Ichiro Abe

Smad2 Protein Disruption in the Central Nervous System Leads to Aberrant Cerebellar Development and Early Postnatal Ataxia in Mice

Smad2 is a critical mediator of TGF-β signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.

Pituitary and adrenal involvement in diffuse large B-cell lymphoma, with recovery of their function after chemotherapy

BackgroundDiffuse large B-cell lymphoma sometimes involves the endocrine organs, but involvement of both the pituitary and adrenal glands is extremely rare. Involvement of these structures can lead to hypopituitarism and adrenal insufficiency, and subsequent recovery of their function is rarely seen. The present report describes an extremely rare case of pituitary and adrenal diffuse large B-cell lymphoma presenting with hypopituitarism and adrenal insufficiency with subsequent recovery of pituitary and adrenal function after successful treatment of the lymphoma.Case presentationA 63-year-old Japanese man was referred to our hospital due to miosis, ptosis, hypohidrosis of his left face, polydipsia and polyuria. 18F-fluorodeoxy glucose positron emission tomography / computed tomography revealed hotspots in the pituitary gland, bilateral adrenal glands and the apex of his left lung. Surgical biopsy from the pituitary lesion confirmed the diagnosis of diffuse large B-cell lymphoma, with lymphoma cells replacing normal pituitary tissue. Endocrine function tests revealed adrenal insufficiency and panhypopituitarism, including a possible affection of the posterior pituitary. Hormone replacement therapy with desmopressin and hydrocortisone was started. Chemotherapy consisted of six courses of R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone) and two courses of high-dose methotrexate followed by autologous hematopoietic stem cell transplantation. Subsequently, his pituitary and bilateral adrenal lesions resolved, and serial endocrine function tests showed gradual improvement in pituitary and adrenal function.ConclusionsThe present report describes an extremely rare case of diffuse large B-cell lymphoma with involvement of both the pituitary and bilateral adrenal glands. R-CHOP and high-dose methotrexate therapy followed by autologous hematopoietic stem cell transplantation was quite effective, and panhypopituitarism and adrenal insufficiency improved to almost normal values after successful treatment of the lymphoma with chemotherapy.

Successful management of cryptococcosis of the bilateral adrenal glands and liver by unilateral adrenalectomy with antifungal agents: A case report

BackgroundCryptococcus species usually affect the central nervous system and lungs in immunocompromised hosts. Although the adrenal glands can be involved in disseminated cryptococcosis, primary adrenal insufficiency caused by the fungal infection is uncommon.Case presentationWe present a case of primary adrenal insufficiency with bilateral adrenal masses and liver invasion in a 43-year-old man with mild type 2 diabetes mellitus. Cryptococcosis was diagnosed by fine-needle aspiration biopsy of the liver mass. The serum cryptococcal antigen titer was elevated to 1:256. After 6 months of antifungal therapy with fluconazole and amphotericin B, the size of the liver mass was decreased, but no significant changes were observed in the bilateral adrenal masses and the serum cryptococcal antigen titer remained elevated at 1:128. To control the cryptococcosis, a laparoscopic left adrenalectomy was performed, followed by antifungal therapy. After the unilateral adrenalectomy, the size of the remaining right adrenal mass was reduced and the serum cryptococcal antigen titer declined to 1:4.ConclusionsThis is the first report describing adrenal cryptococcosis with adrenal insufficiency and liver invasion without central nervous system involvement. Adrenal cryptococcosis should be considered in the differential diagnosis for patients with bilateral adrenal masses with primary adrenal deficiency. Unilateral adrenalectomy was quite effective in controlling the cryptococcosis in this case. Even in patients with bilateral adrenal cryptococcosis, unilateral adrenalectomy should be an option for treatment of disseminated cryptococcosis.

HMGA1a induces alternative splicing of estrogen receptor alpha in MCF-7 human breast cancer cells

The high-mobility group A protein 1a (HMGA1a) protein is known as an oncogene whose expression level in cancer tissue correlates with the malignant potential, and known as a component of senescence-related structures connecting it to tumor suppressor networks in fibroblasts. HMGA1 protein binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. Our previous studies have shown that sequence-specific RNA-binding of HMGA1a induces exon-skipping of Presenilin-2 exon 5 in sporadic Alzheimer disease. Here we show that HMGA1a induced exon-skipping of the estrogen receptor alpha (ERα) gene and increased ERα46 mRNA expression in MCF-7 breast cancer cells. An RNA-decoy of HMGA1a efficiently blocked this event and reduced ERα46 protein expression. Blockage of HMGA1a RNA-binding property consequently induced cell growth through reduced ERα46 expression in MCF-7 cells and increased sensitivity to tamoxifen in the tamoxifen-resistant cell line, MCF-7/TAMR1. Stable expression of an HMGA1a RNA-decoy in MCF-7 cells exhibited decreased ERα46 protein expression and increased estrogen-dependent tumor growth when these cells were implanted in nude mice. These results show HMGA1a is involved in alternative splicing of the ERα gene and related to estrogen-related growth as well as tamoxifen sensitivity in MCF-7 breast cancer cells.

Association of Symptoms of Gastroesophageal Reflux with Metabolic Syndrome Parameters in Patients with Endocrine Disease

Background. Metabolic syndrome (MetS) and obesity are known risk factors for gastroesophageal reflux disease (GERD), which is often found in patients with endocrine disorders, such as thyroid dysfunction and hypopituitarism. To clarify the relationship of endocrine disease with GERD, we investigated the symptoms of GERD in patients with various endocrine diseases. Methods. Patients with various endocrine disorders who visited Kyushu University Hospital were included. GERD symptoms were examined using a self-administered questionnaire, the frequency scale for the symptoms of GERD (FSSG). Metabolic parameters, including body-mass index (BMI), waist circumference, blood pressure, hemoglobin A1c, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides, and values of endocrine function, including thyroid stimulating hormone, free thyroxin, cortisol, and insulin-like growth factor-1, were assessed. Results. A total of 111 consecutive patients were recruited for the study. Among these, 18 (16.2%) patients were considered to have GERD. Among the parameters, BMI (P = 0.03) and triglycerides (P = 0.001) showed a positive association and HDL-C (P = 0.0007) showed an inverse association with the FSSG score. However, none of the endocrine values were associated with the FSSG score. Conclusion. Symptoms of GERD in patients with endocrine disorders might be attributed to MetS as comorbidity.

Complete Remission of Anaplastic Thyroid Carcinoma after Concomitant Treatment with Docetaxel and Radiotherapy

Anaplastic thyroid carcinoma (ATC) although rare is the most lethal form of thyroid cancer. The mortality rate for ATC is very high, with a median survival time of only 5 months; the survival rate at 1 year after diagnosis is <20%. Management of ATC is extremely difficult and rife with uncertainties. Herein, we describe a 75-year-old woman who presented with ATC and was successfully treated using concomitant treatment with docetaxel and high-dose radiotherapy. This case appears to be the first to have been reported in the literature involving complete remission of ATC confirmed by autopsy, suggesting the therapeutic potential of this combination.

Pheochromocytoma crisis caused by Campylobacter fetus.

Pheochromocytoma crisis is a life‐threatening endocrine emergency associated with symptoms of excess release of catecholamines. It might present spontaneously or be unmasked by triggers including trauma, surgery and certain medications that provoke catecholamine release by tumors. Here we report a case of pheochromocytoma crisis associated with abscess formation in the tumor and bacteremia of Campylobacter fetus, which was successfully treated with antibiotics and a surgical resection. This case appears to be the first reported case in the literature of abscess formation by C. fetus in pheochromocytoma, leading to catecholamine crisis.

HMGA1a Induces Alternative Splicing of the Estrogen Receptor-αlpha Gene by Trapping U1 snRNP to an Upstream Pseudo-5′ Splice Site

Objectives: The high-mobility group A protein 1a (HMGA1a) protein is known as a transcription factor that binds to DNA, but recent studies have shown it exerts novel functions through RNA-binding. We were prompted to decipher the mechanism of HMGA1a-induced alternative splicing of the estrogen receptor alpha (ERα) that we recently reported would alter tamoxifen sensitivity in MCF-7 TAMR1 cells. Methods: Endogenous expression of full length ERα66 and its isoform ERα46 were evaluated in MCF-7 breast cancer cells by transient expression of HMGA1a and an RNA decoy (2′-O-methylated RNA of the HMGA1a RNA-binding site) that binds to HMGA1a. RNA-binding of HMGA1a was checked by RNA-EMSA. In vitro splicing assay was performed to check the direct involvement of HMGA1a in splicing regulation. RNA-EMSA assay in the presence of purified U1 snRNP was performed with psoralen UV crosslinking to check complex formation of HMGA1a-U1 snRNP at the upstream pseudo-5′ splice site of exon 1. Results: HMGA1a induced exon skipping of a shortened exon 1 of ERα in in vitro splicing assays that was blocked by the HMGA1a RNA decoy and sequence-specific RNA-binding was confirmed by RNA-EMSA. RNA-EMSA combined with psoralen UV crosslinking showed that HMGA1a trapped purified U1 snRNP at the upstream pseudo-5′ splice site. Conclusions: Regulation of ERα alternative splicing by an HMGA1a-trapped U1 snRNP complex at the upstream 5′ splice site of exon 1 offers novel insight on 5′ splice site regulation by U1 snRNP as well as a promising target in breast cancer therapy where alternative splicing of ERα is involved.

Clinical Investigation of Adrenal Incidentalomas in Japanese Patients of the Fukuoka Region with Updated Diagnostic Criteria for Sub-clinical Cushing's Syndrome

Objectives We retrospectively investigated the clinical and endocrinological characteristics of adrenal incidentalomas. Methods We studied 61 patients who had been diagnosed with adrenal incidentalomas and had undergone detailed clinical and endocrinological evaluations while hospitalized. We used common criteria to diagnose the functional tumors, but for sub-clinical Cushings syndrome, we used an updated set of diagnosis criteria: serum cortisol ≥1.8 μg/dL after a positive response to a 1-mg dexamethasone suppression test if the patient has a low morning adrenocorticotropic hormone (ACTH) level (<10 pg/mL) and a loss of the diurnal serum cortisol rhythm. Results Of the 61 patients, none (0%) had malignant tumors, 8 (13.1%) had pheochromocytoma, and 15 (24.6%) had primary aldosteronism; when diagnosed by our revised criteria, 13 (21.3%) had cortisol-secreting adenomas (Cushings syndrome and sub-clinical Cushings syndrome), and 25 (41.0%) had non-functional tumors. Compared with the non-functional tumor group, the primary aldosteronism group and the cortisol-secreting adenoma group were significantly younger and had significantly higher rates of hypokalemia, whereas the pheochromocytoma group had significantly larger tumors and a significantly lower body mass index. Conclusion Our study found a larger percentage of functional tumors among adrenal incidentalomas than past reports, partly because we used a lower serum cortisol level after a dexamethasone suppression test to diagnose sub-clinical Cushings syndrome and because all of the patients were hospitalized and could therefore receive more detailed examinations. Young patients with hypokalemia or lean patients with large adrenal tumors warrant particularly careful investigation.