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Neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) that usually results in poor clinical outcomes and may be accompanied by paraneoplastic syndromes (PNS). NEPC is becoming more frequent. It can initially manifest as PNS, complicating diagnosis. Therefore, we reviewed the literature on the different PNS associated with NEPC. We systematically reviewed English-language articles from January 2017 to September 2023, identifying 17 studies meeting PRISMA guidelines for NEPC and associated PNS. A total of 17 articles were included in the review. Among these, Cushing's Syndrome (CS) due to ectopic Adrenocorticotropic hormone (ACTH) secretion was the most commonly reported PNS. Other PNS included syndrome of inappropriate Anti-Diuretic Hormone secretion (SIADH), Anti-Hu-mediated chronic intestinal pseudo-obstruction (CIPO), limbic encephalitis, Evans Syndrome, hypercalcemia, dermatomyositis, and polycythemia. Many patients had a history of prostate adenocarcinoma treated with androgen deprivation therapy (ADT) before neuroendocrine features developed. The mean age was 65.5 years, with a maximum survival of 9 months post-diagnosis. NEPC is becoming an increasingly more common subtype of PCa that can result in various PNS. This makes the diagnosis and treatment of NEPC challenging. Further research is crucial to understanding these syndromes and developing standardized, targeted treatments to improve patient survival. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Beta‐hCG‐producing anal cancer, though rare, poses significant diagnostic challenges and may resist standard therapies. Recognizing the potential for hormone production in anal cancer is important, as it underscores the need for more specialized diagnostic techniques and tailored treatments. This case report describes the second reported case of ectopic production of beta‐hCG in anal cancer. A 53‐year‐old female presented with a new anal lesion. Biopsy showed a poorly differentiated squamous cell cancer (SCC) with undifferentiated sarcomatoid features, stage IIIA (cT2cN1cM0). Before starting concurrent chemotherapy and radiation, the patient had a positive urine pregnancy test. The beta‐human chorionic gonadotropin (beta‐hCG) production was attributed to the tumor, and upon completion of treatment, beta‐hCG normalized. Six weeks from treatment completion, recurrence was noted along with a positive beta‐hCG urine test. This case aims to highlight beta‐hCG as an ectopic hormone that can indicate the presence of squamous cell anal cancer and discuss the potential implications it may have on management. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does Cushing's syndrome (CS) differently affect the gonadotrope axis and testicular functions (GA/TF) according to the hypercortisolism intensity and underlying etiology? SUMMARY ANSWER Endogenous cortisol excess caused by CS leads to varying degrees of hypogonadotropic hypogonadism (HH) with more severe GA/TF impairment and altered spermatogenesis in men with intense hypercortisolism associated with paraneoplastic/ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS). WHAT IS KNOWN ALREADY CS is very rarely studied in men due to its lower prevalence in men than in women. In a few old reports focusing exclusively on a limited number of men with Cushing's disease (CD), the occurrence of hypogonadism was reported. However, a detailed assessment of the impact of CS on the GA/TF in a significant series of patients has not been performed. Yet, hypogonadism could worsen CS-associated comorbidities such as osteoporosis and myopathy. To date, the full spectrum of GA/TF impairment in men with CS of different etiologies and intensity remains unknown. STUDY DESIGN, SIZE, DURATION In this monocentric study, 89 men with CS diagnosed at a tertiary endocrine university center (Bicêtre, Paris Saclay) between January 1990 and July 2021 were evaluated and compared to 40 normal men of similar age. PARTICIPANTS/MATERIALS, SETTING, METHODS The CS patient cohort of 89 men included 51 with CD, 29 with EAS and 9 with CS of adrenal origin i.e. (ACTH-independent CS (AI-CS)). They all had frank hypercortisolism, with increased 24 h-urinary-free cortisol (24 h-UFC) in two separate samples. A case–control study was performed focusing on pituitary gonadotrope function and testicular sex steroids and peptides. An additional set of six CS men had an evaluation including semen analysis. In a subgroup of 20 men with available data after CS remission, a longitudinal analysis was conducted to assess the reversibility of GA/TF defects. MAIN RESULTS AND THE ROLE OF CHANCE Compared to controls, men with CS had significantly lower total testosterone (TT), bioavailable TT, and free TT (P  < 0.0001). Hypogonadism, defined as serum TT levels <3.0 ng/ml, was present in 83% of men with EAS, in 61% of men with CD, and in 33% of men with AI-CS. Low-normal LH concentrations in the included men with hypercortisolism indicated HH. Serum sex hormone-binding globulin levels were moderately decreased in men with CD (P  = 0.01 vs controls). Among the CS men, those with EAS had significantly lower TT, LH, and FSH levels than those with CD or AI-CS. When compared to controls, patients with EAS were the only group exhibiting a significant decrease in both serum FSH (P  = 0.002) and the testicular peptides inhibin B (P  < 0.0001) and anti-Müllerian hormone (P  = 0.003). Serum INSL3 levels were significantly lower in men with CD than in the controls (P  = 0.03). Of note, 24 h-UFC and ACTH were inversely and significantly associated with the majority of reproductive hormones including LH, FSH, TT, and inhibin B. Following successful curative therapy, reproductive assessment at a mean of 6.0 ± 4.3 years showed a significant increase in serum TT (P  < 0.0001) and plasma LH (P  = 0.02) levels, indicating a reversal of HH in 75% of the affected males. Among the six patients with available semen analysis, the two EAS cases exhibited a decrease in Sertoli cell peptides associated with a severe oligozoospermia, which completely normalized following removal of the source of hypercortisolism. LIMITATIONS, REASONS FOR CAUTION The potential bias due to the retrospective design is counteracted by the analysis of the largest male CS cohort to date as well as the use of stringent inclusion and exclusion criteria. Due to the low number of patients with semen analysis in this study, further research is needed to unravel the full spectrum of spermatogenesis defects in men with CS. WIDER IMPLICATIONS OF THE FINDINGS This work reveals the variable spectrum of reproductive impact in men with CS. We demonstrate that GA/TF impairment depends on the intensity of hypercortisolism which in turn is related to the underlying etiology. The causal link between hypercortisolism and GA/TF impairment was attested by its reversibility in most patients after CS remission. The wider implications of our findings lie in the potential generalization to a much commoner entity, iatrogenic CS due to chronic exposure to exogenous glucocorticoids. STUDY FUNDING/COMPETING INTEREST(S) Several research grants were attributed to J.Y.: (i) a grant from Programme Hospitalier de Recherche Clinique (PHRC # P081212 HYPOPROTEO); (ii) a grant from the French Association of Patients with Adrenal Diseases ('Association surrénales'); and (iii) independent Investigator Research Grants from HRA Pharma, Novartis and Recordati Pharma. A SICPA Foundation grant (Lausanne, Switzerland) allowed protected research time for G.E.P. The above sponsors were not involved in any part of the study. The authors have no competing or other conflicts of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Introduction: Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a serious life-threatening disease. Tumor localization is crucial in EAS management. This underscores the importance of evaluating imaging methods and prognostic factors to provide a clear basis for patient diagnosis and management. Objective: The aim of this study was to investigate imaging methods and analyze the relevant prognostic factors for EAS. Methods: The retrospective study followed 64 cases of EAS diagnosed between 1992 and 2020. Clinical features, biochemical analysis, and imaging studies were collected, and survival data were followed up and analyzed. Results: Of 64 patients, 41% were female with a mean (±SD) age at diagnosis of 47 ± 16 years. Computed tomography (CT), 18-F fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT, and octreotide scintigraphy had similar sensitivity in localizing ectopic ACTH-secreting tumors. However, in cases with negative imaging on CT, both of 18F-FDG PET-CT and octreotide scintigraphy further localized 25% tumors. The combination of all three modalities failed to further increase the sensitivity. Patients with thymic tumors survived longer than those with pulmonary or pancreatic tumors (p = 0.013 and 0.047, respectively). Multivariate analyses showed that hypokalemia (p = 0.004) and treatment modality (p = 0.048) were independent prognostic factors. The optimal serum potassium cutoff based on maximum log-rank statistics (p = 0.012) was 2.90 mmol/L. Conclusion: CT is the first choice for tumor localization in EAS. CT in combination with a nuclear medicine or molecular imaging modality is necessary for further identification of an ectopic source. Serum potassium <2.90 mmol/L is associated with shorter overall survival, and tumor resection plays the most important role in the survival improvement. [ABSTRACT FROM AUTHOR]

Ectopic pituitary adenoma (EPA) is a pituitary adenoma unrelated to the intrasellar component and is an extremely rare disease. EPA resembles typical pituitary adenomas in morphology, immunohistochemistry, and hormonal activity, and it may present with specific or non-specific endocrine manifestations. Here, we report a rare case of ectopic adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma in the clival region. Only three patients with ACTH-secreting pituitary adenomas occurring in the clivus have been previously reported, and the present case was diagnosed as a clivus-ectopic ACTH-secreting pituitary macroadenoma. Thus, in addition to the more common organs, such as the lung, thymus, and pancreas, in the diagnosis of ectopic ACTH syndrome, special attention should be paid to the extremely rare ectopic ACTH-secreting pituitary adenoma of the clivus region. [ABSTRACT FROM AUTHOR]

This study assesses the association between use of levonorgestrel intrauterine systems containing 52, 19.5, and 13.5 mg of hormone and ectopic pregnancy in a nationwide cohort study. [ABSTRACT FROM AUTHOR]

Cushing's syndrome (CS) secondary to ectopic adrenocorticotrophic hormone (ACTH)-producing prostate cancer is rare with less than 50 cases reported. The diagnosis can be challenging due to atypical and variable clinical presentations of this uncommon source of ectopic ACTH secretion. We report a case of Cushing's syndrome secondary to prostate adenocarcinoma who presented with symptoms of severe hypercortisolism with recurrent hypokalaemia, limb oedema, limb weakness, and sepsis. He presented with severe hypokalaemia and metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), with elevated 8 am cortisol 1229 nmol/L. ACTH-dependent Cushing's syndrome was diagnosed with inappropriately normal ACTH 57.4 ng/L, significantly elevated 24-hour urine free cortisol and unsuppressed cortisol after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests. 68Ga-DOTANOC PET/CT showed an increase in DOTANOC avidity in the prostate gland, and his prostate biopsy specimen was stained positive for ACTH and markers for neuroendocrine differentiation. He was started on ketoconazole, which was switched to IV octreotide in view of liver dysfunction from hepatic metastases. He eventually succumbed to the disease after 3 months of his diagnosis. It is imperative to recognize prostate carcinoma as a source of ectopic ACTH secretion as it is associated with poor clinical outcomes, and the diagnosis can be missed due to atypical clinical presentations. [ABSTRACT FROM AUTHOR]

Ectopic Cushing's syndrome due to ectopic ACTH&CRH-secreting by pheochromocytoma is extremely rare and can be fatal if not properly diagnosed. It remains unclear whether a unique cell type is responsible for multiple hormones secreting. In this work, we performed single-cell RNA sequencing to three different anatomic tumor tissues and one peritumoral tissue based on a rare case with ectopic ACTH&CRH-secreting pheochromocytoma. And in addition to that, three adrenal tumor specimens from common pheochromocytoma and adrenocortical adenomas were also involved in the comparison of tumor cellular heterogeneity. A total of 16 cell types in the tumor microenvironment were identified by unbiased cell clustering of single-cell transcriptomic profiles from all specimens. Notably, we identified a novel multi-functionally chromaffin-like cell type with high expression of both POMC (the precursor of ACTH) and CRH, called ACTH+&CRH + pheochromocyte. We hypothesized that the molecular mechanism of the rare case harbor Cushing's syndrome is due to the identified novel tumor cell type, that is, the secretion of ACTH had a direct effect on the adrenal gland to produce cortisol, while the secretion of CRH can indirectly stimulate the secretion of ACTH from the anterior pituitary. Besides, a new potential marker (GAL) co-expressed with ACTH and CRH might be involved in the regulation of ACTH secretion. The immunohistochemistry results confirmed its multi-functionally chromaffin-like properties with positive staining for CRH, POMC, ACTH, GAL, TH, and CgA. Our findings also proved to some extent the heterogeneity of endothelial and immune microenvironment in different adrenal tumor subtypes. [ABSTRACT FROM AUTHOR]

Purpose: Localizing the source of ectopic adrenocorticotropic hormone secretion (EAS) is challenging. This study compared the diagnostic value of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT in tumors with EAS. Methods: Thirty-six patients with a suspicion of EAS were enrolled to undergo both 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT within 4 weeks for comparison. Twenty-three underwent surgical resection or biopsy. Immunohistochemical staining for SSTR2 and Ki-67 was performed to correlate with 68Ga-DOTATATE uptake and 18F-FDG uptake, respectively. Results: EAS tumors were observed in 20/23 patients. Among the 20 patients with histologically proven EAS tumors, 68Ga-DOTATATE PET/CT correctly identified the tumor in 15 (75.0%), with an SUVmax ranging from 1.4 to 20.7 (6.7 ± 5.5). 18F-FDG PET/CT correctly identified the tumor in 12 (60.0%) patients, with an SUVmax ranging from 1.8 to 10.0 (4.0 ± 2.1). Moreover, 68Ga-DOTATATE PET/CT unmasked the sources of EAS in 6 patients with negative 18F-FDG uptake, and 18F-FDG PET/CT unmasked the sources in 3 patients with negative 68Ga-DOTATATE uptake, resulting in EAS tumors being identified in 18 (90%) patients by combining 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT. Conclusions: 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT are complementary in localizing and discriminating the source of EAS. 68Ga-DOTATATE PET/CT combined with 18F-FDG PET/CT had higher detection rate than each alone. Trial registration: 68Ga-DOTATATE PET/CT in Neuroendocrine Tumors (NCT04041882) URL of registry: https://clinicaltrials.gov/ct2/show/NCT04041882 [ABSTRACT FROM AUTHOR]

Background: Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) secondary to an ectopic source is an uncommon condition, accounting for 4-5% of all cases of CS. Refractory hypokalemia can be the presenting feature in patients with ectopic ACTH syndrome (EAS), and is seen in up to 80% of cases. EAS can be rapidly progressive and life-threatening without timely diagnosis and intervention. Case Report: We present a case of a 74-year-old White woman who first presented with hypokalemia, refractory to treatment with potassium supplementation and spironolactone. She progressively developed generalized weakness, recurrent falls, bleeding peptic ulcer disease, worsening congestive heart failure, and osteoporotic fracture. A laboratory workup showed hypokalemia, hypernatremia, and primary metabolic alkalosis with respiratory acidosis. Hormonal evaluation showed elevated ACTH, DHEA-S, 24-h urinary free cortisol, and unsuppressed cortisol following an 8 mg dexamethasone suppression test, suggestive of ACTH-dependent CS. CT chest, abdomen, and pelvis, and FDG/PET CT scan showed a 1.4 cm right lung nodule and bilateral adrenal enlargement, confirming the diagnosis of EAS, with a 1.4-cm lung nodule being the likely source of ectopic ACTH secretion. Due to the patient's advanced age, comorbid conditions, and inability to attend to further evaluation and treatment, her family decided to pursue palliative and hospice care. Conclusions: This case illustrates that EAS is a challenging condition and requires a multidisciplinary approach in diagnosis and management, which can be very difficult in resource-limited areas. In addition, a delay in diagnosis and management often results in rapid deterioration of clinical status. [ABSTRACT FROM AUTHOR]

Pediatric solid tumors have a range of clinical presentations, including those driven by the ectopic production of hormones secreted by some malignancies. Functional tumors lead to a variety of presentations, including Cushing syndrome, growth acceleration, abnormal virilization or feminization, and hypertension with electrolyte abnormalities. Precocious puberty, the onset of secondary sexual characteristics before age 8 in girls or 9 in boys, may be a warning sign of occult malignancy. Early referral is critical to optimize survival and limit disease- and treatment-related morbidities. Diagnostic workup and treatment should be guided by an interdisciplinary specialist team. Some tumors are associated with inherited cancer predisposition syndromes, which may have implications for surveillance and screening of family members. We describe a series of patients with rare functional tumors who presented with peripheral precocity to our tertiary referral centre at BC Children's Hospital to highlight key concepts for physicians: recognize, refer early, and review recommendations for genetic screening. [ABSTRACT FROM AUTHOR]

Ectopic hormone production may be present in neuroendocrine and non-endocrine neoplasms. Ectopic sources of growth hormone, adrenocorticotropin (ACTH), or their releasing factors are uncommon but clinically relevant. Ectopic ACTH tumors have been studied more than the rest, but there are still no comprehensive multidisciplinary guidelines that include all the pitfalls in the diagnosis and management of ectopic hormonal syndromes and the neoplasms associated with ectopic Cushing or acromegaly. The frequency of neuroendocrine neoplasms and other neoplasms with neuroendocrine differentiation has been increasing in recent decades. The review of the available data on these tumors, their classification, and improvements in diagnostic and therapeutic procedures is important to understand the relevance of ectopic Cushing's syndrome and acromegaly in clinical practice. [Display omitted] [ABSTRACT FROM AUTHOR]

A case study of 48 years old woman presented for a telephone consultation with continuing shortness of breath on exertion since an illness is presented. Topics include examines that ECG shows monomorphic ventricular ectopic beats in trigeminy as the heart rate is 84 beats per minute, and the corrected QT interval is 389 ms.

Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is exceedingly rare in children and scarcely reported. Pancreatic neuroendocrine tumours (NETs) can rarely lead to secretion of ectopic ACTH. A 14-year-old boy presented with hyperpigmentation, hypertension and intermittent abdominal pain, and was diagnosed with endogenous hypercortisolism. An incidental pancreatic mass discovered on routine ultrasonogram (USG) revealed the source of ACTH. He underwent successful excision of the mass with resolution of hypercortisolism. The histopathology revealed a Pancreatic NET and immunohistochemistry was positive for ACTH stain. [ABSTRACT FROM AUTHOR]

Objectives: Localization of ectopic ACTH‐secreting tumours causing Cushing syndrome (ECS) is essential for clinical management, yet often difficult. [68Ga]‐DOTATATE PET/CT ([68Ga]‐DOTA‐(Tyr3)‐octreotate)] is an FDA‐approved high‐resolution diagnostic tool for imaging neuroendocrine tumours. Data on the clinical utility of [68Ga]‐DOTATATE in patients with ECS, however, are scarce. The objectives of this study were to determine the efficacy for ECS localization and the clinical benefit of [68Ga]‐DOTATATE imaging. Method: We conducted a retrospective review of all cases with ECS evaluated with [68Ga]‐DOTATATE from November 2016 through October 2018 at three referral centres. The clinical benefit of [68Ga]‐DOTATATE was based on detection of new tumours and resultant changes in management. Results: Over the study period, 28 patients with ECS underwent [68Ga]‐DOTATATE: 17 for identification of the primary tumour and 11 during follow‐up. [68Ga]‐DOTATATE identified the suspected primary ECS in 11/17 patients (65%). Of these, nine patients underwent surgery: eight with confirmed ECS (5 bronchial, 1 thymic, 1 pancreatic and 1 metastatic neuroendocrine tumour of unknown primary origin) and one patient with a false‐positive scan (adrenal gland). Of the 11 patients with ECS who underwent [68Ga]‐DOTATATE evaluation during follow‐up, the study led to changes in clinical management in 7/11 (64%) patients. Conclusions: [68Ga]‐DOTATATE is sensitive in detecting primary and metastatic ECS, often identifies occult tumours after conventional imaging, and impacts clinical care in the majority of patients. [ABSTRACT FROM AUTHOR]

Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3–1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5–75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb +/− mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association. [ABSTRACT FROM AUTHOR]

We report here that the androgen receptor (AR) and ABCB1 are upregulated in a model of acquired taxol resistance (txr) in ovarian carcinoma cells. AR silencing sensitizes txr cells to taxol threefold, whereas ectopic AR expression in AR‐null HEK293 cells induces resistance to taxol by 1.7‐fold. AR activation using the agonist dihydrotestosterone (DHT) or sublethal taxol treatment upregulates ABCB1 expression in both txr cells and AR‐expressing HEK293 cells. In contrast, AR inactivation using the antagonist bicalutamide downregulates ABCB1 expression and enhances cytotoxicity to taxol. A functional ABCB1 promoter containing five predicted androgen‐response elements (AREs) is cloned. Deletion assays reveal a taxol‐responsive promoter segment which harbors ARE4. Notably, DHT‐ or taxol‐activated AR potentiates binding of the AR to ARE4 as revealed by the chromatin immunoprecipitation. On the other hand, txr cells display an increase in chromatin remodeling. AR/H3K9ac and AR/H3K14ac complexes bind specifically to ARE4 in response to taxol. Furthermore, acetyltransferase protein levels (p300 and GCN5) are upregulated in txr cells. Silencing of p300 or GCN5 reduces chromatin modification and enhances cytotoxicity in both parental and txr SKOV3 cells. While the phosphatidylinositol 3‐kinase (PI3K)/serine/threonine protein kinase (AKT) pathway is significantly activated by taxol, taxol‐induced ABCB1 expression, histone posttranslational modifications, and p300 binding to ARE4 are suppressed following inhibition of the PI3K/AKT cellular pathway. These results demonstrate that the AKT/p300/AR axis can be activated to target ABCB1 gene expression in response to taxol, thus revealing a new treatment target to counter taxol resistance. Androgen receptor and ABCB1 are upregulated in a model of acquired taxol resistance (txr) in ovarian carcinoma cells. We demonstrate that the AKT/p300/AR axis can be activated to target ABCB1 gene expression in response to taxol, thus revealing a new treatment target to counter taxol resistance. [ABSTRACT FROM AUTHOR]

Initiation of expression of fibroblast growth factor receptor 1 (FGFR1) concurrent with loss of FGFR2 expression is a welldocumented event in the progression of prostate cancer (PCa). Although it is known that some FGFR isoforms confer advantages in cell proliferation and survival, the mechanism by which the subversion of different FGFR isoforms contributes to PCa progression is incompletely understood. Here, we report that fibroblast growth factor (FGF) promotes NF-κB signaling in PCa cells and that this increase is associated with FGFR1 expression. Disruption of FGFR1 kinase activity abrogated both FGF activity and NF-κB signaling in PCa cells. Of note, the three common signaling pathways downstream of FGFR1 kinase, extracellular signal-regulated kinase 1/2 (ERK1/2), phosphoinositide 3-kinase (PI3K/AKT), and phosphoinositide phospholipase Cγ (PLCγ), were not required for FGF-mediated NF-κB signaling. Instead, transforming growth factor β-activating kinase 1 (TAK1), a central regulator of the NF-κB pathway, was required for FGFR1 to stimulate NF-κB signaling. Moreover, we found that FGFR1 promotes NF-κB signaling in PCa cells by reducing TAK1 degradation and thereby supporting sustained NF-κB activation. Consistently, Fgfr1 ablation in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model reduced inflammation in the tumor microenvironment. In contrast, activation of the FGFR1 kinase in the juxtaposition of chemical-induced dimerization (CID) and kinase 1 (JOCK1) mouse model increased inflammation. As inflammation plays an important role in PCa initiation and progression, these findings suggest that ectopically expressed FGFR1 promotes PCa progression, at least in part, by increasing inflammation in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Ectopic thyroid tissue is a rare clinical entity wherein malignant lesions may arise, the most common one being papillary carcinoma. We present a case of a 68-year-old female who presented with a growing mass in the right clavicle. An MR of the shoulder showed a soft tissue mass arising from the anterior margin of the right distal clavicle. A fine needle aspiration of the mass showed papillary thyroid carcinoma. PET/CT confirmed the clavicular and mediastinal mass. Excision of the clavicular mass and total thyroidectomy with modified right neck dissection were performed. Pathology revealed no evidence of malignancy in the thyroid; lymph nodes were positive for metastatic thyroid carcinoma. Postsurgery CT showed the superior mediastinal mass with surrounding adenopathy; radioiodine (RAI) treatment with dose of 142.1 mCi [5257.7 MBq] was recommended. Posttherapy whole-body scan (WBS) showed RAI avid tissue in the neck and superior mediastinum. Follow-up chest CT revealed pulmonary nodules that increased in number and size; a second RAI therapeutic dose was given. The posttherapy RAI WBS was negative. Repeat PET/CT showed multiple hypermetabolic lesions in the mediastinum, neck, lymph nodes, pulmonary nodes, and right shoulder. The FDG avid lesions with no RAI uptake suggested tumor dedifferentiation. [ABSTRACT FROM AUTHOR]

Objective. Ectopic posterior pituitary gland (EPP) is usually characterized by an abnormal pituitary stalk and hypoplasia of the anterior hypophysis. The genetic mechanisms involved in the development of EPP remain uncertain. The aim of this study is to determine whether mutations in the three genes, PROP-1, LHX2, and POU1F1, are associated with the risk for and the characteristics of EPP. Methods. In the Endocrinology Outpatient Clinic of "Dr. Behcet Uz" Children's Hospital, 27 patients with EPP were submitted to sequencing analyses of the PROP-1, LHX2, and POU1F1 genes. Results. Growth hormone, thyrotropin, corticotropin, gonadotropin, and vasopressin deficiency were observed in 22 (81.5%), 23 (85.2%), 17 (63%), 14 (51.9%), and two (7.4%) patients. Thirteen patients (48.1%) presented with hyperprolactinemia. Fourteen patients (51%) had a history of birth dystocia, and 12 cases (42.1%) had a history of breech presentation. Central nervous system abnormalities included five cases with corpus callosum agenesis, one case with schizencephaly, and one case with Chiari type 1 malformation. We identified a homozygous p.S109* mutation in exon 2 in one male patient with EPP and two different PROP1 gene polymorphisms (A142T or c.109+3 G>A polymorphism) in thirteen patients. Conclusions. Our results suggest that PROP1 gene abnormalities might explain the genetic mechanisms involved in the development of EPP. [ABSTRACT FROM AUTHOR]

SRY-box 9 (SOX9) is an important transcription factor required for development, which has additionally been reported to be an independent prognostic indicator for the survival of patients with non-small cell lung cancer (NSCLC). Accumulating evidence has indicated that dysregulation of microRNAs (miRNAs/miRs) may contribute to the initiation and progression of cancer. SOX9 may be regulated by a number of miRNAs in different types of cancer, including in NSCLC. The present study sought to identify novel candidate miRNAs associated with SOX9 in NSCLC using online tools, and investigated the detailed functions of miR-185, which suppressed SOX9 mRNA expression most strongly out of the candidate miRNAs. It was observed that ectopic miR-185 expression significantly suppressed NSCLC cell proliferation, invasion and migration. Using luciferase reporter gene and RNA immunoprecipitation assays, SOX9 was confirmed to be a direct target of miR-185. In addition, the downstream Wnt signaling-associated factors β-catenin and c-Myc proto-oncogene protein (Myc) were demonstrated to be inhibited by miR-185 overexpression. SOX9, β-catenin and c-Myc mRNA expression was significantly upregulated in NSCLC tissues, and was inversely correlated with miR-185 expression. The results of the present study demonstrated that rescuing miR-185 expression in NSCLC, thereby inhibiting SOX9 expression and the downstream Wnt signaling, and leading to the suppression of NSCLC cell proliferation, invasion and migration, may be a promising strategy for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Background Excessive atrial ectopic activity (EAEA) has been related with an increased risk of atrial fibrillation (AF) and stroke but different cutoff values have been used. We aimed to determine the association between EAEA and stroke, AF and overall death. Methods Consecutive 24-hour Holter monitoring performed between 2005 and 2010 in a single center was evaluated. Patients with a previous diagnosis of stroke or AF were excluded. The number of premature atrial contractions (PACs) during 24 h was analyzed in 2480 subjects and according to that 3 sub-groups were defined: > 97 PACs/h (above the top 5th percentile of the population) (EAEA +); intermediate value of PACs/h (below the top 5th percentile but above 30 PACs/h) (EAEA +/−) and < 30 PACs/h (EAEA −). Results After adjusting for risk factors, laboratory findings and medication, EAEA + was associated with ischemic stroke (hazard ratio [HR] 2.83; 95% confidence interval [CI], 1.65–4.84, p < 0.001). Both EAEA + and EAEA +/− were independently associated with AF (HR 2.05; 95% CI 1.31–3.23, p = 0.010 for EAEA + and HR 1.90; 95% CI 1.10–2.78, p = 0.020 for EAEA +/−) and overall death (HR 2.17; 95% CI 1.48–3.28, p = 0.031 for EAEA +; HR 2.01; 95% CI 1.06–2.52, p = 0.029 for EAEA +/−). Conclusion In this population, having > 30 PACs/h was independently associated with a higher risk of AF and overall death but only subjects with > 97 PACs/h had a higher risk of ischemic stroke. In the majority of subjects with stroke and EAEA +, AF has not been detected before stroke event. [ABSTRACT FROM AUTHOR]

Viral infection of different cell types induces a unique spectrum of host defence genes, including interferon-stimulated genes (ISGs) and genes encoding other proteins with antiviral potential. Although hundreds of ISGs have been described, the vast majority have not been functionally characterised. Cellular proteins with putative antiviral activity (hereafter referred to as "restriction factors") can target various steps in the virus life-cycle. In the context of influenza virus infection, restriction factors have been described that target virus entry, genomic replication, translation and virus release. Genome wide analyses, in combination with ectopic overexpression and/or gene silencing studies, have accelerated the identification of restriction factors that are active against influenza and other viruses, as well as providing important insights regarding mechanisms of antiviral activity. Herein, we review current knowledge regarding restriction factors that mediate anti-influenza virus activity and consider the viral countermeasures that are known to limit their impact. Moreover, we consider the strengths and limitations of experimental approaches to study restriction factors, discrepancies between in vitro and in vivo studies, and the potential to exploit restriction factors to limit disease caused by influenza and other respiratory viruses. [ABSTRACT FROM AUTHOR]

Introduction Chronic low-grade inflammation is associated with obesity and diabetes. However, what causes and mediates chronic inflammation in metabolic disorders is not well understood. Toll-like receptor 4 (TLR4) mediates both infection-induced and sterile inflammation by recognizing pathogen-associated molecular patterns and endogenous molecules, respectively. Saturated fatty acids can activate TLR4, and TLR4-deficient mice were protected from high fat diet (HFD)-induced obesity and insulin resistance, suggesting that TLR4-mediated inflammation may cause metabolic dysfunction, such as obesity and insulin resistance. Methods We generated two transgenic (TG) mouse lines expressing a constitutively active TLR4 in adipose tissue and determined whether these TG mice would show increased insulin resistance. Results TG mice fed a high fat or a normal chow diet did not exhibit increased insulin resistance compared to their wild-type controls despite increased localized inflammation in white adipose tissue. Furthermore, females of one TG line fed a normal chow diet had improved insulin sensitivity with reduction in both adiposity and body weight when compared with wild-type littermates. There were significant differences between female and male mice in metabolic biomarkers and mRNA expression in proinflammatory genes and negative regulators of TLR4 signaling, regardless of genotype and diet. Conclusions Together, these results suggest that constitutively active TLR4-induced inflammation in white adipose tissue is not sufficient to induce systemic insulin resistance, and that high fat diet-induced insulin resistance may require other signals in addition to TLR4-mediated inflammation. [ABSTRACT FROM AUTHOR]

ABSTRACT Heterotopic ossification (HO) is a debilitating sequela of high-energy injuries. It frequently requires surgical excision once symptomatic and there is no practical prophylaxis for combat-injured patients. In this study, we examined the effect of local vancomycin powder on HO formation in a small animal model of blast-related, post-traumatic HO. Male Sprague-Dawley rats were subjected to a polytraumatic extremity injury and amputation with or without methicillin-resistant Staphylococcus aureus infection. Animals were randomized to receive a single local application of vancomycin (20 mg/kg) at the time of injury (POD-0, n = 34) or on postoperative day-3 (POD-3, n = 11). Quantitative volumetric measurement of ectopic bone was calculated at 12-weeks post-injury by micro-CT. Bone marrow and muscle tissues were also collected to determine the bacterial burden. Blood for serum cytokine analysis was collected at baseline and post-injury. Vancomycin treatment on POD-0 suppressed HO formation by 86% and prevented bone marrow and soft tissue infections. We concurrently observed a marked reduction histologically in nonviable tissue, chronic inflammatory cell infiltrates, bone infection, fibrous tissue, and areas of bone necrosis within this same cohort. Delayed treatment was significantly less efficacious. Neither treatment had a marked effect on the production of pro-inflammatory cytokines. Our study demonstrates that local vancomycin treatment at the time of injury significantly reduces HO formation in both the presence and absence of infection, with decreased efficacy if not given early. These findings further support the concept that the therapeutic window for prophylaxis is narrow, highlighting the need to develop early treatment strategies for clinical management. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2397-2406, 2017. [ABSTRACT FROM AUTHOR]

Direct reprogramming of pancreatic beta cells is of great interest due to its possible use in diabetes treatment. Various studies have demonstrated direct reprogramming of insulin expressing beta cells from other somatic cells by overexpressing important pancreatic transcription factors through viral vectors. However, concerns about using viral vectors in the clinic have prompted scientists to find new approaches for gene delivery and expression. In vitro synthesis and transfection of mRNAs is a safer strategy for ectopic gene expression. In this study we aimed to design and in vitro synthesize human pancreatic transcription factors' mRNAs: Pdx1, Ngn3, and MafA. We also aimed to assess their expression efficiency in cultured cells. First we ligated the open reading frames of these genes to modified 5′ and 3′ UTRs. Ligation products were then cloned into a plasmid and subjected to in vitro transcription to get their corresponding mRNAs. Modified mRNAs were subsequently examined for their quality, quantity, and protein translation efficiency. In vitro-transcribed mRNAs were successfully transfected to the human fibroblast cells. Efficiently translated proteins were correctly localized into the nucleus. It is concluded that pancreatic mRNAs designed and in vitro-transcribed in this study can be used in further direct beta cell reprogramming studies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the microRNA expression profiling in endometriosis-associate infertility, and relationship between the microRNA expression and endometrial receptivity evaluated by ultrasound. METHODS: First, miRNA expression profiling difference of ectopic endometrium between 8 endometriosis patients and 6 endometriosis-free patients were compared. Bioinformatics analyses detected 61 differentially expressed (DE) known miRNAs and 57 DE novel miRNAs. Next, other 24 patients were selected for checking the microRNAs in differential expression by RT-PCR. Among them, case and control groups include 14 endometriosis and 10 endometriosis-free infertility patients, respectively. Last, endometrial receptivity of other 20 endometriosis patients was evaluated by ultrasound. In this group of patients, 12 had high endometrial receptivity, in which infertility is caused by fallopian tube occlusion, and 8 had low endometrial receptivity. The study compared endometrial miRNAs expression between two groups, and also evaluated the relationship between the endometrial miRNAs expression and the endometrial receptivity. RESULTS: First, study indicated that “proteinaceous extracellular matrix,” “laminin binding” and “extracellular matrix binding” were enriched in 6 up-regulated miRNA targets, while “cell proliferation” was enriched in the 4 down-regulated miRNA targets. Second, 10 miRNAs in different expression (miR-1304- 3p, miR-544b, miR-3684, miR-494-5p, miR-4683, miR-6747-3p; miR-3935, miR-4427, miR-652-5p, miR-205-5p) were detected byRT-PCR, and the results showed statistically significant differences between 2 groups in all 10 miRNAs. Third, the expression levels of miR-1304-3p, miR-494-5p, and miR-4427 were different between the two groups with different endometrial receptivity. But for the miR-544b, there was no statistically significant difference between two groups. CONCLUSIONS: The study provided a comprehensive understanding to the current knowledge in the field of miRNAs in endometriosis and the relationship between them and the endometrial receptivity. miRNAs could be used as diagnostic biomarkers and therapeutic agents for this disease. The combination of ultrasound and miRNAs detection could be a better choice for the diagnosis of infertility in the future. [ABSTRACT FROM AUTHOR]

Temperature-sensitive (ts) mutants of simian rotavirus (RV) strain SA11 have been previously created to investigate the functions of viral proteins during replication. One mutant, SA11-tsC, has a mutation that maps to the gene encoding the VP1 polymerase and shows diminished growth and RNA synthesis at 39°C compared to that at 31°C. In the present study, we sequenced all 11 genes of SA11-tsC, confirming the presence of an L138P mutation in the VP1 N-terminal domain and identifying 52 additional mutations in four other viral proteins (VP4, VP7, NSP1, and NSP2). To investigate whether the L138P mutation induces a ts phenotype in VP1 outside the SA11-tsC genetic context, we employed ectopic expression systems. Specifically, we tested whether the L138P mutation affects the ability of VP1 to localize to viroplasms, which are the sites of RV RNA synthesis, by expressing the mutant form as a green fluorescent protein (GFP) fusion protein (VP1L138P-GFP) (i) in wild-type SA11-infected cells or (ii) in uninfected cells along with viroplasm-forming proteins NSP2 and NSP5. We found that VP1L138P-GFP localized to viroplasms and interacted with NSP2 and/or NSP5 at 31°C but not at 39°C. Next, we tested the enzymatic activity of a recombinant mutant polymerase (rVP1L138P) in vitro and found that it synthesized less RNA at 39°C than at 31°C, as well as less RNA than the control at all temperatures. Together, these results provide a mechanistic basis for the ts phenotype of SA11-tsC and raise important questions about the role of leucine 138 in supporting key protein interactions and the catalytic function of the VP1 polymerase. [ABSTRACT FROM AUTHOR]

Endometriosis is a benign estrogen-dependent chronic gynecological disease characterized by the presence of endometrial-like tissue outside the uterine cavity. In both women and experimental endometriotic rats, endometriosis lesions endow autonomic and sensory nerves, which are thought to contribute to the disease-associated pain. Some evidence indicates that the reinnervation of lesions is regulated by factors produced by the endometrial tissue as well as by environmental factors from the peritoneum. In this study, we examined the reinnervation of the rat endometrial tissue in an ectopic environment different from the peritoneum employing the anterior eye chamber model of experimental endometriosis. At 3 and 6 weeks following transplantation, endometrial grafts retained many histological features of the eutopic tissue. Both sympathetic and sensory nerves reinnervated endometrial grafts and distributed in the stroma-like tissue, around blood vessels and in close proximity to the glands and lining epithelium. Sympathetic innervation was more robust than sensory innervation. No significant topographical relationship between sympathetic nerves and macrophages was observed. These results suggest that the rat endometrium possesses intrinsic neuritogenic capacities and can be reinnervated by sympathetic and sensory nerves in ectopic sites different from the peritoneum. [ABSTRACT FROM AUTHOR]

Ectopic insertion of the ureter in the genitourinary tract is a rare congenital disorder, usually associated with ureteral duplication. Identification of the insertion open is critical for ureteric re-implantation. However, the challenge in the diagnosis of ectopic insertion of the ureter usually is to identify its insertion, particularly when the affected ureter is not dilated. Multi-detector computed tomography (MDCT) urography with nonionic iodinated contrast media delineates the ureteric course in the normal functioning kidney in the excretory phase [1]. This report presented a young male patient with ectopic insertion of a duplicated ureter diagnosed by MDCT urography. Three-dimensional (3D) analysis technology, such as volume rendering (with a color display improving the visualization of complex anatomy and 3D relationships) and maximum intensity projection (similar in principle to projection angiography), is useful for the illustration of urinary tract anatomy [1]. Rotated volume rendering reconstruction images and continual thinner maximum intensity projection reformatted images can be viewed as videos, which provides detail delineation of the ectopic ureteral insertion and its associated ureteral duplication. In this study, we reported MDCT urography and 3D analysis technology as an appropriate diagnostic method for the ectopic ureteral insertion and its associated complications. [ABSTRACT FROM AUTHOR]

Macrophages are highly plastic cells with the ability to differentiate into both M1- and M2-polarized phenotypes. As a distinct M2-polarized population, tumour-associated macrophages (TAMs) promote tumorigenesis owing to their pro-angiogenic and immune-suppressive functions in tumour microenvironment. In the present study, we found that the microRNA-720 (miR-720) was down-regulated in TAMs isolated from breast carcinomas and M2-polarization macrophages. Overexpression of miR-720 attenuated M2 phenotype expression and thus inhibited M2 polarization. We further identified GATA binding protein 3 (GATA3), a transcriptional factor that plays an important role in M2 macrophage polarization, was the downstream target of miR-720. Ectopic expression of GATA3 restored the M2 phenotype in miR-720 overexpressed macrophages. Importantly, overexpression of miR-720 inhibited pro-migration behaviour and phagocytic ability ofM2-polarized macrophages. Thus, our data suggest that miR-720 plays an important role in regulating M2 macrophage polarization and function. [ABSTRACT FROM AUTHOR]

Introduction: Endocrine and metabolic paraneoplastic syndromes in the course of malignant tumours result from ectopic production of hormones or hormone precursors in tumour cells. Production of hormones by endocrine tumours is relatively frequent, while such a production by adenocarcinoma cells is definitely rare. The study presents a case of a triple-negative invasive breast cancer, with ectopic secretion of ACTH (adrenocorticotropic hormone), which provokes serious metabolic disorders. Materials and methods: The patient was admitted to hospital with symptoms of Cushing's syndrome. Diagnostic tests revealed that the cause of metabolic disorders was breast cancer. After proper preparation, the patient was qualified for surgery. Results: After mastectomy the patient's metabolism stabilised. The patient underwent adjuvant chemotherapy and radiotheraphy. Four months after the last cycle of systemic treatment, cancer dissemination was found. The patient was treated with second-line chemotherapy, however control CT revealed progression. The patient died 20 months after surgery and two months after the last cycle of chemotherapy. Conclusions: The case reported in this study - triple-negative invasive breast cancer, responsible for ectopic production of ACTH and causing Cushing's syndrome - is a rare phenomenon. Treatment of patients with breast cancer showing hormonal activity should not differ from general rules applied for breast cancer. However, due to accompanying metabolic disturbances, the patients need individualised oncological approach, precise diagnostic tests and adequate preoperative preparation. [ABSTRACT FROM AUTHOR]

Summary: The crest in chicken consists of elongated and upraised feathers, as seen in various breeds such as the Silkie chicken. Recently, the still unknown causative mutation for the crest phenotype was assigned to chromosome 33 and an ectopic expression of HOXC8 was shown. The aim this study was to evaluate whether the crest phenotype in a local Swiss chicken breed, the Appenzeller Spitzhaubenhuhn, is associated with HOXC8. Three previously reported crest‐associated flanking markers at the HOXC8 locus were genotyped in cohorts of this breed and two other local breeds without the crest phenotype. For the Appenzeller Spitzhaubenhuhn chicken showing the crest phenotype, no clear association of the reported markers could be revealed. Furthermore, the two exons of HOXC8 were sequenced in crested chicken of the Appenzeller Spitzhaubenhuhn and Silkie breeds and revealed no evidence of polymorphisms within the coding region of HOXC8. Therefore, the molecular genetic etiology for the crest phenotype in the investigated breeds remains unclear. [ABSTRACT FROM AUTHOR]

The analysis of the surface Electrocardiogram (ECG) is the most extended non-invasive technique in cardiological diagnosis. The ectopic beats are heart beats remarkably different to the normal beat morphology that provoke serious disturbances in electrocardiographic analysis. These beats are very common in atrial fibrillation (AF), causing important residua when ventricular activity has to be removed for atrial activity (AA) analysis. These beats may occur in both normal subjects and patients with heart disease, and their presence represents an important source of error which must be handled before any other analysis. In this work, a method is proposed to cancel out ectopics by classification between normal and abnormal beats. The systems is based on Radial Basis Function Neural Network (RBFNN). This new approach is compared to state-of-the-art techniques for the ectopic classification and cancellation in the MIT database. The results clearly demonstrated the improved ECG beats classification accuracy compared with other alternatives and a very accurate reduction of ectopic beats together with low distortion of the QRST complex. [ABSTRACT FROM AUTHOR]

The article reports on congenital cystic neck mass, Thyroglossal duct cyst (TGDC), preoperative diagnosis inclding Magnetic Resonance Imaging (MRI), computed tomography (CT), and fine-needle aspiration cytology (FNAC) to determine ectopic thyroid and malignancy, its treatment via surgical excision by Sistrunk's procedure, and statistical analysis of patient demographics. The article observes relationship between demography, symptoms, recurrence, TGDC extending posterior to the hyoid bone.

The contribution of microRNAs to lymphoma biology is not fully understood. In particular, it remains untested whether microRNA dysregulation could contribute to the emergence of the aggressive subset of B-cell lymphomas that coexpress MYC and BCL2. Here, we identify microRNA-124 (miR-124) as a negative regulator of MYC and BCL2 expression in B-cell lymphomas. Concordantly, stable or transient ectopic expression of miR-124 suppressed cell proliferation and survival, whereas genetic inhibition of this miRNA enhanced the fitness of these tumors. Mechanistically, the activities of miR-124 towards MYC and BCL2 intersect with both oncogenic and tumor-suppressive pathways. In respect to the former, we show that miR-124 directly targets nuclear factor-κB (NF-κB) p65, and using genetic approaches, we demonstrate that this interaction accounts for the miR-124-mediated suppression of MYC and BCL2. We also characterized miR-124 promoter region and identified a functional p53 binding site. In agreement with this finding, endogenous or ectopic expression of wild-type, but not mutant, p53 increased miR-124 levels and suppressed p65, MYC and BCL2. Our data unveil an miRNA-dependent regulatory circuitry that links p53 to the NF-κB pathway, which when disrupted in B-cell lymphoma may be associated with aberrant coexpression of MYC and BCL2 and poor prognosis. [ABSTRACT FROM AUTHOR]

Background & Aims Hepatocellular carcinoma ( HCC) is one of the most common human cancers. Recently, emerging evidence has suggested the role of long non-coding RNAs (lnc RNAs) in human carcinogenesis. In this study, we aimed to investigate the expression and functional implications of lnc RNAs in human HCC. Methods Eighty-eight well-annotated lnc RNAs were profiled in primary HCC by quantitative RT- PCR. Functional relevance of lnc RNAs was elucidated in HCC cell lines and nude mice models. The regulatory relationship between mi RNA and lnc RNA was predicted in silico and further validated by luciferase reporter assay and expression analysis. Results In our profiling study, HOTTIP was identified as the most significantly up-regulated lnc RNA in human HCCs, even in early stage of HCC formation. Functionally, knock-down of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumourigenicity in vivo. In addition, knock-down of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lnc RNA mapped to the distal end of the HOXA gene cluster. Knock-down of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR-125b as a post-transcriptional regulator of HOTTIP. Ectopic expression of miR-125b reduced HOTTIP-coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR-125b. Conclusions HOTTIP is a novel oncogenic lnc RNA, which negatively regulated by miR-125b. Overexpression of HOTTIP contributes to hepatocarcinogenesis by regulating the expression of its neighbouring protein-coding genes. [ABSTRACT FROM AUTHOR]

Cysteine proteases and cystatins have many functions that remain poorly characterised, particularly in crop plants. We therefore investigated the responses of these proteins to nitrogen deficiency in wild-type soybeans and in two independent transgenic soybean lines (OCI-1 and OCI-2) that express the rice cystatin, oryzacystatin-I (OCI). Plants were grown for four weeks under either a high (5 mM) nitrate (HN) regime or in the absence of added nitrate (LN) in the absence or presence of symbiotic rhizobial bacteria. Under the LN regime all lines showed similar classic symptoms of nitrogen deficiency including lower shoot biomass and leaf chlorophyll. However, the LN-induced decreases in leaf protein and increases in root protein tended to be smaller in the OCI-1 and OCI-2 lines than in the wild type. When LN-plants were grown with rhizobia, OCI-1 and OCI-2 roots had significantly more crown nodules than wild-type plants. The growth nitrogen regime had a significant effect on the abundance of transcripts encoding vacuolar processing enzymes (VPEs), LN-dependent increases in VPE2 and VPE3 transcripts in all lines. However, the LN-dependent increases of VPE2 and VPE3 transcripts were significantly lower in the leaves of OCI-1 and OCI-2 plants than in the wild type. These results show that nitrogen availability regulates the leaf and root cysteine protease, VPE and cystatin transcript profiles in a manner that is in some cases influenced by ectopic OCI expression. Moreover, the OCI-dependent inhibition of papain-like cysteine proteases favours increased nodulation and enhanced tolerance to nitrogen limitation, as shown by the smaller LN-dependent decreases in leaf protein observed in the OCI-1 and OCI-2 plants relative to the wild type. [ABSTRACT FROM AUTHOR]

Objective Cardiac ectopic fat depositions are thought to play a role in the pathogenesis of cardiovascular disease ( CVD), the main cause of death in patients with type 2 diabetes. Diet-induced weight loss results in a decrease in cardiac ectopic fat stores, however if this is the same for surgically induced weight loss is less clear. Therefore, we assessed myocardial triglyceride ( TG) content, pericardial fat and cardiac function in obese patients with insulin-dependent type 2 diabetes before and 16 weeks after Roux-en- Y gastric bypass ( RYGB) surgery. Patients Ten obese patients with insulin-dependent type 2 diabetes [40% male, age 53·7 ± 8·9 years (mean ± SD)] scheduled to undergo RYGB surgery were included. Measurements Ectopic fat accumulation and cardiovascular function were assessed with magnetic resonance ( MR) imaging and myocardial TG content with MR spectroscopy before and 16 weeks after RYGB surgery. Results Body mass index decreased from 41·3 ± 4·3 at baseline to 34·1 ± 2·8 kg/m2 ( P < 0·001) after 16 weeks. Glycemic control improved as well [ Hb A1c: 7·8 ± 1·1 to 6·8 ± 1·3% (62 ± 12 to 51 ± 14 m m) ( P < 0·05)]. We did not observe an effect of the RYGB surgery on myocardial TG content, cardiac function or pulse wave velocity. There was a greater relative decrease in visceral (−35·5 ± 9·6%) as compared to subcutaneous fat volume (−25·0 ± 6·3%) and in paracardial (−17·3 ±17·2%) as compared to epicardial fat volume (−6·4 ± 6·0%). Conclusions This study shows that surgical-induced weight loss leads to a larger decrease in paracardial than epicardial fat. Myocardial TG and cardiovascular function did not change. [ABSTRACT FROM AUTHOR]

Objective: Heart rate variability (HRV) analysis, which is an important tool for activity assessment of the cardiac autonomic nervous system, very often includes the estimation of power spectra for series of interbeat intervals (IBI). Ectopic beats and artifacts have a destructive effect on the standard methods (Fourier transform, FFT) for frequency analysis. This study investigates an alternative method for calculation of the periodogram using a robust period detection (RPD). Method: Error free IBI series of 5 minutes for 221 subjects during one day were artificially distorted by randomly changing IBI values by ±15-40%. The low to high frequency rate (LF/HF) were calculated from periodograms estimated by the FFT, RPD and Lomb (LSP) methods for both error free and distorted series and for series with removed beats. Log transformed LF/HF values for series with distorted/removed beats were compared to undistorted values by linear regression. Results: For series with 10% of distorted IBI values the regression analysis between distorted and undistorted series showed a goodness of fit, coefficient and intercept of 0.98, 0.94 and 0.02, respectively. In comparison, the values of these parameters were (0.34, 0.46, −1.61) and (0.28, 0.42,-1.32) for the FFT and LSP methods, respectively. Similarly, the comparison between series with removed and undistorted beats yielded goodness of fit, coefficient and intercept of (0.98, 0.96, −0.01), (0.93, 0.78, −0.02) and (0.98, 0.95, 0.19) for RPD, FFT and LSP, respectively. Conclusion: The RPD method demonstrated superior performance compared to the FFT and LSP method by estimation of power spectral characteristics for HRV analysis. [ABSTRACT FROM AUTHOR]

Most frequent causes of androgenic manifestation are Cushing’s syndrome, PCO, benign and malignant androgen-secreting non adrenal tumors and iatrogenic hirsutism. Hyperplasia or neoplasms of ectopic adrenocortical gland are rare. We report a case of a 63-year old female with hirsutism and alopecia. Laboratory data highlighted increased levels of androgens. Diagnostic imaging revealed normal morphology of adrenocortical gland and ovaries. In view of the clinical picture and suspected diagnosis of extra-adrenal cause, she underwent bilateral salpingo-oophorectomy. Histologic examination showed an ectopic adrenal gland with adenoma in the ovarian and peri-ovarian tissue. At six months of follow up, the patients has no sign of hyperandrogenism. In case of hyperandrogenism in postmenopausal women and in the absence of the adrenocortical gland abnormality, ovarian origin should be considered in the differential diagnosis. [ABSTRACT FROM PUBLISHER]

Heterophilic antibodies are well described, but poorly appreciated interferents and is often not a recognized problem affecting most immunoassays. We report a patient presented with ectopic Cushing’s syndrome (CS), but repeated plasma adrenocorticotropic hormone (ACTH) concentrations conducted by immunoassay were inappropriately within the reference range and not elevated, most probably as a result of antibody interference. A 36-year-old woman, presented with large gastric neuroendocrine carcinoma and severe ectopic CS, while repeated plasma ACTH concentrations conducted by immunoassay were inappropriately within the reference range. As we expected ACTH concentration to be higher, we performed several tests to evaluate whether there was any assay interference causing falsely lower than expected ACTH results. We measured ACTH using a different immunoassay, assayed the sample in dilution, assayed the sample after being incubated in heterophilic antibody blocking agent tube and performed recovery studies. Tests indicated the presence of interfering compounds, most probably heterophilic antibodies. When clinicians find ACTH concentrations to be lower than expected, we recommend the laboratory investigate antibody interference. [ABSTRACT FROM PUBLISHER]

The noncluster homeobox gene HOX11/TLX1 (TLX1) is detected at the breakpoint of the t(10;14)(q24;q11) chromosome translocation in patients with T cell acute lymphoblastic leukemia (T-ALL). This translocation results in the inappropriate expression of TLX1 in T cells. The oncogenic potential of TLX1 was demonstrated in IgHμ-TLX1Tg mice which develop mature B cell lymphoma after a long latency period, suggesting the requirement of additional mutations to initiate malignancy. To determine whether dysregulation of genes involved in the DNA damage response contributed to tumor progression, we crossed IgHμ-TLX1Tg mice with mice deficient in the DNA repair enzyme DNA-PK (PrkdcScid/Scid mice). IgHµ-TLX1TgPrkdcScid/Scid mice developed T-ALL and acute myeloid leukemia (AML) with reduced latency relative to control PrkdcScid/Scid mice. Further analysis of thymi from premalignant mice revealed greater thymic cellularity concomitant with increased thymocyte proliferation and decreased apoptotic index. Moreover, premalignant and malignant thymocytes exhibited impaired spindle checkpoint function, in association with aneuploid karyotypes. Gene expression profiling of premalignant IgHµ-TLX1TgPrkdcScid/Scid thymocytes revealed dysregulated expression of cell cycle, apoptotic and mitotic spindle checkpoint genes in double negative 2 (DN2) and DN3 stage thymocytes. Collectively, these findings reveal a novel synergy between TLX1 and impaired DNA repair pathway in leukemogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Longan (Dimocarpus longan Lour.) is a subtropical evergreen fruit tree, mainly cultivated in Asia. Two putative floral integrator genes, D. longan FLOWERING LOCUS T1 and 2 (DlFT1 and DlFT2) were isolated and both translated sequences revealed a high homology to FT sequences from other plants. Moreover, two APETALA1-like (DlAP1-1 and DlAP1-2) sequences from longan were isolated and characterized. Results indicate that the sequences of these genes are highly conserved, suggesting functions in the longan flowering pathway. Ectopic expression of the longan genes in arabidopsis resulted in different flowering time phenotypes of transgenic plants. Expression experiments reveal a different action of the longan FT genes and indicate that DlFT1 is a flowering promoter, while DlFT2 acts as flowering inhibitor. Overexpression of longan AP1 genes in transgenic arabidopsis results in a range of flowering time phenotypes also including early and late flowering individuals. [Copyright &y& Elsevier]

Abstract: The cold-inducible promoter is ideal for regulating ectopic gene expression in plants to cope with the cold stress. The promoters of two cold-regulated genes, cor15a and cor15b, were cloned from Arabidopsis thaliana and their strengths were assayed in potato and tobacco. Although the cis-element composition and cold-inducible property were similar between the two promoters, the cor15b promoter showed significantly higher activity than the cor15a promoter in both potato and tobacco. In order to elucidate the factors determining this discrepancy, cor15a and cor15b promoters were separately truncated from 5′-end to construct short promoters with similar size containing a single C-repeat/dehydration-responsive element (CRT/DRE). Subsequently, two synthetic promoters were constructed by swapping the flanking sequences of CRT/DRE in the truncated promoters. The promoter strength comparison demonstrated that the flanking sequence could affect the promoter strength. These findings provide a potential regulatory mechanism to control the promoter strength without impact on other properties. [Copyright &y& Elsevier]

The MIR396 family, composed of ath-miR396a and ath-miR396b in Arabidopsis, is conserved among plant species and is known to target the Growth-Regulating Factor ( GRF) gene family. ath-miR396 overexpressors or grf mutants are characterised by small and narrow leaves and show embryogenic defects such as cotyledon fusion. Heterologous expression of ath-miR396a has been reported in tobacco and resulted in reduction of the expression of three Nt GRF genes. In this study, the precursor of the Populus trichocarpa ptc-miR396c, with a mature sequence identical to ath-miR396b, was expressed under control of the Ca MV35S promoter in tobacco. Typical phenotypes of GRF down-regulation were observed, including cotyledon fusion and lack of shoot apical meristem ( SAM). At later stage of growth, transgenic plants had delayed development and altered specification of organ type during flower development. The third and fourth whorls of floral organs were modified into stigmatoid anthers and fasciated carpels, respectively. Several Nt GRF genes containing a miR396 binding site were found to be down-regulated, and the cleavage of their corresponding m RNA at the miR396 binding site was confirmed for two of them using RACE- PCR analysis. The data obtained agree with the functional conservation of the miR396 family in plants and suggest a role for the miR396/ GRF network in determination of floral organ specification. [ABSTRACT FROM AUTHOR]

Abstract: The primary axis of cnidarians runs from the oral pole to the apical tuft and defines the major body axis of both the planula larva and adult polyp. In the anthozoan cnidarian Nematostella vectensis, the primary oral–aboral (O–Ab) axis first develops during the early embryonic stage. Here, we present evidence that pharmaceutical activators of canonical wnt signaling affect molecular patterning along the primary axis of Nematostella. Although not overtly morphologically complex, molecular investigations in Nematostella reveal that the O–Ab axis is demarcated by the expression of differentially localized signaling molecules and transcription factors that may serve roles in establishing distinct ectodermal domains. We have further characterized the larval epithelium by determining the position of a nested set of molecular boundaries, utilizing several newly characterized as well as previously reported epithelial markers along the primary axis. We have assayed shifts in their position in control embryos and in embryos treated with the pharmacological agents alsterpaullone and azakenpaullone, Gsk3β inhibitors that act as canonical wnt agonists, and the Wnt antagonist iCRT14, following gastrulation. Agonist drug treatments result in an absence of aboral markers, a shift in the expression boundaries of oral markers toward the aboral pole, and changes in the position of differentially localized populations of neurons in a dose-dependent manner, while antagonist treatment had the opposite effect. These experiments are consistent with canonical wnt signaling playing a role in an orally localized wnt signaling center. These findings suggest that in Nematostella, wnt signaling mediates O–Ab ectodermal patterning across a surprisingly complex epithelium in planula stages following gastrulation in addition to previously described roles for the wnt signaling pathway in endomesoderm specification during gastrulation and overall animal–vegetal patterning at earlier stages of anthozoan development. [Copyright &y& Elsevier]