Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

Alzheimer-Type Cerebral Amyloidosis in the Context of HIV Infection: Implications for a Proposed New Treatment Approach.

Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.

Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling.

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Development and impact of a tailored eHealth resource on fibromyalgia patient's self-management and self-efficacy: A mixed methods approach.

Aim: To develop an eHealth resource to support fibromyalgia patients and explore it for usability and impact on their self-management and self-efficacy. Background: Fibromyalgia is a complex, non-progressive chronic condition characterised by a bewildering array of symptoms for patients to self-manage. International guidelines recommend patients receive illness-specific information once diagnosed to promote self-management and improve health-related quality of life. Design: A 3-phase mixed methods exploratory sequential design. Methods: Qualitative interviews explored the information and self-management needs of fibromyalgia patients attending a large tertiary hospital in Dublin. Identified themes together with an extensive review of the literature of interventions proven to be impactful by patients with fibromyalgia were utilised in the design and development of the eHealth resource. The resource was tested for usability and impact using pre and post-intervention outcomes measures. Results: Patient interviews highlighted a lack of easy accessible evidenced information to support self-management implicating the urgent need for a practical solution through development of a tailored eHealth resource. Six themes emerged for inclusion; illness knowledge, primary symptoms, treatment options, self-management strategies, practical support and reliable resources. Forty-five patients who tested the site for usability and impact demonstrated a statistically significant improvement in self-efficacy after 4 weeks access with a medium positive effect size. Patients with the most severe fibromyalgia impact scores pre-intervention demonstrated the most improvement after 4 weeks. Patients gave the resource a System Usability Score A rating, highly recommending it for fellow patients diagnosed with fibromyalgia. Conclusions: The study demonstrated how the development of a novel eHealth resource positively impacted fibromyalgia patients' self-efficacy to cope with this debilitating condition. Impact: This study suggests that access to eHealth can positively impact patients self-efficacy, has the potential to be a template for eHealth development in other chronic conditions, supporting advanced nurse practitioners working in chronic disease management.

Hippo-YAP/TAZ signalling coordinates adipose plasticity and energy balance by uncoupling leptin expression from fat mass.

Adipose tissues serve as an energy reservoir and endocrine organ, yet the mechanisms that coordinate these functions remain elusive. Here, we show that the transcriptional coregulators, YAP and TAZ, uncouple fat mass from leptin levels and regulate adipocyte plasticity to maintain metabolic homeostasis. Activating YAP/TAZ signalling in adipocytes by deletion of the upstream regulators Lats1 and Lats2 results in a profound reduction in fat mass by converting mature adipocytes into delipidated progenitor-like cells, but does not cause lipodystrophy-related metabolic dysfunction, due to a paradoxical increase in circulating leptin levels. Mechanistically, we demonstrate that YAP/TAZ-TEAD signalling upregulates leptin expression by directly binding to an upstream enhancer site of the leptin gene. We further show that YAP/TAZ activity is associated with, and functionally required for, leptin regulation during fasting and refeeding. These results suggest that adipocyte Hippo-YAP/TAZ signalling constitutes a nexus for coordinating adipose tissue lipid storage capacity and systemic energy balance through the regulation of adipocyte plasticity and leptin gene transcription.

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models.

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.

Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spatial niches of T cells and macrophages increased with clonal neoantigen burden, whereas such an increase was observed for niches of plasma and B cells in immune-excluded squamous cell carcinomas (LUSC). Immune-low TMEs were associated with fibroblast barriers to immune infiltration. The fourth archetype, characterized by sparse lymphocytes and high tumor-associated neutrophil (TAN) infiltration, had tumor cells spatially separated from vasculature and exhibited low spatial intratumor heterogeneity. TAN-high LUSC had frequent PIK3CA mutations. TAN-high tumors harbored recently expanded and metastasis-seeding subclones and had a shorter disease-free survival independent of stage. These findings delineate genomic, immune, and physical barriers to immune surveillance and implicate neutrophil-rich TMEs in metastasis. SIGNIFICANCE: This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897.

Transcutaneous Ablation of Lung Tissue in a Porcine Model Using Magnetic-Resonance-Guided Focused Ultrasound (MRgFUS).

Focused ultrasound (FUS) is a minimally invasive treatment that utilizes high-energy ultrasound waves to thermally ablate tissue. Magnetic resonance imaging (MRI) guidance may be combined with FUS (MRgFUS) to increase its accuracy and has been proposed for lung tumor ablation/debulking. However, the lungs are predominantly filled with air, which attenuates the strength of the FUS beam. This investigation aimed to test the feasibility of a new approach using an intentional lung collapse to reduce the amount of air inside the lung and a controlled hydrothorax to create an acoustic window for transcutaneous MRgFUS lung ablation. Eleven pigs had one lung mechanically ventilated while the other lung underwent a controlled collapse and subsequent hydrothorax of that hemisphere. The MRgFUS lung ablations were then conducted via the intercostal space. All the animals recovered well and remained healthy in the week following the FUS treatment. The location and size of the ablations were confirmed one week post-treatment via MRI, necropsy, and histological analysis. The animals had almost no side effects and the skin burns were completely eliminated after the first two animal studies, following technique refinement. This study introduces a novel methodology of MRgFUS that can be used to treat deep lung parenchyma in a safe and viable manner.

Radiosensitization of Allogenic Subcutaneous C6 Glioma Model with Focused Ultrasound-Induced Mild Hyperthermia.

The radiosensitization potential of focused ultrasound (FUS)-induced mild hyperthermia was assessed in an allogenic subcutaneous C6 glioma tumor model in rats. Mild hyperthermia at 42 °C was induced in tumors using a single-element 350 kHz FUS transducer. Radiation was delivered with a small animal radiation research platform using a single-beam irradiation technique. The combined treatment involved 20 min of FUS hyperthermia immediately before radiation. Tumor growth changes were observed one week post-treatment. A radiation dose of 2 Gy alone showed limited tumor control (30% reduction). However, when combined with FUS hyperthermia, there was a significant reduction in tumor growth compared to other treatments (tumor volumes: control-1174 ± 554 mm3, FUS-HT-1483 ± 702 mm3, 2 Gy-609 ± 300 mm3, FUS-HT + 2 Gy-259 ± 186 mm3; ANOVA p < 0.00001). Immunohistological analysis suggested increased DNA damage as a short-term mechanism for tumor control in the combined treatment. In conclusion, FUS-induced mild hyperthermia can enhance the effectiveness of radiation in a glioma tumor model, potentially improving the outcome of standard radiation treatments for better tumor control.

Functional Outcomes of Congenital Scoliosis at a Mean 35-Year Follow-up Post In Situ Fusion. Revisiting Patients From the 2002 Goldberg et al Study.

BACKGROUND: The management of congenital scoliosis poses a significant challenge for treating surgeons. The aim of our study was to provide insight into the long-term clinical results of spinal fusion in congenital scoliosis. METHODS: We performed a retrospective review of the scoliosis database in our institution for the period 1976 until 2002 identifying 43 patients with congenital scoliosis who underwent spinal fusion. Patient demographics, diagnosis, levels fused, and radiographs were evaluated. Patients were evaluated for unplanned return to the operating room (UPROR) via SRS 22, EQ5D-5L, and Oswestry Disability Index (ODI). RESULTS: Of the 43 patients who fulfilled the inclusion criteria, 22 patients agreed to participate, 3 patients were known to be deceased and 18 patients were lost to follow-up or declined to participate and were excluded. The mean age of the respondents was 40.7 years (range, 30 to 47 y) with a mean follow-up from index surgery of 35 years (range, 20 to 44 y). At most recent follow-up, 12 patients (54%) underwent UPROR. The mean age at diagnosis was 3.4 years (range, birth to 11.5 y), and the mean age for first surgery was 5.8 years (range, 1 to 13 y). As regards radiologic follow-up; the mean number of levels fused was 5.2 (range, 2 to 12). Thoracic fusion was performed in 17 patients (77%). The mean T1 to T12 height at index surgery and maturity was 166 mm (range, 130 to 240 mm) and 202 mm (range, 125 to 270 mm), respectively. The mean functional scores at follow-up were SRS 22: 4.5 (range, 2.4 to 5), cumulative EQ5D-5L score 7.2 (range, 5 to 15), and ODI: 8% (range, 2 to 30%). All respondents completed high school, 10 patients (45%) completed university, and 2 patients were awarded doctorates. Currently, 17 patients (77%) are in paid employment. CONCLUSIONS: This report constitutes the largest series of patients treated by spinal arthrodesis for congenital scoliosis followed into maturity. We demonstrate the thorax continues to grow after index fusion, patient-reported outcomes were satisfactory with superior educational and employment rates and unplanned return to theatre is rare in adult life. LEVEL OF EVIDENCE: Therapeutic Level IV.

Human Immunodeficiency Virus Treatment Attitudes and Bacterial Sexually Transmitted Infections Among Gay and Bisexual Men.

BACKGROUNDS: Positive attitudes toward human immunodeficiency virus (HIV) treatment, such as reduced concern about HIV transmissibility, are associated with sexual behaviors that may increase the risk of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM). We examined associations between HIV treatment attitudes and bacterial STI diagnoses among GBM in Canada's three largest cities. METHODS: We fit a structural equation model between HIV treatment attitudes and bacterial STI diagnoses via sexual behaviors in the Engage study's baseline data. We estimated direct and indirect paths between scores on HIV treatment attitudes and STIs via number of male anal sex partners, condomless anal sex, and oral sex. We conducted sub-analyses with participants stratified by HIV serostatus. RESULTS: Among 2449 GBM recruited in 2017 to 2019, there was a direct association between HIV treatment attitudes and current STI diagnoses (ß = 0.13; 95% CI, 0.07-0.19; P < 0.001). The mediated model revealed a positive total indirect effect through 2 pathways: (1) engaging in condomless anal sex and (2) number of male anal sex partners and condomless anal sex. These 2 indirect pathways remained in the stratified mediation models for both HIV negative GBM and for GBM living with HIV. CONCLUSIONS: The association between HIV treatment attitudes and diagnosed STIs is mediated through a higher number of male anal sex partners and condomless anal sex. The results highlight the importance of providers educating patients when providing effective STI counseling, testing, and prevention for GBM about how accurate HIV treatment attitudes may inadvertently be associated with the bacterial STI epidemic.

Latent Profile Analysis of Cognitive Performance and Depressive Symptoms Among People with HIV.

Depression and cognitive impairment are prevalent conditions among people with HIV (PWH), likely attributable to shared causes and common risk factors. Identifying subtypes of PWH with similar patterns of neurocognitive impairment (NCI) and depressive symptoms may inform development of patient-centered interventions that target-specific profiles. This study aimed to (1) classify PWH based on patterns of domain-specific NCI and depression; and (2) determine the relationship between latent class membership and pertinent clinical characteristics. PWH (N = 580, 86.2% male, 57.1% non-Hispanic White, 69.2% unemployed) completed a comprehensive neuropsychological test battery assessing global and domain-specific cognition. Domain-specific NCI was classified as deficit score >0.5. Participants completed the Beck Depression Inventory-II (BDI-II), and domain-specific BDI-II scores reflecting cognitive, affective, and somatic symptoms were computed. Latent profile analysis (LPA) was used to determine latent subgroups of NCI and depression. The optimal LPA solution consisted of five classes: minimal NCI and minimal depression (Class 1), amnestic and minimal depression (Class 2), severe multi-domain NCI and moderate depression (somatic and affective; Class 3), mild NCI and mild depression (Class 4), and moderate multi-domain NCI and severe depression (Class 5). Despite similar levels of functional impairment, Class 5 had a significant psychiatric profile, whereas Class 3 had a complex medical profile (i.e., higher frailty index, higher medications, greater proportion of AIDS diagnosis). In contrast, Class 1 had the lowest medication use and frailty index, with similar HIV disease characteristics to Classes 3 and 5. Our results suggest there are multiple pathways to cognitive and functional impairment among PWH with co-occurring depression and cognitive impairment, and these groups may respond differently to interventions. Of note, our sample was majority non-Hispanic White and male, which is nonrepresentative of the US population of PWH. Future interventions should consider a more integrated, person-centered approach that addresses cognitive and emotional health to optimize health outcomes in PWH.

A comprehensive deep venous thrombosis prophylaxis regimen in isolated coronary artery bypass grafting.

Objectives: Deep venous thrombosis (DVT) is a known surgical complication that can lead to pulmonary embolism with subsequent morbidity and mortality. The incidence of DVT following coronary artery bypass grafting is unclear. Prophylaxis regimens vary and some guidelines advocate against use of routine chemoprophylaxis in patients at low-moderate risk for venous thromboembolism. We utilized postoperative lower extremity venous ultrasound to determine the incidence of DVT following coronary artery bypass grafting in patients with low- to moderate-risk of venous thromboembolism receiving aggressive postoperative DVT prophylaxis. Methods: This is a single-center, retrospective study of all patients who underwent coronary artery bypass grafting between April 2022 and January 2023. All patients who completed postoperative venous ultrasound of the bilateral lower extremities were initially included. Patients who underwent concurrent valve or aortic surgery, were at high risk of venous thromboembolism, or were receiving anticoagulation therapy for nonvenous thromboembolism indications were excluded. The primary outcome was in-hospital incidence of DVT. Secondary outcomes were rates of mortality, postoperative bleeding, and thromboembolic events from discharge to 30 days postoperatively and from 30 days to 3 months postoperatively. Results: No DVTs were observed in 211 included patients. In hospital, there were 3 significant bleeding events and 1 stroke. Following discharge there were 3 additional bleeding events, 1 death, 1 transient ischemic attack, and 1 pulmonary embolism. Conclusions: We observed a 0% rate of DVT in low- to moderate-risk patients undergoing isolated coronary artery bypass grafting and receiving a comprehensive DVT prophylaxis regimen. In hospital bleeding and other thromboembolic event rates were 2.84% and 0.47% respectively.

The role of sleep disturbance in reduced accuracy on a divided attention task among patients with fibromyalgia.

Introduction: Patients with fibromyalgia show impaired cognitive performance compared with healthy, pain-free controls. Sleep disturbance, anxiety, and depression are highly prevalent among patients with fibromyalgia, and each is associated with impaired cognitive performance. Yet, limited work has explored whether psychosocial factors contribute to group differences in cognitive performance. Objectives: This secondary data analysis investigated differences in cognitive performance between patients with fibromyalgia and healthy controls, and whether psychosocial factors accounted for these differences. Methods: Adults with fibromyalgia (N = 24) and healthy, pain-free controls (N = 26) completed 2 cognitive tasks and the Patient-Reported Outcomes Measurement Information System sleep disturbance, anxiety, and depression short forms. Independent samples t tests were used to test for differences in cognitive performance between patients with fibromyalgia and healthy controls. Pearson correlations were conducted to examine associations between psychosocial factors and cognitive performance. Psychosocial factors significantly related to cognitive performance were explored as potential mediators of group differences in cognitive performance. Results: Patients with fibromyalgia demonstrated poorer accuracy for divided attention compared with healthy controls, and sleep disturbance mediated this group difference. On the attentional switching task, healthy controls showed a greater switch-cost for accuracy compared with patients with fibromyalgia, but there was no group difference in reaction time. Anxiety and depression were not related to cognitive performance. Conclusion: We found that patients with fibromyalgia reported greater sleep disturbance and, in turn, had poorer accuracy on the divided attention task. Sleep disturbance is modifiable with behavioral interventions, such as cognitive behavioral therapy, and may be a target for improving sleep quality and cognitive performance among patients with fibromyalgia.

The artificial intelligence-based model ANORAK improves histopathological grading of lung adenocarcinoma.

The introduction of the International Association for the Study of Lung Cancer grading system has furthered interest in histopathological grading for risk stratification in lung adenocarcinoma. Complex morphology and high intratumoral heterogeneity present challenges to pathologists, prompting the development of artificial intelligence (AI) methods. Here we developed ANORAK (pyrAmid pooliNg crOss stReam Attention networK), encoding multiresolution inputs with an attention mechanism, to delineate growth patterns from hematoxylin and eosin-stained slides. In 1,372 lung adenocarcinomas across four independent cohorts, AI-based grading was prognostic of disease-free survival, and further assisted pathologists by consistently improving prognostication in stage I tumors. Tumors with discrepant patterns between AI and pathologists had notably higher intratumoral heterogeneity. Furthermore, ANORAK facilitates the morphological and spatial assessment of the acinar pattern, capturing acinus variations with pattern transition. Collectively, our AI method enabled the precision quantification and morphology investigation of growth patterns, reflecting intratumoral histological transitions in lung adenocarcinoma.

The clinical utility of three frailty measures in identifying HIV-associated neurocognitive disorders.

OBJECTIVE: Frailty measures vary widely and the optimal measure for predicting HIV-associated neurocognitive disorders (HAND) is unclear. DESIGN: A study was conducted to examine the clinical utility of three widely used frailty measures in identifying HIV-associated neurocognitive disorders. METHODS: The study involved 284 people with HIV (PWH) at least 50 years enrolled at UC San Diego's HIV Neurobehavioral Research Program. Frailty measurements included the Fried Phenotype, the Rockwood Frailty Index, and the Veterans Aging Cohort Study (VACS) Index. HAND was diagnosed according to Frascati criteria. ANOVAs examined differences in frailty severity across HAND conditions. ROC analyses evaluated sensitivity and specificity of each measure to detect symptomatic HAND [mild neurocognitive disorder (MND) and HIV-associated dementia (HAD)] from no HAND. RESULTS: Across all frailty measures, frailty was found to be higher in HAD compared with no HAND. For Fried and Rockwood (not VACS), frailty was significantly more severe in MND vs. no HAND and in HAD vs. ANI (asymptomatic neurocognitive impairment). For discriminating symptomatic HAND from no HAND, Fried was 37% sensitive and 92% specific, Rockwood was 85% sensitive and 43% specific, and VACS was 58% sensitive and 65% specific. CONCLUSION: These findings demonstrate that Fried and Rockwood outperform VACS in predicting HAND. However, ROC analyses suggest none of the indices had adequate predictive validity in detecting HAND. The results indicate that the combined use of the Rockwood and Fried indices may be an appropriate alternative.

Circadian dysfunction induces NAFLD-related human liver cancer in a mouse model.

BACKGROUND & AIMS: Chronic circadian dysfunction increases the risk of non-alcoholic fatty liver disease (NAFLD)-related hepatocellular carcinoma (HCC), but the underlying mechanisms and direct relevance to human HCC have not been established. In this study, we aimed to determine whether chronic circadian dysregulation can drive NAFLD-related carcinogenesis from human hepatocytes and human HCC progression. METHODS: Chronic jet lag of mice with humanized livers induces spontaneous NAFLD-related HCCs from human hepatocytes. The clinical relevance of this model was analysed by biomarker, pathological/histological, genetic, RNA sequencing, metabolomic, and integrated bioinformatic analyses. RESULTS: Circadian dysfunction induces glucose intolerance, NAFLD-associated human HCCs, and human HCC metastasis independent of diet in a humanized mouse model. The deregulated transcriptomes in necrotic-inflammatory humanized livers and HCCs bear a striking resemblance to those of human non-alcoholic steatohepatitis (NASH), cirrhosis, and HCC. Stable circadian entrainment of hosts rhythmically paces NASH and HCC transcriptomes to decrease HCC incidence and prevent HCC metastasis. Circadian disruption directly reprogrammes NASH and HCC transcriptomes to drive a rapid progression from hepatocarcinogenesis to HCC metastasis. Human hepatocyte and tumour transcripts are clearly distinguishable from mouse transcripts in non-parenchymal cells and tumour stroma, and display dynamic changes in metabolism, inflammation, angiogenesis, and oncogenic signalling in NASH, progressing to hepatocyte malignant transformation and immunosuppressive tumour stroma in HCCs. Metabolomic analysis defines specific bile acids as prognostic biomarkers that change dynamically during hepatocarcinogenesis and in response to circadian disruption at all disease stages. CONCLUSION: Chronic circadian dysfunction is independently carcinogenic to human hepatocytes. Mice with humanized livers provide a powerful preclinical model for studying the impact of the necrotic-inflammatory liver environment and neuroendocrine circadian dysfunction on hepatocarcinogenesis and anti-HCC therapy. IMPACT AND IMPLICATIONS: Human epidemiological studies have linked chronic circadian dysfunction to increased hepatocellular carcinoma (HCC) risk, but direct evidence that circadian dysfunction is a human carcinogen has not been established. Here we show that circadian dysfunction induces non-alcoholic steatohepatitis (NASH)-related carcinogenesis from human hepatocytes in a murine humanized liver model, following the same molecular and pathologic pathways observed in human patients. The gene expression signatures of humanized HCC transcriptomes from circadian-disrupted mice closely match those of human HCC with the poorest prognostic outcomes, while those from stably circadian entrained mice match those from human HCC with the best prognostic outcomes. Our studies establish a new model for defining the mechanism of NASH-related HCC and highlight the importance of circadian biology in HCC prevention and treatment.

Post-transplant lymphoproliferative disorder in pediatric liver transplant recipients: Experience from a South African transplant center.

INTRODUCTION: Post-transplant lymphoproliferative disorder (PTLD) is a clinically heterogeneous potentially fatal complication of pediatric liver transplantation (PLT). We determined the prevalence, complications, and associated factors for PTLD in PLT recipients from Wits Donald Gordon Medical Centre, South Africa from January 2012 to August 2019. METHODS: We performed a retrospective record review of 150 PLT recipients. RESULTS: Histologically proven PTLD occurred in 17/150 PLT recipients (11.3%). Children with PTLD were significantly younger at transplant (17.9 vs. 32.7 months, p = 0.001) with a significantly higher prevalence of obstructive etiology (17/17 vs. 81/133, p = 0.001). Fifteen (88.2%) children with PTLD were Epstein-Barr virus (EBV) seronegative at transplant. High post-transplant EBV viral load at a threshold value of 4.8 log10 DNA copies/mL (sensitivity: 80.0% [95% confidence interval {CI}, 46.7%-100.0%]; specificity: 73.1% [95% CI 42.3%-93.3%; area under the curve {AUC} 75.8%]) and low post-transplant albumin levels at a threshold value of 21.5 g/L (sensitivity: 70.6% [95% CI, 41.2%-94.1%]; specificity: 85.7% [95% CI, 60.4%-94.5%; {AUC} 74.8%]) were associated with PTLD. The prevalence of cytomegalovirus (CMV) disease was significantly higher in children who developed PTLD versus non-PTLD (12/17 vs. 18/133; p < 0.001). CMV disease and the combination of post-transplant high EBV viral load and low albumin were independently associated with an increased risk of developing PTLD. Four (23.5%) children with PTLD died, however, survival was equivalent to non-PTLD PLT (p = 0.580). CONCLUSION: The prevalence of PTLD in our cohort mirrors international cohorts, with mortality similar to non-PTLD PLT recipients.

The use of Beauveria bassiana for the control of the larger grain borer, Prostephanus truncatus, in stored maize: Semi-field trials in Ghana.

Laboratory research in Ghana demonstrated the effectiveness of an isolate of Beauveria bassiana (IMI 389521) from the United Kingdom against the larger grain borer Prostephanus truncatus (Horn) (Coleoptera: Bostrichidae), a major pest of stored maize. The minimum effective concentration, following artificial infestation trials on maize, was between 109 and 1010 cfu/kg maize. Before moving out to village-level control, a major requirement was to determine if the product could effect control in artificially infested maize held under real environmental conditions in several locations in Ghana. Therefore, this study investigated the efficacy of formulated conidia of B. bassiana, IMI 389521, at two concentrations (1 × 109 and 3.16 × 109 cfu/kg maize) to control P. truncatus on stored maize kernels under semi-field conditions in Ghana. Maize ('Obatanpa' cultivar) kernels were treated with the formulated B. bassiana product and stored in polypropylene woven bags in cribs in Southern Ghana. After 24 h, one hundred adults of P. truncatus were placed into each bag containing the treated maize. Mortality and the percent of weight loss of kernels were assessed every two weeks for three months. The semi-field trials revealed the possibility of successfully controlling adult P. truncatus on maize kernels treated with B. bassiana at 3.16 × 109 cfu/kg maize. However, due to the minimal protection of kernels after four weeks, re-treating maize kernels after this period is recommended to ensure maximum protection during prolonged storage.

Focused ultrasound for brain metastases: an update on global clinical trials.

BACKGROUND: Despite advances in immunotherapy and targeted treatments for malignancies of the central nervous system (CNS), the treatment of brain metastases (BMs) remains a formidable challenge, due largely to difficulties in crossing the blood-brain barrier (BBB), drug resistance, and molecular discrepancies. Focused ultrasound (FUS) is a non-invasive tool for BBB breaching, tumor ablation, enhancing drug delivery, promoting the release of tumor biomarkers for liquid biopsy, or the tumor microenvironment disruption. This paper presents a comprehensive review of the current literature related to FUS and its application in the treatment of brain metastasis. METHODS: This review of the current literature via PubMed, Google Scholar, and Clincaltrials.gov focused on clinical trials in which FUS is used in the intracranial treatment of metastatic tumor, glioma, or GBM. RESULTS: FUS is safe and effective for treatment of primary or metastatic brain tumors. FUS-augmented drug delivery can open BBB to facilitate the transport of chemotherapeutic agents, immunotherapies, and targeted treatments. The integration of FUS with liquid biopsy has considerable potential for early tumor detection, precise gene profiling, and personalized therapy. Sonodynamic therapy can induce tumor cell apoptosis and could potentially be used to enhance the outcomes of other tumor treatments, such as surgery and chemotherapy. CONCLUSION: Further work is required to establish FUS as a standard therapy for BMs. FUS has the potential to transform brain tumor treatment, particularly when combined with immunotherapy and targeted therapy as a non-invasive alternative to surgery and radiation therapy.