American Association of Clinical Endocrinology Disease State Clinical Review: Evaluation and Management of Immune Checkpoint Inhibitor-Mediated Endocrinopathies: A Practical Case-Based Clinical Approach

ObjectiveThe aim of this case-based clinical review was to provide a practical approach for clinicians regarding the management of patients with immune checkpoint inhibitor (ICI)-mediated endocrinopathies.MethodsA literature search of PubMed, Embase, and Scopus was conducted using appropriate keywords. The discussions and strategies for the diagnosis and management of ICI-mediated endocrinopathies are based on evidence available from prospective, randomized clinical studies; cohort studies; cross-sectional studies; case-based studies; and an expert consensus.ResultsImmunotherapy with ICIs has transformed the treatment landscape of diverse types of cancers but frequently results in immune-mediated endocrinopathies that can cause acute and persistent morbidity and, rarely, death. The patterns of endocrinopathies differ between the inhibitors of the cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 or programmed cell death protein 1 ligand pathways but most often involve the thyroid and pituitary glands. The less common but important presentations include insulin-deficient diabetes mellitus, primary adrenal insufficiency, primary hypoparathyroidism, central diabetes insipidus, primary hypogonadism, and pancreatitis, with or without subsequent progression to diabetes mellitus or exocrine insufficiency.ConclusionIn recent years, with increasing numbers of patients with cancer being treated with ICIs, more clinicians in a variety of specialties have been called upon to diagnose and treat ICI-mediated endocrinopathies. Herein, we reviewed case scenarios of various clinical manifestations and emphasized the need for a high index of clinical suspicion by all clinicians caring for these patients, including endocrinologists, oncologists, primary care providers, and emergency department physicians. We also provided diagnostic and therapeutic approaches for ICI-induced endocrinopathies and proposed that patients on ICI therapy be evaluated and treated by a multidisciplinary team in collaboration with endocrinologists.     

Arterial Stiffness,Carotid Intima-Media Thickness,Endocan, and A Disintegrin and Metalloproteinase With Thrombospondin Type I Motif 9 Levels and Their Relationship With Disease Activity in Patients With Acromegaly With and Without Cardiovascular Risk Factors

ObjectiveCardiovascular complications such as cardiomyopathy and endothelial dysfunction, which are frequently seen in patients with acromegaly, are among the most important causes of morbidity and mortality. In this study, we aimed to investigate arterial stiffness, carotid intima-media thickness, endocan level, and A disintegrin and metalloproteinase with thrombospondin type I motif 9 level and their relationship with disease activity in patients with acromegaly with and without cardiovascular risk factors.MethodsA total of 60 patients with acromegaly—25 with active disease, 26 with well-controlled disease, and 9 with newly diagnosed disease—and 60 age-, sex-, and body mass index (BMI)-matched healthy control subjects were enrolled in this study. All the subjects’ height, weight, BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting plasma glucose (FPG) level, insulin, hemoglobin A1C (HbA1C), C-reactive protein , lipid, endocan, A disintegrin and metalloproteinase with thrombospondin type I motif 9 levels, pulse wave velocity (PWV), and carotid intima-media thickness were measured.ResultsThe SBP, DBP, FPG level, HbA1C level, and PWV of the acromegaly group were higher than those of the control group. In patients with acromegaly with cardiovascular disease (CVD) risk factors, the PWV was higher than that in the control group, and in patients with acromegaly without CVD risk factors, the PWV was similar to that in the control group. In a correlation analysis, a positive correlation was found between PWV and age, BMI, SBP, DBP, FPG level, and HbA1C level in the acromegaly group.ConclusionIn our study, we found that arterial stiffness increased in patients with acromegaly with CVD risk factors and that increased arterial stiffness was associated with hemodynamic (SBP and DBP) and metabolic (BMI, FPG level, and HbA1C level) parameters.     

Directed Inter-domain Motions Enable the IsdH Staphylococcus aureus Receptor to Rapidly Extract Heme from Human Hemoglobin

Pathogenic Staphylococcus aureus actively acquires iron from human hemoglobin (Hb) using the IsdH surface receptor. Heme extraction is mediated by a tri-domain unit within the receptor that contains its second (N2) and third (N3) NEAT domains joined by a helical linker domain. Extraction occurs within a dynamic complex, in which receptors engage each globin chain; the N2 domain tightly binds to Hb, while substantial inter-domain motions within the receptor enable its N3 domain to transiently distort the globin’s heme pocket. Using molecular simulations coupled with Markov modeling, along with stopped-flow experiments to quantitatively measure heme transfer kinetics, we show that directed inter-domain motions within the receptor play a critical role in the extraction process. The directionality of N3 domain motion and the rate of heme extraction is controlled by amino acids within a short, flexible inter-domain tether that connects the N2 and linker domains. In the wild-type receptor directed motions originating from the tether enable the N3 domain to populate configurations capable of distorting Hb’s pocket, whereas mutant receptors containing altered tethers are less able to adopt these conformers and capture heme slowly via indirect processes in which Hb first releases heme into the solvent. Thus, our results show inter-domain motions within the IsdH receptor play a critical role in its ability to extract heme from Hb and highlight the importance of directed motions by the short, unstructured, amino acid sequence connecting the domains in controlling the directionality and magnitude of these functionally important motions.     

Resting-state coupling between HbO and Hb measured by fNIRS in autism spectrum disorder

To distinguish between children with autism spectrum disorder (ASD) and typically developing (TD) children, we have uncovered a new discriminative feature, hemoglobin coupling. Functional near-infrared spectroscopy (fNIRS) was used to record resting-state hemodynamic fluctuations in the bilateral temporal lobes in 25 children with ASD and 22 TD children, in which the coupling between low frequency oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb) fluctuations was evaluated by Pearson correlation coefficient. The results showed significantly weak coupling in children with ASD in both the left and right, and throughout the whole temporal cortex. To explain this observation, a simulation study was performed using a balloon model, in which we found four related parameters could impact the coupling. This study suggested that hemoglobin coupling might be applied as a new cerebral hemodynamic characteristic for ASD screening or diagnostics.     

Incorporation of glycosylated amino acid into protein by an in vitro translation system

O-GalNAcα-modified proteins are the precursor of mucin-type O-glycosylated proteins. Homogeneously O-glycosylated proteins are required to investigate the biological functions of glycoproteins and to develop biopharmaceuticals. Here we show that the incorporation of GalNAcα-Thr into proteins successfully proceeded by the use of a chemically aminoacylated tRNA. GalNAcα-Thr was chemoenzymatically attached to amber suppressor tRNA and the product was subjected to in vitro translation together with streptavidin mRNA containing the UAG codon. Gel electrophoresis and mass analysis showed that GalNAcα-Thr was successfully incorporated into the N-terminus, although it was not incorporated at the interior. This method will facilitate the preparation of homogeneous GalNAcα-proteins.     

Peripheral skin temperature effects on muscle oxygen levels

In both hot and cold environments, tissue oxygen saturation levels may affect muscle performance. Using near-infrared spectroscopy, muscle oxygen saturation (StO2) and total hemoglobin levels were measured during exercise. Lowering skin temperature caused a greater StO2 and total hemoglobin decrease by 16% and 15.9%, respectively, compared to controls. Increasing skin temperature resulted in a smaller decrease in both StO2 and total hemoglobin by 12.2% and 8.2%, respectively, compared to controls. These data indicate that warming the skin will cause less of decrease in StO2 and total hemoglobin, while cooling the skin has the opposite effect.     

Myoglobin with modified tetrapyrrole chromophores: Binding specificity and photochemistry

Complexes were prepared of horse heart myoglobin with derivatives of (bacterio)chlorophylls and the linear tetrapyrrole, phycocyanobilin. Structural factors important for binding are (i) the presence of a central metal with open ligation site, which even induces binding of phycocyanobilin, and (ii) the absence of the hydrophobic esterifying alcohol, phytol. Binding is further modulated by the stereochemistry at the isocyclic ring. The binding pocket can act as a reaction chamber: with enolizable substrates, apo-myoglobin acts as a 13²-epimerase converting, e.g., Zn-pheophorbide a' (13²S) to a (13²R). Light-induced reduction and oxidation of the bound pigments are accelerated as compared to solution. Some flexibility of the myoglobin is required for these reactions to occur; a nucleophile is required near the chromophores for photoreduction (Krasnovskii reaction), and oxygen for photooxidation. Oxidation of the bacteriochlorin in the complex and in aqueous solution continues in the dark.     

Temperature-dependent conformation change in spin-labeled hemoglobin

Hemoglobin was spin labeled at β-93(F9)-cysteine with N-oxy-2,2,6,6-tetramelhylpiperidinylmaleimide. The inward shift of the high-field hyperfine line (ΔH_XXX) position in the ESR spectra of the Spin label was measured aS a function of temperature. One can expect that an abrupt change in the microenvironment around the tightly bound spin label will be reflected in the function ΔH_XXX(T) as a discontinuity (break point). This was shown for aquo-, azido-. nitro- and oxyhemoglobin derivatives. The presented results suggest that the microenvironment around the tightly hound spin label in those methemoglobin derivatives that exhibit the mixed-spin state of the heme iron is prone to an abrupt change above a certain ligand-specific temperature. The change in microenvironment of the spin label is probably due to a temperature-dependent change in the tertiary structure of the protein.     

Genetic variants of hemoglobin in canine erythrocytes*

Genetic polymorphism of hemoglobin was found in the erythrocytes of dogs of seven Japanese native breeds by using starch gel electrophoresis. Analysis of parentage records of the dogs revealed that the phenotypic variation of hemoglobin is controlled by one autosomal locus with two codominant alleles, Hb^A and Hb^B. The allele Hb^A occurred only in Japanese native breeds except Shikoku. The frequency of Hb^A in the Japanese breeds was low and 0.08. All the dogs belonging to 25 European breeds and 5 oriental origin (except Japan) breeds examined in this experiments had the homozygous genotype constitution Hb^B/Hb^B.     

Evaluation of Lipohypertrophy in Patients With Type 1 Diabetes Mellitus on Multiple Daily Insulin Injections or Continuous Subcutaneous Insulin Infusion

ObjectiveTo determine lipohypertrophy (LH) in patients with type 1 diabetes mellitus (T1DM) on multiple daily insulin injections (MDII) or continuous subcutaneous insulin infusion (CSII) and to reveal the factors associated with the development and severity of LH.MethodsSixty-six patients with T1DM treated with MDII (n = 35, 53%) or CSII (n = 31, 47%) for at least 1 year were included. LH localizations were detected with palpation and ultrasonography (USG).ResultsThe LH detection rate with USG was significantly higher than that by palpation in the whole group (P < .001). The LH was detected with USG in 30 (85.7%) patients in the MDII group and 22 (71.0%) patients in the CSII group (P = .144). Advanced LH was detected in 13 (37.1%) of the patients treated with MDII and in 3 (9.7%) of the patients treated with CSII. LH was more severe in the MDII group than in the CSII group (P = .013). Diabetes duration and length of infusion set use were significantly longer and body mass index, hypoglycemia, and complication rates were higher in patients with LH than those in patients without LH (P < .05). A positive correlation was found between LH severity and HbA1C and insulin dose (P < .05, for both). MDII as insulin administration method, incorrect rotation, and a history of ketosis were found to be the most related factors with LH severity in a multiple linear regression analysis (P < .05).ConclusionUSG might be an effective approach for detecting and evaluating the severity of LH. MDII might cause more severe LH than CSII in patients with T1DM. In this study, LH was found to be associated mostly with incorrect rotation technique and a history of ketosis.