Polycomb group proteins EZH2 and EED directly regulate androgen receptor in advanced prostate cancer.

Polycomb group proteins are important epigenetic regulators for cell proliferation and differentiation, organ development, as well as initiation and progression of lethal diseases, including cancer. Upregulated Polycomb group proteins, including Enhancer of zeste homolog 2 (EZH2), promote proliferation, migration, invasion and metastasis of cancer cells, as well as self-renewal of cancer stem cells. In our study, we report that EZH2 and embryonic ectoderm development (EED) indicate respective direct interaction with androgen receptor (AR). In the context of AR-positive prostate cancer, EZH2 and EED regulate AR expression levels and AR downstream targets. More importantly, we demonstrate that targeting EZH2 with the small-molecule inhibitor astemizole in cancer significantly represses the EZH2 and AR expression as well as the neoplastic capacities. These results collectively suggest that pharmacologically targeting EZH2 might be a promising strategy for advanced prostate cancer.

Overexpression of lipid metabolism genes and PBX1 in the contralateral breasts of women with estrogen receptor-negative breast cancer.

Risk biomarkers for estrogen receptor (ER)-negative breast cancer have clear value for breast cancer prevention. We previously reported a set of lipid metabolism (LiMe) genes with high expression in the contralateral unaffected breasts (CUBs) of ER-negative cancer cases. We now further examine LiMe gene expression in both tumor and CUB, and investigate the role of Pre-B-cell leukemia homeobox-1 (PBX1) as a candidate common transcription factor for LiMe gene expression. mRNA was extracted from laser-capture microdissected epithelium from tumor and CUB of 84 subjects (28 ER-positive cases, 28 ER-negative cases, 28 healthy controls). Gene expression was quantitated by qRT-PCR. Logistic regression models were generated to predict ER status of the contralateral cancer. Protein expression of HMGCS2 and PBX1 was measured using immunohistochemistry. The effect of PBX1 on LiMe gene expression was examined by overexpressing PBX1 in MCF10A cells with or without ER, and by suppressing PBX1 in MDA-MB-453 cells. The expression of DHRS2, HMGCS2, UGT2B7, UGT2B11, ALOX15B, HPGD, UGT2B28 and GLYATL1 was significantly higher in ER-negative versus ER-positive CUBs, and predicted ER status of the tumor in test and validation sets. In contrast, LiMe gene expression was significantly lower in ER-negative than ER-positive tumors. PBX1 overexpression in MCF10A cells up-regulated most LiMe genes, but not in MCF10A cells overexpressing ER. Suppressing PBX1 in MDA-MB-453 cells resulted in decrease of LiMe gene expression. Four binding sites of PBX1 and cofactor were identified in three lipid metabolism genes using ChIP-qPCR. These data suggest a novel role for PBX1 in the regulation of lipid metabolism genes in benign breast, which may contribute to ER-negative tumorigenesis.

Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling.

Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

Platelet distribution width and saphenous vein disease in patients after CABG. Association with graft occlusion.

OBJECTIVE: Platelets are involved in the pathogenesis of atherosclerosis. The inflammatory process in atherosclerosis may cause an increase in red blood cell distribution width (RDW) and platelet distribution width (PDW) values. Therefore, in this study we aimed to investigate whether PDW and RDW are associated with the patency of saphenous vein graft in patients at least 1 year after coronary artery bypass graft (CABG) surgery. METHODS: Patients who had undergone CABG surgery at least 1 year previously with at least one saphenous vein graft were included in the study population. Patients were referred to cardiac catheterization for stable anginal symptoms or positive stress test results. Before coronary angiography, all patients referred had routine blood tests including RDW and PDW values. RESULTS: Saphenous vein grafts were found to be patent in 69 patients and occluded in 40 patients. Although RDW levels were similar between patients with patent and occluded grafts (13.1 ± 1.1% and 13.2 ± 0.7% respectively, p = 0.37), PDW levels were significantly different between the two groups (13.1 ± 1.3% and 14.1 ± 1.1 respectively, p = 0.03). Although time after CABG operation differs significantly between the two groups (p < 0.001), multiple logistic regression analyses showed that PDW levels were found to be significantly associated with the patency of vein graft (ß = 1.682, 95% CI 1.117-2.532, p = 0.013). CONCLUSION: Our results showed that PDW levels were higher in patients with an occluded saphenous vein graft. However no association was found between the saphenous vein graft disease and RDW values. To verify this relationship between PDW values and saphenous vein graft patency, further investigations are needed.

The acute effect of percutaneous mitral balloon valvuloplasty on atrial electromechanical delay and P-wave dispersion in patients with mitral stenosis.

BACKGROUND AND AIM OF THE STUDY: The predisposition to atrial fibrillation (AF) in mitral stenosis (MS) has been demonstrated with several electrocardiographic (increased P-wave dispersion) and echocardiographic parameters (atrial electromechanical delay). Despite the improvement in P-wave dispersion after percutaneous mitral balloon valvuloplasty (PMBV), the changes in echocardiographic parameters related to AF risk are unknown. In this study we aimed to investigate the acute effect of PMBV on atrial electromechanical delay (EMD) assessed by tissue Doppler echocardiography in addition to electrocardiographic parameters. MATERIALS AND METHODS: This single-center study consisted of 30 patients with moderate or severe MS (23 females and seven males, aged 36.5 ± 8.5 years, with a mean MVA of 1.1 ± 0.2 cm) who underwent successful PMBV without complication at our clinic and 20 healthy volunteers from hospital staff as a control group (16 females and four males, aged 35.4 ± 6 years). We compared the two groups in regard to clinical, electrocardiographic and echocardiographic features. The patients with MS were also evaluated after PMBV within 72 h of the procedure. The P-wave dispersion was calculated from12-lead ECG. Interatrial and intra-atrial EMDs were measured by tissue Doppler echocardiography. These ECG and echocardiographic parameters after PMBV were compared with previous values. RESULTS: The maximum P-wave duration (138 ± 15 vs. 101 ± 6 ms, p < 0.01), PWD (58 ± 18 vs 23 ± 4, p < 0.01), the interatrial (55 ± 16 vs 36 ± 11 ms, p < 0.01) and left-sided intra-atrial EMD (40 ± 11 vs 24 ± 12 ms, p < 0.01) were higher in patients with MS than in healthy subjects. The left atrial (LA) diameter, LA volume and LA volume index had positive association with the interatrial (r = 0.5, p < 0.01; r = 0.5, p < 0.01 and r = 0.5, p < 0.01, respectively) and left-sided intra-atrial EMD (r = 0.5, p < 0.01; r = 0.4, p < 0.01; r = 0.4, p < 0.01 respectively). After PMBV, the interatrial (55 ± 16 vs. 40 ± 11 ms, p < 0.01) and left-sided intra-atrial EMD (40 ± 11 vs 31 ± 10, p < 0.01) showed significant improvement compared to previous values. There was also a statistically significant difference in maximum P-wave duration and PWD between pre-and post-PMBV (138 ± 15 vs 130 ± 14, p < 0.01, and 58 ± 18 vs 49 ± 16, p < 0.01, respectively). CONCLUSIONS: Our study shows that PMBV has a favorable effect on the electrocardiographic and echocardiographic parameters related with AF risk in patients with MS.

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial.

Importance: Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Intervention: Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. Main Outcomes and Measures: The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Results: Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. Conclusions and Relevance: In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.

Epidemiology and Survival outcomes of HIV-associated cervical cancer in Nigeria.

Introduction: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. Methods: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. Results: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+). The HIV+/ICC) patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC+) (P<0.001. Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV+/ICC+ diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC+. The HIV-/ICC+ women had better OS compared to HIV+/ICC+ participants (p=0.018), with 12-month OS 84.1% (95%CI: 75% - 90%) and 67.6% (95%CI: 42%-84%) respectively. Conclusion: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Epidemiology and survival outcomes of HIV-associated cervical cancer in Nigeria.

INTRODUCTION: Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria. METHODS: We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America's National Institutes of Health/National Cancer Institute funded project titled 'Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria'. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test. RESULTS: A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC +), and 47 (19.7%) were HIV-positive (HIV +/ICC +). The HIV +/ICC + patients were younger with median age 46 (IQR: 40-51) years compared to 57 (IQR: 45-66) among HIV-/ICC + (P < 0.001). Squamous cell carcinoma was the commonest histopathologic variant in 80.4% of ICC diagnosis, moderately differentiated tumor grade in 68.1% in both groups. HIV +/ICC + diagnosis was at FIGO advanced stages in 64.9% compared to 47.9% in HIV-/ICC +. The HIV-/ICC + women had better OS compared to HIV +/ICC + participants (p = 0.018), with 12-month OS 84.1% (95%CI 75-90%) and 67.6% (95%CI 42-84%) respectively. CONCLUSION: ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival.

Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model.

PURPOSE: In this study we investigated the treatment response and survival of intra-arterial (IA) compared to intra-peritoneal (IP) delivery of bevacizumab (BV) in a glioblastoma (GBM) xenograft mouse model. METHODS: 3x10(5) U87-Luc cells were stereotactically implanted into the cortex of 35 nude mice and grouped for treatment (n = 7 in each group): IP saline (group 1), single IP BV (group 2), biweekly IP BV for 3 weeks (group 3), single intra-arterial (IA) BV alone (group 4) and single IA BV with blood brain barrier disruption (BBBD) (group 5). Tumor growth was monitored every 3 to 4 days using bioluminescence imaging (BLI) and survival was analyzed by the Kaplan Meier method. Tumor tissue was analyzed using H&E staining and immunohistochemistry. RESULTS: Based on BLI, BV treated mice showed a delayed tumor growth over time compared to control. Kaplan Meier analysis demonstrated a median survival time of 28 days for group 1,31 days for group 2, 34 days for group 3, 36 days for group 4 and 36 days for group 5 (p < 0.0001). Mice treated with repeated IP BV (p = 0.003) or single IA BV with (p = 0.015) or without (p = 0.005) BBBD showed a significant survival benefit compared to single IP BV treated mice. Post mortem analysis revealed a histological pattern with a more discontinuous border between tumor and mouse brain in the repeated IP BV and single IA BV with or without BBBD treated mice compared to the sharply defined edges of single IP BV treated and control mice. CONCLUSIONS: In this study we showed a significant survival benefit of repeated IP BV and single IA BV with or without BBBD treated mice compared to single IP BV treated and control mice in a U87 xenograft model.

Telepathology in Nigeria for Global Health Collaboration.

Inadequate pathology personnel and high cost of running a Pathology facility are factors affecting access to timely and quality pathology services in resource-constrained settings. Telepathology is a novel technology that allows Pathologists to remotely assess collected samples. Though the initial cost of setting up a telepathology facility is high, its overall benefits far outweigh the cost. Its usefulness as a quality assurance measure, as a permanent image data storage system, in reducing costs associated with repeated slide preparations, reducing turn-around time of pathology reports, in collaborative research and in teaching has been well documented. This paper highlights the experiences, gains and challenges encountered in the deployment of telepathology in two resource-constrained settings in Nigeria. Overcoming the challenges associated with setting up a telepathology service in sub-Saharan Africa is important as it has the potential to improve overall health outcomes in a medically underserved region while ensuring technology and knowledge transfer are achieved.

Accelerated Epigenetic Age Among Women with Invasive Cervical Cancer and HIV-Infection in Nigeria.

Background: Invasive cervical cancer (ICC) is a serious public health burden in Nigeria, where human immunodeficiency virus (HIV) remains highly prevalent. Previous research suggested that epigenetic age acceleration (EAA) could play a role in detection of HIV-associated ICC. However, little research has been conducted on this topic in Africa where the population is most severely affected by HIV-associated ICC. Here, we investigated the association between ICC and EAA using cervical tissues of ICC-diagnosed Nigerian women living with HIV. Methods: We included 116 cervical tissue samples from three groups of Nigerian women in this study: (1) HIV+/ICC+ (n = 39); (2) HIV+/ICC- (n = 53); and (3) HIV-/ICC + (n = 24). We utilized four DNA methylation-based EAA estimators; IEAA, EEAA, GrimAA, and PhenoAA. We compared EAA measurements across the 3 HIV/ICC groups using multiple linear regression models. We also compared EAA between 26 tumor tissues and their surrounding normal tissues using paired t-tests. We additionally performed a receiver operating characteristics (ROC) curve analysis to illustrate the area under the curve (AUC) of EAA in ICC. Results: We found the most striking associations between HIV/ICC status and PhenoAge acceleration (PhenoAA). Among HIV-positive women, PhenoAA was on average 13.4 years higher in women with ICC compared to cancer-free women (P = 0.005). PhenoAA was 20.7 and 7.1 years higher in tumor tissues compared to surrounding normal tissues among HIV-positive women (P = 0.009) and HIV-negative women (P = 0.284), respectively. We did not find substantial differences in PhenoAA between HIV-positive and HIV-negative women with ICC. Conclusion: PhenoAA is associated with ICC in HIV-infected women in our study. Our findings suggest that PhenoAA may serve as a potential biomarker for further risk stratification of HIV-associated ICC in Nigeria and similar resource-constrained settings.

Optimization of glioblastoma multiforme stem cell isolation, transfection, and transduction.

It has been postulated that brain tumor stem cells (TSCs) may be the population of cells responsible for the maintenance and recurrence of glioblastoma multiforme (GBM). The purpose of this study was to optimize a reproducible protocol for generating TSCs for their subsequent transfection or transduction. Patient GBMs were enzymatically and mechanically dissociated and tumor spheres were resuspended in appropriate media and analyzed to ensure they met stem cell criteria. These cells were then transfected with a plasmid or transduced with a viral vector to introduce a previously absent gene and then allowed to form tumor spheres. Tumor spheres were generated from patient GBMs without contamination. These cells met stringent criteria as stem cells, including multipotentiality and self-renewal. High efficiency transfection and transduction of tumor spheres was possible, even at the core of the sphere. This allowed for the introduction of new genes to the TSCs, as evidenced by fluorescent microscopy and Western blot analysis. This study is a guide to optimize the generation of patient derived GBM tumor spheres without RBC and dead cell contamination. GBM TSCs within tumor spheres can easily be transfected with plasmids or transduced with a virus. This is important from a therapeutic perspective if gene replacement is to be successful in replacing genes lost in GBM progression or to knock down or silence genes that are over-expressed in malignant brain tumors.

The access rate to diagnosis and treatment modalities in breast cancer patients in Turkey; multicenter observational study.

PURPOSE: To determine the time elapsed between the first notification of the disease and the access to the diagnosis and treatment modalities and the associated factors in female patients with breast cancer in Turkey. METHODS: Data was acquired from a questionnaire involving 535 patients who applied to 14 various oncology clinics in Turkey between 1st and 28th of February 2010. Analyses were performed by the participating clinics and were divided into 3 groups: centers located in metropolitan areas formed group 1 (n=161), those located in Marmara and central Anatolia region formed group 2 (n=189), and centers located in Karadeniz and East-Southeast Anatolia region formed group 3 (n=185). The groups of these centers were formed according to the socioeconomic development of the provinces. RESULTS: The median patient age was 48 years, 56.1% of patients were less than 50 years of age. Eighty-five percent of the patients detected a mass in their breast by self examination and 27% of the patients older than 50 years never had breast imaging until the definite diagnosis was established. The median time elapsed between disease noticed by the patient and application to a health care center was 10 days, between application and biopsy 19 days, between biopsy and surgery 10 days, and between surgery and systemic therapy 31 days. The median time elapsed between patients applying for surgery in groups 1 and 2 centers was 11 and 21 days, respectively (p=0.01). The median time elapsed between biopsy and surgery in groups 1,2 and 3 centers was 14,1.5, and 12 days, respectively (p<0.05). CONCLUSION: A high level of awareness regarding breast cancer in our country is related with the time that is defined as 10 days between disease recognition and medical application. The time elapsed between the application and biopsy, surgery and systemic therapy was longer compared with the corresponding figures in developed countries.

A pan-cancer organoid platform for precision medicine.

Patient-derived tumor organoids (TOs) are emerging as high-fidelity models to study cancer biology and develop novel precision medicine therapeutics. However, utilizing TOs for systems-biology-based approaches has been limited by a lack of scalable and reproducible methods to develop and profile these models. We describe a robust pan-cancer TO platform with chemically defined media optimized on cultures acquired from over 1,000 patients. Crucially, we demonstrate tumor genetic and transcriptomic concordance utilizing this approach and further optimize defined minimal media for organoid initiation and propagation. Additionally, we demonstrate a neural-network-based high-throughput approach for label-free, light-microscopy-based drug assays capable of predicting patient-specific heterogeneity in drug responses with applicability across solid cancers. The pan-cancer platform, molecular data, and neural-network-based drug assay serve as resources to accelerate the broad implementation of organoid models in precision medicine research and personalized therapeutic profiling programs.

EGFR signaling is differentially activated in patient-derived glioblastoma stem cells.

Evidence suggests that stem-like cells are responsible for initiation, maintenance and recurrence of solid tumors, including Glioblastoma Multiforme (GBM). GBM is an intractable, highly lethal tumor of the central nervous system. Although epidermal growth factor receptor (EGFR) is highly expressed in many GBMs, anti-EGFR therapies have been unsuccessful as treatment. Few studies have examined EGFR activation in GBM stem cells (GSCs) to determine if patient-specific GSCs are amenable to anti-EGFR therapy pre-clinically. We hypothesized that EGFR activation in GSCs varied between patients and was an important determinant of responsiveness to anti-EGFR therapy. Cell cycle and apoptosis analysis was performed on tumor-spheres by immuncytochemistry in the presence and absence of the AG1478. Second messenger pathways operative in these processes were elucidated by immunoblotting. EGFR activated AKT and inactivated GSK3beta in EGFR+/PTEN+ GSCs. AG1478 and erlotinib significantly decreased the total number of tumor-spheres that EGFR+/ PTEN+ GSCs generated and the rate of sphere formation. Inhibition of EGFR signaling by AG1478 increased GSC senescence and apoptosis, likely via inhibition of AKT and activation of GSK3beta. Sphere formation by EGFR-/ PTEN- GSCs was independent of EGF stimulation, but dependant on B27 growth supplement. Our data suggest that EGFR+/PTEN+ GSCs are susceptible to anti-EGFR therapy in vitro.

Hypoglycemia induced by long-acting somatostatin analogues in a patient with nonfunctional neuroendocrine tumor.

Somatostatin and its long-acting analogues are effective in symptom control in patients with functional neuroendocrine tumors; they are also able to control tumor growth. Somatostatin analogues are safe and generally well tolerated. In some cases they may cause serious complications. Somatostatin analogues are potent inhibitors of growth hormone (GH) and glucagon secretion. They cause impairment of hepatic glucose output and delay in intestinal absorption of carbohydrates. Patients with huge tumor mass and multiple liver metastases have increased risk of tumor-induced hypoglycemia. In these patients, long-acting octreotide may trigger serious hypoglycemia. The patients whose glucose control is dependent on counter-regulatory hormones should be monitored for the possibility of hypoglycemia. Herein, we present a patient with severe and prolonged hypoglycemia after long-acting octreotide treatment.

Highly sensitive carbon-based nanohybrid sensor platform for determination of 5-hydroxytryptamine receptor agonist (Eletriptan).

Highly sensitive nanosensors such as graphene oxide/ platinum-iridium nanohybrid, carboxylic acid functionalized multiwalled carbon nanotubes (GO/Pt-Ir/MWCNT-COOH) and amine functionalized multiwalled carbon nanotubes (GO/Pt-Ir/MWCNT-NH2) modified glassy carbon electrode were developed for the determination of 5-hydroxytryptamine receptor agonist, Eletriptan. Graphene oxide/platinum-iridium nanohybrid was synthesized using sonication method and then characterized by spectroscopic and microscopic methods such as Raman, TEM, HRTEM, XPS, and XRD. The prepared nanohybrids modified on glassy carbon electrodes were well characterized and applied for electrochemical determination of Eletriptan. The significant enhancement of the oxidation peak current of Eletriptan was observed in GO/Pt-Ir/MWCNT-COOH as a best nanosensor in all prepared ones. The pH, scan rate and the amount of GO/Pt-Ir/MWCNT-COOH were also optimized for Eletriptan analysis. After obtaining of the optimum conditions, the identification of Eletriptan was performed between the linear range of 1 × 10-7 M and 4 × 10-6 M with a detection limit of 6.1 × 10-9 M. The developed method was successfully applied for the determination of the drug in tablets with acceptable recoveries. Moreover, it can be elicited that, in electrochemical studies, electroactive interferences from the tablet excipients did not interfere with the results.

Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial.

CONTEXT: Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti-PD-1 nivolumab. OBJECTIVE: The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. DESIGN: Single-arm, multicenter, phase 2 clinical trial with two-stage design. SETTING: Comprehensive cancer center. PATIENTS: Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. INTERVENTION: Nivolumab (240 mg) IV every 2 weeks. RESULTS: Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. CONCLUSION: Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.

A pilot study for human tumor/DNA banking: returned more questions than answers.

A pilot study was performed for setting up the Dokuz Eylül University Breast Tumor DNA Bank (DEUBTB) to facilitate the sharing of tumor DNA/RNA samples and related data from cases collected by collaborators specializing in the breast cancer diseases between 2004 and 2006. The pilot study aimed to provide answers for certain questions on: (1) ethical concerns (informing the volunteer for donating specimen, anonymizing the sample information, procedure on sample request), (2) obtaining and processing samples (technical issues, flowchart), (3) storing samples and their products (storing forms and conditions), (4) clinical database (which clinical data to store), (5) management organization (quality and quantity of personnel, flowchart for management relations), (6) financial issues (establishment and maintenance costs). When the bank had 64 samples, even though it is quite ready to supply samples for a research project, it revealed many questions on details that may be answered in more than one way, pointing that all biobanks need to be controlled by a higher degree of management party which develops and offers quality standards for these establishments.