Patients with Heart Failure: Internet Use and Mobile Health Perceptions.

BACKGROUND: Heart failure is a complex clinical syndrome noted on approximately 1 in 8 death certificates in the United States. Vital to reducing complications of heart failure and preventing hospital readmissions is adherence to heart failure self-care routines. Mobile health offers promising opportunities for enhancing self-care behaviors by facilitating tracking and timely reminders. OBJECTIVE: We sought to investigate three characteristics of heart failure patients with respect to their heart failure self-care behaviors: (1) internet use to search for heart failure information; (2) familiarity with mobile health apps and devices; and (3) perceptions of using activity trackers or smartwatches to aid in their heart failure self-care. METHODS: Forty-nine heart failure patients were asked about their internet and mobile health usage. The structured interview included questions adapted from the Health Information National Trends Survey. RESULTS: Over 50% of the patients had utilized the internet to search for heart failure information in the past 12 months, experience using health-related apps, and thoughts that an activity tracker or smartwatch could help them manage heart failure. Qualitative analysis of the interviews revealed six themes: trust in their physicians, alternatives to mobile health apps, lack of need for mobile health devices, financial barriers to activity tracker and smartwatch ownership, benefits of tracking and reminders, and uncertainty of their potential due to lack of knowledge. CONCLUSIONS: Trust in their physicians was a major factor for heart failure patients who reported not searching for health information on the internet. While those who used mobile health technologies found them useful, patients who did not use them were generally unaware of or unknowledgeable about them. Considering patients' preferences for recommendations from their physicians and tendency to search for heart failure information including treatment and management options, patient-provider discussions about mobile health may improve patient knowledge and impact their usage.

Targeting pancreatic cancer metabolic dependencies through glutamine antagonism.

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.

Autophagy supports mitochondrial metabolism through the regulation of iron homeostasis in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) cells maintain a high level of autophagy, allowing them to thrive in an austere microenvironment. However, the processes through which autophagy promotes PDAC growth and survival are still not fully understood. Here, we show that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis, while other tumor types assessed require macropinocytosis, with autophagy being dispensable. We observed that cancer-associated fibroblasts can provide bioavailable iron to PDAC cells, promoting resistance to autophagy ablation. To overcome this cross-talk, we used a low-iron diet and demonstrated that this augmented the response to autophagy inhibition therapy in PDAC-bearing mice. Our work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression.

Increased relative risk of delayed hemorrhage in patients taking anticoagulant/antiplatelet medications with concurrent aspirin therapy: implications for clinical practice based on 3-year retrospective analysis in a large health system.

PURPOSE: The incidence of delayed posttraumatic intracranial hemorrhage (DH) in patients on anticoagulant (AC) and antiplatelet (AP) medications, especially with concurrent aspirin therapy, is not well established, with studies reporting disparate results with between 1-10% risk of DH and 0-3% mortality. The purpose of this 3-year retrospective study is to evaluate the true risk of DH in patients on AP/AC medications with or without concurrent aspirin therapy. METHODS: One thousand forty-six patients taking AP and AC medications presenting to network emergency departments with head trauma who had repeat CT to evaluate for DH were included in the study. Repeat examinations were typically performed within 24 h (average follow-up time was 21 h and 99% were within 3 days). Mean time to DH was 20 h. All positive studies were reviewed by two board-certified neuroradiologists. Patients were excluded from the study if hemorrhage was retrospectively identified on the initial examination. Cases were reclassified as negative if hemorrhage on the follow-up examination was thought to be not present or artifactual. Cases were considered positive if the initial examination was negative and the follow-up examination demonstrated new hemorrhage. RESULTS: Overall, there was 1.91% incidence (20 patients) of DH and 0.3% overall mortality (3 patients). The group of patients taking warfarin or AP agents demonstrated a significantly higher rate of DH (3.2% compared to 0.9%) and higher mortality (0.9% compared to 0.0%) compared to the DOAC group (p < 0.01). The risk of DH in patients taking AC or AP agents with aspirin (13/20 cases) was significantly higher (RR 3.8, p < 0.01) than that of patients taking AC or AP alone (7/20 cases). CONCLUSION: The risk of DH was significantly higher in patients taking aspirin in addition to AC/AP medications. Repeat imaging should be obtained for trauma patients taking AC/AP agents with concurrent aspirin. The rate of DH was also significantly higher in patients taking warfarin or AP agents when compared to patients taking DOACs. Repeat examination should be strongly considered on patients taking warfarin or AP agents without aspirin. Given the relatively low risk of DH in patients taking DOACs alone, repeat imaging could be reserved for patients with external signs of trauma or dangerous mechanism of injury.

Unique enlarging cavernous malformation secondary to abnormal arteriovenous shunting through an associated developmental venous anomaly.

Cavernous malformations are angiographically occult vascular malformations. They are often associated with a developmental venous anomaly through poorly understood mechanisms. We present an unusual case of a gradually enlarging cavernous malformation associated with a developmental venous anomaly with arteriovenous shunting, suggesting venous hypertension or reflux as a potential cause of progressive growth.

The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway.

Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1-4 and cancers with HPDL overexpression5.

Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters.

α-ketoglutarate (KG), also referred to as 2-oxoglutarate, is a key intermediate of cellular metabolism with pleiotropic functions. Cell-permeable esterified analogs are widely used to study how KG fuels bioenergetic and amino acid metabolism and DNA, RNA, and protein hydroxylation reactions, as cellular membranes are thought to be impermeable to KG. Here we show that esterified KG analogs rapidly hydrolyze in aqueous media, yielding KG that, in contrast to prevailing assumptions, imports into many cell lines. Esterified KG analogs exhibit spurious KG-independent effects on cellular metabolism, including extracellular acidification, arising from rapid hydrolysis and de-protonation of α-ketoesters, and significant analog-specific inhibitory effects on glycolysis or mitochondrial respiration. We observe that imported KG decarboxylates to succinate in the cytosol and contributes minimally to mitochondrial metabolism in many cell lines cultured in normal conditions. These findings demonstrate that nuclear and cytosolic KG-dependent reactions may derive KG from functionally distinct subcellular pools and sources.

Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer characterized by complex metabolic adaptations that promote survival in a severely hypoxic and nutrient-limited tumor microenvironment (TME). Modeling microenvironmental influences in cell culture has been challenging, and technical limitations have hampered the comprehensive study of tumor-specific metabolism in vivo. To systematically interrogate metabolic vulnerabilities in PDA, we employed parallel CRISPR-Cas9 screens using in vivo and in vitro systems. This work revealed striking overlap of in vivo metabolic dependencies with those in vitro. Moreover, we identified that intercellular nutrient sharing can mask dependencies in pooled screens, highlighting a limitation of this approach to study tumor metabolism. Furthermore, metabolic dependencies were similar between 2D and 3D culture, although 3D culture may better model vulnerabilities that influence certain oncogenic signaling pathways. Lastly, our work demonstrates the power of genetic screening approaches to define in vivo metabolic dependencies and pathways that may have therapeutic utility.

Integrating remote monitoring into heart failure patients' care regimen: A pilot study.

BACKGROUND: Around 50% of hospital readmissions due to heart failure are preventable, with lack of adherence to prescribed self-care as a driving factor. Remote tracking and reminders issued by mobile health devices could help to promote self-care, which could potentially reduce these readmissions. OBJECTIVE: We sought to investigate two factors: (1) feasibility of enrolling heart failure patients in a remote monitoring regimen that uses wireless sensors and patient-reported outcome measures; and (2) their adherence to using the study devices and completing patient-reported outcome measures. METHODS: Twenty heart failure patients participated in piloting a remote monitoring regimen. Data collection included: (1) physical activity using wrist-worn activity trackers; (2) body weight using bathroom scales; (3) medication adherence using smart pill bottles; and (4) patient -reported outcomes using patient-reported outcome measures. RESULTS: We evaluated 150 hospitalized heart failure patients and enrolled 20 individuals. Two factors contributed to 50% (65/130) being excluded from the study: smartphone ownership and patient discharge. Over the course of the study, 60.0% of the subjects wore the activity tracker for at least 70% of the hours, and 45.0% used the scale for more than 70% of the days. The pill bottle was used less than 10% of the days by 55.0% of the subjects. CONCLUSIONS: Our method of recruiting heart failure patients prior to hospital discharge may not be feasible as the enrollment rate was low. Once enrolled, the majority of subjects maintained a high adherence to wearing the activity tracker but low adherence to using the pill bottle and completing the follow-up surveys. Scale usage was fair, but it received positive reviews from most subjects. Given the observed usage and feedback, we suggest mobile health-driven interventions consider including an activity tracker and bathroom scale. We also recommend administering a shorter survey more regularly and through an easier interface.

Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) tumors have a nutrient-poor, desmoplastic, and highly innervated tumor microenvironment. Although neurons can release stimulatory factors to accelerate PDAC tumorigenesis, the metabolic contribution of peripheral axons has not been explored. We found that peripheral axons release serine (Ser) to support the growth of exogenous Ser (exSer)-dependent PDAC cells during Ser/Gly (glycine) deprivation. Ser deprivation resulted in ribosomal stalling on two of the six Ser codons, TCC and TCT, and allowed the selective translation and secretion of nerve growth factor (NGF) by PDAC cells to promote tumor innervation. Consistent with this, exSer-dependent PDAC tumors grew slower and displayed enhanced innervation in mice on a Ser/Gly-free diet. Blockade of compensatory neuronal innervation using LOXO-101, a Trk-NGF inhibitor, further decreased PDAC tumor growth. Our data indicate that axonal-cancer metabolic crosstalk is a critical adaptation to support PDAC growth in nutrient poor environments.

Respiratory Supercomplexes Promote Mitochondrial Efficiency and Growth in Severely Hypoxic Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive fibrosis and hypovascularization, resulting in significant intratumoral hypoxia (low oxygen) that contributes to its aggressiveness, therapeutic resistance, and high mortality. Despite oxygen being a fundamental requirement for many cellular and metabolic processes, and the severity of hypoxia in PDAC, the impact of oxygen deprivation on PDAC biology is poorly understood. Investigating how PDAC cells survive in the near absence of oxygen, we find that PDAC cell lines grow robustly in oxygen tensions down to 0.1%, maintaining mitochondrial morphology, membrane potential, and the oxidative metabolic activity required for the synthesis of key metabolites for proliferation. Disrupting electron transfer efficiency by targeting mitochondrial respiratory supercomplex assembly specifically affects hypoxic PDAC proliferation, metabolism, and in vivo tumor growth. Collectively, our results identify a mechanism that enables PDAC cells to thrive in severe, oxygen-limited microenvironments.

Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I.

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy1-3. However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found5 despite the frequent downregulation of MHC-I expression6-8. Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8+ T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.

Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGNIFICANCE: This work identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.This article is highlighted in the In This Issue feature, p. 890.

Assessment of Heart Failure Patients' Interest in Mobile Health Apps for Self-Care: Survey Study.

BACKGROUND: Heart failure is a serious public health concern that afflicts millions of individuals in the United States. Development of behaviors that promote heart failure self-care may be imperative to reduce complications and avoid hospital re-admissions. Mobile health solutions, such as activity trackers and smartphone apps, could potentially help to promote self-care through remote tracking and issuing reminders. OBJECTIVE: The objective of this study was to ascertain heart failure patients' interest in a smartphone app to assist them in managing their treatment and symptoms and to determine factors that influence their interest in such an app. METHODS: In the clinic waiting room on the day of their outpatient clinic appointments, 50 heart failure patients participated in a self-administered survey. The survey comprised 139 questions from previously published, institutional review board-approved questionnaires. The survey measured patients' interest in and experience using technology as well as their function, heart failure symptoms, and heart failure self-care behaviors. The Minnesota Living with Heart Failure Questionnaire (MLHFQ) was among the 11 questionnaires and was used to measure the heart failure patients' health-related quality of life through patient-reported outcomes. RESULTS: Participants were aged 64.5 years on average, 32% (16/50) of the participants were women, and 91% (41/45) of the participants were determined to be New York Heart Association Class II or higher. More than 60% (30/50) of the survey participants expressed interest in several potential features of a smartphone app designed for heart failure patients. Participant age correlated negatively with interest in tracking, tips, and reminders in multivariate regression analysis (P<.05). In contrast, MLHFQ scores (worse health status) produced positive correlations with these interests (P<.05). CONCLUSIONS: The majority of heart failure patients showed interest in activity tracking, heart failure symptom management tips, and reminder features of a smartphone app. Desirable features and an understanding of factors that influence patient interest in a smartphone app for heart failure self-care may allow researchers to address common concerns and to develop apps that demonstrate the potential benefits of mobile technology.

Compensatory metabolic networks in pancreatic cancers upon perturbation of glutamine metabolism.

Pancreatic ductal adenocarcinoma is a notoriously difficult-to-treat cancer and patients are in need of novel therapies. We have shown previously that these tumours have altered metabolic requirements, making them highly reliant on a number of adaptations including a non-canonical glutamine (Gln) metabolic pathway and that inhibition of downstream components of Gln metabolism leads to a decrease in tumour growth. Here we test whether recently developed inhibitors of glutaminase (GLS), which mediates an early step in Gln metabolism, represent a viable therapeutic strategy. We show that despite marked early effects on in vitro proliferation caused by GLS inhibition, pancreatic cancer cells have adaptive metabolic networks that sustain proliferation in vitro and in vivo. We use an integrated metabolomic and proteomic platform to understand this adaptive response and thereby design rational combinatorial approaches. We demonstrate that pancreatic cancer metabolism is adaptive and that targeting Gln metabolism in combination with these adaptive responses may yield clinical benefits for patients.

Intracerebral Distribution of the Oncometabolite d-2-Hydroxyglutarate in Mice Bearing Mutant Isocitrate Dehydrogenase Brain Tumors: Implications for Tumorigenesis.

The prevalence of mutant isocitrate dehydrogenase 1 (IDH1) brain tumors has generated significant efforts to understand the role of the mutated enzyme product d-2-hydroxyglutarate (D2HG), an oncometabolite, in tumorigenesis, as well as means to eliminate it. Glymphatic clearance was proposed as a pathway that could be manipulated to accelerate D2HG clearance and dictated the study design that consisted of two cohorts of mice bearing U87/mutant IDH1 intracerebral tumors that underwent two microdialysis - providing D2HG interstitial fluid concentrations - sampling periods of awake and asleep (activate glymphatic clearance) in a crossover manner. Glymphatic clearance was found not to have a significant effect on D2HG brain tumor interstitial fluid concentrations that were 126.9 ± 74.8 µM awake and 117.6 ± 98.6 µM asleep. These concentrations, although low relative to total brain tumor concentrations of 6.8 ± 3.6 mM, were considered sufficient to be transported by interstitial fluid and taken up into normal cells to cause deleterious effects. A model of D2HG CNS distribution supported this contention and was further supported by in vitro studies that showed D2HG could interfere with immune cell function. The study provides insight into the compartmental distribution of D2HG in the brain, wherein the interstitial fluid serves as a dynamic pathway for D2HG to enter normal cells and contribute to tumorigenesis.

Use of Fluorodeoxyglucose-Positron Emission Tomography in the Diagnosis of Intravascular Diffuse Large B-Cell Lymphoma.

Patients with intravascular large B-cell lymphoma often pose a significant diagnostic challenge, particularly in the early stages of the disease, but use of fluorodeoxyglucose-positron emission tomography could result in a more timely diagnosis.

Axl-/- mice have delayed recovery and prolonged axonal damage following cuprizone toxicity.

Activation of the receptor tyrosine kinase Axl recruits signaling molecules that regulate cell growth and survival. To evaluate Axl's role in brain during cuprizone toxicity, mice were fed cuprizone and evaluated at 3-, 4-, and 6-week cuprizone treatment and 3- and 5-week post-cuprizone withdrawal. At 4-week cuprizone treatment, the corpora callosa of wildtype (WT) mice had robust Oil Red O+ staining indicative of ongoing phagocytosis. Axl-/- mice had minimal Oil Red O+ staining, fewer microglia, and significantly more TUNEL+/ASPA+ mature oligodendrocytes than the WT. At 6-week cuprizone treatment, there was significantly more Oil Red O+ staining in the Axl-/- corpora callosa than in the WT indicating a lag in the clearance of cellular and myelin debris. Relative to WT mice, there were fewer mature oligodendrocytes and significantly more SMI-32+ axons at 3-week post-cuprizone withdrawal, indicative of axonal damage in the Axl-/- corpora callosa. Electron microscopy determined that at 3-week post-cuprizone withdrawal the number of dystrophic axons and axons containing autophagosome-like vacuoles/mouse was increased in the Axl-/- mice relative to the WT mice. In Axl-/- corpora callosa, 5-week post-cuprizone withdrawal, the number of mature oligodendrocytes was comparable to the WT mice, but axons in the Axl-/- mice were SMI-32+, suggesting that Axl-/- mice have delayed clearance of apoptotic oligodendrocytes and myelin debris resulting in prolonged axonal damage and recovery from cuprizone toxicity.