATS) rated trainees and the mean OSATS score of junior versus senior residents was compared. Results: As per trainees, the model was 86% (4.3/5) realistic, which was backed by experts who found this model to be 87.6% (4.38/5) realistic. The overall face validity of the model was 86.4% (4.32/5). The overall content validity of this model was 83.4% (4.17/5). Majority of the participants thought that this tool is useful for learning technique (4.38 ± 0.49) and safe-conduct (4.31 ± 0.73) of the procedure. The trainees concurred that the skills acquired are transferable to the operating room (4.23 ± 0.76). However, the construct validity by comparing mean OSATS score of junior versus senior residents was 19.5 ± 3.5 and 23 ± 4.5. A p value of 0.11 could not be established. Conclusion: This study has demonstrated the face, content, and construct validity of the bench-top training model for RIRS. Further evaluation is necessary to compare its effectiveness against other available models to demonstrate concurrent validity.
Hepatitis B Vaccination Response in Hemodialysis Patients: The Impact of Dialysis Shift
Authors: Han Maggie , Ye Xiaoling , Rao Sharon , Williams Schantel , Thijssen Stephan , Hymes Jeffrey , Maddux Franklin W. , Kotanko Peter
Published: January 2021

Background/Aims: Hepatitis B (HB) vaccination in hemodialysis patients is important as they are at a higher risk of contracting HB. However, hemodialysis patients have a lower HB seroconversion rate than their healthy counterparts. As better sleep has been associated with better seroconversion in healthy populations and early hemodialysis start has been linked to significant sleep-wake disturbances in hemodialysis patients, we examined if hemodialysis treatment start time is associated with HB vaccination response. Methods: Demographics, standard-of-care clinical, laboratory, and treatment parameters, dialysis shift data, HB antigen status, HB vaccination status, and HB titers were collected from hemodialysis patients in Fresenius clinics from January 2010 to December 2015. Patients in our analysis received 90% of dialysis treatments either before or after 8:30 a.m., were negative for HB antigen, and received a complete series of HB vaccination (Engerix B® or Recombivax HB™). Univariate and multivariate regression models examined whether dialysis start time is a predictor of HB vaccination response. Results: Patients were 65 years old, 57% male, and had a HD vintage of 10 months. Patients whose dialysis treatments started before 8:30 a.m. were more likely to be younger, male, and have a greater dialysis vintage. Patients receiving Engerix B® and starting dialysis before 8:30 a.m. had a significantly higher seroconversion rate compared to patients who started dialysis after 8:30 a.m. Early dialysis start was a significant predictor of seroconversion in univariate and multivariate regression including male gender, but not in multivariate regression including age, neutrophil-to-lymphocyte ratio, and vintage. Conclusion: While better sleep following vaccination is associated with seroconversion in the general population, this is not the case in hemodialysis patients after multivariate adjustment. In the context of end-stage kidney disease, early dialysis start is not a significant predictor of HB vaccination response. The association between objectively measured postvaccination sleep duration and seroconversion rate should be investigated.
Incidence of Adverse Cutaneous Reactions to Epidermal Growth Factor Receptor Inhibitors in Patients with Non-Small-Cell Lung Cancer
Authors: Gisondi Paolo , Geat Davide , Mattiucci Alessandra , Lombardo Fiorella , Santo Antonio , Girolomoni Giampiero
Published: January 2021

Background: Epidermal growth factor receptor (EGFR) inhibitors are routinely used in advanced non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, their use is associated with gastrointestinal and cutaneous toxicities, including acneiform eruptions, pruritus, xerosis, nail and hair changes. Aside from reducing patients’ quality of life, such cutaneous reactions have a considerable impact on the oncologic treatment given that dose reduction or even drug discontinuation may be necessary, especially for the severe forms. Objectives: To assess the incidence, impact on treatment and management of EGFR inhibitor-related cutaneous reactions in patients with NSCLC. Methods: We conducted a prospective observational study on 87 consecutive patients with advanced NSCLC treated with EGFR-tyrosine kinase inhibitors from January to December 2019. Patients who developed mucocutaneous reactions were evaluated and treated by both oncologists and dermatologists, and underwent dermatologic follow-up until resolution of the cutaneous reaction. Demographic and clinical data were collected for each patient, and the severity of the cutaneous reaction was graded using the Common Terminology Criteria for Adverse Events. Results: Seventy-one patients (81.6%) developed cutaneous reactions. The number of cutaneous reactions per patient was 1 in 37%, 2 in 41% and 3 or more in 22%. The most common cutaneous reactions included acneiform eruptions (56.3%), xerosis ± asteatotic eczema (48.3%), nail changes (39.1%), mucositis (29.9%), pruritus (24.1%) and hair changes (12.6%). Afatinib was associated with a higher rate of nail changes and mucositis (p < 0.01 and p < 0.005, respectively) compared to other agents, while no patient-related predictive factors were identified. Dose reduction was performed in 18% of patients. Multidisciplinary management involving dermatologists allowed to resume the drug in all patients who had discontinued it due to the cutaneous reactions. Conclusions: A multidisciplinary approach to EGFR inhibitor-related cutaneous reactions is advantageous and can reduce the need to discontinue oncologic treatment.
A Systematic Review on the Impact of Genetic Testing for Familial Melanoma II: Psychosocial Outcomes and Attitudes
Authors: Primiero Clare A. , Yanes Tatiane , Finnane Anna , Soyer H. Peter , McInerney-Leo Aideen M.
Published: January 2021

Background: Although genetic testing for known familial melanoma genes is commercially available, clinical implementation has been restrained as utility is unclear, concerns of causing psychological distress are often cited, and consumer interest and perceptions are not well understood. A review of studies exploring participant-reported psychosocial outcomes and attitudes towards genetic testing for familial melanoma will provide insight into common emotional and cognitive responses. Methods: Database searches of PubMed, Embase, CINAHL, PsycINFO and the Cochrane Library were conducted using a date range of January 1995 to June 2020. Studies examining any psychosocial outcomes alongside genetic testing (real or hypothetical), in participants described as having a high risk of melanoma, were eligible. A narrative synthesis of results was used to describe psychosocial outcomes and summarise participant beliefs and attitudes towards genetic testing. Results: Limited evidence of adverse psychosocial outcomes was found. No impacts on perceived risk or control were reported, and minimal decisional regret was recorded. Generalised distress was comparable between both genetic mutation carriers and non-carriers, often decreasing over time from pretesting levels. Melanoma-specific distress was frequently higher in carriers than non-carriers; however, this difference was present prior to testing and often associated with personal melanoma history. Overall, participants’ attitudes towards testing were largely positive, with benefits more frequently described than limitations, and support for testing minors was strong. Conclusions: This review has found evidence of few adverse psychological outcomes following genetic testing. There was no indication of increased distress after genetic test results had been disclosed. If these findings were replicated in additional, larger, diverse populations over a longer follow-up period, this would be compelling evidence to guide clinical recommendations.
Dual-Tracer (68Ga-DOTATOC and 18F-FDG-)-PET/CT Scan and G1-G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Single-Center Retrospective Evaluation of 124 Nonmetastatic Resected Cases
Authors: Paiella Salvatore , Landoni Luca , Tebaldi Sarah , Zuffante Michele , Salgarello Matteo , Cingarlini Sara , D’Onofrio Mirko , Parisi Alice , Deiro Giacomo , Manfrin Erminia , Bianchi Beatrice , Montagnini Greta , Crinò Stefano Francesco , Bassi Claudio , Salvia Roberto
Published: January 2021

Introduction: The combined use of 68gallium (68Ga)-DOTA-peptides and 18fluorine-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans in the workup of pancreatic neuroendocrine tumors (PanNETs) is controversial. This study aimed at assessing both tracers’ capability to identify tumors and to assess its association with pathological predictors of recurrence. Methods: Prospectively collected, preoperative, dual-tracer PET/CT scan data of G1-G2, nonmetastatic, PanNETs that underwent surgery between January 2013 and October 2019 were retrospectively analyzed. Results: The final cohort consisted of 124 cases. There was an approximately equal distribution of males and females (50.8%/49.2%) and G1 and G2 tumors (49.2%/50.8%). The disease was detected in 122 (98.4%) and 64 (51.6%) cases by 68Ga-DOTATOC and by 18F-FDG PET/CT scans, respectively, with a combined sensitivity of 99.2%. 18F-FDG-positive examinations found G2 tumors more often than G1 (59.4 vs. 40.6%; p = 0.036), and 18F-FDG-positive PanNETs were larger than negative ones (median tumor size 32 mm, interquartile range [IQR] 21 vs. 26 mm, IQR 20; p = 0.019). The median Ki67 for 18F-FDG-positive and -negative examinations was 3 (IQR 4) and 2 (IQR 4), respectively (p = 0.029). At least 1 pathological predictor of recurrence was present in 74.6% of 18F-FDG-positive cases (vs. 56.7%; p = 0.039), whereas this was not found when dichotomizing the PanNETs by their dimensions (≤/>20 mm). None of the 2 tracers predicted nodal metastasis. The receiver operating characteristic curve analysis showed that 18F-FDG uptake higher than 4.2 had a sensitivity of 49.2% and specificity of 73.3% for differentiating G1 from G2 (AUC = 0.624, p = 0.009). Conclusion: The complementary adoption of 68Ga-DOTATOC and 18F-FDG tracers may be valuable in the diagnostic workup of PanNETs despite not being a game-changer for the management of PanNETs ≤20 mm.
Early Kidney Dysfunction in Metabolic-Associated Fatty Liver Disease: Is Transient Elastography Useful as a Screening Method?
Authors: Freitas Marta , Macedo Silva Vítor , Xavier Sofia , Magalhães Joana , Marinho Carla , Cotter José
Published: January 2021

Introduction: Increasing evidence suggests an association between metabolic-associated fatty liver disease (MAFLD) and CKD. Timely prediction of early kidney dysfunction (EKD) is thus essential in this population although a screening method is not stablished. We aimed to evaluate the role of transient elastography (TE) in predicting EKD in patients with MAFLD. Materials and Methods: A prospective cohort study that included patients with MAFLD scheduled for evaluation was performed between May 2019 and January 2020. Demographic, clinical, and laboratory data and TE parameters were prospectively obtained. EKD was defined as microalbuminuria (urinary albumin-to-Cr ratio 30–300 mg/g) and estimated glomerular filtration rate ≥60 mL/min/1.73 m2. Significant liver fibrosis was defined as liver stiffness measurement (LSM) ≥8.2 kPa. Results: Of the included 45 patients with MALFD, 53.3% were of female gender with mean age of 53.5 ± 10.9 years. EKD was found in 17.8% of patients. MAFLD patients with EKD were significantly more obese (BMI ≥30) (75.0 vs. 32.4%, p = 0.045) and had significantly higher LSM (8.5 ± 4.1 vs. 5.8 ± 2.2 kPa, p = 0.01). After adjustment of potential confounders for EKD, the presence of liver fibrosis remained a significant predictor of EKD, being associated with a 14.3-fold increased risk of EKD (p = 0.04). The optimal cutoff value of LSM to predict EKD was 6.1 kPa (sensitivity: 85.7%; specificity: 67.6%). Conclusion: Significant liver fibrosis is associated with a significant increased risk of EKD in patients with MAFLD, regardless of other comorbidities. Higher levels of LSM, particularly >6.1 kPa, alert for timely identification of EKD and associated comorbidities, as well as their control, in order to prevent the development of CKD in the long term.
Uma abordagem histórico-crítica do Design Inteligente e sua chegada ao Brasil
Authors: Hentges Cristiano Roberto , Araújo Aldo Mellender de
Published: January 2021

Este artigo apresenta uma breve história do movimento criacionista representado hoje pelos defensores do Design inteligente (DI). Estes se colocam como proponentes de uma teoria científica em confronto explícito com os defensores da teoria da evolução biológica. Discute dois conceitos neocriacionistas mediante críticas que lhes foram feitas por evolucionistas. Com o objetivo de retomar momentos históricos relevantes, relata brevemente as principais disputas jurídicas entre o criacionismo e a teoria da evolução biológica que ocorreram nos Estados Unidos ao longo do século XX, caracterizando algumas das estratégias utilizadas de ambos os lados do confronto. Levando em conta o estabelecimento de um centro de pesquisa de design inteligente em 2017, procura apontar outras ações recentes voltadas à inclusão do criacionismo no currículo da escola básica no país, notadamente, dois projetos de lei em nível federal. O artigo também analisa entrevistas de alguns defensores do design inteligente com o objetivo de identificar estratégias de seus argumentos. Conclui-se que os conceitos defendidos pelos proponentes do design inteligente não têm correspondência com as evidências científicas discutidas por eles, o que torna ilegítima a pretensão de cientificidade alegada. Estima-se ainda que a comunidade acadêmica deve posicionar-se franca e ativamente em defesa do ensino da teoria da evolução biológica, teoria consensual e cientificamente exclusiva que fundamenta os estudos da vida.
La labor paleontológica de Thomas Huxley
Authors: García-Peralta Luis Eduardo , Pérez-Malváez Carlos , Bribiesca-Escutia Guadalupe
Published: January 2021

Si toda la vida en la Tierra comparte un ancestro común, con la evolución como mecanismo diversificando gradualmente a través del tiempo, entonces, el registro fósil debería proporcionar formas graduadas intermedias. Sin embargo, para 1859 (año de la publicación de El origen de las especies), éstas aún no habían sido descubiertas. Para Charles Darwin (1809-1882), esto representaba una seria objeción a su teoría evolutiva e intentó explicar esta evidencia negativa a través de la imperfección del registro fósil. Por lo tanto, la paleontología era la clave que podía presentar evidencia a favor de la evolución. Thomas Henry Huxley (1825-1895), hallaría formas de transición que unirían grandes grupos animales sin relación aparente, por ejemplo, las aves con los reptiles a través de los dinosaurios. El objetivo del presente trabajo fue llevar a cabo una investigación sobre la obra paleontológica de Thomas Huxley, haciendo un especial énfasis en su apoyo a las ideas evolutivas de Darwin. Se llegó a la conclusión de que su labor paleontológica demostró que los hechos de la paleontología, en lo que concierne a las aves y a los reptiles, no se oponen a la doctrina de la evolución, sino que, al contrario, eran muy parecidos a los que la doctrina nos llevaría a esperar.
Perivascular Adipose Tissue Inflammation in Ischemic Heart Disease
Authors: Mazzotta Celestina , Basu Sanchita , Gower Adam C. , Karki Shakun , Farb Melissa G. , Sroczynski Emily , Zizza Elaina , Sarhan Anas , Pande Ashvin N. , Walsh Kenneth , Dobrilovic Nikola , Gokce Noyan
Published: January 2021

Objective:

There is growing recognition that adipose tissue–derived proatherogenic mediators contribute to obesity-related cardiovascular disease. We sought to characterize regional differences in perivascular adipose tissue (PVAT) phenotype in relation to atherosclerosis susceptibility.

Approach and Results:

We examined thoracic PVAT samples in 34 subjects (body mass index 32±6 kg/m
2
, age 59±11 years) undergoing valvular, aortic, or coronary artery bypass graft surgeries and performed transcriptomic characterization using whole-genome expression profiling and quantitative polymerase chain reaction analyses. We identified a highly inflamed region of PVAT surrounding the human aortic root in close proximity to coronary takeoff and adjoining epicardial fat. In subjects undergoing coronary artery bypass graft, we found 300 genes significantly upregulated (false discovery rate
Q
<0.1) in paired samples of PVAT surrounding the aortic root compared with nonatherosclerotic left internal mammary artery. Genes encoding proteins mechanistically implicated in atherogenesis were enriched in aortic PVAT consisting of signaling pathways linked to inflammation,
WNT
(wingless-related integration site) signaling, matrix remodeling, coagulation, and angiogenesis. Overexpression of several proatherogenic transcripts, including
IL1β
,
CCL2
(
MCP-1
), and
IL6
, were confirmed by quantitative polymerase chain reaction and significantly bolstered in coronary artery disease subjects. Angiographic coronary artery disease burden quantified by the Gensini score positively correlated with the expression of inflammatory genes in PVAT. Moreover, periaortic adipose inflammation was markedly higher in obese subjects with striking upregulation (≈8-fold) of
IL1β
expression compared to nonobese individuals.

Conclusions:

Proatherogenic mediators that originate from dysfunctional PVAT may contribute to vascular disease mechanisms in human vessels. Moreover, PVAT may adopt detrimental properties under obese conditions that play a key role in the pathophysiology of ischemic heart disease.

Graphic Abstract:

A graphic abstract is available for this article.
Suppression-Replacement
KCNQ1
Gene Therapy for Type 1 Long QT Syndrome
Authors: Dotzler Steven M. , Kim C.S. John , Gendron William A.C. , Zhou Wei , Ye Dan , Bos J. Martijn , Tester David J. , Barry Michael A. , Ackerman Michael J.
Published: January 2021

Background:

Type 1 long QT syndrome (LQT1) is caused by loss-of-function variants in the
KCNQ1
-encoded K
v
7.1 potassium channel α-subunit that is essential for cardiac repolarization, providing the slow delayed rectifier current. No current therapies target the molecular cause of LQT1.

Methods:

A dual-component suppression-and-replacement (SupRep)
KCNQ1
gene therapy was created by cloning a
KCNQ1
short hairpin RNA and a short hairpin RNA-immune
KCNQ1
cDNA modified with synonymous variants in the short hairpin RNA target site, into a single construct. The ability of KCNQ1-SupRep gene therapy to suppress and replace LQT1-causative variants in
KCNQ1
was evaluated by means of heterologous expression in TSA201 cells. For a human in vitro cardiac model, induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) were generated from 4 patients with LQT1 (KCNQ1-Y171X, -V254M, -I567S, and -A344A/spl) and an unrelated healthy control. CRISPR-Cas9 corrected isogenic control iPSC-CMs were made for 2 LQT1 lines (correction of KCNQ1-V254M and KCNQ1-A344A/spl). FluoVolt voltage dye was used to measure the cardiac action potential duration (APD) in iPSC-CMs treated with KCNQ1-SupRep.

Results:

In TSA201 cells, KCNQ1-SupRep achieved mutation-independent suppression of wild-type
KCNQ1
and 3 LQT1-causative variants (KCNQ1-Y171X, -V254M, and -I567S) with simultaneous replacement of short hairpin RNA-immune
KCNQ1
as measured by allele-specific quantitative reverse transcription polymerase chain reaction and Western blot. Using FluoVolt voltage dye to measure the cardiac APD in the 4 LQT1 patient-derived iPSC-CMs, treatment with KCNQ1-SupRep resulted in shortening of the pathologically prolonged APD at both 90% and 50% repolarization, resulting in APD values similar to those of the 2 isogenic controls.

Conclusions:

This study provides the first proof-of-principle gene therapy for complete correction of long QT syndrome. As a dual-component gene therapy vector, KCNQ1-SupRep successfully suppressed and replaced
KCNQ1
to normal wild-type levels. In TSA201 cells, cotransfection of LQT1-causative variants and KCNQ1-SupRep caused mutation-independent suppression and replacement of
KCNQ1
. In LQT1 iPSC-CMs, KCNQ1-SupRep gene therapy shortened the APD, thereby eliminating the pathognomonic feature of LQT1.
Improvement of Maximal Exercise Performance After Catheter‐Ablation of Atrial Fibrillation and Its Prognostic Significance for Long‐Term Rhythm Outcome
Authors: Mujović Nebojša M. , Marinković Milan M. , Nedeljković Ivana , Marković Nebojša , Banović Marko , Vučićević Vera , Stanković Goran , Potpara Tatjana S.
Published: January 2021

Background

Rhythm control may improve functional capacity in patients with atrial fibrillation (AF). Long‐term exercise tolerance improvement and its prognostic implications following catheter‐ablation (CA) of paroxysmal and nonparoxysmal AF are underreported.

Methods and Results

Consecutive patients underwent cardiopulmonary exercise testing just before and 12 months after their index CA of AF. Follow‐up 24‐hour Holter recordings were obtained at 6‐month intervals post‐CA, and any atrial arrhythmia >30 seconds detected after 3 months postprocedure was considered AF recurrence. Of 110 patients (mean age 57.5±10.6 years, 77.2% males) with paroxysmal AF (n=66) or nonparoxysmal AF (n=44), the 12‐month exercise tolerance improved significantly in those who maintained sinus rhythm during the first 12 months post‐CA (n=96), but not in patients with AF recurrence (n=14). After CA, the 12‐month respiratory exchange ratio at maximal workload significantly increased in patients with paroxysmal AF, whereas those with nonparoxysmal AF significantly reduced their heart rate during the 12‐month cardiopulmonary exercise testing (all
P
≤0.001). During the follow‐up of 42.8±7.8 months, a total of 29 patients (26.3%) experienced recurrent AF. On multivariate analysis including patients without recurrent AF at 12 months after CA, the extent of work time improvement at follow‐up cardiopulmonary exercise testing was independently associated with the rhythm outcome beyond 12 months postprocedure (hazard ratio of 0.936 [95% CI, 0.894–0.979] for each 10 seconds increase in the work time following ablation,
P
=0.004).

Conclusions

CA of AF was associated with recovery of exercise intolerance in patients with paroxysmal AF or nonparoxysmal AF. Inability to improve exercise capacity at 12 months post‐CA was an independent risk factor for later AF recurrence.
Liver Fibrosis Scoring Systems as Novel Tools for Predicting Cardiovascular Outcomes in Patients Following Elective Percutaneous Coronary Intervention
Authors: Liu Hui‐Hui , Cao Ye‐Xuan , Jin Jing‐Lu , Hua Qi , Li Yan‐Fang , Guo Yuan‐Lin , Zhu Cheng‐Gang , Wu Na‐Qiong , Gao Run‐Lin , Li Jian‐Jun
Published: January 2021

Background

Previous studies have suggested a strong association of liver fibrosis scores (LFSs) with cardiovascular outcomes in patients with different cardiovascular diseases. Nonetheless, it is basically blank regarding the prognostic significance of LFSs in patients following percutaneous coronary intervention (PCI). This study sought to examine the potential role of LFSs in predicting long‐term outcomes in a large cohort of patients with stable coronary artery disease after elective PCI.

Methods and Results

In this multicenter, prospective study, we consecutively enrolled 4003 patients with stable coronary artery disease undergoing PCI. Eight currently available noninvasive LFSs were assessed for each subject. All patients were followed up for the occurrence of cardiovascular events including cardiovascular death, nonfatal myocardial infarction, and stroke. During an average follow‐up of 5.0±1.6 years, 315 (7.87%) major cardiovascular events were recorded. Subjects who developed cardiovascular events were more likely to have intermediate or high LFSs, including nonalcoholic fatty liver disease fibrosis score; fibrosis‐4 score; body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes mellitus score (BARD); and aspartate aminotransferase/alanine aminotransferase ratio. Furthermore, compared with subjects with low scores, those with intermediate plus high score levels had significantly increased risk of cardiovascular events (adjusted hazard ratios ranging 1.57–1.92). Moreover, the addition of non‐alcoholic fatty liver disease fibrosis score; fibrosis‐4 score; or body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes mellitus score into a model with established cardiovascular risk factors significantly improved the prediction ability.

Conclusions

High LFSs levels might be useful for predicting adverse prognosis in patients with stable coronary artery disease following PCI, suggesting the possibility of the application of LFSs in the risk stratification before elective PCI.
Cancer and Embolic Stroke of Undetermined Source
Authors: Navi Babak B. , Kasner Scott E. , Elkind Mitchell S.V. , Cushman Mary , Bang Oh Young , DeAngelis Lisa M.
Published: January 2021

One-quarter to one-third of ischemic strokes have no established mechanism after standard diagnostic evaluation and are classified as embolic stroke of undetermined source (ESUS). Failure of randomized trials to demonstrate a benefit of direct oral anticoagulants over aspirin for the treatment of ESUS as a single homogeneous entity has led to renewed interest by stroke experts to divide ESUS into subgroups. Emerging data suggest that active cancer, which is present in 5% to 10% of patients with ESUS, is a distinct and important subgroup of ESUS with unique clinical characteristics, underlying pathophysiologies, and treatment and prognostic considerations. Furthermore, the prevalence of cancer-related ESUS is expected to increase as patients with cancer, even those with distant metastases, survive longer due to improvements in cancer treatments. In this topical review, we examine the epidemiological link between ESUS and cancer, the clinical features and potential mechanistic underpinnings of ESUS with cancer (with a focus on novel biomarkers and their relationship to recurrent stroke and other thromboembolic events), and the potential treatment strategies for cancer-related ESUS. We include a critical appraisal of existing data and ongoing or planned clinical trials of different antithrombotic approaches. As cancer-related ESUS is a dynamic disease with variable course, we recommend close collaboration between neurologists and oncologists to develop individualized management plans.
Challenging Western Legal Orientalism
Authors: Infantino Marta , Wang Weiwei
Published: January 2021

In 2014 the Chinese State Council announced the establishment of a nationwide comprehensive social credit system. Western narratives often describe the initiative as a technologically enhanced tool of autocratic control for scoring people. Yet, as the paper aims to show, similar accounts are tainted by several misunderstandings which perpetuate Western orientalist postures towards Chinese law.

For the purpose of comparatively assessing the Chinese social credit system, the paper analyses the pilot programs set up to monitor people and enterprises’ behaviour by twenty-eight Chinese cities. The analysis will demonstrate that these pilot programs rely on low-tech methodologies, have limited strings attached, and are based on a relatively transparent legal framework. From a comparative perspective, our findings suggest that Chinese cities’ experiments raise problems that are similar to those posed by measurement practices widely employed in the West.
A new species of square-headed wasp Dasyproctus Lepeletier & Brullé (Hymenoptera: Crabronidae: Crabronini) from India, with notes on its biology
Authors: BINOY C. , KUMAR P. GIRISH , SANTHOSH S.
Published: January 2021

Dasyproctus geethae Binoy & Girish Kumar sp. nov. is described with illustrations of both sexes, and of preimaginal stages with notes on its biology and ethology. New prey records of Diptera of the families Drosophilidae, Hybotidae, Stratiomyidae and Dolichopodidae are recorded for the genus.
Review of Indian Allacta Saussure & Zehntner, 1895 (Blattodea: Ectobiidae: Pseudophyllodromiinae), with description of three new species
Authors: SENRAJ M. , PACKIAM S. MARIA , PRABAKARAN S. , LUCANAS CRISTIAN C. , JAISWAL DEEPA
Published: January 2021

The known species of Allacta Saussure & Zehntner, 1895 in India are reviewed. Three new species, A. jcenpro sp. nov., A. vellimalai sp. nov., and A. kollimalai sp. nov., are described. All are placed under hamifera species group. The new species can be differentiated from other members of hamifera species group by the pronotal and facial markings, the structure of the male genitalia and other morphological characters. Additional reports to A. kalakadensis Prabakaran & Senraj 2019 and A. figurata (Walker, 1871) are provided. A key to the known species of Indian Allacta is provided.
Bolbelasmus (Bolbelasmus) zagrosensis (Coleoptera: Scarabaeoidea: Bolboceratidae), a new species from Iran, along with an updated key to the western Palaearctic species of the subgenus
Authors: SOMMER DAVID , HILLERT OLIVER , HRŮZOVÁ LUCIE , KRÁL DAVID
Published: January 2021

Bolbelasmus (Bolbelasmus) zagrosensis Sommer, Hillert, Hrůzová & Král, new species, from Iran is described, illustrated and compared with its congeners known from the western Palaearctic region. An updated key to the western Palaearctic species of the nominotypical subgenus is provided. New country record of B. (B.) nireus (Reitter, 1895) from Greece (island of Rhodes) is reported. Distribution of B. (B.) makrisi Miessen, 2011, B. (B.) nireus and the new species is summarized and mapped.