bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases
Authors: Jiang Cecilia , Kleber Troy J. , Switchenko Jeffrey M. , Khan Mohammad K. 
Published: February 2021

Abstract
Background
The management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis.

Methods
A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured.

Results
63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07–0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits.

Conclusions
Outcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context.
Analysis of patient access to orphan drugs in Turkey
Authors: Koçkaya Güvenç , Atalay Sibel , Oğuzhan Gülpembe , Kurnaz Mustafa , Ökçün Selin , Sar Gedik Çiğdem , Şaylan Mete , Şencan Nazlı 
Published: February 2021

Abstract
Background
Rare diseases are life-threatening, serious, and chronic conditions that require complex care and have a low prevalence. An estimated one in 15 people worldwide are affected by rare diseases. This study aims to analyze the accessibility, reimbursement status, licensed status, and Anatomical Therapeutic Chemical (ATC) codes of drugs that the European Medicines Agency (EMA) in Turkey considers to be “orphan” pharmaceuticals.

Methods
The drugs included in this analysis were obtained from the list of orphan drugs published by the EMA. Orphan drugs’ accessibility and licensing status in Turkey were obtained from the Health Implementation Communiqué published by the Social Security Institution (SGK) and the List of Abroad Active Substance and List of Licensed Products published by the Turkey Pharmaceuticals and Medical Devices Agency (TİTCK). Descriptive analysis was applied to determine the accessibility status of orphan drugs identified by the EMA in Turkey.

Results
Based on the EMA, 105 pharmaceuticals were approved with “orphan drug” status except for drugs that have lost orphan drug status, decommissioned in the European Union and withdrawn from the European Community Register by January 2020. Of the 105 rare drugs on the EMA list, 34 were inaccessible in Turkey. Of the 71 available drugs, 23 (32%) were licensed and 48 (68%) were unlicensed in Turkey. 17 (74%) of licensed products and 17 (35%) of unlicensed products were covered by reimbursement. When orphan drugs’ ATC codes were examined, the most common ATC group was found to be “L—Antineoplastic and Immunomodulatory” agents.

Conclusion
An orphan drug incentive policy is very important to ensure early access to the drugs used to treat rare diseases. Considering the capacity and prices for orphan drugs in Turkey, it can be said that many patients with rare diseases have difficulty in their treatment. It is obvious that such a policy must prepare for the regulation of orphan drugs in Turkey.
Novel bone repairing scaffold consisting of bone morphogenetic Protein-2 and human Beta Defensin-3
Authors: He Wei , Wei Daixu , Zhang Jun , Huang Xiaonan , He Da , Liu Bo , Wang Qilong , Liu Mingming , Liu Ling , Liu Yajun , Tian Wei 
Published: February 2021

Abstract
Background
Synthetic biomaterials assist in modulating the vascular response in an injured bone by serving as delivery vehicles of pro-angiogenic molecules to the site of injury or by serving as mimetic platforms which offer support to cell growth and proliferation.

Methods
This study applied natural phospholipid modified protein technologies together with low temperature three-dimensional printing technology to develop a new model of three-dimensional artificial bone scaffold for potential use in repairing body injuries. The focus was to create a porous structure (PS) scaffold of two components, Bone Morphogenetic Protein-2 and Human Beta Defensin-3 (BMP2 and hBD3), which can synchronously realize directional bone induction, angiogenesis and postoperative antibacterial effects. BMP2 induces osteogenesis, whereas hBD3 is antibacterial.

Results
Our data showed that in the BMP2-hBD3-PS or hBD3-PS scaffolds, BMP2 had a slow-release rate of about 40% in 30 days, ensuring that BMP2 could penetrate into stem cells for osteogenic differentiation for a long time. The scaffolds promoted cell growth when in combination with BMP2, thus showing its importance in promoting cell growth. Alkaline Phosphatase (ALP) staining showed that the ALP content of BMP2-hBD3-PS and BMP2-PS had a significant increase in samples that contained BMP2, thus showing that these scaffolds promoted osteogenic differentiation. In all the constructs that had hBD3, they displayed antibacterial properties with hBD3, having a slow release of about 35% in 30 days, thus ensuring they provided protection.

Conclusion
Based on this study, the 3D printed BMP2 scaffolds show a great potential for the development of biodegradable bone implants.

Level of evidence
Level II, experimental comparative design.
2-Pentadecyl-2-oxazoline ameliorates memory impairment and depression-like behaviour in neuropathic mice: possible role of adrenergic alpha2- and H3 histamine autoreceptors
Authors: Boccella Serena , Guida Francesca , Iannotta Monica , Iannotti Fabio Arturo , Infantino Rosmara , Ricciardi Flavia , Cristiano Claudia , Vitale Rosa Maria , Amodeo Pietro , Marabese Ida , Belardo Carmela , de Novellis Vito , Paino Salvatore , Palazzo Enza , Calignano Antonio , Di Marzo Vincenzo , Maione Sabatino , Luongo Livio 
Published: February 2021

AbstractNeuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine altered levels after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.
The de novo CACNA1A pathogenic variant Y1384C associated with hemiplegic migraine, early onset cerebellar atrophy and developmental delay leads to a loss of Cav2.1 channel function
Authors: Gandini Maria A. , Souza Ivana A. , Ferron Laurent , Innes A. Micheil , Zamponi Gerald W. 
Published: February 2021

AbstractCACNA1A pathogenic variants have been linked to several neurological disorders including familial hemiplegic migraine and cerebellar conditions. More recently, de novo variants have been associated with severe early onset developmental encephalopathies. CACNA1A is highly expressed in the central nervous system and encodes the pore-forming CaVα1 subunit of P/Q-type (Cav2.1) calcium channels. We have previously identified a patient with a de novo missense mutation in CACNA1A (p.Y1384C), characterized by hemiplegic migraine, cerebellar atrophy and developmental delay. The mutation is located at the transmembrane S5 segment of the third domain. Functional analysis in two predominant splice variants of the neuronal Cav2.1 channel showed a significant loss of function in current density and changes in gating properties. Moreover, Y1384 variants exhibit differential splice variant-specific effects on recovery from inactivation. Finally, structural analysis revealed structural damage caused by the tyrosine substitution and changes in electrostatic potentials.
Narrative enhancement and cognitive therapy (NECT) to improve social functioning in people with serious mental illness: study protocol for a stepped-wedge cluster randomized controlled trial
Authors: Dubreucq J. , Faraldo M. , Abbes M. , Ycart B. , Richard-Lepouriel H. , Favre S. , Jermann F. , Attal J. , Bakri M. , Cohen T. , Cervello C. , Chereau I. , Cognard C. , De Clercq M. , Douasbin A. , Giordana J. Y. , Giraud-Baro E. , Guillard-Bouhet N. , Legros-Lafarge E. , Polosan M. , Pouchon A. , Rolland M. , Rainteau N. , Roussel C. , Wangermez C. , Yanos P. T. , Lysaker P. H. , Franck N. 
Published: February 2021

Abstract
Background
Self-stigma is highly prevalent in serious mental illness (SMI) and is associated with poorer clinical and functional outcomes. Narrative enhancement and cognitive therapy (NECT) is a group-based intervention combining psychoeducation, cognitive restructuring and story-telling exercises to reduce self-stigma and its impact on recovery-related outcomes. Despite evidence of its effectiveness on self-stigma in schizophrenia-related disorders, it is unclear whether NECT can impact social functioning.

Methods
This is a 12-centre stepped-wedge cluster randomized controlled trial of NECT effectiveness on social functioning in SMI, compared to treatment as usual. One hundred and twenty participants diagnosed with schizophrenia, bipolar disorder or borderline personality disorder will be recruited across the 12 sites. The 12 centres participating to the study will be randomized into two groups: one group (group 1) receiving the intervention at the beginning of the study (T0) and one group (group 2) being a control group for the first 6 months and receiving the intervention after (T1). Outcomes will be compared in both groups at T0 and T1, and 6-month and 12-month outcomes for groups 1 and 2 will be measured without a control group at T2 (to evaluate the stability of the effects over time). Evaluations will be conducted by assessors blind to treatment allocation. The primary outcome is personal and social performance compared across randomization groups. Secondary outcomes include self-stigma, self-esteem, wellbeing, quality of life, illness severity, depressive symptoms and personal recovery.

Discussion
NECT is a promising intervention for reducing self-stigma and improving recovery-related outcomes in SMI. If shown to be effective in this trial, it is likely that NECT will be implemented in psychiatric rehabilitation services with subsequent implications for routine clinical practice.

Trial registration
ClinicalTrials.gov NCT03972735. Trial registration date 31 May 2019.
Poly(4-amino-3-hydroxynaphthalene-1-sulfonic acid) modified glassy carbon electrode for square wave voltammetric determination of amoxicillin in four tablet brands
Authors: Kassa Adane , Amare Meareg 
Published: February 2021

Abstract
Background
Amoxicillin (AMX), which is one of the β-lactam antibiotics used in the treatment of bacterial infections, is known to have a serious mechanism of resistance necessitating continuous monitoring of its level in pharmaceutical and serum samples.

Results
In this study, we presented selective, accurate, and precise square wave voltammetric method based on poly(4-amino-3-hydroxynaphthalene-1-sulfonic acid) modified glassy carbon electrode (poly(AHNSA/GCE)) for determination of amoxicillin in four selected tablet brands. Appearance of a peak in the oxidative scan direction without a peak in the reductive direction of cyclic voltammograms of both bare GCE and poly(AHNSA/GCE) with four folds current and much reduced potential on the modified electrode showed catalytic property of the modifier towards oxidation of AMX. While cyclic voltammetric studies of effect of scan rate showed predominantly diffusion controlled oxidation of AMX with one electron participation, effect of pH revealed participation of protons and electrons in a 1:1 ratio. The square wave voltammetric peak current response of the modified electrode for AMX showed linear dependence on the concentration of the spiked standard AMX in the range 10–150 µmol L−1 with 9.9 nmol L−1 LOD. The AMX content of the studied tablet brands were found in the range 97.84–100.78% of the labeled value. Spike recovery results of 99.6–100.5%, and interference recovery results of 95.4–100.8% AMX in the presence of 50–200% of ampicillin and cloxicillin validated the applicability of the method for determination of amoxicillin in tablet formulation.

Conclusion
In contrast to the previously reported works on determination of amoxicillin, the present method showed an excellent performance making it a potential method for determination of amoxicillin in real samples including serum samples.
Histone crotonylation-centric gene regulation
Authors: Li Kun , Wang Ziqiang 
Published: February 2021

AbstractHistone crotonylation is a recently described post-translational modification that occurs at multiple identified histone lysine crotonylation sites. An increasing number of studies have demonstrated that histone crotonylation at DNA regulatory elements plays an important role in the activation of gene transcription. However, among others, we have shown that elevated cellular crotonylation levels result in the inhibition of endocytosis-related gene expression and pro-growth gene expression, implicating the complexity of histone crotonylation in gene regulation. Therefore, it is important to understand how histone crotonylation is regulated and how it, in turn, regulates the expression of its target genes. In this review, we summarize the regulatory factors that control histone crotonylation and discuss the role of different histone crotonylation sites in regulating gene expression, while providing novel insights into the central role of histone crotonylation in gene regulation.
Adults with Prader–Willi syndrome exhibit a unique microbiota profile
Authors: Dahl Wendy J. , Auger Jérémie , Alyousif Zainab , Miller Jennifer L. , Tompkins Thomas A. 
Published: February 2021

Abstract
Objective
Adults with Prader–Willi syndrome (PWS) require less energy intake to maintain body weight than the general adult population. This, combined with their altered gastrointestinal transit time, may impact microbiota composition. The aim of the study was to determine if the fecal microbiota composition of adults with PWS differed from non-affected adults. Using usual diet/non-interventional samples, fecal microbiota composition was analyzed using 16S rRNA gene amplicon sequencing and data from adults with PWS were merged with four other adult cohorts that differed by geographical location and age. QIIME 2™ sample-classifier, machine learning algorithms were used to cross-train the samples and predict from which dataset the taxonomic profiles belong. Taxa that most distinguished between all datasets were extracted and a visual inspection of the R library PiratePlots was performed to select the taxa that differed in abundance specific to PWS.

Results
Fecal microbiota composition of adults with PWS showed low Blautia and enhanced RF39 (phyla Tenericutes), Ruminococcaceae, Alistipes, Erysipelotrichacaea, Parabacteriodes and Odoribacter. Higher abundance of Tenericutes, in particular, may be a signature characteristic of the PWS microbiota although its relationship, if any, to metabolic health is not yet known.
Mind the translational gap: using iPS cell models to bridge from genetic discoveries to perturbed pathways and therapeutic targets
Authors: Pintacuda Greta , Martín Jacqueline M. , Eggan Kevin C. 
Published: February 2021

AbstractAutism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by impaired social interactions as well as the presentation of restrictive and repetitive behaviors. ASD is highly heritable but genetically heterogenous with both common and rare genetic variants collaborating to predispose individuals to the disorder. In this review, we synthesize recent efforts to develop human induced pluripotent stem cell (iPSC)-derived models of ASD-related phenotypes. We firstly address concerns regarding the relevance and validity of available neuronal iPSC-derived models. We then critically evaluate the robustness of various differentiation and cell culture protocols used for producing cell types of relevance to ASD. By exploring iPSC models of ASD reported thus far, we examine to what extent cellular and neuronal phenotypes with potential relevance to ASD can be linked to genetic variants found to underlie it. Lastly, we outline promising strategies by which iPSC technology can both enhance the power of genetic studies to identify ASD risk factors and nominate pathways that are disrupted across groups of ASD patients that might serve as common points for therapeutic intervention.
A bedridden young lady with hypophosphatemic rickets treated with denosumab: a case report
Authors: Al-Sharafi Butheinah A. , Al-Yousfi Nuha A. , Bamashmus Said A. 
Published: February 2021

Abstract
Background
Hypophosphatemic rickets is associated with delayed walking, bone deformities, growth failure and physical dysfunction that can limit daily activities. Treatment consists of phosphate salts and calcitriol. We report a case that received denosumab with marked improvement in her condition.

Case presentation
A 24-year-old Yemeni female with hypophosphatemic rickets presented to an endocrinologist with severe weakness and severe pain in the extremities, she had been bedridden for the last 4 years. Bone density showed severe osteoporosis (T score of hip was − 5.0 and Z score of hip was − 5.0, T score of the spine was − 6.0 and Z score of the spine was − 6.1) so the patient was started on denosumab in addition to calcitriol and after 7months she was feeling stronger and felt she could stand assisted and was walking with assistance within 9 months and after 1.5 years of treatment she was walking unassisted.

Conclusion
Denosumab is an effective treatment for osteoporosis, we used it in our patient in addition to calcitriol because she had severe osteoporosis due to long standing hypophosphatemic rickets that had not been treated properly, the patient improved markedly and regained the ability to walk again after being bedridden for 4 years. It may be a drug to consider in such cases although further studies need to be done to confirm this.
Beneficial effects of dantrolene in the treatment of rhabdomyolysis as a potential late complication associated with COVID-19: a case report
Authors: Chiba Nobutaka , Matsuzaki Masakazu , Mawatari Takayuki , Mizuochi Minori , Sakurai Atsushi , Kinoshita Kosaku 
Published: February 2021

Abstract
Background
Patients with severe COVID-19 have disorders of the respiratory, cardiovascular, coagulation, skeletal muscle, and central nervous systems. These systemic failures may be associated with cytokine release syndrome, characterized by hyperpyrexia, thrombocytopenia, hyperferritinemia, and the elevation of other inflammatory markers. Rhabdomyolysis with high fever is a complication that is rarely found in COVID-19. The exact relations of these clinical conditions in patients with COVID-19 remain unknown.

Case presentation
We present the case of a 36-year-old man with severe COVID-19 complicated by rhabdomyolysis and high fever. After admission, his condition continued to deteriorate, with a high body temperature. On day 9, the patient had elevated creatine kinase and myoglobin levels consistent with rhabdomyolysis (26,046 U/L and 3668 ng/mL, respectively). In addition to viral therapy, he was immediately treated with hydration. However, the patient had persistent fever and elevated creatine kinase levels. The patient was diagnosed with malignant hyperthermia as a late complication of COVID-19, although he had no hereditary predisposition to malignant hyperthermia or neuroleptic malignant syndrome. The administration of dantrolene with muscle relaxation and anti-inflammatory function showed potential efficacy for rhabdomyolysis, high fever, and increased plasma inflammatory markers.

Conclusions
Malignant hyperthermia is triggered by not only anesthetic agents but also viral infections. A possible mechanism of malignant hyperthermia is hypersensitivity of calcium release from the sarcoplasmic reticulum. These include mutations in or the activation of the skeletal muscle ryanodine receptor calcium release channel. Dantrolene is a ryanodine receptor antagonist and is used as an anti-inflammatory agent. The administration of dantrolene showed potential efficacy for rhabdomyolysis, high body temperature due to inflammation, and increased inflammatory markers. The underlying mechanism of the association of rhabdomyolysis and high fever in COVID-19 might be similar to the pathogenesis of malignant hyperthermia.