tbuckley/cabot-search huggingface dataset:
A Modified Method of Botulinum Toxin Injection in Patients with Achalasia: a Pilot Trial
Authors: J Martínek, J Spicàk
Journal: Endoscopy (2003)

Background and aims: Injection of botulinum toxin (BT) from direct vision into the lower esophageal sphincter (LES) lowers its basal tone and improves symptomatology in most of the patients with achalasia. We hypothesized that the effect could be improved by better degree of LES infiltration by toxin administered from both prograde and retrograde views. The aim of the study was to investigate the feasibility, safety and efficacy of this modified method of intrasphincteric BT injection in patients with achalasia. Patients and method: Sixteen patients with achalasia were treated with BT injection. Hundred units of BT (Botox®) were diluted with 4 ml of normal saline. Aliquots of 0.5 ml were injected into four quadrants of the LES from retrovision and then into each quadrant from direct vision. The patients were followed up for a median of 25.5 months (range 19 - 31). Results: No serious adverse events were noted. All patients responded well to the injection within one week and 3 patients (18.7 %) experienced an early relapse. The remaining 13 patients were classified as responders. After a single BT injection, 11 responders reported a relapse and 2 patients remained asymptomatic. The median symptom-free interval was 17 months (8 - 28). Five patients with a relapse underwent BT reinjection. Three of them remained asymptomatic and two experienced the second relapse. After BT reinjection, the median symptom-free interval was 16 months (10 - 19). All other patients with a relapse and without BT reinjection were treated with either balloon dilatation or surgery and are currently asymptomatic Conclusion: Combining injection of BT into the LES from both direct vision and retrovision was feasible, safe and produced a rapid response which was sustained for more than 1 year in the majority of patients. This method of BT administration might be superior to the traditional injection from direct view only, and a randomized and prospective study comparing those techniques of administration should be performed.
Abstract 4468: Targeted deep sequencing of plasma circulating cell-free DNA shows VIM and FBLN1 methylation as potential biomarkers for hepatocellular carcinoma
Authors: Reetta Holmila, Athena Sklias, David C. Muller, Davide Degli Esposti, Paule Guilloreau, James Mckay, Suleeporn Sangrajrang, Petcharin Srivatanakul, Pierre Hainaut, Philippe Merle, Andre Nogueira da Costa, Zdenko Herceg
Journal: Cancer Research (2016)

Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, but is still lacking sensitive and specific biomarkers for diagnosis and prognosis. HCC carcinogenesis is a multi-step process that usually arises in background chronic metabolic, inflammatory and/or infectious liver disease and it exhibits a wide range of epigenetic alterations that could potentially be used as biomarkers. In this study, we applied the targeted massively parallel semiconductor sequencing to assess in plasma circulating cell-free DNA (cfDNA) the methylation of a panel of genes (FBLN1, HINT2, LAMC1, LTBP1, LTBP2, PSMA2, PSMA7, PXDN, TGFB1, UBE2L3, VIM and YWHAZ) and to evaluate the potential of these genes as novel HCC biomarkers in two different series, one from France and one from Thailand. Methylation in cfDNA was detected for FBLN1, PSMA7, PXDN and VIM, with substantial differences in methylation patterns between cases and controls for FBLN1 and VIM. Further, the average methylation level across analyzed CpG-sites was associated with higher odds of HCC for VIM (1.48 [1.02, 2.16] for French cases, and 2.18 [1.28, 3.72] for Thai cases), and lower odds of HCC for FBLN1 (0.89 [0.76, 1.03] for French cases and 0.75 [0.63, 0.88] for Thai cases). We also analyzed a set of HCC and adjacent tissues as well as The Cancer Genome Atlas’ (TCGA) data to further investigate the origin of methylation pattern in cfDNA and noted that the analysis of VIM could be improved based on the methylation pattern detected in TCGA data. Overall, our study provides evidence that changes in methylation levels of cfDNA could be used as potential cancer biomarkers and that VIM and FBLN1 methylation in cfDNA are associated with HCC and may represent useful plasma-based biomarkers for improved detection and patient surveillance. Citation Format: Reetta Holmila, Athena Sklias, David C. Muller, Davide Degli Esposti, Paule Guilloreau, James Mckay, Suleeporn Sangrajrang, Petcharin Srivatanakul, Pierre Hainaut, Philippe Merle, Andre Nogueira da Costa, Zdenko Herceg. Targeted deep sequencing of plasma circulating cell-free DNA shows VIM and FBLN1 methylation as potential biomarkers for hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4468.
Prognostic significance of immunoglobulin kappa C in node-negative breast cancer is both conserved across and independent from molecular subtypes.
Authors: M. Schmidt, I. Petry, D. Boehm, A. Lebrecht, H. Koelbl, M. Gehrmann, J. G. Hengstler
Journal: Journal of Clinical Oncology (2010)

10616 Background: Immunological defense mechanisms play an important prognostic role in breast cancer. We examined the prognostic impact of immunoglobulin kappa C (IGKC) in 766 node-negative breast cancer patients without adjuvant systemic therapy according to molecular subtypes. Methods: IGKC (probe set ID 211645_x_at) was analysed utilizing microarray based gene-expression data of three independent and previously published cohorts of node-negative breast cancer patients (Mainz, Rotterdam, TRANSBIG). In addition to IGKC, we examined the prognostic impact of age, histological grade, tumor size, estrogen receptor (ER) and HER2. Furthermore, we investigated the prognostic significance of IGKC in luminal (ER+/HER2-), erbB2-like (HER2 +), and basal- like (ER-/HER2-) molecular subtypes, respectively. Metastasis-free survival (MFS) was analyzed with univariate and multivariate Cox regression. Results: Patients with higher expression of IGKC showed better MFS in the whole cohort of patients (HR 0.795, 95% CI 0.711-0.890, p < 0.001). Using multivariate Cox regression, IGKC retained its independent prognostic significance (HR 0.731, 95% CI 0.621-0.861, p < 0.001). Besides IGKC histological grade (HR 2.318, 95% CI 1.522-3.532, p < 0.001), tumor size (HR 1.536, 95% CI 1.131-2.085, p = 0.006), and HER2 (HR 1.829, 95% CI 1.079-3.101, p = 0.025) showed an independent association with MFS. 521 patients (68%) belonged to the luminal subtype, 106 (14%) were erbB2-like, and 139 (18%) basal-like, respectively. Prognostic impact of IGKC was conserved across luminal (HR 0.796, 95% CI 0.688-0.923, p = 0.002), erbB2-like (HR 0.542, 95% CI 0.387-0.757, p < 0.001), and basal-like (HR 0.760, 95% CI 0.600-0.963, p = 0.023) subtypes, respectively. In multivariate analysis IGKC had independent prognostic significance additionally to molecular subtypes (HR 0.746, 95% CI 0.664-0.837, p < 0.001). Conclusions: IGKC has independent prognostic impact in breast cancer. Its prognostic significance is both conserved across and independent from molecular breast cancer subtypes. Incorporating IGKC should lead to a more appropriate assessment of outcome in node-negative breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Siemens Healthcare Diagnostics Siemens Healthcare Diagnostics
Abstract 2533: Interlukin-1 (IL-1) may induce prostate cancer (PCa) stem-like cells
Authors: Shayna Thomas, Sana Merchant, Rachel Meade, Afshan Fathima Nawas, Nikki Delk
Journal: Cancer Research (2016)

Abstract Inflammation is implicated in prostate cancer initiation and progression. Our lab found that the inflammatory cytokine, interleukin-1 beta (IL-1β) concomitantly upregulates the pro-survival scaffold protein, Sequestome-1 (SQSTM1/p62) and represses androgen receptor accumulation in a relatively small cell subpopulation within various prostate cancer cell lines. Given that cancer stem cell subpopulations have been isolated from isogenic cell lines and given that prostate cancer stem cells are androgen receptor negative, we hypothesized that the IL-1β-responsive subpopulation might be stem-like cells. Cancer stem cells are significant in prostate cancer because they are resistant to chemo-radiation and androgen-targeted therapies and can contribute to the tumor cell pool through asymmetric division. Thus, we analyzed the mRNA and protein accumulation of several stem cell markers in various prostate cancer cells lines exposed to IL-1β. We also have experiments underway to analyze stem cell biology in order to determine the functional significance of the IL-1β-responsive subpopulation. Thus far, we have discovered that IL-1β can induce stem cell marker mRNA and protein accumulation, suggesting that IL-1β alters prostate cell fate and supports the notion that inflammation contributes to prostate cancer initiation and progression. Citation Format: Shayna Thomas, Sana Merchant, Rachel Meade, Afshan Fathima Nawas, Nikki Delk. Interlukin-1 (IL-1) may induce prostate cancer (PCa) stem-like cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2533.
Abstract 3081: Novel cucurbitacin analogue Cuc D exhibits potent anti-cancer activity in cervical cancer
Authors: Mohammed Sikander, Bilal Bin Hafeez, Fathi T. Halaweish, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan
Journal: Cancer Research (2016)

Abstract Background: Cervical cancer is one of the leading cause of mortality among women in US. Naturally occurring dietary compounds have gained increasing attention for their anticancer effects. Cucurbitacins, tetracyclic triterpenoid compound, belong to a family of Cucurbitaceae have shown promising anti-cancer activity. Herein, we investigated the potential anti-cancer effects of a novel analogue of cucurbitacin D (Cuc D) against cervical cancer in in vitro and in a xenograft mouse model. Methods: In our study, we used human cervical cancer cells (CaSki and SiHa). Cells were treated with Cuc D (0.05 to 1μM) for 48 and 72 hrs. MTS and colony formation assays were performed to investigate the effects of Cuc D on cell viability and proliferation. Western Blot analysis was performed to investigate the effects of Cuc D on cell proliferation and apoptotic markers. To determine the therapeutic effects of Cuc D, we used female athymic nude mice and injected CaSki cells (4 × 106) into the cervix to develop orthotopic xenograft tumors. Cuc D (1 mg/kg body weight) was administered through intratumoral injection four weeks post-tumor cell injection. Tumor volume in these mice were recorded bi-weekly. Results: Cuc D inhibited cell viability of cervical cancer cells in a dose-dependent manner. IC50 of Cuc D was observed 400 nM and 250 nM in Caski and SiHa cells, respectively. Cuc D treatment effectively inhibited growth of cervical cancer cells which was determined by decreased cell proliferation and colony formation assays. Cuc D treatment induced apoptosis in cervical cancer cells as measured by enhanced Annexin V staining. Western blot result also illustrated cleavage in PARP protein in Cuc D treated cells which further confirms apoptosis induction. Cuc D treatment also inhibited PI3K and c-Myc protein levels and phosphorylation of STAT3 and Rb proteins. In addition, Cuc D treatment induced the cell cycle inhibitory proteins (p21 and p27) and PTEN and the expression of a tumor suppressor microRNA, miR-145, as determined by qRT-PCR. In an orthotopic tumor xenograft mouse model, Cuc D treatment effectively inhibited tumor growth as compared to vehicle control treated mice. Conclusion: Taken together, our results demonstrate potent anti-cancer efficacy of Cuc D in cervical cancer cells via modulation of key onco/tumor suppressor proteins. Thus, Cuc D could be a useful therapeutic agent for cervical cancer treatment. Citation Format: Mohammed Sikander, Bilal Bin Hafeez, Fathi T. Halaweish, Murali M. Yallapu, Meena Jaggi, Subhash C. Chauhan. Novel cucurbitacin analogue Cuc D exhibits potent anti-cancer activity in cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3081.
Trends in Seniors’ Use of Digital Health Technology in the United States, 2011-2014
Authors: David M. Levine, Stuart R. Lipsitz, Jeffrey A. Linder
Journal: JAMA (2016)

The sickest, most expensive, and fastest growing segment of the US population are seniors 65 years and older. 1 Digital health technology has been advocated as a solution to improve health care quality, cost, and safety.However, little is known about digital health use among seniors.Methods | The Partners HealthCare Human Research Committee exempted this study from review.The National Health and Aging Trends Study (NHATS) is an annual in-home, computerassisted, longitudinal, nationally representative survey of community-dwelling Medicare beneficiaries 65 years and older drawn from the Medicare enrollment database through a complex sampling design. 2Each year, NHATS asks the same respondents about everyday (nonhealth) technology use and 4 digital health modalities: use of the internet to fill prescrip-
Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatanib plus paclitaxel (P) versus investigator’s choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatanib—LUX-Lung 5 (LL5).
Authors: Martin H. Schuler, Chih-Hsin Yang, Keunchil Park, Jaafar Bennouna, Yuh-Min Chen, Christos Chouaid, Filippo De Marinis, Ji Feng Feng, Francesco Grossi, Dong-Wan Kim, Xiaoqing Liu, Shun Lu, Janos Strausz, Yurii Vinnyk, Rainer Wiewrodt, Caicun Zhou, Vikram K. Chand, Bushi Wang, Joo-Hang Kim, David Planchard
Journal: Journal of Clinical Oncology (2014)

8019^ Background: Improved disease control with continuation of EGFR inhibition beyond progression has been suggested in retrospective/non-randomized studies, however, this has yet to be prospectively evaluated in a randomized trial. LL5 is a randomized trial, which assessed the efficacy of continuation of the irreversible ErbB family blocker, afatinib (A), beyond progression with the addition of P in NSCLC pts with prior benefit from reversible EGFR tyrosine kinase inhibitors (E/G) and A. Methods: In this open-label, global phase III trial, pts with NSCLC who had failed ≥1 line of CT and E/G (after ≥12 wks treatment) were treated with A (50 mg/day) in Part A (n=1154). Upon progression, those with ≥12 wks on A were eligible to be randomized 2:1 to A+P (40 mg/day; 80 mg/m2/week) or single agent investigator's choice CT in Part B. Primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety. Results: 202 pts were randomized (A+P, n=134; CT, n=68) and baseline characteristics were well balanced (median age 60 yrs, females 49%, ECOG PS 0–1 91% overall). A statistically significant improvement in PFS was observed on A + P vs CT arm (median 5.6 vs 2.8 months, hazard ratio (HR) 0.60 (95% CI 0.43, 0.85; p=0.003). ORR was also significantly higher in A+P arm vs CT (32.1% vs 13.2%; p=0.005). OS was similar in both arms 12.2 vs. 12.2 months, HR 1.00 (95% CI 0.70, 1.43; p=0.994). Most common related adverse events (AEs) with A+P vs CT were diarrhea (53.8% vs 6.7%), alopecia (32.6% vs 15.0%) and asthenia (27.3% vs 28.3%). Conclusions: ContinuedErbB family blockade with A with the addition of P significantly improved PFS and ORR vs CT alone in heavily pretreated pts with acquired resistance to E/G and progression on A monotherapy. AEs were considered manageable. Our data support that tumors progressing on E/G and A continue to depend on signalling through the receptors of the ErbB family and can benefit from continuous ErbB family blockade with A. Clinical trial information: NCT01085136.
Abstract 2192: Fusogenic targeted liposomes as next-generation nanomedicine for prostate cancer
Authors: Jihane M. Mriouah, Rae Lynn Nesbitt, Deborah Sosnowski, Desmond Pink, Roy Duncan, Andries Ziljstra, John D. Lewis
Journal: Cancer Research (2016)

Abstract Metastatic or castrate-resistant is the second-leading cause of cancer mortality in males. In the past 3 years, chemotherapies have extended survival, but efficacy is limited by dose-limiting toxicities due to suboptimal biodistribution. We address the lack of specificity and accumulation in Castrate Resistant Prostate Cancer (CRPC) by developing a unique nano-carrier for drug delivery: targeted fusogenic liposomes. We have developed a platform whereby liposomes are formulated with fusion associated small transmembrane protein p14 displaying targeting ligands. The p14 protein catalyzes mixing of the liposomal bilayer with cell membranes to deliver the cargo directly into the cytoplasm, while the targeting ligand bombesin, allows for targeting to the Gastrin-releasing Peptide (GRPR) that is overexpressed in prostate cancer. We hypothesized that this novel targeted fusogenic liposome formulation would significantly improve the biodistribution and efficacy of chemotherapy. A clinical liposomal doxorubicin formulation (DOXIL) was modified to incorporate targeted fusogenic p14 protein. We then evaluated the efficacy and biodistribution of these new formulations using in vitro and in vivo models of CRPC. In PC3 cells, compared to conventional liposomes, intracellular levels of doxorubicin are increased by 15 and 25 times when p14 or p14-bombesin liposomes are used. Additionally, the IC50 is reduced from 85mM to 2mM. In mice bearing PC3 tumors treated with targeted fusogenic liposomal doxorubicin, we observed tumor growth inhibition of 57% (vs control). This establishes a proof of concept for an innovative targeted drug delivery system that may improve the outcome of patients with CRPC by enhancing the effect of approved drugs. Citation Format: Jihane M. Mriouah, Rae Lynn Nesbitt, Deborah Sosnowski, Desmond Pink, Roy Duncan, Andries Ziljstra, John D. Lewis. Fusogenic targeted liposomes as next-generation nanomedicine for prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2192.
NHS England to appeal against ruling that it can fund PrEP to prevent HIV
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

NHS England has said that it will appeal against the High Court ruling that it had responsibility for commissioning pre-exposure prophylaxis (PrEP) for preventing HIV.

The ruling effectively overturns the position that NHS England took in March,1 and reiterated in May after taking legal advice,2 that it was down to local councils to commission preventative services, including PrEP. The ruling has been welcomed by charities and local government.

The National AIDS Trust (NAT), which challenged NHS England’s stance in court, said that it was delighted by the judgment but disappointed that NHS England was appealing the decision. Deborah Gold, chief executive of the trust, said of the judgment, “This is fantastic news. It is vindication for the many people who were let down when NHS England absolved itself of responsibility for PrEP. The …
Abstract 4130: A novel tumor-suppressor role for squalene epoxidase in human colorectal metastasis
Authors: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Ji-Yong Yoon, Jun-Ho Ahn, Ju-Sik Min, Sujin Jeon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim
Journal: Cancer Research (2016)

Abstract Malignancy cancer cells are reported to develop mechanisms to resist anoikis (apoptotic cell death from deprivation of cell-cell/matrix interactions), thereby enhancing the survival of cancer cells and secondary tumor formation in distant organs, which is responsible for 90% of cancer-related fatalities. A high serum level of cholesterol (hypercholesterolemia) in patients with colorectal cancers (CRCs) metastasis is reported, but the underlying relationship were never elucidated. Human CRC tissues revealed that the expression of squalene epoxidase (SqE), the rate-limiting enzyme in cholesterol synthesis, is significantly reduced in the advanced stages of CRC. Here we report that the knockdown/degradation of SqE by either the application of small-interfering RNA against SqE or a high-level of cholesterol significantly potentiates CRC cell survival/metastasis via the induction of an epithelial-mesenchymal transition as well as of anoikis resistance. We identified the interactions of SqE with glycogen synthase kinase 3β (GSK3β) and/or p53: SqE knockdown induced the dissociation of GSK3β and p53, thereby resulting in the downregulation of E-cadherin via the inhibition of GSK3 activity and of -catenin degradation, as well as the p53 degradation by the hdm2 upregulation. Overall, the present study demonstrates SqE is a key negative regulator of cancer cell survival and of CRC metastasis. Citation Format: Soo Young Jun, Hyun-Soo Cho, Jeong-Ju Lee, Ji-Yong Yoon, Jun-Ho Ahn, Ju-Sik Min, Sujin Jeon, Jae-Hye Lee, Min Hyuk Choi, Nam-Soon Kim. A novel tumor-suppressor role for squalene epoxidase in human colorectal metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4130.