Function Of Na Research Articles

Combined Lanreotide Autogel and Temozolomide Treatment of Progressive Pancreatic and Intestinal Neuroendocrine Tumors: The Phase II SONNET Study.

In advanced neuroendocrine tumors (NET), antiproliferative treatment options beyond somatostatin analogs remain limited. Temozolomide (TMZ) has shown efficacy in NET alone or combined with other drugs. SONNET (NCT02231762) was an open, multicenter, prospective, phase II study to evaluate lanreotide autogel 120 mg (LAN) plus TMZ in patients with progressive advanced/metastatic grade 1/2 gastroenteropancreatic (GEP) NET or of unknown primary. Patients could be enrolled at first-line or higher therapy line. The primary endpoint was disease control rate ([DCR], rate of stable disease [SD], partial [PR], and complete response [CR]) at 6 months of LAN and TMZ. Patients with nonfunctioning (NF) NET without progression at 6 months were randomized to 6-month LAN maintenance or watch and wait, patients with functioning (F)-NET with clinical benefit (PR, SD) continued on LAN. Fifty-seven patients were recruited. The majority of patients received the study drug at second or higher treatment line and had an NET G2. DCR at 6 months LAN and TMZ was 73.5%. After 6 months of further LAN maintenance, 54.5% of patients with F-NET and 71.4% with NF-NET had SD or PR vs 41.7% with NF-NET on observation only. LAN and TMZ were effective in all subgroups analyzed. At 12 months of follow-up, median progression-free survival was 11.1 months. Median serum chromogranin A decreased except in NF-NET on observation. O6-methylguanine DNA methyltransferase promoter methylation appeared to better reflect TMZ response than loss of gene expression. During combination therapy, the most frequent treatment-emergent adverse events grade 3/4 reported were nausea (14%), thrombocytopenia (12.3%), and neutropenia (8.8%). Four deaths were reported resulting from severe adverse events not considered related to study medication. LAN plus TMZ is a treatment option for patients with progressive GEP-NET with more aggressive biological profile showing a manageable safety profile.

Immunohistochemical and in situ hybridization analyses of glucose transporter 2 in pancreatic neuroendocrine tumors: Possible glucose transporter 2 association with neoplastic insulin production

BackgroundPancreatic neuroendocrine tumors (PanNETs) are rare neoplasms. Additionally, glucose transporter 2 (GLUT2) is associated with insulin production and is essential for glucose transport to normal pancreatic β-cells. Neoplastic cell GLUT2 expression may also influence insulin production by using this transporter. GLUT2 expression and its clinical significance remain unclear in PanNETs. This study aimed to provide GLUT2 expression profiles and evidence of correlation with insulin in PanNETs. MethodsClinical data were retrieved from 113 surgically resected paraffin-embedded PanNET tissue samples fixed with 10% formalin. PanNETs are categorized as insulinoma, non-functional (NF)-PanNET, or PanNET-not otherwise specified (NOS). A GLUT2 score was used to evaluate cytoplasmic GLUT2 immunoreactivity. The immunoreactive score (IRS) was used to determine membranous GLUT2, cytoplasmic insulin, and proinsulin immunoreactivities. A commercially available in situ hybridization (ISH) kit detected human SLC2A2 (GLUT2) mRNA on tissues in all seven positive- and 20 negative-GLUT2 IRS cases. ResultsGLUT2 and IRSs significantly differed among insulinoma, NF-PanNET, and PanNET-NOS. Insulinomas exhibited significantly higher GLUT2 scores and IRSs than did NF-PanNETs. GLUT2 IRS positive cases demonstrated significantly higher insulin and proinsulin IRSs than did negative cases. Additionally, GLUT2 ISH-positive cases demonstrated positive GLUT2 scores and IRSs, with significantly higher GLUT2 IRSs than did negative cases. PanNET histological grade categories did not significantly affect GLUT2 scores and IRSs. ConclusionThe first evidence of a correlation between GLUT2 expressions and insulin in PanNETs is shown in this study.

Extraction of Na+ ions by dibenzo-18-crown-6 in biphasic aqueous systems of ionic liquid and chloroform

The molecular dynamics simulations were carried out to explore the extraction of Na+ ions in the ionic liquid (IL)–water, chloroform–water biphasic systems containing the crown ether: dibenzo-18-crown-6 (DB18C6) to compare organic solvents such as chloroform to ionic liquid (IL) as receiving solvent phase. The free DB18C6 was found to be highly interacted with IL as compared to chloroform. The Na+–DB18C6 complex interacts preferentially with IL at the interface. The complex has higher interaction energies with IL (-47.04 kcal/mol) as compared to chloroform (-0.11 kcal/mol). The large sharp peak height for the radial distribution function in Na+–DB18C6 complex suggests high stability and strong interaction. At the IL–water interface, it was observed that the Na+–DB18C6 complex had a lower self-diffusion coefficient (0.538 × 10−9 m2/s) than other species. The spatial distribution functions further indicated that the surfaces of Na+ were very closely distributed around the active sides of crown ether in the IL–water system whereas, in chloroform–water systems, it was distributed very far from the crown ether. The present results may help us to understand the role of solvents in heavy metal ion extraction and also in the future design of crown ethers and solvents.

THU511 Somatostatin Analogs Or Active Surveillance In Sporadic And MEN1 Associated Non-functioning Pancreatic Neuroendocrine Tumors

Abstract Disclosure: S. Raia: None. S. Chiloiro: None. M. Maratta: None. B. Maiorano: None. E. Rossi: None. M. Brizi: None. V. Rufini: None. L. De Marinis: None. G. Rindi: None. G. Schinzari: None. A. Pontecorvi: None. G. Tortora: None. A. Bianchi: None. Introduction: Non-functioning (NF), sporadic and MEN1 associated, G1-G2 pancreatic neuroendocrine tumors (PanNETs) usually display an indolent course. Surgery is the first-choice treatment for localized tumors >2 cm. Unresectable or metastatic PanNETs expressing somatostatin receptors (SSTRs) are treated with somatostatin analogs (SSAs). The standard treatment for patients with PanNETs ≤2cm is active surveillance (AS). Yet no evidence of the value of SSA treatment exist in such patient population. Aim(s): To assess the clinical value of SSAs in patients with PanNETs ≤2cm. Material and methods: Data from patients (pts) NF, G1-G2 PanNETs≤2cm were retrospectively collected. Median progression-free survival (mPFS) and response rate (RR) were analyzed in SSA group and AS group. Results: From June 2007 to June 2022, data from 46 pts were considered: 29 pts, who declined an AS program but had not indication for surgery, entered in the SSA group (21 sporadic and 8 MEN1 associatd PanNET) and 17 in the AS group. At a median follow-up of 64.8 months for sporadic and of 63.9 for MEN1 associated PanNET, no disease progression (PD) was reported in the SSA group, without differences between sporadic and MEN1 associated PanNET. While the PD rate was 23.5 % in the AS group, with a mPFS of 36.2 months. Conclusion: SSAs therapy showed significant antiproliferative activity in patients with both sporadic and MEN1 associated NF, G1-G2 PanNETs ≤2cm. SSAs treatment delay tumor progression and distant spread in small lesions that sometimes may reveal an unpredictable aggressiveness. Presentation: Thursday, June 15, 2023

FRI298 Serum Prolactin To Tumor Size Ratio As An Effective Parameter To Accurately Distinguish Prolactinoma From NFPT

Abstract Disclosure: I. Mishra: None. A. Pradhan: None. A.K. Baliarsinha: None. Preoperative diagnosis of prolactinomas is critical because dopamine agonists therapy have been regarded as a primary treatment. Multiple studies have compared serum prolactin levels in clinically nonfunctioning (NF) tumors and prolactinomas to identify cutoffs that may distinguish primary tumoral secretion from stalk effect. Prolactin levels are correlated with the size of prolactinomas but are not associated with tumor size in non prolactin-secreting lesions or the degree of stalk deviation and compression. By using the tumor size, we investigated an effective parameter for the discrimination between prolactinoma and NFPT. 33 patients with pituitary lesion of histological diagnosis were retrospectively recruited for this study. The data obtained was entered into Microsoft Excel Worksheet and analysed using Statistical Package for Social Sciences (SPSS, IBM Corp. Released 2020. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.).The Prolactinoma group (n=16) showed higher serum prolactin (mean=418 ng/mL) than those in the NFPT group (n=17) (mean=33.34 ng/mL, p-values < 0.001).Using receiver operating curve analyses, we compared diagnostic performances of serum prolactin (PRL)/ tumor volume ratio in both groups. Unlike NFPT, serum prolactin values significantly correlated with tumor volume in Prolactinoma group. At a cut off of 12.2ng/ml/cm3,serum PRL/tumor volume was found to have a sensitivity of75.8% in diagnosing prolactinomas. However the specificity was 24.2%. Burke et al and Wright et al studied significantly smaller groups of patients and reported a linear relationship between prolactin levels and prolactinoma volume as estimated by a simplified ellipsoid volume equation. Our study demonstrates that the assessment of prolactin secretory density, based on a calculation of serum prolactin per unit tumor volume, can be used as a potential method to distinguish prolactinomas from hyperprolactinemia secondary to stalk effect and could be valuable in guiding patient management in equivocal or challenging patient cases wherein the etiology of hyperprolactinemia is uncertain. Reference: (1) Burke WT, Penn DL, Castlen JP, et al. Prolactinomas and nonfunctioning adenomas: preoperative diagnosis of tumor type using serum prolactin and tumor size. J Neurosurg. 2019:1e8.(2) Wright K, Lee M, Escobar N, et al. Tumor volume improves preoperative differentiation of prolactinomas and nonfunctioning pituitary adenomas.Endocrine.2021;74(1):138e145 Presentation: Friday, June 16, 2023

Dysglycemia in non-functioning pancreatic neuroendocrine tumors (NF-PNET): Further insights into an under recognized entity

ObjectivePancreatic neuroendocrine tumors (PNETs) are rare, but their incidence has risen significantly in recent years. Whereas diabetes mellitus (DM) is recognized in association with chronic pancreatitis and pancreatic cancer, it has not been well-characterized concerning non-functioning (NF)-PNETs.Study aim:to determine whether NF-PNETs are associated with DM/ Pre-DM and characterize the features of this putative association. MethodsRetrospective study to evaluate rate of Pre-DM /DM in subjects with NF-PNETs. ResultsStudy cohort of 129 patients with histologically confirmed NF-PNETs, ∼60% were men (M/F: 77/52). Abnormal glucose metabolism that preceded any treatment was seen in 70% of this cohort: overt DM in 34% and Pre-DM in 36% of the subjects. However, during follow-up, the overall prevalence rose to 80.6%, owing exclusively to newly diagnosed DM in subjects who received treatment.Patients with DM/Pre-DM were older (65 ± 11; 54 ± 14; p < 0.0001), the tumor was more commonly localized in the pancreatic body and tail (76.5% vs. 23.5% p = 0.03), while BMI (27 ± 6 vs. 28 ± 5 kg/m2), and tumor size (2.4 ± 2 vs. 2.9 ± 3.2 cm) were similar. The relative prevalence of DM in our cohort of NF-PNETs was 1.6 higher than that in the age and gender-adjusted general Israeli population (95 %CI: 1.197–2.212p = 0.03). ConclusionsWe found a high rate of impaired glucose metabolism, either DM or Pre-DM, in a large cohort of NF-PNETs. The high prevalence of diabetes/pre-diabetes was unrelated to obesity or tumor size. This observation should increase awareness of the presence of DM on presentation or during treatment of “NF”-PNETs.

Activity of Na+/K+- and Ca2+-ATPases in human erythrocyte membranes: Protocol improvement, relation to cholesterol content, and effects of polyphenols

It is known that the activities of Na+/K+- and Ca2+-ATPases in the plasma membrane with an excess of cholesterol are compromised. Our main goal was to find out whether quercetin, resveratrol, or caffeic acid, in the nano- and low micromolar concentration ranges, can improve the ATPase activity in human erythrocyte membranes with excess cholesterol. These molecules belong to different chemical classes of polyphenols and are widely present in plant foods. Also, due to some variations in the protocol for determining the ATPase activity, we first analyzed several key parameters of the protocol to improve the accuracy of the results. The activities of Na+/K+- and Ca2+-ATPases were reduced in membranes with moderate and high cholesterol levels compared to membranes from normocholesterolemic subjects (p < 0.01). All three polyphenols affected the ATPase activity in a similar biphasic manner. Namely, the ATPase activity gradually increased with increasing polyphenol concentration up to 80–200 nM, and then gradually decreased with further increase in polyphenol concentration. Moreover, the stimulating effect of the polyphenols was highest in membranes with high cholesterol content, making ATPase activity values close/equal to those in normal cholesterol membranes. In other words, quercetin, resveratrol, and caffeic acid at nanomolar concentrations were able to improve/restore the functioning of Na+/K+- and Ca2+-ATPases in erythrocyte membranes with high cholesterol levels. This suggests a common membrane-mediated mechanism of action for these polyphenols, related to the content of membrane cholesterol.

Mild autonomous cortisol secretion in adrenal incidentalomas and risk of fragility fractures: a large cross-sectional study.

Mild autonomous cortisol secretion (MACS) has been associated with a higher prevalence of osteoporosis, although most data rely on single-center studies with limited sample size. We aimed to assess the prevalence of fragility fractures and contributing factors in a large cohort of patients with adrenal incidentalomas. Medical records of 1023 patients with adrenal incidentalomas from 1990 to 2019 were reviewed, and 735 patients were selected. Clinically obtained electronic radiological images closest to first endocrine evaluation, such as lateral views of spine X-rays or CT thoraco-abdominal scans, were reviewed to screen for asymptomatic morphometric vertebral fractures. Clinical fragility fractures, hormonal, and dual-energy x-ray absorptiometry (DXA) indices were also recorded. Four hundred seventy-four patients had nonfunctioning (NF) adrenal incidentalomas, 238 had MACS and 23 adrenal Cushing's syndrome (AC). Prevalence of fragility fractures was different (P = .018) between groups, respectively, 24.1% (NF), 34.0% (MACS), and 30.4% (AC), with significant difference between NF and MACS (P = .012). When analyzed separately by sex and menopausal status, this difference remained significant in postmenopausal women (P = .011), with a fracture prevalence of 22.2% (NF) and 34.6% (MACS). Fracture prevalence was similar in males. Women with MACS aged ≥65 years reported a 48.8% prevalence of fractures, as compared with 29.5% in NF (P < .01). In postmenopausal women, fragility fractures were associated with age (odds ratio [OR] 1.1, P < .001), smoking (OR 1.8, P = .048), and 1 mg-dexamethasone suppression test (DST) cortisol (OR 3.1, P = .029), while in men, only age was associated with fragility fractures. A considerable fracture burden was shown in postmenopausal women with adrenal incidentalomas and MACS, with clinical implications for the evaluation and management of bone metabolism.

The Na+/K+-ATPase: A potential therapeutic target in cardiometabolic diseases.

Cardiometabolic diseases (CMD) are a direct consequence of modern living and contribute to the development of multisystem diseases such as cardiovascular diseases and diabetes mellitus (DM). CMD has reached epidemic proportions worldwide. A sodium pump (Na+/K+-ATPase) is found in most eukaryotic cells' membrane and controls many essential cellular functions directly or indirectly. This ion transporter and its isoforms are important in the pathogenesis of some pathological processes, including CMD. The structure and function of Na+/K+-ATPase, its expression and distribution in tissues, and its interactions with known ligands such as cardiotonic steroids and other suspected endogenous regulators are discussed in this review. In addition, we reviewed recent literature data related to the involvement of Na+/K+-ATPase activity dysfunction in CMD, focusing on the Na+/K+-ATPase as a potential therapeutic target in CMD.

Abstract 11566: Distribution and New Function of Na, K-ATPase and Its Phosphoprotein Regulator Phospholemman in Cardiac Myocytes

Introduction: Na, K-ATPase (NKA), regulated by phosphoprotein phospholemman (PLM), contributes to excitation-contraction via the Na,Ca-exchanger at cardiac T-tubules (TTs). It is known that the intercalated discs (IDs) contain concentrated specific Na channels and K channels, that rely on ion gradients set by NKA. Yet, the coordinated trafficking and localization of NKA and PLM in cardiomyocytes (CMs) remains incompletely understood, Hypothesis: NKA and PLM are concentrated in the ID and essential for cardiac conduction. Methods: We have made five antibodies (Abs) that specifically identify PLM (B8, PLM-N-term, and PLM-C-term) or NKA (NKA-α1 and Pan-α, recognizing both α1 and α2 subunits of NKA). Confocal immunofluorescence assays were used to determine the intracellular distribution of PLM and NKA. Optical mapping studies were performed in rabbit hearts. Results: These five Abs all displayed specific fluorescence signals in dog CMs that were more intense at the IDs than TTs. These signals were eliminated by competing peptides. B8 and NKA-α1 signals highly overlapped, with similar intensity ratios between ID and TT at ~3. Immunostaining of connexin 43, γ-catenin, or N-cadherin confirmed the co-localization of NKA and PLM to the ID. PLM and NKA co-enriched with ID protein markers in sarcolemma/ID membrane preparations. To corroborate the localization of PLM at the ID, we expressed dog PLM in rat CMs. By 30h post-infection, B8 detected newly synthesized dog PLM that paralleled the pattern of its steady-state distribution in tissue, with concentrated protein apparent at IDs (B8 fluorescence intensity ratio of ID/TT = 2.6 ± 0.5, 50CMs). Nocodazole prevented newly-made dog PLM trafficking to ID. Finally, optical mapping studies showed that the NKA inhibitor ouabain and digoxin significantly increased activation times in a dose-dependent manner (n=5 and 4 rabbits, respectively). Conclusions: The α1 subunit of NKA and PLM are each expressed at a ~3X higher concentration in ID compared to TT in CMs, contributing to cardiac conduction. Mechanisms of PLM and NKA protein trafficking to the two disparate subcellular sites, and associated effects of PLM regulation by adrenergic signaling, provide important new insights into the physiology of cardiac conduction.

Imbalance between the function of Na+-K+-2Cl and K+-Cl impairs Cl- homeostasis in human focal cortical dysplasia.

Altered expression patterns of Na+-K+-2Cl- (NKCC1) and K+-Cl- (KCC2) co-transporters have been implicated in the pathogenesis of epilepsy. Here, we assessed the effects of imbalanced NKCC1 and KCC2 on γ-aminobutyric acidergic (GABAergic) neurotransmission in certain brain regions involved in human focal cortical dysplasia (FCD). We sought to map a micro-macro neuronal network to better understand the epileptogenesis mechanism. In patients with FCD, we resected cortical tissue from the seizure the onset zone (SOZ) and the non-seizure onset zone (non-SOZ) inside the epileptogenic zone (EZ). Additionally, we resected non-epileptic neocortical tissue from the patients with mesial temporal lobe epilepsy (MTLE) as control. All of tissues were analyzed using perforated patch recordings. NKCC1 and KCC2 co-transporters expression and distribution were analyzed by immunohistochemistry and western blotting. Results revealed that depolarized GABAergic signals were observed in pyramidal neurons in the SOZ and non-SOZ groups compared with the control group. The total number of pyramidal neurons showing GABAergic spontaneous postsynaptic currents was 11/14, 7/17, and 0/12 in the SOZ, non-SOZ, and control groups, respectively. The depolarizing GABAergic response was significantly dampened by the specific NKCC1 inhibitor bumetanide (BUM). Patients with FCD exhibited higher expression and internalized distribution of KCC2, particularly in the SOZ group. Our results provide evidence of a potential neurocircuit underpinning SOZ epileptogenesis and non-SOZ seizure susceptibility. Imbalanced function of NKCC1 and KCC2 may affect chloride ion homeostasis in neurons and alter GABAergic inhibitory action, thereby contributing to epileptogenesis in FCDs. Maintaining chloride ion homeostasis in the neurons may represent a new avenue for the development of novel anti-seizure medications (ASMs).

Pituitary adenomas in the elderly: Retrospective comparative analysis of clinical/tumor features and surgical data by age group.

The increase in life expectancy along with technological advances has translated into a higher number of pituitary adenomas (PA) diagnosed from the age of 65. In the elderly, symptoms related to comorbidities might overlap with endocrine dysfunction, in addition to increasing anesthetic and surgical risks. This study aimed to compare baseline clinical and tumor features between patients with PA from different age groups: younger adults (YA), 18 to 64 years, and older adults (OA), ≥65 years. As secondary outcomes, we also intended to assess: clinical characteristics and tumor features in patients undergoing surgical intervention and surgical data and complications in patients undergoing transphenoidal surgery (TSS). This retrospective cohort study included patients diagnosed with PA in adulthood divided into YA and OA groups. The secondary outcomes were evaluated in the subgroups: patients who underwent pituitary surgery and patients specifically submitted to TSS, who had completed postoperative follow-up ≥ 6 months until July/2020. A total of 401 patients were included, 327 (81.5%) in the YA and 74 (18.5%) in the OA group. Hormone-secreting effects were more common in the YA group (P < .001) and mass effects in the OA group (P = .070). The prevalence of hypertension and diabetes was higher in the OA group (P = .002, P = .011). A larger proportion of nonfunctioning (NF) PA and prolactinomas was found in OA (P < .001) and YA (P = .012), respectively. Macroadenomas were more common in the OA group (P < .001). No differences were found in terms of invasiveness. In the secondary outcome analysis, there was a higher prevalence of NF-PA in those who underwent pituitary surgery. The rate of TSS-related complications was similar between the groups for major, minor and endocrine/electrolyte complications. OA-PA clinically differ from the younger: tend to present more frequently with chronic comorbidities and less frequently with hormone-secreting effects, are more often NF and larger in size without a significant increase in invasiveness. The TSS results were reassuring, proving to be equally safe for the elderly.

Genome wide analysis of circulating miRNAs in growth hormone secreting pituitary neuroendocrine tumor patients' plasma.

BackgroundCirculating plasma miRNAs have been increasingly studied in the field of pituitary neuroendocrine tumor (PitNET) research. Our aim was to discover circulating plasma miRNAs species associated with growth hormone (GH) secreting PitNETs versus assess how the plasma levels of discovered miRNA candidates are impacted by SSA therapy and whether there is a difference in their levels between GH secreting PitNETs versus other PitNET types and healthy individuals.DesignWe compared plasma miRNA content and levels before and after surgery focusing on GH secreting PitNET patients. Selected miRNA candidates from our data and literature were then tested in a longitudinal manner in somatostatin analogues (SSA) treatment group. Additionally, we validated selected targets in an independent GH secreting PitNET group.MethodsmiRNA candidates were discovered using the whole miRNA sequencing approach and differential expression analysis. Selected miRNAs were then analyzed using real-time polymerase chain reaction (qPCR).ResultsWhole miRNA sequencing discovered a total of 16 differentially expressed miRNAs (DEMs) in GH secreting PitNET patients’ plasma 24 hours after surgery and 19 DEMs between GH secreting PitNET patients’ plasma and non-functioning (NF) PitNET patients’ plasma. Seven miRNAs were selected for further testing of which miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p showed a significant downregulation in plasma after 1 month of SSA treatment. mir-625-5p was found to be significantly downregulated in plasma of GH secreting PitNET patients vs. NF PitNET patients. miR-625-5p alongside miR-130b-3p were also found to be downregulated in GH PitNETs compared to healthy individuals.ConclusionsOur study suggests that expression of plasma miRNAs miR-625-5p, miR-503-5p miR-181a-2-3p and miR-130b-3p in GH secreting PitNETs is affected by SSA treatment. Additionally, miR-625-5p can distinguish GH secreting PitNETs from other PitNET types and healthy controls warranting further research on these miRNAs for treatment efficacy.

Long-Term Outcomes for Patients with Multiple Endocrine Neoplasia Type 1 and Duodenopancreatic Neuroendocrine Neoplasms.

Liver metastasis from duodenopancreatic neuroendocrine neoplasms (DP-NENs) is a major cause of mortality in multiple endocrine neoplasia type 1 (MEN1) patients, yet much of their natural history is unknown. This longitudinal, retrospective cohort study analyzed all MEN1 patients with imageable functional (F) and nonfunctional (NF) DP-NENs (1990-2021)for liver metastasis-free survival (LMFS) and overall survival (OS). Of 138 patients, 85 (61.6%) had imageable DP-NENs (28 F, 57 NF), and the mean largest tumor size was 1.8 ± 1.4 cm. Multifocality was present in 32 patients (37.7%). Surgery was performed for 49 patients (57.7%). During an 11-year median follow-up period (IQR, 6-17 years), 23 (27.1%) of the patients had liver metastasis, and 19 (22.4%) patients died. Death was attributed to liver metastasis in 60% of cases. The patients with F-DP-NENs versus NF-DP-NENs more often had liver metastasis (46.4% vs. 15.8%; p = 0.002) but had similar 10-year LMFS (80.9 vs. 87.0%; p = 0.44) and OS (82.7 vs. 94.3%; p = 0.69). The patients with NF-DP-NENs had surgery when their tumors were larger (p < 0.001). Tumor size was not associated with liver metastasis (p = 0.89). The average growth rate was 0.04 cm/year (SE, 0.02 cm/year; p = 0.01) during active surveillance for NF-DP-NENs (n = 38). Liver metastasis developed in four patients with tumors smaller than 2 cm. The risk of liver metastasis was independent of surgery (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.21-2.93; p = 0.72) and death (HR, 0.51; 95% CI, 0.08-3.06; p = 0.46). Although the observed outcomes in this study were better than historical data, small NF-DP-NENs still developed liver metastasis and liver metastasis remains a major cause of death. These results suggest that size as a sole criterion for surgery may be insufficient to predict tumor behavior.

Two Step Selection for Bias in β Chain V-J Pairing.

The β chain rearrangement in T cells is a two-step process where first Dβ and Jβ bind, and only then Vβ is joined to the complex. We here show that the frequency of human and mouse Vβ Jβ combinations deviates from the one expected based on each gene usage frequency. This bias is observed mainly in functional (F) rearrangements, but also slightly in non-functional (NF) rearrangements. Preferred Vβ Jβ combinations in F clones are shared between donors and samples, suggesting a common structural mechanism for these biases in addition to any host-specific antigen-induced peripheral selection. The sharing holds even in clones with J β 1 that share the same Dβ 1 gene. Vβ Jβ usage is correlated with the Molecular Weight and Isoelectric Point in F clones. The pairing is also observed in the Double Positive cells in mice thymocytes, suggesting that the selection leading to such a pairing occurs before thymic selection. These results suggest an additional structural checkpoint in the beta chain development prior to thymic selection during the T cell receptor expression. Understanding this structural selection is important for the distinction between normal and aberrant T cell development, and crucial for the design of engineered TCRs.

Controversy: asymptomatic small pancreatic neuroendocrine neoplasms : Current standards in diagnostics and treatment

For the increasingly diagnosed entity of small asymptomatic, sporadic, nonfunctional, pancreatic neuroendocrine neoplasms (pNEN), a negligible or at least unclear prognostic relevance of the disease for patient survival has often been observed. Safety and acceptance of awatch-and-wait strategy versus surgical resection for small, asymptomatic nonfunctional (NF) pNEN. Presentation and evaluation of the relevant literature as well as the corresponding national and European guidelines. Surgery of small NF-pNEN shows complication rates of 15-32% (Clavien-Dindo ≥ 3) and amortality of 3.6%. Even for pNEN < 2 cm the presence of lymph node metastases has been observed in 11% of cases, while their prognostic relevance in G1-pNEN compared with active surveillance remains unclear. On average 14% of patients under active surveillance for small NF-pNEN, underwent a resection. Relevant tumor growth during surveillance was found in < 20% of cases. In all well-selected surveillance cohorts no metachronous lymphatic or distant metastases occurred during active surveillance and especially no cases of a metachronous no longer curable disease. Even small asymptomatic NF-pNEN have acertain metastatic potential but the clinical relevance has prospectively not yet been clearly determined. Controlled surveillance of these tumors is at least an alternative to immediate tumor resection. Especially patients above 70years old do not seem to benefit from resection. The pros and cons of a resection should therefore be individually evaluated with the patient.

Structure, Function, and Regulation of the Plasma Membrane Na+/H+ Antiporter Salt Overly Sensitive 1 in Plants.

Physiological studies have confirmed that export of Na+ to improve salt tolerance in plants is regulated by the combined activities of a complex transport system. In the Na+ transport system, the Na+/H+ antiporter salt overly sensitive 1 (SOS1) is the main protein that functions to excrete Na+ out of plant cells. In this paper, we review the structure and function of the Na+/H+ antiporter and the physiological process of Na+ transport in SOS signaling pathway, and discuss the regulation of SOS1 during phosphorylation activation by protein kinase and the balance mechanism of inhibiting SOS1 antiporter at molecular and protein levels. In addition, we carried out phylogenetic tree analysis of SOS1 proteins reported so far in plants, which implied the specificity of salt tolerance mechanism from model plants to higher crops under salt stress. Finally, the high complexity of the regulatory network of adaptation to salt tolerance, and the feasibility of coping strategies in the process of genetic improvement of salt tolerance quality of higher crops were reviewed.

The Prolactin per Unit Tumor Volume Ratio Accurately Distinguishes Prolactinomas From Secondary Hyperprolactinemia due to Stalk Effect

ObjectiveThe prolactin levels alone are insufficient to distinguish between some cases of prolactinomas and stalk effect. We aimed to formally characterize the relationship between serum prolactin and prolactinoma volume, determine a cutoff for prolactin/mm3 that accurately distinguishes prolactinomas from stalk effect, and validate this cutoff in a cohort selected to include ambiguous prolactin values ranging from 50 to 150 ng/mL. MethodsWe used the Research Patient Data Registry and transsphenoidal surgery database in our institution to retrospectively identify adult patients with clinically nonfunctioning (NF) tumors (primary analysis, n = 279; validation cohort, n = 10) and prolactinomas (primary analysis, n = 94; validation cohort, n = 18). Solid tumor volumes were measured by Visage 7 software, and cystic foci within tumors were excluded. ResultsProlactin levels were significantly correlated with prolactinoma volume (r2 = 0.801) but were not a relevant predictor of NF tumor size (r2 = 0.015). The prolactin/mm3 values did not overlap between NF tumors (median, 0.016; interquartile range, 0.009-0.028) and prolactinomas (median, 0.551; interquartile range, 0.265-0.845) (P < .0001). A cutoff of 0.065 ng/mL)/mm3 correctly discriminated between prolactinomas and NF tumors in all 401 patients in the primary analysis and validation cohort. ConclusionThe prolactin/volume ratio correctly distinguished all prolactinomas from stalk effect in this study, including a validation cohort specifically chosen for potential ambiguity. To our knowledge, this study is the first formal volumetric analysis of prolactin secretion in pituitary adenomas, and our results suggest that the measurement of prolactin/mm3 is a valuable tool to better characterize challenging cases of primary tumoral secretion versus secondary hyperprolactinemia due to stalk effect.

Angpt2/Tie2 autostimulatory loop controls tumorigenesis

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non‐resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF‐PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin‐2 (ANGPT2) is elevated in patients with NF‐PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF‐PitNETs in the GH3 PitNET cell line, primary human NF‐PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF‐PitNET model. We show that PitNET cells express a functional TIE2 receptor and secrete bioactive ANGPT2, which promotes, besides angiogenesis, tumor cell growth in an autocrine and paracrine fashion. ANGPT2 stimulation of TIE2 in tumor cells activates downstream cell proliferation signals, as previously demonstrated in endothelial cells (ECs). Tie2 gene deletion blunts PitNETs growth in xenograft models, and pharmacological inhibition of Angpt2/Tie2 signaling antagonizes PitNETs in primary cell cultures, tumor xenografts in mice, and in MENX rats. Thus, the ANGPT2/TIE2 axis provides an exploitable therapeutic target in NF‐PitNETs and possibly in other tumors expressing ANGPT2/TIE2. The ability of tumor cells to coopt angiogenic signals classically viewed as EC‐specific expands our view on the microenvironmental cues that are essential for tumor progression.

Developing a novel nitrogen-doped hollow porous carbon sphere (N-HPCS) blended nanofiltration membrane with superior water permeance characteristic for high saline and colored wastewaters treatment

• A porous shell of nitrogen-doped hollow carbon sphere (N-HPCS) is synthesized. • The N-HPCS is incorporated in the NF membrane as a novel nanofiller. • Loading 0.25 wt% of N-HPCS manifested an excellent flux, antifouling, and long-term stability. • A novel fabricated membrane is desired for dye rejection with high salt recovery. This study developed a novel mixed matrix polyethersulfone (PES) nanofiltration membrane by blending nitrogen-doped hollow carbon sphere with a mesoporous shell (N-HPCS). By loading only 0.25 wt% of N-HPCS into membrane matrix (M2), hydrophilicity (28.9°), pure water flux (105.6 L/m 2 h), mean pore diameter (1.59 nm), and fouling resistance extensively increased. Compared to the unmodified membrane (M0), the rejection of four studied salts at 3 bar enhanced averagely by 2.4-times using the M2 membrane. M2 showed 97.0%, 98.7%, and 99.2% of dye retention for methylene blue, rhodamine B, and reactive red 195, respectively. In addition, its removal percentage for Pb(II) and Cd(II) was above 98%. The results showed that the Na 2 SO 4 concentration adversely affected its rejection due to the reduction in Debye length at higher ionic strength. While the reactive red 195 retention and Pb(II) removal almost remained constant by increasing their concentration. For studying the potential ability of M2 for high saline textile wastewater treatment, reactive red 195 retention was studied as a function of Na 2 SO 4 concentrations from 100 to 5000 mg/L. At the highest salt concentration of 5000 mg/L, outstanding dye retention of > 97.9% with water permeate > 104.1 L/m 2 was observed. Furthermore, 58 h successful continuous filtration of high concentration of Na 2 SO, reactive red 195, and Pb(II) demonstrated long-term stability of M2. Overall, our study provides a promising new approach for fabricating a high-performance modified membrane by N-HPCS for application in the practical context of wastewater treatment, especially in dye and textile industries.