Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

Phosphoproteome Integration Reveals Patient-Specific Networks in Prostate Cancer.

We used clinical tissue from lethal metastatic castration-resistant prostate cancer (CRPC) patients obtained at rapid autopsy to evaluate diverse genomic, transcriptomic, and phosphoproteomic datasets for pathway analysis. Using Tied Diffusion through Interacting Events (TieDIE), we integrated differentially expressed master transcriptional regulators, functionally mutated genes, and differentially activated kinases in CRPC tissues to synthesize a robust signaling network consisting of druggable kinase pathways. Using MSigDB hallmark gene sets, six major signaling pathways with phosphorylation of several key residues were significantly enriched in CRPC tumors after incorporation of phosphoproteomic data. Individual autopsy profiles developed using these hallmarks revealed clinically relevant pathway information potentially suitable for patient stratification and targeted therapies in late stage prostate cancer. Here, we describe phosphorylation-based cancer hallmarks using integrated personalized signatures (pCHIPS) that shed light on the diversity of activated signaling pathways in metastatic CRPC while providing an integrative, pathway-based reference for drug prioritization in individual patients.

Adolescent pregnancy is associated with child undernutrition: Systematic review and meta-analysis.

Adolescent pregnancy is associated with poor fetal growth and development which, in turn, increases the risk of childhood wasting and underweight. However, evidence on how young maternal age affects childhood anthropometry beyond the neonatal period is limited. This systematic review and meta-analysis examined associations between adolescent pregnancy and child wasting and underweight and explored potential underlying social and biological factors. Peer-reviewed literature published in English since 1990 was systematically searched. Eligible studies presented data on wasting and/or underweight in children (≤59 months) born to adolescent mothers (10-19, or ≤24 years where applicable) from low- and middle-income countries. Data extraction used a predefined extraction sheet. Both meta-analysis and qualitative synthesis were performed. Of 92 identified studies, 57 were included in the meta-analysis. The meta-analysis showed that children born to adolescent versus adult mothers were at a higher risk of moderate (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.00-1.26 p = 0.04) and severe underweight (OR: 1.21, 95% CI: 1.08-1.35 p < 0.01). Associated risk of wasting was not statistically significant: (OR: 1.05, 95% CI: 0.98-1.12 p = 0.17); severe wasting (OR: 1.16, 95% CI: 0.68-1.96 p = 0.59). These findings were supported by the qualitative synthesis. Evidence on the potential role of biological/social factors was limited, but suggested an intermediary role of maternal nutritional status which warrants further exploration. Particularly in contexts where adolescent pregnancy remains common, interventions to both delay adolescent pregnancy and improve adolescent nutritional status could help reduce the risk of undernutrition in children and contribute to breaking the intergenerational cycle of malnutrition.

Accurate cancer phenotype prediction with AKLIMATE, a stacked kernel learner integrating multimodal genomic data and pathway knowledge.

Advancements in sequencing have led to the proliferation of multi-omic profiles of human cells under different conditions and perturbations. In addition, many databases have amassed information about pathways and gene "signatures"-patterns of gene expression associated with specific cellular and phenotypic contexts. An important current challenge in systems biology is to leverage such knowledge about gene coordination to maximize the predictive power and generalization of models applied to high-throughput datasets. However, few such integrative approaches exist that also provide interpretable results quantifying the importance of individual genes and pathways to model accuracy. We introduce AKLIMATE, a first kernel-based stacked learner that seamlessly incorporates multi-omics feature data with prior information in the form of pathways for either regression or classification tasks. AKLIMATE uses a novel multiple-kernel learning framework where individual kernels capture the prediction propensities recorded in random forests, each built from a specific pathway gene set that integrates all omics data for its member genes. AKLIMATE has comparable or improved performance relative to state-of-the-art methods on diverse phenotype learning tasks, including predicting microsatellite instability in endometrial and colorectal cancer, survival in breast cancer, and cell line response to gene knockdowns. We show how AKLIMATE is able to connect feature data across data platforms through their common pathways to identify examples of several known and novel contributors of cancer and synthetic lethality.

From education to action: Development and evaluation of a student-directed service learning program.

PURPOSE: Service learning consists of service activities that respond to community-identified concerns, active learning about the population being served, and self-reflecting on the experience. The Service Learning Program (SLP) is a novel, student-led, longitudinal volunteering experience designed to address social determinants of health (SDOH) education in the undergraduate medical school curriculum. In this program, medical students complete requirements in three domains of service, education, and self-reflection over the span of one academic year. METHODS AND MATERIALS: Participating students are sent surveys prior to and after a year of participation in SLP, which are aimed to measure changes in their perceived knowledge, attitudes, and skills in multiple domains related to service learning and social determinants of health. RESULTS: Over the course of the 2019-2020 year, 110 students who participated in SLP responded to both pre- and post-surveys. These students reported significant improvements in their confidence in various knowledge and skills related to SDOH, such as identifying vulnerable populations and assessing community needs. They also were more likely to report that learning about social determinants of health was 'very important' after participating the program. CONCLUSIONS: Medical students participating in a longitudinal service learning program focused on SDOH can acquire knowledge and skills that will empower them to understand, advocate, and care for underserved populations as future physicians. This program provides a model for integrating service learning into undergraduate medical education.

A risk-associated Active transcriptome phenotype expressed by histologically normal human breast tissue and linked to a pro-tumorigenic adipocyte population.

BACKGROUND: Previous studies have identified and validated a risk-associated Active transcriptome phenotype commonly expressed in the cancer-adjacent and histologically normal epithelium, stroma, and adipose containing peritumor microenvironment of clinically established invasive breast cancers, conferring a 2.5- to 3-fold later risk of dying from recurrent breast cancer. Expression of this Active transcriptome phenotype has not yet been evaluated in normal breast tissue samples unassociated with any benign or malignant lesions; however, it has been associated with increased peritumor adipocyte composition. METHODS: Detailed histologic and transcriptomic (RNAseq) analyses were performed on normal breast biopsy samples from 151 healthy, parous, non-obese (mean BMI = 29.60 ± 7.92) women, ages 27-66 who donated core breast biopsy samples to the Komen Tissue Bank, and whose average breast cancer risk estimate (Gail score) at the time of biopsy (1.27 ± 1.34) would not qualify them for endocrine prevention therapy. RESULTS: Full genome RNA sequencing (RNAseq) identified 52% (78/151) of these normal breast samples as expressing the Active breast phenotype. While Active signature genes were found to be most variably expressed in mammary adipocytes, donors with the Active phenotype had no difference in BMI but significantly higher Gail scores (1.46 vs. 1.18; p = 0.007). Active breast samples possessed 1.6-fold more (~ 80%) adipocyte nuclei, larger cross-sectional adipocyte areas (p < 0.01), and 0.5-fold fewer stromal and epithelial cell nuclei (p < 1e-6). Infrequent low-level expression of cancer gene hotspot mutations was detected but not enriched in the Active breast samples. Active samples were enriched in gene sets associated with adipogenesis and fat metabolism (FDR q ≤ 10%), higher signature scores for cAMP-dependent lipolysis known to drive breast cancer progression, white adipose tissue browning (Wilcoxon p < 0.01), and genes associated with adipocyte activation (leptin, adiponectin) and remodeling (CAV1, BNIP3), adipokine growth factors (IGF-1, FGF2), and pro-inflammatory fat signaling (IKBKG, CCL13). CONCLUSIONS: The risk-associated Active transcriptome phenotype first identified in cancer-adjacent breast tissues also occurs commonly in healthy women without breast disease who do not qualify for breast cancer chemoprevention, and independently of breast expressed cancer-associated mutations. The risk-associated Active phenotype appears driven by a pro-tumorigenic adipocyte microenvironment that can predate breast cancer development.

A Meta-analysis of Long-term Mortality and Associated Risk Factors following Lower Extremity Amputation.

BACKGROUND: A majority of patients undergoing lower limb amputations have diabetes or peripheral artery disease. Despite improvements in care, there remains a substantial perioperative mortality associated with these procedures. Less well-defined is the mortality risk to these patients going forward, once outside the perioperative period. The aim of this systematic review is to summarize and pool the available data to determine the long-term mortality associated with amputation in the diabetic and peripheral vascular patient, as well as to define specific factors associated with increased mortality risk. METHODS: Four databases were searched from January 2005 through July 2015 using the Medical Subject Headings terms "amputation," "lower extremity," and "mortality." Inclusion criteria were observational and cohort studies where ≥50% of amputations were attributable to diabetic or vascular etiologies. Final article inclusion was approved by reviewer consensus. Bias was assessed with the Joanna Briggs Institute Critical Appraisal Tool for cohort studies. RESULTS: Of the 365 unique records screened, 43 abstracts and 21 full articles were reviewed and 16 studies ultimately included. The overall mortality rate was 47.9%, 61.3%, 70.6%, and 62.2% at 1-, 2-, 3- and 5-year follow-up, respectively. In addition to diabetes and peripheral vascular disease, comorbid factors associated with at least a 2-fold increased mortality were coronary artery disease, cerebrovascular disease, renal dysfunction, American Society of Anesthesiologists class ≥4, dementia, and nonambulatory status. Surgical factors, including higher amputation level and need for staged surgery with up-front guillotine amputation, were also correlated with increased mortality. CONCLUSIONS: The overall mortality rate after primary lower limb amputation in the diabetic and peripheral vascular population is substantial, and should not be underestimated when making decisions regarding limb salvage. Similar to patients undergoing revascularization, comorbid conditions associated with higher mortality should be optimized before surgery whenever possible.

The UCSC Interaction Browser: multidimensional data views in pathway context.

High-throughput data sets such as genome-wide protein-protein interactions, protein-DNA interactions and gene expression data have been published for several model systems, especially for human cancer samples. The University of California, Santa Cruz (UCSC) Interaction Browser (http://sysbio.soe.ucsc.edu/nets) is an online tool for biologists to view high-throughput data sets simultaneously for the analysis of functional relationships between biological entities. Users can access several public interaction networks and functional genomics data sets through the portal as well as upload their own networks and data sets for analysis. Users can navigate through correlative relationships for focused sets of genes belonging to biological pathways using a standard web browser. Using a new visual modality called the CircleMap, multiple 'omics' data sets can be viewed simultaneously within the context of curated, predicted, directed and undirected regulatory interactions. The Interaction Browser provides an integrative viewing of biological networks based on the consensus of many observations about genes and their products, which may provide new insights about normal and disease processes not obvious from any isolated data set.

Single-cell signatures identify microenvironment factors in tumors associated with patient outcomes.

The cellular components of tumors and their microenvironment play pivotal roles in tumor progression, patient survival, and the response to cancer treatments. Unveiling a comprehensive cellular profile within bulk tumors via single-cell RNA sequencing (scRNA-seq) data is crucial, as it unveils intrinsic tumor cellular traits that elude identification through conventional cancer subtyping methods. Our contribution, scBeacon, is a tool that derives cell-type signatures by integrating and clustering multiple scRNA-seq datasets to extract signatures for deconvolving unrelated tumor datasets on bulk samples. Through the employment of scBeacon on the The Cancer Genome Atlas (TCGA) cohort, we find cellular and molecular attributes within specific tumor categories, many with patient outcome relevance. We developed a tumor cell-type map to visually depict the relationships among TCGA samples based on the cell-type inferences.

A scoping review of postoperative early rehabilitation programs after dysvascular-related amputations.

BACKGROUND: After amputation, people face challenges including wound healing and decreased functional mobility. Early mobilization in acute hospital care has proved safe, improved function, and sped discharge. Still, loss of a leg complicates standing and early mobilization after amputation. Approaches to early mobilization and rehabilitation after amputation surgery have not been widely studied. OBJECTIVES: To map the evidence regarding early postoperative mobilization after dysvascular amputation. Specific aims included identifying research designs and populations, describing rehabilitation approaches, and identifying gaps within the literature. STUDY DESIGN: Scoping review following PRISMA-Sc guidelines. METHODS: The a priori scoping review methodology conducted in June 2022 with English language and 20-year limits used the OVID Medline, OVID Allied and Complementary Medicine Database, Cumulative Index to Nursing and Allied Health Literature, Cochrane databases, and Journal of Prosthetics and Orthotics archive. Reviewer pairs used Covidence software to screen for inclusion (subjects with major lower limb dysvascular amputations, seen immediately postoperatively for hospital-based rehabilitation) with decisions by concurrence. Data for best practice scoping reviews were synthesized for analysis. RESULTS: Two hundred ninety-six citations were screened, 13 full texts reviewed, and 8 articles included: 2 cohort studies, 3 case-control studies, 2 single-group interventional studies, and 1 case study. There were no randomized control trials or prospective comparison group trials. CONCLUSIONS: Few studies were identified regarding acute rehabilitation after major lower extremity amputation. The limited evidence in this review suggested that early mobilization in the days after amputation was safe with or without use of temporary prostheses, although further research is certainly warranted.

Single-cell chromatin accessibility reveals malignant regulatory programs in primary human cancers.

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting that dispersed, nonrecurrent, noncoding mutations in cancer are functional. Overall, these data and interpretable gene regulatory models for cancer and healthy tissue provide a framework for understanding cancer-specific gene regulation.

Beyond exercise. Can application of manual therapy before exercise benefit a low functioning person with limb loss? A case study.

BACKGROUND: Most people with lower-limb loss (PLL) have musculoskeletal conditions and range-of-motion and muscle performance impairments. Such impairments limit potential for functional movement but can be reduced with manual therapy. Manual therapy, however, is rarely used for PLL. This case demonstrated how integrating manual therapy, exercise, and functional training led to lasting benefits for one low functioning PLL. CASE DESCRIPTION: A 54-year-old woman more than 1 year after transtibial amputation due to peripheral artery disease presented with multiple comorbidities and yellow flags. Her function remained limited to the Medicare K-1 household walking level with slow gait speed <0.25 m/s. Treatment included four weekly sessions each beginning with manual therapy, followed by exercise and functional training. OUTCOMES: After 1 month, performance-based strength, balance, walking speed, and physical activity increased. She advanced to the K-2 limited community walking level and maintained her functional level without further treatment after 3 months. DISCUSSION: Improvements maintained without treatment expanded upon research that lacked follow-up and excluded K-1 level walkers. Marked improvement after only four sessions was noteworthy since exercise protocols require ≥4 sessions. CONCLUSION: Manual therapy followed by exercise and functional training may optimize movement potential and contribute to improving strength, balance, gait, and physical activity among PLL.

Preliminary analysis of reliability and validity of the Life Space Questionnaire as a real-world mobility measure for people with lower limb loss: A technical note.

People with lower-limb loss (PLL) often have reduced mobility that translates into limited community access. The Life Space Questionnaire (LSQ) measures a person's real-world mobility within their home environment and community but has not been used among PLL. This study assessed preliminary LSQ test-retest reliability and discriminant validity from subjective and objective balance and walking measures in PLL. In addition, LSQ was hypothesized to have an inverse association with overall health status. Nine subjects were analyzed with mean age 48.2 ± 13.1 years and 4.8 ± 3.9 years' time since amputation. Six had transtibial and three had transfemoral amputations due to diabetes (4), vascular disease (3), and trauma (2). The primary outcome was the LSQ, a 9-level scale quantifying the extent to which people accessed their life space including home, yard, and community. Test-retest reliability for the LSQ was moderate (intraclass coefficient = 0.61 with 90% confidence interval: 0.19-0.87). Discriminant validity from balance and walking function was demonstrated by lack of correlation between LSQ score and the Activities-specific Balance Confidence and Berg Balance Scale and the Prosthetic Evaluation Questionnaire mobility subscale and walking speed (r < 0.50, P > .05). LSQ correlated with health status assessed with the Charlson Comorbidity Index (r = -0.84, P = .005). In this sample of PLL, the LSQ demonstrated moderate test-retest reliability as a measure of real-world mobility distinct as a construct from subjective and objective balance or walking measures. People may access their communities using various levels of assistance and methods of transportation. For this sample of PLL, health status was most strongly associated with LSQ score.

Walking asymmetry and its relation to patient-reported and performance-based outcome measures in individuals with unilateral lower limb loss.

Gait asymmetry persists for most people after lower limb amputation and is associated with slower walking speeds. However, the relationship between gait asymmetry and patient-reported function remains unclear because they are not commonly assessed together. The purpose of this study was to determine relationships between gait asymmetries in people with lower limb loss and (1) patient-reported outcomes and (2) performance-based prosthetic functional measures. This cross-sectional analysis included nine people with unilateral limb loss aged 48.2 ± 13.1 years of mixed amputation etiology. Patient-reported outcomes included the Prosthetic Evaluation Questionnaire mobility subscale and Activities-specific Balance Confidence scale. Performance outcomes included the Berg Balance Scale and the 30-second sit-to-stand test. Walking performance measures included the 2-Minute Walk Test, during which APDM Opal sensors recorded spatiotemporal gait parameters, and daily step-counts from StepWatch4 activity monitors. The study found that the most asymmetric gait symmetry ratios (prosthetic-limb divided by intact-limb) could be attributed to prosthetic foot dorsiflexion-plantarflexion and rotation motion limitations: prosthetic-limb trailing double support (0.789 ± 0.052), toe-off (0.760 ± 0.068) and toe-out angle (0.653 ± 0.256). Single limb stance, and stance and swing phase durations were most strongly associated with balance and walking performance measures. Notably, no symmetry ratio was significantly associated with patient-reported prosthetic function (unadjusted Pearson correlation coefficients r < 0.50, P > 0.05). More gait symmetry was associated with better balance and walking performance but had no significant relationship with patient-reported function. Although achieving gait symmetry after lower limb loss is a common walking goal, symmetry was unrelated to the perception of functional mobility for people with lower limb loss.

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

Quantifying the risk of falls and injuries for amputees beyond annual fall rates-A longitudinal cohort analysis based on person-step exposure over time.

People with lower-limb loss (PLL) have high annual fall and injury rates. People with transtibial amputations have better walking function than those with transfemoral amputations but paradoxically incur more fall-related injuries. Risk exposure, however, has not been previously considered. This study examined whether all-cause fall and injury incidence per person-step exposure over time varied in PLL of different walking abilities. The prospective cohort design, conducted at a major medical center, included five assessments 1-month apart. Walking ability level was categorized by Houghton Scale scores: ≥9 indicating community walking and ≤ 8 indicating limited community-household walking. Accelerometer-measured daily step counts were collected via StepWatch4 monitors. The main outcome measures, self-reported all-cause falls and injuries were assessed using the standard National Health Injury Survey. Generalized estimating equations, using Poisson distributions and log of step count as an offset, determined fall and injury incidence rate ratio [IRR] according to walking ability level. Ten people, aged 33-63 years with amputations of different causes and levels, were assessed monthly over five months. The community walking group (n = 6) had six falls and seven injuries; the limited community walking group (n = 4) had four falls and three injuries. For PLL, limited community walking ability was associated with higher incidence of falls (IRR = 6.10, 95%CI = 1.12-33.33, p = 0.037) and injuries (IRR = 8.56, 95%CI = 1.73-42.40, p = 0.009) when accounting for person-steps. Considering per person-step exposure over time added precision to fall and injury risk assessment that clarified the risks: PLL with limited community walking ability have higher fall and injury risks.

A Scoping Review of Physical Activity in People With Lower-Limb Loss: 10,000 Steps Per Day?

OBJECTIVE: After amputation, people with lower-limb loss (PLL) face challenges to regain their previous physical activity level. Assessing the scope of evidence regarding physical activity in PLL can identify sources of evidence and gaps within the literature that can influence amputation-related research, outcome assessment choices, and wellness activities. The purpose of this scoping review was to map the evidence regarding steps per day as a physical activity measure for PLL. Specific aims were to (1) identify research designs, (2) catalog population subgroups, (3) document steps per day measurement methods, and (4) provide descriptive data for steps per day in PLL. METHODS: The MEDLINE, CINAHL, Embase, Web of Science, and AMED databases; and the Journal of Prosthetics and Orthotics archive were searched without language or time limits. Exclusion criteria included no PLL subjects, not peer-reviewed, and no direct step count measure. Inclusion criteria allowed any sample size, nonprosthetic use, and self-reported step count. As a scoping review, only descriptive statistics were compiled, and no methodologic quality assessment was performed. RESULTS: Twenty-one articles using crossover (8), cohort (4), cross-section (8), and case-study (1) designs were included that reported accelerometer (19) or pedometer (2) data. Studies often mixed amputation etiologies (15/21) and most (13/21) excluded transfemoral amputations. Studies primarily examined people with transtibial amputations (81.2%) and people at independent community walking levels (Medicare functional classifications: K3 = 49.2%, K4 = 36.3%). All 21 studies had fewer than 100 participants, and overall included 515 subjects (343, 66.6% male), mean (SD) age 53.2 (22.1) years. Mean (SD) number of pooled steps per day for PLL was 5087 (2998): 5929 (3047) for transtibial amputations and 3553 (2030) for transfemoral amputations. CONCLUSIONS: Most PLL have low activity levels compared with the 10,000 steps per day generally recommended or 6000 common in people with diabetes. Research with larger samples, defined subgroups, and data along the recovery continuum would enhance knowledge of physical activity level in PLL. IMPACT: This scoping review has identified gaps in the research related to steps per day as a measure of physical activity in people with lower-limb loss to guide future research. LAY SUMMARY: People with lower-limb loss take fewer steps per day than suggested for general health. Increasing steps per day may be a useful goal for this population, and this study is a first step in improving knowledge of physical activity levels in people with lower-limb loss.

Whole-genome characterization of lung adenocarcinomas lacking the RTK/RAS/RAF pathway.

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(-) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+) in 28 (33%) of the 85 samples. Among the remaining 57 cases, we observe focal deletions targeting the promoter or transcription start site of STK11 (n = 7) or KEAP1 (n = 3), and promoter mutations associated with the increased expression of ILF2 (n = 6). We also identify complex structural variations associated with high-level copy number amplifications. Moreover, an enrichment of focal deletions is found in TP53 mutant cases. Our results indicate that RPA(-) cases demonstrate tumor suppressor deletions and genome instability, but lack unique or recurrent genetic lesions compensating for the lack of RPAs. Larger WGS studies of RPA(-) cases are required to understand this important LUAD subset.

Relevance of medical comorbidities for functional mobility in people with limb loss: retrospective explanatory models for a clinical walking measure and a patient-reported functional outcome.

OBJECTIVES: Various modifiable and non-modifiable factors affect functional mobility, but subjective patient-reported and objective performance-based measures are rarely combined in explanatory analyses of functional mobility in people with limb loss. This study determined separate explanatory models for patient-reported function using the Prosthetic Evaluation Questionnaire Mobility Subscale (PEQ-MS), and performance-based 2-Minute Walk Test (2MWT). DESIGN: Retrospective cross-sectional observational analysis. SETTING: Wellness-walking program. PARTICIPANTS: Three hundred five volunteers with lower limb loss participated. Sixty nine percent were men, mean age 56 (15) years. Fifty two percent had vascular amputation causes, 42% had surgical levels above the knee, and 82% had medical comorbidities. Walking levels included limited-household (21%), limited-community (30%), and independent-community (49%). Outcome measures included patient-reported PEQ-MS, Activities-specific Balance Confidence (ABC) and Houghton scales; and performance-based balance and walking. MAIN OUTCOMES: Separate PEQ-MS and 2MWT multiple regression models fit using backward deletion. RESULTS: Modifiable (balance ability, ABC, Houghton score; P<0.05) and non-modifiable factors (sex, amputation cause, surgical level; P<0.05) explained the variance in 2MWT (adjusted R2=0.685). Patient-reported and performance-based modifiable factors (Houghton score, 2MWT; P<0.001) explained PEQ-MS variance (adjusted R2=0.660). Integumentary (P=0.022) and cardiopulmonary (P<0.001) comorbidities explained an additional 4% of PEQ-MS variance, while surgical level was insignificant. CONCLUSIONS: Both modifiable and non-modifiable factors explained prosthetic functional mobility. Performance-based walking was explained by modifiable factors including balance ability and confidence, prosthesis and walking aid use. Patient-reported function was also explained by prosthesis and walking aid use, walking speed and medical comorbidities. Modifiable factors for objective and subjective prosthetic mobility may provide a clinical roadmap for rehabilitation.