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PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer
Get PDFTo grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines2, in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates—7-dehydrocholesterol and 7-dehydrodesmosterol—with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC
Blood pressure is associated with ultra-processed food intake in a sex- and age-specific manner during the transition to adulthood in Cebu, Philippines.
Get PDFProgression toward elevated blood pressure (BP) may begin as early as adolescence. In low- and middle-income countries (LMICs), consumption of ultra-processed foods (UPFs), which are linked to poor cardiometabolic health, is often highest in adolescence. We examined sex- and age-specific associations of systolic and diastolic BP (SBP and DBP) with concurrent and lagged UPF intake from age 15 to 25 in a Filipino cohort. We used data from the 1998-2009 waves of the Cebu Longitudinal Health and Nutrition Survey (n=2,124, 52% male); participants were 15, 18, 21, and 25 years old. UPFs (% daily kilocalories) were classified using NOVA. Linear mixed-effects models estimated differences in SBP and DBP associated with a 5-percentage point difference in concurrent and lagged UPF intake (3-4 years earlier). Mean UPF intake was 10-11% of total energy intake among males and 14-17% among females over the study period. At age 21, intake of ultra-processed meats and fish was positively associated with DBP (β=0.48 [95% CI: 0.02, 0.94]) among males and intake of ultra-processed sugary beverages was positively associated with SBP (0.80 [0.13, 1.48]) and DBP (0.93 [0.34, 1.51]) among females. Among females only, SBP at age 18 was positively associated with total UPF intake at age 15 (0.25 [0.00, 0.50]). In this cohort, there were modest, positive associations between BP and UPF intake, which varied by sex and age. UPF intake during the transition to adulthood may be linked to higher BP, supporting efforts to limit adolescents' intake in LMICs
From Symptom to Outcome: Defining Clinically Meaningful Patient‐Reported Appetite Loss in Non‐Small‐Cell Lung Cancer
Get PDFBACKGROUND: Appetite loss is a common and distressing symptom in non-small-cell lung cancer (NSCLC), driven by both treatment side effects and disease progression. It often leads to unintended weight loss and cancer cachexia, significantly impairing patients' quality of life and survival. Yet, appetite loss remains under-recognized in oncology care, with no standard assessment tools or universal management guidelines. In this study, we developed a predictive model to identify clinically meaningful thresholds of appetite loss that were associated with significant weight reduction and decreased survival. We aim to highlight the clinical consequences of appetite loss and advocate for more patient-centred treatment strategies that address this often overlooked but impactful symptom in cancer care. METHODS: We analysed longitudinal patient-reported appetite scores, measured by the Lung Cancer Symptom Scale (LCSS), and body weight data from 476 NSCLC patients receiving supportive care and recovering from prior chemoradiotherapy (recovering cohort). A mechanism-based population modelling approach was used to predict the impact of appetite changes on body weight, accounting for significant data variability. Model validation was conducted using data from 380 NSCLC patients undergoing docetaxel chemotherapy (chemotherapy cohort). Clinically meaningful appetite loss thresholds were determined based on the model-predicted appetite loss associated with a 3.5-kg body weight loss and significantly worse survival (hazard ratio > 1, p < 0.05). RESULTS: We found that, according to the LCSS (100-mm visual analogue scale), a 30-mm (90% CI, 28-32) improvement in appetite corresponded to a 3.5-kg weight gain in the recovering cohort, while a 23-mm (90% CI, 17-30) decline correlated with a 3.5-kg weight loss in the chemotherapy cohort. Significant associations were observed between appetite loss trajectories and overall survival (p < 0.001). Clinically meaningful thresholds for appetite loss were identified as 4 mm at 1 month and 11 mm at 3 months, both significantly associated with reduced OS in patients receiving docetaxel chemotherapy (p < 0.05). CONCLUSIONS: We developed a population predictive model to characterize the relationship between patient-reported appetite and body weight, identifying clinically meaningful thresholds for appetite loss. This work highlights the importance of managing appetite loss in oncology care and supports its use as a quantitative endpoint in clinical trials and practice
Topical versus oral metronidazole for post‐haemorrhoidectomy pain: A systematic review and meta‐analysis of randomized controlled trials
Get PDFBACKGROUND: Excisional haemorrhoidectomy is often associated with intense post-operative pain and delayed recovery. Bacterial colonization may contribute to this discomfort, and metronidazole has been proposed as an analgesic adjunct. This study compared the analgesic efficacy of topical metronidazole with oral metronidazole. METHODS: A systematic search was conducted in PubMed, Scopus, and the Cochrane Central Register through May 2025. Randomized controlled trials comparing topical metronidazole with oral metronidazole for post-operative pain after haemorrhoidectomy were included. Visual analogue scale (VAS) scores on post-operative days 1, 3, and 7 were pooled. Mean differences (MDs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Heterogeneity was assessed with the I2 statistic. Risk of bias (RoB 2) and certainty of evidence (GRADE) were evaluated. RESULTS: Four RCTs involving 439 patients (218 topical, 221 oral) met inclusion criteria. No significant differences were found between topical and oral metronidazole at day 1 (MD -0.1; 95% CI -0.3 to 0.2; I2 = 25%), day 3 (MD -0.4; 95% CI -1.3 to 0.6; I2 = 94%), or day 7 (MD -0.2; 95% CI -1.0 to 0.5; I2 = 90%). CONCLUSION: Topical and oral metronidazole showed similar short-term analgesic efficacy after haemorrhoidectomy
Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy
Get PDFWe analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA–nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA–nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied
The Use of Solitary Confinement and In-Custody Mortality in North Carolina State Prisons, 2021-2023
Get PDFPurpose Solitary confinement is associated with increased mortality post-release. Little is known about its use following recent reforms and COVID-19 challenges, and its association with in-custody deaths. We investigated patterns of and associations between solitary confinement and mortality in North Carolina (NC) state prisons. Methods Using weekly housing data from Disability Rights NC, we created a retrospective cohort of those newly incarcerated in NC prisons between 2021-2023. We calculated the weekly proportion of individuals experiencing solitary confinement for 2+ weeks by type (e.g., administrative purposes). We calculated all-cause mortality rates stratified by those who did and did not experience solitary confinement. Results Nearly one-quarter of 41,525 individuals in NC state prisons experienced solitary confinement. By the end of follow-up, over 6.0% of individuals were in solitary confinement per week, and there were 43 in-custody deaths. Those who never experienced solitary confinement had an all-cause mortality rate of 1.96 per 100,000 person-weeks (95% CI: 1.32, 2.82), and those who experienced solitary confinement had an all-cause mortality rate of 4.23 per 100,000 person-weeks (95% CI: 2.31, 7.09). Conclusions Solitary confinement is common in NC prisons and is associated with elevated death rates in custody. There is an urgent need to document the types and duration of solitary stays to ultimately end this punitive practice
A luminescence-based biosensor to measure endogenous UBE3A activity
Get PDFLoss- and gain-of-function (LOF and GOF) mutations in the E3 ubiquitin ligase UBE3A cause distinct neurodevelopmental disorders. The AZUL domain of UBE3A binds with low nanomolar affinity to a 45 amino acid (aa) region of PSMD4. We fused this 45-aa sequence to Firefly luciferase to generate a luminescence-based biosensor, Firefly-45aa, that acts as an artificial UBE3A substrate and exhibits exceptional sensitivity at measuring UBE3A activity. Testing UBE3A variants using Firefly-45aa in HEK293T cells revealed distinct biosensor activity profiles, enabling classification of LOF and GOF mutations based on maximum activity, inhibitory concentration-50 and activity per unit of protein. Some strong LOF mutations had dominant negative activity. In addition, Firefly-45aa can be used to quantify endogenous UBE3A activity in primary cells from Angelman syndrome and GOF mouse models. This biosensor reveals a mutational spectrum of UBE3A enzyme activity and is a sensitive tool for functional characterization and therapeutic development in UBE3A-related disorders
Pseudomonas aeruginosa differentially influences antibiotic-resistant Staphylococcus aureus emergence and expansion in hyperglycemic environments.
Get PDFIndividuals with poorly controlled diabetes mellitus often develop multispecies skin and soft tissue infections, with Staphylococcus aureus and Pseudomonas aeruginosa among the most prevalent bacteria isolated from infection sites worldwide. Diabetic infections are recalcitrant to conventional antibiotic regimens and may be a reservoir for emergent antibiotic-resistant bacterial strains. Supporting this, we have previously shown that rifampicin treatment elicits the emergence and expansion of rifampicin-resistant (Rif-r) S. aureus only in diabetic mice, potentially due to greater bacterial outgrowth increasing the frequency of resistance-conferring mutations. However, whether S. aureus exhibits altered resistance outcomes during multispecies diabetic infections is unclear. During co-infection with P. aeruginosa under normoglycemic conditions, S. aureus exhibits reduced growth and altered susceptibility to several antibiotics. In contrast, we previously observed that glucose availability allows S. aureus to largely overcome P. aeruginosa-mediated growth inhibition. Here, we explored S. aureus resistance outcomes under hyperglycemic conditions in the context of co-infection with P. aeruginosa during antibiotic challenge. We found that P. aeruginosa exoproducts regulated by the Pseudomonas quinolone signal quorum sensing system inhibit the emergence but not the expansion of Rif-r S. aureus in vitro under glucose-replete conditions. In contrast, we recovered equivalent Rif-r S. aureus burdens from diabetic mice during mono- and co-infection with P. aeruginosa. These results demonstrate that the diabetic infection microenvironment is conducive to emergent Rif-r S. aureus despite external pressures elicited by P. aeruginosa.IMPORTANCEPoorly controlled diabetes mellitus confers an increased susceptibility to bacterial infections, with Staphylococcus aureus and Pseudomonas aeruginosa frequently isolated from diabetic skin wounds. S. aureus readily develops antibiotic resistance during diabetic mono-infection under antibiotic pressure, but whether this occurs during diabetic co-infection is unclear. Under normoglycemic conditions, secreted P. aeruginosa factors alter S. aureus tolerance to several antibiotics. Here, we show that these P. aeruginosa exoproducts further inhibit the emergence of antibiotic-resistant S. aureus regardless of glucose availability in vitro, but this does not occur during subcutaneous co-infection in diabetic mice. These results provide initial insights regarding conditions that may inhibit S. aureus resistance development in hyperglycemic environments but underscore the influence of the host infection microenvironment in shaping resistance outcomes
N ‑Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad-Spectrum Antialphaviral Activity
Get PDFThe emergence of mosquito-borne alphaviruses that cause chronic arthritis or encephalitis underscores the urgent need for broad-spectrum antiviral therapeutics. The viral nsP2 cysteine protease, which is essential for alphavirus replication, is a promising antiviral target. Vinyl sulfone covalent inhibitors potently inhibit nsP2 protease but suffer from glutathione reactivity and species-dependent systemic clearance catalyzed by glutathione S-transferase. To address these liabilities, we explored alternative electrophilic warheads and identified acetamide inhibitors bearing N-alkyl sulfamate warheads with improved biochemical and antiviral profiles. 2-((5-(2-Ethoxyphenyl)-1H-pyrazol-3-yl)amino)-2-oxoethyl methylsulfamate emerged as a lead compound with potency against New and Old World alphaviruses, low GSH reactivity, and proteome-wide selectivity. Despite its promising antialphaviral activity, 2-((5-(2-ethoxyphenyl)-1H-pyrazol-3-yl)amino)-2-oxoethyl methylsulfamate exhibited rapid clearance due to hepatic glucuronidation. Structure-activity studies revealed modifications that improve metabolic stability while retaining antiviral activity. These findings introduce sulfamate acetamides as a new class of covalent nsP2 protease inhibitors and direct-acting pan-alphavirus drugs
Clinician documentation of social circumstances of older and younger women receiving chemotherapy for early breast cancer
Get PDFBACKGROUND: The Institute of Medicine (IOM) recommends that essential aspects of a patient's sociodemographic, psychological and behavioral characteristics be documented in the electronic health record (EMR). PATIENTS AND METHODS: For this study of women receiving chemotherapy for early breast cancer (Stage I-III), EMR clinician notes were queried with regard to documentation of the patient's current (1) living situation, (2) caregiver responsibilities, and (3) accompaniment during chemotherapy. Descriptive statistics for patient sociodemographic and tumor characteristics, and clinician-reported social circumstances were reported for older and younger patients and compared between two age groups using Fisher's exact tests for categorical variables and t-tests for continuous variables. RESULTS: The sample includes 104 women aged 65 or older (range 65-83) (17% Black) and 250 under age 65 (range 23-64) (22% Black). Mean number of comorbidities was 3.7 (range 0-8) among older patients and 1.7 (range 0-9) among younger patients (p<.0001). There were no significant inter-group differences in breast cancer stage or phenotype. Clinician notes affirmatively documented that the patient was living with someone (70% older/85% younger) (p=.002), the patient had caregiver responsibilities (12% older/44% younger) (p<.0001) and was accompanied by someone during chemotherapy (79% older/89% younger) (p=.02). CONCLUSION: Clinician notes pertaining to younger patients as compared to older patients more often provided affirmative and specific documentation that the patient was living with someone, a caregiver for someone, and accompanied by someone during the chemotherapy infusion visit. These three factors are important to document and monitor in patients of all ages as they can impact treatment experience and quality of life during and after chemotherapy