HUNK Phosphorylates Rubicon to Support Autophagy

Background: Autophagy is a catabolic cellular recycling pathway that is essential for maintaining intracellular homeostasis. Autophagosome formation is achieved via the coordination of the Beclin-1 protein complex. Rubicon is a Beclin-1 associated protein that suppresses autophagy by impairing the activity of the class III PI3K, Vps34. However, very little is known about the molecular mechanisms that regulate Rubicon function. Methods: In this study, co-immunoprecipitation and kinase assays were used to investigate the ability of Hormonally Upregulated Neu-associated Kinase (HUNK) to bind to and phosphorylate Rubicon. LC3B was monitored by immunofluorescence and immunoblotting to determine whether phosphorylation of Rubicon by HUNK controls the autophagy suppressive function of Rubicon. Results: Findings from this study identify Rubicon as a novel substrate of HUNK and show that phosphorylation of Rubicon inhibits its function, promoting autophagy

A comparison of skinfolds and leg-to-leg bioelectrical impedance for the assessment of body composition in children

BACKGROUND: This field-based investigation examined the congruence between skinfolds and bioelectrical impedance in assessing body composition in children. METHODS: Subjects were 162 female and 160 male children 10–15 years of age. Skinfold measures obtained at the triceps and medial calf and a leg-to-leg bioelectrical impedance system were used to determine percent fat using child-specific equations. Pearson product moment correlations were performed on the percent fat values obtained using skinfolds and bioelectric impedance for the entire data set. Separate correlations were also conducted on gender and age/gender subsets. Dependent t tests were used to compare the two techniques. RESULTS: Percent fat did not differ between skinfolds and bioelectrical impedance for the total subject pool. Bioelectrical impedance overestimated percent fat in girls by 2.6% and underestimated percent fat in boys by 1.7% (p < 0.01). Correlations between skinfolds and bioelectrical impedance ranged from r = 0.51 to r = 0.90. CONCLUSIONS: Leg-to-leg bioelectrical impedance may be a viable alternative field assessment technique that is comparable to skinfolds. The small differences in percent fat between the two techniques may have limited practical significance in school-based health-fitness settings

A comparison of skinfolds and leg-to-leg bioelectrical impedance for the assessment of body composition in children

BACKGROUND: This field-based investigation examined the congruence between skinfolds and bioelectrical impedance in assessing body composition in children. METHODS: Subjects were 162 female and 160 male children 10–15 years of age. Skinfold measures obtained at the triceps and medial calf and a leg-to-leg bioelectrical impedance system were used to determine percent fat using child-specific equations. Pearson product moment correlations were performed on the percent fat values obtained using skinfolds and bioelectric impedance for the entire data set. Separate correlations were also conducted on gender and age/gender subsets. Dependent t tests were used to compare the two techniques. RESULTS: Percent fat did not differ between skinfolds and bioelectrical impedance for the total subject pool. Bioelectrical impedance overestimated percent fat in girls by 2.6% and underestimated percent fat in boys by 1.7% (p < 0.01). Correlations between skinfolds and bioelectrical impedance ranged from r = 0.51 to r = 0.90. CONCLUSIONS: Leg-to-leg bioelectrical impedance may be a viable alternative field assessment technique that is comparable to skinfolds. The small differences in percent fat between the two techniques may have limited practical significance in school-based health-fitness settings

Associations between physical activity, sedentary behaviour, and alcohol consumption among UK adults: Findings from the Health Behaviours during the COVID-19 pandemic (HEBECO) study

Introduction The COVID-19 pandemic and attendant lockdowns have had a substantial negative effect on alcohol consumption and physical activity globally. Pre-pandemic evidence in the adult population suggests that higher levels of physical activity were associated with higher levels of drinking, but it is unclear how the pandemic may have affected this. Therefore, this study aims to assess the association between alcohol consumption and physical activity in a UK cohort established during the COVID-19 pandemic. Methods Analyses utilized data from the Health Behaviours during the COVID-19 pandemic (HEBECO) study involving 2,057 UK adults (≥18 years). Participants completed self-report measures of alcohol consumption [frequency, quantity, frequency of heavy episodic drinking (HED) and AUDIT-C score] and physical activity [moderate-vigorous physical activity (MVPA), frequency of muscle strengthening activity (MSA) and sedentary behaviour] between November 2020 and January 2021. Ordinal logistic regression models were conducted, adjusting for sociodemographic factors. Results Fifteen percent of the sample reported abstinence from drinking. Overall, 23.4% of participants drank ≥4 times/week, 13.9% drank more than 6 units/single drinking occasion (HED), 7.5% reported HED daily/almost daily and 4.2% scored ≥11 on AUDIT-C. MSA 3 days/ week compared with no MSA was significantly associated with higher odds of alcohol frequency [OR (95 CI%) = 1.41 (1.04–1.91)], quantity [OR (95 CI%) = 1.38 (1.02–1.87)], HED [OR (95 CI%) = 1.42 (1.05–1.94)] and possible dependence [OR (95 CI%) = 1.47 (1.05–2.06)]. The association of MVPA and sedentary behaviour with drinking measures was not significant (p>0.05). Conclusion In contrast with previous research, MSA rather than aerobic physical activity was associated with increased alcohol consumption during the COVID-19 pandemic. It is conceivable that during lockdown while drinking was used as a coping strategy, limited opportunities for aerobic exercise made MSA a more convenient form of physical activity. To guide public health interventions, more research is required to examine the temporal relationship between different forms of physical activity and alcohol consumption

NF-κB Signaling Is Regulated by Fucosylation in Metastatic Breast Cancer Cells

A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis of 4T1 metastatic mammary tumor cells in the presence and absence of a fucosylation inhibitor, 2-fluorofucose (2FF). Of significant interest, pathway analysis based on our results revealed a reduction in the NF-κB and TNF signaling pathways, which regulate the inflammatory response. NF-κB is a transcription factor that is pro-tumorigenic and a prime target in human cancer. We validated our results, confirming that treatment of 4T1 cells with 2FF led to a decrease in NF-κB activity through increased IκBα. Based on these observations, we conclude that fucosylation is an important post-translational modification that governs breast cancer cell signaling

Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status

INTRODUCTION: Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk. METHODS: We developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status. RESULTS: We identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors. CONCLUSIONS: Our data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors

Trends in deceased donor liver enzymes prior to transplant: The impact on graft selection and outcomes

We sought to characterize the trend in alanine aminotransferase elevations prior to transplant and the impact on the pattern of enzyme elevations on organ utilization and graft function. We performed a retrospective cohort study of UNOS data on all deceased donors between 2007 and 2016. Serum alanine aminotransferase (ALT) was categorized into six study groups with peak ALT 3000 IU/L. The change from peak ALT to terminal ALT prior to transplant was categorized as no change/increasing at time transplant, 0.1-9.9%, 10-24.9%, 25-49.9%, 50-74.9% and >75% change. In multivariable models evaluating liver utilization, the interaction between peak ALT and percent change in ALT was most pronounced at the highest peak ALT levels, where liver utilization varied markedly as a function of percentage drop from peak to terminal ALT. There was no increased risk of graft failure based on peak ALT. Markers of ischemic liver injury and recovery are significantly associated with liver utilization, yet among transplanted livers they were not associated with graft outcomes and may represent an area to expand the donor pool

Co-Targeting of JNK and HUNK in Resistant HER2-Positive Breast Cancer

<div><p>Strategies for successful primary treatment of HER2-positive breast cancer include use of the HER2 inhibitors trastuzumab or lapatinib in combination with standard chemotherapy. While successful, many patients develop resistance to these HER2 inhibitors indicating an unmet need. Consequently, current research efforts are geared toward understanding mechanisms of resistance and the signaling modalities that regulate these mechanisms. We have undertaken a study to examine whether signaling molecules downstream of epidermal growth factor receptor, which often act as compensatory signaling outlets to circumvent HER2 inhibition, can be co-targeted to overcome resistance. We identified JNK signaling as a potential area of intervention and now show that inhibiting JNK using the pan-JNK inhibitor, SP600125, is effective in the HER2-positive, resistant JIMT-1 xenograft mammary tumor model. We also investigate potential combination strategies to bolster the effects of JNK inhibition and find that co-targeting of JNK and the protein kinase HUNK can prohibit tumor growth of resistant HER2-positive mammary tumors <i>in vivo</i>.</p></div