Recommendations to Address Barriers to Patient Portal Use Among Persons With Diabetes Seeking Care at Community Health Centers: Interview Study With Patients and Health Care Providers.

BACKGROUND: Community health centers (CHCs) are safety-net health care facilities in the United States that provide care for a substantial number of low-income, non-English speaking adults with type 2 diabetes (T2D). Whereas patient portals have been shown to be associated with significant improvements in diabetes self-management and outcomes, they remain underused in CHCs. In addition, little is known about the specific barriers to and facilitators of patient portal use in CHCs and strategies to address the barriers. OBJECTIVE: The objectives of this qualitative study were to explore the barriers to and facilitators of the use of patient portals for managing diabetes in 2 CHCs from the perspective of adults with T2D and clinicians (community health workers, nurses, nurse practitioners, and physicians) and to make recommendations on strategies to enhance use. METHODS: A qualitative description design was used. A total of 21 participants (n=13, 62% clinicians and n=8, 38% adults with T2D) were purposively and conveniently selected from 2 CHCs. Adults with T2D were included if they were an established patient of one of the partner CHCs, aged ≥18 years, diagnosed with T2D ≥6 months, and able to read English or Spanish. Clinicians at our partner CHCs who provided care or services for adults with T2D were eligible for this study. Semistructured interviews were conducted in either Spanish or English based on participant preference. Interviews were audio-recorded and transcribed. Spanish interviews were translated into English by a bilingual research assistant. Data were collected between October 5, 2022, and March 16, 2023. Data were analyzed using a rapid content analysis method. Standards of rigor were implemented. RESULTS: Themes generated from interviews included perceived usefulness and challenges of the patient portal, strategies to improve patient portal use, and challenges in diabetes self-management. Participants were enthusiastic about the potential of the portal to improve access to health information and patient-clinician communication. However, challenges of health and technology literacy, maintaining engagement, and clinician burden were identified. Standardized implementation strategies were recommended to raise awareness of patient portal benefits, provide simplified training and technology support, change clinic workflow to triage messages, customize portal notification messages, minimize clinician burden, and enhance the ease with which blood glucose data can be uploaded into the portal. CONCLUSIONS: Adults with T2D and clinicians at CHCs continue to report pervasive challenges to patient portal use in CHCs. Providing training and technical support on patient portal use for patients with low health literacy at CHCs is a critical next step. Implementing standardized patient portal strategies to address the unique needs of patients receiving care at CHCs also has the potential to improve health equity and health outcomes associated with patient portal use.

Adnexal Clear Cell Carcinoma Exhibiting Comedonecrosis of the Ear: A Rare Case Treated With Mohs Micrographic Surgery.

Adnexal clear cell carcinoma exhibiting comedonecrosis (ACCCC) is a rare, cutaneous, malignant neoplasm with limited reported cases since its discovery. ACCCC is characterized by unique clinical and histological features, demanding a precise diagnosis due to its potential for aggressive behavior and early metastases, distinct from other cutaneous tumors with clear cytoplasmic cells. We present the case of an 81-year-old male with a history of multiple non-melanoma skin cancers, who presented with a 5 mm erythematous papule on his left tragus. Initial tangential shave biopsy results were invasive clear cell squamous cell carcinoma that was moderately differentiated. Subsequent Mohs micrographic surgery (MMS) necessitating a full-thickness skin graft reconstruction was performed. Histopathological examination afterward confirmed ACCCC with pleomorphic epithelial cells, clear cytoplasm, and central comedonecrosis. Immunohistochemistry supported adnexal differentiation and squamous features. To our knowledge, this is the fifteenth reported case of ACCCC as well as the first documented case of ACCCC treated with MMS, offering a novel approach to managing this rare malignancy.

All "Roads" Lead to Rocksalt Structure.

Rocksalt is the most common crystal structure among binary compounds. Moreover, no long-lived, metastable polymorphs are observed in compounds with the rocksalt ground state. We investigate the absence of polymorphism via first-principles random structure sampling and transformation kinetics modeling of three rocksalt compounds: MgO, TaC, and PbTe. Random structure sampling reveals that for all three systems the rocksalt basin of attraction covers much more of configuration space than any other, making it statistically the most significant structure. The kinetics modeling shows that virtually all other relevant structures, including most of the 457 known A1B1 prototypes, transform rapidly to rocksalt, making it the only option at ambient conditions. These results explain the absence of polymorphism in binary rocksalts, answer why rocksalt is the structure of choice for high-entropy ceramics and disordered ternary nitrides, and help understand/predict metastable states in crystalline solids more generally.

CD44-hyaluronan mediating endocytosis of iron-platinum alloy nanoparticles induces ferroptotic cell death in mesenchymal-state lung cancer cells with tyrosine kinase inhibitor resistance.

While tyrosine kinase inhibitor resistance in cancer is a critical issue in the medical field, it is important for clinical testing as well, since it affects the ultimate outcome of cancer therapy. Yet, no effective solutions have been implemented till date. Clinical observations after tyrosine kinase inhibitor treatment reveal that acquired resistance inevitably limits the curative effects of non-small cell lung cancer treatment because of mutations in the epidermal growth factor receptor gene, which are accompanied by epithelial-mesenchymal transition. Here, for the first time, we report that the transmembrane glycoprotein CD44, which is associated with epithelial-mesenchymal transition, chemoresistance, and cancer progression, mediates enhanced endocytosis of iron-platinum alloy nanoparticles (FePt NPs) in the mesenchymal-state gefitinib-resistant (GR+ and M6) cells, via the binding of the CD44 ligand, hyaluronan, to the surface-absorbed hyaluronan-binding protein 2. Upon treatment with FePt NPs, there was higher cellular uptake in mesenchymal-state GR+ and M6 cells, resulting from cell death through ferroptosis and mitochondrial dysfunction, as compared to that observed in the epithelial-state cells. Mechanistically, inactivation of dihydroorotate dehydrogenase elevated the production of mitochondrial lipid peroxidation, and enhanced the cell death in the epithelial-state HCC827 cells, thereby indicating its role in defense against FePt NPs-induced ferroptosis. Furthermore, induction of ferroptosis has been shown to specifically promote the cell death of drug-tolerant "persister" cells and reverse their resistance as well. Therefore, we concluded that FePt NPs preferentially target mesenchymal drug-tolerant "persister" cells and promote ferroptosis, to overcome their resistance. STATEMENT OF SIGNIFICANCE: In the present study, we identified FePt NPs as an innovative agent for cancer treatment, particularly in mesenchymal-state cells that exhibit TKI resistance. Mesenchymal-state cancer cells showed enhanced uptake of FePt NPs via CD44-HA-mediated endocytosis, accompanied by severe cell death and mitochondrial morphology alterations, in comparison to epithelial-state cells. We further elucidated the mechanism underlying FePt NPs-induced ferroptotic cell death as via a burst of mitochondrial LPO and DHODH protein inactivation. In addition, we found that FePt NPs inhibit tumor growth in TKI-resistant mesenchymal GR+ cell-bearing mice with better efficacy than the ferroptotic inducer RSL3. Our current findings on using FePt NPs to overcome TKI resistance through ferroptosis activation may offer a alternative strategy for improved cancer treatment.

Modulation of anxiety-like behavior in galactooligosaccharide-fed mice: A potential role for bacterial tryptophan metabolites and reduced microglial reactivity.

Prebiotic galactooligosaccharides (GOS) reduce anxiety-like behaviors in mice and humans. However, the biological pathways behind these behavioral changes are not well understood. To begin to study these pathways, we utilized C57BL/6 mice that were fed a standard diet with or without GOS supplementation for 3 weeks prior to testing on the open field. After behavioral testing, colonic contents and serum were collected for bacteriome (16S rRNA gene sequencing, colonic contents only) and metabolome (UPLC-MS, colonic contents and serum data) analyses. As expected, GOS significantly reduced anxiety-like behavior (i.e., increased time in the center) and decreased cytokine gene expression (Tnfa and Ccl2) in the prefrontal cortex. Notably, time in the center of the open field was significantly correlated with serum methyl-indole-3-acetic acid (methyl-IAA). This metabolite is a methylated form of indole-3-acetic acid (IAA) that is derived from bacterial metabolism of tryptophan. Sequencing analyses showed that GOS significantly increased Lachnospiraceae UCG006 and Akkermansia; these taxa are known to metabolize both GOS and tryptophan. To determine the extent to which methyl-IAA can affect anxiety-like behavior, mice were intraperitoneally injected with methyl-IAA. Mice given methyl-IAA had a reduction in anxiety-like behavior in the open field, along with lower Tnfa in the prefrontal cortex. Methyl-IAA was also found to reduce TNF-α (as well as CCL2) production by LPS-stimulated BV2 microglia. Together, these data support a novel pathway through which GOS reduces anxiety-like behaviors in mice and suggests that the bacterial metabolite methyl-IAA reduces microglial cytokine and chemokine production, which in turn reduces anxiety-like behavior.

Phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: adrenocortical carcinoma cohort.

OBJECTIVES: Multiple common cancers benefit from immunotherapy; however, less is known about efficacy in rare tumors. We report the results of the adrenocortical carcinoma cohort of NCI/SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors. DESIGN/SETTING: A prospective, phase 2 clinical trial of ipilimumab plus nivolumab was conducted by the SWOG Early Therapeutics and Rare Cancers Committee for multiple rare tumor cohorts across >1,000 National Clinical Trial Network sites. PARTICIPANTS: 21 eligible patients were registered. Median age was 53 years (range 26-69); 16 (76%) were women. INTERVENTIONS: Ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks was administered until disease progression, symptomatic deterioration, treatment delay for any reason >56 days, unacceptable or immune-related toxicity with inability to decrease prednisone to <10 mg daily, or per patient request. MAIN OUTCOME MEASURES: The primary endpoint was the overall response rate (ORR) (RECIST V.1.1). Secondary endpoints include clinical benefit rate (CBR) (includes stable disease (SD)>6 months), progression-free survival (PFS), overall survival (OS), and toxicity. Immune-related outcomes included immune ORR (iORR), immune CBR (iCBR), and immune PFS (iPFS). A two-stage design was used assuming: null=5% alternative=30%, n=6 in the first stage, 16 max, one-sided alpha=13%. RESULTS: The median number of prior therapy lines was 2 (range: 1-9). 3 of 21 patients attained confirmed partial response (PR) (ORR=14%). In addition, one patient had an unconfirmed PR; one, stable disease (SD)>6 months; one, immune-related RECIST (iRECIST) PR (iPR); and one patient attained iSD>6 months: clinical benefit rate (response or SD>6 months)=5/21 (24%), iORR=4/21 (19%), iCBR=7/21 (33%). The 6-month PFS was 24%; 6-month iPFS, 33%. The PFS for patients (N=7) with iRECIST clinical benefit were 57, 52, 18, 15, 13, 7, and 7 months. The 6-month OS was 76%; the median OS, was 15.8 months. The most common toxicities were fatigue (62%) and rash (38%), and the most common grade 3/4 immune-related adverse events were hepatic dysfunction (9.5%) and adrenal insufficiency (9.5%). Treatment-related adverse events leading to discontinuation of therapy in four patients (21%). There were no grade 5 adverse events. CONCLUSIONS: Ipilimumab plus nivolumab is active in refractory metastatic adrenocortical cancer meeting the primary endpoint of the study, with a 19% iORR and 33% iCBR (includes SD/iSD>6 months) and with the longest PFS/iPFS of 52 and 57 months. TRIAL REGISTRATION NUMBER: NCT02834013 (registered 15 July, 2016; https://clinicaltrials.gov/ct2/show/NCT02834013).

Cytoplasmic preassembly of the flagellar outer dynein arm complex in Trypanosoma brucei.

The outer dynein arm (ODA) is a large, multimeric protein complex essential for ciliary motility. The composition and assembly of ODA are best characterized in the green algae Chlamydomonas reinhardtii, where individual ODA subunits are synthesized and preassembled into a mature complex in the cytosol prior to ciliary import. The single-cellular parasite Trypanosoma brucei contains a motile flagellum essential for cell locomotion and pathogenesis. Similar to human motile cilia, T. brucei flagellum contains a two-headed ODA complex arranged at 24 nm intervals along the axonemal microtubule doublets. The subunit composition and the preassembly of the ODA complex in T. brucei, however, have not been investigated. In this study, we affinity-purified the ODA complex from T. brucei cytoplasmic extract. Proteomic analyses revealed the presence of two heavy chains (ODAα and ODAß), two intermediate chains (IC1and IC2) and several light chains. We showed that both heavy chains and both intermediate chains are indispensable for flagellar ODA assembly. Our study also provided biochemical evidence supporting the presence of a cytoplasmic, preassembly pathway for T. brucei ODA.

High-Resolution Ocular Surface Imaging: Real-Time Visualization of Tear Film Dysfunction.

PURPOSE: Recent advancements in infrared sensing technology have made it possible to visualize tear film dynamics in real time, enabling evaluation of tear film quality during blinking. A retrospective clinical evaluation was conducted to explore this by grading videos of the tear film and comparing grading data with dry eye diagnostic results using the OCULUS keratograph (K5M). METHODS: Videos were used to grade patients' tear film perturbations as compared with healthy control subjects. The grading was then correlated with the ocular surface disease index (OSDI) scores, tear film breakup time (TFBUT), tear meniscus height (TMH), corneal staining, redness, and meibography data. RESULTS: Infrared imaging of the ocular surface revealed instantaneous and recurring dynamic characteristics of the tear film, allowing for the differentiation between normal and abnormal tear films. Abnormal features included a complete absence of a spreading tear film, hindered spreading of the tear film after blinking, areas of tear film instability, or a combination of the latter 2. Some of these features show a resemblance to the tear film appearance after fluorescein staining. The grading of these features correlated with TFBUT and, to a lesser extent, with TMH but did not show significant correlation with any other diagnostic data from the K5M. Furthermore, the speed of tear film spreading after blinking showed a positive correlation with TMH. CONCLUSIONS: Direct visualization of the tear film across the entire palpebral aperture using infrared sensing offers a noninvasive, reproducible, and rapid method for assessing the health and quality of the tear film.

Uncovering Shortcomings in Advertising Strategies for Over-the-Counter Minoxidil Products on Amazon.

Introduction The over-the-counter (OTC) market for hair loss products, particularly those containing minoxidil, has significantly expanded due to the increased prevalence of hair loss. Minoxidil, a vasodilator medication, is known for its potential to stimulate hair growth. However, the rise in OTC formulations has led to misleading advertising and marketing, with some companies exaggerating the benefits of their products while minimizing potential adverse effects. Methods A Google Boolean Search was conducted to identify OTC minoxidil products. The topmost non-sponsored search engine result page was used for analysis. Products not containing any dosage of minoxidil were excluded, resulting in nine products. These were individually searched on Amazon and eight were analyzed for any addressed safety information and adverse effects profile. Results The analysis revealed that only two out of eight products (25%) reported safety information, and none of the products (0%) reported any adverse effects. Significant observations were found surrounding the transparency and accuracy of the advertising and marketing of these products. Many companies made bold claims about their products without providing supporting scientific evidence or studies. Furthermore, many of these OTC hair loss brands did not adequately mention and explain the adverse effects of the product. Conclusions The study highlights the need for greater transparency in the marketing of OTC minoxidil products. Companies should provide clear and accessible information about the safety and potential adverse effects of their products. This will empower consumers to make informed decisions and foster trust between the industry and the consumer. Furthermore, the authenticity and accuracy of marketing images should be ensured to avoid giving false hopes to consumers.

Modulation of Oxidative Stress and Neuroinflammation by Cannabidiol (CBD): Promising Targets for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of dementia globally. Although the direct cause of AD remains under debate, neuroinflammation and oxidative stress are critical components in its pathogenesis and progression. As a result, compounds like cannabidiol (CBD) are being increasingly investigated for their ability to provide antioxidant and anti-inflammatory neuroprotection. CBD is the primary non-psychotropic phytocannabinoid derived from Cannabis sativa. It has been found to provide beneficial outcomes in a variety of medical conditions and is gaining increasing attention for its potential therapeutic application in AD. CBD is not psychoactive and its lipophilic nature allows its rapid distribution throughout the body, including across the blood-brain barrier (BBB). CBD also possesses anti-inflammatory, antioxidant, and neuroprotective properties, making it a viable candidate for AD treatment. This review outlines CBD's mechanism of action, the role of oxidative stress and neuroinflammation in AD, and the effectiveness and limitations of CBD in preclinical models of AD.

Physician perceptions of medically unexplained symptoms in adolescent patients presenting to the emergency department.

INTRODUCTION: Adolescents presenting with medically unexplained symptoms (MUS) in non-mental healthcare settings, particularly Emergency Departments (EDs), pose diagnostic challenges necessitating a comprehensive bio-psycho-social approach. Amid the youth mental health crisis, recognising psychological distress is imperative. This study delved into physicians' perceptions and diagnostic tendencies regarding such cases, exploring the potential overshadowing of psychosomatic presentations by medicalized diagnoses in EDs. METHODS: Our study involved 74 physicians, representing 82% of eligible respondents in the Paediatric Emergency Medicine Department, and was conducted using an online questionnaire examining perceptions of case scenarios with psychosomatic presentations. RESULTS: Results disclosed a prevalent inclination toward medical diagnoses, with less than 10% of physicians considering psychosomatic conditions in specific scenarios. Interestingly, psychosomatic diagnoses were more probable for symptoms like headaches, shortness of breath, and chest pain. The study uncovered a possible bias among physicians towards medical diagnoses in EDs for adolescents with MUS, possibly stemming from physicians' focus on physical care, diagnostic uncertainties, cognitive biases, and concerns about stigmatisation. CONCLUSION: Adolescents with MUS seeking assistance in non-mental health settings may encounter delayed mental health diagnoses and interventions. Psychosomatic symptoms could signify stressors or underlying mental health disorders. Recognising psychosocial distress early on is crucial for optimal mental health outcomes. Consequently, the study advocates for a paradigm shift towards a holistic bio-psychosocial approach in both medical education and practice.

Vitamin C Deficiency Masquerading as Vasculitis in a Patient With Crohn's Disease.

This case study features a 40-year-old male with Crohn's disease (CD) who was initially misdiagnosed with vasculitis but was later shown to have scurvy owing to vitamin C deficiency. The patient's diet was nearly exclusively made up of highly processed fast food, with no fresh fruits or vegetables. A mildly sensitive, violaceous rash on his lower legs, mild gingival hemorrhage and enlargement, and muscle soreness were among his symptoms. Anemia and undetectable vitamin C levels were discovered in laboratory studies. A skin sample revealed follicular hyperkeratosis, coiled hairs, and perifollicular bleeding, eliminating the possibility of vasculitis. Scurvy was confirmed by undetectable vitamin C levels and intramuscular bleeding discovered during a muscle biopsy. After one month of vitamin C administration, the patient's skin was entirely clear. This instance emphasizes the significance of taking vitamin C insufficiency into account in patients with CD and other disorders that can cause malabsorption. Misdiagnosis might result in unneeded treatments and medical expenses. Scurvy must be diagnosed as soon as possible because it might cause gastrointestinal/intracerebral hemorrhage and death.

Microglial function interacts with the environment to affect sex-specific depression risk.

There is a two-fold higher incidence of depression in females compared to men with recent studies suggesting a role for microglia in conferring this sex-dependent depression risk. In this study we investigated the nature of this relation. Using GWAS enrichment, gene-set enrichment analysis and Mendelian randomization, we found minimal evidence for a direct relation between genes functionally related to microglia and sex-dependent genetic risk for depression. We then used expression quantitative trait loci and single nucleus RNA-sequencing resources to generate polygenic scores (PGS) representative of individual variation in microglial function in the adult (UK Biobank; N = 54753-72682) and fetal (ALSPAC; N = 1452) periods. The adult microglial PGS moderated the association between BMI (UK Biobank; beta = 0.001, 95 %CI 0.0009 to 0.003, P = 7.74E-6) and financial insecurity (UK Biobank; beta = 0.001, 95 %CI 0.005 to 0.015, P = 2E-4) with depressive symptoms in females. The fetal microglia PGS moderated the association between maternal prenatal depressive symptoms and offspring depressive symptoms at 24 years in females (ALSPAC; beta = 0.04, 95 %CI 0.004 to 0.07, P = 0.03). We found no evidence for an interaction between the microglial PGS and depression risk factors in males. Our results illustrate a role for microglial function in the conferral of sex-dependent depression risk following exposure to a depression risk factor.

Investigating Factors Associated with the Development of Postnatal Depression After Cesarean Delivery: A Validation Cohort Study.

Purpose: This study aimed to validate a proposed association model previously published to determine the clinical relevance of pre-operative determinants in the development of PND after Cesarean delivery (CD). Patients and Methods: Parturients undergoing elective CD under neuraxial anesthesia were recruited for a prospective cohort study between Oct 2021 and Oct 2022 at KK Women's and Children's Hospital, Singapore. Predelivery pain, psychological and mechanical temporal summation, and demographic data were recorded. A follow-up survey was conducted at 6 to 10 weeks after CD. The primary outcome was the incidence of PND, defined as an Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10. Results: A total of 180 patients were recruited for validation. PND 6 to 10 weeks post-delivery occurred in 18.9% of recruited parturients. Multivariate regression analyses showed that higher pre-operative CSI scores (p=0.0156), higher anxiety levels about upcoming surgery (p=0.0429), increased pre-operative pain scores on movement (p=0.0110), and higher pre-operative HADS subscale scores on anxiety (p=0.0041) were independently associated with the development of PND weeks post-CD. Lower anticipation of pain medication needs (p=0.0038) was independently associated with the development of PND post-CD. The area under curve (AUC) of this multivariable model (training cohort), internal cross validation (training cohort) and external cross validation (validation cohort) were 0.818 (95% CI, 0.746 to 0.889), 0.785 (95% CI, 0.707 to 0.864) and 0.604 (95% CI, 0.497 to 0.710) respectively. Conclusion: The proposed model performed well in a local population. Further refinement is necessary to test the proposed model in populations with social and cultural differences.

Validating part of the social media infodemic listening conceptual framework using structural equation modelling.

Background: The literature has identified various factors that promote or hinder people's intentions towards COVID-19 vaccination, and structural equation modelling (SEM) is a common approach to validate these associations. We propose a conceptual framework called social media infodemic listening (SoMeIL) for public health behaviours. Hypothesizing parameters retrieved from social media platforms can be used to infer people's intentions towards vaccination behaviours. This study preliminarily validates several components of the SoMeIL conceptual framework using SEM and Twitter data and examines the feasibility of using Twitter data in SEM research. Methods: A total of 2420 English tweets in Toronto or Ottawa, Ontario, Canada, were collected from March 8 to June 30, 2021. Confirmatory factor analysis and SEM were applied to validate the SoMeIL conceptual framework in this cross-sectional study. Findings: The results showed that sentiment scores, the log-numbers of favourites and retweets of a tweet, and the log-numbers of a user's favourites, followers, and public lists had significant direct associations with COVID-19 vaccination intention. The sentiment score of a tweet had the strongest relationship, whereas a user's number of followers had the weakest relationship with the intention of COVID-19 vaccine uptake. Interpretation: The findings preliminarily validate several components of the SoMeIL conceptual framework by testing associations between self-reported COVID-19 vaccination intention and sentiment scores and the log-numbers of a tweet's favourites and retweets as well as users' favourites, followers, and public lists. This study also demonstrates the feasibility of using Twitter data in SEM research. Importantly, this study preliminarily validates the use of these six components as online reaction behaviours in the SoMeIL framework to infer the self-reported COVID-19 vaccination intentions of Canadian Twitter users in two cities. Funding: This study was supported by the 2023-24 Ontario Graduate Scholarship.

Perturbed liver gene zonation in a mouse model of non-alcoholic steatohepatitis.

Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating gene expression in perivenous hepatocytes, while suppressing gene expression in their periportal counterparts. However, the understanding as to the liver gene zonation and zonation regulators in diseases is limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combining spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt-target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt-target gene expression levels and zonation spatial patterns were in line with the up regulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control liver but expanded to the periportal zone in NASH liver. AAV8-mediated RSPO3 overexpression in controls resulted in zonation changes, and further amplified the disturbed zonation of Wnt-target genes in NASH, similarly Rspo3 knockdown in Rspo3+/- mice resulted in zonation changes of Wnt-target genes in both chow and HFD mouse. Interestingly, there were no impacts on steatosis, inflammation, or fibrosis NASH pathology from RSPO3 overexpression nor Rspo3 knockdown. In summary, our study demonstrated the alteration of Wnt signaling in a mouse NASH model, leading to perturbed liver zonation.

Phase I/II Study of Combined BCL-xL and MEK Inhibition with Navitoclax and Trametinib in KRAS or NRAS Mutant Advanced Solid Tumors.

PURPOSE: MEK inhibitors (MEKi) lack monotherapy efficacy in most RAS-mutant cancers. BCL-xL is an anti-apoptotic protein identified by a synthetic lethal shRNA screen as a key suppressor of apoptotic response to MEKi. PATIENTS AND METHODS: We conducted a dose escalation study (NCT02079740) of the BCL-xL inhibitor navitoclax and MEKi trametinib in patients with RAS-mutant tumors with expansion cohorts for: pancreatic, gynecologic (GYN), non-small cell lung cancer (NSCLC), and other cancers harboring KRAS/NRAS mutations. Paired pretreatment and day 15 tumor biopsies and serial cell-free (cf)DNA were analyzed. RESULTS: A total of 91 patients initiated treatment, with 38 in dose escalation. Fifty-eight percent had ≥3 prior therapies. A total of 15 patients (17%) had colorectal cancer, 19 (11%) pancreatic, 15 (17%) NSCLC, and 32 (35%) GYN cancers. The recommended phase II dose (RP2D) was established as trametinib 2 mg daily days 1 to 14 and navitoclax 250 mg daily days 1 to 28 of each cycle. Most common adverse events included diarrhea, thrombocytopenia, increased AST/ALT, and acneiform rash. At RP2D, 8 of 49 (16%) evaluable patients achieved partial response (PR). Disease-specific differences in efficacy were noted. In patients with GYN at the RP2D, 7 of 21 (33%) achieved a PR and median duration of response 8.2 months. No PRs occurred in patients with colorectal cancer, NSCLC, or pancreatic cancer. MAPK pathway inhibition was observed in on-treatment tumor biopsies. Reductions in KRAS/NRAS mutation levels in cfDNA correlated with clinical benefit. CONCLUSIONS: Navitoclax in combination with trametinib was tolerable. Durable clinical responses were observed in patients with RAS-mutant GYN cancers, warranting further evaluation in this population.

A Single Arm Phase 2 Trial of Trametinib in Patients With Locally Advanced or Metastatic Epithelioid Hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. PATIENTS AND METHODS: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. RESULTS: 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% CI: 0.094, 19.0), median PFS was 10.4 months (95% CI: 7.1, NA), and 2-year OS rate was 33.3% (95% CI: 19.1, 58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. CONCLUSIONS: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.