Successful novel use of dupilumab for gastrointestinal involvement of idiopathic hypereosinophilic syndrome: case report and review of the literature.

Hypereosinophilic syndrome (HES) is characterized by blood and tissue hypereosinophilia leading to organ damage. Gastrointestinal involvement is the third most common manifestation. We present a patient with idiopathic HES with secondary eosinophilic esophagitis (EoE), gastritis, and enteritis, corticosteroids-dependent, azathioprine- and mepolizumab-refractory. The patient achieved clinical and histopathologic remission following dupilumab treatment. A 28 year-old female presented with chronic episodic nausea and emesis since childhood and initial diagnosis of primary eosinophilic gastrointestinal disease (EGID), improved with corticosteroids, refractory to azathioprine. She was found to have peripheral eosinophilia and multifactorial anemia, with iron, B12, and folate deficiencies. Esophageal, gastric, duodenal, and terminal ileum biopsies showed significant eosinophilic infiltrate. Bone marrow biopsy at age 31 confirmed HES diagnosis. By age 32, she became total parental nutrition (TPN)-dependent. She failed trials of benralizumab and mepolizumab [anti-interleukin (IL)-5 inhibitors], and cromolyn (mast-cell stabilizer). After developing new esophageal stricture, we initiated dupilumab (IL-4/13 inhibitor), recently FDA-approved for EoE. After 9 weeks, esophageal stricture, gut tissue eosinophilia, and prior intestinal ulcerations resolved. She ceased TPN and is tolerating a non-restricted diet, with complete symptom resolution. Our patient's complete remission with dupilumab shows promise for broadening its use in treating GI involvement in HES, along with primary EGIDs.

Promoter Methylation Leads to Hepatocyte Nuclear Factor 4A Loss and Pancreatic Cancer Aggressiveness.

Background and Aims: Decoding pancreatic ductal adenocarcinoma heterogeneity and the consequent therapeutic selection remains a challenge. We aimed to characterize epigenetically regulated pathways involved in pancreatic ductal adenocarcinoma progression. Methods: Global DNA methylation analysis in pancreatic cancer patient tissues and cell lines was performed to identify differentially methylated genes. Targeted bisulfite sequencing and in vitro methylation reporter assays were employed to investigate the direct link between site-specific methylation and transcriptional regulation. A series of in vitro loss-of-function and gain-of function studies and in vivo xenograft and the KPC (LSL-Kras G12D/+ ; LSL-Trp53 R172H/+ ; Pdx1-Cre) mouse models were used to assess pancreatic cancer cell properties. Gene and protein expression analyses were performed in 3 different cohorts of pancreatic cancer patients and correlated to clinicopathological parameters. Results: We identify Hepatocyte Nuclear Factor 4A (HNF4A) as a novel target of hypermethylation in pancreatic cancer and demonstrate that site-specific proximal promoter methylation drives HNF4A transcriptional repression. Expression analyses in patients indicate the methylation-associated suppression of HNF4A expression in pancreatic cancer tissues. In vitro and in vivo studies reveal that HNF4A is a novel tumor suppressor in pancreatic cancer, regulating cancer growth and aggressiveness. As evidenced in both the KPC mouse model and human pancreatic cancer tissues, HNF4A expression declines significantly in the early stages of the disease. Most importantly, HNF4 loss correlates with poor overall patient survival. Conclusion: HNF4A silencing, mediated by promoter DNA methylation, drives pancreatic cancer development and aggressiveness leading to poor patient survival.

Oncogenic pathway signatures predict the risk of progression and recurrence in well-differentiated pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are genomically diverse tumors. The management of newly diagnosed well-differentiated pNETs is limited by a lack of sensitivity of existing biomarkers for prognostication. Our goal was to investigate the potential utility of genetic markers as a predictor of progression-free survival (PFS) and recurrence-free survival (RFS). METHODS: Whole-exome sequencing of resected well-differentiated, low and intermediate-grade (G1 and G2) pNETs and normal adjacent tissue from patients who underwent resection from 2005 to 2015 was performed. Genetic alterations were classified using pan-genomic and oncogenic pathway classifications. Additional samples with genetic and clinicopathologic data available were obtained from the publicly available International Cancer Genome Consortium (ICGC) database and included in the analysis. The prognostic relevance of these genomic signatures on PFS and RFS was analyzed. RESULTS: Thirty-one patients who underwent resection for pNET were identified. Genomic analysis of mutational, copy number, cytogenetic, and complex phenomena revealed similar patterns to prior studies of pNETs with relatively few somatic gene mutations but numerous instances of copy number changes. Analysis of genomic and clinicopathologic outcomes using the combined data from our study as well as the ICGC pNET cohort (n = 124 patients) revealed that the recurrent pattern of whole chromosome loss (RPCL) and metastatic disease were independently associated with disease progression. When evaluating patients with local disease at the time of resection, RPCL and alterations in the TGFß oncogenic pathway were independently associated with the risk of recurrence. CONCLUSIONS: Well-differentiated pNETs are genomically diverse tumors. Pathway signatures may be prognostic for predicting disease progression and recurrence.

Perceived Change Processes in Dialectical Behaviour Therapy From the Perspective of Clients With a Diagnosis or Traits of Borderline Personality Disorder: A Systematic Literature Review.

PURPOSE: To synthesise qualitative research on individuals diagnosed with (or reportedly showing traits of) borderline pattern personality disorder who underwent dialectical behaviour therapy, aiming to comprehend their perceptions of change processes and the therapy's effects. METHOD: A comprehensive literature search was conducted across multiple online databases and grey literature sources. Papers were quality appraised using an adapted version of the Critical Appraisal Skills Programme tool. A metaethnographic approach was employed during the synthesis. RESULTS: Eleven studies met criteria for inclusion in the review. The main themes identified through the synthesis process were the impact of DBT, the supportive structure and the 1:1 therapy component. CONCLUSIONS: The synthesis uncovered the importance of various processes within DBT that patients perceived as active ingredients for their change. Many of these processes aligned with proposed theoretical processes of change and quantitative research on DBT's effectiveness.

A Systematic Quality Review of Single-Case Experimental Designs Using Acceptance and Commitment Therapy in Adult Clinical Populations.

Recent publications within Contextual Behavioral Science provided a rationale for the expansion of intervention efficacy research using methods that capture idiographic factors and processes. We conducted a systematic review of the use and quality of single-case experimental designs (SCED) within the Acceptance and Commitment Therapy (ACT) literature in adult clinical populations. The systematic review was conducted according to PRISMA guidelines and the databases CINAHL, MEDLINE, PsycINFO, PsycArticles and OpenGrey were searched for peer-reviewed articles. Further studies were sought through review of reference lists of all full text studies. Studies were assessed against What Works Clearinghouse (WWC) single-case design standards. Twenty-six studies met eligibility criteria and were conducted within research teams all implementing multiple-baseline designs. Twenty-four studies did not meet WWC standards with most failing to ensure a degree of concurrence across participants. The extent of randomisation methods was also captured. The review highlights the sparsity of SCEDs within ACT literature in clinical populations and current methodological practices. Limitations of the review and implications for future research are discussed.

Factors influencing migration of short-finned eels (Anguilla australis) over 3 years from a wetland system, Lake Condah, south-east Australia, downstream to the sea.

Anguillid eel populations are under threat globally. A particularly vulnerable life-cycle stage is the migration of mature adult eels downstream from freshwater habitats through estuaries into the sea to spawn. This study investigated the factors associated with downstream migration of the short-finned eel Anguilla australis (Richardson 1841) from a coastal wetland (Lake Condah) in south-east Australia, using acoustic telemetry. Migration was associated with time of the year, higher water level and river flows, decreasing water temperature, and darker moon phases. Larger individuals and those in better condition were more likely to migrate from the wetland. Downstream migration peaked in spring, in contrast to the typical autumn migration period for other temperate anguillids. Variable responses, in comparison to other studies, highlight how migration cues may not be universal. In south-east Australia, short-finned eels may have evolved to migrate in multiple phases by first migrating to the estuary during typical seasonal spring flow pulses (e.g., to avoid being stranded in upland reaches during dry summer periods) and then migrating into the ocean in autumn. More research is needed to unravel these processes and causes, especially considering that the relationship between migration and hydrology may be complex and confounded (e.g., by human-induced disruptions to migratory pathways).

Cell polarity proteins promote macropinocytosis in response to metabolic stress.

Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι as novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for cell polarity proteins in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

Functional neurological disorder: A qualitative study exploring individuals' experiences of psychological services.

OBJECTIVES: Individuals with a diagnosis of FND report experiencing stigma in medical settings, however, there is a paucity of research exploring their experiences in psychological services. The aim of this research was to explore experiences of accessing UK psychological services, from the perspective of those with FND. METHODS: This study utilised a qualitative approach with data collected from semi-structured interviews (n = 15) and analysed using reflexive thematic analysis. RESULTS: One superordinate theme, 'the stigmatised self within the therapeutic relationship', and five interrelated subthemes were identified: 'internalised stigma and self-doubt', 'selective disclosure to professionals', 'perceptions of psychological explanations', 'having to educate the professionals' and 'attunement and trust within the therapeutic relationship'. Positive therapeutic relationships were perceived to mitigate the impact of these perceived barriers. The conceptualisation of FND and the perception of how this was responded to by services and professionals was a central tenet throughout the related themes. CONCLUSIONS: Intra-personal, interpersonal and organisational stigma impact access and engagement to psychological treatment. The findings of this study highlight the need for increased training provision for practitioners with a focus on actively challenging FND stigma within services at both an individual and systemic level.

Group psychological intervention for emotional distress in haematopoietic stem cell transplantation: A feasibility randomised clinical trial.

PURPOSE: Haematopoietic stem cell transplantation (HSCT) is an intensive procedure associated with elevated psychological distress, particularly during the initial stages. Based on self-regulatory theory, a prophylactic group intervention was developed to mitigate this distress by targeting perceptions of HSCT and coping. This study evaluated the feasibility of delivering the intervention and of conducting a randomised clinical trial to assess efficacy. METHODS: Adults from consecutive referrals at two transplant centres were randomised to the intervention or to treatment as usual at each site. Psychological distress (primary outcome), HSCT perceptions, and coping were assessed at baseline, on transplant day, and two and four weeks after transplantation. RESULTS: Of 99 eligible patients, 45 consented. Main barriers to consent were insufficient time prior to transplantation, competing priorities, being unwell, and travel distance. Of 21 participants randomised to the intervention, five attended. Main barriers to attendance included insufficient time prior to transplantation and having competing priorities. Groups could not be held sufficiently frequently to enable attendance prior to transplantation, as randomising participants to the control group limited accrual. Anxiety peaked two weeks following transplantation. Depression increased throughout the acute phase. Clinical levels of distress were observed in 42% of patients during HSCT. Intervention effects were small but sample sizes for a full trial appeared feasible. CONCLUSIONS: Multimodal prehabilitation is required but there are specific barriers to delivering a group-based intervention and conducting a trial. Group prehabilitation requires customisation and better integration with routine care, such as patient screening, personalisation, and options for remote delivery.

Fibroblast Activation Protein Expression in Sarcomas.

Objectives: Fibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas. Methods: Available tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, <25%, 25-75%; >75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168). Results: The majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression. Conclusion: The majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.

FAPI PET Signal in Hibernoma Reflects FAP Expression in Tumor Vasculature Cells.

ABSTRACT: A 43-year-old man with a growing mass in the right groin, concerned for liposarcoma, underwent MRI and 68 Ga-fibroblast activation protein inhibitor (FAPI)-46 PET/CT before surgery. Fibroblast activation protein inhibitor PET/CT demonstrated increased uptake (SUV max , 3.2) predominantly in the solid portion, where MRI showed gadolinium enhancement. The patient subsequently underwent surgery and was diagnosed with hibernoma. The immunohistochemistry of the tumor revealed the fibroblast activation protein expression in the fibrovascular network and myofibroblastic cells of the tumor. This case suggests that the FAPI uptake can be affected by the vascular cells, and thus, a careful interpretation of the FAPI PET signal may be needed.

Construction of a radiogenomic association map of pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) persists as a malignancy with high morbidity and mortality that can benefit from new means to characterize and detect these tumors, such as radiogenomics. In order to address this gap in the literature, constructed a transcriptomic-CT radiogenomic (RG) map for PDAC. METHODS: In this Institutional Review Board approved study, a cohort of subjects (n = 50) with gene expression profile data paired with histopathologically confirmed resectable or borderline resectable PDAC were identified. Studies with pre-operative contrast-enhanced CT images were independently assessed for a set of 88 predefined imaging features. Microarray gene expression profiling was then carried out on the histopathologically confirmed pancreatic adenocarcinomas and gene networks were constructed using Weighted Gene Correlation Network Analysis (WCGNA) (n = 37). Data were analyzed with bioinformatics analyses, multivariate regression-based methods, and Kaplan-Meier survival analyses. RESULTS: Survival analyses identified multiple features of interest that were significantly associated with overall survival, including Tumor Height (P = 0.014), Tumor Contour (P = 0.033), Tumor-stroma Interface (P = 0.014), and the Tumor Enhancement Ratio (P = 0.047). Gene networks for these imaging features were then constructed using WCGNA and further annotated according to the Gene Ontology (GO) annotation framework for a biologically coherent interpretation of the imaging trait-associated gene networks, ultimately resulting in a PDAC RG CT-transcriptome map composed of 3 stage-independent imaging traits enriched in metabolic processes, telomerase activity, and podosome assembly (P < 0.05). CONCLUSIONS: A CT-transcriptomic RG map for PDAC composed of semantic and quantitative traits with associated biology processes predictive of overall survival, was constructed, that serves as a reference for further mechanistic studies for non-invasive phenotyping of pancreatic tumors.

Mental health mobile application self-help for adolescents exhibiting psychological distress: A single case experimental design.

OBJECTIVES: The present demand for child and adolescent mental health services exceeds the capacity for service provision. Greater research is required to understand the utility of accessible self-help interventions, such as mobile apps. This study sought to investigate whether use of a mental health app, underpinned by CBT, led to changes in psychological distress amongst adolescents. Mechanisms of change were examined, specifically whether changes are attributable to cognitive strategies. DESIGN: This study utilised a multiple-baseline single-case experimental design, tracking variables across baseline and intervention phases. Surveys assessing participant experience were also administered. METHODS: Five participants with moderate-to-severe levels of psychological distress engaged with a CBT-based app over five weeks. Participants were recruited from both a well-being service and the general population. Supplementary weekly calls to participants offered clarification of app content. RESULTS: A small overall effect of the intervention of psychological distress was evident; however, outcomes were dependent on the analysis conducted. The intervention appeared to promote an increase in use of adaptive cognitive strategies but not negative thinking styles. The CBT app did not promote changes in participant well-being. Participant feedback highlighted practical challenges of utilising the app. CONCLUSIONS: The clinical benefits of app-based CBT were small, and a range of barriers to engagement were recognised. While further research is required, caution should be exercised in the interpretation of studies reporting on app effectiveness.

Specificity and sensitivity of the social communication questionnaire lifetime screening tool for autism spectrum disorder in a UK CAMHS service.

INTRODUCTION: The Social Communication Questionnaire is used to identify children and young people (CYP) who may require formal ASD assessment. However, there is a paucity of research on its utility in Children and Adolescent Mental Health Services. This evaluation aimed to determine the sensitivity and specificity of the Social Communication Questionnaire (SCQ) in a UK, Midlands CAMHS service. METHOD: Forty young people (mean age 13.75 years) were screened using the caregiver reported SCQ before completing 'gold standard' assessment. RESULTS: The SCQ had a sensitivity of 80% and a specificity of 25.7%. ROC curve analysis indicated low diagnostic accuracy. Differences in predictive accuracy of SCQ and diagnostic standard were statistically significant (p < 0.0001). CONCLUSION: This evaluation builds on previous research suggesting that the SCQ may not be an efficient screening tool in CAMHS settings.

Mental Health Recovery Using the Individual Recovery Outcomes Counter (I.ROC) in a Community Rehabilitation Team: A Service Evaluation.

There are many definitions of recovery in mental health. Community Rehabilitation Teams (CRTs) aim to support the mental health recovery of people. The Individual Recovery Outcomes Counter (I.ROC) is a way to measure recovery. To determine if being supported by a CRT helps mental health recovery for people transitioning from an inpatient service to the community. Individual reliable and clinically meaningful change indices were calculated for a total of 31 people. Two I.ROC questionnaires were completed by 31 people. Of these 31 people, 14 people had three completed I.ROC questionnaires. Of the 31 people, 17 showed a positive reliable change and three people made a clinically meaningful change. Of the 14 people, one had a positive reliable change, two had a negative reliable change, and no-one had a clinically meaningful change. The I.ROC shows the CRT to successfully support recovery in people with mental health difficulties.

Proteomes of Extracellular Vesicles From Pancreatic Cancer Cells and Cancer-Associated Fibroblasts.

OBJECTIVES: Extracellular vesicles (EVs) are lipid bound vesicles secreted by cells into the extracellular environment. Studies have implicated EVs in cell proliferation, epithelial-mesenchymal transition, metastasis, angiogenesis, and mediating the interaction of tumor cells and microenvironment. A systematic characterization of EVs from pancreatic cancer cells and cancer-associated fibroblasts (CAFs) would be valuable for studying the roles of EV proteins in pancreatic tumorigenesis. METHODS: Proteomic and functional analyses were applied to characterize the proteomes of EVs released from 5 pancreatic cancer lines, 2 CAF cell lines, and a normal pancreatic epithelial cell line (HPDE). RESULTS: More than 1400 nonredundant proteins were identified in each EV derived from the cell lines. The majority of the proteins identified in the EVs from the cancer cells, CAFs, and HPDE were detected in all 3 groups, highly enriched in the biological processes of vesicle-mediated transport and exocytosis. Protein networks relevant to pancreatic tumorigenesis, including epithelial-mesenchymal transition, complement, and coagulation components, were significantly enriched in the EVs from cancer cells or CAFs. CONCLUSIONS: These findings support the roles of EVs as a potential mediator in transmitting epithelial-mesenchymal transition signals and complement response in the tumor microenvironment and possibly contributing to coagulation defects related to cancer development.

Strengthening Mental Abilities with Relational Training (SMART) in multiple sclerosis (MS): study protocol for a feasibility randomised controlled trial.

BACKGROUND: Multiple sclerosis (MS) is a chronic condition of the central nervous system, affecting around 1 in every 600 people in the UK, with 130 new diagnoses every week. Cognitive difficulties are common amongst people with MS, with up to 70% experiencing deficits in higher-level brain functions-such as planning and problem-solving, attention, and memory. Cognitive deficits make it difficult for people with MS to complete everyday tasks and limit their abilities to work, socialise, and live independently. There is a clear need-and recognised research priority-for treatments that can improve cognitive functioning in people with MS. The absence of effective cognitive interventions exacerbates burdens on the services accessed by people with MS-requiring these services to manage sequelae of untreated cognitive deficits, including reduced quality of life, greater disability and dependence, and poorer adherence to disease-modifying treatments. Our planned research will fill the evidence gap through developing-and examining the feasibility of trialling-a novel online cognitive rehabilitation programme for people with MS (SMART). The SMART programme directly trains relational skills (the ability to flexibly relate concepts to one another) based on theory that these skills are critical to broader cognitive functioning. METHODS: The primary objective of this study aims to conduct a feasibility study to inform the development of a definitive trial of SMART for improving cognitive functioning in people with MS. The secondary objective is to develop the framework for a cost-effectiveness analysis alongside a definitive trial, and the exploratory objective is to assess the signal of efficacy. DISCUSSION: As a feasibility trial, outcomes are unlikely to immediately effect changes to NHS practice. However, this is a necessary step towards developing a definitive trial-and will give us a signal of efficacy, a prerequisite for progression to a definitive trial. If found to be clinically and cost-effective, the latter trial could create a step-change in MS cognitive rehabilitation-improving service delivery and optimising support with limited additional resources. TRIAL REGISTRATION: Registration ID: ClnicalTrials.gov: NCT04975685-registered on July 23rd, 2021. PROTOCOL VERSION: 2.0, 25 November 2021.