bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted tumor-derived cellular immunotherapy in advanced breast cancer patients induces initial immune responses and tumor regression.
Authors: Sunkari Vivekananda , Williams William , Peoples George , Graeve Sanne , Wiseman Charles , Lacher Markus
Published: July 2019

6

Background: SV-BR-1-GM is a GM-CSF secreting breast cancer cell line which also expresses HLA class I & II antigens. In a previous clinical trial, a partial response of widely metastatic breast cancer was seen in a patient who allele-matched SV-BR-1-GM at HLA-DRB3. Here we report regression of metastatic breast cancer and efficacy analysis with immunologic correlates in subjects of a Phase I/IIa trial of SV-BR-1-GM in patients with advanced breast cancer. Methods: 24 patients with recurrent and/or metastatic breast cancer refractory to standard therapies have been dosed with SV-BR-1-GM in a Phase I/IIa trial. Patients who have undergone at least one cycle of SV-BR-1-GM therapy were analyzed. Patients first received low-dose cyclophosphamide, then intradermal injection of SV-BR-1-GM (20-40x106 cells/four sites) with interferon-α injected into inoculation sites (10,000 IU/site) ~2 & 4 days subsequently. Immunologic responses were measured by delayed type hypersensitivity (DTH) after inoculation and IgG titers of antibodies against SV-BR-1 were measured in sera samples collected prior to and after the first dose of SV-BR-1-GM by flow cytometry. Results: 24 patients have been inoculated with SV-BR-1-GM cells with no unexpected adverse events. None of the patients exhibited immediate hypersensitivity to SV-BR-1. DTH response was recorded in 18 subjects till date, of these, 61% exhibited DTH to cell inoculations. The patient with the most marked DTH response, 01-002, also had a clinical response with regression of multiple lung metastases. Two other patients had evidence of tumor regression (tumor regression is matched SV-BR-1-GM at least at one HLA allele). Sera samples from 6 patients were evaluated and found to contain anti-SV-BR-1 antibodies. Conclusions: SV-BR-1-GM in this regimen appears to be safe and well-tolerated. Initial analysis of SV-BR-1-GM showed significant DTH and antibody responses. HLA matching improves the response rate and is being evaluated as a predictor of response. Clinical trial information: NCT03066947.
PD-1 blockade after PD-(L)1 inhibitors in head and neck cancer: Role of immunotherapy rechallenge.
Authors: Cabezas-Camarero Santiago , Pérez-Segura Pedro
Published: July 2019

69

Background: Immunotherapy (IO) has shown to improve survival in recurrent or metastatic (R/M) squamous cell cancer of the head and neck (SCCHN) with a better toxicity profile than chemotherapy (CT). An increased objective response rate (ORR) to CT has been shown after PD(L)1 blockade in SCCHN and other solid tumors. However, there are no data regarding the safety and efficacy of PD(L)1 rechallenge in SCCHN. Methods: Retrospective study of patients with R/M SCCHN treated with PD-1 inhibitors after an overt clinical and radiological progression to PD(L)1 blockade. Post-IO CT regimens, overall survival (OS), objective response rates (ORR) and percentage of tumor reduction (PTR) with post-IO CT and toxicity of IO rechallenge were recorded. Results: Eight patients treated between October 2016 and October 2018, were included. All patients received the first IO (1st-IO) treatment within clinical trials (anti-PDL1: 7; anti-PD1: 1), and received rescue cetuximab-based CT at progression (PD) (ERBITAX: 7; EXTREME: 1). ORR to post-IO 1st rescue CT (1RCT): 7 partial responses (PR), 1 stable disease (SD). PTR to 1RCT (median): 45% (range: 40-80). All second IO (2nd-IO) treatments consisted of PD1 inhibitors (nivolumab) and 6 received rescue CT (2RCT) at PD (ERBITAX: 1; wkCDDP-Cetuximab: 2; EXTREME: 3). Only 1of 6 evaluable patients responded to 2nd-IO with 5 PD as best response. Median duration of 2nd-IO: 3 months (range: 1-6). ORR to 2RCT (5 evaluable): 4 PR, 1 PD. PTR to 2RCT (median): 30% (range: 30-80). No G3/4 toxicities were detected during 2nd-IO. Conclusions: No new safety signals were encountered during PD-1 blockade in patients with SCCHN previously treated with PD-(L)1 inhibitors. First and second IO treatments associated with increased response rates to subsequent CT compared with historical data. Clinical trials should try to address the optimal treatment sequence in the IO era.
Regulatory T cells mediate resistance to radiotherapy in head and neck squamous cell carcinoma.
Authors: Oweida Ayman , Darragh Laurel , Bhatia Shilpa , Raben David , Heasley Lynn , Nemenoff Raphael , Clambey Eric , Karam Sana
Published: July 2019

70

Background: Head and neck tumors are highly enriched in regulatory T cells which dampen the response to radiotherapy by creating an immune-inhibitory microenvironment. We explored mechanisms of Treg infiltration and assessed their modulation by RT in murine models of HNSCC. Methods: Mechanisms of Treg infiltration were investigated in murine HNSCC tumors using whole genome sequencing and flow cytometry. Mice were treated with anti-CTLA-4, anti-CD-25 and/or anti-PD-L1 alone and in combination with RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T cell populations. Multiplex ELISA was performed for assessment of cytokines. RNA Sequencing was performed to interrogate mechanisms of response and resistance to treatment. Results: Treatment with anti-CD-25 concurrently with RT led to significant tumor growth delay, enhanced T cell cytotoxicity, decreased Tregs and improved survival. In contrast CTLA-4 blockade did not affect tumor growth or survival. Treg depletion induced an influx of CD8 and CD4 T cells when combined with RT. In addition, Treg depletion in combination with RT transformed myeloid populations decreasing M2 macrophages and MDSCs and increasing M1 macrophages. Mechanistically, tumors secrete CCL20, a potent Treg chemoattractant responsible for creating a highly immunuosuppressive tumor microenvironment and potentially responsible for treatment resistance. Conclusions: These data reveal a critical role for regulatory T cells in mediating resistance to RT. Targeted depletion of Tregs represents an important mechanism of sensitizing tumors to RT. Our data support the design of clinical trials integrating targeted Treg inhibitors in the standard of care for cancer patients receiving RT.
Clinical practice guidelines: Machine learning and natural language processing for automating the rapid identification and annotation of new evidence.
Authors: Whittington Craig , Feinman Todd , Zelman Lewis Sandra , Lieberman Greg , del Aguila Michael
Published: July 2019

77

Background: In February 2018, ASCO published a guideline on how clinicians should manage immune-related adverse events (irAEs) in cancer patients treated with immune checkpoint inhibitors (ICPis). Recommendations were based on informal consensus due to a lack of "high-quality" evidence. Our objective was to determine whether DOC Search, a cloud-based AI search engine, could be used to rapidly determine if any new evidence matches the inclusion criteria of the guideline. Methods: PubMed, ASCO abstracts, and 85 RSS feeds were queried within DOC Search to identify publications since the guideline search was last conducted. DOC Search automatically includes comprehensive synonym lists for the search terms entered, and annotates co-occurring characteristics, interventions and outcomes. Results: Between 11/1/2017 and 10/31/2018, 1178 published references were identified (85.7% from PubMed, 13.8% from ASCO, and 0.5% from official RSS feeds). Title/abstract screening of a sample of the most recent articles indicated that 44% were relevant, and of these, 8% specifically reported research on the management of irAEs. Through automated term indexing of search results, some of the most frequently reported terms were melanoma, corticosteroids, and colitis (Table). Conclusions: DOC Search employs robust ontology mapping—including UMLS, ASCO’s proprietary toxonomy, and more—which obviated the need for complex search strings. The machine learning and natural language processing technology provided real-time analysis and automated term indexing of search results, improving our understanding of the rapidly changing evidence landscape. This analysis met the objective to use DOC Search for rapid identification and review of new published evidence for an existing guideline.[Table: see text]
Assessing community physician ability to identify and manage immune-mediated adverse events (imAEs) through online continuing medical education (CME).
Authors: Pender Lori Keys , Caracio Richard
Published: July 2019

78

Background: Immune checkpoint inhibitors (ICIs) produce a wide variety of imAEs that differ dramatically from chemotherapy adverse events. This study assessed whether online CME activities improve the knowledge, competence, and confidence of community physicians across disciplines in guideline management of imAEs in patients receiving ICI therapy. Methods: Data from a series of online, CME-certified, educational activities consisting of case-based video discussion between expert faculty were analyzed to determine the efficacy of education among oncologists and other specialists regarding imAE recognition, management, and referral. Three multiple-choice knowledge/competence questions and 1 confidence question were presented to learners before and immediately after each activity. A pre-/post-assessment study design was used. Chi-square tests assessed educational effect for each activity. The activities launched online in March 2018. Data were collected through July 15, 2018. Results: Over 18,000 community physicians completed the assessment questions and were included in the study. Results are summarized by discipline in the table. Conclusions: This study demonstrates the success of online, case-based video discussions on improving knowledge, competence, and confidence of community-based specialists related to diagnosis and management of imAEs among patients who are receiving ICI-based therapy. [Table: see text]
A multispecialty approach to immuno-oncology education for community providers.
Authors: Perloff Tara , Dawkins Monique , Crews Jennie Robertson , Gregg Jeffrey P. , Abraham Ivo , Schwartzberg Lee S.
Published: July 2019

80

Background: The Association of Community Cancer Centers (ACCC) Immuno-Oncology Institute was developed in 2015 to prepare all members of the multidisciplinary cancer care team for the complex implementation of immuno-oncology in the community setting. Today, with more than 50 cancer immunotherapy indications and over 2,500 clinical trials with cancer immunotherapies, the challenges and issues related to recognizing and managing immune-related adverse events (irAEs) have grown even more complex for community practitioners. Methods: The ACCC Immuno-Oncology Institute assembled 4 working groups focused on addressing the diverse issues around the delivery and management of patients on cancer immunotherapies. The working groups were divided by 4 topics: staff training and education; multispecialty care coordination and communication; telemedicine; and big data. A detailed systemic review of the literature was conducted for each topic in the context of immuno-oncology, to determine the current landscape of information and available resources. The findings were then shared with the working group members and collaborative discussions ensued over 12 virtual committee meetings. The 19 working group members are diverse by discipline, including specialties such as emergency medicine, dermatology, primary care, survivorship, pathology, and academic researchers. Results: The ACCC Working Group Summit convened in September 2018 to develop innovative educational opportunities for community practitioners related to managing irAEs across the 4 topic areas. Eight unique action plans were developed by working group members. Conclusions: For each of the 4 key areas, working group members identified a list of opportunities that would improve how clinicians are managing irAEs for patients being treated with immunotherapy. It is critical for future educational interventions to encompass the multispecialty team perspective related to the management of irAEs.
Immune-related adverse events in advanced NSCLC treated with immunotherapy alone or concurrent chemotherapy and immunotherapy.
Authors: Melson John , Reed Daniel , Horton Bethany J. , Moore Margaret , Brown Jacqueline Theresa , Gentzler Ryan D. , Hall Richard Delmar
Published: July 2019

83

Background: Concurrent chemotherapy (CTX) with checkpoint inhibitors (CPI) has become a new standard of care for treatment naïve stage IV non-small cell lung cancer (NSCLC). Little is known about the timing and pattern of immune-related adverse events (irAEs) when CTX and CPI are combined. We sought to characterize irAEs and determine if combination CTX+CPI affects time to first irAE in comparison to patients (pts) receiving CPI alone. Methods: Advanced NSCLC patients who received at least one dose of a CPI at our institution between 2015 and 2018, either alone or with CTX, were identified. Retrospective review for occurrence of irAEs and clinical outcomes was performed. Proportional hazards models were used to assess time to first irAE for CPI vs CTX+CPI and overall survival (OS) for CPI alone. Results: 149 pts were identified. 112 pts received CPI alone and 37 received CTX+CPI. The proportion of pts with at least 1 irAE was higher in the combination therapy group than the monotherapy group (59% vs 34% of patients). Time to any grade first irAE was shorter with CTX+CPI vs CPI alone (6.0 m vs 36.7 m, HR 1.8, p = 0.0304). Among pts treated with CPI alone, OS was significantly longer with any irAE (38.0 m vs 11.4 m, HR 2.9, p = 0.0026). While there were more irAEs in the CTX+CPI cohort, the frequency of irAEs by organ system was similar to previous reports. Conclusions: For patients receiving CTX+CPI, there is an increased risk of irAEs and a significantly shorter time to first irAE occurrence compared to CPI alone. Among patients receiving CPI alone, the presence of irAE was associated with a 3-fold improvement in OS. Further analysis of OS for the CTX+CPI group is planned with additional follow-up. [Table: see text]
Identifying obstacles to optimal integration of cancer immunotherapies in the community setting.
Authors: Shivakumar Latha , Weldon Christine B. , Lucas Lorna , Perloff Tara
Published: July 2019

87

Background: The rapidly expanding indications for cancer immunotherapies pose a significant challenge to community clinicians to integrate this new class of agents into practice. Community cancer centers need guidance around the practical issues that must be addressed to implement immunotherapy safely and effectively to patients in their own communities. The Association of Community Cancer Centers (ACCC) initiated a quality improvement (QI) research study to assess the impact of comprehensive educational interventions targeting the multidisciplinary cancer care (MDCC) team on evidence-based integration of immunotherapies in the community setting. Methods: The QI study collected baseline data from two community cancer centers to identify barriers to optimal implementation of immunotherapies at each institution for the following metrics: co-morbidities in patients, immune-related adverse events (irAEs), laboratory tests, ER visits and hospitalizations, patient education materials, and immunotherapeutic adherence. Retrospective data was collected for 100 patients initiating immunotherapy between Dec 2017-April 2018. Results: Analysis of the data revealed that only 61% of the patients fully completed the immunotherapy treatment as planned. Eighty-one percent of patients were found to have 4 or more irAEs. On average patients were each diagnosed with more than 2 co-morbidities, including cardiac disease, diabetes, dyslipidemia, hypothyroidism, hypertension, and obesity. Using Fisher’s exact test to calculate two-tailed P values, we attempted to investigate a correlation between the number of co-morbidities to the lack of treatment adherence. We found a trend towards statistical significance between lack of treatment adherence and patients with two or more co-morbidities ( P value = 0.1256). Conclusions: Timely management of irAEs is crucial for the adherence to the immunotherapy regimen. The baseline data collected in our QI study revealed a trend towards the impact of the presence of two or more co-morbidities on treatment adherence. However, we did not find a statistically significant correlation between treatment adherence and the number of irAEs recorded in patients.
Publication statuses of clinical trials supporting immune checkpoint inhibitors recently approved by the United States Food and Drug Administration: A meta-epidemiological investigation.
Authors: Omae Kenji , Kataoka Yuki , Tsujimoto Yasushi , Tsutsumi Yusuke , Fukuhara Shunichi , Furukawa Toshi
Published: July 2019

89

Background: The low trial publication rate for drugs approved by the U.S. Food and Drug Administration (FDA) and the discrepancies between data submitted to the FDA and data found in published trials remain concerning. We investigated the publication statuses of trials of recently approved anticancer drugs documented by the FDA, especially immune checkpoint inhibitors (ICPis), to determine the discrepancies between data submitted to the FDA and those published. Methods: We identified all ICPis approved between 2011 (the year the first ICPi was approved by the FDA) and 2014 (selected to assure a follow-up of at least 3 years post-approval). We assessed the clinical trials for each drug indication and matched each trial with publications in the literature. The primary outcome was the publication status 2 years post-approval. We examined the association between time to publication and drug type using a multilevel Cox regression model, adjusted for clustering within drug indications and individual covariates. Results: Between 2011 and 2014, 36 anticancer drugs including 3 ICPis were newly approved by the FDA. Of 19 trials investigating the 3 ICPis, 11 (58%) were published within 2 years post-approval. We randomly selected 10 of the 33 remaining anticancer drugs; 68 of 101 trials investigating these drugs (67%) were published. Overall, the publication rate was 66% at 2 years post-approval with a median time to publication of 2.3 years. There was no significant difference in time to trial publication between ICPis and other anticancer drugs (adjusted hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.8–1.7; P = 0.55); however, non-ICPIs investigated specifically in randomized phase 2 or 3 trials were significantly more likely to be published earlier than ICPis (adjusted HR, 7.4; 95% CI, 1.8–29.5; P = 0.005). Conclusions: One in three trials of the newest anticancer drugs remained unpublished 2 years after FDA approval. The ICPi publication rate was similar to that of other anticancer drugs. (Protocol registration: UMIN000030475).
Emotional and cognitive disturbances in long-term melanoma survivors treated with ipilimumab.
Authors: Rogiers Anne , Awada Gil , Schwarze Julia , De Cremer Jennifer , Ben Salama Laila , Theuns Peter , Neyns Bart
Published: July 2019

97

Background: Immunotherapy with the CTLA-4 blocking mAb ipilimumab (IPI) has improved the long-term (>3 y) survival of a subpopulation (15-20%) of patients (pts) with metastatic melanoma. Little is known about the psychosocial outcome and the long-term effects of immune-related adverse events in these survivors. Methods: Pts with advanced melanoma (AJCC stages IIIC or IV) who were in complete remission for at least 2 y after treatment initiation, were eligible for this ongoing study. Data on health related quality of life (HRQOL), psychosocial outcome and neurocognitive function (NCF) were collected using 5 validated questionnaires, a semi-structured psychiatric examination (SSPE), and computer-based NCF testing. Results: Test results from 17 pts (5 F/12 M), median age 57 y (range 33-86) were analyzed. Median time since start of IPI was 5.5 y (range 2-7). Seven pts (41%) had elevated scores on the Cognitive Failure Questionnaire (CFQ). Nine pts (53%) had elevated scores on the Hospitalization Depression Scale (HADS) indicating moderate anxiety (4 pts), severe anxiety (2 pts), and moderate depression (3 pts). The SSPE revealed that all 10 pts who were professionally active at the time of diagnosis, had to change or stop work due to their illness. Nine pts (53%) reported persisting emotional distress: anxiety, existential problems, survivor guilt, post-traumatic stress symptoms or daily worrying about the disease. Three pts were referred for suicidal ideation in relation with their disease. Four pts (24%) developed hypophysitis and suffered from comorbid depression (1 pt), adjustment disorder (2 pt), or post-traumatic stress disorder related to the symptoms of hypopituitarism (1 pt). Five years after the incidence of hypophysitis, all pts had elevated scores on the Fatigue Severity Scale, the HADS; and 3 pts on the CFQ. All cases of skin toxicity (8 pts), hepatitis (2 pts), colitis (2 pts), sarcoidosis (2 pts), and Guillain-Barre syndrome (1 pt) resolved without long-term impact on HRQOL. Conclusions: A majority of melanoma survivors treated with IPI continues to suffer from emotional distress and cognitive problems impacting their HRQOL. Timely detection and providing adaptive care is imperative.
Stool donor qualification and collection from metastatic melanoma (MM) patients (pts) who have responded to checkpoint inhibitors (CPI) for manufacturing of fecal microbiota transplantation (FMT).
Authors: Burton Elizabeth M. , Glitza Isabella Claudia , Mahoney Jennifer , Wortman Jennifer , Aunis John , Litcofsky Kevin , Cook David , Jayaraman Lata , Ibrahim Ramy A. , LaVallee Theresa , Tawbi Hussein Abdul-Hassan , Wargo Jennifer A.
Published: July 2019

TPS146

Background: There have been remarkable improvements in responses rates (RR) and outcomes for pts with MM with the use of single agent CPIs. However, only 35% of pts respond to therapy and less than 10% achieve a complete response (CR). Although CPIs are approved for advanced MM treatment, there is a critical need to identify predictors of response and improve outcomes for these pts, the majority of whom will die from their disease. In an analysis of stool from MM pts prior to receiving CPI (anti-PD1), MD Anderson reported the association of higher alpha diversity and a favorable “Type I” signature with improved RR and prolonged PFS. Subsequently, FMT in mice via oral gavage using stool from CR MM pts responding to anti-PD1 with a favorable microbiome signature and treated with CPI demonstrated improved RR compared to FMT with stool from non-responders. Although FMT has been studied and has shown efficacy in other diseases, clinical safety and utility in pts with MM requires investigation. We hypothesize that FMT from MM pts with CR to CPIs and a Type I signature will be tolerable and demonstrate favorable outcomes. Methods: To initiate the testing of this hypothesis, we designed a study to identify and screen pts with MM who have responded to anti-PD1 for FMT stool donation. Pts must be in CR from MM for 6 months on 2 consecutive scans. Screening procedures per standard practice of approved INDs for FMT include health history questionnaires, physical exam, confirmation of current disease status, infectious disease screening, and an evaluation of the stool sample to ensure Type I signature requirements. Notably, there have been specific modifications made to this protocol in donor eligibility criteria, as accepted by the FDA, to accommodate this unique patient population. Participants will donate stool for up to 4 weeks and may be considered for subsequent donation cycles after undergoing re-screening. Stool will be manufactured into capsule form and used in the clinical trial. This study is open and active at three sites, MD Anderson, MGH, and DFCI.
Hafnium oxide nanoparticles activated by SABR in combination with PD-1 inhibitors for the treatment of patients with advanced HNSCC or NSCLC: A phase I/II trial.
Authors: Seiwert Tanguy Y. , Foster Corey Christian , Le Tourneau Christophe , Calugaru Valentin , Bonvalot Sylvie
Published: July 2019

TPS23

Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic resistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance. Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with significant superiority compared to RT alone. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infiltration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC. To date, no early dose limiting toxicities (DLTs) have been observed. Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts. The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s). [NCT02379845] [NCT01946867]. Clinical trial information: NCT03589339.
Human Trophoblast Differentiation Is Associated With Profound Gene Regulatory and Epigenetic Changes
Authors: Kwak Youn-Tae , Muralimanoharan Sribalasubashini , Gogate Aishwarya A , Mendelson Carole R
Published: July 2019

Defective placental implantation and vascularization with accompanying hypoxia contribute to preeclampsia (PE), a leading cause of maternal and neonatal morbidity and mortality. Genetic and epigenetic mechanisms underlying differentiation of proliferative cytotrophoblasts (CytTs) to multinucleated syncytiotrophoblast (SynT) are incompletely defined. The SynT performs key functions in nutrient and gas exchange, hormone production, and protection of the fetus from rejection by the maternal immune system. In this study, we used chromatin immunoprecipitation sequencing of midgestation human trophoblasts before CytT and after SynT differentiation in primary culture to analyze changes in binding of RNA polymerase II (Pol II) and of active and repressive histone marks during SynT differentiation. Our findings reveal that increased Pol II binding to promoters of a subset of genes during trophoblast differentiation was closely correlated with active histone marks. This gene set was enriched in those controlling immune response and immune modulation, including interferon-induced tetratricopeptide repeat and placenta-specific glycoprotein gene family members. By contrast, genes downregulated during SynT differentiation included proinflammatory transcription factors ERG1, cFOS, and cJUN, as well as members of the NR4A orphan nuclear receptor subfamily, NUR77, NURR1, and NOR1. Downregulation of proinflammatory transcription factors upon SynT differentiation was associated with decreased promoter enrichment of endogenous H3K27Ac and H3K9Ac and enhanced binding of H3K9me3 and histone deacetylase 1. However, promoter enrichment of H3K27me3 was low in both CytT and SynT and was not altered with changes in gene expression. These findings provide important insight into mechanisms underlying human trophoblast differentiation and may identify therapeutic targets for placental disorders, such as PE.
Dancing Queens
Authors: Shomali Mejdulene B.
Published: July 2019

This article analyzes two popular Golden Era belly-dance films, Sigara wa Kass (A Cigarette and a Glass, 1955) and Habibi al Asmar (My Dark Darling, 1958), through concepts of queer spectatorship, queer time and space, homoerotic triangulation, and queer containment. The analysis centers women, attends to women’s homoeroticism and nonnormative desires, and reads popular film as constituted by and constituting of mainstream conventions of gender and sexuality. It argues that mainstream belly-dance films made considerable space for homoerotic exchanges amid women. Golden Era belly-dance films reveal a rich gender and sexual diversity in Egyptian cultural production, rather than the Orientalist representation of an explicitly homophobic “traditional” Arab culture. In this sense, the article recovers women’s nonnormative and queer legacies within popular Egyptian texts. It does not insinuate homosexuality as inherent but instead locates possible Arab cultural engagements with women’s queerness that have been overlooked.
Parcas is the predominant Rab11-GEF for rhodopsin transport in Drosophila photoreceptors
Authors: Otsuka Yuna , Satoh Takunori , Nakayama Nozomi , Inaba Ryota , Yamashita Hitomi , Satoh Akiko K.
Published: July 2019

Rab11 is essential for polarized post-Golgi vesicle trafficking to photosensitive membrane rhabdomeres in Drosophila photoreceptors. Here, we found that Parcas (Pcs), recently shown to have guanine nucleotide exchange (GEF) activity toward Rab11, co-localizes with Rab11 on the trans-side of Golgi units and post-Golgi vesicles at the base of the rhabdomeres in pupal photoreceptors. Pcs fused with the electron micrography tag APEX2 localizes on 150–300 nm vesicles at the trans-side of Golgi units, which are presumably fly recycling endosomes. Loss of Pcs impairs Rab11 localization on the trans-side of Golgi units and induces the cytoplasmic accumulation of post-Golgi vesicles bearing rhabdomere proteins, as observed in Rab11 deficiency. In contrast, loss of Rab11-specific subunits of the TRAPPII complex, another known Rab11-GEF, does not cause any defects in eye development nor the transport of rhabdomere proteins; however, simultaneous loss of TRAPPII and Pcs results in severe defects in eye development. These results indicate that both TRAPPII and Pcs are required for eye development, but Pcs functions as the predominant Rab11-GEF for post-Golgi transport to photosensitive membrane rhabdomeres.
Feasibility of Two High-Intensity Interval Training Protocols in Cancer Survivors
Authors: SCHLÜTER KATHRIN , SCHNEIDER JUSTINE , SPRAVE TANJA , WISKEMANN JOACHIM , ROSENBERGER FRIEDERIKE
Published: July 2019

Purpose

High-intensity interval training (HIIT) is a time-efficient and promising tool for enhancing physical fitness. However, there is lack of research concerning safety and feasibility of HIIT in cancer survivors. Therefore, two different HIIT protocols were investigated in terms of safety, feasibility, and acute exercise responses.

Methods

Forty cancer survivors (20 breast and 20 prostate cancer survivors, 62.9 ± 9.2 yr, BMI 27.4 ± 3.9 kg·m−2, 6 to 52 wk after the end of primary therapy) completed a maximal cardiopulmonary exercise test and two HIIT protocols on a cycle ergometer: 10 × 1 min at peak power output (10 × 1) and 4 × 4 min at 85%–95% peak HR (4 × 4). Safety (adverse events), acute physiological responses (HR, blood lactate concentration) and acute psychological responses (RPE, enjoyment) were recorded.

Results

No major but three minor adverse events occurred. Ninety-five percent of participants were able to complete each HIIT protocol. Estimated energy expenditure (159 ± 15 vs 223 ± 45 kcal, P < 0.001), HR (128 ± 20 vs 139 ± 18 bpm; P < 0.001), blood lactate concentration (5.4 ± 1.0 vs 5.9 ± 1.9 mmol·L−1; P = 0.035), and RPE legs/breathing (13.8 ± 2.0/13.1 ± 2.0 vs 14.6 ± 2.1/14.3 ± 2.0; P = 0.038/0.003) were significantly higher in the 4 × 4. Enjoyment did not differ between protocols (P = 0.301).

Conclusions

The two HIIT protocols as single sessions appear safe and in the vast majority of breast and prostate cancer survivors after the end of primary therapy also feasible and enjoyable. The 4 × 4 elicited higher energy expenditure and higher cardio-circulatory and metabolic strain and might therefore be preferred if a high training stimulus is intended.
Precision neuroradiology: mapping the nodes and networks that link genes to behaviour
Authors: Sugrue Leo P. , Desikan Rahul S.
Published: July 2019

What is the future of neuroradiology in the era of precision medicine? As with any big change, this transformation in medicine presents both challenges and opportunities, and to flourish in this new environment we will have to adapt. It is difficult to predict exactly how neuroradiology will evolve in this shifting landscape, but there will be changes in both what we image and what we do. In terms of imaging, we will need to move beyond simply imaging brain anatomy and toward imaging function, both at the molecular and circuit level. In terms of what we do, we will need to move from the periphery of the clinical enterprise toward its center, with a new emphasis on integrating imaging with genetic and clinical data to form a comprehensive picture of the patient that can be used to direct further testing and care.

The payoff is that these changes will align neuroradiology with the emerging field of precision psychiatry, which promises to replace symptom-based diagnosis and trial-and-error treatment of psychiatric disorders with diagnoses based on quantifiable genetic, imaging, physiologic, and behavioural criteria and therapies targeted to the particular pathophysiology of individual patients. Here we review some of the recent developments in behavioural genetics and neuroscience that are laying the foundation for precision psychiatry. By no means comprehensive, our goal is to introduce some of the perspectives and techniques that are likely to be relevant to the precision neuroradiologist of the future.
Complexity metrics for IMRT and VMAT plans: a review of current literature and applications
Authors: Chiavassa Sophie , Bessieres Igor , Edouard Magali , Mathot Michel , Moignier Alexandra
Published: July 2019

Modulated radiotherapy with multileaf collimators is widely used to improve target conformity and normal tissue sparing. This introduced an additional degree of complexity, studied by multiple teams through different properties. Three categories of complexity metrics were considered in this review: fluence, deliverability and accuracy metrics. The first part of this review is dedicated to the inventory of these complexity metrics. Different applications of these metrics emerged. Influencing the optimizer by integrating complexity metrics into the cost function has been little explored and requires more investigations. In modern treatment planning system, it remains confined to MUs or treatment time limitation. A large majority of studies calculated metrics only for analysis, without plan modification. The main application was to streamline the patient specific quality assurance workload, investigating the capability of complexity metrics to predict patient specific quality assurance results. Additionally complexity metrics were used to analyze behaviour of TPS optimizer, compare TPS, operators and plan properties, and perform multicentre audit. Their potential was also explored in the context of adaptive radiotherapy and automation planning. The second part of the review gives an overview of these studies based on the complexity metrics.
Secondary cancer risk after whole-breast radiation therapy: field-in-field versus intensity modulated radiation therapy versus volumetric modulated arc therapy
Authors: Haciislamoglu Emel , Cinar Yunus , Gurcan Fatih , Canyilmaz Emine , Gungor Gorkem , Yoney Adnan
Published: July 2019

Objective:

In this study, we used the concept of organ-equivalent dose (OED) to evaluate the excess absolute risk (EAR) for secondary cancer in various organs after radiation treatment for breast cancer.

Methods:

Using CT data set of 12 patients, we generated three different whole-breast radiation treatment plans using 50 Gy in 2 Gy fractions: three-dimensional conformal radiotherapy with a field-in-field (FinF) technique, intensity modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT). The OEDs were calculated from differential dose–volume histograms on the basis of the “linear–exponential,” “plateau,” and “full mechanistic” dose–response models. Secondary cancer risks of the contralateral breast (CB), contralateral lung (CL), and ipsilateral lung (IL) were estimated and compared.

Results:

The lowest EARs for the CB, CL, and IL were achieved with FinF, which reduced the EARs by 77%, 88%, and 56% relative to those with IMRT, and by 77%, 84%, and 58% relative to those with VMAT, respectively. The secondary cancer risk for FinF was significantly lower than those of IMRT and VMAT. OED-based secondary cancer risks for CB and IL were similar when IMRT and VMAT were used, but the risk for CL was statistically lower when VMAT was used.

Conclusion:

The overall estimation of EAR indicated that the radiation-induced cancer risk of breast radiation therapy was lower with FinF than with IMRT and VMAT. Therefore, when secondary cancer risk is a major concern, FinF is considered to be the preferred treatment option in irradiation of whole-breast.

Advances in knowledge:

Secondary malignancy estimation after breast radiotherapy is becoming an important subject for comparative treatment planning.When secondary cancer risk a major concern, FinF technique is considered the preferred treatment option in whole breast patients.
A representação escrava em O Jornal do Pilar: a execução de Francisco e a crise do escravismo em Alagoas (1874-1876)
Authors: Castilho Fábio Francisco de Almeida
Published: July 2019

Este artigo problematiza o caso do escravo Francisco, condenado a morte pelo assassinato do capitão João Lima e esposa. O crime se tornou célebre pois Francisco foi o último condenado a pena capital no Brasil. Com efeito, toda a trajetória de Francisco foi documentada em O Jornal do Pilar. Nossa intenção é perscrutar as páginas desse periódico e acompanhar o julgamento do cativo. Para, partindo desse fato, tecer considerações sobre a representação da escravidão no mesmo jornal. Nossa intenção é entender a postura do editor, que se compadecia com o sofrimento dos escravizados, mas não abraçava a causa abolicionista. Desta forma, discutiremos a bibliografia sobre os crimes violentos cometidos por escravos e a legislação específica que previa a pena capital desde 1835. Por último, analisaremos o Censo de 1872 e os dados sobre a população escravizada, cruzando as informações qualitativas e quantitativas para compreender as transformações observadas no mundo do trabalho em Alagoas.
Sob um mercado imperfeito: notas de pesquisa sobre corpos, africanos e médicos no Rio de Janeiro Oitocentista.
Authors: Viana Iamara Da Silva , Gomes Fávio Dos Santos
Published: July 2019

Neste artigo abordamos a montagem de tópicas e narrativas sobre o corpo africano na primeira metade do século XIX no Rio de Janeiro. Consideramos as décadas de 30 a 50 – contexto de expansão econômica e entrada massiva de africanos no sudeste via a cidade do Rio de Janeiro— enquanto novos períodos na construção da ideia de africano (depois os crioulos e negros) e suas dimensões físicas e corporais. Analisamos – com base em anúncios de jornais, registros policiais e manuais agrícolas escritos por médicos -- as narrativas sobre o corpo entre vários sinais diacríticos, como importantes estruturas de identidades. Acionadas por mercadores, senhores, médicos, agentes policiais mas também os próprios escravizados.
Preventing complications and managing symptoms of CKD
Authors: Rainey Helen
Published: July 2019

Chronic kidney disease (CKD) is a common long-term condition frequently seen in people with diabetes, hypertension and in the elderly population. It rarely causes symptoms in its early stages and practice nurses have a key role in monitoring patients for signs of complications and supporting their treatment. It is important to discuss potential symptoms with patients and encourage lifestyle measures, as well as considering medication to treat them. Close working between primary care and renal services is essential to allow patients with worsening CKD to make timely decisions about their treatment and receive coordinated care closer to home.
Cattle Review
Authors: Barrett David C
Published: July 2019

Introduction:

This edition of Cattle Review considers three open access papers describing veterinary and farmer beliefs with respect to antimicrobial use, the concept of the ‘antibiotic footprint’, and the spread of bovine viral diarrhoea virus (BVDV).
Social factors influencing swallowing difficulties
Authors: Ager Kate , Little Lorena
Published: July 2019

Dysphagia often occurs as the result of another condition, usually a neurological one. It can be managed with the use of texture-modified foods and thickened drinks, but social factors play a part in food intake as well: Kate Ager and Lorena Little explain.
Community of practice: shared purpose, shared knowledge
Authors: Henry Claire , Cooper Marie , Hayes Anita
Published: July 2019

Working and learning together is the best way forward for professional development and to address industry-specific issues. Claire Henry, Marie Cooper and Anita Hayes describe their work in setting up community of practice networks and discuss three examples.
Upholding person-centred principles in the care plan
Authors: Ashurst Adrian
Published: July 2019

A personalised care plan is key to delivering good care to residents; therefore, care staff should be trained to carry out care assessments and draw up care plans. This month, Adrian Ashurst talks about how he trains carers to devise the care plan itself.
Competition and Cooperation between Financial Capital and Functional Capital in the Era of Financialization: A Theoretical and Empirical Analysis of US Financialization
Authors: Zhao Feng , Ma Shenxiao
Published: July 2019

The in-depth analysis of the relationship between financial capital and functional capital together with its changes is not only helpful for us to understand the inherent contradictions of the current capitalist economy, but it is also the key to clarify the inner logic of capitalist financialization. This article analyzes the logic and consequences of changes in the mutual relationship between financial capital and functional capital in capitalist reproduction and accumulation in a unified framework by researching on the contradictory relationship between financial capital and functional capital from the two traditional Marxist approaches, namely the Capital Circuit Approach and the Class Approach. The article holds that the cyclical relationship between interest rates and corporate profitability reflects the cooperation of financial capital and functional capital in capital circulation, and reveals the power confrontation of the two in the distribution of surplus value, which provides important clues to understanding the financialization of contemporary capitalism.
For Him, Art, Research, Creation and Politics Were the Same Thing: In
Memory of Paul Boccara
Authors: Herrmann Peter
Published: July 2019

Although the concept is a familiar one, it tends not to be fully accepted that
economics, and political economy in particular, is in fact a social science.
Focusing today on capital and commodities, economics does so in the light of
their being social relationships. Paul Boccara, on whose work this article
centres its attention, focused especially on the following concept: that social
relations—both in general, and in the form of market relations—are interwoven
with, and are expressions of, the rules of a general though historically
specific human nature. Furthermore, we find even in so-called free market
societies a complex apparatus that controls economic regulations, making them
possible as well as determining their thrust. The article will explain how
political life shaped Boccara personally, and how he in turn influenced the
development of political economy, basing it firmly on the methodology of Karl
Marx while applying it in new ways. The article also reflects on the need to
consider the current crisis as a crisis of civilisation, one whose economic core
is to be found in over-accumulation and devaluation on a global scale.
A Hybrid Detection Method Based on Peroxidase-mediated Signal Amplification and Click Chemistry for Highly Sensitive Background-free Immunofluorescent Staining
Authors: Antonov Stanislav A. , Novosadova Ekaterina V. , Kobylansky Andrey G. , Tarantul Vyacheslav Z. , Grivennikov Igor A.
Published: July 2019

The copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is increasingly used for detection of various macromolecules and metabolites in biological samples. Here, we present a detailed analysis of the CuAAC reaction conditions in cells and tissue sections. Using the optimized CuAAC conditions, we have devised a highly sensitive immunostaining technique, based on the tyramide signal amplification/catalyzed reporter deposition (TSA/CARD) method with a novel alkyne tyramide substrate. The described method offers improved detection threshold compared to conventional immunofluorescent staining and produces significantly lower non-specific background than TSA/CARD with fluorescent tyramides.
Nuclear families and radical feminism in 2000’s American TV series
Authors: Morin Céline
Published: July 2019

Representations of the nuclear family have undergone significant redefinitions on American television over the last fifteen years: recent 40-something heroines are examining the slow decline of the nuclear family, aided by the return of radical feminism. This article analyses this critical New Wave, which appeared on television with Desperate Housewives (2004–2012) and continues in dramas such as The Good Wife (2009–2016) and dramedies such as The Big C (2010–2013), Nurse Jackie (2009–2015) and Weeds (2005–2012). The complexity of television’s treatment of the explosion of the nuclear family is due to the fact that TV series marry a broken – shattered, even – dream with its residual forms: families are falling apart and yet the heroines are confronted with the pressing need to continue upholding its social representation. To escape traditional roles, women are according emotions a new place and witnessing a redistribution of skills in various forms. In place of the predetermined structure of the nuclear family, intimate public spheres are emerging, where women are establishing themselves as long-oppressed individuals on the road to an emancipation that can occur only in the context of a fundamental rethinking of the organization of the private sphere.
What Quality Metrics Should We Apply in Barrett's Esophagus?
Authors: Desai Madhav , Sharma Prateek
Published: July 2019

A GI Quality improvement consortium registry study published in this issue of The American Journal of Gastroenterology confirms the lack of adherence to surveillance intervals and guidelines in patients with Barrett's esophagus (BE). Given the widespread use of upper endoscopy for evaluation of patients with gastroesophageal reflux disease and surveillance of BE, the lack of well-defined standard criteria for performing a high quality upper endoscopy calls for the establishment of valid quality indicators in BE endoscopy. These quality metrics should be able to help define and rate endoscopist performance for screening, surveillance, and management of patients with BE. Neoplasia detection rate and Barrett's inspection time could serve as key benchmarks. The issue of nonadherence and overutilization of endoscopy can be addressed by continuing education, feedback, and incorporation of better healthcare models.