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A major goal of cancer research is to understand how mutations distributed across diverse genes affect common cellular systems, including multiprotein complexes and assemblies. Two challenges—how to comprehensively map such systems and how to identify which are under mutational selection—have hindered this understanding. Accordingly, we created a comprehensive map of cancer protein systems integrating both new and published multi-omic interaction data at multiple scales of analysis. We then developed a unified statistical model that pinpoints 395 specific systems under mutational selection across 13 cancer types. This map, called NeST (Nested Systems in Tumors), incorporates canonical processes and notable discoveries, including a PIK3CA-actomyosin complex that inhibits phosphatidylinositol 3-kinase signaling and recurrent mutations in collagen complexes that promote tumor proliferation. These systems can be used as clinical biomarkers and implicate a total of 548 genes in cancer evolution and progression. This work shows how disparate tumor mutations converge on protein assemblies at different scales.

Systems biology requires not only genome-scale data but also methods to integrate these data into interpretable models. Previously, we developed approaches that organize omics data into a structured hierarchy of cellular components and pathways, called a "data-driven ontology." Such hierarchies recapitulate known cellular subsystems and discover new ones. To broadly facilitate this type of modeling, we report the development of a software library called the Data-Driven Ontology Toolkit (DDOT), consisting of a Python package (https://github.com/idekerlab/ddot) to assemble and analyze ontologies and a web application (http://hiview.ucsd.edu) to visualize them. Using DDOT, we programmatically assemble a compendium of ontologies for 652 diseases by integrating gene-disease mappings with a gene similarity network derived from omics data. For example, the ontology for Fanconi anemia describes known and novel disease mechanisms in its hierarchy of 194 genes and 74 subsystems. DDOT provides an easy interface to share ontologies online at the Network Data Exchange.

It is clear that alcohol consumption is a major risk factor in the pathogenesis of head and neck squamous cell carcinoma (HNSCC); however, the molecular mechanism underlying the pathogenesis of alcohol-associated HNSCC remains poorly understood. The aim of the present study was to identify and characterize P-element-induced wimpy testis (PIWI)-interacting RNAs (piRNAs) and PIWI proteins dysregulated in alcohol-associated HNSCC to elucidate their function in the development of this cancer. Using next generation RNA-sequencing (RNA-seq) data obtained from 40 HNSCC patients, the piRNA and PIWI protein expression of HNSCC samples was compared between alcohol drinkers and non-drinkers. A separate piRNA expression RNA-seq analysis of 18 non-smoker HNSCC patients was also conducted. To verify piRNA expression, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed on the most differentially expressed alcohol-associated piRNAs in ethanol and acetaldehyde-treated normal oral keratinocytes. The correlation between piRNA expression and patient survival was analyzed using Kaplan-Meier estimators and multivariate Cox proportional hazard models. A comparison between alcohol drinking and non-drinking HNSCC patients demonstrated that a panel of 3,223 piRNA transcripts were consistently detected and differentially expressed. RNA-seq analysis and in vitro RT-qPCR verification revealed that 4 of these piRNAs, piR-35373, piR-266308, piR-58510 and piR-38034, were significantly dysregulated between drinking and non-drinking cohorts. Of these four piRNAs, low expression of piR-58510 and piR-35373 significantly correlated with improved patient survival. Furthermore, human PIWI-like protein 4 was consistently upregulated in ethanol and acetaldehyde-treated normal oral keratinocytes. These results demonstrate that alcohol consumption may cause dysregulation of piRNA expression in HNSCC and in vitro verifications identified 4 piRNAs that may be involved in the pathogenesis of alcohol-associated HNSCC.

Introduction: The media can play a vital role in determining to what extent the general public understands scientific concepts. The understanding and acceptance of evolution are often influenced by factors beyond scientific knowledge alone, including education, politics, and media consumption habits. Although discussion of the COVID-19 pandemic and evolution had fixed itself in public discourse on many fronts, the media often avoided the usage of the word "evolve" and showed a preference for alternatives such as "emerge" or "mutate." Methods: We conducted a systematic analysis to gauge the prominence of the concept of evolution in media discussions across seven English-speaking countries. This involved assessing the frequency of the term "evolve" concerning viral evolution within newspaper articles using electronic databases. Of the 4,951 newspaper articles examined in this study, 11% discussed viral evolution. Out of those articles, 12% explicitly used the word "evolve." Results: We found that countries did not significantly differ in their "evolve" usage, which may reflect similarities in views about COVID-19 and its evolution across countries or reliance on shared information sources when reporting on COVID-19. We also found that, as the pandemic progressed, the discussion on viral evolution as a topic had increased, but the frequency with which the word "evolve" was explicitly used had decreased. Discussion: The COVID-19 pandemic has had a substantial impact on science and health news reporting. Although evolution plays a crucial role in the progression of the COVID-19 pandemic, the term "evolve" is not frequently highlighted in COVID-19 news coverage. Our research underscores the significant implications of language choice when describing evolutionary events, particularly in shaping the public's understanding of evolution, both in general and in the context of pandemics and infectious diseases. [ABSTRACT FROM AUTHOR]

Internationalisation of the curriculum (IoC) is on the agenda of many higher education (HE) institutions worldwide. Typically seen as associated with a top-down strategy, IoC often meets resistance from university teachers, many of whom struggle to understand its relevance to teaching practice. This phenomenographic study investigates university teachers' conceptions of IoC. Five conceptions ranging in sophistication have been identified. The least sophisticated focuses on making the curriculum content internationally relevant, whereas the most sophisticated centres around developing self-awareness, awareness of others, and a change in mindset in students. The latter is realised by embracing reflexivity and criticality and, more importantly, utilising societal and political issues as learning opportunities for identity development. Situated in the Hong Kong context, the findings not only suggest the need for teachers to shift their focus from curriculum content to value-based development but also for educators to reflect on their role in helping students to reconcile their identity in relation to their counterparts regionally and globally.

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer.

Gene networks are rapidly growing in size and number, raising the question of which networks are most appropriate for particular applications. Here, we evaluate 21 human genome-wide interaction networks for their ability to recover 446 disease gene sets identified through literature curation, gene expression profiling, or genome-wide association studies. While all networks have some ability to recover disease genes, we observe a wide range of performance with STRING, ConsensusPathDB, and GIANT networks having the best performance overall. A general tendency is that performance scales with network size, suggesting that new interaction discovery currently outweighs the detrimental effects of false positives. Correcting for size, we find that the DIP network provides the highest efficiency (value per interaction). Based on these results, we create a parsimonious composite network with both high efficiency and performance. This work provides a benchmark for selection of molecular networks in human disease research.

BackgroundGlobal but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.ResultsWe first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.ConclusionsThis study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

We have developed a general progressive procedure, Active Interaction Mapping, to guide assembly of the hierarchy of functions encoding any biological system. Using this process, we assemble an ontology of functions comprising autophagy, a central recycling process implicated in numerous diseases. A first-generation model, built from existing gene networks in Saccharomyces, captures most known autophagy components in broad relation to vesicle transport, cell cycle, and stress response. Systematic analysis identifies synthetic-lethal interactions as most informative for further experiments; consequently, we saturate the model with 156,364 such measurements across autophagy-activating conditions. These targeted interactions provide more information about autophagy than all previous datasets, producing a second-generation ontology of 220 functions. Approximately half are previously unknown; we confirm roles for Gyp1 at the phagophore-assembly site, Atg24 in cargo engulfment, Atg26 in cytoplasm-to-vacuole targeting, and Ssd1, Did4, and others in selective and non-selective autophagy. The procedure and autophagy hierarchy are at http://atgo.ucsd.edu/.

Lichen planus (LP) of the eyelid is an under-reportedmanifestation of a common inflammatory condition.To the best of our knowledge fewer than 20 cases ofeyelid LP have been described in the English literature.We report a case of a 29-year-old woman whopresented with 3-month history of bilateral eyelidpruritic violaceous papules and similar lesions on herchest and lower extremity. Histology examinationrevealed characteristic findings and a diagnosisof LP was established. This report further reviewsthe previously reported 18 cases and discussesmanagement strategies.

Leukemia cutis (LC) is an extramedullary manifestationof leukemia owing to cutaneous infiltration ofneoplastic cells resulting in characteristic firm,erythematous nodules. Most cases of LC occur inpatients with acute myelogenous leukemia andchronic myelogenous leukemia. However in rarecases, LC has presented in patients with acutelymphoblastic leukemia (ALL). In these rare ALLassociatedcases, only 10 cases of precursor-B-ALL(pre-B-ALL) have been described in the literature.We report a case of a 22-year-old man with relapsingpre-B-ALL who presented with a 4-day history ofmultiple asymptomatic, soft, dome-shaped, lipomalikemounds on his scalp and chin, which exhibitedcutaneous involvement by leukemic cells. To date, thisis the first case of pre-B-ALL associated leukemia cutispresenting as soft, dome-shaped mounds resemblinglipomas.

Introduction Objective Materials and Methods Results Discussion The public health response (PHR) to the COVID‐19 pandemic significantly disrupted healthcare services worldwide. Our hospital, a major tertiary centre, is a unique two‐state service across Queensland and New South Wales (NSW).The primary objective is to describe changes in service demand and delivery in our hospital resulting from the COVID‐19 PHR. The secondary objective is to investigate patient perceptions of this impact.We performed a retrospective interrupted time series analysis and a population‐based survey to examine patient perceptions of the impact of the COVID‐19 PHR. The study periods were demarcated by the initiation of the COVID‐19 PHR on 1 March 2020 with the ‘pre’ and ‘during’ COVID‐19 periods defined as the 12 months before and after this date respectively.More patients were seen during the COVID‐19 PHR period. The number or stage of cancer diagnoses was not different (P > 0.05). There was evidence (P = 0.03) of an increase in overall occasions of service and fewer failed attendances (P = 0.005). Fewer surgeries were performed on NSW patients (P = 0.005). The survey response rate was 19.3% (n = 185) with 48% stating that COVID‐19 had negatively affected their emotional wellbeing. More participants from NSW than Queensland identified border closures as the most significant impact of the COVID‐19 PHR.The COVID‐19 PHR resulted in an unexpected increase in unit service demand and delivery. The necessary implementation of telephone appointments, while less preferred by patients, sustained service requirements. Cross‐border tertiary healthcare services should consider the significant impact of border restrictions on patient wellbeing. [ABSTRACT FROM AUTHOR]

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Background and Objective: The objective was to evaluate factors associated with clinical presentation of uveal melanoma (UM) during the initial two years of the coronavirus disease 2019 pandemic. Patients and Methods: This was a multi-site, retrospective cohort study of patients treated for uveal melanoma during the first (early) and second (late) year of the pandemic compared with the year prior (control). Results: A total of 48, 67, and 75 patients were in the control, early, and late cohorts, respectively. The early cohort had a higher frequency of large tumors (control: 29.2%, early: 40.3%, late: 29.3%; P < 0.001) at presentation. Both the early and late cohorts had higher rates of enucleation (control: 8.33%, early: 20.9%, late: 18.67%; P ≤ 0.0338) compared to the control cohort. Conclusions: While there was an increase in large tumors along with a rise in enucleation during the first year of the pandemic, enucleation rates remained elevated even while tumor sizes normalized. [Ophthalmic Surg Lasers Imaging Retina 2024;55:278–284.] [ABSTRACT FROM AUTHOR]