Next-generation characterization of the Cancer Cell Line Encyclopedia.

Large panels of comprehensively characterized human cancer models, including the Cancer Cell Line Encyclopedia (CCLE), have provided a rigorous framework with which to study genetic variants, candidate targets, and small-molecule and biological therapeutics and to identify new marker-driven cancer dependencies. To improve our understanding of the molecular features that contribute to cancer phenotypes, including drug responses, here we have expanded the characterizations of cancer cell lines to include genetic, RNA splicing, DNA methylation, histone H3 modification, microRNA expression and reverse-phase protein array data for 1,072 cell lines from individuals of various lineages and ethnicities. Integration of these data with functional characterizations such as drug-sensitivity, short hairpin RNA knockdown and CRISPR-Cas9 knockout data reveals potential targets for cancer drugs and associated biomarkers. Together, this dataset and an accompanying public data portal provide a resource for the acceleration of cancer research using model cancer cell lines.

Temporal and Geographic Patterns of Documentation of Sexual Orientation and Gender Identity Keywords in Clinical Notes.

OBJECTIVE: Disclosure of sexual orientation and gender identity correlates with better outcomes, yet data may not be available in structured fields in electronic health record data. To gain greater insight into the care of sexual and gender-diverse patients in the Veterans Health Administration (VHA), we examined the documentation patterns of sexual orientation and gender identity through extraction and analyses of data contained in unstructured electronic health record clinical notes. METHODS: Salient terms were identified through authoritative vocabularies, the research team's expertise, and frequencies, and the use of consistency in VHA clinical notes. Term frequencies were extracted from VHA clinical notes recorded from 2000 to 2018. Temporal analyses assessed usage changes in normalized frequencies as compared with nonclinical use, relative growth rates, and geographic variations. RESULTS: Over time most terms increased in use, similar to Google ngram data, especially after the repeal of the "Don't Ask Don't Tell" military policy in 2010. For most terms, the usage adoption consistency also increased by the study's end. Aggregated use of all terms increased throughout the United States. CONCLUSION: Term usage trends may provide a view of evolving care in a temporal continuum of changing policy. These findings may be useful for policies and interventions geared toward sexual and gender-diverse individuals. Despite the lack of structured data, the documentation of sexual orientation and gender identity terms is increasing in clinical notes.

Predicting Gay Affirmative Practice from the Theory of Planned Behavior.

This study utilized the theory of planned behavior to examine individual intentions to engage in gay affirmative practice among aging-focused professionals (N = 83) in the Midwestern United States. Participants completed self-report measures of perceived agency norms and individual attitudes related to the treatment of gay men and lesbians, intentions to provide gay affirmative care, and perceived behavioral control. Attitudes, norms and perceived behavioral control were examined as predictors of intentions; attitudes of individual aging-service professionals emerged as the strongest predictor. Results indicated that affirmative attitudes within the agency may be important in predicting intentions to provide this type of care.

"We've been here all along:" The collective resilience of transgender and gender diverse U.S. service members.

Transgender and gender diverse (TGD) people in the United States face high rates of minority stressors, such as social rejection, homelessness, discrimination, and identity-based violence (James et al., 2016). Transgender and gender diverse service members are also exposed to unique military-specific stressors such as discriminatory military policies, combat stress, and military sexual trauma (Tucker et al., 2019). However, little is known about TGD troops' experiences of resilience when navigating stress and trauma exposure during their military service. A transaffirmative participatory research design and interpretative phenomenological analysis (IPA) analytic method were used to explore how troops made sense of their experiences of oppression and resilience. Researchers interviewed TGD service members (N = 40) about their gender identity and military service. Superordinate themes included: (a) understanding oppression; (b) survival strategies; (c) individual stress and resilience factors; and (d) collective resilience factors. Results suggest that both intrasubjective and intersubjective factors impacted how TGD troops made sense of their experiences of oppression and resilience. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Intimate partner violence among lesbian, gay, and bisexual veterans.

The present study describes intimate partner violence (IPV) perpetration and victimization alongside theoretically associated variables in a sample of lesbian, gay, and bisexual veterans. We conducted bivariate analyses (chi-square tests and independent t test) to examine whether the frequencies of IPV perpetration and victimization varied by demographic characteristics, military sexual trauma, alcohol use, and mental health symptoms. Out of the 69 lesbian, gay, and bisexual (LGB) veterans who answered the questions on IPV, 16 (23.2%) reported some form of IPV victimization in the past year, and 38 (55.1%) reported past-year perpetration. Among the 43 veterans who reported psychological IPV, roughly half (48.9%) reported bidirectional psychological IPV, 39.5% reported perpetration only, and 11.6% reported victimization only. LGB veterans who reported bidirectional psychological IPV in their relationships were younger and reported greater symptoms of posttraumatic stress disorder symptoms and depression. The results presented here call for universal screening of IPV perpetration and victimization to both accurately assess and ultimately intervene among all veterans. Inclusive interventions are needed for all genders and sexual orientations, specifically interventions that do not adhere to gendered assumptions of perpetrators and victims. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Relationship Between Pain and LGBT Status Among Veterans in Care in a Retrospective Cross-Sectional Cohort.

Background: Pain assessment is performed in many healthcare systems, such as the Veterans Health Administration, but prior studies have not assessed whether pain screening varies in sexual and gender minority populations that include individuals who identify as lesbian, gay, bisexual, and/or transgender (LGBT). Objective: The purpose of this study was to evaluate pain screening and reported pain of LGBT Veterans compared to non-LGBT Veterans. Methods: Using a retrospective cross-sectional cohort, data from the Corporate Data Warehouse, a national repository with clinical/administrative data, were analyzed. Veterans were classified as LGBT using natural language processing. We used a robust Poisson model to examine the association between LGBT status and binary outcomes of pain screening, any pain, and persistent pain within one year of entry in the cohort. All models were adjusted for demographics, mental health, substance use, musculoskeletal disorder(s), and number of clinic visits. Results: There were 1,149,486 Veterans (218,154 (19%) classified as LGBT) in our study. Among LGBT Veterans, 94% were screened for pain compared to 89% among those not classified as LGBT (non-LGBT) Veterans. In adjusted models, LGBT Veterans' probability of being screened for pain compared to non-LGBT Veterans was 2.5% higher (95% CI 2.3%, 2.6%); risk of any pain was 2.1% lower (95% CI 1.6%, 2.6%); and there was no significant difference between LGBT and non-LGBT Veterans in persistent pain (RR = 1.00, 95% CI (0.99, 1.01), p = 0.88). Conclusions: In a nationwide sample, LGBT Veterans were more likely to be screened for pain but had lower self-reported pain scores, though adjusted differences were small. It was notable that transgender and Black Veterans reported the greatest pain. Reasons for these findings require further investigation.

Identifying suicide documentation in clinical notes through zero-shot learning.

Background and Aims: In deep learning, a major difficulty in identifying suicidality and its risk factors in clinical notes is the lack of training samples given the small number of true positive instances among the number of patients screened. This paper describes a novel methodology that identifies suicidality in clinical notes by addressing this data sparsity issue through zero-shot learning. Our general aim was to develop a tool that leveraged zero-shot learning to effectively identify suicidality documentation in all types of clinical notes. Methods: US Veterans Affairs clinical notes served as data. The training data set label was determined using diagnostic codes of suicide attempt and self-harm. We used a base string associated with the target label of suicidality to provide auxiliary information by narrowing the positive training cases to those containing the base string. We trained a deep neural network by mapping the training documents' contents to a semantic space. For comparison, we trained another deep neural network using the identical training data set labels, and bag-of-words features. Results: The zero-shot learning model outperformed the baseline model in terms of area under the curve, sensitivity, specificity, and positive predictive value at multiple probability thresholds. In applying a 0.90 probability threshold, the methodology identified notes documenting suicidality but not associated with a relevant ICD-10-CM code, with 94% accuracy. Conclusion: This method can effectively identify suicidality without manual annotation.

Phosphate dysregulation via the XPR1-KIDINS220 protein complex is a therapeutic vulnerability in ovarian cancer.

Despite advances in precision medicine, the clinical prospects for patients with ovarian and uterine cancers have not substantially improved. Here, we analyzed genome-scale CRISPR-Cas9 loss-of-function screens across 851 human cancer cell lines and found that frequent overexpression of SLC34A2-encoding a phosphate importer-is correlated with sensitivity to loss of the phosphate exporter XPR1, both in vitro and in vivo. In patient-derived tumor samples, we observed frequent PAX8-dependent overexpression of SLC34A2, XPR1 copy number amplifications and XPR1 messenger RNA overexpression. Mechanistically, in SLC34A2-high cancer cell lines, genetic or pharmacologic inhibition of XPR1-dependent phosphate efflux leads to the toxic accumulation of intracellular phosphate. Finally, we show that XPR1 requires the novel partner protein KIDINS220 for proper cellular localization and activity, and that disruption of this protein complex results in acidic "vacuolar" structures preceding cell death. These data point to the XPR1-KIDINS220 complex and phosphate dysregulation as a therapeutic vulnerability in ovarian cancer.

"When the pain is so acute or if I think that I'm going to die": Health care seeking behaviors and experiences of transgender and gender diverse people in an urban area.

INTRODUCTION: Approximately 1.4 million transgender and gender diverse (TGD) adults in the United States have unique health and health care needs, including anatomy-driven cancer screening. This study explored the general healthcare experiences of TGD people in the Washington, DC area, and cancer screening experiences in particular. METHODS: Twenty-one TGD people were recruited through word of mouth and Lesbian Gay Bisexual Transgender Queer (LGBTQ)-specific community events. Participant interviews were conducted and recorded via WebEx (n = 20; one interview failed to record). Interviews were transcribed using Rev.com. Two coders conducted line-by-line coding for emergent themes in NVivo 12, developed a codebook by consensus, and refined the codebook throughout the coding process. Member checking was conducted to ensure credibility of findings. RESULTS: Three major themes served as parent nodes: health-care seeking behaviors, quality care, and TGD-specific health care experiences. Within these parent nodes there were 14 child nodes and 4 grand-child nodes. Subthemes for health care seeking behaviors included coverage and costs of care, convenience, trust/mistrust of provider, and provider recommendations for screening. Subthemes for quality of care included professionalism, clinical competence in transgender care, care coordination, provider communication, and patient self-advocacy. Overall, transgender men were less satisfied with care than transgender women. CONCLUSIONS: Results suggest a need for improved provider communication skills, including clear explanations of procedures and recommendations for appropriate screenings to TGD patients. Results also suggest a need for improved clinical knowledge and cultural competency. Respondents also wanted better care coordination and insurance navigation. Overall, these findings can inform health care improvements for TGD people.

Global computational alignment of tumor and cell line transcriptional profiles.

Cell lines are key tools for preclinical cancer research, but it remains unclear how well they represent patient tumor samples. Direct comparisons of tumor and cell line transcriptional profiles are complicated by several factors, including the variable presence of normal cells in tumor samples. We thus develop an unsupervised alignment method (Celligner) and apply it to integrate several large-scale cell line and tumor RNA-Seq datasets. Although our method aligns the majority of cell lines with tumor samples of the same cancer type, it also reveals large differences in tumor similarity across cell lines. Using this approach, we identify several hundred cell lines from diverse lineages that present a more mesenchymal and undifferentiated transcriptional state and that exhibit distinct chemical and genetic dependencies. Celligner could be used to guide the selection of cell lines that more closely resemble patient tumors and improve the clinical translation of insights gained from cell lines.

Examining Health Care Mobility of Transgender Veterans Across the Veterans Health Administration.

Purpose: Transgender veterans are overrepresented in the Veterans Health Administration (VHA) compared with in the general population. Utilization of multiple different health care systems, or health care mobility, can affect care coordination and potentially affect outcomes, either positively or negatively. This study examines whether transgender veterans are more or less health care mobile than nontransgender veterans and compares the patterns of geographic mobility in these groups. Methods: Using an established cohort (n = 5,414,109), we identified 2890 transgender veterans from VHA electronic health records from 2000 to 2012. We compared transgender and nontransgender veterans on sociodemographic, clinical, and health care system-level measures and conducted conditional logistic regression models of mobility. Results: Transgender veterans were more likely to be younger, White, homeless, have depressive disorders, post-traumatic stress disorder (PTSD), and hepatitis C. Transgender veterans were more likely to have been health care mobile (9.9%) than nontransgender veterans (5.2%) (unadjusted odds ratio = 2.02, 95% confidence interval = 1.73-2.36). In a multivariable model, transgender status, being separated/divorced, receiving care in less-complex facilities, and diagnoses of depression, PTSD, or hepatitis C were associated with more mobility, whereas older age was associated with less mobility. For the top three health care systems utilized, a larger proportion of transgender veterans visited a second health care system in a different state (56.2%) than nontransgender veterans (37.5%). Conclusions: Transgender veterans were more likely to be health care mobile and more likely to travel out of state for health care services. They were also more likely to have complex chronic health conditions that require multidisciplinary care.

A first-generation pediatric cancer dependency map.

Exciting therapeutic targets are emerging from CRISPR-based screens of high mutational-burden adult cancers. A key question, however, is whether functional genomic approaches will yield new targets in pediatric cancers, known for remarkably few mutations, which often encode proteins considered challenging drug targets. To address this, we created a first-generation pediatric cancer dependency map representing 13 pediatric solid and brain tumor types. Eighty-two pediatric cancer cell lines were subjected to genome-scale CRISPR-Cas9 loss-of-function screening to identify genes required for cell survival. In contrast to the finding that pediatric cancers harbor fewer somatic mutations, we found a similar complexity of genetic dependencies in pediatric cancer cell lines compared to that in adult models. Findings from the pediatric cancer dependency map provide preclinical support for ongoing precision medicine clinical trials. The vulnerabilities observed in pediatric cancers were often distinct from those in adult cancer, indicating that repurposing adult oncology drugs will be insufficient to address childhood cancers.

Development of a Transgender and Gender Nonconforming Language Self-Efficacy Scale for Social Service Providers Working With Older Adults.

There is consensus that providers who work with transgender and gender nonconforming (TGNC) older adults should use the language preferred by the older adult; however, assessment tools to document professional training efforts are lacking. This study presents data on a new TGNC Language Self-Efficacy Scale, using responses collected from employees and volunteers of area agencies on aging (AAA) across the United States (N = 155). Exploratory factor analysis supports a two-factor model: Interactions and Information subscales significantly correlated with knowledge of TGNC terminology, genderism and transphobia, gender role beliefs, beliefs about gender and gender identity, and attitudes toward lesbians and gay men. Future directions include additional measurement development work and replication of these findings outside of AAAs.

Reactions and Preferences for Training Among Area Agency on Aging Providers Working With Transgender and Gender Nonconforming Older Adults.

Transgender and gender nonconforming (TGNC) older adults face numerous barriers to healthy aging. These older adults may be less likely to seek out aging-focused services due to fear of discrimination and a lack of culturally competent services. There is a dearth of trainings for aging-focused professionals that would contribute to the development of affirming service environments for TGNC older adults. The current study explores providers' responses to a professional development training made available nationwide to staff and volunteers of area agencies on aging. Participants' (N = 155) reflections on what would be most helpful in their future work with TGNC older adults included requests for role-plays, instructions on creating more inclusive agency documents, increased contact with TGNC older adults, and managing discriminatory language in the workplace. Future directions include creating professional development opportunities that incorporate experiences with and exposure to both other aging-focused providers and TGNC elders.

Multiplexed single-cell transcriptional response profiling to define cancer vulnerabilities and therapeutic mechanism of action.

Assays to study cancer cell responses to pharmacologic or genetic perturbations are typically restricted to using simple phenotypic readouts such as proliferation rate. Information-rich assays, such as gene-expression profiling, have generally not permitted efficient profiling of a given perturbation across multiple cellular contexts. Here, we develop MIX-Seq, a method for multiplexed transcriptional profiling of post-perturbation responses across a mixture of samples with single-cell resolution, using SNP-based computational demultiplexing of single-cell RNA-sequencing data. We show that MIX-Seq can be used to profile responses to chemical or genetic perturbations across pools of 100 or more cancer cell lines. We combine it with Cell Hashing to further multiplex additional experimental conditions, such as post-treatment time points or drug doses. Analyzing the high-content readout of scRNA-seq reveals both shared and context-specific transcriptional response components that can identify drug mechanism of action and enable prediction of long-term cell viability from short-term transcriptional responses to treatment.

Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity.

Cultured cell lines are the workhorse of cancer research, but the extent to which they recapitulate the heterogeneity observed among malignant cells in tumors is unclear. Here we used multiplexed single-cell RNA-seq to profile 198 cancer cell lines from 22 cancer types. We identified 12 expression programs that are recurrently heterogeneous within multiple cancer cell lines. These programs are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial-mesenchymal transition and protein metabolism. Most of these programs recapitulate those recently identified as heterogeneous within human tumors. We prioritized specific cell lines as models of cellular heterogeneity and used them to study subpopulations of senescence-related cells, demonstrating their dynamics, regulation and unique drug sensitivities, which were predictive of clinical response. Our work describes the landscape of heterogeneity within diverse cancer cell lines and identifies recurrent patterns of heterogeneity that are shared between tumors and specific cell lines.