bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neratinib causes non-recoverable gut injury and reduces intestinal cytochrome P450 3A enzyme in mice
Authors: Tao Gabriel , Dagher Fatima , Ghose Romi 
Published: November 2021

Abstract
Neratinib is a pan-HER tyrosine kinase inhibitor newly approved by FDA in 2017 to treat HER2-positive breast cancer, but the phase III trial of neratinib showed that 96% of the patients taking neratinib experienced diarrhea. So far very few mechanistic studies explore neratinib-induced gastrointestinal (GI) toxicity. Hereby, we performed toxicity studies in mice to characterize the potential mechanism underlying this adverse effect. C57BL/6 J mice were separated into three groups A, B, C. Group A received vehicle; group B was orally dosed with 100 mg/kg neratinib once daily for 18 days. Group C was dosed with 100 mg/kg neratinib for 12 days and switched to vehicle for 6 days. Intestine and liver were collected for further analysis. Human intestine-derived cells were treated with neratinib in vitro. Our results showed that 12 days treatment of neratinib caused persistent histological damage in mouse GI tract. Both gene expression and activity of Cyp3a11, the major enzyme metabolizing neratinib in mice was reduced in small intestine. The gene expression of proinflammatory cytokines increased throughout the GI tract. Such damages were not recovered after 6 days without neratinib treatment. In addition, in vitro data showed that neratinib was potent in killing human intestine-derived cell lines. Based on such findings, we hypothesized that neratinib downregulates intestinal CYP3A enzyme to cause excessive drug disposition, eventually leading to gut injury.
Bilateral Hand Metastases From a Pleomorphic/Dedifferentiated Leiomyosarcoma: A Case Report
Authors: Bubau Marina , Georgiu Carmen , Fodor Lucian 
Published: November 2021

Abstract:
Leiomyosarcomas of the lower extremity are heterogeneous tumors with high recurrence and metastasizing rates, which, rarely, can suffer a dedifferentiation process, making them extremely aggressive and unpredictable. We report the case of a 72-year-old female patient who presented the clinical and histopathological features of a rare leiomyosarcoma of the foot that was completely excised, but because of the interruption of adjuvant oncological treatment and lack of compliance for the follow-up, the patient suffered a dedifferentiation process and the tumor metastasized in the fingers—an unprecedented site for this type. The present case proves the fact that there is still a lot we do not know about the behavior of this disease, and there is always room to learn. Also, through this report, we are emphasizing a frequently encountered and never-ending problem in our country—that of difficult and resource-consuming cases derived from disconsidering medical advice by noncompliant patients when faced with a malignant diagnosis, making all attempts to offer them a better quality of life futile.
Multifocal Cutaneous Granular Cell Tumor in Children: A Rare Entity
Authors: El-Khalawany Mohamed , Rageh Mahmoud A. , Hassab-El-Naby Hussein M. M. 
Published: November 2021

Abstract:Granular cell tumors (GCTs) are rare soft tissue tumors of Schwann cell origin that manifest as papulonodular lesions and occur mainly in adults. The diagnosis is usually confirmed by histopathology. Most of GCTs are benign, but some lesions may exhibit malignant criteria. This study is a retrospective case series including all children with histopathologically documented multiple GCTs who attended the dermatology department of the university hospitals between February 2008 and March 2021. The objective of our study was to raise awareness to this unrecognized and rare entity in such age group. The study included 9 patients (6 girls and 3 boys) with multiple GCTs. Their age ranged between 5 and 13 years. The lesions were skin-colored to light brown, firm, smooth-surfaced nodules. Most of the lesions were on the extremities, and their mean diameter was 160.5 mm2. None of the lesions exhibited any malignant criteria on histopathology. No extracutaneous or mucosal lesions were detected. Dermatologists should be aware of this rare condition in children because early recognition allows more conservative resection of the tumor and less invasive reconstruction of the defect. Our study highlights that multifocality does not necessarily indicate malignancy or other systemic comorbidities.
Estrogen modulates metabolic risk profile after resistance training in early postmenopausal women: a randomized controlled trial
Authors: Dam Tine Vrist , Dalgaard Line Barner , Thomsen Christian Bejlegaard , Hjortebjerg Rikke , Ringgaard Steffen , Johansen Frank Ted , Bengtsen Mads Bisgaard , Mose Maike , Lauritsen Katrine Meyer , Søndergaard Esben , Gravholt Claus H. , Hansen Mette 
Published: November 2021

Abstract

Objective:
Women experience an unhealthy change in metabolic risk profile at menopause. The purpose of the present study was to determine effects of resistance training with or without transdermal estrogen therapy (ET) on adipose tissue mass and metabolic risk profile in early postmenopausal women.

Methods:
A double-blinded randomized controlled trial, where healthy, untrained postmenopausal women were allocated to supervised resistance training with placebo (PLC, n = 16) or transdermal ET (n = 15) for 12 weeks. Endpoints with prespecified hypotheses were the change in total fat mass (FM) (main endpoint) and the change in visceral FM (secondary endpoint) from before to after the intervention. Additionally, prespecified endpoints of body composition, metabolic health-related blood markers, fat%, fat cell size, and lipogenic markers in subcutaneous adipose tissue (SAT) from abdominal and femoral region were explored.

Results:
Compared with the ET group, the PLC group experienced a greater reduction (time × treatment interaction P < 0.05) in total FM (PLC vs ET: −5.6% vs −1.1%) and visceral FM (−18.6% vs −6.8%), and femoral SAT (−5.6% vs 1.0%), but not abdominal SAT mass (−8.5% vs −2.8%, P = 0.15).
The ET group improved their metabolic blood profile by reduced low-density lipoprotein, glucose and hemoglobin A1c compared with PLC (time × treatment interaction P < 0.05). The intervention induced changes in lipolytic markers of abdominal SAT, whereas no changes were detected in femoral SAT.

Conclusion:
Use of transdermal ET reduced adipose tissue loss, but improved metabolic blood markers when combined with 12 weeks of progressive resistance training in early postmenopausal women.
Cardiovascular mortality after bilateral oophorectomy: a prospective cohort study
Authors: Olesen Cathrine S. , Koch Trine , Uldbjerg Cecilie S. , Gregersen Laura S. , Christensen Jane , Dehlendorff Christian , Priskorn Lærke , Wilson Louise F. , Lim Youn-Hee , Jørgensen Jeanette T. , Andersen Zorana J. , Juul Anders , Abildgaard Julie , Hickey Martha , Bräuner Elvira V. 
Published: November 2021

Abstract

Objectives:
Bilateral oophorectomy permanently reduces endogenous estrogen exposure and may increase cardiovascular mortality in women. This study aimed to investigate the association between bilateral oophorectomy and cardiovascular mortality and whether this association was conditional on hysterectomy or on the use of hormone therapy at the time of study entry.

Methods:
A prospective cohort study of 25,338 female nurses aged ≥ 45 years within the Danish Nurse Cohort. Nurses were enrolled in 1993 or 1999 and followed until death, emigration, or end of follow-up on December 31, 2018, whichever came first. Exposure was bilateral oophorectomy. Outcome was cardiovascular mortality. Associations were estimated using Poisson regression models with log person-years as the offset.

Results:
A total of 2,040 (8.1%) participants underwent bilateral oophorectomy. During a mean follow-up of 21.2 (SD: 5.6) years, 772 (3.0%) nurses died from cardiovascular disease. In adjusted analyses, a 31% higher rate of cardiovascular mortality was observed after bilateral oophorectomy (aMRR 1.31; 95% CI, 0.88-1.96) compared with women who retained their ovaries. No evidence of effect modification by use of hormone therapy at baseline or by hysterectomy on the association between bilateral oophorectomy and cardiovascular mortality was observed.

Conclusion:
Bilateral oophorectomy may be associated with cardiovascular mortality in women, but the estimate was not statistically significant. Additionally, we were unable to make firm conclusions regarding the possible modifying role of hormone therapy and hysterectomy on this potential association. Additional studies are needed to replicate this work.
Conduit-assisted Allograft Neurorrhaphy for the Treatment of Intractable Lower Extremity Pain Due to Neuromas-in-continuity
Authors: Rodriguez-Collazo Edgardo , Laube Ward Kaitlyn 
Published: November 2021

Background:
We present a novel technique for the management of intractable lower extremity pain, due to neuromas-in-continuity of two peripheral nerves, through combined neurectomies proximal to the zone of initial injury and subsequent bridging utilizing an allograft-coupled conduit construct.

Methodology:
A retrospective chart review of 36 patients (18 women and 18 men) with recalcitrant nerve pain secondary to neuromas-in-continuity of two peripheral nerves following lower extremity trauma was conducted. Subjects underwent superficial peroneal nerve (SPN) to deep peroneal nerve neurorrhaphy (19 patients) or SPN to sural nerve neurorrhaphy (17 patients) proximal to the zone of initial injury. Patient demographics, comorbidities, procedure details, complications, and preoperative and postoperative pain assessments using a visual analog scale were evaluated.

Results:
Residual nerve pain from previous lower extremity trauma was included. Analysis of preprocedure and postprocedure visual analog scale scores demonstrated a mean decrease of 7.45 points (mean: pre 8.89, mean: post 1.44). All patients voiced satisfaction with postoperative ambulatory tolerance and pain relief at last follow-up (mean: 30.86 months).

Conclusions:
The sequelae of neuromas-in-continuity of the SPN, deep peroneal nerve, and sural nerves were noted to have significantly improved with proximal neurectomy and subsequent bridging utilizing a nerve allograft and conduit construct. We present this coaptation technique as a viable treatment option for reduction in neurogenic pain involving peripheral nerve injury of two dermatome distributions.
IMPAIRMENTS IN CONE PIGMENT REGENERATION AND ABSOLUTE THRESHOLD IN MACULAR TELANGIECTASIA TYPE 2
Authors: Simunovic Matthew P. , Hess Kristina , Gillies Mark C. 
Published: November 2021

Purpose:
To test the hypothesis that Müller cell dysfunction in macular telangiectasia type 2 (MacTel) results in delayed cone adaptation kinetics and to assess absolute cone and rod thresholds in this condition.

Methods:
Adaptation after an approximate 63.5% full-field cone photopigment bleach was assessed for Goldmann size V (1.7° diameter) 640 nm (red) and 480 nm (blue) targets presented at a retinal locus corresponding to 2° temporal to fixation. The cone time constant of adaptation and absolute cone and rod thresholds were calculated from exponential functions fitted to the resultant dark adaptation curves.

Results:
Eighteen eyes with MacTel (from 11 patients) were compared with 19 control eyes (from 16 normal subjects). Cone adaptation kinetics were significantly impaired in MacTel, as was the absolute cone threshold. Final thresholds for blue targets were also significantly elevated in MacTel, consistent with impaired rod absolute threshold. Losses in sensitivity observed in MacTel were consistent with a so-called d1/2 mechanism (i.e., receptoral) site of sensitivity loss.

Conclusion:
In addition to previously documented impairments in rod dark adaptation, MacTel results in a significant elevation in cone thresholds because of pathology at the level of the photoreceptors. The delays in cone adaptation that we found in eyes with MacTel may reflect impairment of the Müller cell–mediated cone-specific visual cycle.
IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies
Authors: Bennett Joshua , Starczynowski Daniel T. 
Published: November 2021

Purpose of review
Cell intrinsic and extrinsic perturbations to inflammatory signaling pathways are a hallmark of development and progression of hematologic malignancies. The interleukin 1 receptor-associated kinases (IRAKs) are a family of related signaling intermediates (IRAK1, IRAK2, IRAK3, IRAK4) that operate at the nexus of multiple inflammatory pathways implicated in the hematologic malignancies. In this review, we explicate the oncogenic role of these kinases and review recent therapeutic advances in the dawning era of IRAK-targeted therapy.

Recent findings
Emerging evidence places IRAK signaling at the confluence of adaptive resistance and oncogenesis in the hematologic malignancies and solid tissue tumors. Preclinical investigations nominate the IRAK kinases as targetable molecular dependencies in diverse cancers.

Summary
IRAK-targeted therapies that have matriculated to early phase trials are yielding promising preliminary results. However, studies of IRAK kinase signaling continue to defy conventional signaling models and raise questions as to the design of optimal treatment strategies. Efforts to refine IRAK signaling mechanisms in the malignant context will inspire deliberate IRAK-targeted drug development and informed combination therapy.
Lack of evidence for a role of anthrax toxin receptors as surface receptors for collagen VI and for its cleaved off C5 domain (endotrophin)
Authors: Przyklenk Matthias , Heumüller Stefanie Elisabeth , Lütke Steffen , Sengle Gerhard , Koch Manuel , Paulsson Mats , Schiavinato Alvise , Wagener Raimund 
Published: November 2021

AbstractThe widely expressed microfibril-forming collagen VI is subject to proteolytic cleavage and it has been proposed that the cleaved off C-terminal Kunitz domain (C5) of the α3 chain is an adipokine important for tumor progression and fibrosis. Under the name “endotrophin” the C5 fragment has also been shown to be a potent biomarker for fibro-inflammatory diseases. However, the biochemical mechanisms behind endotrophin activity have not been investigated. In earlier studies, the anthrax toxin receptor 1 was found to bind to C5, but this potential interaction has not been further studied. Given the proposed physiological role of endotrophin we aimed to determine how the endotrophin signal is transmitted to the recipient cells. Surprisingly, we could not detect any interaction between endotrophin and anthrax toxin receptor 1 or its close relative, anthrax toxin receptor 2. Moreover, we could not detect binding of fully assembled collagen VI to either anthrax toxin receptor. We also performed similar experiments with the collagen VI surface receptor NG2 (CSPG4). We could confirm that NG2 is a collagen VI receptor that binds to assembled collagen VI, but not to the cleaved C5/endotrophin. A cellular receptor for C5/endotrophin therefore still remains elusive.
Comparative genomics and characterization of SARS-CoV-2 P.1 (Gamma) Variant of Concern (VOC) from Amazonas, Brazil
Authors: Zimerman Ricardo Ariel , Gröhs Ferrareze Patrícia Aline , Cadegiani Flávio Adsuara , Wambier Carlos Gustavo , Fonseca Daniel do Nascimento , de Souza Andrea Roberto , Goren Andy , Rotta Liane Nanci , Ren Zhihua , Thompson Claudia Elizabeth 
Published: November 2021

AbstractBackgroundP.1 lineage (Gamma) was first described in the State of Amazonas, northern Brazil, in the end of 2020, and has emerged as a very important variant of concern (VOC) of SARS-CoV-2 worldwide. P.1 has been linked to increased infectivity, higher mortality and immune evasion, leading to reinfections and potentially reduced efficacy of vaccines and neutralizing antibodies.MethodsThe samples of 276 patients from the State of Amazonas were sent to a central referral laboratory for sequencing by gold standard techniques, through Illumina MiSeq platform. Both global and regional phylogenetic analyses of the successfully sequenced genomes were conducted through maximum likelihood method. Multiple alignments were obtained including previously obtained unique human SARS-CoV-2 sequences. The evolutionary histories of spike and non-structural proteins from ORF1a of northern genomes were described and their molecular evolution was analyzed for detection of positive (FUBAR, FEL, and MEME) and negative (FEL and SLAC) selective pressures. To further evaluate the possible pathways of evolution leading to the emergence of P.1, we performed specific analysis for copy-choice recombination events. A global phylogenomic analysis with subsampled P.1 and B.1.1.28 genomes was applied to evaluate the relationship among samples.ResultsForty-four samples from the State of Amazonas were successfully sequenced and confirmed as P.1 (Gamma) lineage. In addition to previously described P.1 characteristic mutations, we find evidence of continuous diversification of SARS-CoV-2, as rare and previously unseen P.1 mutations were detected in spike and non-structural protein from ORF1a. No evidence of recombination was found. Several sites were demonstrated to be under positive and negative selection, with various mutations identified mostly in P.1 lineage. According to the Pango assignment, phylogenomic analyses indicate all samples as belonging to the P.1 lineage.ConclusionP.1 has shown continuous evolution after its emergence. The lack of clear evidence for recombination and the positive selection demonstrated for several sites suggest that this lineage emergence resulted mainly from strong evolutionary forces and progressive accumulation of a favorable signature set of mutations.
Mitonuclear interactions affect locomotor activity and sleep in Drosophila melanogaster
Authors: Anderson Lucy , Camus M. Florencia , Monteith Katy M. , Salminen Tiina S. , Vale Pedro F. 
Published: November 2021

AbstractMitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved between many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. The results demonstrate that Drosophila strains from different locations differ in sleep and activity, and the extent of variation differs between sexes, females in general being more active. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we establish that mtDNA variation affects both traits, sex specifically. Furthermore, by using previously published mtDNA copy number data, we detected a positive correlation between mtDNA copy number and the activity levels of the cybrid flies. Altogether, our study shows that both mtDNA variation and mitonuclear interactions affect activity and sleep patterns, highlighting the important role that both genomes play on life-history trait evolution.
Multi-area recordings and optogenetics in the awake, behaving marmoset
Authors: Jendritza Patrick , Klein Frederike J. , Fries Pascal 
Published: November 2021

AbstractThe common marmoset has emerged as a key primate model in neuroscience. Marmosets are small in size, show great potential as transgenic models and exhibit complex behaviors. These advantages place the marmoset model in the critical gap between rodents and larger primates. Thus, it is necessary to develop technology that enables monitoring and manipulation of the neural circuits underlying the behavior of the marmoset. Here, we present a novel approach to record and optogenetically manipulate neural activity in the awake, behaving marmoset. Our design utilizes a light-weight, 3D printed titanium chamber that can house several high-density silicon probes for semi-chronic recordings, while enabling simultaneous optogenetic stimulation. Surgical procedures are streamlined via custom 3D printed guides and implantation holders. We demonstrate the application of our method by recording multi- and single-unit data from areas V1 and V6 with 192 channels simultaneously, and show for the first time that optogenetic activation of excitatory neurons in area V6 can influence behavior in a detection task. Together, the work presented here will support future studies investigating the neural basis of perception and behavior in the marmoset.
Silencing neuronal activity is required for developmental circuit remodeling
Authors: Mayseless Oded , Rachad El Yazid , Shapira Gal , Fiala André , Schuldiner Oren 
Published: November 2021

SummaryPostnatal refinement of neuronal connectivity shapes the mature nervous system. Pruning of exuberant connections involves both cell autonomous and non-cell autonomous mechanisms, such as neuronal activity. While the role of neuronal activity in the plasticity of excitatory synapses has been extensively studied, the involvement of inhibition is less clear. Furthermore, the role of activity during stereotypic developmental remodeling, where competition is not as apparent, is not well understood.Here we use the Drosophila mushroom body as a model to show that regulated silencing of neuronal activity is required for developmental axon pruning of the γ-Kenyon cells. We demonstrate that silencing neuronal activity is mechanistically achieved by cell autonomous expression of the inward rectifying potassium channel (irk1) combined with inhibition by the GABAergic APL neuron. These results support the Hebbian-like rule ‘use it or lose it’, where inhibition can destabilize connectivity and promote pruning while excitability stabilizes existing connections.