bluuebunny/crossref_metadata_2025_split huggingface dataset:
Case Report: Pheochromocytoma and Synchronous Neuroblastoma in a Family With Hereditary Pheochromocytoma Associated With a MAX Deleterious Variant
Authors: Duarte Diana Borges , Ferreira Lia , Santos Ana P. , Costa Cláudia , Lima Jorge , Santos Catarina , Afonso Mariana , Teixeira Manuel R. , Carvalho Rui , Cardoso Maria Helena 
Published: March 2021

IntroductionPheochromocytomas are rare catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal sympathetic paraganglia. Recent studies have indicated that up to 40% of pheochromocytomas could be attributable to an inherited germline variant in an increasing list of susceptibility genes. Germline variants of the MYC-associated factor (MAX) gene have been associated with familial pheochromocytomas and paragangliomas with an autosomal dominant pattern of inheritance, a median age at onset of 33 years and an overall frequency estimated at 1.9%. We describe a deleterious MAX variant associated with hereditary pheochromocytoma in a family with four affected individuals.Case presentationThe first patient presented with bilateral pheochromocytoma in 1995; genetic testing was proposed to his oldest son, when he was diagnosed with a bilateral pheochromocytoma with a synchronous neuroblastoma. Upon the identification of the MAX variant c.97C&gt;T, p.(Arg33Ter), in the latter individual, his two siblings and their father were tested and the same variant was identified in all of them. Both siblings were subsequently diagnosed with pheochromocytoma (one of them bilateral) and choose to remain on active surveillance before they were submitted to adrenalectomy. All the tumours secreted predominantly norepinephrine, accordingly to the typical biochemical phenotype ascribed to variants in the MAX gene.ConclusionThis case series is, to our knowledge, the one with the largest number of individuals with hereditary pheochromocytoma with a deleterious MAX variant in the same family. It is also the first case with a synchronous pheochromocytoma and neuroblastoma in carriers of a MAX deleterious variant. This report draws attention to some ill-defined features of pheochromocytoma and other malignancies associated with a MAX variant and highlights the importance of understanding the genotype-phenotype correlation in hereditary pheochromocytoma and the impact of oriented genetic testing to detect, survey and treat patients and kindreds at risk.
Pasireotide in the Personalized Treatment of Acromegaly
Authors: Puig-Domingo Manel , Bernabéu Ignacio , Picó Antonio , Biagetti Betina , Gil Joan , Alvarez-Escolá Cristina , Jordà Mireia , Marques-Pamies Montserrat , Soldevila Berta , Gálvez María-Angeles , Cámara Rosa , Aller Javier , Lamas Cristina , Marazuela Mónica 
Published: March 2021

The delay in controlling the disease in patients who do not respond to first-line treatment with first generation somatostatin receptor ligands (first-generation SRLs) can be quantified in years, as every modification in the medical therapy requires some months to be fully evaluated. Considering this, acromegaly treatment should benefit from personalized medicine therapeutic approach by using biomarkers identifying drug response. Pasireotide has been positioned mostly as a compound to be used in first-generation SRLs resistant patients and after surgical failure, but sufficient data are now available to indicate it is a first line therapy for patients with certain characteristics. Pasireotide has been proved to be useful in patients in which hyperintensity T2 MRI signal is shown and in those depicting low SST2 and high expression of SST5, low or mutated AIP condition and sparsely granulated immunohistochemical pattern. This combination of clinical and pathological characteristics is unique for certain patients and seems to cluster in the same cases, strongly suggesting an etiopathogenic link. Thus, in this paper we propose to include this clinico-pathologic phenotype in the therapeutic algorithm, which would allow us to use as first line medical treatment those compounds with the highest potential for achieving the fastest control of GH hypersecretion as well as a positive effect upon tumor shrinkage, therefore accelerating the implementation of precision medicine for acromegaly. Moreover, we suggest the development, validation and clinical use of a pasireotide acute test, able to identify patients responsive to pasireotide LAR as the acute octreotide test is able to do for SRLs.
Case Report: Irreversible Watery Diarrhea, Severe Metabolic Acidosis, Hypokalemia and Achloridria Syndrome Related to Vasoactive Intestinal Peptide Secreting Malignant Pheochromocytoma
Authors: Negro Aurelio , Verzicco Ignazio , Tedeschi Stefano , Campanini Nicoletta , Zanelli Magda , Negri Emanuele , Farnetti Enrico , Nicoli Davide , Palladini Barbara , Santi Rosaria , Cunzi Davide , Calvi Anna , Coghi Pietro , Gerra Luigi , Volpi Riccardo , Graiani Gallia , Cabassi Aderville 
Published: March 2021

BackgroundPheochromocytoma (PHEO) clinical manifestations generally mirror excessive catecholamines secretion; rarely the clinical picture may reflect secretion of other hormones. Watery diarrhea, hypokalemia and achlorhydria (WDHA) is a rare syndrome related to excessive secretion of vasoactive intestinal peptide (VIP).Clinical CaseA 73-year-old hypotensive man affected by adrenal PHEO presented with weight loss and watery diarrhea associated with hypokalemia, hyperchloremic metabolic acidosis (anion gap 15 mmol/l) and a negative urinary anion gap. Abdominal computed tomography scan showed a right adrenal PHEO, 8.1 cm in maximum diameter, with tracer uptake on 68GaDOTA-octreotate positron emission tomography. Metastasis in lumbar region and lung were present. Both chromogranin A and VIP levels were high (more than10 times the normal value) with slightly elevated urine normetanephrine and metanephrine excretion. Right adrenalectomy was performed and a somatostatin analogue therapy with lanreotide started. Immunostaining showed chromogranin A and VIP co-expression, with weak somatostatin-receptor-2A positivity. In two months, patient clinical conditions deteriorated with severe WDHA and multiple liver and lung metastasis. Metabolic acidosis and hypokalemia worsened, leading to hemodynamic shock and exitus.ConclusionsA rare case of WDHA syndrome caused by malignant VIP-secreting PHEO was diagnosed. High levels of circulating VIP were responsible of the rapidly evolving clinical picture with massive dehydration and weight loss along with severe hyperchloremic metabolic acidosis and hypokalemia due to the profuse untreatable diarrhea. The rescue treatment with lanreotide was unsuccessful because of the paucity of somatostatin-receptor-2A on VIP-secreting PHEO chromaffin cells.
Systematic Characterization of Expression Profiles and Prognostic Values of the Eight Subunits of the Chaperonin TRiC in Breast Cancer
Authors: Xu Wen-Xiu , Song Wei , Jiang Meng-Ping , Yang Su-Jin , Zhang Jian , Wang Dan-Dan , Tang Jin-Hai 
Published: March 2021

BackgroundChaperonin-containing TCP-1 (TRiC or CCT) was demonstrated to be involved in oncogenesis of cancers carcinogenesis and development of various malignancies. Increasing experimental evidence indicated that dysregulation of TRiC was implicated in the tumor progression of breast cancer (BCa). However, few definitive studies have addressed the diverse expression patterns and prognostic values of eight TRiC subunits. Thus, we aimed to investigate the clinical significance of TRiC subunit expression and prognostic values for their possible implications in diagnosis and treatment of BCa.MethodsBased on updated public resources and comprehensive bioinformatics analysis, we used some online databases (e.g., UALCAN, GEPIA, cBioPortal, TIMER, BC-GenExMiner, metascape, and GeneMANIA) to comprehensively explore the expression levels and the prognostic effects of eight TRiC subunits in patients with BCa.ResultsThe transcriptional levels of most subunits of the Chaperonin TRiC (CCT2, CCT3, CCT4, CCT5, CCT6A, and CCT7) were significantly elevated compared with normal breast tissues, whereas TCP1, CCT4, and CCT6B were lower in BCa tissues than in normal tissues. Besides, copy-number alterations (CNA) of eight TRiC subunits positively regulated their mRNA expressions. Furthermore, high mRNA expression of TCP1/CCT2/CCT4/CCT5/CCT6A/CCT7/CCT8 was significantly associated with poor overall survival (OS) in BCa patients. The eight subunits of the chaperonin TRiC was related to tumor purity and immune infiltration levels of BCa. Co-expression analysis showed CCT6B was negatively associated with other subunits of TRiC and other subunits of TRiC were positively correlated with each other. Additionally, TRiC and their interactive proteins were correlated with positive regulation of biological process, localization, and biological regulation.ConclusionThis study systematically illustrated the expression profiles and distinct prognostic values of chaperonin TRiC in BCa, providing insights for further investigation of subunits of the chaperonin TRiC as novel therapeutic targets and potential prognostic biomarkers in BCa.
Immune Checkpoint-Associated Locations of Diffuse Gliomas Comparing Pediatric With Adult Patients Based on Voxel-Wise Analysis
Authors: Zhang Li , Zhang Buyi , Dou Zhangqi , Wu Jiawei , Iranmanesh Yasaman , Jiang Biao , Sun Chongran , Zhang Jianmin 
Published: March 2021

Objective: Pediatric diffuse gliomas (pDGs) are relatively rare and molecularly distinct from pediatric pilocytic astrocytoma and adult DGs. Immunotherapy is a promising therapeutic strategy, requiring a deep understanding of tumor immune profiles. The spatial locations of brain tumors might be related to the molecular profiles. We aimed to analyze the relationship between the immune checkpoint molecules with the locations of DGs comparing pediatric with adult patients.Method: We studied 20 pDGs patients (age ≤ 21 years old), and 20 paired adult patients according to gender and histological types selected from 641 adult patients with DGs. Immune checkpoint molecules including B7-H3, CD47, and PD-L1, as well as tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs), were manifested by immunohistochemical staining. Expression difference analyses and Spearman's correlation were performed. MRI data were voxel-wise normalized, segmented, and analyzed by Fisher's exact test to construct the tumor frequency and p value heatmaps. Survival analyses were conducted by Log-rank tests.Result: The median age of pediatric patients was 16 years. 55% and 30% of patients were WHO II and III grades, respectively. The left frontal lobe and right cerebellum were the statistically significant locations for pDGs, while the anterior horn of ventricles for adult DGs. A potential association between the expression of PD-L1 and TAMs was found in pDGs (p = 0.002, R = 0.670). The right posterior external capsule and the lateral side of the anterior horn of the left ventricle were predominant locations for the adult patients with high expression of B7-H3 and low expression of PD-L1 compared to pediatric ones, respectively. Pediatric patients showed significantly improved overall survival compared with adults. The prognostic roles of immune checkpoint molecules and TILs/TAMs were not significantly different between the two groups.Conclusion: Immune checkpoint-associated locations of diffuse gliomas comparing pediatric with adult patients could be helpful for the immunotherapy decisions and design of clinical trials.
Monocytes From Patients With Macrophage Activation Syndrome and Secondary Hemophagocytic Lymphohistiocytosis Are Hyperresponsive to Interferon Gamma
Authors: Pascarella Antonia , Bracaglia Claudia , Caiello Ivan , Arduini Alessia , Moneta Gian Marco , Rossi Marianna Nicoletta , Matteo Valentina , Pardeo Manuela , De Benedetti Fabrizio , Prencipe Giusi 
Published: March 2021

ObjectiveTo investigate the activation of the IFNγ signaling pathway in monocytes of patients with secondary hemophagocytic lymphohistiocytosis (sHLH)/macrophage activation syndrome (MAS) and to evaluate whether levels of phosphorylated STAT1 represent a biomarker for the identification of patients at early stages of the disease.MethodsFresh whole blood samples from pediatric patients with active sHLH/MAS, not receiving (n=10) and receiving glucocorticoids (n=14) at time of sampling, were prospectively collected. As disease control groups, patients with active systemic juvenile idiopathic arthritis (sJIA) without MAS, patients with sHLH/MAS in remission and patients with other rheumatic diseases were also sampled. Whole blood cells were left unstimulated or stimulated with increasing concentrations of IFNγ for 10 minutes and the intracellular Tyrosine (701)-phosphorylated STAT1 (pSTAT1) levels were evaluated in monocytes by flow cytometry.ResultsMonocytes from untreated sHLH/MAS patients showed significantly higher basal levels of pSTAT1 compared to those observed in monocytes from glucocorticoid-treated sHLH/MAS patients and from all the other disease controls. In addition, a significant increase in responsiveness to IFNγ, as assessed by increased levels of pSTAT1 following ex vivo stimulation, was observed in monocytes from untreated sHLH/MAS patients. pSTAT1 levels in monocytes distinguished patients with sHLH/MAS not treated with glucocorticoids from patients with active sJIA or with other rheumatic diseases [AUC, 0.93; 95% confidence interval 0.85-1.00, p&lt;0.001]. Statistically significant correlations between IFNG mRNA levels in whole blood cells, circulating IFNγ levels and pSTAT1 levels in sHLH/MAS monocytes were found.ConclusionOur data demonstrating higher basal levels of pSTAT1 as well as a hyperreactivity to IFNγ stimulation in monocytes from patients with sHLH/MAS point to perturbations in the activation of downstream IFNγ signaling pathway as a contributor to the hyperinflammation occurring in these patients. Finally, the observation that glucocorticoids affect pSTAT1 levels in vivo, makes it difficult to consider the measurement of pSTAT1 levels as a biomarker to identify patients at early stages of sHLH/MAS in clinical practice.
Case Report: Administration of Amniotic Fluid-Derived Nanoparticles in Three Severely Ill COVID-19 Patients
Authors: Mitrani Maria Ines , Bellio Michael A. , Sagel Anthony , Saylor Marie , Kapp William , VanOsdol Kathryn , Haskell Gwendolyn , Stewart Danique , Abdullah Zanub , Santos Ivan , Milberg Julian , Arango Alissa , Mitrani Albert , Shapiro George C. 
Published: March 2021

Rationale/Objectives: A human coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak worldwide. There is an urgent need to develop new interventions to suppress the excessive immune response, protect alveolar function, and repair lung and systemic organ damage. Zofin (previously known as Organicell Flow) is a novel therapeutic that is derived from the soluble and nanoparticle fraction (extracellular vesicles and exosomes) of human amniotic fluid. Here within, we present the clinical outcomes after Zofin treatment in three critically ill patients suffering from severe, multi-organ complications induced by COVID-19 infection. All patients were diagnosed with COVID-19, developed respiratory failure, and were hospitalized for more than 40 days.Methods: Zofin was administered to patients concurrently with ongoing medical care who were monitored for 28-days post-therapy. SOFA score assessment, chest X-rays, and inflammatory biomarker testing was performed.Main Results: There were no adverse events associated with the therapy. The patients showed improvements in ICU clinical status and experienced respiratory improvements. Acute delirium experienced by patients completely resolved and inflammatory biomarkers improved.Conclusions: Primary outcomes demonstrate the therapy was safe, accessible, and feasible. This is the first demonstration of human amniotic fluid-derived nanoparticles as a safe and potentially efficacious therapeutic treatment for respiratory failure induced by COVID-19 infection.
Exergaming as Part of the Telerehabilitation Can Be Adequate to the Outpatient Training: Preliminary Findings of a Non-randomized Pilot Study in Parkinson's Disease
Authors: Cikajlo Imre , Hukić Alma , Zajc Dejana 
Published: March 2021

Parkinson's disease is a long-term and progressive degenerative disorder of the nervous system, affecting primarily motor coordination, noticeable as a tremor in one hand. Recent studies reported on positive outcomes of intensive physiotherapy of upper extremities. We built a telerehabilitation system with virtual pick and place tasks for small scale hand movements, and designed a pilot study to find whether such exergaming as a telerehabilitation service provides comparable outcomes as an outpatient exergaming service. A non-randomized pilot trial was designed. Hospital outpatients (28/40) with Parkinson's disease were recruited. Those meeting the inclusion criteria were divided into two groups; seven outpatients were assigned to the home (H) group and 21 outpatients to the hospital (URI) group. Both groups received 10 days of exergaming over the course of 2 weeks, each daily session lasting a maximum of 1 h. Primary outcomes were clinical tests; Box and Blocks Test (BBT), Jebsen Hand Function Test (JHFT), and Unified Parkinson's Disease Rating Scale (UPDRS part III) were carried out before and after the study. Secondary outcomes were hand kinematics and exergaming results; number of successfully moved objects and task time. Statistical analysis was carried out to find significant (p &lt; 0.05) differences and Cohen's U3 was used to determine effect sizes. The differences between the groups in gender (p = 0.781), age (p = 0.192), and duration of the disease (p = 0.195) were tested with Bartlett's test and no statistical differences were found with an F test. Both groups demonstrated statistically significant improvements in clinical test UDPRS III (p = 0.006 and p = 0.011) and the hospital group also in BBT (p = 0.002) and JHFT (p = 0.015) and with UDPRS III and JHFT even in favor of the home group (χ2 = 5.08, p = 0.024, χ2 = 7.76, p = 0.005). Nevertheless, the exergaming results show significant improvement after training (U3 &gt; 0.86). Exergaming has already been suggested as an effective approach in the planning of rehabilitation tasks for persons with Parkinson's disease. We have prepared a pilot study demonstrating that exergaming at home with telerehabilitation support may provide comparable clinical outcomes. The study shall be followed by a randomized study with higher statistical power to provide clinical evidence. Nevertheless, carrying out even part of the rehabilitation program at home is crucial for the development of future telerehabilition clinical services.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03175107.
Functional Network Alterations as Markers for Predicting the Treatment Outcome of Cathodal Transcranial Direct Current Stimulation in Focal Epilepsy
Authors: Hao Jiaxin , Luo Wenyi , Xie Yuhai , Feng Yu , Sun Wei , Peng Weifeng , Zhao Jun , Zhang Puming , Ding Jing , Wang Xin 
Published: March 2021

Background and PurposeTranscranial direct current stimulation (tDCS) is an emerging non-invasive neuromodulation technique for focal epilepsy. Because epilepsy is a disease affecting the brain network, our study was aimed to evaluate and predict the treatment outcome of cathodal tDCS (ctDCS) by analyzing the ctDCS-induced functional network alterations.MethodsEither the active 5-day, −1.0 mA, 20-min ctDCS or sham ctDCS targeting at the most active interictal epileptiform discharge regions was applied to 27 subjects suffering from focal epilepsy. The functional networks before and after ctDCS were compared employing graph theoretical analysis based on the functional magnetic resonance imaging (fMRI) data. A support vector machine (SVM) prediction model was built to predict the treatment outcome of ctDCS using the graph theoretical measures as markers.ResultsOur results revealed that the mean clustering coefficient and the global efficiency decreased significantly, as well as the characteristic path length and the mean shortest path length at the stimulation sites in the fMRI functional networks increased significantly after ctDCS only for the patients with response to the active ctDCS (at least 20% reduction rate of seizure frequency). Our prediction model achieved the mean prediction accuracy of 68.3% (mean sensitivity: 70.0%; mean specificity: 67.5%) after the nested cross validation. The mean area under the receiver operating curve was 0.75, which showed good prediction performance.ConclusionThe study demonstrated that the response to ctDCS was related to the topological alterations in the functional networks of epilepsy patients detected by fMRI. The graph theoretical measures were promising for clinical prediction of ctDCS treatment outcome.
Behavior of Nutritional Supplements Use in Association With Inflammatory Skin Diseases in Chinese College Students
Authors: Yuan Yan , Su Juan , Li Ji , Tao Juan , Kang Xiaojing , Wu Bin , Shan Shijun , Wang Xiaohui , Chen Xiang , Shen Minxue , Jiang Liyuan 
Published: March 2021

Objectives: It is understudied how frequently adolescents use nutritional supplements (NS) and whether the corresponding behavior is associated with skin diseases that may cause unpleasant symptoms and disfigurement. The current study aimed to investigate the prevalence of NS use in Chinese college students and its association with inflammatory skin diseases.Methods: This was a university-based epidemiologic investigation that included 20,138 students who underwent dermatological examinations. A questionnaire survey was conducted to inquire about the use of NS along with related information. Skin diseases were diagnosed by dermatologists during the health examination. Logistic regression models were used for analysis. Adjusted odds ratios (aORs) were presented as the effect size.Results: Survey responses from a total of 20,138 participants were analyzed. Specifically, 18.3% of the participants reported the use of NS in the past year. The use of vitamin C was most frequently reported, accounting for a proportion of 12.9%, followed by vitamin B and mineral supplements. The use of NS was found to be associated with female sex, Han ethnicity, higher annual household income, and a series of healthy lifestyles such as more physical activity, less second-hand smoke exposure, less alcohol consumption, and higher intake of milk and yogurt (p &lt; 0.001). Participants with chronic urticaria (aOR = 1.3; 95% CI, 1.0–1.7), atopic dermatitis (aOR = 1.4; 95% CI, 1.2–1.6), or acne (aOR = 1.17; 95% CI, 1.04–1.31) were more likely to use NS, especially herbs (aOR = 2.7; 95% CI, 1.2–3.7), followed by vitamin B (aOR = 1.6; 95% CI, 1.2–2.0) and mineral supplements (aOR = 1.4; 95% CI, 1.0–2.0).Conclusion: College students with inflammatory skin diseases are more likely to use NS.