We have reviewed data pertinent to three tumor syndromes that derive from overproduction of three GEP peptide hormones. The clinical syndrome of somatostatin excess remains well defined with diabetes, diarrhea, steatorrhea being predominant features. With the availability of assays and increasing awareness, more cases are being diagnosed in the intestine and these differ somewhat in their presentation with cholecystitis, GI bleeding, or a mass as the cardinal features. An unusual association with MEN II pheochromacytoma and neurofibromatosis is emerging. PPomas remain enigmatic. Although diarrhea is a feature, these tumors are usually silent and present with hypatomegally, abdominal pain, and jaundice because of the large size and malignant nature. Neurotensinomas remain rare and truly difficult to separate from the symptom complex produced by VIP excess. Edema, hypotension, cyanosis and flushing should alert one to the possibility of a neurotensin-secreting tumor.

OBJECTIVE

We have investigated the prevalence of MEN 1 in patients with recognized pituitary adenomas. Since hyperparathyroidism is present in nearly 95-100% of patients with MEN 1 and frequently is the first condition to be identified, the study was limited to the identification of patients with hyperparathyroidism while the screening for gastroenteropancreatic (GEP) lesions was carried out in patients with both pituitary and parathyroid lesions.

METHODS

Serum total and ionized calcium, phosphate and intact PTH 1-84 (EASIA) were measured in 166 patients (68 with non-functioning pituitary adenoma, 42 with prolactinoma, 35 with GH-secreting adenoma, 17-with ACTH-screening adenoma, 1 with TSH-secreting adenoma, 1 with FSH-secreting adenoma and 2 with an only alpha-subunit secreting adenoma) referred to our clinic from 1990 to 1996. Plasma gastrin, somatostatin, pancreatic polypeptide and vasoactive intestinal peptide were measured by RIA in patients with hyperparathyroidism.

RESULTS

Eight of 166 patients (4.8%) were found to have primary hyperparathyroidism and among these 2 also had a gastrinoma while there was no evidence of other GEP tumours. Considering the tumour type, 6 had prolactinoma (14.3%), 1 GH-secreting adenoma (2.8%) and 1 non-functioning adenoma (1.5%). In most patients the diagnosis of pituitary tumour was made several years before that of hyperparathyroidism (from 1 to 15 years) although 6 patients had previously suffered from urolithiasis and one had undergone gastric resections for recurrent peptic ulcers. One patient was identified as a MEN 1 gene carrier and 2 had relatives with signs and symptoms referable to parathyroid or GEP lesions.

CONCLUSIONS

The study shows a prevalence of 4.8% of primary hyperparathyroidism in unselected patients with known pituitary tumours similar to that reported in a previous study. By contrast, the prevalence of MEN 1 in patients with prolactinoma was definitely high (14.3%). In most patients the diagnosis of pituitary tumours was made several years before that of hyperparathyroidism. Although the patients were believed to harbour a sporadic pituitary tumour, most of them had had signs and/or symptoms referable to one or both of the other organs involved in MEN 1, often concomitantly with those of pituitary tumours. These data indicate that the diagnosis of MEN 1 syndrome is missed in a substantial proportion of patients with prolactinomas and therefore the screening of these patients for the syndrome is strongly recommended.

The morphology of the gastroenteropancreatic (GEP) system of fish was reviewed with the objective of providing the phylogenetic and ontogenetic development of the system in this vertebrate group, which includes agnathans and gnathostome cartilaginous, actinoptyerygian, and sarcopterygian fish. Particular emphasis is placed on the fish homolog of the endocrine pancreas of other vertebrates, which is referred to as the islet organ. The one-hormone islet organ (B cells) of larval lampreys is the most basic pattern seen among a free-living vertebrate, with the two-hormone islet organ (B and D cells) of hagfish and the three-hormone islet organ (B, D, and F cells) of adult lampreys implying a phylogenetic trend toward the classic four-hormone islet tissue (B, D, F, and A cells) in most other fish. An earlier stage in the development of this phylogenetic sequence in vertebrates may have been the restriction of islet-type hormones to the alimentary canal, like that seen in protochordates. The relationship of the islet organ to exocrine pancreatic tissue, or its equivalent, is variable among bony, cartilaginous, and agnathan fishes and is likely a manifestation of the early divergence of these piscine groups. Variations in pancreatic morphology between individuals of subgroups within both the lamprey and chondrichthyan taxa are consistent with their evolutionary distance. A comparison of the distribution and degree of concentration of the components of the islet organ among teleosts indicates a diffuse distribution of relatively small islets in the generalized euteleosts and the tendency for the concentration into Brockmann bodies of large (principal) islets (with or without secondary islets) in the more derived forms. The holostean actinopterygians (Amiiformes and Semiontiformes) share with the basal teleosts (osteoglossomorphs, elopomorphs) the diffuse arrangement of the components of the islet organ that is seen in generalized euteleosts. Since principal islets are also present in adult lampreys the question arises whether principal islets are a derived or a generalized feature among teleosts. There is a paucity of studies on the ontogeny of the GEP system in fish but it has been noted that the timing of the appearance of the islet cell types parallels the time that they appear during phylogeny; the theory of recapitulation has been revisited. It is stressed that the lamprey life cycle provides a good opportunity for studying the development of the GEP system. There are now several markers of cell differentiation in the mammalian endocrine pancreas which would be useful for investigating the development of the islet organ and cells of the remaining GEP system in fish.

It is well documented that dysregulation of microRNAs is a hallmark of human cancers. Thus, this family of small non-coding regulatory molecules represents an excellent source of sensitive biomarkers. Unique microRNAs expression profiles have been associated with different types and subsets of gastrointestinal tumors including gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs are a heterogeneous group of epithelial neoplasms with neuroendocrine differentiation. At present, early detection and surgical resection of GEP-NETs represent the best chance for a cure. Thus, clinically useful biomarkers for GEP-NETs that strongly correlate with early detection are urgently needed. The purpose of this review is to summarize the role of miRNAs in GEP-NET carcinogenesis and their possible use as novel diagnostic, prognostic and predictive biomarkers.

Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints.Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550).Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127-37. ©2017 AACR.

OBJECTIVE

Activated signal transducer and activator of transcription 3 (STAT3) regulates tumor growth, invasion, cell proliferation, angiogenesis, immune response, and survival. Data regarding expression of phosphorylated (activated) STAT3 in diffuse large B-cell lymphoma (DLBCL) and the impact of phosphorylated STAT3 (pSTAT3) on prognosis are limited.

METHODS

We evaluated expression of pSTAT3 in de novo DLBCL using immunohistochemistry, gene expression profiling (GEP), and gene set enrichment analysis (GSEA). Results were analyzed in correlation with cell-of-origin (COO), critical lymphoma biomarkers, and genetic translocations.

RESULTS

pSTAT3 expression was observed in 16% of DLBCL and was associated with advanced stage, multiple extranodal sites of involvement, activated B-cell-like (ABC) subtype, MYC expression, and MYC/BCL2 expression. Expression of pSTAT3 predicted inferior overall survival (OS) and progression-free survival (PFS) in patients with de novo DLBCL. When DLBCL cases were stratified according to COO or MYC expression, pSTAT3 expression did not predict inferior outcome, respectively. Multivariate analysis showed that the prognostic predictability of pSTAT3 expression was due to its association with the ABC subtype, MYC expression, and adverse clinical features. GEP demonstrated upregulation of genes, which can potentiate function of STAT3. GSEA showed the JAK-STAT pathway to be enriched in pSTAT3(+) DLBCL.

CONCLUSIONS

The results of this study provide a rationale for the ongoing successful clinical trials targeting the JAK-STAT pathway in DLBCL.

C/EBPβ (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPβ responsible for ALK-mediated oncogenesis. C/EBPβ was knocked down in ALK+ ALCL cell lines with a C/EBPβ-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPβ. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPβ was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPβ-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPβ in ALK-mediated oncogenesis.

Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEPGEPGEPGEPGEPGEPGEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.

Recent clinical successes with immunotherapy have resulted in expanding indications for cancer therapy. To enhance antitumor immune responses, and to better choose specific strategies matched to patient and tumor characteristics, genomic-driven precision immunotherapy will be necessary. Herein, we explore the role that tumor gene-expression profiling (GEP) may have in the prediction of an immunotherapeutic response. Genetic markers associated with response to immunotherapy are addressed as they pertain to the tumor genomic landscape, the extent of DNA damage, tumor mutational load and tumor-specific neoantigens. Furthermore, genetic markers associated with resistance to checkpoint blockade and relapse are reviewed. Finally, the utility of GEP to identify new tumor types for immunotherapy and implications for combinatorial strategies are summarized.

BACKGROUND

The objectives of this study were to investigate the disposition of gemcitabine, epirubicin, paclitaxel, 2',2'-difluorodeoxyuridine and epirubicinol, and characterize the pharmacokinetic and pharmacodynamic profile of treatment in patients with breast cancer.

METHODS

The drug dispostion in 15 patients who received gemcitabine 1000 mg/m2, epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (GEP) on day 1 of a 21-day cycle, was compared with that of patients treated with epirubicin 90 mg/m2 and paclitaxel 175 mg/m2 (EP, n = 6) and epirubicin 90 mg/m2 alone (n = 6). Drug and metabolite levels in plasma and urine were assessed by high-performance liquid chromatography and parameters of drug exposure were related to hematological toxicity by a sigmoid-maximum effect (Emax) model.

RESULTS

Paclitaxel administration significantly increased the epirubicinol area under the concentration-time curve, from 357+/-146 (epirubicin) to 603+/-107 (EP) and 640+/-81 h x ng/ml (GEP), and reduced the renal clearance of epirubicin and epirubicinol by 38 and 52.2% and 34.5 and 53% in GEP- and EP-treated patients, respectively, compared with epirubicin alone. Gemcitabine had no apparent effect on paclitaxel and epirubicin pharmacokinetics, and renal clearance of epirubicin and epirubicinol. The only pharmacokinetic/pharmacodynamic relationship observed was between neutropenia and the time spent above the threshold plasma level of 0.1 micromol/l (tC0.1) of paclitaxel, with the time required to obtain a 50% decrease in neutrophil count (Et50) of GEP being 7.8 h, similar to that of EP.

CONCLUSIONS

Paclitaxel and/or its vehicle, Cremophor EL, interferes with the disposition and renal excretion of epirubicin and epirubicinol; gemcitabine has no affect on epirubicin and paclitaxel plasma pharmacokinetics and renal excretion of epirubicin, while neutropenia is not enhanced by gemcitabine.

The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients.

This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival.

The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each).

The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.

Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes.

Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) are currently classified as grade (G) 1, G2 and G3, in accordance with the 2010 WHO classification. G1 and G2 are named neuroendocrine tumors (NETs) whereas G3 neuroendocrine carcinomas (NECs). While advanced G1 and G2 are usually treated with several different therapies, including somatostatin analogs, chemotherapy, interferon, molecular targeted agents, peptide receptor radionuclide therapy (PRRT) and liver-directed treatments, advanced G3 NECs are usually treated with a platinum-etoposide chemotherapy, trusting their clinical homogeneity is similar to that of small cell lung cancer. However, over the last years a number of reports suggested that 2010 WHO G3 GEP NECs are more heterogeneous than expected. Therefore, we critically reviewed the literature about this topic and reported pathological and clinical considerations on 2010 WHO G3 GEP NEC category proposing new sub-categories. Over the last five years, six studies specifically investigating large series of G3 GEP NECs have been published, including around 800 patients. Tumor morphology and Ki-67 Labeling Index (that will be mentioned as Ki-67 in this manuscript) combination has been reported as a tool to define two or even three subgroups of this category with different prognosis and potentially different therapeutic approach. Prospective trials are warranted to investigate if several types of therapy other than the platinum/etoposide chemotherapy can be effective in well differentiated GEP NEN with 21-55% Ki-67 and alkylating-based chemotherapy in poorly differentiated GEP NEN with 21-55% Ki-67.

Treatment of somatostatin receptor-positive tumors with radiolabeled somatostatin analog is a promising option. Several phase I and phase II studies done at a few centers around the world reported encouraging results with [⁹⁰Y-DOTA-Tyr³]-octreotide (DOTATOC) and/or [(177)Lu-DOTA-Tyr³-Thr⁸]-octreotate (DOTATATE). The current article is a selective review of patients who were treated mainly with ⁹⁰Y-DOTATOC after failure with conventional therapy. The aim is to provide an updated comprehensive evaluation of the overall effectiveness of ⁹⁰Y-DOTATOC therapy in patients with somatostatin-positive tumors. Review of several studies revealed an objective response rate ranging from 20 to 28% for all neuroendocrine tumors (NET)s. For gastroenteropancreatic-NET (GEP-NET), the response rate was found to be consistently better in the range 28-38%. Overall, the cumulative response rate was found to be 24%. An important issue in peptide receptor radionuclide therapy (PRRT) is the dose-response relationship and finding the correct dose of ⁹⁰Y-DOTATOC that will achieve an optimum tumor kill. Nephrotoxicity was common but could be minimized by taking adequate renal protective measures. In conclusion, PRRT remains a good option in patients with inoperable and/or metastatic NETs particularly of GEP origin. Over a decade of experience with ⁹⁰Y-DOTATOC proves that it is still an effective tool for the treatment of large infiltrative NETs with achievement of objective radiological responses in nearly a quarter and disease stabilization in more than half the patients studied so far.

Detection of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and monitoring of treatment response relies mainly on morphological imaging such as computed tomography (CT) and magnetic resonance imaging (MRI). Molecular imaging techniques also in combination with CT (hybrid imaging) greatly benefit patient management, including better localization of occult tumours and better staging. Somatostatin receptor scintigraphy (SRS) and somatostatin receptor (SSTR) positron emission tomography (PET) play a central role in the diagnostic work-up of patients with well-differentiated GEP-NETs. SSTR PET/CT is superior to SRS and should be used whenever available. (18)F-DOPA and (18)F-FDG PET/CT is inferior to SSTR PET/CT at least in patients with well-differentiated GEP-NETs. Both SSTR PET/CT and SRS have limitations, such as relatively low detection rate of benign insulinomas, poorly differentiated GEP-NETs and liver metastases. New innovations such as SSTR PET/MRI, radiolabelled SSTR antagonists and glucagon-like peptide-1 receptor (GLP-1R) agonists might further improve imaging of GEP-NETs.

BACKGROUND

Complementary and alternative medicine (CAM) is a growing industry in the health care system. In Ireland, to date there has not been a study that evaluates the knowledge of, interest in, and attitude of Irish medical students toward CAM.

OBJECTIVE

This research can serve as a pilot study to inform Irish medical schools on the need to introduce CAM into the medical curriculum.

METHODS

The survey instrument was a modified design based on previously published studies carried out in other geographical areas. All medical students within the undergraduate and graduate entry programs (GEP) at the Royal College of Surgeons in Ireland were invited to participate in the study. SPSS software was used to analyze the results of the questionnaires.

RESULTS

The survey completion rate was 20.1%. A majority of students (78.4%) thought that CAM knowledge is important for their future career as physicians. Approximately 65% of students reported that they have not acquired sufficient knowledge about CAM from medical school, and 50.2% of students believe CAM should be incorporated into the medical curriculum. Preclinical years (49.4%) were suggested as the most appropriate time to learn about CAM. Knowledge of CAM modalities was generally rated as minimal or none by students. Among the 15 CAM modalities incorporated in the survey, massage, acupuncture, and meditation received the highest interest from students. Students who believe in a religion had a higher interest in CAM (p<0.05). In terms of their personal view, massage, spirituality, and acupuncture received the highest positive responses. Attitudes toward CAM were positive from students. Lower willingness to use CAM was seen in clinical students (p<0.05).

CONCLUSIONS

It is important for the faculty of Irish medical schools to consider the possibility of integrating CAM education into the conventional medical curriculum in a systematic manner to better prepare students in their future career.

Acute myeloid leukaemia (AML) with CEBPA mutations is listed as a provisional entity in the current World Health Organization classification. A difference in clinical outcome between single- (sm) and double-mutated (dm) cases has been reported, whereupon CEBPAdm cases were shown to be associated with better overall survival (OS). The occurrence and prognostic impact of concomitant molecular mutations in addition to CEBPAdm has not been assessed until now with exception of GATA2 mutations. Here, we investigated a cohort of 95 AML CEBPAdm cases for concomitant mutations. TET2 was found to be most frequently mutated (34·0%) gene, followed by GATA2 (21·0%), WT1 (13·7%), DNMT3A (9·6%), ASXL1 (9·5%), NRAS (8·4%), KRAS (3·2%), IDH1/2 (6·3%), FLT3-internal tandem duplication (6·3%), FLT3-tyrosine kinase domain (2·1%), NPM1 (2·1%), and RUNX1 (1/94). Patients harbouring additional mutations in the TET2 gene showed significantly worse OS than TET2 wild-type cases (P = 0·035), whereas GATA2-mutated patients showed improved OS (P = 0·032). Serial analyses were performed for 39 CEBPAdm cases with concomitant mutations. Here, we observed that CEBPA mutations present the primary pathogenetic event in the majority of cases (76·9%). Further, a distinct gene expression profile (GEP) was confirmed for CEBPAdm versus CEBPAsm or CEBPA wild-type cases while no significant changes in GEP were observed related to additional mutations within the CEBPAdm AML.

OBJECTIVE

Tumor microenvironment, defined by a variety of growth factors including lysophosphatidic acid (LPA), whose levels are increased in pancreatic cancer patients, plays a major role in the genesis and progression of pancreatic cancer. Because the gep proto-oncogenes, Gα12 and Gα13, are implicated in LPA-stimulated oncogenic signaling, this study is focused on evaluating the role of these proto-oncogenes in LPA-stimulated invasive migration of pancreatic cancer cells.

METHODS

Effect of LPA on the migration and proliferation of pancreatic cancer cells was assessed using BxPC3, Dan-G, MDAPanc-28, Panc-1, and PaCa-2 cell lines. The role of Gα13 in the migration of pancreatic cancer cells was interrogated by disrupting lysophosphatidic acid receptor-Gα13 interaction using CT13, a dominant negative mutant of Gα13, and by silencing the expression of Gα13.

RESULTS

Results indicate that LPA stimulates the migration of pancreatic cancer cells and such LPA-stimulated migratory response is mediated by Gα13. Furthermore, the results establish that the silencing of Gα13, but not Gα12, abrogates LPA-stimulated invasive migration of pancreatic cancer cells.

CONCLUSIONS

These results report for the first time a critical role for Gα13 in LPA-stimulated invasive migration of pancreatic cancer cells. These findings identify LPA-lysophosphatidic acid receptor-Gα13 signaling node as a novel therapeutic target for pancreatic cancer treatment and control.

BACKGROUND

Gene expression profiling (GEP) is being used increasingly for risk stratification to identify women with lymph node-negative, estrogen receptor-positive, early stage breast cancer who are most likely to benefit from adjuvant chemotherapy. The authors of this report evaluated the cost effectiveness of recurrence score-guided treatment using 2 commercially available GEP tests, Oncotype DX (Genomic Health, Redwood City, Calif) and MammaPrint (Agendia Inc., Irvine, Calif), from a third-party payer's perspective.

METHODS

A 10-year Markov model was developed to compare the costs and quality-adjusted life-years (QALYs) of treatment decisions guided by either Oncotype DX or MammaPrint in a hypothetical cohort of women with early stage, lymph node-negative, estrogen receptor-positive breast cancer who may experience recurrence. Outcomes included no recurrence, recurrence, and death. The costs considered included gene test costs, the costs of adjuvant chemotherapy and other chemotherapy (including premedication, oncology visits, and monitoring for adverse events), the cost of treating recurrence, costs associated with the treatment of adverse events, and end-of-life care costs.

RESULTS

The model demonstrated that the patients who received the Oncotype DX test to guide treatment spent $27,882 (in US dollars) and gained 7.364 QALYs, whereas patients who received the MammaPrint test to guide treatment spent $21,598 and gained 7.461 QALYs. Sensitivity analyses demonstrated that the results were robust to changes in all parameters.

CONCLUSIONS

The model suggested that MammaPrint is a more cost-effective GEP test compared with Oncotype DX at a threshold willingness-to-pay of $50,000 per QALY. Because Oncotype DX is the most frequently used GEP in clinical practice in the United States, the authors concluded that the current findings have implications for health policy, particularly health insurance reimbursement decisions.

BACKGROUND

Essential proteins are indispensable for cell survive. Identifying essential proteins is very important for improving our understanding the way of a cell working. There are various types of features related to the essentiality of proteins. Many methods have been proposed to combine some of them to predict essential proteins. However, it is still a big challenge for designing an effective method to predict them by integrating different features, and explaining how these selected features decide the essentiality of protein. Gene expression programming (GEP) is a learning algorithm and what it learns specifically is about relationships between variables in sets of data and then builds models to explain these relationships.

RESULTS

In this work, we propose a GEP-based method to predict essential protein by combing some biological features and topological features. We carry out experiments on S. cerevisiae data. The experimental results show that the our method achieves better prediction performance than those methods using individual features. Moreover, our method outperforms some machine learning methods and performs as well as a method which is obtained by combining the outputs of eight machine learning methods.

CONCLUSIONS

The accuracy of predicting essential proteins can been improved by using GEP method to combine some topological features and biological features.

Chromogranins (Cg) are large acidic proteins, co-stored with amines or peptides in the secretory granules of a wide variety of paraneurons. By immunohistochemistry performed on serial semithin sections, the distribution of Cg in the gastroenteropancreatic (GEP) system was analyzed in the endocrine pancreas of 10 mammalian species and in enteroendocrine cells of 6 species. Of the Cg families, CgA is primarily localized in GEP endocrine cells. CgA was regularly present in amine containing cells (EC and EC-like cells). In 11 other endocrine cell types, CgA-immunoreactivities showed inter-species and intra-species variations in their distribution or in the intensity of staining. However, no endocrine cell type lacked CgA-immunoreactivities in all species investigated. Findings from extended studies indicate that CgA is involved in the intracellular storage of resident amines, and in the storage of newly formed amines after exogenous application of the corresponding precursors. Finally, densitometric findings on possible reciprocal relationships between CgA- and peptide-immunoreactivities suggest that CgA also participates in the intragranular storage of peptide hormones in certain GEP endocrine cells.

Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs). (90)Y-DOTATOC and (177)Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15-35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of (90)Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished.

A brefeldin A (BFA)-inhibited guanine nucleotide-exchange protein (<em>GEP</em>) for ADP-ribosylation factors (ARF) was purified earlier from bovine brain cytosol. Cloning and expression of the cDNA confirmed that the recombinant protein (p200) is a BFA-sensitive ARF <em>GEP</em>. p200 contains a domain that is 50% identical in amino acid sequence to a region in yeast Sec7, termed the Sec7 domain. Sec7 domains have been identified also in other proteins with ARF <em>GEP</em> activity, some of which are not inhibited by BFA. To identify structural elements that influence <em>GEP</em> activity and its BFA sensitivity, several truncated mutants of p200 were made. Deletion of sequence C-terminal to the Sec7 domain did not affect <em>GEP</em> activity. A protein lacking 594 amino acids at the N terminus, as well as sequence following the Sec7 domain, also had high activity. The mutant lacking 630 N-terminal amino acids was, however, only 1% as active, as was the Sec7 domain itself (mutant lacking 697 N-terminal residues). It appears that the Sec7 domain of p200 contains the catalytic site but additional sequence (perhaps especially that between positions 595 and 630) modifies activity dramatically. Myristoylated recombinant ARFs were better than non-myristoylated as substrates; ARFs 1 and 3 were better than ARF5, and no activity was detected with ARF6. Physical interaction of the Sec7 domain with an ARF1 mutant was demonstrated, but it was much weaker than that of the cytohesin-1 Sec7 domain with the same ARF protein. Effects of BFA on p200 and all mutants with high activity were similar with approximately 50% inhibition at </=50 microM. The inactive BFA analogue B36 did not inhibit the Sec7 domain or p200. Thus, the Sec7 domain of p200, like that of Sec7 itself (Sata, M., Donaldson, J. G., Moss, J., and Vaughan, M. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 4204-4208), plays a role in BFA inhibition as well as in <em>GEP</em> activity, although the latter is markedly modified by other structural elements.