Pituitary neuroendocrine tumors (PitNETs), which were formerly known as pituitary adenomas, are classified in 5th Edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. Since thyrotroph PitNETs are rare PitNETs, most previous studies about former thyroid stimulating hormone (TSH)-secreting pituitary adenoma have focused on a small number of cases. However, the diagnostic rate of thyrotroph PitNET has increased because of increased sensitivity of serum TSH measurement and widespread recognition that thyrotroph PitNETs are the cause of syndrome of inappropriate secretion of TSH (SITSH). Therefore, knowledge on the molecular mechanism of thyrotroph PitNET is gradually accumulating. Recently, comprehensive chromosomal, genetic, and epigenomic alterations in thyrotroph PitNET have been revealed with the availability of comprehensive gene and protein analyses, and the nature of thyrotroph PitNET is gradually being elucidated. However, further analysis is needed to determine whether the causes of these changes are directly responsible for the development of tumors.

Graves’ disease has been reported to affect the clinical features of moyamoya disease (MMD), an occlusion of the circle of Willis. This study aimed to clarify the characteristics of MMD in patients with Graves’ disease. This was a single-center, retrospective study. The prevalence and clinical features of MMD patients among all patients with thyroid disease who visited Ito Hospital from January 2005 to December 2019 were evaluated. The relationship between MMD and hyperthyroidism was analyzed in new-onset Graves’ disease patients during the same period. Of all 394,422 patients with thyroid disease, 88,180 had Graves’ disease, and 40 had MMD with Graves’ disease, i.e., the prevalence was 45.36 per 100,000 patients with Graves’ disease (0.0454%). The median age at onset of MMD was 39 years (interquartile range, 31–54 years), with a male to female ratio of 1:12. The most common time that MMD was diagnosed was within 1 year after the onset of Graves’ disease, in 9 of 40 patients (22.5%), and 19 of 40 patients (47.5%) underwent bypass surgery for MMD. In MMD with Graves’ disease, headache was the most frequent symptom, and ischemic types of stroke and bilateral lesions were common. Of 23,347 patients with new-onset Graves’ disease, 7 were diagnosed with MMD and the incidence of MMD was 5.94 patients per 100,000 person-years. Most patients developed MMD symptoms during hyperthyroidism. Although MMD is a rare condition, it should be noted that it can occur with Graves’ disease.

Metformin, an oral medication, is prescribed to patients with type 2 diabetes mellitus. Although the efficacy, safety, and low economic burden of metformin on patients have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea and discontinue the treatment. We previously reported that 1,000 mg·kg^–1·day^–1 of metformin induced diarrhea in diabetic obese (db/db) mice and wood creosote (traditional medication for diarrhea) ameliorated the symptoms. In this study, we attempted to elucidate the molecular mechanisms by which metformin induces diarrhea. Cystic fibrosis transmembrane conductance regulator (CFTR) is a key ion (chloride) channel in cyclic adenosine monophosphate (cAMP)-induced diarrhea. Metformin treatment increased bile flow (bile acids and bilirubin) in the ileum of mice. In addition, the treatment was accompanied by an increase in mRNA and protein levels of CFTR in the mucosa of the ileum and colon in both wild-type (C57BL/6J) and db/db mice. Glucagon-like peptide-1 (GLP-1), as well as cholic acid, induces CFTR mRNA expression in human colon carcinoma Caco-2 cells through cAMP signaling. Although wood creosote (10 mg/kg) ameliorated diarrhea symptoms, it did not alter the mRNA levels of Glp-1 or Cftr. Similar to overeating, metformin upregulated GLP-1 and CFTR expression, which may have contributed to diarrhea symptoms in mice. Although we could not identify db/db mouse-specific factors associated with metformin-induced diarrhea, these factors may modulate colon function. Wood creosote may not interact with these factors but ameliorates diarrhea symptoms.

Humoral factors that are secreted from skeletal muscles can regulate bone metabolism and contribute to muscle-bone relationships. Although extracellular vesicles (EVs) play important roles in physiological and pathophysiological processes, the roles of EVs that are secreted from skeletal muscles in bone repair have remained unclear. In the present study, we investigated the effects of the local administration of muscle cell-derived EVs on bone repair in control and streptozotocin-treated diabetic female mice. Muscle cell-derived EVs (Myo-EVs) were isolated from the conditioned medium from mouse muscle C2C12 cells by ultracentrifugation, after which Myo-EVs and gelatin hydrogel sheets were transplanted on femoral bone defect sites. The local administration of Myo-EVs significantly improved delayed bone repair that was induced by the diabetic state in mice 9 days after surgery. Moreover, this administration significantly enhanced the ratio of bone volume to tissue volume at the damaged sites 9 days after surgery in the control mice. Moreover, the local administration of Myo-EVs significantly blunted the number of Osterix-positive cells that were suppressed by the diabetic state at the damage sites after bone injury in mice. Additionally, Myo-EVs significantly blunted the mRNA levels of Osterix and alkaline phosphatase (ALP), and ALP activity was suppressed by advanced glycation end product 3 in ST2 cells that were treated with bone morphogenetic protein-2. In conclusion, we have shown for the first time that the local administration of Myo-EVs improves delayed bone repair that is induced by the diabetic state through an enhancement of osteoblastic differentiation in female mice.

The aim of this study was to investigate the effect of arteriosclerosis on new-onset renal damage in a Chinese community population with diabetes. Patients with diabetes who had attended at least one physical examination after the Brachial-ankle pulse wave velocity (BaPWV) test from 2010 to 2018 were selected as subjects. A total of 4,462 patients were included in the study cohort. BaPWV levels <1,400 cm/s, 1,400–1,799 cm/s, and ≥1,800 cm/s were applied to divide the subjects into a normal arterial stiffness group, borderline atherosclerosis group and atherosclerosis group. Renal damage was defined by isolated proteinuria, isolated eGFR <60 mL/min/1.73 m², proteinuria and eGFR <60 mL/min/1.73 m². A Cox proportional risk model was used to analyze the effect of different groups on new-onset renal damage. After a median follow-up of 2.85 (1.88–4.90) years, Cox proportional risk models showed that after adjusting for risk factors, compared with the normal group, the HR and 95% CI of the risk of new-onset renal damage were 1.29 (95% CI: 0.95–1.76) and 1.59 (95% CI: 1.14–2.22) in the borderline atherosclerosis group and the atherosclerosis group, respectively. Atherosclerosis is a risk factor for new-onset renal damage, especially new-onset proteinuria, in diabetic patients.

Iron overload can lead to chronic complications, serious organ dysfunction or death in the body. Under hypoxic conditions, the body needs more iron to produce red blood cells to adapt to the hypoxic environment. The prevalence of iron overload in the Tibetan population is higher than that in the Han population. To explore the molecular mechanism of iron-overload in the Tibetan population, this study investigated the transcriptome of the Tibetan iron overload population to obtain differentially expressed genes (DEGs) between the iron-overloaded population and the normal iron population. Functional enrichment analysis identified key related pathways, gene modules and coexpression networks under iron-overload conditions, and the 4 genes screened out have the potential to become target genes for studying the development of iron overload. A total of 28 pathways were screened to be closely related to the occurrence and development of iron overload, showing that iron overload is extremely related to erythrocyte homeostasis, cell cycle, oxidative phosphorylation, immunity, and transcriptional repression.

Neuroendocrine tumors (NETs) are a type of rare tumor that can occur at multiple organs. Rectal NETs are the most common NETs in gastrointestinal tract. Due to the rarity of rectal NETs in rectal cancer, the molecular features and the correlation with patient therapeutic response and prognosis have not been investigated in detail. In this review, we focused on the molecular features, potential therapeutic targets and prognosis of rectal NETs. By summarizing the relevant studies, we established the mutational landscape of rectal NETs and identified a series of large fragment variations. Driver genes including TP53, APC, KRAS, BRAF, RB1, CDKN2A and PTEN were found as the top mutated genes. Large fragment alterations mainly involved known driver genes, including APC, TP53, CCNE1, MYC, TERT, RB1 and ATM. Germline mutations of APC, MUTYH, MSH6, MLH1 and MSH2 associated with Lynch syndrome or FAP were also found in rectal NETs. The BRAF-V600E mutation was reported as an actionable target in rectal NETs, and the combined BRAF/MEK inhibitors were found to be effective targeting BRAF-V600E in advanced or metastatic NETs. The known prognostic risk factors of rectal adenocarcinoma, including a series of demographic and clinicopathological factors were also prognostic factors for rectal NETs. Furthermore, three types of markers, including genetic alterations, protein expression levels and methylation, were also suggested as prognostic factors for rectal NETs. In summary, we established the landscape of mutations and large-fragment alterations of rectal NETs, and identified potential therapeutic targets and a series of prognostic factors. Future studies may focus on the optimization of therapeutic strategies based on potential actionable biomarkers.

The diagnosis of painless thyroiditis (PT) during antithyroid drug (ATD) treatment of Graves’ disease (GD) is difficult. We evaluated the thyroidal radioactive iodine uptake (RAIU) in 100 patients with relapsed thyrotoxicosis during or after careful ATD treatment. The RAIU was <5%/5 h in 35 patients (35%) (Group A - PT), 5%–15%/5 h in 6 patients (6%) (Group B - indefinite) and >15%/5 h in 59 patients (59%) (Group C - relapsed GD [rGD]). TSH receptor antibody (TBII) was positive in 4 (11.4%), 3 (50.0%) and 39 (only 66.1%) patients in Groups A, B and C, respectively. In Group A, the serum fT₄ level spontaneously normalized after 35 (26–56) days, sometimes followed by transient hypothyroidism, confirming the diagnosis of PT. Nineteen (54.3%) had been treated with potassium iodide, and PT frequently occurred ironically when the ATD dosage was reduced. PT repeatedly occurred in nine patients. All went into remission smoothly or developed hypothyroidism, except one patient with strongly positive TBII who developed rGD after the resolution of PT (PT on GD). In 10 (50%) of 20 patients with negative TBII despite rGD in Group C, TBII became positive afterwards. In conclusion, it is important to recognize that PT can occur in the clinical course of GD, resulting in frequent remission despite relapse of PT. The thyroid function reflects the balance between the stimulating TBII activity and the responsiveness of the thyroid tissue (sometimes unresponsive and other times autostimulated). The RAIU is still a valuable tool in cases of ambiguous thyrotoxicosis.

Anaplastic thyroid carcinoma (ATC) is a highly malignant tumor with invasive nature. Most patients present with locally advanced and/or distant metastatic diseases that are difficult to treat. We report a case of a previously inoperable patient with v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated ATC. After a trial of neoadjuvant Dabrafenib/Trametinib with immunotherapy, the tumor became operable, and surgical pathology indicated a pathologic complete response (pCR). We also reviewed cases from the literature that utilized neoadjuvant BRAF-directed therapy in ATCs. These cases emphasize that BRAF-and immune-directed therapy is a feasible option in patients with inoperable ATC and may lead to improved outcomes.

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing’s Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.