bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Sevoflurane versus Propofol on Endogenous Nitric Oxide Metabolism during Laparoscopic Surgery
Authors: Wang Ning , Zhang Jing , Zhao Ruiling , Zhao Bin , Li Yongzhang , Zhang Xiaoqing , Liu Peng
Published: February 2021

For laparoscopic surgery, it is very difficult to assess the effect of different medicines used in the surgical procedure on the surgical results. In the past, doctors could use sevoflurane to numb and calm patients. For decades, this type of treatment has been fairly reliable and effective, but for laparoscopic surgery, the use of sevoflurane can lead to a wide range of blood glucose changes, so in recent years, sevoflurane compared to propofol in laparoscopic surgery on endogenous and nitrogen oxide metabolism has been studied more and more. In this paper, a variety of research methods were used to study the phenomenon of shock and excessive anesthesia encountered by patients in the treatment process. Through observation and drug experiment of patients in different treatment courses and treatment stages, patients were asked to use sevoflurane and propofol to conduct double-blind experiments on their own drug effects. At the same time, through the long-term observation of patients with different diseases and patients who need laparoscopic surgery, the nitrogen oxide metabolism in patients with sevoflurane compared with propofol endogenous was studied and analyzed. Through three groups of different conditions, the experimental group, the blind test group, and the control group were studied. To conclude, in laparoscopic surgery, the use of sevoflurane compared with propofol can have a good impact on the endogenous drug and nitrogen oxide metabolism. It can achieve a good effect on the anesthesia effect of surgery, the maintenance of patient’s physical signs and heart rate, which is very beneficial to the operation. Conclusion. Sevoflurane compared with propofol has a good effect on endogenous nitrogen oxide metabolism in laparoscopic surgery.
Assessment of the Presence of Resistance Genes Detected from the Environment and Selected Food Products in Benin
Authors: Dougnon Victorien , Houssou Vincentia Marie Camille , Anago Eugénie , Nanoukon Chimène , Mohammed Jibril , Agbankpe Jerrold , Koudokpon Hornel , Bouraima Birikissou , Deguenon Esther , Fabiyi Kafayath , Hidjo Marie , Djegui Fidélia , Baba-Moussa Lamine , Aïna Martin Pépin
Published: February 2021

Gram-negative bacilli can spread from the environment and through food products. This study aimed to characterize ESBL production and virulence genes from multidrug-resistant Gram-negative bacilli isolated from specimen collected from the environment, kitchen, and food products. A total of 130 samples were collected at local markets in seven different communities in Benin (Abomey-Calavi, Ouidah, Bohicon, Abomey, Parakou, Djougou, and Grand-Popo). Samples were cultured on McConkey and ChromID™ ESBL agar plates. The isolates were identified by the API 20E gallery. An antibiotic susceptibility test was carried out, and the detection of ESBL production and virulence-associated genes was carried out by Polymerase Chain Reaction (PCR). The data collected was coded and analyzed using GraphPad prism 7 software and Excel. The software R was used to calculate the correlation coefficient between the results of the detection of ESBL+ on agar and by the effect of the double synergy. The results showed that sixty-three (63) bacterial strains were isolated from the 130 samples, of which the dominant species was Chryseomonas luteola (10/63). The kitchen samples were the most contaminated with 36.50%. More than 40% of the isolates were resistant to at least three different classes of antibiotics. Also, blaSHV gene was detected in 33.33% (21/63) of the isolates and in all isolates of Pseudomonas aeruginosa (5/5%). 11.11% (7/63) of isolates were virulent with dominance of the fimH gene, especially with Escherichia coli (83.33%). The kitchen samples showed a high prevalence of ESBL-producing strains with fimH gene. This raises the problem of non-compliance with hygiene rules in community cooking and food handling.
Atrial Fibrillation is Associated with Femoropopliteal Totally Occlusive In-Stent Restenosis: A Single-Center, Retrospective, Observational Study
Authors: Honda Yohsuke , Hirano Keisuke , Yamawaki Masahiro , Araki Motoharu , Kobayashi Norihiro , Sakamoto Yasunari , Mori Shinsuke , Tsutsumi Masakazu , Makino Kenji , Shirai Shigemitsu , Mizusawa Masafumi , Nakano Takahiro , Ito Yoshiaki
Published: February 2021

Introduction. The proportion of patients with comorbid atrial fibrillation (AF) and peripheral artery disease (PAD) has increased in this era. This study aimed to assess the relationship between AF and totally occlusive in-stent restenosis (ISR) in femoropopliteal (FP) lesions. Methods. In this study, 363 patients (461 stents) who underwent endovascular therapy with de novo stent implantation in our hospital between April 2007 and December 2016 were retrospectively evaluated. The patients were divided into two groups according to the AF status (AF group, 61 patients; sinus group, 302 patients). The primary endpoint was the incidence of totally occlusive ISR within 3 years. The secondary endpoint was the incidence of acute limb ischemia (ALI) due to FP stent occlusion. Results. Baseline characteristics were similar, except for higher age and a lower prevalence of dyslipidemia in the AF group. The incidence of a totally occlusive ISR was higher in the AF group than in the sinus group (29.5% vs. 14.6%,

p
=
0.004

). A multiple Cox regression model suggested that presence of AF (hazard ratio, 2.10) and CTO lesion (hazard ratio, 1.97) which were the independent predictors of a totally occlusive ISR within 3 years. The incidence of ALI was significantly higher in the AF group than in the sinus group (3.9% vs. 0%,

p
=
0.0001

). In the AF group, the introduction of an anticoagulant did not prevent the occurrence of totally occlusive ISR (

p
=
0.71

) for ALI (

p
=
0.79

). Conclusions. AF is independently associated with totally occlusive ISR of FP stents; however, anticoagulant use does not prevent stent occlusion.
Vegetation Change and Its Response to Climate Change in Yunnan Province, China
Authors: Sun Huaizhang , Wang Jiyan , Xiong Junnan , Bian Jinhu , Jin Huaan , Cheng Weiming , Li Ainong
Published: February 2021

The impact of global climate change on vegetation has become increasingly prominent over the past several decades. Understanding vegetation change and its response to climate can provide fundamental information for environmental resource management. In recent years, the arid climate and fragile ecosystem have led to great changes in vegetation in Yunnan Province, so it is very important to further study the relationship between vegetation and climate. In this study, we explored the temporal changes of normalized difference vegetation index (NDVI) in different seasons based on MOD13Q1 NDVI by the maximum value composite and then analyzed spatial distribution characteristics of vegetation using Sen’s tendency estimation, Mann–Kendall significance test, and coefficient of variation model (CV) combined with terrain factors. Finally, the concurrent and lagged effects of NDVI on climate factors in different seasons and months were discussed using the Pearson correlation coefficient. The results indicate that (1) the temporal variation of the NDVI showed that the NDVI values of different vegetation types increased at different rates, especially in growing season, spring, and autumn; (2) for spatial patterns, the NDVI, CV, and NDVI trends had strong spatial heterogeneity owning to the influence of altitudes, slopes, and aspects; and (3) the concurrent effect of vegetation on climate change indicates that the positive effect of temperature on NDVI was mainly in growing season and autumn, whereas spring NDVI was mainly influenced by precipitation. In addition, the lag effect analysis results revealed that spring precipitation has a definite inhibition effect on summer and autumn vegetation, but spring and summer temperature can promote the growth of vegetation. Meanwhile, the precipitation in the late growing season has a lag effect of 1-2 months on vegetation growth, and air temperature has a lag effect of 1 month in the middle of the growing season. Based on the above results, this study provided valuable information for ecosystem degradation and ecological environment protection in the Yunnan Province.
Aberrant Hypermethylation-Mediated Suppression of PYCARD Is Extremely Frequent in Prostate Cancer with Gleason Score ≥ 7
Authors: Miyauchi Toshiya , Takahashi Masahiro , Mitsuzuka Koji , Saiki Yuriko , Okubo Teppei , Vertino Paula M. , Goto Akiteru , Arai Yoichi , Horii Akira , Fukushige Shinichi
Published: February 2021

Epigenetic gene silencing by aberrant DNA methylation leads to loss of key cellular pathways in tumorigenesis. In order to analyze the effects of DNA methylation on prostate cancer, we established LNCaP-derived human prostate cancer cells that can pharmacologically induce global reactivation of hypermethylated genes by the methyl-CpG targeted transcriptional activation (MeTA) method. The MeTA suppressed the growth of LNCaP-derived cells and induced apoptosis. Microarray analysis indicated that PYCARD (PYD and CARD domain containing) encoding an apoptosis-inducing factor was upregulated by 65-fold or more after treatment with MeTA. We analyzed DNA methylation statuses using 50 microdissected primary prostate cancer tissues and found an extremely high frequency of tumor-specific promoter hypermethylation of PYCARD (90%, 45/50). Moreover, DNA methylation status was significantly associated with Gleason score (

P
=
0.0063

); the frequency of tumor-specific hypermethylation was 96% (44/46) in tumors with Gleason

score
≥
7

, whereas that in tumors with Gleason score 6 was 25% (1/4). Immunohistochemical analyses using these 50 cases indicated that only 8% (4/50) of cancerous tissues expressed PYCARD, whereas 80% (40/50) of corresponding normal prostate epithelial and/or basal cells expressed PYCARD. In addition, there was no relationship between PYCARD immunostaining and the Gleason score in cancerous tissue and surrounding normal tissue. Inducible expression of PYCARD inhibited cell proliferation by induction of apoptosis. These results suggest that aberrant methylation of PYCARD is a distinctive feature of prostate cancers with Gleason

score
≥
7

and may play an important role in escaping from apoptosis in prostatic tumorigenesis.
An Evolutionary Game Analysis on Public Information Communication between the Government and the Public in China
Authors: Luo Hongsen , Gao Ying , Shi Fulei
Published: February 2021

Public information is a social resource that connects all aspects of social life, regulates social activities and public behaviors, and plays a very important role in influencing public trust. Based on the perspective of communication, we divide the government into two ways to release public information, that is, mass communication and personalized recommendation. Moreover, the public can choose to acquire or not acquire a strategy. Then, this study conducts an evolutionary game between the government and the public to analyze the influence of public information on the public in China. Our objective is to find how the evolutionary path changes between the two players when strategies are changing. Then, a simulation analysis is presented in six scenarios to illustrate the results. The results show that the two players can converge to different stable statuses under different situations.
Characterization and Hepatoprotections of Ganoderma lucidum Polysaccharides against Multiple Organ Dysfunction Syndrome in Mice
Authors: Zhang Yiwen , Feng Yanbo , Wang Wenshuai , Jia Le , Zhang Jianjun
Published: February 2021

Background. The liver is one of the most commonly affected organs in multiple organ dysfunction syndrome (MODS). In recent years, there have been many studies on Ganoderma lucidum polysaccharides (GLP), but the role of GLP in MODS is still unclear. The purpose of this work was to explore the antioxidant, anti‐inflammatory, and protective effects of GLP on the liver in MODS model mice. Methods. The characteristic properties of GLP were processed by physicochemical analysis. The MODS models were successfully established with intraperitoneal injection of zymosan in Kunming strain mice. The antioxidant, anti‐inflammatory, and hepatoprotective effects of GLP were processed both in vitro and in vivo by evaluating the oxidative parameters, inflammatory factors, and liver pathological observations. Results. The characterization analysis revealed that GLP was a pyranose mainly composed of glucose with the molecular weights (Mw) of 8309 Da. The experimental results proved that GLP had potential hepatoprotection possibly by improving the antioxidant status (scavenging excessive oxygen radicals, increasing the antioxidant enzyme activities, and reducing the lipid peroxide), alleviating the inflammatory response (reducing the inflammatory factor levels), and guaranteeing the liver functions. Conclusions. This research suggested that GLP had the potential to be developed as a natural medicine for the treatment of multiple organ failure.
Next-Generation Sequencing for Molecular Diagnosis of Cystic Fibrosis in a Brazilian Cohort
Authors: Cambraia Amanda , Junior Mario Campos , Zembrzuski Verônica Marques , Junqueira Ricardo Magrani , Cabello Pedro Hernán , de Cabello Giselda Maria Kalil
Published: February 2021

Cystic fibrosis (CF), an autosomal recessive genetic disease, is recognized as one of the most prevalent diseases in Caucasian populations. Epidemiological data show that the incidence of CF varies between countries and ethnic groups in the same region. CF occurs due to pathogenic variants in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), located on chromosome 7q31.2. To date, more than 2,000 variants have been registered in the CFTR database. The study of these variants leads to the diagnosis and the possibility of a specific treatment for each patient through precision medicine. In this study, complete screening of CFTR was performed through next-generation sequencing (NGS) to gain insight into the variants circulating in the population of Rio de Janeiro and to provide patient access to treatment through genotype-specific therapies. Samples from 93 patients with an inconclusive molecular diagnosis were subjected to full-length screening of CFTR using an Illumina NGS HiSeq platform. Among these patients, 46 had two pathogenic variants, whereas 12 had only one CFTR variant. Twenty-four variants were not part of our routine screening. Of these 24 variants, V938Gfs

∗

37 had not been described in the CF databases previously. This research achieved a molecular diagnosis of the patients with CF and identification of possible molecular candidates for genotype-specific treatments.
Optimized EGFR Blockade Strategies in EGFR Addicted Gastroesophageal Adenocarcinomas
Authors: Corso Simona , Pietrantonio Filippo , Apicella Maria , Migliore Cristina , Conticelli Daniela , Petrelli Annalisa , D'Errico Laura , Durando Stefania , Moya-Rull Daniel , Bellomo Sara E. , Ughetto Stefano , Degiuli Maurizio , Reddavid Rossella , Fumagalli Uberto , De Pascale Stefano , Sgroi Giovanni , Rausa Emanuele , Baiocchi Gian Luca , Molfino Sarah , De Manzoni Giovanni , Bencivenga Maria , Siena Salvatore , Sartore-Bianchi Andrea , Morano Federica , Corallo Salvatore , Prisciandaro Michele , Di Bartolomeo Maria , Gloghini Annunziata , Marsoni Silvia , Sottile Antonino , Sapino Anna , Marchiò Caterina , Dahle-Smith Asa , Miedzybrodzka Zosia , Lee Jessica , Ali Siraj M. , Ross Jeffrey S. , Alexander Brian M. , Miller Vincent A. , Petty Russell , Schrock Alexa B. , Giordano Silvia
Published: February 2021

Purpose:

Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.

Experimental Design:

We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).

Results:

The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.

Conclusions:

This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors.

See related commentary by Openshaw et al., p. 2964
Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer
Authors: Wang Xian , Veeraraghavan Jamunarani , Liu Chia-Chia , Cao Xixi , Qin Lanfang , Kim Jin-Ah , Tan Ying , Loo Suet Kee , Hu Yiheng , Lin Ling , Lee Sanghoon , Shea Martin J. , Mitchell Tamika , Li Shunqiang , Ellis Matthew J. , Hilsenbeck Susan G. , Schiff Rachel , Wang Xiao-Song
Published: February 2021

Purpose:

Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)–positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer.

Experimental Design:

The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models.

Results:

NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or de novo endocrine resistance.

Conclusions:

Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
ONC201 Shows Potent Anticancer Activity Against Medullary Thyroid Cancer via Transcriptional Inhibition of RET, VEGFR2, and IGFBP2
Authors: Bagheri-Yarmand Rozita , Dadu Ramona , Ye Lei , Shiny Jebaraj Yaashmin , Martinez Jade A. , Ma Junsheng , Tarapore Rohinton S. , Allen Joshua E. , Sherman Steven I. , Williams Michelle D. , Gagel Robert F.
Published: February 2021

Gain-of-function point mutations in the receptor tyrosine kinase RET, a driver oncogene in medullary thyroid carcinoma (MTC), prevent apoptosis through inhibition of ATF4, a critical transcriptional regulator of endoplasmic reticulum stress. However, the critical regulatory mechanisms driving RET-dependent oncogenesis remain elusive, and there is a clinical need to identify a transcriptional RET inhibitor. Here, we found that RET depletion decreased IGFBP2 and VEGFR2 mRNA and protein expression in MTC cells. IGFBP2 knockdown decreased cell survival and migration of MTC cells. In patients, IGFBP2 expression increased in metastatic MTC, and high IGFBP2 associated with poor overall survival. VEGFR2 protein levels were positively associated with RET expression in primary tumors, and VEGF-mediated increased cell viability was RET dependent. The small-molecule ONC201 treatment of MTC cells caused apoptotic cell death, decreased transcription of RET, VEGFR2, IGFBP2, increased mRNA levels of ATF4, and ATF4 target genes including DDIT3, BBC3, DUSP8, MKNK2, KLF9, LZTFL1, and SESN2. Moreover, IGFBP2 depletion increased ONC201-induced cell death. ONC201 inhibited tumor growth at a well-tolerated dose of 120 mg/kg/week administered by oral gavage and decreased MTC xenograft cell proliferation and angiogenesis. The protein levels of RET, IGFBP2, and VEGFR2 were decreased in ONC201-treated xenografts. Our study uncovered a novel ONC201 mechanism of action through regulation of RET and its targets, VEGFR2 and IGFBP2; this mechanism could be translated into the clinic and represent a promising strategy for the treatment of all patients with MTC, including those with TKI-refractory disease and other cancer with RET abnormalities.
Anti-LYPD1/CD3 T-Cell-Dependent Bispecific Antibody for the Treatment of Ovarian Cancer
Authors: Lo Amy A. , Johnston Jennifer , Li Ji , Mandikian Danielle , Hristopoulos Maria , Clark Robyn , Nickles Dorothee , Liang Wei-Ching , Hötzel Kathy , Dunlap Debra , Pham Thinh , Cai Hao , Ovacik Meric , Bravo-Perez Daniel , Mai Elaine , Slaga Dionysos , Ellerman Diego , Ziai James , Totpal Klara , Lee Genee , Boswell C. Andrew , Payandeh Jian , Wu Yan , Junttila Teemu T.
Published: February 2021

Ovarian cancer is a diverse class of tumors with very few effective treatment options and suboptimal response rates in early clinical studies using immunotherapies. Here we describe LY6/PLAUR domain containing 1 (LYPD1) as a novel target for therapeutic antibodies for the treatment of ovarian cancer. LYPD1 is broadly expressed in both primary and metastatic ovarian cancer with ∼70% prevalence in the serous cancer subset. Bispecific antibodies targeting CD3 on T cells and a tumor antigen on cancer cells have demonstrated significant clinical activity in hematologic cancers. We have developed an anti-LYPD1/CD3 T-cell-dependent bispecific antibody (TDB) to redirect T-cell responses to LYPD1 expressing ovarian cancer. Here we characterize the nonclinical pharmacology of anti-LYPD1/CD3 TDB and show induction of a robust polyclonal T-cell activation and target dependent killing of LYPD1 expressing ovarian cancer cells resulting in efficient in vivo antitumor responses in PBMC reconstituted immune-deficient mice and human CD3 transgenic mouse models. Anti-LYPD1/CD3 TDB is generally well tolerated at high-dose levels in mice, a pharmacologically relevant species, and showed no evidence of toxicity or damage to LYPD1 expressing tissues.
ERK Inhibitor LY3214996-Based Treatment Strategies forRAS-Driven Lung Cancer
Authors: Köhler Jens , Zhao Yutong , Li Jiaqi , Gokhale Prafulla C. , Tiv Hong L. , Knott Aine R. , Wilkens Margaret K. , Soroko Kara M. , Lin Mika , Ambrogio Chiara , Musteanu Monica , Ogino Atsuko , Choi Jihyun , Bahcall Magda , Bertram Arrien A. , Chambers Emily S. , Paweletz Cloud P. , Bhagwat Shripad V. , Manro Jason R. , Tiu Ramon V. , Jänne Pasi A.
Published: February 2021

RAS gene mutations are the most frequent oncogenic event in lung cancer. They activate multiple RAS-centric signaling networks among them the MAPK, PI3K, and RB pathways. Within the MAPK pathway, ERK1/2 proteins exert a bottleneck function for transmitting mitogenic signals and activating cytoplasmic and nuclear targets. In view of disappointing antitumor activity and toxicity of continuously applied MEK inhibitors in patients with KRAS-mutant lung cancer, research has recently focused on ERK1/2 proteins as therapeutic targets and on ERK inhibitors for their ability to prevent bypass and feedback pathway activation. Here, we show that intermittent application of the novel and selective ATP-competitive ERK1/2 inhibitor LY3214996 exerts single-agent activity in patient-derived xenograft (PDX) models of RAS-mutant lung cancer. Combination treatments were well tolerated and resulted in synergistic (ERKi plus PI3K/mTORi LY3023414) and additive (ERKi plus CDK4/6i abemaciclib) tumor growth inhibition in PDX models. Future clinical trials are required to investigate if intermittent ERK inhibitor-based treatment schedules can overcome toxicities observed with continuous MEK inhibition and—equally important—to identify biomarkers for patient stratification.
Isoform- and Phosphorylation-specific Multiplexed Quantitative Pharmacodynamics of Drugs Targeting PI3K and MAPK Signaling in Xenograft Models and Clinical Biopsies
Authors: Herrick William G. , Kilpatrick Casey L. , Hollingshead Melinda G. , Esposito Dominic , O'Sullivan Coyne Geraldine , Gross Andrea M. , Johnson Barry C. , Chen Alice P. , Widemann Brigitte C. , Doroshow James H. , Parchment Ralph E. , Srivastava Apurva K.
Published: February 2021

Ras/Raf/MEK/ERK (MAPK) and PI3K/AKT signaling pathways influence several cell functions involved in oncogenesis, making them attractive drug targets. We describe a novel multiplex immunoassay to quantitate isoform-specific phosphorylation of proteins in the PI3K/AKT and MAPK pathways as a tool to assess pharmacodynamic changes. Isoform-specific assays measuring total protein and site-specific phosphorylation levels of ERK1/2, MEK1/2, AKT1/2/3, and rpS6 were developed on the Luminex platform with validated antibody reagents. The multiplex assay demonstrated satisfactory analytic performance. Fit-for-purpose validation was performed with xenograft models treated with selected agents. In PC3 and HCC70 xenograft tumors, the PI3Kβ inhibitor AZD8186 suppressed phosphorylation of AKT1, AKT2, and rpS6 for 4 to 7 hours post single dose, but levels returned to baseline by 24 hours. AKT3 phosphorylation was suppressed in PC3 xenografts at all doses tested, but only at the highest dose in HCC70. The AKT inhibitor MK-2206 reduced AKT1/2/3 phosphorylation in SW620 xenograft tumors 2 to 4 hours postdose, and the MEK inhibitor selumetinib reduced MEK1/2 and ERK1/2 phosphorylation by up to 50% and >90%, respectively. Clinical utility was demonstrated by analyzing biopsies from untreated patients with plexiform neurofibromas enrolled in a clinical trial of selumetinib (NCT02407405). These biopsies showed MEK and ERK phosphorylation levels sufficient for measuring up to 90% inhibition, and low AKT and rpS6 phosphorylation. This validated multiplex immunoassay demonstrates the degree and duration of phosphorylation modulation for three distinct classes of drugs targeting the PI3K/AKT and MAPK pathways.
Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures
Authors: Kotlov Nikita , Bagaev Alexander , Revuelta Maria V. , Phillip Jude M. , Cacciapuoti Maria Teresa , Antysheva Zoya , Svekolkin Viktor , Tikhonova Ekaterina , Miheecheva Natalia , Kuzkina Natalia , Nos Grigorii , Tabbo Fabrizio , Frenkel Felix , Ghione Paola , Tsiper Maria , Almog Nava , Fowler Nathan , Melnick Ari M. , Leonard John P. , Inghirami Giorgio , Cerchietti Leandro
Published: February 2021

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.

Significance:

In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

This article is highlighted in the In This Issue feature, p. 1307
Pilomatrixoma with Atypical Features: A Case Report
Authors: Missak Meina , Haig Aaron , Gabril Manal
Published: February 2021

Pilomatrixoma is an uncommon, benign tumor with differentiation towards both the hair matrix and cells arising in the cortex, most frequently appearing in the first or second decade of life. In rare instances, pilomatrixomas can show malignant transformation. Pilomatrix carcinoma is extremely uncommon and has traditionally been considered a tumor of low malignant potential; however, a high local recurrence rate has been reported. There is a paucity of literature on these lesions, with only a few reports describing the spectrum of malignant changes seen in these lesions. In this case report, we present a case of pilomatrixoma in an adult patient showing atypical features. While the tumor is small, there are focal features that suggest progression to malignancy, but do not fulfill the criteria for pilomatrix carcinoma. These focal atypical features include a focal infiltrative pattern at the periphery, with a variable cytological atypia and an increased mitotic rate, up to five mitotic events/high-power field. Irregular foci of central necrosis (comedonecrosis) were present in several lobules. Some of the features identified were similar to a subset of pilomatrixoma, known as “proliferating pilomatrixoma.” However, our case did not have the diffuse changes or larger size that has been frequently reported in “proliferating pilomatrixoma.” In conclusion, given the lack of focality of the changes, the lesion in our case is best described as a pilomatricoma with atypical features. Furthermore, our case may highlight the need to ensure close clinical follow-up for these lesions with unexpected atypical features that raise concern of recurrence and malignant transformation.
The Expanding Phenotypic Spectrums Associated with ATP1A3 Mutation in a Family with Rapid-Onset Dystonia Parkinsonism
Authors: Yuan Yi , Ran Longfeng , Lei Lifang , Zhu Haixia , Zhu Xiying , Chen Han
Published: February 2021

Introduction: Rapid-onset dystonia parkinsonism (RDP), also referred to as Dystonia 12, is a rare autosomal dominant genetic disease characterized by abrupt onset of a rostrocaudal gradient of dystonia with prominent bulbar symptoms, and parkinsonian features, primarily bradykinesia and postural instability without tremor. The purpose of this study was to identify the genetic defect in a Chinese pedigree with familial RDP and to explore genotype-phenotype correlation. Methods: A 3-generation Chinese Han pedigree consisting of 9 members and 3 patients with RDP, and 200 unrelated ethnically matched normal subjects were recruited in this study. Exome sequencing was performed in the proband, and Sanger sequencing was then conducted in other family members and 200 normal controls. Results: In addition to the typical clinical manifestations of RDP, the proband and her sister presented tongue tremor which developed at the onset, and intriguingly the proband showed a “re-emergent” tongue tremor. Both the proband and her sister had a medical history of hyperthyroidism, and at the psychiatric interview they both received diagnoses of depression and anxiety. Excessive grammar errors existed in most sentences written by the proband, and this written-expression disorder occurred years before the onset of RDP. The mother of the proband presented tongue enlargement, oromandibular dystonia, and limb dystonia, which were not observed in her 2 daughters at the time of study. A missense variant, c.1838C>T (p.T613M), in the ATP1A3 gene, was identified in the 3 patients in the family and in 2 young children but was absent in family members without RDP and in the 200 normal controls. Conclusion: These findings may broaden the phenotypic spectrums of RDP with mutations in the ATP1A3 gene, provide new insights into the diagnosis of RDP, and have implications for genetic counseling.
A Severe Course of Relapsing-Remitting Acute-Onset Chronic Inflammatory Demyelinating Polyneuropathy in a Young Man
Authors: Patnaik Anna P. , Mininni Joseph , Porter Neil C. , Morris Nicholas A.
Published: February 2021

Acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is an immune mediated neuropathy characterized by progressive weakness and sensory impairment lasting over 2 months. Guillain-Barré-Strohl syndrome (GBS) is an immune mediated polyneuropathy with a similar presentation often over less than 4 weeks. While some have argued for the existence of recurrent GBS, most classify the syndrome as a form of relapsing-remitting CIDP. However, there are cases of GBS with treatment-related fluctuations that must be distinguished from A-CIDP as patients with A-CIDP require long-term immunotherapy. In this case report, we discuss a patient with multiple relapses over 3 years, who is more likely to have A-CIDP. His ganglioside profile, which has rarely been reported in A-CIDP, included high concentrations of anti-GM1, anti-GD1a, and anti-GD1b antibodies, which may account for his severe disease course.
Common and Rare Histological Variants of Hepatoblastoma in Children: A Pathological Diagnosis and Review of the Literature
Authors: Bharti Sushma , Bharti Jyotsna Naresh , Sinha Arvind , Yadav Taruna
Published: February 2021

Hepatoblastoma (HB) is a rare tumor, but it is the most common primary liver malignancy in children and comprised of approximately 1% of all pediatric malignancies. Mostly, this tumor is sporadic in nature but can show a syndrome association. Upregulation in Wnt/β-catenin pathway can be there in 70–80% cases of HB. Most often present as abdominal mass and has a raised alpha-fetoprotein levels. Distant metastasis usually occurs in the lungs. HB is classified into 2 broad categories: epithelial and mesenchymal type. The majority of HB are epithelial type. The HB must be distinguished from focal nodular hyperplasia, hepatocellular adenoma, and hepatocellular carcinoma, while small-cell undifferentiated HB from the malignant rhabdoid tumor. The histomorphology and immunohistochemistry are essential for the diagnosis of different HB. The neoadjuvant chemotherapy followed by surgery is the mainstay of the treatment. The 2 well-established prognostic factors of HB are stage and histological type. Herein, we report a case series of common and rare histological variants of HB.
Anthropometric Evaluation and Assessment of Food Intake of Parents of Pediatric Patients with Chronic Rheumatic Diseases
Authors: Pereira Lucila , Previdelli Ágatha Nogueira , Rossi Rosana Gomes de Torres , Rodrigues Wellington Douglas , Fonseca Fernando Luiz Affonso , Len Claudio Arnaldo , Terreri Maria Teresa , Saccardo Sarni Roseli Oselka
Published: February 2021

Introduction: Parents’ eating behavior, lifestyle, and food choices can interfere with their children’s eating habits, bringing new perspectives for the development of beneficial interventions in the context of chronic rheumatic diseases. Objectives: The objective is to evaluate BMI, dietary intake, physical activity, and biomarkers of lipid metabolism in parents of children and adolescents with chronic rheumatic diseases and to verify the association with those of their children. Methods: This is a cross-sectional study with 91 parents, and their respective children diagnosed with juvenile idiopathic arthritis (n = 30, 33.0%), juvenile systemic lupus erythematosus (n = 41, 45.0%), and juvenile dermatomyositis (n = 20, 22.0%). Anthropometric and dietary data, physical activity, lipid profile, and apolipoproteins A-I and B were evaluated. Results: In total, 67% of parents and 27.5% of children were overweight; 80% of overweight children/adolescents also had parents with the same nutritional diagnosis. We found a moderate association of total fat intake (Cramer’s V test = 0.254; p = 0.037), and a weak association of saturated fat intake (Cramer’s V test = 0.219; p = 0.050) and cholesterol intake (Cramer’s V test = 0.234; p = 0.025) between parents and their children. A high prevalence of dyslipidemia was observed for parents (82.4%) and children (83.5%), however, with no association between both. A weak association was found between parents and children (Cramer’s V test = 0.238; p = 0.024) for triglycerides, and no association was found between parents and children concerning physical activity. Conclusion: The high frequency of overweight and dyslipidemia observed in parents, combined with the association between the fat intake by parents and their children with chronic rheumatic diseases, points to the importance of intervention strategies with the engagement and participation of families.
Wilson’s Disease Presenting in Late Adult Life
Authors: AlDhaleei Wafa , AlAhmad Maryam , Alhosani Ibrahim
Published: February 2021

Wilson’s disease (WD) is an autosomal recessive disease affecting the copper metabolism resulting in various clinical presentations. Diagnosis includes the presence of low serum copper and ceruloplasmin concentrations, increased urinary copper excretion, and/or increased hepatic copper concentrations. Yet, genetic testing remains diagnostic. Management includes copper chelating agents and liver transplant in advance cases. We report a case of WD presenting with liver function impairment in late adult life and started on treatment. Therefore, early diagnosis and treatment of WD can prevent related complications.
Vitamin D3 Controls TLR4- and TLR2-Mediated Inflammatory Responses of Endometrial Cells
Authors: Ghanavatinejad Alireza , Rashidi Nesa , Mirahmadian Mahroo , Rezania Simin , Mosalaei Mahdokht , Ghasemi Jamileh , Zarnani Amir-Hassan
Published: February 2021

Objectives: Vitamin D has potent immunoregulatory features and modulates innate and adaptive immune responses. There is a significant association between intrauterine infection-associated inflammatory responses and pregnancy complications such as abortion and preterm labor. Here, we investigated how 1,25 (OH)2 D3 could modulate inflammatory responses of endometrial cells. Design: This is an in vitro experimental study. Endometrial stromal cells (ESCs) and whole endometrial cells (WECs) were collected from 15 apparently normal women, and the immunomodulatory effects of 1,25 (OH)2 D3 on lipopolysaccharide (LPS)- or lipoteichoic acid (LTA)-treated ESCs and WECs were investigated. Participants/Materials, Setting, and Methods: Women with no history of abortion, infertility, endometriosis, or sign of vaginal infection were enrolled in this study. Endometrial samples were collected by gynecologists using a Pipelle pipette in the proliferative phase of the menstrual cycle. WECs and ESCs were collected and treated with either LPS or LTA. The levels of IL-6, IL-8, and TNF-α in culture supernatants were quantified using the ELISA technique. TLR2, TLR4, and MyD88 expressions were assessed by RT-qPCR. TLR4 expression at the protein level was studied by the Western blot technique. Results: 1,25 Dihydroxycholecalciferol (1,25 (OH)2 D3) significantly reduced TNF-α production in LPS-activated ESCs and TNF-α and IL-6 production by LTA-stimulated WECs. In contrast, 1,25 (OH)2 D3 pretreatment increased the production of IL-8 by LPS- and LTA-stimulated endometrial cells. 1,25 (OH)2 D3 pretreatment markedly reduced LPS-induced TLR4 protein expression by ESCs. LPS treatment of ESCs significantly induced MyD88 gene expression. This effect was reversed when these cells were pretreated with 1,25 (OH)2 D3 before stimulation with LPS. Limitations: Because of the small size of samples, doing experiments all together on some samples was not feasible. Confirmation of the results obtained here needs well-designed in vivo studies. Conclusions: 1,25 (OH)2 D3 is an immunomodulatory molecule essential for maintaining endometrial immune homeostasis by controlling potentially harmful inflammatory responses associated with female reproductive tract infections.
Heart Rate Variability-Measured Stress and Academic Achievement in Medical Students
Authors: Yoo Hyo Hyun , Yune So Jung , Im Sun Ju , Kam Bee Sung , Lee Sang Yeoup
Published: February 2021

Objectives: Stress can affect learning and memory in students. Previous studies on stress in students were conducted mainly through surveys. We investigated how heart rate variability (HRV)-measured stress is related to academic achievement in medical students during clerkship. Subjects and Methods: A cross-sectional study was conducted. HRV measurements were performed in 97 third-year medical students during their family medicine clerkship course. Data on written and skilled examination scores of the end of the school year were also collected. We assessed the association between HRV-measured stress and written/skilled examination scores. Results: Written examination scores showed a positive correlation with standard deviation of the normal-to-normal intervals (SDNNs) (r = 0.245, p = −0.016), sympathetic nervous system/parasympathetic nervous system (SNS/PNS) balance (r = 0.218, p = 0.033), and stress index (r = 0.381, p = 0.004). Students with an unhealthy SDNN, a dominant SNS, and a high stress index had higher scores in written examinations than students with a healthy SDNN, a balanced SNS/PNS, and a normal stress index, respectively (p = 0.004, 0.018, and 0.012, respectively). Moreover, skilled examination scores were negatively correlated with BMI (r = −0.249, p = 0.014) and were higher in female students (r = 0.240, p = 0.018). Students with an abnormal autonomic balance diagram (ABD) had a higher score than students with a normal ABD (p = 0.03). Conclusions: This study shows that medical students with higher stress measured by HRV have higher academic achievement, especially in written examinations. Further studies are needed to confirm the results of this study and to assess the long-term effects of HRV-measured stress on medical students.
Evaluation of Macular Changes in the Long Term after Pars Plana Vitrectomy with Internal Limiting Membrane Peeling for Diabetic Macular Edema
Authors: Gunay Betul Onal , Erdogan Gurkan
Published: February 2021

Aim: To evaluate long-term macular changes following pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling for diabetic macular edema (DME). Methods: Forty eligible eyes of 37 patients were included in this retrospective study. Best corrected visual acuity (BCVA), central macular thickness (CMT), and 5-mm macular volume (5-MV) were examined preoperatively, postoperatively after 1, 2, 3, 6, 12, and 24 months, and at a final visit. Response to surgical treatment was considered as recurrence, reincrease, or recovery of DME based on macular changes. Results: Mean follow-up time was 51.1 ± 19.0 months after surgery. Recurrence (n = 5) and reincrease (n = 17) of DME was observed in 22 eyes (55%) and additional treatments were applied. Recovery of DME was observed in 18 eyes (45%). Preoperative and final-visit mean BCVA (logMAR) was 1.08 ± 0.37 and 0.93 ± 0.45, respectively (p = 0.02). Preoperative and final-visit mean CMT was 514.74 ± 155.65 and 281.87 ± 112.58 µm, respectively (p < 0.001). The 5-MV significantly decreased following surgery (from 8.18 ± 1.57 to 6.52 ± 1.39 mm3; p < 0.001). DME was present in 12 eyes (30%) at the final visit. Conclusion: Although PPV with ILM peeling had efficacy in DME management, this effect tended to decrease over time, such that a considerable number of patients required additional treatment.
Rise-Up mist-netting (RUM): a mobile protocol for trapping wary territorial birds
Authors: Amorim Paulo Sérgio , Rossi Mariana Fonseca , Guaraldo André de Camargo
Published: February 2021

Many bird species avoid traditional traps such as mist nets, thus alternative trapping methods are often needed. The Rufous Hornero (Furnariidae: Furnarius rufus) is one such species that was captured so far using conventional mist netting in rural areas or using nest-targeted traps, which risk nest damage and abandonment. Here we describe the novel rise-up mist-netting (RUM) protocol and its catchability for the wary and territorial Rufous Hornero in an urban area. The RUM trap allowed us quickly capturing 40 Rufous Hornero individuals even in paved parking lots and streets during the bird’s breeding period. The RUM is an active and targeted protocol that demands a single and quickly trainable field assistant. Therefore, it should also enable the capture of many understudied territorial but wary species. Moreover, it has enough mobility to fit studies in urban areas, and whenever researchers may deal with limited space and, at the same time, should reduce negative visual impacts to the general public of birds’ capturing and banding procedures.
Record of the non-indigenous species Sternaspis aff. nana Zhadan, Tzetlin & Salazar-Vallejo, 2017 (Annelida: Sternaspidae) in the Southwest Atlantic Ocean
Authors: Craveiro Nykon , Rosa Filho José Souto
Published: February 2021

The introduction of non-indigenous marine species in new habitats is generally associated with ships arriving at ports, driven by species transported in ballast water and sediment and biofouling communities on ship hulls, drifting object and underwater surfaces in dock areas. The present paper reports the record of the specie Sternaspis aff. nana in the Atlantic Ocean, discussing its possible conservation status and method of arrival to Brazil. Sediments samples were collected in the external area (11 m depth) of the Suape Harbor (Brazil) in February 2018. Two individuals of Sternaspis aff. nana were recorded, representing the first record of this species in the Southwest Atlantic Ocean. The way S. aff. nana arrived in Brazilian waters cannot be easily determined, the short-lived lecithotrophic larvae of sternaspids suggest that the specimens found in Suape have arrived in ballast sediment. An increase in trade between Brazil and Asian countries since the 2000s has led to that more ships coming from China having arrived in Brazilian harbors. The arrival of S. aff. nana, originally described in the South China Sea, in the Suape harbor area may have resulted from this intense movement of ships between China and Brazil.