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The field of career development faces challenges in light of the significant ecological, economic, and political changes occurring globally. In response to these challenges, Guichard (2022) identified the need for new conceptual frameworks and interventions in the career field consistent with Arendt's (1958) broad perspective of action and the active life rather than simply making smooth transitions to occupations. In this article, contextual action theory is proposed as one alternative approach that addresses some of these issues regarding reconceptualizing career theory and practice. Specifically contextual action theory focuses on goal-directed action, provides a theoretical connection between action and career, incorporates social context, and provides a new framework for interventions. Specific approaches to career interventions and counseling are provided.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

A 70-year-old man was admitted to the hospital for planned chemotherapy for recently diagnosed CNS lymphoma. His medical history included follicular lymphoma (achieved remission 1 year prior with chemotherapy) and tonic-clonic seizure 1 month prior to admission, which led to his eventual biopsy-confirmed diagnosis of CNS lymphoma. Physical examination revealed temperature 36.4 °C, heart rate of 60 beats/min, BP of 160/81 mm Hg, and 98% oxygen saturation on room air. Neurologic condition, including mental status examination, was normal. His cardiac examination revealed regular rate and rhythm with normal first and second heart sounds without murmurs, rubs, or gallops. The remainder of the examination was unremarkable. Review of systems noted progressive and intermittent confusion prior to his seizure. He denied any shortness of breath, dyspnea on exertion, orthopnea, lower extremity edema, palpitations, or syncope. Laboratory data were unremarkable.

Heart failure with reduced ejection fraction (HFrEF) is associated with high mortality, highlighting an urgent need for new therapeutic strategies. As stress-activated cardiac signaling cascades converge on the nucleus to drive maladaptive gene programs, interdicting pathological transcription is a conceptually attractive approach for HFrEF therapy. Here, we demonstrate that CDK7/12/13 are critical regulators of transcription activation in the heart that can be pharmacologically inhibited to improve HFrEF. CDK7/12/13 inhibition using the first-in-class inhibitor THZ1 or RNAi blocks stress-induced transcription and pathologic hypertrophy in cultured rodent cardiomyocytes. THZ1 potently attenuates adverse cardiac remodeling and HFrEF pathogenesis in mice and blocks cardinal features of disease in human iPSC-derived cardiomyocytes. THZ1 suppresses Pol II enrichment at stress-transactivated cardiac genes and inhibits a specific pathologic gene program in the failing mouse heart. These data identify CDK7/12/13 as druggable regulators of cardiac gene transactivation during disease-related stress, suggesting that HFrEF features a critical dependency on transcription that can be therapeutically exploited.

BackgroundImmune checkpoint inhibitor (ICI) therapy has improved survivals with a favorable toxicity profile in a variety of cancer patients. We hypothesized that hospitalized cancer patients who have acute or chronic comorbidities may have suppressed immune systems and poor clinical outcomes to ICIs. The objective of this study was to explore clinical outcomes and predictive factors of hospitalized cancer patients who received ICI therapy at an NCI-designated Comprehensive Cancer Center.MethodsA retrospective review of electronic medical records was conducted for adult cancer patients who received an FDA-approved ICI during admission from 08/2016 to 01/2022. For each patient we extracted demographics, cancer histology, comorbidities, reasons for hospitalization, ICI administered, time from treatment to discharge, time from treatment to progression or death, and complete blood counts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. The 95% confidence interval for survival was calculated using the exact binomial distribution. Statistical significance was defined as 2-sided p4 in hospitalized patients was associated with poor survival outcomes.

Critical developmental “master transcription factors” (MTFs) can be subverted during tumorigenesis to control oncogenic transcriptional programs. Current approaches to identifying MTFs rely on ChIP-seq data, which is unavailable for many cancers. We developed the CaCTS (Cancer Core Transcription factor Specificity) algorithm to prioritize candidate MTFs using pan-cancer RNA sequencing data. CaCTS identified candidate MTFs across 34 tumor types and 140 subtypes including predictions for cancer types/subtypes for which MTFs are unknown, including e.g. PAX8, SOX17, and MECOM as candidates in ovarian cancer (OvCa). In OvCa cells, consistent with known MTF properties, these factors are required for viability, lie proximal to superenhancers, co-occupy regulatory elements globally, co-bind loci encoding OvCa biomarkers, and are sensitive to pharmacologic inhibition of transcription. Our predictions of MTFs, especially for tumor types with limited understanding of transcriptional drivers, pave the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

Oncogenic mutations and amplifications in the erythroblastic oncogene B (ERBB2), or human epidermal growth factor receptor 2 (HER2), have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer (NSCLC). Each genomic alteration occurs in 2-4% of NSCLC by next generation sequencing and is associated with constitutive HER2 activation. The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular domain. Unlike in breast and gastric cancer, HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted agents. High HER2 protein overexpression by immunohistochemistry (3+) only occurs in 2-4% of NSCLC. Until now HER2-targeted agents (such as afatinib and ado-trastuzumab emtansine) only demonstrate modest clinical activity in patients with HER2-mutant NSCLC. Retrospective studies show concern for inferior clinical benefit of immune checkpoint inhibitors in HER2-mutated NSCLC. Therefore, platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this patient population. In May 2020 trastuzumab deruxtecan (T-DXd) received the U.S. Food and Drug Administration breakthrough therapy designation for HER2-mutant metastatic NSCLC, and was added as an option for HER2-mutant NSCLC to the NCCN guidelines V1.2021. A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring HER2 exon 20 mutations was just opened for enrollment in September 2020. In this review, we highlight the current knowledge and perspectives on targeting-HER2 genomic alterations in NSCLC.

Within the context of an ongoing reform of the curriculum for English as a foreign language (EFL) in China, we present the implicit association test (IAT) as a new way to measure Chinese EFL teachers' implicit attitudes to a communicative language teaching (CLT) curriculum and to compare their attitudes to traditional language teaching (TLT) approaches. Our study is framed within the theory of teacher cognition -- what teachers know, think, and believe as active decision makers (Borg, 2003) -- and we propose the IAT as a new instrument for education researchers and policy makers. The IAT was used to discover the implicit attitudes of 24 Chinese EFL teachers, all graduates of the same teacher training institution in China, currently teaching at middle, high school, or college level in the same Chinese city. Results showed different degrees of implicit preference for CLT over TLT of the 24 teacher participants. We also found differences between implicit attitudes and explicit attitudes expressed by three teachers in interviews and we attributed those differences to the personal, institutional, and social contexts in which they were teaching. Results revealed that what teachers say is not necessarily what they think. By using the IAT, we have been able to measure implicit attitudes in a way that has never been done in teacher education study. We argue that such measures of teacher cognition are important for successfully implementing curriculum reform.

Problem and Objective: Transition to adulthood for young people with (IDD) is challenging for both youth and parents. Prospection, an important human adaptive tool and critical for independent living, involves constructing, encoding, and remembering the future. It may be jointly enacted between parents and young people as they discuss the future. This study identified and described evidence of prospective content in parent-youth conversations about the transition to adulthood. Method: This study involved the content analysis is of eight parent-youth conversations about this transition. Two mother-daughter, three father-daughter, and three mother-son dyads, representing a range of IDD diagnoses, provided 790 min of joint conversations and reflection on them. These conversations were examined for the following characteristics of prospection: simulation, reasoning about counterfactuals, constructing multiple possible futures, and episodic memory of the past. Findings: Among the four characteristics, simulation and episodic memory of the past were used most frequently and reasoning about counterfactuals the least. Giving advice and scaffolding were additional strategies that emerged from the data. Conclusion: Identifying how prospection may be fostered in joint parent-youth conversations provides a step toward future research.

To address the challenges of realising decent work, Contextual Action Theory (CAT) is proposed as an innovative, relational approach. Grounded on the notion of goal-directed actions that occur in daily life, many involving significant others, the approach provides a framework for a relationally oriented supportive counselling intervention that shifts the emphasis to one's relation with others as the way in which one constructs meaning in life and work. This intervention is illustrated with a case of young immigrants in pursuit of decent work as they transition to a new country. Strengths, limitations, and future directions of the approach are discussed.

Intestinal production of endocannabinoid and oleoylethanolamide (OEA) is impaired in high-fat diet/obese rodents, leading to reduced satiety. Such diets also alter the intestinal microbiome in association with enhanced intestinal permeability and inflammation; however, little is known of these effects in humans. This study aimed to 1) evaluate effects of lipid on plasma anandamide (AEA), 2-arachidonyl- sn-glycerol (2-AG), and OEA in humans; and 2) examine relationships to intestinal permeability, inflammation markers, and incretin hormone secretion. Twenty lean, 18 overweight, and 19 obese participants underwent intraduodenal Intralipid infusion (2 kcal/min) with collection of endoscopic duodenal biopsies and blood. Plasma AEA, 2-AG, and OEA (HPLC/tandem mass spectrometry), tumor necrosis factor-α (TNFα), glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP) (multiplex), and duodenal expression of occludin, zona-occludin-1 (ZO-1), intestinal-alkaline-phosphatase (IAP), and Toll-like receptor 4 (TLR4) (by RT-PCR) were assessed. Fasting plasma AEA was increased in obese compared with lean and overweight patients ( P < 0.05), with no effect of BMI group or ID lipid infusion on plasma 2-AG or OEA. Duodenal expression of IAP and ZO-1 was reduced in obese compared with lean ( P < 0.05), and these levels related negatively to plasma AEA ( P < 0.05). The iAUC for AEA was positively related to iAUC GIP ( r = 0.384, P = 0.005). Obese individuals have increased plasma AEA and decreased duodenal expression of ZO-1 and IAP compared with lean and overweight subjects. The relationships between plasma AEA with duodenal ZO-1, IAP, and GIP suggest that altered endocannabinoid signaling may contribute to changes in intestinal permeability, inflammation, and incretin release in human obesity.

The transition from elementary to middle or high school is an important experience common to most adolescents in North America. However, very little research has been conducted to understand the experiences of students with a disability status and the stakeholders involved in the transition. Clearly, there is a need to generate information that views the transition as a process between students and stakeholders that takes place over time. This investigation illustrates the utility of the action-project method for studying the transition to middle or high school. Three cases involving Canadian adolescents with different disabilities (learning, sensory/motor and emotional/behavioural) and their parents, as key stakeholders, are presented.

Adult stem cells must limit their rate of protein synthesis, but the underlying mechanisms remain largely unexplored. Differences in protein synthesis among hematopoietic stem cells (HSCs) and progenitor cells did not correlate with differences in proteasome activity, total RNA content, mRNA content, or cell division rate. However, adult HSCs had more hypophosphorylated eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and 4E-BP2 as compared with most other hematopoietic progenitors. Deficiency for 4E-BP1 and 4E-BP2 significantly increased global protein synthesis in HSCs, but not in other hematopoietic progenitors, and impaired their reconstituting activity, identifying a mechanism that promotes HSC maintenance by attenuating protein synthesis.

PurposeWhile methods for imaging tumor hypoxia with positron emission tomography (PET) have been developed, optimal methods for interpreting and utilizing these datasets in the clinic remain unclear. In this study, we analyzed hypoxia PET images of head and neck cancer patients and compared imaging metrics with human papilloma virus (HPV) status and clinical outcome.MethodsForty-one patients treated as part of a phase III trial of the hypoxic cytotoxin tirapazamine (TROG 02.02) were imaged with PET using fluorodeoxyglucose (FDG) and fluoroazomycin arabinoside (FAZA). FDG and FAZA PET images were interpreted qualitatively and quantitatively, and compared with tumor T stage, HPV status, and treatment outcome using multivariate statistics.ResultsPET signals in the tumor and lymph nodes exhibited significant intra- and inter-patient variability. The FAZA hypoxic volume demonstrated a significant correlation with tumor T stage. PET-hypoxic tumors treated with cisplatin exhibited significantly worse treatment outcomes relative to PET-oxic tumors or PET-hypoxic tumors treated with tirapazamine.ConclusionQuantitative analysis of FAZA PET yielded metrics that correlated with clinical T stage and were capable of stratifying patient outcome. These results encourage further development of this technology, with particular emphasis on establishment of robust quantitative methods.

Studying cancer metabolism gives insight into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a melanoma tumor suppressor that responds to nucleotide stress. HEXIM1 expression is low in melanoma. Its overexpression in a zebrafish melanoma model suppresses cancer formation, while its inactivation accelerates tumor onset in vivo. Knockdown of HEXIM1 rescues zebrafish neural crest defects and human melanoma proliferation defects that arise from nucleotide depletion. Under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to inhibit elongation at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic RNAs to bind to and be stabilized by HEXIM1. HEXIM1 plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals an important role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.

Health care researchers and practitioners are increasingly asked to work across disciplines (or, in keeping with the conference theme, "Between the Tides") to deal with complex health issues. But working with individuals from different fields is more challenging than it sounds. Working across disciplines can result in tension and miscommunications. Furthermore, to explore interactions among disciplines requires breaking down disciplinary boundaries and creating a common framework and language to define, analyze, and develop new approaches. This paper explores the benefits and challenges of teaching transdisciplinarity in a discipline-centred world, including a description of the journey of one post-graduate research training program as it strives to help student researchers break down disciplinary borders and develop a common framework to approach a particular health issue--in this case, the problem of substance misuse and addictions.

Eight dyads (N = 16) residing in Western Canada participated in this investigation of how young adults with intellectual and developmental disabilities (IDD) and their parents jointly construct, articulate, and act on goals pertinent to the young adults' transition to adulthood. Using the action-project method to collect and analyze conversations and video recall data, cases were grouped representing the ways goal-directed projects brought relationship (n = 4), planning (n = 3) or both (n = 1) to the foreground as joint projects. Resources internal to the dyad such as emotional resources, and external to the dyad, facilitated formulation and pursuit of projects. Lack of external supports and limited parental knowledge about IDD hindered joint project formulation.

Introduction: Parents have found the transition to adulthood for their sons or daughters with intellectual and/or developmental disabilities (IDD) particularly challenging. The literature has not examined how parents work together and with others in face of this transition nor has it highlighted parental goals in this process. This study used a perspective based on joint, goal-direct action to describe the projects that Canadian parents engaged in together and with others relative to this transition. Methods: Using the qualitative action-project method, joint projects between parents and with others were identified from their conversations and followed for 6 months. Findings: Three groups of projects were described: equipping the young adult for adult life, connecting for personal support and managing day-to-day while planning for the future. Conclusions: Parents act together and with others relative to the transition to adulthood of their young adult children with IDD. These projects are complex and differ in goals, steps, resources and emotional regulation and motivation.

We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.

Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.