Citations

Extracellular matrix stiffness controls DNA damage response.

Background: The retear rate after rotator cuff repair remains unacceptably high. Various biological engineered scaffolds have been proposed to reduce the retear rate. We have developed a double rip-stop repair with medial row knot (DRSK) technique to enhance suture-tendon strength and a novel engineered tendon-fibrocartilage-bone composite (TFBC) for rotator cuff repair. Hypothesis: DRSK rotator cuff repair augmented with TFBC will have better biomechanical properties than that of DRSK repair with an acellular dermal graft (DG). Study Design: Controlled laboratory study. Methods: Fresh-frozen canine shoulders (n = 30) and knees (n = 10) were used. TFBCs were harvested from the patellar tendon–tibia complex and prepared for rotator cuff repair. The infraspinatus tendon was sharply detached from its bony attachment and randomly assigned to the (1) control group: DRSK repair alone, (2) TFBC group: DRSK repair with TFBC, and (3) DG group: DRSK repair with DG. All specimens were tested to failure, and videos were recorded. The footprint area, tendon thickness, load to create 3-mm gap formation, failure load, failure modes, and stiffness were recorded and compared. Data were recorded as mean ± SD. Results: The mean load to create a 3-mm gap in both the control group (206.8 ± 55.7 N) and TFBC group (208.9 ± 39.1 N) was significantly higher than that in the DG group (157.7 ± 52.3 N) ( P < .05 for all). The failure load of the control group (275.7 ± 75.0 N) and TFBC group (275.2 ± 52.5 N) was significantly higher compared with the DG group (201.5 ± 49.7 N) ( P < .05 for both comparisons). The stiffness of the control group (26.4 ± 4.7 N/mm) was significantly higher than of the TFBC group (20.4 ± 4.4 N/mm) and the DG group (21.1 ± 4.8 N/mm) ( P < .05 for both comparisons). Conclusion: TFBC augmentation showed superior biomechanical performance to DG augmentation in rotator cuff tears repaired using the DRSK technique, while there was no difference between the TFBC and control groups. Clinical Relevance: TFBC may help to reduce retear or gap formation after rotator cuff repair using the DRSK technique.

Abstract Although high-grade serous ovarian cancers (HGSOC) are highly chemosensitive with an 85% initial response rate to platinum-based chemotherapy, 15% of patients are “exceptional nonresponders,” with platinum-refractory tumors that remain stable or progress during treatment. Unfortunately, we have no predictive biomarkers to identify refractory patients up front, and they receive futile chemotherapy through which most patients become too ill to be eligible for clinical trials. Hence, no progress has been made in treating these deadly tumors. The goal of this study is to identify mechanisms of platinum refractoriness to: i) predict refractory HGSOCs up front and ii) identify potential new drug targets in refractory disease to point to desperately needed new therapeutic approaches. Of note, 80-90% of patients who are initially platinum responsive will relapse and develop platinum-resistant disease, and it is possible that findings in platinum-refractory tumors might also provide insights into platinum-resistant tumors. Our NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC)-funded approach combines genomic and proteomic (“proteogenomic”) analyses of both preclinical models (0, 8, and 24 hours post-platinum exposure) and treatment-naïve human tumors. For preclinical models, we studied a well-characterized collection of patient-derived xenograft (PDX) models (10 sensitive, 10 refractory), as well as intrapatient HGSOC cell line pairs derived from patients before and after the development of platinum resistance. For the PDX models, proteogenomic profiling included RNASeq, WES, global proteomics, and phosphoproteomics at all 3 time points (0, 8, 24 hours). For cell line models (3 sensitive, 3 resistant), proteogenomic profiling was performed at all 3 timepoints (0, 8, 24 hours), and experiments were performed in complete biologic triplicate. Analyses included RNASeq, WES, global proteomics, phosphoproteomics, ubiquitin proteome, acetylated proteome, and pTyr. A large collection of 275 human HGSOCs (an approximate equal balance of platinum sensitive and refractory tumors) is currently undergoing proteomic profiling, and genomic profiles (WGS, RNASeq) will be performed on a subset. In parallel, we have performed a comprehensive review of 31 years of published work on platinum responses of human cancers, identifying ~700 genes implicated in the response and scoring each gene with respect to strength of the published evidence. Using a Bayesian approach, we are integrating the curated candidates from the literature with our empirical proteogenomic datasets to identify a candidate signature for detecting platinum-refractory disease prior to chemotherapy. We are also performing gene-regulatory network analysis to identify potential drivers of chemo response. NextGen, targeted, multiplex, multiple reaction monitoring mass spectrometry-based assays are being developed to quantify proteins in the signature for validation studies, using independent patient cohorts. This abstract is also being presented as Poster A62. Citation Format: Jacob J. Kennedy, Shrabanti Chowdhury, Sara R. Savage, Xiaonan Hou, Catherine J. Huntoon, Richard G. Ivey, Qing Yu, Chenwei Lin, Dongqing Huang, Lei Zhao, Uliana J. Voytovich, Regine M. Schoenherr, Zahra Shire, Steven J. Skates, Jeffrey R. Whiteaker, Andrew N. Hoofnagle, Samuel C. Mok, Bing Zhang, Larry M. Karnitz, S. John Weroha, Steven P. Gygi, Scott H. Kaufmann, Pei Wang, Michael J. Birrer, Amanda G. Paulovich. Proteogenomic approach to identify mechanisms of platinum refractoriness in high-grade serous ovarian cancers [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR02.

e19031 Background: Useful predictors of survival in cancer patients have been found including such as gender, race, age, marital status, state of disease and tumor location. We set to explore the prognostic value of baseline QOL assessments on overall survival in lung cancer patients. Methods: A total of 1,319 lung cancer patients were followed at Mayo Clinic between 1997 and 2007. Overall QOL was assessed by either Lung Cancer Symptom Scale (LCSS) or a single-item Linear Analogue Self Assessment (LASA) with comparable wording. QOL scores were transformed to a 0–100 scale with higher scores representing better status. Patients QOL scores assessed within the first 6 months of follow-up were dichotomized using a priori definition for clinically deficiency score (CDS, ≤50 vs. >50). The Kaplan-Meier method was used to estimate the distribution of survival times by QOL clinical deficient categorization. Cox Proportional Hazards Models were used to evaluate the prognostic importance of QOL on OS alone and in the presence of age, smoking category, gender, treatment, stage of disease, smoking cessation and years of consuming a pack every day. Results: Baseline QOL was significantly associated with OS univariately (HR=0.46 with p<0.0001 based on the CDS categorization). After controlling for all these other factors, the indication of a clinically deficient baseline QOL contributed significantly to the prediction of patient survival (p=0.0002; HR=0.67). Age, treatment, disease stage, smoking cessation and smoking category were also significant predictors of OS multivariately. The median survival for patients that had an overall QOL score less than the CDS (≤50) was 1.6 versus 4.6 years for patients with QOL >50. Conclusions: Baseline overall QOL measured by LCSS or LASA is a significant and independent prognostic factor for OS in lung cancer patients. A meaningful next step in this research is to investigate interventions to improve lung cancer patient QOL and thereby increase their likelihood of survival as well. No significant financial relationships to disclose.

4025 Background: Cumulative sNT is the dose-limiting toxicity of oxaliplatin which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant setting. We recently demonstrated the protective effect of CaMg against oxaliplatin-induced sNT as assessed by NCI-CTC (Nikcevich ASCO 2008). It is unclear, though, if CaMg reduced acute and/or chronic, cumulative sNT. Methods: 104 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to IV CaMg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo (PL) in a double-blinded manner. NCI-CTC, an oxaliplatin-specific sNT scale and patient-reported outcome (PRO) questionnaires were used to differentially assess the effect of CaMg on acute (effect on sNT on days 1–4 after oxaliplatin) and chronic sNT (area between curves over whole course of therapy). Results: A total of 102 pts (50 CaMg, 52 PL; 96 mFOLFOX6, 6 FOLFOX4) were available for analysis. Apart from a strong reduction in muscle cramps with CaMg (p=0.002), no difference was found between CaMg and PL in PRO with regard to items reflecting acute sNT (e.g. sensitivity to cold, swallowing of cold liquids, throat discomfort) on days 1–4 after oxaliplatin of any treatment cycle. In contrast, CaMg was able to significantly reduce cumulative sNT in form of numbness in fingers (p=0.02), impaired ability to button shirts (p=0.05), tingling in fingers (p=0.06), and muscle cramps over the course of therapy (p=0.01). Conclusions: In our phase III, placebo-controlled trial, CaMg was able to significantly reduce chronic, cumulative sNT related to oxaliplatin as evaluated by specific PRO questionnaires. No effect was noted on phenomena associated with acute sNT. CaMg can be recommended as neuroprotectant against oxaliplatin-related chronic sNT, oxaliplatin's dose-limiting toxicity. [Table: see text]

AbstractIntroductionCerebrovascular pathologies including cerebral amyloid angiopathy (CAA) and blood‐brain barrier (BBB) dysregulation are prominent features in the majority of Alzheimer's disease (AD) cases.MethodsWe performed neuropathologic and biochemical studies on a large, neuropathologically confirmed human AD cohort (N = 469). Amounts of endothelial tight junction proteins claudin‐5 (CLDN5) and occludin (OCLN), and major AD‐related molecules (amyloid beta [Aβ40], Aβ42, tau, p‐tau, and apolipoprotein E) in the temporal cortex were assessed by ELISA.ResultsHigher levels of soluble tau, insoluble p‐tau, and apolipoprotein E (apoE) were independently correlated with lower levels of endothelial tight junction proteins CLDN5 and OCLN in AD brains. Although high Aβ40 levels, APOE ε4, and male sex were predominantly associated with exacerbated CAA severity, those factors did not influence tight junction protein levels.DiscussionRefining the molecular mechanisms connecting tau, Aβ, and apoE with cerebrovascular pathologies is critical for greater understanding of AD pathogenesis and establishing effective therapeutic interventions for the disease.

With the widespread use of high-resolution ultrasonography, ultrasonic examination has been shown to be useful as a diagnostic method for carpal tunnel syndrome. The main advantages of ultrasonography are that it is simple, quick, non-invasive, and economical. Another advantage is that tissue dynamics can be observed with real-time imaging. In recent reports, it has been shown that ultrasonic examination can provide similar diagnostic accuracy as nerve conduction study in the diagnosis of carpal tunnel syndrome. It has been expected that ultrasound demand in daily medical care will continue to increase. Ultrasonography in carpal tunnel syndrome shows an enlarged median nerve in proximal carpal tunnel, thickening of the flexor retinaculum, and edema around flexor tendons in cross-sectional images. In addition, with the introduction of new technologies such as ultrasonic elastography and speckle tracking, it has become possible to quantify dynamics and material property changes of nerves, tendons, and their surrounding structures. In this review, we describe recent advancements of carpal tunnel syndrome diagnosis based on ultrasound dynamic images, and discuss its pathology.

Background Women have decreased hemodialysis arteriovenous fistula (AVF) maturation and patency rates. We determined the mechanisms responsible for the sex‐specific differences in AVF maturation and stenosis formation by performing whole transcriptome RNA sequencing with differential gene expression and pathway analysis, histopathological changes, and in vitro cell culture experiments from male and female smooth muscle cells. Methods and Results Mice with chronic kidney disease and AVF were used. Outflow veins were evaluated for gene expression, histomorphometric analysis, Doppler ultrasound, immunohistologic analysis, and fibrosis. Primary vascular smooth muscle cells were collected from female and male aorta vessels. In female AVFs, RNA sequencing with real‐time polymerase chain reaction analysis demonstrated a significant decrease in the average gene expression of BMP7 (bone morphogenetic protein 7) and downstream IL17Rb (interleukin 17 receptor b) , with increased transforming growth factor‐β1 ( Tgf‐β1) and transforming growth factor‐β receptor 1 ( Tgfβ‐r1) . There was decreased peak velocity, negative vascular remodeling with higher venous fibrosis and an increase in synthetic vascular smooth muscle cell phenotype, decrease in proliferation, and increase in apoptosis in female outflow veins at day 28. In vitro primary vascular smooth muscle cell experiments performed under hypoxic conditions demonstrated, in female compared with male cells, that there was increased gene expression of Tgf‐β1 , Tgfβ‐r1 , and Col1 with increased migration. Conclusions In female AVFs, there is decreased gene expression of BMP7 and IL17Rb with increased Tgf‐β1 and Tgfβ‐r1 , and the cellular and vascular differences result in venous fibrosis with negative vascular remodeling.

Background: Asymptomatic recurrences of atrial fibrillation (AF) are common after ablation of AF. Objective: We aimed to analyze the performance of the mobile ECG device using artificial intelligence (AI) algorithm in detection of AF after ablation. Method: A randomized controlled trial of AF screening using a handheld single-lead ECG monitor (BigThumb®) or a traditional follow-up strategy was conducted in patients with non-valvular AF after catheter ablation. Consecutive patients were randomized to either BigThumb Group (BT Group) or Traditional Follow-up Group (TF Group). Monitoring data was collected and analyzed. The ECGs collected by BigThumb were compared using the automated AF detection algorithm, AI algorithm and cardiologists’ manual review. Subsequent changes in adherence on oral anticoagulation of patients were also recorded. Result: We studied 218 patients (109 in BT Group, 109 in TF Group). After a follow-up of 345.4±60.2 days, AF-free survival rate was 64.2% in BT Group and 78.9% in TF Group (P=0.0163), with more adherence on oral anticoagulation in BT Group (P=0.0052). The participants in the BT Group recorded 26133 ECGs during the follow-up, among which 3299 (12.6%) were diagnosed as AF by cardiologists’ manual review. The sensitivity and specificity of the AI algorithm were 94.4% and 98.5% respectively, which are significantly higher than the automated AF detection algorithm (90.7% and 96.2%). Conclusion: We found that follow-up after AF ablation using BigThumb leads to a more frequent detection of AF recurrence and more adherence on oral anticoagulation. Artificial intelligence algorithm improves the accuracy of ECG diagnosis.

Abstract Background: Next-generation sequencing provides comprehensive information about individuals’ genetic makeup and is commonplace in oncology clinical practice. However, the utility of genetic information in clinical decision-making process has not been examined extensively from a real-world, data-driven perspective. Through mining real-world data (RWD) from clinical notes, we could extract patients’ genetic information and further associate treatment decisions with genetic information.Methods: We proposed a real-world evidence (RWE) study framework that incorporates context-based natural language processing (NLP) methods and data quality examination before final association analysis. The framework was demonstrated on a Foundation-tested women cancer cohort (N=196). Upon retrieval of patients’ genetic information using NLP system, we assessed completeness of genetic data captured in unstructured clinical notes according a genetic data-model. We examined the distribution of different topics regarding BRCA1/2 throughout patients’ treatment process, and then analyzed the association between BRCA1/2 mutation status and the discussion/prescription of targeted therapy. Results: We identified seven topics in clinical context of genetic mentions including: Information, Evaluation, Insurance, Order, Negative, Positive, and Variants of unknown significance (VUS). Our rule-based system achieved a precision of 0.87, recall of 0.93 and F-measure of 0.91. Our machine learning system achieved a precision of 0.901, recall of 0.899 and F-measure of 0.9 for four-topic classification and a precision of 0.833, recall of 0.823 and F-measure of 0.82 for seven-topic classification. We found in result-containing sentences, capture of BRCA1/2 mutation information was 75%, but detailed variant information (e.g. variant types) is largely missing. Using cleaned RWD, significant associations were found between BRCA1/2 positive mutation and targeted therapies.Conclusions: In conclusion, we demonstrated a framework to generate RWE using RWD from different clinical sources. Rule-based NLP system achieved the best performance for resolving contextual variability when extracting RWD from unstructured clinical notes. Data quality issue such as incompleteness and discrepancies exist thus manual data cleaning is needed before further analysis can be performed. Finally, we were able to use cleaned RWD to evaluate real-world utility of genetic information to initiate prescription of targeted therapy.