Idiopathic isolated adrenocorticotropic hormone deficiency: a systematic review of a heterogeneous and underreported disease.

Isolated adrenocorticotropic hormone deficiency (IAD) is considered to be a rare disease. Due to the nonspecific clinical presentation, precise data on the prevalence and incidence are lacking. In this systematic review, we aimed to analyse the clinical characteristics, association with autoimmune diseases, and management of acquired idiopathic IAD cases. A structured search was conducted after developing a search strategy combining terms for acquired (idiopathic) IAD. Articles describing an adult case with a diagnosis of ACTH deficiency using dynamic testing, no deficiency of other pituitary axes, and MRI of the brain/pituitary protocolled as normal, were included. Exclusion criteria were cases describing congenital IAD, cases with another aetiology for IAD, and articles where full text was not available. In total 42 articles were included, consisting of 85 cases of acquired idiopathic IAD. Distribution by sex was approximately equal (F:M; 47:38). Lethargy was the most common presenting symptom (38%), followed by weight loss (25%), anorexia (22%), and myalgia/arthralgia (12%). Eight cases (9.5%) presented with an Addison crisis. 31% of cases had an autoimmune disease at diagnosis of which Hashimoto hypothyroidism was the most frequent. Data about follow-up was scarce; dynamic testing was repeated in 4 cases of which 2 showed recovery of the adrenal axis. We report the largest case series of acquired idiopathic IAD to date. Our systematic review highlights the lack of a clear definition and diagnostic work-up. Based on the findings in this review a proposition is made for a flowchart to diagnose acquired idiopathic IAD.

Giant right atrial aneurysm associated with persistent left cranial vena cava in a cat.

A 10-month-old female spayed Scottish Fold was referred to cardiology for incidental radiographic cardiomegaly. Echocardiography was suspicious for a right atrial or right auricular aneurysm. The differential diagnosis also included peritoneal-pericardial diaphragmatic hernia, mass lesion (cyst, granuloma, or neoplasia), or cardiac malformation. A giant right atrial aneurysm associated with a persistent left cranial vena cava was subsequently confirmed with computed tomography.

FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis.

Aberrant expression of the Forkhead box transcription factor, FOXQ1, is a prevalent mechanism of epithelial-mesenchymal transition (EMT) and metastasis in multiple carcinoma types. However, it remains unknown how FOXQ1 regulates gene expression. Here, we report that FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. We first establish that FOXQ1 promoter recognition precedes MLL complex assembly and histone-3 lysine-4 trimethylation within the promoter regions of critical genes in the EMT program. Mechanistically, we identify that the Forkhead box in FOXQ1 functions as a transactivation domain directly binding the MLL core complex subunit RbBP5 without interrupting FOXQ1 DNA binding activity. Moreover, genetic disruption of the FOXQ1-RbBP5 interaction or pharmacologic targeting of KMT2/MLL recruitment inhibits FOXQ1-dependent gene expression, EMT, and in vivo tumor progression. Our study suggests that targeting the FOXQ1-MLL epigenetic axis could be a promising strategy to combat triple-negative breast cancer metastatic progression.

DDR2 coordinates EMT and metabolic reprogramming as a shared effector of FOXQ1 and SNAI1.

While multiple transcription factors (TFs) have been recognized to drive epithelial-mesenchymal transition (EMT) in cancer, their interdependence and context-dependent functions are poorly understood. In this study, we show that FOXQ1 and SNAI1 act as independent TFs within the EMT program with a shared ability to upregulate common EMT TFs without reciprocally impacting the expression of one another. Despite this independence, human mammary epithelial cells (HMLE) with ectopic expression of either FOXQ1 or SNAI1 share a common gene set that is enriched for a DDR2 coexpression signature. Further analysis identified DDR2 as the most upregulated receptor tyrosine kinase and a shared downstream effector of FOXQ1 and SNAI1 in triple-negative breast cancer (TNBC) cell lines. Alteration of DDR2 expression in either FOXQ1 or SNAI1 driven EMT models or in TNBC cells resulted in a profound change of cell motility without significantly impacting EMT marker expression, cell morphology, or the stem cell population. Lastly, we demonstrated that knockdown of DDR2 in the FOXQ1-driven EMT model and TNBC cell line significantly altered the global metabolic profile, including glutamine-glutamate and Aspartic acid recycling.

RNA binding protein RBMS3 is a common EMT effector that modulates triple-negative breast cancer progression via stabilizing PRRX1 mRNA.

The epithelial-to-mesenchymal transition (EMT) has been recognized as a driving force for tumor progression in breast cancer. Recently, our group identified the RNA Binding Motif Single Stranded Interacting Protein 3 (RBMS3) to be significantly associated with an EMT transcriptional program in breast cancer. Additional expression profiling demonstrated that RBMS3 was consistently upregulated by multiple EMT transcription factors and correlated with mesenchymal gene expression in breast cancer cell lines. Functionally, RBMS3 was sufficient to induce EMT in two immortalized mammary epithelial cell lines. In triple-negative breast cancer (TNBC) models, RBMS3 was necessary for maintaining the mesenchymal phenotype and invasion and migration in vitro. Loss of RBMS3 significantly impaired both tumor progression and spontaneous metastasis in vivo. Using a genome-wide approach to interrogate mRNA stability, we found that ectopic expression of RBMS3 upregulates many genes that are resistant to degradation following transcriptional blockade by actinomycin D (ACTD). Specifically, RBMS3 was shown to interact with the mRNA of EMT transcription factor PRRX1 and promote PRRX1 mRNA stability. PRRX1 is required for RBMS3-mediated EMT and is partially sufficient to rescue the effect of RBMS3 knockdown in TNBC cell lines. Together, this study identifies RBMS3 as a novel and common effector of EMT, which could be a promising therapeutic target for TNBC treatment.

A simplified blood culture sampling protocol for reducing contamination and costs: a randomized controlled trial.

OBJECTIVES: Blood culture contamination carries risks for patients, such as unnecessary antimicrobial therapy and other additional hazards and costs. One method shown to be effective in reducing contamination is initial blood specimen diversion during collection. We hypothesized that initial blood specimen diversion without a designated device or procedure would suffice for reduction in blood culture contamination rate. METHODS: From 1 September 2017 through to 6 September 2018, we conducted a randomized controlled trial to assess the effect of an initial-specimen diversion technique (ISDT) on the rate of blood-culture contamination by changing the order of sampling using regular vacuum specimen tubes instead of commercially available sterile diversion devices. We included adults from whom the treating physician planned to take blood cultures and additional blood chemistry tests. Additionally, we evaluated the potential economic benefits of an ISDT. This was a researcher-initiated trial, Clinicaltrials.gov NCT03088865. RESULTS: In all, 756 patients were enrolled. This method, compared with the standard procedure in use at our medical centre, reduced contamination by 66% (95% CI 17%-86%), from 20/400 (5%) with the standard method to 6/356 (1.6%) with the ISDT, without compromising detection of true bloodstream infection and at no additional cost. Hospital-wide implementation of ISDT was associated with a 1.1% saving in hospitalization days. CONCLUSIONS: We offer this novel approach as a simple, cost-effective measure to reduce risks to patient safety from contaminated blood cultures, without the need for using costly devices.

Prediction of exocrine and endocrine insufficiency after pancreaticoduodenectomy using volumetry.

Objectives: The aim of this study is to evaluate the use of pancreatic volumetric assessment to predict exocrine and endocrine insufficiency after pancreaticoduodenectomy.Methods: Thirty-seven patients who underwent pancreaticoduodenectomy were included in the study. Endocrine function was assessed in all patients without a history of diabetes using an oral glucose tolerance test. A 13C-labeled mixed triglyceride (MTG) breath test evaluated exocrine function before and after resection. Volumetric measurements were performed on CT or MRI.Results: The volumetric measurements could not predict pre- or postoperative diabetes. Moreover, the resected volume was significantly lower in patients who developed diabetes after resection. Comparing patients with a normal and disturbed postoperative MTG, postoperative volumes and parenchymal thickness were significantly different. The parenchymal thickness on postoperative imaging is withheld as a predictive factor (OR = .85 [95% CI .71-1.01], p = .049). The best cutoff value to predict exocrine insufficiency is a parenchymal thickness of less than 11.4 mm (AUC = .76, p = .025, sensitivity = 88.9%, specificity = 70.0%).Conclusions: Pancreatic remnant volumetry and parenchymal thickness measurement after pancreaticoduodenectomy are correlated with exocrine insufficiency, but with limited predictive value. None of the preoperative measurements are withheld to predict postoperative exocrine function. Pre- and postoperative volumetry appear to have no use in predicting postoperative diabetes.

EGFL9 promotes breast cancer metastasis by inducing cMET activation and metabolic reprogramming.

The molecular mechanisms driving metastatic progression in triple-negative breast cancer (TNBC) patients are poorly understood. In this study, we demonstrate that epidermal growth factor-like 9 (EGFL9) is significantly upregulated in basal-like breast cancer cells and associated with metastatic progression in breast tumor samples. Functionally, EGFL9 is both necessary and sufficient to enhance cancer cell migration and invasion, as well as distant metastasis. Mechanistically, we demonstrate that EGFL9 binds cMET, activating cMET-mediated downstream signaling. EGFL9 and cMET co-localize at both the cell membrane and within the mitochondria. We further identify an interaction between EGFL9 and the cytochrome c oxidase (COX) assembly factor COA3. Consequently, EGFL9 regulates COX activity and modulates cell metabolism, promoting a Warburg-like metabolic phenotype. Finally, we show that combined pharmacological inhibition of cMET and glycolysis reverses EGFL9-driven stemness. Our results identify EGFL9 as a therapeutic target for combating metastatic progression in TNBC.

A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer.

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content.

Pulmonary artery banding in a kitten with a partial atrioventricular septal defect.

A 9-month-old kitten with increased resting respiratory rate and exercise intolerance was diagnosed with a congenital partial atrioventricular septal defect causing pulmonary over circulation and presumed pulmonary hypertension based on echocardiogram. Invasive pressure measurements and contrast angiography confirmed this diagnosis. The cat underwent pulmonary artery banding under general anesthesia. Findings of echocardiogram 10 days postoperatively suggested reduced left-to-right shunt volume. Echocardiographic findings were static 4 months postoperatively.

Disulfiram and BKM120 in Combination with Chemotherapy Impede Tumor Progression and Delay Tumor Recurrence in Tumor Initiating Cell-Rich TNBC.

Tumor initiating cells (TIC) have been suggested as a mechanism for driving chemoresistance and tumor recurrence in human cancers including triple negative breast cancer (TNBC). Significant progress has been made in targeting TICs. However, methods for simultaneously targeting heterogeneous TIC populations are lacking. In this study, we found that treating TNBC cells with chemotherapeutic agents led to a significant accumulation of the ALDH+ TIC population. Treating TNBC cells with a disulfiram and copper mixture (DSF/Cu) specifically decreased the ALDH+ TIC population and treatment with BKM120, a pan-PI3K inhibitor, significantly decreased the CD44+/CD24- TIC population. Furthermore, treatment with DSF/Cu or BKM120 induced higher levels of apoptosis in ALDH+ or CD44+/CD24- populations, respectively, than in bulk tumor cells. Combining DSF/Cu and BKM120 treatment simultaneously decreased the ALDH+ and CD44+/CD24- TICs. Using a TNBC tumor xenograft mouse model, we found that DSF/BKM in combination with Taxol significantly reduced the tumor burden and delayed tumor recurrence compared to Taxol treatment alone. Our study is the first of its kind to use two different drugs to abolish two major TIC subtypes simultaneously and inhibit tumor recurrence. These results lay a foundation for developing a novel therapy that can improve chemotherapeutic efficacy.

Trainee perspectives on postdoctoral recruitment in clinical neuropsychology: reflections on commentaries by Bodin and Grote (2016) and Nelson et al. (2016).

OBJECTIVE: The aim of the current invited paper is to provide the trainees' perspective on recent commentaries on recruitment for postdoctoral fellowship in clinical neuropsychology. The current system of recruitment includes both a match and non-match process and has been problematic for trainees and training programs alike. METHOD: The author team completed a non-systematic review of previously published commentaries on the current state of postdoctoral fellowship recruitment, which are briefly summarized in the current paper. The trainee perspective is addressed using both survey data and anecdotal experiences of the authors. RESULT: Trainees report high levels of dissatisfaction with the current dual recruitment system; however, there is no clear preference from trainees for either a match or non-match system. Trainees from both recruitment systems report high levels of satisfaction with their training experience. CONCLUSION: It seems that either a match or non-match approach, if it led to a unified system, would improve trainee satisfaction.

Cooperative oncogenic effect and cell signaling crosstalk of co­occurring HER2 and mutant PIK3CA in mammary epithelial cells.

Though incidence of PI3K oncogenic mutation is prominent in breast cancer (20-30%), pharmacological targeting of this signaling pathway alone has failed to provide meaningful clinical benefit. To better understand and address this problem, we conducted genome-wide analysis to study the association of mutant PI3K with other gene amplification events. One of the most significant copy number gain events associated with PIK3CA mutation was the region within chromosome 17 containing HER2. To investigate the oncogenic effect and cell signaling regulation of co-occurring PIK3CA-H1047R and or HER2 gene, we generated cell models ectopically expressing mutant PIK3CA, HER2 or both genetic alterations. We observed that cells with both genetic alterations demonstrate increased aggressiveness and invasive capabilities than cells with either genetic change alone. Furthermore, we found that the combination of the HER2 inhibitor (CP-724714) and pan PI3K inhibitor (LY294002) is more potent than either inhibitor alone in terms of inhibition of cell proliferation and colony formation. Significantly, four cell signaling pathways were found in common for cells with HER2, mutant PIK3CA and cells with both genetic alterations through an Affymetric microarray analysis. Moreover, the cells with both genetic alterations acquired more significant replication stress as shown by enriched signaling pathways of cell cycle checkpoint control and DNA damage response signaling. Our study suggests co-occurrence of oncogenic HER2 and mutant PIK3CA cooperatively drives breast cancer progression. The cells with both genetic alterations obtain additional features of replication stress which could open new opportunity for cancer diagnostics and treatment.

Not performing an OGTT results in significant underdiagnosis of (pre)diabetes in a high risk adult Caucasian population.

OBJECTIVE: Type 2 diabetes (T2DM) is known to be underdiagnosed. Tests for diagnosis include fasting plasma glucose (FPG), oral glucose tolerance test (OGTT) and HbA1c. HbA1c can be tested in non-fasting conditions. Therefore, general practitioners almost no longer execute OGTT's. We evaluated the performance of OGTT versus HbA1c in a population consisting of overweight and obese subjects, which can be considered a 'high risk' population. RESEARCH DESIGN AND METHODS: A total of, 1241 overweight and obese subjects without a history of diabetes (male/female: 375/866, age 44±13 years, body mass index 38.0±6.1 kg m-2) were tested for glucose tolerance status using FPG, OGTT and HbA1c. RESULTS: Exactly, 46.8% were found to have prediabetes and 11.9% were newly diagnosed with T2DM (male/female=18.9/8.9%) using ADA criteria. Testing only HbA1c would have resulted in 78 subjects being diagnosed with T2DM, but 47.3% of newly diagnosed patients would have been missed if OGTT would not have been done. Exactly 581 subjects were diagnosed with prediabetes, 1.4% subjects had impaired fasting glucose (IFG) 30.5% had impaired glucose tolerance (IGT), 5.1% subjects had a combined IFG+IGT, and 9.8% had an isolated elevated HbA1c (5.7-6.4%). Of the 581 subjects with prediabetes, 257 had an HbA1c <5.7%. Therefore, 44.2% subjects would have been missed when OGTT would not have been done. CONCLUSION: In a population with only overweight and obese adult subjects, 46.8% were diagnosed with prediabetes and 11.9% were newly diagnosed with diabetes. Exactly, 5.6 and 20.7% of total population met the diagnostic criteria of the OGTT for diabetes and prediabetes, respectively, but did not meet the diagnostic criteria of the HbA1c. These data suggest that not performing an OGTT results in significant underdiagnose of T2DM in an overweight and obese adult population.

Circadian waveform bifurcation, but not phase-shifting, leaves cued fear memory intact.

In mammals, memory acquisition and retrieval can be affected by time of day, as well as by manipulations of the light/dark cycle. Under bifurcation, a manipulation of circadian waveform, two subjective days and nights are experimentally induced in rodents. We examined the effect of bifurcation on Pavlovian fear conditioning, a prominent model of learning and memory. Here we demonstrate that bifurcation of the circadian waveform produces a small deficit in acquisition, but not on retrieval of fear memory. In contrast, repeated phase-shifting in a simulated jet-lag protocol impairs retrieval of memory for cued fear. The results have implications for those attempting to adjust to shift-work or other challenging schedules.

Seasonality of tuberculosis in Israel, 2001-2011.

BACKGROUND: Several studies have suggested that the incidence of tuberculosis (TB) varies with the seasons. OBJECTIVE: To determine the seasonality of TB in Israel and to explore possible associations with climatic variables. METHODS: Laboratory-confirmed TB cases reported between 2001 and 2011 in individuals resident in Israel for at least 1 year before diagnosis were included in the study. Climatic variables included average temperature and average ultraviolet radiation. The mean serum 25-hydroxyvitamin D level of the population was also recorded. RESULTS: Of all 2653 TB cases, incidence peaked during spring (n = 712) and reached its nadir during the fall (n = 577), with a case proportion amplitude (CPA) of 5.1% (P = 0.036). Individuals born in the Horn of Africa exhibited a CPA of 9.5% (P = 0.077). Mean population 25-hydroxyvitamin D level was significantly correlated with the seasonal pattern of the disease. Southern Israel had the highest global radiation and, counter-instinctively, the highest TB incidence. CONCLUSIONS: TB exhibited a seasonal tendency in Israel, with the spring peak/fall nadir pattern found elsewhere. Vitamin D is suspected to be an explanatory variable for this seasonal phenomenon. The finding that the highest incidence is in the area receiving the highest global radiation suggests population-related vulnerability to vitamin D deficiency.

Improving diet, activity and wellness in adults at risk of diabetes: randomized controlled trial.

OBJECTIVE: The purpose of this analysis is to examine the effect of an algorithm-driven online diabetes prevention program on changes in eating habits, physical activity and wellness/productivity factors. METHODS: The intervention, Alive-PD, used small-step individually tailored goal setting and other features to promote changes in diet and physical activity. A 6-month randomized controlled trial was conducted among patients from a healthcare delivery system who had confirmed prediabetes (n =339). Change in weight and glycemic markers were measured in the clinic. Changes in physical activity, diet and wellness/productivity factors were self-reported. Mean age was 55 (s.d. 8.9) years, mean body mass index was 31 (s.d. 4.4) kg m(-2), 68% were white and 69% were male. RESULTS: The intervention group increased fruit/vegetable consumption by 3.71 (95% confidence interval (CI) 2.73, 4.70) times per week (effect size 0.62), and decreased refined carbohydrates by 3.77 (95% CI 3.10, 4.44) times per week both significantly (P<0.001) greater changes than in the control group. The intervention group also reported a significantly greater increase in physical activity than in the control group, effect size 0.49, P<0.001. In addition, the intervention group reported a significant increase in self-rated health, in confidence in ability to make dietary changes and in ability to accomplish tasks, and a decrease in fatigue, compared with the control group. These changes paralleled the significant treatment effects on glycemic markers and weight. CONCLUSIONS: In addition to promoting improvements in weight and glycemic markers, the Alive-PD program appears to improve eating habits and physical activity, behaviors important not just for diabetes prevention but for those with diagnosed diabetes or obesity. The improvements in wellness/productivity may derive from the diet and activity improvements, and from the satisfaction and self-efficacy of achieving goals.

Screening for type 2 diabetes mellitus in overweight and obese subjects made easy by the FINDRISC score.

AIM: To evaluate the use of the FINDRISC score in an overweight and obese population to predict glucose status. METHODS: In 651 overweight/obese subjects (M/F: 193/458, age 43±13 y, BMI 38.2±6.1kg/m(2)) glucose status was tested using OGTT and HbA1c. Furthermore, the FINDRISC questionnaire and CT visceral fat (VAT) and subcutaneous fat (SAT) were examined. RESULTS: Exactly 50.4% were found to have prediabetes and 11.1% were newly diagnosed with type 2 diabetes (T2DM) (M/F=22.2/8.8%). Subjects without T2DM had a FINDRISC score of 11±3, those with pre-DM 13±4, and subjects with de novo T2DM 15±5. The aROC of the FINDRISC for detecting T2DM was 0.76 (95% CI 0.72-0.82), with 13 as cutoff point. The FINDRISC score correlated with VAT (r=0.34, p<0.001) and VAT/SAT ratio (r=0.39, p<0.001). The aROC of the FINDRISC to detect excess VAT was 0.79 (95%CI 0.72-0.84). CONCLUSIONS: In a large group of overweight and obese subjects, 50.4% were found to have pre-DM and 11.1% were newly diagnosed with T2DM. The FINDRISC score increased with worsening of glucose tolerance status and proved to be an independent predictor of T2DM status, as did HOMA-B, HOMA-S and VAT. The FINDRISC can also function as a good tool to predict visceral obesity.