tbuckley/cabot-search huggingface dataset:
INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma
Authors: Martin Van Den Bent, Marica Eoli, Juan Manuel Sepulveda, Marion Smits, Annemiek Walenkamp, Jean-Sebastian Frenel, Enrico Franceschi, Paul M Clement, Olivier Chinot, Filip De Vos, Nicolas Whenham, Paul Sanghera, Michael Weller, H J Dubbink, Pim French, Jim Looman, Jyotirmoy Dey, Scott Krause, Pete Ansell, Sarah Nuyens, Maarten Spruyt, Joana Brilhante, Corneel Coens, Thierry Gorlia, Vassilis Golfinopoulos
Journal: Neuro-Oncology (2019)

Abstract Background Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody–drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma. Methods Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival. Results Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3–4 adverse events in 25–30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93). Conclusion This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406)
Perceptions of prognosis and goals of care in patients receiving radiation therapy.
Authors: Claudia Sofia Roldan, Jie Jane Chen, Alexandra N. Nichipor, Tracy A. Balboni, Monica Shalini Krishnan, Anna Revette, Aileen B. Chen, Lauren Michelle Hertan
Journal: Journal of Clinical Oncology (2019)

30 Background: We aimed to gain insight into the experiences and perceptions of patients with advanced metastatic cancer surrounding palliative radiation therapy (RT). Methods: In-depth structured interviews were conducted from 9/2016 to 10/2018 with 17 patients with bone or lung metastases receiving their first course of palliative RT. Patient answers about understandings of goals of care and disease prognosis were recorded and analyzed through qualitative content analysis. Medical records were reviewed to obtain demographic and clinical data. Results: The median age of patients was 64 years (range: 21-82). The median survival from time of metastatic diagnosis was 17.6 months (range: 1-46). When asked about goals of RT, qualitative analysis revealed that half (53%) linked receiving palliative RT to improving their quality of life, however 35% believed RT would completely get rid of their tumor. Words that were used commonly throughout patient answers included alleviating pain (41%), cure (29%), and reducing tumor growth (24%). All patients reported they received their information about goals of care from their medical teams. When asked about prognosis, 53% said prognosis had been discussed with them, whereas 76.5% said they were interested in information about prognosis. When asked “What do you believe lies ahead?,” about half (47%) expressed uncertainty about the future, while others (41%) were focused on the next steps in treatment. In the patients interested in learning more about their prognosis, there was a strong preference for this information to come from their medical teams. Conclusions: More than half of patients accurately identified the goal of RT as improving their quality of life, however some patients believed that the palliative RT would cure their tumor. This highlights the ongoing gap in patient provider communication and the need for improvement in this area. Inaccurate perceptions of goals of treatment and prognosis may motivate some patients to pursue unnecessarily aggressive treatments, which could affect quality of life without improving survival. Referrals to radiation oncologists present a potential opportunity to reopen discussions on goals of care and prognosis to adjust patient expectations.
Comparison of Rural vs Urban Direct-to-Physician Commercial Promotion of Medications for Treating Opioid Use Disorder
Authors: Thuy Nguyen, Barbara Andraka-Christou, Kosali Simon, W. David Bradford
Journal: JAMA Network Open (2019)

In the United States, access to medications prescribed for opioid use disorder (OUD) is lower in rural counties than in urban counties. Considering the positive associations between direct-to-physician promotion of opiates and OUD medications and their prescribing rates, a study examining the association between pharmaceutical promotion of these medications and county-level rurality has merit.To assess whether rural counties received less pharmaceutical promotion of OUD medications compared with urban counties.This cross-sectional county-level study used all reported direct-to-physician pharmaceutical payments from manufacturers of medications prescribed for OUD from January 1, 2014, through December 31, 2017, as well as demographic and economic data at the county level from 3140 US counties. Logistic regression was used with year and state-level fixed effects to compare rural county and urban county odds of receiving any promotion of OUD medications. A negative binomial model was used with year and state-level fixed effects to compare the mean pharmaceutical payments per physician and per population in rural vs urban counties.A binary indicator for whether physicians in a county received any promotion related to OUD medications in a year. The second outcome was the value of promotion (eg, meals), with dollar amount of payments for each county by year. Counties were separated into metropolitan, micropolitan, and rural categories using the National Center for Health Statistics Urban-Rural Classification Scheme.Of 3140 US counties with 18 318 physicians to whom promotion of OUD medications was directed, 1166 (37.1%) were metropolitan (16 740 physicians [91.4%]), 641 (20.4%) were micropolitan (1049 physicians [5.7%]), and 1333 (42.5%) were rural (529 physicians [2.9%]). Compared with physicians in metropolitan counties, physicians in rural counties had reduced odds of receiving any promotion (adjusted odds ratio, 0.57; 95% CI, 0.44-0.74) and received lower payments (adjusted incidence rate ratio, 0.24; 95% CI, 0.17-0.34).The study findings suggest that promotion for OUD medications is less likely to occur in rural counties and that this difference in promotion of OUD medications may be associated with differential commercial costs and benefits of promotion in rural settings.
Peritumoral administration of DRibbles-pulsed antigen-presenting cells enhances the antitumor efficacy of anti-GITR and anti-PD-1 antibodies via an antigen presenting independent mechanism
Authors: Jaina M. Patel, Zhihua Cui, Zhi-Fa Wen, Catherine T. Dinh, Hong-Ming Hu
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> TNF receptor family agonists and checkpoint blockade combination therapies lead to minimal tumor clearance of poorly immunogenic tumors. Therefore, a need to enhance the efficacy of this combination therapy arises. Antigen-presenting cells (APCs) present antigen to T cells and steer the immune response through chemokine and cytokine secretion. DRibbles (DR) are tumor-derived autophagosomes containing tumor antigens and innate inflammatory adjuvants. <h3>Methods</h3> Using preclinical murine lung and pancreatic cancer models, we assessed the triple combination therapy of GITR agonist and PD-1 blocking antibodies with peritumoral injections of DRibbles-pulsed-bone marrow cells (BMCs), which consisted mainly of APCs, or CD103+ cross-presenting dendritic cells (DCs). Immune responses were assessed by flow cytometry. FTY720 was used to prevent T-cell egress from lymph nodes to assess lymph node involvement, and MHC-mismatched-BMCs were used to assess the necessity of antigen presentation by the peritumorally-injected DR-APCs. <h3>Results</h3> Tritherapy increased survival and cures in tumor-bearing mice compared to combined antibody therapy or peritumoral DR-BMCs alone. Peritumorally-injected BMCs remained within the tumor for at least 14 days and tritherapy efficacy was dependent on both CD4+ and CD8+ T cells. Although the overall percent of tumor-infiltrating T cells remained similar, tritherapy increased the ratio of effector CD4+ T cells-to-regulatory T cells, CD4+ T-cell cytokine production and proliferation, and CD8+ T-cell cytolytic activity in the tumor. Despite tritherapy-induced T-cell activation and cytolytic activity in lymph nodes, this T-cell activation was not required for tumor regression and enhanced survival. Replacement of DR-BMCs with DR-pulsed-DCs in the tritherapy led to similar antitumor effects, whereas replacement with DRibbles was less effective but delayed tumor growth. Interestingly, peritumoral administration of DR-pulsed MHC-mismatched-APCs in the tritherapy led to similar antitumor effects as MHC-matched-APCs, indicating that the observed enhanced antitumor effect was mediated independently of antigen presentation by the administered APCs. <h3>Conclusions</h3> Overall, these results demonstrate that peritumoral DR-pulsed-BMC/DC administration synergizes with GITR agonist and PD-1 blockade to locally modulate and sustain tumor effector T-cell responses independently of T cell priming and perhaps through innate inflammatory modulations mediated by the DRibbles adjuvant. We offer a unique approach to modify the tumor microenvironment to benefit T-cell-targeted immunotherapies.
DNA methylation aging clocks: challenges and recommendations
Authors: Christopher G. Bell, Robert Lowe, Peter D. Adams, Andrea A. Baccarelli, Stephan Beck, Jordana T. Bell, Brock C. Christensen, Vadim N. Gladyshev, Bastiaan T. Heijmans, Steve Horvath, Trey Ideker, Jean-Pierre J. Issa, Karl T. Kelsey, Riccardo E. Marioni, Wolf Reik, Caroline L. Relton, Leonard C. Schalkwyk, Andrew E. Teschendorff, Wolfgang Wagner, Kang Zhang, Vardhman K. Rakyan
Journal: Genome biology (2019)

Abstract Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.
Wild-type Cu/Zn-superoxide dismutase is misfolded in cerebrospinal fluid of sporadic amyotrophic lateral sclerosis
Authors: Eiichi Tokuda, Yo-ichi Takei, Shinji Ohara, Noriko Fujiwara, Isao Hozumi, Yoshiaki Furukawa
Journal: Molecular Neurodegeneration (2019)

Abstract Background A subset of familial forms of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene coding Cu/Zn-superoxide dismutase (SOD1). Mutant SOD1 proteins are susceptible to misfolding and abnormally accumulated in spinal cord, which is most severely affected in ALS. It, however, remains quite controversial whether misfolding of wild-type SOD1 is involved in more prevalent sporadic ALS (sALS) cases without SOD1 mutations. Methods Cerebrospinal fluid (CSF) from patients including sALS as well as several other neurodegenerative diseases and non-neurodegenerative diseases was examined with an immunoprecipitation assay and a sandwich ELISA using antibodies specifically recognizing misfolded SOD1. Results We found that wild-type SOD1 was misfolded in CSF from all sALS cases examined in this study. The misfolded SOD1 was also detected in CSF from a subset of Parkinson’s disease and progressive supranuclear palsy, albeit with smaller amounts than those in sALS. Furthermore, the CSF samples containing the misfolded SOD1 exhibited significant toxicity toward motor neuron-like NSC-34 cells, which was ameliorated by removal of the misfolded wild-type SOD1 with immunoprecipitation. Conclusions Taken together, we propose that misfolding of wild-type SOD1 in CSF is a common pathological process of ALS cases regardless of SOD1 mutations.
Supporting family caregivers: Needs beyond direct caregiving.
Authors: Diane E. Holland, Catherine E. Vanderboom, Joan M. Griffin, Ann Marie Dose, Ellen M. Wild, Cory J. Ingram, Jorge Loyo Lopez
Journal: Journal of Clinical Oncology (2019)

16 Background: Family caregivers have been shown to have their own unique challenges when caring for someone with advanced cancer. These challenges may be more pronounced among rural caregivers. We present early lessons regarding caregiver needs from an intervention study that provides teaching, guidance, and counseling to rural family caregivers of individuals who received palliative care in the hospital and transitioned home. Methods: A randomized clinical trial is underway to test the efficacy of a care model that focuses on supporting rural family caregivers’ medical needs, self-care, and direct caregiving needs. We have developed a nurse-led, technology-enhanced intervention for family caregivers delivered over 8 weeks after hospital discharge of those receiving palliative care consults. The intervention includes video and phone visits between a palliative care nurse and caregiver. Caregiver needs and nurse strategies are documented using a standardized terminology in an electronic datafile. Results: Preliminary data from 21 family caregivers of individuals with advanced cancer who completed the intervention to date indicate caregivers personally had an average of 2.2 chronic conditions (up to 10) and were taking an average of 3.14 (up to 11) medications. In addition to challenges providing direct care, caregivers reported difficulty managing stress or depression (7/21; 33.3%); issues related to grief (6/21; 28.5%); inadequate sleep and rest (6/21; 28.5%), low or no income or uninsured medical expenses (5/21; 23.8%); and interpersonal challenges within families and with friends (5/21, 23.8%). Conclusions: Preliminary data from our study suggest that assessing the caregiver’s individual needs related to well being and self-care as well as direct caregiving is imperative to delivering caregiver support services that can improve the ability of family caregivers to provide care for their loved ones with advanced cancer. Clinical trial information: NCT03339271.
microRNA overexpression in slow transit constipation leads to reduced Na<sub>V</sub>1.5 current and altered smooth muscle contractility
Authors: Amelia Mazzone, Peter R Strege, Simon J Gibbons, Constanza Alcaino, Vikram Joshi, Andrew J Haak, Daniel J Tschumperlin, Cheryl E Bernard, Robert R Cima, David W Larson, Heidi K Chua, Rondell P Graham, Mona El Refaey, Peter J Mohler, Yujiro Hayashi, Tamas Ordog, Stefan Calder, Peng Du, Gianrico Farrugia, Arthur Beyder
Journal: Gut (2019)

This study was designed to evaluate the roles of microRNAs (miRNAs) in slow transit constipation (STC).All human tissue samples were from the muscularis externa of the colon. Expression of 372 miRNAs was examined in a discovery cohort of four patients with STC versus three age/sex-matched controls by a quantitative PCR array. Upregulated miRNAs were examined by quantitative reverse transcription qPCR (RT-qPCR) in a validation cohort of seven patients with STC and age/sex-matched controls. The effect of a highly differentially expressed miRNA on a custom human smooth muscle cell line was examined in vitro by RT-qPCR, electrophysiology, traction force microscopy, and ex vivo by lentiviral transduction in rat muscularis externa organotypic cultures.The expression of 13 miRNAs was increased in STC samples. Of those miRNAs, four were predicted to target SCN5A, the gene that encodes the Na+ channel NaV1.5. The expression of SCN5A mRNA was decreased in STC samples. Let-7f significantly decreased Na+ current density in vitro in human smooth muscle cells. In rat muscularis externa organotypic cultures, overexpression of let-7f resulted in reduced frequency and amplitude of contraction.A small group of miRNAs is upregulated in STC, and many of these miRNAs target the SCN5A-encoded Na+ channel NaV1.5. Within this set, a novel NaV1.5 regulator, let-7f, resulted in decreased NaV1.5 expression, current density and reduced motility of GI smooth muscle. These results suggest NaV1.5 and miRNAs as novel diagnostic and potential therapeutic targets in STC.
Tumor-intrinsic signaling pathways: key roles in the regulation of the immunosuppressive tumor microenvironment
Authors: Li Yang, Aitian Li, Qingyang Lei, Yi Zhang
Journal: Journal of Hematology & Oncology (2019)

Abstract Immunotherapy is a currently popular treatment strategy for cancer patients. Although recent developments in cancer immunotherapy have had significant clinical impact, only a subset of patients exhibits clinical response. Therefore, understanding the molecular mechanisms of immunotherapy resistance is necessary. The mechanisms of immune escape appear to consist of two distinct tumor characteristics: a decrease in effective immunocyte infiltration and function and the accumulation of immunosuppressive cells in the tumor microenvironment. Several host-derived factors may also contribute to immune escape. Moreover, inter-patient heterogeneity predominantly results from differences in somatic mutations between cancers, which has led to the hypothesis that differential activation of specific tumor-intrinsic pathways may explain the phenomenon of immune exclusion in a subset of cancers. Increasing evidence has also shown that tumor-intrinsic signaling plays a key role in regulating the immunosuppressive tumor microenvironment and tumor immune escape. Therefore, understanding the mechanisms underlying immune avoidance mediated by tumor-intrinsic signaling may help identify new therapeutic targets for expanding the efficacy of cancer immunotherapies.
Codes, functions, and causes: A critique of Brette's conceptual analysis of coding
Authors: David Barack, Andrew Jaegle
Journal: Behavioral and Brain Sciences (2019)

Brette argues that coding as a concept is inappropriate for explanations of neurocognitive phenomena. Here, we argue that Brette's conceptual analysis mischaracterizes the structure of causal claims in coding and other forms of analysis-by-decomposition. We argue that analyses of this form are permissible and conceptually coherent and offer essential tools for building and developing models of neurocognitive systems like the brain.
Demographics of a Large International Population of Patients Affected by Leber’s Hereditary Optic Neuropathy
Authors: Lissa Poincenot, Alexander L. Pearson, Rustum Karanjia
Journal: Ophthalmology (2019)

To study the demographics of Leber's hereditary optic neuropathy (LHON) using a large international database of people affected by LHON.Cross-sectional study.One thousand five hundred seventeen people affected by LHON with a known pathogenic genetic mutation.Self-reported genetic and demographic data were collected. The data were de-identified and then analyzed.Leber's hereditary optic neuropathy mutation, gender, age at vision loss onset, and geographical region.The data showed that both females and males can experience symptom onset at any age. We found a 3:1 male-to-female ratio. Interestingly, at younger than 5 years and older than 45 years, the male-to-female ratio of those becoming affected was approximately 1:1. A dramatic peak in age at onset of vision loss was found among males between 14 and 26 years of age. Disease onset in females occurred across all age groups, without any comparable dramatic peak of onset age. This study found that 10% of individuals become affected with LHON after 50 years of age. According to the literature, we found that the m.11778, m.14484, and m.3460 mutations were the most common LHON point mutations in both males and females, with a similar age at onset distribution.This was the largest study of LHON demographics to date. It showed that women carrying an LHON mutation are at higher risk of losing vision than is generally expected. Unlike the traditional 5:1 male-to-female ratio commonly reported in the literature, we found a 3:1 male-to-female ratio. Earlier studies may have harbored an ascertainment bias of overemphasizing the confirmation of this being a disease of young men. However, our data suggest that LHON is a disease that affects both females and males of all ages. This should prompt physicians to conduct genetic testing for LHON in all patients who meet the clinical criteria, regardless of whether they fit the demographics traditionally associated with the disease. Counseling about LHON should be offered to all maternal bloodline relatives, females and males of all ages, because they are at risk of sudden-onset legal blindness.
Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRNAs
Authors: Claudia Chiodoni, Valeria Cancila, Tiziana A. Renzi, Milena Perrone, Andrea M. Tomirotti, Sabina Sangaletti, Laura Botti, Matteo Dugo, Matteo Milani, Lucia Bongiovanni, Maurizio Marrale, Claudio Tripodo, Mario P. Colombo
Journal: Cancer Research (2019)

The presence of a growing tumor establishes a chronic state of inflammation that acts locally and systemically. Bone marrow responds to stress signals by expanding myeloid cells endowed with immunosuppressive functions, further fostering tumor growth and dissemination. How early in transformation the cross-talk with the bone marrow begins and becomes detectable in blood is unknown. Here, gene expression profiling of the bone marrow along disease progression in a spontaneous model of mammary carcinogenesis demonstrates that transcriptional modifications in the hematopoietic compartment occurred as early as preinvasive disease stages. The transcriptional profile showed downregulation of adaptive immunity and induction of programs related to innate immunity and response to danger signals triggered by activating transcription factor 3. Transcriptional reprogramming was paralleled by the expansion of myeloid populations at the expense of erythroid and B lymphoid fractions. Hematopoietic changes were associated with modifications of the bone marrow stromal architecture through relocalization and increased density in the interstitial area of Nestin+ mesenchymal cells expressing CXCL12 and myeloid cells expressing CXCL12 receptor CXCR4. These early events were concomitant with deregulation of circulating miRNAs, which were predicted regulators of transcripts downregulated in the bone marrow and involved in lymphoid differentiation and activation. These data provide a link between sensing of peripheral cancer initiation by the bone marrow and hematopoietic adaptation to distant noxia through transcriptional rewiring toward innate/inflammatory response programs. SIGNIFICANCE: The bone marrow senses distant tissue transformation at premalignant/preinvasive stages, suggesting that circulating messengers, intercepted in the blood, could serve as early diagnostic markers.