Arrayed CRISPR libraries for the genome-wide activation, deletion and silencing of human protein-coding genes.

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms.

TSH-secreting pituitary adenomas and bone.

TSH-secreting pituitary adenoma (TSHoma) is the rarest functioning pituitary tumor, with an increasing incidence over the last decades. Diagnosis is often delayed, exposing patients to a high risk of developing chronic complications of long-standing hyperthyroidism. Although thyroid hormone excess is a recognized cause of secondary osteoporosis, very few studies have investigated skeletal damage in patients with TSHoma, with data limited to bone turnover markers (BTM) and a study on the prevalence of radiological vertebral fractures (VFs) incidentally detected on chest X-ray, whereas data on bone mineral density (BMD) are anecdotal.

The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis.

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis.

Longitudinal microbiome investigation throughout prion disease course reveals pre- and symptomatic compositional perturbations linked to short-chain fatty acid metabolism and cognitive impairment in mice.

Commensal intestinal bacteria shape our microbiome and have decisive roles in preserving host metabolic and immune homeostasis. They conspicuously impact disease development and progression, including amyloid-beta (Aβ) and alpha (α)-synuclein pathology in neurodegenerative diseases, conveying the importance of the brain-gut-microbiome axis in such conditions. However, little is known about the longitudinal microbiome landscape and its potential clinical implications in other protein misfolding disorders, such as prion disease.

High prevalence of morphometric vertebral fractures opportunistically detected on thoracic radiograms in patients with non-functioning pituitary adenoma.

Purpose: Vertebral fractures (VFs), the hallmark of skeletal fragility, have been reported as an emerging complication in patients with pituitary diseases associated with hormonal excess and/or deficiency, independently from bone mineral density. Non-functioning pituitary adenoma (NFPA) is amongst the most frequent pituitary adenomas; however, skeletal health in this context has never been investigated. We aimed at assessing the prevalence and the determinants of morphometric VFs in patients with NFPA.

Single Versus Fractionated Gamma Knife Radiosurgery for Nonfunctioning Pituitary Adenomas Close to the Optic Pathway: A Multicenter Propensity Score Matched Study.

Background And Objectives: Gamma Knife radiosurgery (GKRS), typically administered in a single session (S-GKRS), is an effective treatment for nonfunctioning pituitary adenoma (NFPA). For lesions close to the optic pathway, the use of hypofractionated radiosurgery is growing. This study seeks to compare the results of S-GKRS vs fractionated-GKRS (F-GKRS) for NFPAs adjacent to the optic pathway.

A novel somatostatin receptor ligand for human ACTH - and GH -secreting pituitary adenomas.

Objective: Somatostatin receptor ligands have come to play a pivotal role in the treatment of both ACTH- and GH-secreting pituitary adenomas. Clinical efficacy averages 30-50%, thus a considerable number of patients with Cushing's disease or acromegaly remain unresponsive to this therapeutic approach. HTL0030310 is a new somatostatin receptor ligand selective for subtype 5 over subtype 2, thus with a different receptor profile compared to clinical somatostatin receptor ligands.

The role of surgical management for prolactin-secreting tumors in the era of dopaminergic agonists: An international multicenter report.

Objective: First-line prolactin-secreting tumor (PST) management typically involves treatment with dopamine agonists and the role of surgery remains to be further explored. We examined the international experience of 12 neurosurgical centers to assess the patient characteristics, safety profile, and effectiveness of surgery for PST management.

Methods: Patients surgically treated for PST from January 2017 through December 2020 were evaluated for surgical characteristics, outcomes, and safety.

Crooke Cell Adenoma Confers Poorer Endocrinological Outcomes Compared with Corticotroph Adenoma: Results of a Multicenter, International Analysis.

Background: Crooke cell adenomas (CCAs) are a rare, aggressive subset of secretory pituitary corticotroph adenomas (sCTAs) found in 5%-10% of patients with Cushing disease. Multiple studies support worse outcomes in CCAs but are limited by small sample size and single-institution databases. We compared outcomes in CCA and sCTA using a multicenter, international retrospective database of high-volume skull base centers.

Defining benchmark outcomes for transsphenoidal surgery of pituitary adenomas: a multicenter analysis.

Importance: Benchmarks aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery (TS) are not available.

Objective: We aimed to establish standardized outcome benchmarks for TS of pituitary adenomas.

Craniopharyngioma in Pediatrics and Adults.

Craniopharyngiomas are rare malignancies of dysembryogenic origin, involving the sellar and parasellar areas. These low-grade, epithelial tumors account for two main histological patterns (adamantinomatous craniopharyngioma and papillary craniopharyngioma), which differ in epidemiology, pathogenesis, and histomorphological appearance. Adamantinomatous craniopharyngiomas typically show a bimodal age distribution (5-15 years and 45-60 years), while papillary craniopharyngiomas are limited to adult patients, especially in the fifth and sixth decades of life.

Benign and Malignant Tumors of the Pituitary Gland.

Pituitary gland tumors represent approximately 10-15% of all brain tumors and the most common neoplasms of the sellar region. Among them, pituitary adenomas are the widespread accounting for more than 80%. Recently, the fourth edition of the World Health Organization (WHO) 2017 classified pituitary tumors focusing on histopathologic and molecular genetics features and introduced new entities like pituitary blastoma.

Intranasal oxytocin as a treatment for obesity: safety and efficacy.

Introduction: Known for its effect on labor and lactation and on emotional and social functions, oxytocin has recently emerged as a key modulator of feeding behavior and indeed suggested as a potential treatment for obesity. The potential positive effect of oxytocin on both metabolic and psychological-behavioral complications of hypothalamic lesions makes it a promising tool in the management of these conditions.

Areas Covered: The aim of the present review article is to provide an overview of the mechanism of action and clinical experience of the use of oxytocin in different forms of obesity.

Bilateral inferior petrosal sinus sampling with human CRH stimulation in ACTH-dependent Cushing's syndrome: results from a retrospective multicenter study.

Objective: Bilateral inferior petrosal sinus sampling (BIPSS) is regarded as gold standard to differentiate between Cushing´s disease (CD) and ectopic Cushing's syndrome (ECS). However, published data e.g.

A Multicenter, Propensity Score-Matched Assessment of Endoscopic Versus Microscopic Approaches in the Management of Pituitary Adenomas.

Background And Objectives: There is considerable controversy as to which of the 2 operating modalities (microsurgical or endoscopic transnasal surgery) currently used to resect pituitary adenomas (PAs) is the safest and most effective intervention. We compared rates of clinical outcomes of patients with PAs who underwent resection by either microsurgical or endoscopic transnasal surgery.

Methods: To independently assess the outcomes of each modality type, we sought to isolate endoscopic and microscopic PA surgeries with a 1:1 tight-caliper (0.

Silibinin, an HSP90 Inhibitor, on Human ACTH-Secreting Adenomas.

Introduction: The glucocorticoid receptor is pivotal to control corticotrophin (ACTH) secretion, and its function is closely linked to the heat shock protein 90 (HSP90) chaperone complex. Impaired sensitivity to glucocorticoid feedback is a hallmark of human corticotroph adenomas, i.e.

Calreticulin mutations affect its chaperone function and perturb the glycoproteome.

Calreticulin (CALR) is an endoplasmic reticulum (ER)-retained chaperone that assists glycoproteins in obtaining their structure. CALR mutations occur in patients with myeloproliferative neoplasms (MPNs), and the ER retention of CALR mutants (CALR MUT) is reduced due to a lacking KDEL sequence. Here, we investigate the impact of CALR mutations on protein structure and protein levels in MPNs by subjecting primary patient samples and CALR-mutated cell lines to limited proteolysis-coupled mass spectrometry (LiP-MS).

Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome.

Objective: To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS).

Methods: Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency.