Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs), also known as neuroendocrine tumors (NETs), are rare tumors derived from cells with characteristics of both nerve and endocrine cells. The clinical presentation, diagnosis, and treatment of NENs vary significantly depending on the type, location, whether the neoplasm is hormonally functional, how aggressive it is, and whether it has metastasized to other parts of the body. This article provides an overview of specific types of NETs, clinical presentations and related syndromes, diagnosis, and approach to management of common NENs.

Endocrine Emergencies.

Endocrine emergencies encompass a group of conditions that occur when hormonal deficiency or excess results in acute presentation. If these endocrine disorders are not rapidly identified or if specific treatment is delayed, significant complications or even death may occur. This article outlines the basics of endocrine emergencies involving the thyroid, parathyroid, pituitary, pancreas, and adrenal glands.

Weight regain after total meal replacement very low-calorie diet program with and with-out anti-obesity medications.

Background: Very low-calorie diets (VLCDs) employing total meal replacement (TMR) offer substantial short-term weight loss. Concurrently, anti-obesity medications (AOMs) have shown promise as adjunctive treatments when combined with VLCDs.

Aims: This study aimed to investigate the impact of adjuvant AOMs on weight loss and weight regain within a comprehensive lifestyle program.

Incidence of postoperative hyponatremia after endoscopic endonasal pituitary transposition for skull base pathologies.

Purpose: Pituitary transposition is a novel surgical approach to access the retroinfundibular space and interpeduncular cistern. Few studies have evaluated post-surgical outcomes, including incidence of hyponatremia, following pituitary transposition.

Methods: This is a retrospective study including 72 patients who underwent endoscopic endonasal surgery involving pituitary transposition for non-pituitary derived tumors over a decade at the University of Pittsburgh Medical Center.

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Background And Objective: Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling.

IGF-1 is positively associated with BMI in patients with acromegaly.

Purpose: Acromegaly is a disorder characterized by IGF-1 excess due to autonomous GH secretion. In individuals without acromegaly, IGF-1 is not only influenced by GH secretion but is also sensitive to other factors including nutritional status, as evidenced by the inverted U-shaped association between BMI and IGF-1; in low-weight individuals (BMI < 18.5 kg/m) and those who are obese, IGF-1 levels may be frankly low.

Major Genetic Motifs in Pituitary Adenomas: A Practical Literature Update.

Background: The literature includes many studies examining the genetic abnormalities that influence pituitary adenomas (PAs). We aimed to state the collective knowledge on the genetic underpinnings of PAs by organizing, summarizing, and consolidating the literature to serve as a comprehensive review for scientists and clinicians of the most up-to-date information underlying the genetic landscape of PAs.

Methods: The PubMed and Google Scholar databases were searched using multiple key words and combined Medical Subject Headings terms; only articles published in English between January 2000 and January 2022 were included.

Rapidly Progressive Pituitary Apoplexy in a Patient with COVID-19 Disease Treated with Endoscopic Endonasal Surgery.

This report describes a case of pituitary apoplexy with rapidly evolving hemorrhage in a 74-year-old female with coronavirus disease 2019 (COVID-19) disease. The patient presented with severe headache and mild respiratory symptoms, with laboratories concerning for pituitary hypofunction. Brain imaging demonstrated a sellar mass concerning for a pituitary adenoma with ischemic apoplexy.

Paraneoplastic Hypoglycemia Leading to Insulin Independence in a Patient With Type 1 Diabetes.

Objective: Non-islet cell tumor hypoglycemia (NICTH) is an uncommon paraneoplastic syndrome associated with mesenchymal neoplasms such as gastrointestinal stromal tumors (GISTs). We report the case of a patient with type 1 diabetes (T1D) and recurrent GIST who not only required discontinuation of insulin therapy but also required continuous parenteral glucose infusions to prevent hypoglycemia.

Methods: A 59-year-old woman with a 24-year history of T1D and recurrent GIST presented with frequent episodes of symptomatic hypoglycemia despite continuous reductions in her insulin therapy.

Designer proteins that competitively inhibit Gα by targeting its effector site.

During signal transduction, the G protein, Gα, binds and activates phospholipase C-β isozymes. Several diseases have been shown to manifest upon constitutively activating mutation of Gα, such as uveal melanoma. Therefore, methods are needed to directly inhibit Gα.

Association of the systemic host immune response with acute hyperglycemia in mechanically ventilated septic patients.

Hyperglycemia during sepsis is associated with increased organ dysfunction and higher mortality. The role of the host immune response in development of hyperglycemia during sepsis remains unclear. We performed a retrospective analysis of critically ill adult septic patients requiring mechanical ventilation (n = 153) to study the relationship between hyperglycemia and ten markers of the host injury and immune response measured on the first day of ICU admission (baseline).

Endogenous Glucose Production in Critical Illness.

Regulation of endogenous glucose production (EGP) by hormonal, neuronal, and metabolic signaling pathways contributes to the maintenance of euglycemia under normal physiologic conditions. EGP is defined by the generation of glucose from substrates through glycogenolysis and gluconeogenesis, usually in fasted states, for local and systemic use. Abnormal increases in EGP are noted in patients with diabetes mellitus type 2, and elevated EGP may also impact the pathogenesis of nonalcoholic fatty liver disease and congestive heart failure.

Therapeutic Effects of Endogenous Incretin Hormones and Exogenous Incretin-Based Medications in Sepsis.

Background: Sepsis, a complex disorder characterized by a dysregulated immune response to an inciting infection, affects over one million Americans annually. Dysglycemia during sepsis hospitalization confers increased risk of organ dysfunction and death, and novel targets for the treatment of sepsis and maintenance of glucose homeostasis are needed. Incretin hormones are secreted by enteroendocrine cells in response to enteral nutrients and potentiate insulin release from pancreatic β cells in a glucose-dependent manner, thereby reducing the risk of insulin-induced hypoglycemia.

Engineering a Protein Binder Specific for p38α with Interface Expansion.

Protein binding specificities can be manipulated by redesigning contacts that already exist at an interface or by expanding the interface to allow interactions with residues adjacent to the original binding site. Previously, we developed a strategy, called AnchorDesign, for expanding interfaces around linear binding epitopes. The epitope is embedded in a loop of a scaffold protein, in our case a monobody, and then surrounding residues on the monobody are optimized for binding using directed evolution or computational design.

Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes Mellitus.

People with type 2 diabetes mellitus are at high risk of morbidity and mortality from cardiovascular disease (CVD). Based on observed relationships between hyperglycemia and CVD, several large clinical trials have investigated the ability of treatment strategies to achieve hemoglobin A less than 7% (53 mmol/mol) as a way of reducing this risk. These studies demonstrate that intensified glycemic therapy may reduce CVD risk in younger patients with recent-onset type 2 diabetes mellitus but not in high-risk older individuals with established disease.

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1.

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma.

Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation.

Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex.

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.

Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor.

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells.

Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (MΦs) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MΦs represents a promising approach to increase levels of this cytokine specifically in gut tissues.

Palladium-catalyzed chemoselective allylic substitution, Suzuki-Miyaura cross-coupling, and allene formation of bifunctional 2-B(pin)-substituted allylic acetate derivatives.

A formidable challenge at the forefront of organic synthesis is the control of chemoselectivity to enable the selective formation of diverse structural motifs from a readily available substrate class. Presented herein is a detailed study of chemoselectivity with palladium-based phosphane catalysts and readily available 2-B(pin)-substituted allylic acetates, benzoates, and carbonates. Depending on the choice of reagents, catalysts, and reaction conditions, 2-B(pin)-substituted allylic acetates and derivatives can be steered into one of three reaction manifolds: allylic substitution, Suzuki-Miyaura cross-coupling, or elimination to form allenes, all with excellent chemoselectivity.

A 23-year-old female with a mixed germ cell tumor of the pituitary infundibulum: the challenge of differentiating neoplasm from lymphocytic infundibuloneurohypophysitis-a case report and literature review.

The pathologic spectrum of diseases that infiltrate the pituitary infundibulum includes a broad variety of clinical entities. There are significant differences in the prevalence of these etiologies depending on the age of presentation. Lymphocytic infundibuloneurohypophysitis (LINH) predominates over other causes of infundibular disease in adults over age 21.

Breaking Conjugation: Unusual Regioselectivity with 2-Substituted Allylic Substrates in the Tsuji-Trost Reaction.

η-Allyl palladium complexes are key intermediates in Tsuji-Trost allylic substitution reactions. It is well known that (η-1-aryl-3-alkyl substituted allyl)Pd intermediates result in nucleophilic attack at the alkyl substituted terminus. In contrast, the chemistry of (η-1,2,3-trisubstituted allyl)Pd intermediates is relatively unexplored.

Synthesis of piperlogs and analysis of their effects on cells.

Piperlongumine (PL) is a naturally occurring small molecule previously shown to induce cell death preferentially in cancer cells relative to non-cancer cells. An initial effort to synthesize analogs highlighted the reactivities of both of piperlongumine's α,β-unsaturated imide functionalities as key features determining PL's cellular effects. In this study, a second-generation of analogs was synthesized and evaluated in cells to gain further insight into how the reactivity, number, and orientation of PL's reactive olefins contribute to its ability to alter the physiology of cells.

Scaffold diversification enhances effectiveness of a superlibrary of hyperthermophilic proteins.

The use of binding proteins from non-immunoglobulin scaffolds has become increasingly common in biotechnology and medicine. Typically, binders are isolated from a combinatorial library generated by mutating a single scaffold protein. In contrast, here we generated a "superlibrary" or "library-of-libraries" of 4 × 10(8) protein variants by mutagenesis of seven different hyperthermophilic proteins; six of the seven proteins have not been used as scaffolds prior to this study.