Temporal Trends in Body Composition and Metabolic Markers Prior to Diagnosis of Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Changes in body composition and metabolic factors may serve as biomarkers for the early detection of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to capture the longitudinal changes in body composition and metabolic factors before diagnosis of PDAC. METHODS: We performed a retrospective cohort study in which all patients (≥18 years) diagnosed with PDAC from 2002 to 2021 were identified. We collected all abdominal computed tomography scans and 10 different blood-based biomarkers up to 36 months before diagnosis. We applied a fully automated abdominal segmentation algorithm previously developed by our group for 3-dimensional quantification of body composition on computed tomography scans. Longitudinal trends of body composition and blood-based biomarkers before PDAC diagnosis were estimated using linear mixed models, compared across different time windows, and visualized using spline regression. RESULTS: We included 1690 patients in body composition analysis, of whom 516 (30.5%) had ≥2 prediagnostic computed tomography scans. For analysis of longitudinal trends of blood-based biomarkers, 3332 individuals were included. As an early manifestation of PDAC, we observed a significant decrease in visceral and subcutaneous adipose tissue (ß = -1.94 [95% confidence interval (CI), -2.39 to -1.48] and ß = -2.59 [95% CI, -3.17 to -2.02]) in area (cm2)/height (m2) per 6 months closer to diagnosis, accompanied by a decrease in serum lipids (eg, low-density lipoprotein [ß = -2.83; 95% CI, -3.31 to -2.34], total cholesterol [ß = -2.69; 95% CI, -3.18 to -2.20], and triglycerides [ß = -1.86; 95% CI, -2.61 to -1.11]), and an increase in blood glucose levels. Loss of muscle tissue and bone volume was predominantly observed in the last 6 months before diagnosis. CONCLUSIONS: This study identified significant alterations in a variety of soft tissue and metabolic markers that occur in the development of PDAC. Early recognition of these metabolic changes may provide an opportunity for early detection.

A Historic Cohort Analysis of Radiographic and Serologic Findings in Patients With Scleroderma and Interstitial Lung Disease.

BACKGROUND/OBJECTIVE: Few studies have investigated associations between rheumatologic serology patterns and different interstitial lung disease (ILD) patterns. METHODS: We present novel findings of a historic cohort study (n = 454) with data collected from 2011 to 2021 within our hospital system. In this institutional review board-approved study, data regarding rheumatologic serologies and ILD patterns were noted based on chart review in patients with scleroderma. The Kruskal-Wallis rank sum and χ2 tests were used for statistical analysis. RESULTS: Results showed a statistically significant association between anti-U1 snRNP with lymphoid interstitial pneumonia, which has not been previously described. CONCLUSIONS: We demonstrated novel serologic associations with ILD patterns, which have important clinical implications. More robust and high-powered studies are needed to elucidate the role of serologic testing and their association with ILD phenotypes.

Risk factors for post-acute sequelae of COVID-19: Survey results from a tertiary care hospital.

Identifying risk factors for post-acute sequelae of COVID-19 (PASC) is important. We conducted a multicenter cross-sectional survey study to define and characterize risk factors for severe COVID-19 in adults (≥18 years) treated at our virtual COVID-19 clinic from March 1, 2020, through March 31, 2021. We assessed patient demographics, symptom types, and persistence, incidence of PASC, and COVID-19-caused hospitalizations. Surveyed patients were also asked to rate their perception of the severity of their acute COVID-19 symptoms. Continuous variables were summarized descriptively. Differences among groups categorized by acute COVID-19 symptom severity level (mild/very mild, moderate, and severe/very severe) were evaluated with the Kruskal-Wallis rank sum test for continuous measures and the Pearson χ2 test for categorical measures. A total of 3094 adults completed the survey. More respondents with severe/very severe acute COVID-19 symptoms reported having PASC than did those with mild/very mild and moderate acute symptoms. A significantly greater proportion of respondents with PASC were women (68.4% vs 56.7%, p < 0.001), had been hospitalized (12.2% vs 4.4%, p < 0.001), reported having negative psychological COVID-19-related repercussions (39.9% vs 15.3%, p < 0.001), and required more than 1 month to resume normal activities (38.8% vs 12.9%, p < 0.001) than did those without PASC. These findings may improve our understanding of PASC and provide a framework for early recognition of and intervention for patients at higher risk for PASC. Further research is needed to understand the predictors of persistent symptoms after acute SARS-CoV-2 infection and the risk of PASC.

Distinct spatial immune microlandscapes are independently associated with outcomes in triple-negative breast cancer.

The utility of spatial immunobiomarker quantitation in prognostication and therapeutic prediction is actively being investigated in triple-negative breast cancer (TNBC). Here, with high-plex quantitative digital spatial profiling, we map and quantitate intraepithelial and adjacent stromal tumor immune protein microenvironments in systemic treatment-naïve (female only) TNBC to assess the spatial context in immunobiomarker-based prediction of outcome. Immune protein profiles of CD45-rich and CD68-rich stromal microenvironments differ significantly. While they typically mirror adjacent, intraepithelial microenvironments, this is not uniformly true. In two TNBC cohorts, intraepithelial CD40 or HLA-DR enrichment associates with better outcomes, independently of stromal immune protein profiles or stromal TILs and other established prognostic variables. In contrast, intraepithelial or stromal microenvironment enrichment with IDO1 associates with improved survival irrespective of its spatial location. Antigen-presenting and T-cell activation states are inferred from eigenprotein scores. Such scores within the intraepithelial compartment interact with PD-L1 and IDO1 in ways that suggest prognostic and/or therapeutic potential. This characterization of the intrinsic spatial immunobiology of treatment-naïve TNBC highlights the importance of spatial microenvironments for biomarker quantitation to resolve intrinsic prognostic and predictive immune features and ultimately inform therapeutic strategies for clinically actionable immune biomarkers.

Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early-Stage Breast Cancer Patients: A Post-hoc Analysis of the NCCTG-N9831 (Alliance) Trial.

BACKGROUND: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. PATIENTS AND METHODS: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. RESULTS: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). CONCLUSION: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab. TRIAL REGISTRATION: clinicaltrials.gov NCT00005970.

Association of coccygodynia with pelvic floor symptoms in women with pelvic pain.

BACKGROUND: Coccygodynia is a painful condition of the tailbone that occurs more commonly in females. The association of coccyx pain with pelvic floor symptoms and the prevalence of coccyx pain in women with pelvic pain has not previously been reported. OBJECTIVE: To identify the prevalence of coccygodynia in women with pelvic pain and to describe the association of coccygodynia with pelvic floor examination findings and symptoms. DESIGN: Retrospective cohort analysis. SETTING: Tertiary medical institution. PARTICIPANTS: One hundred twenty-seven women presenting for outpatient pelvic floor physical therapy treatment who underwent vaginal and rectal pelvic floor examination. MAIN OUTCOME MEASURES: Prevalence of coccygodynia, pain scores, association of coccygodynia with other comorbidities and diagnoses, and association of coccygodynia with physical examination findings. RESULTS: Sixty-three (49.6%) of 127 women with pelvic pain presented with coccygodynia and 64 (50.4%) did not. Women with coccygodynia had significantly higher rates of muscle spasm (50.8% vs. 31.2%, p = .025) higher visual analog scale pain scores (median 5 vs. 3, p = .014), higher rates of outlet dysfunction constipation (31.7% vs. 10.0%, p = .032), and higher rates of fibromyalgia (15.9% vs. 3.1%, p = .014). On pelvic examination, women with coccygodynia were significantly more likely to have sacrococcygeal joint hypomobility (65.1% vs. 14.1%, p < .001), coccygeus muscle spasm (77.8% vs. 17.2%, p < .001), anococcygeal ligament pain (63.5% vs. 9.4%, p < .001), external anal sphincter pain/spasm (33.3% vs. 13.1%, p < .001), and impaired pelvic floor muscle coordination (77.8% vs. 57.8%, p = .016). CONCLUSIONS: Almost 50% of women seeking pelvic floor physical therapy for pelvic pain had coexisting coccygodynia. These women had higher pain scores, increased pelvic floor dysfunction, and significantly greater abnormal physical exam findings. This study demonstrates a strong link between coccygodynia, pelvic floor symptoms, and pelvic pain and highlights the importance of screening for and identifying coccyx pain when evaluating women with pelvic pain.

Inhibition of microRNA-29b suppresses oxidative stress and reduces apoptosis in ischemic stroke.

MicroRNAs (miRNAs) regulate protein expression by antagonizing the translation of mRNAs and are effective regulators of normal nervous system development, function, and disease. MicroRNA-29b (miR-29b) plays a broad and critical role in brain homeostasis. In this study, we tested the function of miR-29b in animal and cell models by inhibiting miR-29b expression. Mouse models of middle cerebral artery occlusion were established using the modified Zea-Longa suture method. Prior to modeling, 50 nmol/kg miR-29b antagomir was injected via the tail vein. MiR-29b expression was found to be abnormally increased in ischemic brain tissue. The inhibition of miR-29b expression decreased the neurological function score and reduced the cerebral infarction volume and cell apoptosis. In addition, the inhibition of miR-29b significantly decreased the malondialdehyde level, increased superoxide dismutase activity, and Bcl-2 expression, and inhibited Bax and Caspase3 expression. PC12 cells were treated with glutamate for 12 hours to establish in vitro cell models of ischemic stroke and then treated with the miR-29 antagomir for 48 hours. The results revealed that miR-29b inhibition in PC12 cells increased Bcl-2 expression and inhibited cell apoptosis and oxidative damage. These findings suggest that the inhibition of miR-29b inhibits oxidative stress and cell apoptosis in ischemic stroke, producing therapeutic effects in ischemic stroke. This study was approved by the Laboratory Animal Care and Use Committee of the First Affiliated Hospital of Zhengzhou University (approval No. 201709276S) on September 27, 2017.

Systemic anticoagulation is associated with decreased mortality and morbidity in acute pancreatitis.

BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) is a procoagulant state, and markers of coagulopathy are associated with AP severity. We aimed to explore the association of systemic anticoagulation therapy before AP onset with the inpatient outcomes of patients with acute pancreatitis. METHODS: This case-control, retrospective study used data from the Nationwide Inpatient Sample (Jan 2014-Dec 2016). We used medical coding data to identify patients with a principal diagnosis of AP who were receiving systemic anticoagulation therapy. Patients with anticoagulation were matched to those without it on the propensity for having anticoagulation. The propensity for having anticoagulation was estimated using a logistic regression model, matching for age, gender, race, median household income for patients' zip code, Charlson comorbidity score, region of hospital, location of hospital (urban/rural), teaching status of hospital, if admission day was on a weekend, pancreatic cancer class, obesity, tobacco usage. Secondary outcomes were inpatient outcomes and hospital expenditures. RESULTS: A total of 190,474 patients admitted for acute pancreatitis were identified, out of which 7827 patients were on anticoagulation. After propensity matching, 5776 matched pairs were successfully identified. Patients with AP on anticoagulation tended to have lower risk for ICU admission, acute kidney injury, organ failure or inpatient mortality. However, the group with anticoagulation had longer hospital length of stay and higher hospital costs. CONCLUSIONS: Anticoagulation therapy may have a pivotal role in the pathogenesis and progression of AP. These data suggest a potential therapeutic role for anticoagulants in AP. Further studies are needed to better understand these observations.

Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1-positive Triple-negative Breast Cancer.

PURPOSE: Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor-immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1- TNBC. EXPERIMENTAL DESIGN: From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays. RESULTS: 228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation-related proteins correlated most strongly with PD-L1 protein. CONCLUSIONS: In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.See related commentary by Symmans, p. 5446.

NOGEA: A Network-oriented Gene Entropy Approach for Dissecting Disease Comorbidity and Drug Repositioning.

Rapid development of high-throughput technologies has permitted the identification of an increasing number of disease-associated genes (DAGs), which are important for understanding disease initiation and developing precision therapeutics. However, DAGs often contain large amounts of redundant or false positive information, leading to difficulties in quantifying and prioritizing potential relationships between these DAGs and human diseases. In this study, a network-oriented gene entropy approach (NOGEA) is proposed for accurately inferring master genes that contribute to specific diseases by quantitatively calculating their perturbation abilities on directed disease-specific gene networks. In addition, we confirmed that the master genes identified by NOGEA have a high reliability for predicting disease-specific initiation events and progression risk. Master genes may also be used to extract the underlying information of different diseases, thus revealing mechanisms of disease comorbidity. More importantly, approved therapeutic targets are topologically localized in a small neighborhood of master genes in the interactome network, which provides a new way for predicting drug-disease associations. Through this method, 11 old drugs were newly identified and predicted to be effective for treating pancreatic cancer and then validated by in vitro experiments. Collectively, the NOGEA was useful for identifying master genes that control disease initiation and co-occurrence, thus providing a valuable strategy for drug efficacy screening and repositioning. NOGEA codes are publicly available at https://github.com/guozihuaa/NOGEA.

Pan-Cancer Analyses Reveal Oncogenic Role and Prognostic Value of F-Box Only Protein 22.

The F-box protein 22 (FBXO22), an F-box E3 ligase, has been identified to be critically involved in carcinogenesis. However, a systematic assessment of the role of FBXO22 across human cancers is lacking. Here, we performed a pan-cancer analysis to explore the role of FBXO22 in 33 cancer types using multiomic data from The Cancer Genome Atlas (TCGA). First, we found that high FBXO22 expression in multiple cancers was closely associated with poor overall survival and relapse-free survival. Next, we identified ten proteins that interact with FBXO22 and 13 of its target substrates using the STRING database and a literature search to explore the regulatory role of FBXO22 in tumorigenesis. Genes encoding these proteins were found to be significantly enriched in cell cycle negative regulation and ubiquitination pathways. This was confirmed in nonsmall cell lung cancer A549 cells, where FBXO22 overexpression enhanced cyclin-dependent kinase 4 (CDK4) protein levels and promoted cell proliferation. Similarly, overexpression or interference of FBXO22 changed the protein level of one of its substrates, PTEN. Additionally, we found that FBXO22 mutations were accompanied by altered substrate expression, especially in uterine corpus endometrial carcinoma and lung adenocarcinoma; endometrial carcinoma patients with FBXO22 genetic alterations also had better overall and relapse-free survival. Notably, FBXO22 methylation levels were also decreased in most tumors, and hypomethylation of FBXO22 was associated with poor overall survival, relapse-free interval, and progression-free interval in pancreatic adenocarcinoma. Finally, we analyzed the correlation between the abundance of tumor infiltrating lymphocytes (TILs) and FBXO22 expression, copy number variation, and methylation. Multiple algorithms revealed that high FBXO22 expression was associated with lower TIL levels, especially in lung adenocarcinoma, lung squamous cell carcinoma, and sarcoma. Taken together, our findings demonstrate that FBXO22 degrades tumor suppressor genes by ubiquitination and inhibits the cell cycle to promote nonsmall cell lung cancer progression. Our study also provides a relatively comprehensive understanding of the oncogenic role of FBXO22 in different tumors.

Systematic Evaluation of the Diagnostic and Prognostic Significance of Competitive Endogenous RNA Networks in Prostate Cancer.

Long non-coding RNA (lncRNA)-mediated competitive endogenous RNA (ceRNA) networks act as essential mechanisms in tumor initiation and progression, but their diagnostic and prognostic significance in prostate cancer (PCa) remains poorly understood. Presently, using the RNA expression data derived from multiple independent PCa-related studies, we constructed a high confidence and PCa-specific core ceRNA network by employing three lncRNA-gene inference approaches and key node filter strategies and then established a logistic model and risk score formula to evaluate its diagnostic and prognostic values, respectively. The core ceRNA network consists of 10 nodes, all of which are significantly associated with clinical outcomes. Combination of expression of the 10 ceRNAs with a logistic model achieved AUC of ROC and PR curve up to ∼96 and 99% in excluding normal prostate samples, respectively. Additionally, a risk score formula constructed with the ceRNAs exhibited significant association with disease-free survival. More importantly, utilizing the expression of RNAs in the core ceRNA network as a molecular signature, the TCGA-PRAD cohort was divided into four novel clinically relevant subgroups with distinct expression patterns, highlighting a feasible way for improving patient stratification in the future. Overall, we constructed a PCa-specific core ceRNA network, which provides diagnostic and prognostic value.

Systems-level analysis identifies key regulators driving epileptogenesis in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most prevalent and often devastating form of epilepsy. The molecular mechanism underlying the development of TLE remains largely unclear, which hinders the discovery of effective antiepileptogenic drugs. Here we adopted a systems-level approach integrating transcriptomic profiles of three epileptogenesis stages to identify key regulators underlying epilepsy progression. Associating stage-specific gene meta-signatures with brain cell-specialized modules revealed positive regulation of glial migration and adhesion, cytokine production, and neuron death, and downregulation of synaptic transmission and ion transport during epileptogenesis. We identified 265 key regulators driving these processes and 72 of them were demonstrated associating with seizure frequency and/or hippocampal sclerosis in human TLE. Importantly, the upregulation of FAM107A, LAMB2, LTBP1 and TGIF1, which are mainly involved in nervous system development, were found contributing to both conditions. Our findings present the evolution landscape of epileptogenesis and provide candidate regulators that may serve as potential antiepileptogenic targets.

Evolving Role of Liver Transplantation in Elderly Recipients.

The need for liver transplantation (LT) among older patients is increasing, but the role of LT in the elderly (≥70 years) is not well defined. We retrospectively reviewed all primary LTs from 1998 through 2016 at our center. Survival and associated risk factors were analyzed with Cox regression and Kaplan-Meier methods for LT recipients in 3 age groups: <60, 60-69, and ≥70 years. Among 2281 LT recipients, the median age was 56 years (range, 15-80 years), and 162 were aged ≥70 years. The estimated 5- and 10-year patient survival probabilities for elderly LT recipients were lower (70.8% and 43.6%) than for recipients aged 60-69 years (77.2% and 64.6%) and <60 years (80.7% and 67.6%). Patient and graft survival rates associated with LT improved over time from the pre-Model for End-Stage Liver Disease era to Share 15, pre-Share 35, and Share 35 for the cohort overall (P < 0.001), but rates remained relatively stable in septuagenarians throughout the study periods (all P > 0.45). There was no incremental negative effect of age at LT among elderly patients aged 70-75 years (log-rank P = 0.32). Among elderly LT recipients, greater requirement for packed red blood cells and longer warm ischemia times were significantly associated with decreased survival (P < 0.05). Survival of LT recipients, regardless of age, markedly surpassed that of patients who were denied LT, but it was persistently 20%-30% lower than the expected survival of the general US population (P < 0.001). With the aging of the population, select older patients with end-stage liver diseases can benefit from LT, which largely restores their expected life spans.

Protective effect of BAG5 on MPP+-induced apoptosis in PC12 cells.

OBJECTIVES: Parkinson's disease (PD) is the most common neurodegenerative disease in humans, and an abundance of evidence has implicated apoptosis signaling pathways in the neurodegeneration of PD. The purpose of this study was to assess the role of B-cell lymphoma 2 (Bcl-2)-associated athanogene 5 (BAG5) protein, which was previously confirmed to play an important role in the pathogenesis of PD, in the regulation of apoptosis induced by 1-methyl-4-phenyl-pyridinium (MPP(+)) in PC12 cells. METHODS: PC12 cells were treated with MPP(+) for 48 hours to induce apoptosis, and activation of Bcl-2, Bcl-xl, and caspase 3 was measured by western blot. RESULTS: The upregulation of BAG5 in PC12 cells inhibited apoptosis and increased the expression of anti-apoptotic proteins, including Bcl-2 and Bcl-xl, after MPP(+) treatment. In addition, downregulation of BAG5 in PC12 cells enhanced apoptosis and decreased the expression of these proteins after MPP(+) treatment. DISCUSSION: The data suggest that BAG5 inhibits MPP(+)-induced apoptosis through both endogenous and mitochondria-mediated pathways of apoptosis. Through this mechanism, the upregulation of BAG5 levels may occur through its anti-apoptotic activity in PD.