Electron scattering cross sections for pyridine in the energy range 0-100 eV, which we previously measured or calculated, have been critically compiled and complemented here with new measurements of ...electron energy loss spectra and double differential ionization cross sections. Experimental techniques employed in this study include a linear transmission apparatus and a reaction microscope system. To fulfill the transport model requirements, theoretical data have been recalculated within our independent atom model with screening corrected additivity rule and interference effects (IAM-SCAR) method for energies above 10 eV. In addition, results from the R-matrix and Schwinger multichannel with pseudopotential methods, for energies below 15 eV and 20 eV, respectively, are presented here. The reliability of this complete data set has been evaluated by comparing the simulated energy distribution of electrons transmitted through pyridine, with that observed in an electron-gas transmission experiment under magnetic confinement conditions. In addition, our representation of the angular distribution of the inelastically scattered electrons is discussed on the basis of the present double differential cross section experimental results.
Abstract Objective The goal of this report is to review the activity of promising antifolate and folate receptor agents being developed for ovarian cancer including thymidylate synthase inhibitors, ...antifolate receptor antibodies, and folate-chemotherapy conjugates. Methods A literature search was performed over the last 5 years using the terms “folate receptor” and “ovarian cancer” and those that specifically addressed the MOA were included. Abstracts presented within the last 3 years were also searched and included in this review where appropriate. Results Thymidylate synthase inhibitors are a promising avenue for ovarian cancer treatment. Phase II trials have shown pemetrexed to have activity in patients with platinum resistant ovarian cancer. Several other thymidylate synthase inhibitors are in the early phase of development including BGC 945 and ZD-9331. Monoclonal antibodies that target the folate receptor have also shown potential in the development of ovarian cancer therapies. Farletuzumab is one of these antibodies. A recent phase III trial found that farletuzumab in combination with carboplatin and taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing. The folate receptor is also utilized through folate conjugates. Vintafolide is one such agent which is currently in phase III development. Encouraging data from phase II trials showed an improvement in PFS from 2.7 months to 5 months. Folate can also be conjugated to radioisotopes for both therapeutic and imaging purposes, and early studies have shown correlation with amount of disease to therapy response. Conclusion Folate targeted agents continue to show promising antitumor activity in ovarian malignancy and initial clinical experience has demonstrated favorable toxicity profiles. Further development and resources targeted toward these therapies appear to be warranted.
The hedgehog pathway has been implicated in the formation and maintenance of a variety of malignancies, including ovarian cancer; however, it is unknown whether hedgehog signaling is involved in ...ovarian cancer chemoresistance. The goal of this study was to determine the effects of antagonizing the hedgehog receptor, Smoothened (Smo), on chemotherapy response in ovarian cancer. Expression of hedgehog pathway members was assessed in three pairs of parental and chemotherapy-resistant ovarian cancer cell lines (A2780ip2/A2780cp20, SKOV3ip1/SKOV3TRip2, HeyA8/HeyA8MDR) using quantitative PCR and Western blot analysis. Cell lines were exposed to increasing concentrations of two different Smo antagonists (cyclopamine, LDE225) alone and in combination with carboplatin or paclitaxel. Selective knockdown of Smo, Gli1, or Gli2 was achieved using siRNA constructs. Cell viability was assessed by MTT assay. A2780cp20 and SKOV3TRip2 orthotopic xenografts were treated with vehicle, LDE225, paclitaxel, or combination therapy. Chemoresistant cell lines showed higher expression (>2-fold, P < 0.05) of hedgehog signaling components compared with their respective parental lines. Smo antagonists sensitized chemotherapy-resistant cell lines to paclitaxel, but not to carboplatin. LDE225 treatment also increased sensitivity of ALDH-positive cells to paclitaxel. A2780cp20 and SKOV3TRip2 xenografts treated with combined LDE225 and paclitaxel had significantly less tumor burden than those treated with vehicle or either agent alone. Increased taxane sensitivity seems to be mediated by a decrease in P-glycoprotein (MDR1) expression. Selective knockdown of Smo, Gli1, or Gli2 all increased taxane sensitivity. Smo antagonists reverse taxane resistance in chemoresistant ovarian cancer models, suggesting combined anti-hedgehog and chemotherapies could provide a useful therapeutic strategy for ovarian cancer.
Highlights • It is timely to reconsider how patients with recurrent ovarian cancer are classified. • Categorizing recurrent ovarian cancer patients only on basis of a timeline is limited. • A ...multiplex system of categorizing patients with recurrent ovarian cancer is needed.
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. Platinum-based therapy is the standard first line treatment and while most patients initially respond, ...resistance to chemotherapy usually arises. Major signaling pathways frequently upregulated in chemoresistant cells and important in the maintenance of cancer stem cells (CSCs) include Wnt/β-catenin, mTOR, and STAT3. The major objective of our study was to investigate the treatment of ovarian cancer with targeted agents that inhibit these three pathways. Here we demonstrate that niclosamide, a salicylamide derivative, and two synthetically manufactured niclosamide analogs (analog 11 and 32) caused significant inhibition of proliferation of two chemoresistant ovarian cancer cell lines (A2780cp20 and SKOV3Trip2), tumorspheres isolated from the ascites of EOC patients, and cells from a chemoresistant patient-derived xenograft (PDX). This work shows that all three agents significantly decreased the expression of proteins in the Wnt/β-catenin, mTOR and STAT3 pathways and preferentially targeted cells that expressed the ovarian CSC surface protein CD133. It also illustrates the potential of drug repurposing for chemoresistant EOC and can serve as a basis for pathway-oriented in vivo studies.
Purpose of Review
In this review, we discuss modern cytokine delivery systems in oncologic care, focusing on modalities being developed in the clinical trials or currently in use. These include ...pegylation, immune-cytokine drug conjugates, cytokine-expressing plasmid nanoparticles, nonviral cytokine nanoparticles, viral systems, and AcTakines.
Recent Findings
Cytokine therapy has the potential to contribute to cancer treatment options by modulating the immune system towards an improved antitumor response and has shown promise both independently and in combination with other immunotherapy agents. Despite promising preliminary studies, systemic toxicities and challenges with administration have limited the impact of unmodified cytokine therapy. In the last decade, novel delivery systems have been developed to address these challenges and facilitate cytokine-based oncologic treatments.
Summary
Novel delivery systems provide potential solutions to decrease dose-limiting side effects, facilitate administration, and increase the therapeutic activity of cytokine treatments in oncology care. The expanding clinical and translational research in these systems provides an opportunity to augment the armamentarium of immune oncology and may represent the next frontier of cytokine-based immuno-oncology.
Advanced-stage ovarian cancer is characterized by high mortality due to development of resistance to conventional chemotherapy. Novel compounds that can enhance the efficacy of conventional ...chemotherapy in ovarian cancer may overcome this drug resistance. Consumption of green tea (epigallocatechin gallate, EGCG) and cruciferous vegetables (sulforaphane, SFN) is inversely associated with occurrence of ovarian cancer and has anticancer effects through targeting multiple molecules in cancer cells. However, the effects of EGCG and SFN combinational treatment on ovarian cancer cells and on efficacy of cisplatin to these cells are unknown. In this study, EGCG or SFN was used to treat both cisplatin-sensitive (A2780) and cisplatin-resistant (A2780/CP20) ovarian cancer cells alone or in combination with cisplatin. We found that EGCG and SFN combinational treatment can reduce cell viability of both ovarian cancer cell lines time- and dose-dependently. Furthermore, EGCG and SFN combinational treatment can enhance cisplatin-induced apoptosis and G2/M phase arrest, thereby enhancing the efficacy of cisplatin on both cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. EGCG and SFN combinational treatment upregulated p21 expression induced by cisplatin in cisplatin-sensitive ovarian cancer cells, while p27 expression was not regulated by these treatments. Collectively, these studies provide novel approaches to overcoming cisplatin chemotherapy resistance in ovarian cancer.
Abstract Objective. To assess whether the use of a novel optical detection system (ODS) as an adjunct to colposcopy increases the detection of biopsy-confirmed CIN 2,3. Methods. This is a multicenter ...two-arm randomized trial comparing colposcopy alone with colposcopy plus a pre-commercial ODS system that utilizes fluorescence, white light tissue reflectance, and cervical video imaging. Patients were recruited from 13 colposcopy clinics in a variety of practice settings. 2299 women referred for the evaluation of an abnormal cervical cytology were randomized with stratification by cytology; subsequently 113 women were excluded for a variety of reasons. The main study outcomes were differences in true-positive rates (CIN 2,3 and cancer identified) and false-positive rates between the study arms. Results. The true-positive (TP) rates were 14.4% vs. 11.4% ( p = 0.035, one-sided) for the combined colposcopy and ODS arm compared to colposcopy-only arm, respectively, in women with either an atypical squamous cell (ASC) or low-grade squamous intraepithelial lesion (LSIL) cytology result. TP rates were similar between the two arms among women referred for the evaluation of HSIL. The 26.5% gain in true-positives observed with the use of ODS and colposcopy among women referred for an ASC or LSIL cytology was achieved with only a fractional increase in number of biopsies obtained per patient (0.30) and a modest increase in false-positive rate (4%). In the combined colposcopy and ODS arm among women with ASC or LSIL, the PPV of biopsies indicated by ODS was 15.0% and the PPV of biopsies indicated by colposcopy was 15.2%. Joint hypothesis testing indicates that ODS and colposcopy provides benefit compared to colposcopy alone among women with ASC or LSIL. Conclusions. Combining ODS with colposcopy provides a clinically meaningful increase in the detection of CIN 2,3 in women referred for the evaluation of mildly abnormal cytology results.
•MAID (Medical Aid in Dying) is the practice of providing a prescription for a life ending medication to a patient.•MAID is an important topic for gynecologic oncologists and their patients.•SGO ...members desire additional education and guidance regarding MAID.
To assess SGO members’ knowledge, attitudes, and practice patterns regarding Medical Aid In Dying (MAID).
SGO members were surveyed via online survey. The survey included questions regarding demographics, knowledge, attitudes, and practice patterns relating to MAID. Descriptive statistics were calculated. Associations between sociodemographic factors and attitudes related to MAID were analyzed utilizing logistic regression.
Of 1,337 invited members, 225 (17%) responded. Median age was 46. Most were female (58%), white (81%), and in academic practice (64%). Over 50% had heard the term MAID and have had a patient ask about it. Few (20%) reported living in a state where MAID is legal and 61% of these respondents provided MAID. Sixty percent lived in a state that had not legalized MAID and 18% did not know if MAID was legal in their state. 36% of respondents living in a state where MAID was illegal/unknown legality indicated they would provide MAID if it were legal in their state, 30% would not, and 34% were uncertain. The majority (69%) of respondents believed MAID should be legal. Female respondents were more likely to support legalization of MAID (OR 2.44, p=<0.05). Respondents practicing in the southern U.S. were less likely to support legalization of MAID (OR 0.42, p=<0.05). Over 75% of respondents stated an SGO position statement on MAID would be helpful.
MAID is a highly relevant topic for gynecologic oncologists. Gaps in MAID-related knowledge exist among SGO members and there is a desire for additional education and guidance regarding MAID.
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