Law versus Action: How Five Cape Town Organizations Are Combating High Rates of Sexual Assault and the Failure of Progressive Sexual Offences Legislation

This Independent Study Project (ISP) seeks to understand the work various Cape Town organizations are doing to help survivors of sexual assault gain access to justice. Previous research finds that social norms defining masculinity as well as rape myths and stereotypes lead to the high levels of gender-based violence (GBV) in South Africa. This research led to my hypothesis that organizations fighting GBV would target these norms to help survivors access the justice system that so frequently ignores them. Eight organizations were contacted requesting an interview to discuss their work and two agreed to participate. Participants were asked to discuss the goals, successes, and failures of their organizations work. Three additional organizations are included in this report using information from annual reports published on their websites. From the information gleaned from these interviews and annual reports, this ISP finds that while targeting social norms is an objective of some organizations, many directly support survivors in court and other post-trauma processes and still others research and analyze policy and legislation to determine how the law can be changed to support survivors. This report concludes that while progressive legislation is in place, there is still policy that must be changed for survivors to truly be able to access justice. Thus, organizations focus on law as well as social norms within communities to create real change for survivors. This report suggests future research investigating intersectional approaches to organization work to understand how they address the unequal realities of rape survivors

The spatial and velocity bias of linear density peaks and proto-haloes in the Lambda cold dark matter cosmology

We use high resolution N-body simulations to investigate the Lagrangian bias of cold dark matter haloes within the LCDM cosmology. Our analysis focuses on "proto-haloes", which we identify in the simulation initial conditions with the subsets of particles belonging to individual redshift-zero haloes. We then calculate the number-density and velocity-divergence fields of proto-haloes and estimate their auto spectral densities. We also measure the corresponding cross spectral densities with the linear matter distribution. We use our results to test a Lagrangian-bias model presented by Desjacques and Sheth which is based on the assumption that haloes form out of local density maxima of a specific height. Our comparison validates the predicted functional form for the scale-dependence of the bias for both the density and velocity fields. We also show that the bias coefficients are accurately predicted for the velocity divergence. On the contrary, the theoretical values for the density bias parameters do not accurately match the numerical results as a function of halo mass. This is likely due to the simplistic assumptions that relate virialized haloes to density peaks of a given height in the model. We also detect appreciable stochasticity for the Lagrangian density bias, even on very large scales. These are not included in the model at leading order but correspond to higher order corrections.Comment: 10 pages, 4 figures. Matches version accepted for publication in MNRA

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

A plain language summary of results from the GARNET study of dostarlimab in patients with endometrial cancer

Endometrial cancer; Gynecologic cancer; ImmunotherapyCàncer d'endometri; Càncer ginecològic; ImmunoteràpiaCáncer de endometrio; Cáncer ginecológico; InmunoterapiaWhat is this summary about? Dostarlimab, also known by the brand name JEMPERLI, is a medicine that can be used to treat certain types of endometrial cancer. GARNET is an ongoing phase 1 clinical study that is testing the safety and side effects of dostarlimab and the best way to administer it to patients. The results presented in this summary are from a time point in the middle of the study. What were the results? The results from the GARNET study published in 2022 showed how well dostarlimab worked for people participating in the study. Dostarlimab was found to reduce the size of tumors in patients with certain types of endometrial cancer. The patients treated with dostarlimab had side effects that could be managed and few severe side effects. What do the results mean? The results of the GARNET study led to dostarlimab being approved to treat patients with certain types of endometrial cancer. For patients with advanced-stage endometrial cancer, or endometrial cancer that has come back after chemotherapy (recurrent), there are few treatment options. The results suggest that dostarlimab may provide long-term benefits for these patients.This study (NCT02715284) was funded by GSK. Trademarks are owned by or licensed to the GSK group of companies. Full author disclosure information can be found in the original article

Antitumor Activity and Safety of Dostarlimab Monotherapy in Patients With Mismatch Repair Deficient Solid Tumors: A Nonrandomized Controlled Trial

Antitumor activity; Monotherapy; Solid tumorsActividad antitumoral; Monoterapia; Tumores sólidosActivitat antitumoral; Monoteràpia; Tumors sòlidsImportance Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti–programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor. Objective To assess the antitumor activity and safety of dostarlimab in patients with advanced or recurrent dMMR solid tumors. Design, Setting, And Participants The GARNET trial was a phase 1, open-label, single-group, multicenter study that began enrolling May 8, 2017. Participants had advanced or recurrent dMMR and microsatellite instability–high (MSI-H) or polymerase epsilon (POLE)–altered solid tumors. The data cut for this interim analysis was from November 1, 2021, with median follow-up of 27.7 months. Interventions Patients received 500 mg of dostarlimab intravenously every 3 weeks for 4 doses, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. Main Outcomes and Measures The primary objective was to evaluate objective response rate and duration of response in patients with dMMR solid tumors by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The efficacy population included 327 patients (median [range] age, 63 [24-85] years; 235 [71.9%] female; 7 [2.1%] Asian, 6 [1.8%] Black, and 206 [63.0%] White patients), with 141 patients (43.1%) with dMMR endometrial cancer, 105 patients (32.1%) with dMMR colorectal cancer, and 81 patients (24.8%) with other dMMR tumor types. All patients had at least 1 previous line of therapy. Objective response rate assessed per blinded independent central review for dMMR solid tumors was 44.0% (95% CI, 38.6% to 49.6%). Median duration of response was not reached (range, ≥1.18 to ≥47.21 months); 72.2% of responders (104 of 144) had a response lasting 12 or more months. Median progression-free survival was 6.9 months (95% CI, 4.2 to 13.6 months); probability of progression-free survival at 24 months was 40.6% (95% CI, 35.0% to 46.1%). Median overall survival was not reached (95% CI, 31.6 months to not reached). The most frequent immune-related adverse events were hypothyroidism (25 [6.9%]), alanine aminotransferase increase (21 [5.8%]), and arthralgia (17 [4.7%]). No new safety concerns were identified. Conclusions And Relevance In this nonrandomized controlled trial, dostarlimab was a well-tolerated treatment option with rapid, robust, and durable antitumor activity in patients with diverse dMMR solid tumors. These findings suggest that dostarlimab provides meaningful long-term benefit in a population with high unmet need. Trial Registration ClinicalTrials.gov Identifier: NCT02715284This study was funded by GSK

Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET—a phase I, single-arm study

Immunotherapy; Programmed cell death 1 receptorImmunoteràpia; Receptor de mort cel·lular programada 1Inmunoterapia; Receptor de muerte celular programada 1Background Dostarlimab is a humanized monoclonal antibody that binds with high affinity to PD-1, resulting in inhibition of binding to PD-L1 and PD-L2. We report interim data from patients with endometrial cancer (EC) participating in a phase I trial of single-agent dostarlimab. Methods GARNET, an ongoing, single-arm, open-label, phase I trial of intravenous dostarlimab in advanced solid tumors, is being undertaken at 123 sites. Two cohorts of patients with EC were recruited: those with dMMR/MSI-H disease (cohort A1) and those with proficient/stable (MMRp/MSS) disease (cohort A2). Patients received dostarlimab 500 mg every 3 weeks for 4 cycles, then dostarlimab 1000 mg every 6 weeks until disease progression. The primary endpoints were objective response rate (ORR) and duration of response (DOR) per RECIST V.1.1, as assessed by blinded independent central review. Results Screening began on April 10, 2017, and 129 and 161 patients with advanced EC were enrolled in cohorts A1 and A2, respectively. The median follow-up duration was 16.3 months (IQR 9.5–22.1) for cohort A1 and 11.5 months (IQR 11.0–25.1) for cohort A2. In cohort A1, ORR was 43.5% (95% CI 34.0% to 53.4%) with 11 complete responses and 36 partial responses. In cohort A2, ORR was 14.1% (95% CI 9.1% to 20.6%) with three complete responses and 19 partial responses. Median DOR was not reached in either cohort. In the combined cohorts, the majority of treatment-related adverse events (TRAEs) were grade 1–2 (75.5%), most commonly fatigue (17.6%), diarrhea (13.8%), and nausea (13.8%). Grade≥3 TRAEs occurred in 16.6% of patients, and 5.5% discontinued dostarlimab because of TRAEs. No deaths were attributable to dostarlimab. Conclusion Dostarlimab demonstrated durable antitumor activity in both dMMR/MSI-H (ORR 43.5%) and MMRp/MSS EC (ORR 14.1%) with a manageable safety profile

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

Càncer d'ovaris; Biomarcadors tumoralsCáncer de ovarios; Biomarcadores tumoralesOvarian cancer; Tumour biomarkersARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity

Sloan Digital Sky Survey IV: mapping the Milky Way, nearby galaxies, and the distant universe

We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July