A Pseudo-Surfactant Chemical Permeation Enhancer to Treat Otitis Media via Sustained Transtympanic Delivery of Antibiotics.

Chemical permeation enhancers (CPEs) represent a prevalent and safe strategy to enable noninvasive drug delivery across skin-like biological barriers such as the tympanic membrane (TM). While most existing CPEs interact strongly with the lipid bilayers in the stratum corneum to create defects as diffusion paths, their interactions with the delivery system, such as polymers forming a hydrogel, can compromise gelation, formulation stability, and drug diffusion. To overcome this challenge, differing interactions between CPEs and the hydrogel system are explored, especially those with sodium dodecyl sulfate (SDS), an ionic surfactant and a common CPE, and those with methyl laurate (ML), a nonionic counterpart with a similar length alkyl chain. Notably, the use of ML effectively decouples permeation enhancement from gelation, enabling sustained delivery across TMs to treat acute otitis media (AOM), which is not possible with the use of SDS. Ciprofloxacin and ML are shown to form a pseudo-surfactant that significantly boosts transtympanic permeation. The middle ear ciprofloxacin concentration is increased by 70-fold in vivo in a chinchilla AOM model, yielding superior efficacy and biocompatibility than the previous highest-performing formulation. Beyond improved efficacy and biocompatibility, this single-CPE formulation significantly accelerates its progression toward clinical deployment.

Assembly and analysis of the genome of Notholithocarpus densiflorus.

Tanoak (Notholithocarpus densiflorus) is an evergreen tree in the Fagaceae family found in California and southern Oregon. Historically, tanoak acorns were an important food source for Native American tribes, and the bark was used extensively in the leather tanning process. Long considered a disjunct relictual element of the Asian stone oaks (Lithocarpus spp.), phylogenetic analysis has determined that the tanoak is an example of convergent evolution. Tanoaks are deeply divergent from oaks (Quercus) of the Pacific Northwest and comprise a new genus with a single species. These trees are highly susceptible to "sudden oak death" (SOD), a plant pathogen (Phytophthora ramorum) that has caused widespread deaths of tanoaks. In this study, we set out to assemble the genome and perform comparative studies among a number of individuals that demonstrated varying levels of susceptibility to SOD. First, we sequenced and de novo assembled a draft reference genome of N. densiflorus using cobarcoded library processing methods and an MGI DNBSEQ-G400 sequencer. To increase the contiguity of the final assembly, we also sequenced Oxford Nanopore long reads to 30× coverage. To our knowledge, the draft genome reported here is one of the more contiguous and complete genomes of a tree species published to date, with a contig N50 of ∼1.2 Mb, a scaffold N50 of ∼2.1 Mb, and a complete gene score of 95.5% through BUSCO analysis. In addition, we sequenced 11 genetically distinct individuals and mapped these onto the draft reference genome, enabling the discovery of almost 25 million single nucleotide polymorphisms and ∼4.4 million small insertions and deletions. Finally, using cobarcoded data, we were able to generate a complete haplotype coverage of all 11 genomes.

Investigation of AFeO3 (A=Ba, Sr) Perovskites for the Oxidative Dehydrogenation of Light Alkanes under Chemical Looping Conditions.

Oxidative dehydrogenation (ODH) of light alkanes to produce C2 -C3 olefins is a promising alternative to conventional steam cracking. Perovskite oxides are emerging as efficient catalysts for this process due to their unique properties such as high oxygen storage capacity (OSC), reversible redox behavior, and tunability. Here, we explore AFeO3 (A=Ba, Sr) bulk perovskites for the ODH of ethane and propane under chemical looping conditions (CL-ODH). The higher OSC and oxygen mobility of SrFeO3 perovskite contributed to its higher activity but lower olefin selectivity than its Ba counterpart. However, SrFeO3 perovskite is superior in terms of cyclic stability over multiple redox cycles. Transformations of the perovskite to reduced phases including brownmillerite A2 Fe2 O5 were identified by X-ray diffraction (XRD) as a cause of performance degradation, which was fully reversible upon air regeneration. A pre-desorption step was utilized to selectively tune the amount of lattice oxygen as a function of temperature and dwell time to enhance olefin selectivity while suppressing CO2 formation from the deep oxidation of propane. Overall, SrFeO3 exhibits promising potential for the CL-ODH of light alkanes, and optimization through surface and structural modifications may further engineer well-regulated lattice oxygen for maximizing olefin yield.

Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks.

A vexing observation in genome-wide association studies (GWASs) is that parallel analyses in different species may not identify orthologous genes. Here, we demonstrate that cross-species translation of GWASs can be greatly improved by an analysis of co-localization within molecular networks. Using body mass index (BMI) as an example, we show that the genes associated with BMI in humans lack significant agreement with those identified in rats. However, the networks interconnecting these genes show substantial overlap, highlighting common mechanisms including synaptic signaling, epigenetic modification, and hormonal regulation. Genetic perturbations within these networks cause abnormal BMI phenotypes in mice, too, supporting their broad conservation across mammals. Other mechanisms appear species specific, including carbohydrate biosynthesis (humans) and glycerolipid metabolism (rodents). Finally, network co-localization also identifies cross-species convergence for height/body length. This study advances a general paradigm for determining whether and how phenotypes measured in model species recapitulate human biology.

Comprehensive analysis of geographic and breed-purpose influences on genetic diversity and inherited disease risk in the Doberman dog breed.

BACKGROUND: Publicly available phenotype data and genotyping array data from two citizen science projects: "Doberman Health Surveys" and "The Doberman Diversity Project" were analyzed to explore relative homozygosity, diversity, and disorder risk according to geographical locale and breeding purpose in the Doberman. RESULTS: From the phenotypic data cohort, life expectancy of a Doberman at birth is 9.1 years. The leading causes of death were heart disease (accounting for 28% of deaths) and cancers (collectively accounting for 14% of deaths). By genotyping, the world Doberman population exists as four major cohorts (European exhibition-bred, Americas exhibition-bred, European work, Americas pet/informal). Considering the entire Doberman population, four genomic regions longer than 500 Kb are fixed in 90% or more of 3,226 dogs included in this study. The four fixed regions reside on two autosomal chromosomes: CFA3:0.8-2.3 Mb (1.55 Mb); CFA3: 57.9-59.8 Mb (1.8 Mb); CFA31:0-1.2 Mb (1.2 Mb); and CFA31:4.80-6.47 Mb (1.67 Mb). Using public variant call files including variants for eight Doberman pinschers, we observed 30 potentially functional alternate variants that were evolutionarily diverged relative to the wider sequenced dog population within the four strongly homozygous chromosomal regions. Effective population size (Ne) is a statistical measure of breed diversity at the time of sampling that approximates the number of unique individuals. The major identified sub-populations of Dobermans demonstrated Ne in the range 70-236. The mean level of inbreeding in the Doberman breed is 40% as calculated by the number of array variants in runs of homozygosity divided by the assayed genome size (excluding the X chromosome). The lowest observed level of inbreeding in the Dobermans assayed was 15% in animals that were first generation mixes of European and USA bred Dobermans. Array variant analysis shows that inter-crossing between European and USA-bred Dobermans has capacity to re-introduce variation at many loci that are strongly homozygous. CONCLUSIONS: We conclude that efforts to improve breed diversity first should focus on regions with the highest fixation levels, but managers must ensure that mutation loads are not worsened by increasing the frequencies of rarer haplotypes in the identified regions. The analysis of global data identified regions of strong fixation that might impact known disorder risks in the breed. Plausible gene candidates for future analysis of the genetic basis of cardiac disease and cancer were identified in the analysis.

Review of meningioma diagnosis and management.

Meningiomas are the most common intracranial tumors in adult patients. Although the majority of meningiomas are diagnosed as benign, approximately 20% of cases are high-grade tumors that require significant clinical treatment. The gold standard for grading central nervous system tumors comes from the World Health Organization Classification of Tumors of the central nervous system. Treatment options also depend on the location, imaging, and histopathological features of the tumor. This review will cover diagnostic strategies for meningiomas, including 2021 updates to the World Health Organization's grading of meningiomas. Meningioma treatment plans are variable and highly dependent on tumor grading. This review will also update the reader on developments in the treatment of meningiomas, including surgery, radiation therapy and monoclonal antibody treatment.

NDEx IQuery: a multi-method network gene set analysis leveraging the Network Data Exchange.

MOTIVATION: The investigation of sets of genes using biological pathways is a common task for researchers and is supported by a wide variety of software tools. This type of analysis generates hypotheses about the biological processes that are active or modulated in a specific experimental context. RESULTS: The Network Data Exchange Integrated Query (NDEx IQuery) is a new tool for network and pathway-based gene set interpretation that complements or extends existing resources. It combines novel sources of pathways, integration with Cytoscape, and the ability to store and share analysis results. The NDEx IQuery web application performs multiple gene set analyses based on diverse pathways and networks stored in NDEx. These include curated pathways from WikiPathways and SIGNOR, published pathway figures from the last 27 years, machine-assembled networks using the INDRA system, and the new NCI-PID v2.0, an updated version of the popular NCI Pathway Interaction Database. NDEx IQuery's integration with MSigDB and cBioPortal now provides pathway analysis in the context of these two resources. AVAILABILITY AND IMPLEMENTATION: NDEx IQuery is available at https://www.ndexbio.org/iquery and is implemented in Javascript and Java.

Recurrent meningioma: When to intervene.

Meningioma occurs most frequently as a benign tumor central nervous system that is common in old females. Radiation exposure and deletion of the NF2 gene are known risk factors. However, there is no consensus about the role of sex hormones. Meningiomas are usually benign tumors, but 6% can be anaplastic or atypical. Most asymptomatic patients do not require treatment, but complete surgical resection is recommended for symptomatic patients. If a tumor returns after being resected previously, it is recommended to be resected, followed by radiotherapy in some cases. Meningiomas (benign, atypical, and malignant) recurring after standard treatment fails could be treated with hormone therapy, chemotherapy, target therapy, and calcium channel blockers.

Mapping the common gene networks that underlie related diseases.

A longstanding goal of biomedicine is to understand how alterations in molecular and cellular networks give rise to the spectrum of human diseases. For diseases with shared etiology, understanding the common causes allows for improved diagnosis of each disease, development of new therapies and more comprehensive identification of disease genes. Accordingly, this protocol describes how to evaluate the extent to which two diseases, each characterized by a set of mapped genes, are colocalized in a reference gene interaction network. This procedure uses network propagation to measure the network 'distance' between gene sets. For colocalized diseases, the network can be further analyzed to extract common gene communities at progressive granularities. In particular, we show how to: (1) obtain input gene sets and a reference gene interaction network; (2) identify common subnetworks of genes that encompass or are in close proximity to all gene sets; (3) use multiscale community detection to identify systems and pathways represented by each common subnetwork to generate a network colocalized systems map; (4) validate identified genes and systems using a mouse variant database; and (5) visualize and further investigate select genes, interactions and systems for relevance to phenotype(s) of interest. We demonstrate the utility of this approach by identifying shared biological mechanisms underlying autism and congenital heart disease. However, this protocol is general and can be applied to any gene sets attributed to diseases or other phenotypes with suspected joint association. A typical NetColoc run takes less than an hour. Software and documentation are available at https://github.com/ucsd-ccbb/NetColoc .

Predictors of surgical site infection in glioblastoma patients undergoing craniotomy for tumor resection.

OBJECTIVE: Surgical site infections (SSIs) burden patients and healthcare systems, often requiring additional intervention. The objective of this study was to identify the relationship between preoperative predictors inclusive of scalp incision type and postoperative SSI following glioblastoma resection. METHODS: The authors retrospectively reviewed cases of glioblastoma resection performed at their institution from December 2006 to December 2019 and noted preoperative demographic and clinical presentations, excluding patients missing these data. Preoperative nutritional indices were available for a subset of cases. Scalp incisions were categorized as linear/curvilinear, reverse question mark, trapdoor, or frontotemporal. Patients were dichotomized by SSI incidence. Multivariable logistic regression was used to determine predictors of SSI. RESULTS: A total of 911 cases of glioblastoma resection were identified, 30 (3.3%) of which demonstrated postoperative SSI. There were no significant differences in preoperative malnutrition or number of surgeries between SSI and non-SSI cases. The SSI cases had a significantly lower preoperative Karnofsky Performance Status (KPS) than the non-SSI cases (63.0 vs 75.1, p < 0.0001), were more likely to have prior radiation history (43.3% vs 26.4%, p = 0.042), and were more likely to have received steroids both preoperatively and postoperatively (83.3% vs 54.5%, p = 0.002). Linear/curvilinear incisions were more common in non-SSI than in SSI cases (56.9% vs 30.0%, p = 0.004). Trapdoor scalp incisions were more frequent in SSI than non-SSI cases (43.3% vs 24.2%, p = 0.012). On multivariable analysis, a lower preoperative KPS (OR 1.04, 95% CI 1.02-1.06), a trapdoor scalp incision (OR 3.34, 95% CI 1.37-8.49), and combined preoperative and postoperative steroid administration (OR 3.52, 95% CI 1.41-10.7) were independently associated with an elevated risk of postoperative SSI. CONCLUSIONS: The study findings indicated that SSI risk following craniotomy for glioblastoma resection may be elevated in patients with a low preoperative KPS, a trapdoor scalp incision during surgery, and steroid treatment both preoperatively and postoperatively. These data may help guide future operative decision-making for these patients.

Mammalian MutY Homolog (MYH or MUTYH) is Critical for Telomere Integrity under Oxidative Stress.

Telomeres consist of special features and proteins to protect the ends of each chromosome from deterioration and fusion. The telomeric DNA repeats are highly susceptible to oxidative damage that can accelerate telomere shortening and affect telomere integrity. Several DNA repair factors including MYH/MUTYH DNA glycosylase, its interacting partners Rad9/Rad1/Hus1 checkpoint clamp, and SIRT6 aging regulator, are associated with the telomeres. MYH prevents C:G to A:T mutation by removing adenine mispaired with a frequent oxidative DNA lesion, 8-oxoguanine. Here, we show that hMYH knockout (KO) human HEK-293T cells are more sensitive to H2O2 treatment, have higher levels of DNA strand breaks and shorter telomeres than the control hMYH +/+ cells. SIRT6 foci increase at both the global genome and at telomeric regions in H2O2-treated hMYH +/+ cells. However, in untreated hMYH KO HEK-293T cells, SIRT6 foci only increase at the global genome, but not at the telomeric regions. In addition, the hMYH KO HEK-293T cells have increased extra-chromosomal and intra-chromosomal telomeres compared to the control cells, even in the absence of H2O2 treatment. After H2O2 treatment, the frequency of extra-chromosomal telomeres increased in control HEK-293T cells. Remarkably, in H2O2-treated hMYH KO cells, the frequencies of extra-chromosomal telomeres, intra-chromosomal telomeres, and telomere fusions are further increased. We further found that the sensitivity to H2O2 and shortened telomeres of hMYH KO cells, are restored by expressing wild-type hMYH, and partially rescued by expressing hMYHQ324H mutant (defective in Hus1 interaction only), but not by expressing hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions). Thus, MYH interactions with SIRT6 and Hus1 are critical for maintaining cell viability and telomeric stability. Therefore, the failure to coordinate 8-oxoG repair is detrimental to telomere integrity.

Inner Ear Drug Delivery for Sensorineural Hearing Loss: Current Challenges and Opportunities.

Most therapies for treating sensorineural hearing loss are challenged by the delivery across multiple tissue barriers to the hard-to-access anatomical location of the inner ear. In this review, we will provide a recent update on various pharmacotherapy, gene therapy, and cell therapy approaches used in clinical and preclinical studies for the treatment of sensorineural hearing loss and approaches taken to overcome the drug delivery barriers in the ear. Small-molecule drugs for pharmacotherapy can be delivered via systemic or local delivery, where the blood-labyrinth barrier hinders the former and tissue barriers including the tympanic membrane, the round window membrane, and/or the oval window hinder the latter. Meanwhile, gene and cell therapies often require targeted delivery to the cochlea, which is currently achieved via intra-cochlear or intra-labyrinthine injection. To improve the stability of the biomacromolecules during treatment, e.g., RNAs, DNAs, proteins, additional packing vehicles are often required. To address the diverse range of biological barriers involved in inner ear drug delivery, each class of therapy and the intended therapeutic cargoes will be discussed in this review, in the context of delivery routes commonly used, delivery vehicles if required (e.g., viral and non-viral nanocarriers), and other strategies to improve drug permeation and sustained release (e.g., hydrogel, nanocarriers, permeation enhancers, and microfluidic systems). Overall, this review aims to capture the important advancements and key steps in the development of inner ear therapies and delivery strategies over the past two decades for the treatment and prophylaxis of sensorineural hearing loss.

A BioID-Derived Proximity Interactome for SARS-CoV-2 Proteins.

The novel coronavirus SARS-CoV-2 is responsible for the ongoing COVID-19 pandemic and has caused a major health and economic burden worldwide. Understanding how SARS-CoV-2 viral proteins behave in host cells can reveal underlying mechanisms of pathogenesis and assist in development of antiviral therapies. Here, the cellular impact of expressing SARS-CoV-2 viral proteins was studied by global proteomic analysis, and proximity biotinylation (BioID) was used to map the SARS-CoV-2 virus-host interactome in human lung cancer-derived cells. Functional enrichment analyses revealed previously reported and unreported cellular pathways that are associated with SARS-CoV-2 proteins. We have established a website to host the proteomic data to allow for public access and continued analysis of host-viral protein associations and whole-cell proteomes of cells expressing the viral-BioID fusion proteins. Furthermore, we identified 66 high-confidence interactions by comparing this study with previous reports, providing a strong foundation for future follow-up studies. Finally, we cross-referenced candidate interactors with the CLUE drug library to identify potential therapeutics for drug-repurposing efforts. Collectively, these studies provide a valuable resource to uncover novel SARS-CoV-2 biology and inform development of antivirals.

An imidazolium-based zwitterionic polymer for antiviral and antibacterial dual functional coatings.

To reduce the severe health risk and the huge economic impact associated with the fomite transmission of SARS-CoV-2, an imidazolium-based zwitterionic polymer was designed, synthesized, and demonstrated to achieve contact deactivation of a human coronavirus under dry ambient conditions that resemble fomite transmission. The zwitterionic polymer further demonstrated excellent antifouling properties, reducing the adhesion of coronavirus and the formation of bacteria biofilms under wetted conditions. The polymer was synthesized using a substrate-independent and solvent-free process, leveraging an all-dry technique named initiated chemical vapor deposition (iCVD). The broad applicability of this approach was demonstrated by applying the polymer to a range of substrates that are curved and/or with high-aspect-ratio nano/microporous structures, which remained intact after the coating process. The zwitterionic polymer and the synthesis approach reported here present an effective solution to mitigate viral transmission without the need for manual disinfection, reducing the health and economic impact of the ongoing pandemic.

Predicting High-Value Care Outcomes After Surgery for Non-Skull Base Meningiomas.

OBJECTIVE: A need exists to better understand the prognostic factors that influence high-value care outcomes after meningioma surgery. The goal of the present study was to develop predictive models to determine the patients at risk of experiencing an extended hospital length of stay (LOS), nonroutine discharge disposition, and/or a 90-day hospital readmission after non-skull base meningioma resection. METHODS: In the present study, we analyzed the data from 396 patients who had undergone surgical resection of non-skull base meningiomas at a single institution between January 1, 2005 and December 31, 2020. The Mann-Whitney U test was used for bivariate analysis of the continuous variables and the Fisher exact test for bivariate analysis of the categorical variables. A multivariate analysis was conducted using logistic regression models. RESULTS: Most patients had had a falcine or parasagittal meningioma (66.2%), with the remainder having convexity (31.8%) or intraventricular (2.0%) tumors. Nonelective surgery (P < 0.0001) and an increased tumor volume (P = 0.0022) were significantly associated with a LOS >4 days on multivariate analysis. The independent predictors of a nonroutine discharge disposition included male sex (P = 0.0090), nonmarried status (P = 0.024), nonelective surgery (P = 0.0067), tumor location within the parasagittal or intraventricular region (P = 0.0084), and an increased modified frailty index score (P = 0.039). Hospital readmission within 90 days was independently associated with nonprivate insurance (P = 0.010) and nonmarried status (P = 0.0081). Three models predicting for a prolonged LOS, nonroutine discharge disposition, and 90-day readmission were implemented in the form of an open-access, online calculator (available at: https://neurooncsurgery3.shinyapps.io/non_skull_base_meningiomas/). CONCLUSIONS: After external validation, our open-access, online calculator could be useful for assessing the likelihood of adverse postoperative outcomes for patients undergoing surgery of non-skull base meningioma.

The role of anticoagulation for superior sagittal sinus thrombosis following craniotomy for resection of parasagittal/parafalcine meningiomas.

OBJECTIVE: The safety and efficacy of anticoagulation in managing superior sagittal sinus (SSS) thrombosis remains unclear. The present study investigated the relationship between anticoagulation and cerebrovascular complications in parasagittal/parafalcine meningioma patients presenting with post-surgical SSS thrombosis. METHODS: We analyzed 266 patients treated at a single institution between 2005 and 2020. Bivariate analysis was conducted using the Mann-Whitney U test and Fisher's exact test. Multivariate analysis was conducted using a logistic regression model. Blood thinning medications investigated included aspirin, warfarin, heparin, apixaban, rivaroxaban, and other novel oral anticoagulants (NOACs). A symptomatic SSS thrombosis was defined as a radiographically apparent thrombosis with new headaches, seizures, altered sensorium, or neurological deficits. RESULTS: Our patient cohort was majority female (67.3%) with a mean age ([Formula: see text] SD) of 58.82 [Formula: see text] 13.04 years. A total of 15 (5.6%) patients developed postoperative SSS thrombosis and 5 (1.9%) were symptomatic; 2 (0.8%) symptomatic patients received anticoagulation. None of these 15 patients developed cerebrovascular complications following observation or anticoagulative treatment of asymptomatic SSS thrombosis. While incidence of any other postoperative complications was significantly associated with SSS thrombosis in bivariate analysis (p = 0.015), this association was no longer observed in multivariate analysis (OR = 2.15, p = 0.16) when controlling for patient age, sex, and anatomical location of the tumor along the SSS. CONCLUSIONS: Our single-institution study examining the incidence of SSS thrombosis and associated risk factors highlights the need for further research efforts better prognosticate this adverse outcome. Conservative management may represent a viable treatment strategy for patients with SSS thrombosis.

On-Demand Synthesis of Antiseptics at the Site of Infection for Treatment of Otitis Media.

Otitis media (OM) is the main reason for pediatric antibiotic prescriptions. The current treatment mandates a rigorous regimen of multidose antibiotics over 5-10 days. The systemic antibiotic exposure and often prematurely terminated treatment due to the challenge of drug administration to young patients are believed to breed antibiotic resistance. To address these challenges, we designed a local treatment that converted a metabolic product (H2O2) of an OM pathogen (Streptococcus pneumoniae) into a potent antiseptic (HOBr), a reaction catalyzed by locally administered vanadium pentoxide nanowires. The therapeutic, HOBr, was only synthesized in the presence of the pathogen, enabling on-demand generation of therapeutics for OM treatment. Hypohalous acids are broad-spectrum and have a long history in general disinfection applications without breeding substantial drug resistance. A single dose of the nanowire formulation eradicated OM in a standard chinchilla model in 7 days with no observable tissue toxicity or negative impact on hearing sensitivity.

A multi-scale map of cell structure fusing protein images and interactions.

The cell is a multi-scale structure with modular organization across at least four orders of magnitude1. Two central approaches for mapping this structure-protein fluorescent imaging and protein biophysical association-each generate extensive datasets, but of distinct qualities and resolutions that are typically treated separately2,3. Here we integrate immunofluorescence images in the Human Protein Atlas4 with affinity purifications in BioPlex5 to create a unified hierarchical map of human cell architecture. Integration is achieved by configuring each approach as a general measure of protein distance, then calibrating the two measures using machine learning. The map, known as the multi-scale integrated cell (MuSIC 1.0), resolves 69 subcellular systems, of which approximately half are to our knowledge undocumented. Accordingly, we perform 134 additional affinity purifications and validate subunit associations for the majority of systems. The map reveals a pre-ribosomal RNA processing assembly and accessory factors, which we show govern rRNA maturation, and functional roles for SRRM1 and FAM120C in chromatin and RPS3A in splicing. By integration across scales, MuSIC increases the resolution of imaging while giving protein interactions a spatial dimension, paving the way to incorporate diverse types of data in proteome-wide cell maps.

Interpretation of cancer mutations using a multiscale map of protein systems.

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 challenges­how to comprehensively map such systems and how to identify which are under mutational selection­have 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.