Integrin α6 mediates the drug resistance of acute lymphoblastic B-cell leukemia.

Resistance to multimodal chemotherapy continues to limit the prognosis of acute lymphoblastic leukemia (ALL). This occurs in part through a process called adhesion-mediated drug resistance, which depends on ALL cell adhesion to the stroma through adhesion molecules, including integrins. Integrin α6 has been implicated in minimal residual disease in ALL and in the migration of ALL cells to the central nervous system. However, it has not been evaluated in the context of chemotherapeutic resistance. Here, we show that the anti-human α6-blocking Ab P5G10 induces apoptosis in primary ALL cells in vitro and sensitizes primary ALL cells to chemotherapy or tyrosine kinase inhibition in vitro and in vivo. We further analyzed the underlying mechanism of α6-associated apoptosis using a conditional knockout model of α6 in murine BCR-ABL1+ B-cell ALL cells and showed that α6-deficient ALL cells underwent apoptosis. In vivo deletion of α6 in combination with tyrosine kinase inhibitor (TKI) treatment was more effective in eradicating ALL than treatment with a TKI (nilotinib) alone. Proteomic analysis revealed that α6 deletion in murine ALL was associated with changes in Src signaling, including the upregulation of phosphorylated Lyn (pTyr507) and Fyn (pTyr530). Thus, our data support α6 as a novel therapeutic target for ALL.

The Role of Diet in Cancer Prevention and Chemotherapy Efficacy.

Despite great advances in treatment, cancer remains a leading cause of death worldwide. Diet can greatly impact health, while caloric restriction and fasting have putative benefits for disease prevention and longevity. Strong epidemiological associations exist between obesity and cancer, whereas healthy diets can reduce cancer risk. However, less is known about how diet might impact cancer once it has been diagnosed and particularly how diet can impact cancer treatment. In the present review, we discuss the links between obesity, diet, and cancer. We explore potential mechanisms by which diet can improve cancer outcomes, including through hormonal, metabolic, and immune/inflammatory effects, and present the limited clinical research that has been published in this arena. Though data are sparse, diet intervention may reduce toxicity, improve chemotherapy efficacy, and lower the risk of long-term complications in cancer patients. Thus, it is important that we understand and expand the science of this important but complex adjunctive cancer treatment strategy.

Abnormalities in autonomic function in obese boys at-risk for insulin resistance and obstructive sleep apnea.

STUDY OBJECTIVES: Current evidence in adults suggests that, independent of obesity, obstructive sleep apnea (OSA) can lead to autonomic dysfunction and impaired glucose metabolism, but these relationships are less clear in children. The purpose of this study was to investigate the associations among OSA, glucose metabolism, and daytime autonomic function in obese pediatric subjects. METHODS: Twenty-three obese boys participated in: overnight polysomnography; a frequently sampled intravenous glucose tolerance test; and recordings of spontaneous cardiorespiratory data in both the supine (baseline) and standing (sympathetic stimulus) postures. RESULTS: Baseline systolic blood pressure and reactivity of low-frequency heart rate variability to postural stress correlated with insulin resistance, increased fasting glucose, and reduced beta-cell function, but not OSA severity. Baroreflex sensitivity reactivity was reduced with sleep fragmentation, but only for subjects with low insulin sensitivity and/or low first-phase insulin response to glucose. CONCLUSIONS: These findings suggest that vascular sympathetic activity impairment is more strongly affected by metabolic dysfunction than by OSA severity, while blunted vagal autonomic function associated with sleep fragmentation in OSA is enhanced when metabolic dysfunction is also present.

Central diabetes insipidus associated with refeeding in anorexia nervosa: A case report.

Anorexia nervosa (AN) has been associated with a multitude of hypothalamic pituitary abnormalities, although it is unknown which aberrations reflect disease causation and which are the consequences of severe malnutrition. Among these endocrinopathies, hypothalamic-posterior pituitary aberrations have been described, including disorders of osmoregulation. We report the case of an adolescent female with a history of severe AN, restricting subtype, treated aggressively with multiple hospitalizations. During hospitalization for severe weakness and lethargy, her course of medical stabilization was complicated by significant polyuria, ultimately diagnosed as central diabetes insipidus (DI). This is the first reported case, to our knowledge, of a severely malnourished adolescent with AN-restricting subtype developing central DI during the refeeding process for medical stabilization, thus adding to the small body of existing literature on disordered osmoregulation in this patient population. This case report raises the question as to whether the frequency of central DI during refeeding is greater than that previously recognized. Additional research should focus on how neuroendocrine dysregulation of water balance might impact the clinical course of AN and its treatment.

Adipose tissue inflammation in breast cancer survivors: effects of a 16-week combined aerobic and resistance exercise training intervention.

PURPOSE: Obesity is a leading modifiable contributor to breast cancer mortality due to its association with increased recurrence and decreased overall survival rate. Obesity stimulates cancer progression through chronic, low-grade inflammation in white adipose tissue, leading to accumulation of adipose tissue macrophages (ATMs), in particular, the pro-inflammatory M1 phenotype macrophage. Exercise has been shown to reduce M1 ATMs and increase the more anti-inflammatory M2 ATMs in obese adults. The purpose of this study was to determine whether a 16-week exercise intervention would positively alter ATM phenotype in obese postmenopausal breast cancer survivors. METHODS: Twenty obese postmenopausal breast cancer survivors were randomized to a 16-week aerobic and resistance exercise (EX) intervention or delayed intervention control (CON). The EX group participated in 16 weeks of supervised exercise sessions 3 times/week. Participants provided fasting blood, dual-energy X-ray absorptiometry (DXA), and superficial subcutaneous abdominal adipose tissue biopsies at baseline and following the 16-week study period. RESULTS: EX participants experienced significant improvements in body composition, cardiometabolic biomarkers, and systemic inflammation (all p < 0.03 vs. CON). Adipose tissue from EX participants showed a significant decrease in ATM M1 (p < 0.001), an increase in ATM M2 (p < 0.001), increased adipose tissue secretion of anti-inflammatory cytokines such as adiponectin, and decreased secretion of the pro-inflammatory cytokines IL-6 and TNF- α (all p < 0.055). CONCLUSIONS: A 16-week aerobic and resistance exercise intervention attenuates adipose tissue inflammation in obese postmenopausal breast cancer survivors. Future large randomized trials are warranted to investigate the impact of exercise-induced reductions in adipose tissue inflammation and breast cancer recurrence.

Obesity is associated with residual leukemia following induction therapy for childhood B-precursor acute lymphoblastic leukemia.

Obesity is associated with poorer event-free survival (EFS) in pediatric acute lymphoblastic leukemia (ALL). Persistent minimal residual disease (MRD) in the bone marrow as measured by multidimensional flow cytometry (MDF) is a key early prognostic indicator and is strongly associated with EFS. We therefore hypothesized that obesity during induction would be associated with positive end-of-induction MRD (≥0.01%). We analyzed MDF of end-induction bone marrow samples from a historical cohort of 198 children newly diagnosed with B-precursor ALL (BP-ALL) and treated with Children's Oncology Group induction regimens. We assessed the influence of body mass index on risk for positive end-induction MRD in the bone marrow. In our cohort of BP-ALL, 30 children (15.2%) were overweight and 41 (20.7%) were obese at diagnosis. Independent of established predictors of treatment response, obesity during induction was associated with significantly greater risk for persistent MRD (odds ratio, 2.57; 95% confidence interval, 1.19 to 5.54; P = .016). Obesity and overweight were associated with poorer EFS irrespective of end-induction MRD (P = .012). Obese children with newly diagnosed BP-ALL are at increased risk for positive end-induction MRD and poorer EFS.

Institutional adherence to cardiovascular risk factor screening guidelines for young survivors of acute lymphoblastic leukemia.

Survivors of acute lymphoblastic leukemia have increased risk for long-term cardiovascular complications. Early identification of cardiovascular risk factors (CVRF) may allow for effective interventions. In this retrospective cohort study of 194 patients at Children's Hospital Los Angeles, we investigated CVRF screening practices in an established childhood cancer survivorship program relative to both the Children's Oncology Group (COG) Long-Term Follow-Up Guidelines and American Academy of Pediatrics (AAP) recommendations. CVRF screening practices met COG but not the more stringent AAP recommendations, particularly in areas of dyslipidemia and diabetes screening. Implications of our findings are discussed.

A significant proportion of thalassemia major patients have adrenal insufficiency detectable on provocative testing.

Advances in chelation therapy and noninvasive monitoring of iron overload have resulted in substantial improvements in the survival of transfusion-dependent patients with thalassemia major. Myocardial decompensation and sepsis remain the major causes of death. Although endocrine abnormalities are a well-recognized problem in these iron-overloaded patients, adrenal insufficiency and its consequences are underappreciated by the hematology community. The aims of this study were to determine the prevalence of adrenal insufficiency in thalassemia major subjects, to identify risk factors for adrenal insufficiency, and to localize the origin of the adrenal insufficiency within the hypothalamic-pituitary-adrenal axis. Eighteen subjects with thalassemia major (18.9±9.3 y old, 7 female) were tested for adrenal insufficiency using a glucagon stimulation test. Those found to have adrenal insufficiency (stimulated cortisol <18 µg/dL) subsequently underwent an ovine corticotropin-releasing hormone (oCRH) stimulation test to define the physiological basis for the adrenal insufficiency. The prevalence of adrenal insufficiency was 61%, with an increased prevalence in males over females (92% vs. 29%, P=0.049). Ten of 11 subjects who failed the glucagon stimulation test subsequently demonstrated normal ACTH and cortisol responses to oCRH, indicating a possible hypothalamic origin to their adrenal insufficiency.

Neonatal Graves Disease Masquerading as Hemochromatosis.

Thyroid autoimmunity is extremely common in the adult population and can affect pregnancy outcomes. Signs in the newborn can range from absent to severe, making the diagnosis easy to miss. We present an interesting case of neonatal Graves disease associated with intrauterine growth restriction, premature delivery, and liver failure with severely high ferritin, thought to be secondary to hemochromatosis. Treatment of the underlying hyperthyroidism caused a rapid resolution of the elevated ferritin and liver failure. This report highlights the importance of considering Graves disease in newborns with liver failure of unknown etiology.

Wearable Devices Beyond Activity Trackers in Youth With Obesity: Summary of Options.

Background: Current treatment protocols to prevent and treat pediatric obesity focus on prescriptive lifestyle interventions. However, treatment outcomes are modest due to poor adherence and heterogeneity in responses. Wearable technologies offer a unique solution as they provide real-time biofeedback that could improve adherence to and sustainability of lifestyle interventions. To date, all reviews on wearable devices in pediatric obesity cohorts have only explored biofeedback from physical activity trackers. Hence, we conducted a scoping review to (1) catalog other biofeedback wearable devices available in this cohort, (2) document various metrics collected from these devices, and (3) assess safety and adherence to these devices. Methods: This scoping review was conducted adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews checklist. Fifteen eligible studies examined the use of biofeedback wearable devices beyond activity trackers in pediatric cohorts, with an emphasis on feasibility of these devices. Results: Included studies varied in sample sizes (15-203) and in ages 6-21 years. Wearable devices are being used to capture various metrics of multicomponent weight loss interventions to provide more insights about glycemic variability, cardiometabolic function, sleep, nutrition, and body fat percentage. High safety and adherence rates were reported among these devices. Conclusions: Available evidence suggests that wearable devices have several applications aside from activity tracking, which could modify health behaviors through real-time biofeedback. Overall, these devices appear to be safe and feasible so as to be employed in various settings in the pediatric age group to prevent and treat obesity.

The links between insulin resistance, diabetes, and cancer.

The growing epidemic of obesity has resulted in a large increase in multiple related diseases. Recent evidence has strengthened the proposed synergistic relationship between obesity-related insulin resistance (IR) and/or diabetes mellitus (DM) and cancer. Within the past year, many studies have examined this relationship. Although the precise mechanisms and pathways are uncertain, it is becoming clear that hyperinsulinemia and possibly sustained hyperglycemia are important regulators of not only the development of cancer but also of treatment outcome. Further, clinical decision-making regarding the treatment of choice for DM will likely be impacted as we learn more about the non-metabolic effects of the available hyperglycemic agents. In our review, we endeavored to synthesize the recent literature and provide a concise view of the journey from macro-level clinical associations to specific mechanistic relationships being elucidated in cell lines and animal models.

An addiction-based digital weight loss intervention: A multi-centre randomized controlled trial.

OBJECTIVE: This randomized clinical trial tested the effectiveness of an addiction-based digital weight-loss intervention, focusing on withdrawal/abstinence from self-identified problem foods, snacking and excessive amounts at meals, and discomfort displacement, with and without coaching, compared to an in-person, multi-disciplinary, care model among adolescents with obesity. We hypothesized that the digital intervention with coaching would yield greater weight loss and lower delivery burden than the standard clinical arm, and greater participant engagement than the digital arm without coaching. METHODS: Adolescents were randomized to app intervention, with or without coaching, or in-person multidisciplinary obesity intervention for 6 months. The primary outcome was change in %BMIp95 at weeks 12 and 24. A mixed-effects linear regression model was used to assess the association between change in %BMIp95 and intervention arm. We were also interested in assessing delivery burden, participant engagement and evaluating the relationships between weight change and demographic characteristics, mood, executive function and eating behaviours. RESULTS: All adolescents (n = 161; BMI ≥95th%, age 16 ± 2.5 year; 47% Hispanic, 65% female, 59% publicly insured) lost weight over 24-weeks (-1.29%, [-1.82, -0.76], p < 0.0001), with no significant weight loss difference between groups (p = 0.3). Girls lost more weight than boys, whereas binge eating behaviour at baseline was associated with increase in %BMIp95 when controlling for other covariates. There was no association between ethnicity, mood, timing of intervention in relation to the pandemic, or executive function and change in %BMIp95 . CONCLUSIONS: Contrary with our hypothesis, our results showed no difference in the change in BMI status between treatment arms. Since efficacy of this digital intervention was not inferior to in-person, multi-disciplinary care, this could offer a reasonable weight management option for clinicians, based on youth and family specific characteristics, such as accessibility, resources, and communication styles. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT035008353.

Fasting-Mimicking Diet Inhibits Autophagy and Synergizes with Chemotherapy to Promote T-Cell-Dependent Leukemia-Free Survival.

Fasting mimicking diets (FMDs) are effective in the treatment of many solid tumors in mouse models, but their effect on hematologic malignancies is poorly understood, particularly in combination with standard therapies. Here we show that cycles of a 3-day FMD given to high-fat-diet-fed mice once a week increased the efficacy of vincristine to improve survival from BCR-ABL B acute lymphoblastic leukemia (ALL). In mice fed a standard diet, FMD cycles in combination with vincristine promoted cancer-free survival. RNA seq and protein assays revealed a vincristine-dependent decrease in the expression of multiple autophagy markers, which was exacerbated by the fasting/FMD conditions. The autophagy inhibitor chloroquine could substitute for fasting/FMD to promote cancer-free survival in combination with vincristine. In vitro, targeted inhibition of autophagy genes ULK1 and ATG9a strongly potentiated vincristine's toxicity. Moreover, anti-CD8 antibodies reversed the effects of vincristine plus fasting/FMD in promoting leukemia-free survival in mice, indicating a central role of the immune system in this response. Thus, the inhibition of autophagy and enhancement of immune responses appear to be mediators of the fasting/FMD-dependent cancer-free survival in ALL mice.

Sleep fragmentation and intermittent hypoxemia are associated with decreased insulin sensitivity in obese adolescent Latino males.

BACKGROUND: Although sleep-related breathing disorder (SRBD) has been linked to insulin resistance in adults, this has not been as well established in children. We hypothesized that the severity of SRBD in adolescents was associated with metabolic impairment. METHODS: Polysomnography was performed on obese, Latino males referred for snoring. The frequently sampled intravenous glucose tolerance test was used to assess glucose homeostasis. Total-body dual-energy X-ray absorptiometry was used to quantify adiposity. RESULTS: A total of 22 males (mean age ± SD: 13.4 ± 2.1 y, BMI z-score 2.4 ± 0.3, obstructive apnea hypopnea index 4.1 ± 3.2) were studied. After correcting for age and adiposity in multiple-regression models, Log frequency of desaturation (defined as ≥3% drop in oxygen saturation from baseline) negatively correlated with insulin sensitivity. Sleep efficiency was positively correlated with glucose effectiveness (S(G), the capacity of glucose to mediate its own disposal). The Log total arousal index was positively correlated with Log homeostasis model assessment-estimated insulin resistance. CONCLUSION: Sleep fragmentation and intermittent hypoxemia are associated with metabolic impairment in obese adolescent Latino males independent of age and adiposity. We speculate that SRBD potentiates the risk for development of metabolic syndrome and type 2 diabetes in the obese adolescent population.

Pancreatic iron and glucose dysregulation in thalassemia major.

Pancreatic iron overload and diabetes mellitus (DM) are common in thalassemia major patients. However, the relationship between iron stores and glucose disturbances is not well defined. We used a frequently sampled oral glucose tolerance test (OGTT), coupled with mathematical modeling, and magnetic resonance imaging (MRI) to examine the impact of pancreatic, cardiac, and hepatic iron overload on glucose regulation in 59 patients with thalassemia major. According to OGTT results, 11 patients had DM, 12 had impaired glucose tolerance (IGT), 8 had isolated impaired fasting glucose (IFG), and 28 patients had normal glucose tolerance (NGT). Patients with DM had significantly impaired insulin sensitivity and insulin release. Insulin resistance was most strongly associated with markers of inflammation and somatic iron overload, while disposition index (DI) (a measure of beta cell function) was most strongly correlated with pancreas R2*. Patients with DM and IGT had significantly worse DI than those with NGT or IFG, suggesting significant beta cell toxicity. One-third of patients having elevated pancreas R2* had normal glucose regulation (preclinical iron burden), but these patients were younger and had lower hepatic iron burdens. Our study indicates that pancreatic iron is the strongest predictor of beta cell toxicity, but total body iron burden, age, and body habitus also influence glucose regulation. We also demonstrate that MRI and fasting glucose/insulin are complementary screening tools, reducing the need for oral glucose tolerance testing, and identify high-risk patients before irreversible pancreatic damage.

Pituitary iron and volume predict hypogonadism in transfusional iron overload.

Hypogonadism is the most common morbidity in patients with transfusion-dependent anemias such as thalassemia major. We used magnetic resonance imaging (MRI) to measure pituitary R2 (iron) and volume to determine at what age these patients develop pituitary iron overload and volume loss. We recruited 56 patients (47 with thalassemia major, five with chronically transfused thalassemia intermedia and four with Blackfan-Diamond syndrome) to have pituitary MRIs to measure pituitary R2 and volume. Hypogonadism was defined clinically based on the timing of secondary sexual characteristics or the need for sex hormone replacement therapy. Patients with transfusional iron overload begin to develop pituitary iron overload in the first decade of life; however, clinically significant volume loss was not observed until the second decade of life. Severe pituitary iron deposition (Z > 5) and volume loss (Z < -2.5) were independently predictive of hypogonadism. Pituitary R2 correlated significantly with serum ferritin as well as liver, pancreatic, and cardiac iron deposition by MRI. Log pancreas R2* was the best single predictor for pituitary iron, with an area under the receiving operator characteristic curve of 0.88, but log cardiac R2* and ferritin were retained on multivariate regression with a combined r(2) of 0.71. Pituitary iron overload and volume loss were independently predictive of hypogonadism. Many patients with moderate-to-severe pituitary iron overload retained normal gland volume and function, representing a potential therapeutic window. The subset of hypogonadal patients having preserved gland volumes may also explain improvements in pituitary function observed following intensive chelation therapy.

Obese Skeletal Muscle-Expressed Interferon Regulatory Factor 4 Transcriptionally Regulates Mitochondrial Branched-Chain Aminotransferase Reprogramming Metabolome.

In addition to the significant role in physical activity, skeletal muscle also contributes to health through the storage and use of macronutrients associated with energy homeostasis. However, the mechanisms of regulating integrated metabolism in skeletal muscle are not well-defined. Here, we compared the skeletal muscle transcriptome from obese and lean control subjects in different species (human and mouse) and found that interferon regulatory factor 4 (IRF4), an inflammation-immune transcription factor, conservatively increased in obese subjects. Thus, we investigated whether IRF4 gain of function in the skeletal muscle predisposed to obesity and insulin resistance. Conversely, mice with specific IRF4 loss in skeletal muscle showed protection against the metabolic effects of high-fat diet, increased branched-chain amino acids (BCAA) level of serum and muscle, and reprogrammed metabolome in serum. Mechanistically, IRF4 could transcriptionally upregulate mitochondrial branched-chain aminotransferase (BCATm) expression; subsequently, the enhanced BCATm could counteract the effects caused by IRF4 deletion. Furthermore, we demonstrated that IRF4 ablation in skeletal muscle enhanced mitochondrial activity, BCAA, and fatty acid oxidation in a BCATm-dependent manner. Taken together, these studies, for the first time, established IRF4 as a novel metabolic driver of macronutrients via BCATm in skeletal muscle in terms of diet-induced obesity.

Targeting Adiposity and Inflammation With Movement to Improve Prognosis in Breast Cancer Survivors (The AIM Trial): Rationale, Design, and Methods.

Background: Obesity is a significant contributor to breast cancer recurrence and mortality. A central mechanism by which obesity stimulates cancer progression is through chronic, low-grade inflammation in adipose tissue. Exercise interventions to target chronic inflammation has a potential to improve obesity- and breast cancer-related outcomes; however, no studies have investigated the roles of exercise in modulating adipose tissue inflammation in breast cancer survivors. Also, it is unclear which exercise prescription would be optimal to maximize the outcomes. Therefore, we designed a randomized controlled trial (Taking AIM at Breast Cancer: Targeting Adiposity and Inflammation with Movement to Improve Prognosis in Breast Cancer Survivors [AIM] Trial) to examine the mechanisms by which different modalities of exercise impact chronic inflammation as a biomarker of breast cancer prognosis. Methods: The AIM trial is a prospective, three-armed, phase II randomized controlled trial investigating the effects of a 16-week supervised circuit aerobic and resistance exercise (CARE) program versus a traditional aerobic and resistance exercise (TARE) program and attention control (AC) on adipose tissue inflammation in breast cancer survivors. 276 patients who are diagnosed with stage 0-III breast cancer, post-treatment, sedentary, and centrally obese are randomized to one of the three groups. The CARE and TARE groups participate in thrice-weekly supervised exercise sessions for 16 weeks. The AC group are offered the CARE program after the intervention period. The primary endpoint is adipose tissue inflammation assessed by core biopsy and blood draw. The secondary and tertiary endpoints are sarcopenic obesity, physical fitness and function, and patient reported outcomes. The exploratory outcomes are long-term breast cancer outcomes. Discussion: This is the first randomized controlled trial examining the effects of exercise on adipose tissue inflammation in obese, breast cancer survivors. Our findings are anticipated to contribute to a better understanding of exercise modalities and mechanisms on adipose tissue inflammation that can potentially improve breast cancer prognosis. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03091842 identifier [NCT#03091842].