Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 333-333
Author(s):  
Moh'd M. Khushman ◽  
Alexandra Gomez Arteaga ◽  
Liege Diaz ◽  
Gabriel Tinoco ◽  
Richa Dawar ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Mammalian Target Of Rapamycin ◽  
Predictive Marker ◽  
Suppressor Gene ◽  
Small Sample ◽  
Mtor Pathway ◽  
Negative Regulator ◽  
Unknown Primary ◽  
Pten Loss

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.

The categorization of expatriates and the support offered by host country nationals

2016 ◽  
Vol 4 (1) ◽  
pp. 18-43 ◽  
Author(s):  
Shirley C. Sonesh ◽  
Angelo S. DeNisi
Keyword(s):  
Host Country ◽  
Small Sample Size ◽  
Small Sample ◽  
Content Type ◽  
Host Country Nationals ◽  
Group Members ◽  
Expatriate Assignments ◽  
The Right ◽  
National Stereotypes

Purpose – Although several authors have suggested that host country nationals (HCNs) play an important role in the management of expatriates (e.g. Toh and DeNisi, 2003; Farh et al., 2010), research has also suggested that this relationship is not always good, and the flow of critical information to expatriates can be limited. This is especially true when HCNs categorize the expatriates as “out-group” members. The purpose of this paper is to examine potential determinants of categorization decisions as well as potential outcomes related to expatriate socialization. Design/methodology/approach – The paper employs a dyadic survey approach to determine the antecedents to expatriate categorization and HCN socialization behaviors from the perspective of both the expatriate and HCN. Findings – The results of survey data from 65 expatriate-HCN dyads indicated that expatriate ethnocentrism and the salience of the expatriates’ nationality were important predictors of categorization, but that categorization was related to only one dimension of socialization. However, affect was found to play a role in predicting socialization behaviors. Research limitations/implications – There is potential selection bias since expatriates chose HCNs as respondents, but results suggested this was not a serious problem. Other limitations include a relatively small sample size and the fact that a number of contextual issues such as national stereotypes and MNC strategy, are not controlled for. Practical implications – Implications of these findings for the successful management of expatriate assignments include sending over expatriates with the right relational skills, and those low in ethnocentrism, rather than just the right technical skills. Originality/value – The present study was one of the first to empirically test the potential role of categorization in the process of socialization.

The role of polymorphisms occurring in BRCA1/2 genes in determining ovarian cancer risk.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17551-e17551
Author(s):  
Marta Castiglia ◽  
Lorena Incorvaia ◽  
Alessandro Perez ◽  
Chiara Brando ◽  
Antonio Galvano ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Small Sample Size ◽  
Female Genital Tract ◽  
Brca1 Gene ◽  
Small Sample ◽  
Clinicopathological Features ◽  
Age At Diagnosis ◽  
Ovarian Cancer Risk

e17551 Background: Ovarian cancer (OC) is the 10th tumor occurring in women, it accounts for 30% of all malignant tumor affecting female genital tract in Italy. There are several factors that contribute to OC development; in 15-25% of cases family history of breast and ovarian cancer represent the main risk factor. It is well known that pathogenic variants (PVs) occurring in BRCA1/2 genes strongly increase the risk of developing OC, ranging from 50% in BRCA1 PVs carriers to 30% in BRCA2 PVs carriers. Recently genetic polymorphism has been shown to increase cancer risk, consequently polymorphisms in BRCA1/2 genes could represent low penetrance susceptibility alleles and contribute to determine specific clinicopathological features in OC patients harboring BRCA1/2 PVs. Methods: From 2015 to 2021, 338 patients diagnosed with epithelial OC (not mucinous, not borderline) were subjected to BRCA1/2 analysis. After obtaining informed consent, blood samples were processed for genomic DNA isolation; DNA was used for library preparation with the BRaCa Screen kit. Sequencing was performed on the IonS5 platform; variant annotation was performed with Amplicon Suite software. We collected data of both PVs and polymorphisms in BRCA1/2 genes with the aim to evaluate whether a cluster of specific polymorphisms could impact clinicopathological features in BRCA1 PVs carriers. Results: Among the 338 screened EOC, BRCA1/2 PVs were reported in 85 patients (25%). 66% of patients harbored BRCA1 PVs and 34% in BRCA2. The most frequent BRCA1 PVs were the c.4964_4982del (5083del19), c.514delC and c.181T > G; the first and the last are known for their founder effect in Italy and Eastern Europe. Looking at BRCA1 gene, in 75% of patients we identified a polymorphisms cluster (c.2082C > T, c.2311T > C, c.2612C > T, c.3113A > G, c.3548A > G, c.4308T > C, c.4837A > G). The c.514delC and c.181T > G PVs are always associated with the cluster and two additional polymorphisms, the c.2077G > A and the c.1067A > G respectively. Conversely, the cluster seems not to be associated with the PVs 5083del19. Interestingly in BRCA1-5083del19 PV carriers median age at OC diagnosis was 50 years (range 45-69). On average, these patients developed ovarian cancer 6 years earlier than other BRCA1 PV carriers (median age at diagnosis 57 years; range 30-81). Bilateral tumors were frequent and occurred in 57% of the patients versus 33% in OC patients carrying other BRCA1 PVs. Therefore, it seems that the cluster has a “protective” effect and that its absence reduces age at diagnosis. Conclusions: Despite this study has the main limitation of a small sample size, we have reported a possible association between polymorphisms cluster and clinicopathological features in BRCA1 PVs carriers. By further investigating this aspect in a larger cohort, we might be able to prove the role of this cluster in increasing or reducing OC risk and providing clinicians more information useful for patients’ stratification.

scholarly journals Uterus transplantation: joys and frustrations of becoming a ‘complete’ woman—a qualitative study regarding self-image in the 5-year period after transplantation

2020 ◽  
Vol 35 (8) ◽  
pp. 1855-1863 ◽  
Author(s):  
Stina Järvholm ◽  
Anders Enskog ◽  
Catrina Hammarling ◽  
Pernilla Dahm-Kähler ◽  
Mats Brännström
Keyword(s):  
Small Sample Size ◽  
Small Sample ◽  
Post Transplantation ◽  
Uterus Transplantation ◽  
Self Image ◽  
Registration Number ◽  
Competing Interest ◽  
The Government

Abstract STUDY QUESTION How is a women’s self-image affected by uterus transplantation (UTx)? SUMMARY ANSWER Women experienced receiving a uterus in both positive and negative ways, but in general, their self-image was positively affected; regardless of whether they have given birth to a child or not, recipients describe themselves as being ‘back to normal’ after the hysterectomy to remove the transplanted uterus. WHAT IS KNOWN ALREADY UTx has repeatedly proved to be a successful treatment for absolute uterine factor infertility. However, there has been no previous qualitative long-term research into the self-image of women undergoing UTx. STUDY DESIGN, SIZE, DURATION This complete, prospective cohort study included the nine recipients of the first UTxs performed in Sweden mostly in 2013. Interviews took place in the 5 years following surgery. PARTICIPANTS/MATERIALS, SETTING, METHODS Eight out of the nine recipients had congenital absence of the uterus, a characteristic of Mayer–Rokitansky–Küster–Hauser syndrome, and one recipient lacked a uterus after a radical hysterectomy due to cervical cancer. The mean age of participants was 31.5 years at inclusion and at this time they all lived in stable marital relationships. Post-transplantation, interviews were performed annually for 5 years, comprising a total of 43 interviews. The interview followed a semi-structured guide. All interviews (median duration of around 25 minutes) were recorded, transcribed verbatim and then analysed by thematic approach. MAIN RESULTS AND THE ROLE OF CHANCE The joys and frustrations of becoming a ‘complete’ woman are seen as a master theme, which influences the three underlying subthemes, a changed self-perception, a changed body and a changed sexuality. Each of these subthemes have three underlying categories. LIMITATIONS, REASONS FOR CAUTION The small sample size is a limitation. WIDER IMPLICATIONS OF THE FINDINGS The results provide information that will be helpful in pre-operative screening procedures and in the psychological support offered both to women who experienced successful and unsuccessful outcomes following UTx. STUDY FUNDING/COMPETING INTEREST(S) Funding was received from the Jane and Dan Olsson Foundation for Science; the Knut and Alice Wallenberg Foundation; an ALF grant from the Swedish state under an agreement between the government and the county councils; the Swedish Research Council; a Ferring Pharmaceuticals scholarship in memory of Robert Edwards; and the Iris Jonzén-Sandblom and Greta Jonzén Foundation. The authors have no competing interests. TRIAL REGISTRATION NUMBER NCT01844362.

The relationship between food heritage and clan culture: is “familiness” the missing link in SMEs?

2020 ◽  
Vol 123 (1) ◽  
pp. 337-354
Author(s):  
Fahimeh Khatami ◽  
Alberto Ferraris ◽  
Paola De Bernardi ◽  
Valter Cantino
Keyword(s):  
Structural Equation ◽  
Small Sample Size ◽  
Methodological Approach ◽  
Strong Relationship ◽  
Small Sample ◽  
Equation Modeling ◽  
Content Type ◽  
Clan Culture ◽  
The Relationship

PurposeThis paper empirically tests the relationship between food heritage, familiness, and clan culture, thus, highlighting the pivotal role of familiness in building robustly competitive food firms based on clan culture and food heritage.Design/methodology/approachThe methodological approach adopted is based on a quantitative analysis with data from one eco-tourist city in Iran (Torqabeh). In this regard, we developed a structured questionnaire surveying 98 small- and medium-sized enterprises (SMEs) operating in the food industry. We then used partial least squares structural equation modeling (PLS-SEM) to carry out the analysis.FindingsThe results indicate the significant positive relationship between food heritage and clan culture, and highlight the role of familiness as a strong mediator, which is also associated with a strong relationship between food heritage and clan culture.Research limitations/implicationsIn the present study, the main limitation was linked to the small sample size and data collection, which took place in only a single city; however, further research could overcome this limitation by investigating SMEs from a heterogeneous geographical context.Originality/valueThe value of this research relates to studies that have examined food heritage as a possible antecedent of familiness. Moreover, the novelty of this research is to study the concept of familiness in improving resource-based views and organizational theories.

scholarly journals Role of MicroRNAs in Parkinson’s Disease

2019 ◽  
Vol 20 (22) ◽  
pp. 5649 ◽  
Author(s):  
Suh Yee Goh ◽  
Yin Xia Chao ◽  
Shaikali Thameem Dheen ◽  
Eng-King Tan ◽  
Samuel Sam-Wah Tay
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Small Sample Size ◽  
Small Sample ◽  
Biological Molecules ◽  
Incomplete Penetrance ◽  
Cellular Functions ◽  
Druggable Targets ◽  
The Brain

Parkinson’s disease (PD) is a disabling neurodegenerative disease that manifests with resting tremor, bradykinesia, rigidity and postural instability. Since the discovery of microRNAs (miRNAs) in 1993, miRNAs have been shown to be important biological molecules involved in diverse processes to maintain normal cellular functions. Over the past decade, many studies have reported dysregulation of miRNA expressions in PD. Here, we identified 15 miRNAs from 34 reported screening studies that demonstrated dysregulation in the brain and/or neuronal models, cerebrospinal fluid (CSF) and blood. Specific miRNAs-of-interest that have been implicated in PD pathogenesis include miR-30, miR-29, let-7, miR-485 and miR-26. However, there are several challenges and limitations in drawing definitive conclusions due to the small sample size in clinical studies, varied laboratory techniques and methodologies and their incomplete penetrance of the blood–brain barrier. Developing an optimal delivery system and unravelling druggable targets of miRNAs in both experimental and human models and clinical validation of the results may pave way for novel therapeutics in PD.

The similiarity of facial expressions in response to emotion-inducing films in reared-apart twins

2007 ◽  
Vol 38 (10) ◽  
pp. 1475-1483 ◽  
Author(s):  
K. S. Kendler ◽  
L. J. Halberstadt ◽  
F. Butera ◽  
J. Myers ◽  
T. Bouchard ◽  
...  
Keyword(s):  
Facial Expressions ◽  
Positive Emotions ◽  
Genetic Factors ◽  
Small Sample Size ◽  
Small Sample ◽  
Self Report ◽  
Emotional Expressions ◽  
Emotional Facial Expressions ◽  
Minimal Contact

BackgroundWhile the role of genetic factors in self-report measures of emotion has been frequently studied, we know little about the degree to which genetic factors influence emotional facial expressions.MethodTwenty-eight pairs of monozygotic (MZ) and dizygotic (DZ) twins from the Minnesota Study of Twins Reared Apart were shown three emotion-inducing films and their facial responses recorded. These recordings were blindly scored by trained raters. Ranked correlations between twins were calculated controlling for age and sex.ResultsTwin pairs were significantly correlated for facial expressions of general positive emotions, happiness, surprise and anger, but not for general negative emotions, sadness, or disgust or average emotional intensity. MZ pairs (n=18) were more correlated than DZ pairs (n=10) for most but not all emotional expressions.ConclusionsSince these twin pairs had minimal contact with each other prior to testing, these results support significant genetic effects on the facial display of at least some human emotions in response to standardized stimuli. The small sample size resulted in estimated twin correlations with very wide confidence intervals.

The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 43-43
Author(s):  
Da Wang ◽  
Roland Chiu ◽  
John Theodorus Plukker ◽  
Robert P. Coppes
Keyword(s):  
Esophageal Cancer ◽  
Cell Lines ◽  
Mammalian Target Of Rapamycin ◽  
Neoadjuvant Chemoradiotherapy ◽  
Mtor Inhibitors ◽  
Mtor Pathway ◽  
Tumor Biopsy ◽  
Sphere Formation ◽  
Dose Dependent

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.

Molecular profiling of TOPO1: A way to evaluate irinotecan treatment in colorectal cancer?

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 546-546
Author(s):  
Julia Marie Cunningham ◽  
Petra Prins ◽  
Brian Conkright ◽  
Simina Boca ◽  
Shruti Rao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Small Sample Size ◽  
Predictive Marker ◽  
Molecular Profiling ◽  
Small Sample ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Control Group ◽  
Similar Response ◽  
Second Line

546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.

scholarly journals The Role of AMPK/mTOR Signaling Pathway in Anticancer Activity of Metformin

2021 ◽  
pp. 501-508
Author(s):  
Nikola Chomanicova ◽  
Andrea Gazova ◽  
Adriana Adamickova ◽  
Simona Valaskova ◽  
Jan Kyselovic
Keyword(s):  
Anticancer Activity ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Mtor Pathway ◽  
Diabetic Patients ◽  
Beneficial Effects ◽  
Treatment Of Diabetes

Metformin (MTF) is a widely used drug for the treatment of diabetes mellitus type 2 (DM2) and frequently used as an adjuvant therapy for polycystic ovarian syndrome, metabolic syndrome, and in some cases also tuberculosis. Its protective effect on the cardiovascular system has also been described. Recently, MTF was subjected to various analyzes and studies that showed its beneficial effects in cancer treatment such as reducing cancer cell proliferation, reducing tumor growth, inducing apoptosis, reducing cancer risk in diabetic patients, or reducing likelihood of relapse. One of the MTF’s mechanisms of action is the activation of adenosine-monophosphate-activated protein kinase (AMPK). Several studies have shown that AMPK/mammalian target of rapamycin (mTOR) pathway has anticancer effect in vivo and in vitro. The aim of this review is to present the anticancer activity of MTF highlighting the importance of the AMPK/mTOR pathway in the cancer process.

scholarly journals Circulating MicroRNAs for Diagnosis of Acute Pulmonary Embolism: Still a Long Way to Go

2022 ◽  
Vol 2022 ◽  
pp. 1-7
Author(s):  
Matteo Sobrero ◽  
Fabrizio Montecucco ◽  
Federico Carbone
Keyword(s):  
Pulmonary Embolism ◽  
Clinical Application ◽  
Acute Pulmonary Embolism ◽  
Clinical Evidence ◽  
Negative Impact ◽  
Small Sample Size ◽  
Cost Benefit ◽  
Small Sample ◽  
Development Organization

Venous thromboembolism (VTE) represents the third most frequent cause of acute cardiovascular syndrome. Among VTE, acute pulmonary embolism (APE) is the most life-threatening complication. Due to the low specificity of symptoms clinical diagnosis of APE may be sometimes very difficult. Accordingly, the latest European guidelines only suggest clinical prediction tests for diagnosis of APE, eventually associated with D-dimer, a biomarker burdened by a very low specificity. A growing body of evidence is highlighting the role of miRNAs in hemostasis and thrombosis. Due to their partial inheritance and susceptibility to the environmental factors, miRNAs are increasingly described as active modifiers of the classical Virchow’s triad. Clinical evidence on deep venous thrombosis reported specific miRNA signatures associated to thrombosis development, organization, recanalization, and resolution. Conversely, data of miRNA profiling as a predictor/diagnostic marker of APE are still preliminary. Here, we have summarized clinical evidence on the potential role of miRNA in diagnosis of APE. Despite some intriguing insight, miRNA assay is still far from any potential clinical application. Especially, the small sample size of cohorts likely represents the major limitation of published studies, so that extensive analysis of miRNA profiles with a machine learning approach are warranted in the next future. In addition, the cost-benefit ratio of miRNA assay still has a negative impact on their clinical application and routinely test.

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