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Item A clinical nomogram for predicting tumor regression grade in esophageal squamous-cell carcinoma treated with immune neoadjuvant immunotherapy(AME Publishing Company, 2022) Yu, Yongkui; Wang, Wei; Qin, Zimin; Li, Haomiao; Liu, Qi; Ma, Haibo; Sun, Haibo; Bauer, Thomas L.; Pimiento, Jose M.; Gabriel, Emmanuel; Birdas, Thomas; Li, Yin; Xing, Wenqun; Surgery, School of MedicineBackground: There are various treatment options for esophageal squamous cell cancer. including surgery, peri-operative chemotherapy, and radiation. More recently, neoadjuvant immunotherapy has also been shown improve outcomes. In this study, we addressed the question, "Can we predict which patients with esophageal squamous cell cancer will benefit from neoadjuvant immunotherapy?". Methods: All patients with thoracic esophageal squamous-cell carcinoma (T2N+M0-T3-4N0/+M0) (according to the eighth edition of the National Comprehensive Cancer Network guidelines) who underwent immune neoadjuvant immunochemotherapy with programmed cell death protein 1 (PD-1) combined with paclitaxel plus cisplatin or nedaplatin in the Affiliated Cancer Hospital of Zhengzhou University, China, between November 2019 and August 2021 were included in this study. All patients underwent surgical resection. We developed a response [tumor regression grade (TRG)] prediction model using the least absolute shrinkage and selection operator (LASSO) regression incorporating factors associated with response. The accuracy of the prediction model was then validated. Results: We included 79 patients who underwent neoadjuvant immunotherapy combined with chemotherapy, aged 48-78 years (62.05±6.67), including 21 males and 58 females. There were five cases of immune-related pneumonia, of which three cases were diagnosed as immune-related pneumonia during the perioperative period, and one case of immune-related thyroid dysfunction changes. After LASSO regression, the factors that were independently associated with TRG were clinical T stage before neoadjuvant therapy, clinical N stage before neoadjuvant therapy, albumin level difference from before to after neoadjuvant therapy, white blood cell (WBC) count before neoadjuvant therapy, and T stage before surgery. We constructed a prediction model, plotted the nomogram, and verified its accuracy. Its Brier score was 0.13, its calibration slope was 0.98, and its C-index was 0.90 (95% CI: 0.82-0.97). Conclusions: Our prediction model can predict the likelihood of TRG in patients with esophageal squamous cell cancer after immunotherapy combined with neoadjuvant chemotherapy. Using this prediction model, we plan to conduct a subsequent neoadjuvant radiotherapy in patients with of TRG 2-3 patients with neoadjuvant radiotherapy.Item Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation(American Society for Clinical Investigation, 2016-05-19) Maeshima, Keisuke; Stanford, Stephanie M.; Hammaker, Deepa; Sacchetti, Cristiano; Zeng, Li-Fan; Ai, Rizi; Zhang, Vida; Boyle, David L.; Aleman Muench, German R.; Feng, Gen-Sheng; Whitaker, John W.; Zhang, Zhong-Yin; Wang, Wei; Bottini, Nunzio; Firestein, Gary S.; Department of Biochemistry & Molecular Biology, IU School of MedicineThe PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer and PTPN11 expression. Glucocorticoid responsiveness of PTPN11 was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygous Ptpn11 deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA.Item AKI Treated with Renal Replacement Therapy in Critically Ill Patients with COVID-19(Wolters Kluwer, 2021) Gupta, Shruti; Coca, Steven G.; Chan, Lili; Melamed, Michal L.; Brenner, Samantha K.; Hayek, Salim S.; Sutherland, Anne; Puri, Sonika; Srivastava, Anand; Leonberg-Yoo, Amanda; Shehata, Alexandre M.; Flythe, Jennifer E.; Rashidi, Arash; Schenck, Edward J.; Goyal, Nitender; Hedayati, S. Susan; Dy, Rajany; Bansal, Anip; Athavale, Ambarish; Nguyen, H. Bryant; Vijayan, Anitha; Charytan, David M.; Schulze, Carl E.; Joo, Min J.; Friedman, Allon N.; Zhang, Jingjing; Sosa, Marie Anne; Judd, Eric; Velez, Juan Carlos Q.; Mallappallil, Mary; Redfern, Roberta E.; Bansal, Amar D.; Neyra, Javier A.; Liu, Kathleen D.; Renaghan, Amanda D.; Christov, Marta; Molnar, Miklos Z.; Sharma, Shreyak; Kamal, Omer; Boateng, Jeffery Owusu; Short, Samuel A.P.; Admon, Andrew J.; Sise, Meghan E.; Wang, Wei; Parikh, Chirag R.; Leaf, David E.; STOP-COVID Investigators; Medicine, School of MedicineBackground: AKI is a common sequela of coronavirus disease 2019 (COVID-19). However, few studies have focused on AKI treated with RRT (AKI-RRT). Methods: We conducted a multicenter cohort study of 3099 critically ill adults with COVID-19 admitted to intensive care units (ICUs) at 67 hospitals across the United States. We used multivariable logistic regression to identify patient-and hospital-level risk factors for AKI-RRT and to examine risk factors for 28-day mortality among such patients. Results: A total of 637 of 3099 patients (20.6%) developed AKI-RRT within 14 days of ICU admission, 350 of whom (54.9%) died within 28 days of ICU admission. Patient-level risk factors for AKI-RRT included CKD, men, non-White race, hypertension, diabetes mellitus, higher body mass index, higher d-dimer, and greater severity of hypoxemia on ICU admission. Predictors of 28-day mortality in patients with AKI-RRT were older age, severe oliguria, and admission to a hospital with fewer ICU beds or one with greater regional density of COVID-19. At the end of a median follow-up of 17 days (range, 1-123 days), 403 of the 637 patients (63.3%) with AKI-RRT had died, 216 (33.9%) were discharged, and 18 (2.8%) remained hospitalized. Of the 216 patients discharged, 73 (33.8%) remained RRT dependent at discharge, and 39 (18.1%) remained RRT dependent 60 days after ICU admission. Conclusions: AKI-RRT is common among critically ill patients with COVID-19 and is associated with a hospital mortality rate of >60%. Among those who survive to discharge, one in three still depends on RRT at discharge, and one in six remains RRT dependent 60 days after ICU admission.Item Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19(American Medical Association, 2020-10-20) Gupta, Shruti; Wang, Wei; Hayek, Salim S.; Chan, Lili; Mathews, Kusum S.; Melamed, Michal L.; Brenner, Samantha K.; Leonberg-Yoo, Amanda; Schenck, Edward J.; Radbel, Jared; Reiser, Jochen; Bansal, Anip; Srivastava, Anand; Zhou, Yan; Finkel, Diana; Green, Adam; Mallappallil, Mary; Faugno, Anthony J.; Zhang, Jingjing; Velez, Juan Carlos Q.; Shaefi, Shahzad; Parikh, Chirag R.; Charytan, David M.; Athavale, Ambarish M.; Friedman, Allon N.; Redfern, Roberta E.; Short, Samuel A. P.; Correa, Simon; Pokharel, Kapil K.; Admon, Andrew J.; Donnelly, John P.; Gershengorn, Hayley B.; Douin, David J.; Semler, Matthew W.; Hernán, Miguel A.; Leaf, David E.; STOP-COVID Investigators; Medicine, School of MedicineImportance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab–treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.Item Case fatality risk of the first pandemic wave of novel coronavirus disease 2019 (COVID-19) in China(Oxford University Press, 2020-05-15) Deng, Xiaowei; Yang, Juan; Wang, Wei; Wang, Xiling; Zhou, Jiaxin; Chen, Zhiyuan; Li, Jing; Chen, Yinzi; Yan, Han; Zhang, Juanjuan; Zhang, Yongli; Wang, Yan; Qiu, Qi; Gong, Hui; Wei, Xianglin; Wang, Lili; Sun, Kaiyuan; Wu, Peng; Ajelli, Marco; Cowling, Benjamin J.; Viboud, Cecile; Yu, Hongjie; Epidemiology, School of Public HealthObjective To assess the case fatality risk (CFR) of COVID-19 in mainland China, stratified by region and clinical category, and estimate key time-to-event intervals. Methods We collected individual information and aggregated data on COVID-19 cases from publicly available official sources from December 29, 2019 to April 17, 2020. We accounted for right-censoring to estimate the CFR and explored the risk factors for mortality. We fitted Weibull, gamma, and lognormal distributions to time-to-event data using maximum-likelihood estimation. Results We analyzed 82,719 laboratory-confirmed cases reported in mainland China, including 4,632 deaths, and 77,029 discharges. The estimated CFR was 5.65% (95%CI: 5.50%-5.81%) nationally, with highest estimate in Wuhan (7.71%), and lowest in provinces outside Hubei (0.86%). The fatality risk among critical patients was 3.6 times that of all patients, and 0.8-10.3 fold higher than that of mild-to-severe patients. Older age (OR 1.14 per year; 95%CI: 1.11-1.16), and being male (OR 1.83; 95%CI: 1.10-3.04) were risk factors for mortality. The time from symptom onset to first healthcare consultation, time from symptom onset to laboratory confirmation, and time from symptom onset to hospitalization were consistently longer for deceased patients than for those who recovered. Conclusions Our CFR estimates based on laboratory-confirmed cases ascertained in mainland China suggest that COVID-19 is more severe than the 2009 H1N1 influenza pandemic in hospitalized patients, particularly in Wuhan. Our study provides a comprehensive picture of the severity of the first wave of the pandemic in China. Our estimates can help inform models and the global response to COVID-19.Item Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-synuclein(National Academy of Sciences, 2016-08-23) Wang, Wei; Nguyen, Linh T. T.; Burlak, Christopher; Chegini, Fariba; Guo, Feng; Chataway, Tim; Ju, Shulin; Fisher, Oriana S.; Miller, David W.; Datta, Debajyoti; Wu, Fang; Wu, Chun-Xiang; Landeru, Anuradha; Wells, James A.; Cookson, Mark R.; Boxer, Matthew B.; Thomas, Craig J.; Gai, Wei Ping; Ringe, Dagmar; Petsko, Gregory A.; Hoang, Quyen Q.; Department of Biochemistry & Molecular Biology, IU School of MedicineThe aggregation of α-synuclein (aSyn) leading to the formation of Lewy bodies is the defining pathological hallmark of Parkinson's disease (PD). Rare familial PD-associated mutations in aSyn render it aggregation-prone; however, PD patients carrying wild type (WT) aSyn also have aggregated aSyn in Lewy bodies. The mechanisms by which WT aSyn aggregates are unclear. Here, we report that inflammation can play a role in causing the aggregation of WT aSyn. We show that activation of the inflammasome with known stimuli results in the aggregation of aSyn in a neuronal cell model of PD. The insoluble aggregates are enriched with truncated aSyn as found in Lewy bodies of the PD brain. Inhibition of the inflammasome enzyme caspase-1 by chemical inhibition or genetic knockdown with shRNA abated aSyn truncation. In vitro characterization confirmed that caspase-1 directly cleaves aSyn, generating a highly aggregation-prone species. The truncation-induced aggregation of aSyn is toxic to neuronal culture, and inhibition of caspase-1 by shRNA or a specific chemical inhibitor improved the survival of a neuronal PD cell model. This study provides a molecular link for the role of inflammation in aSyn aggregation, and perhaps in the pathogenesis of sporadic PD as well.Item Constructing Kinetically Controlled Denaturation Isotherms of Folded Proteins Using Denaturant-Pulse Chaperonin Binding(Springer Nature, 2018-10-20) O’Neil, Pierce T.; Machen, Alexandra J.; Thompson, Jackie A.; Wang, Wei; Hoang, Quyen Q.; Baldwin, Michael R.; Khar, Karen R.; Karanicolas, John; Fisher, Mark T.; Biochemistry and Molecular Biology, School of MedicineMethods to assess the kinetic stability of proteins, particularly those that are aggregation prone, are very useful in establishing ligand induced stabilizing effects. Because aggregation prone proteins are by nature difficult to work with, most solution based methods are compromised by this inherent instability. Here, we describe a label-free method that examines the denaturation of immobilized proteins where the dynamic unfolded protein populations are captured and detected by chaperonin binding.Item Curcumin therapy to treat vascular dysfunction in children and young adults with autosomal dominant polycystic kidney disease: Design and baseline characteristics of participants(Elsevier, 2020-08-12) Nowak, Kristen L.; Farmer-Bailey, Heather; Cadnapaphornchai, Melissa A.; You, Zhiying; George, Diana; Wang, Wei; Jovanovich, Anna; Soranno, Danielle E.; Gitomer, Berenice; Chonchol, Michel; Pediatrics, School of MedicineAlthough often considered to be a disease of adults, complications of autosomal dominant polycystic kidney disease (ADPKD) begin in childhood. While the hallmark of ADPKD is the development and continued growth of multiple renal cysts that ultimately result in loss of kidney function, cardiovascular complications are the leading cause of death among affected patients. Vascular dysfunction (endothelial dysfunction and large elastic artery stiffness) is evident very early in the course of the disease and appears to involve increased oxidative stress and inflammation. Treatment options to prevent cardiovascular disease in adults with ADPKD are limited, thus childhood may represent a key therapeutic window. Curcumin is a safe, naturally occurring polyphenol found in the Indian spice turmeric. This spice has a unique ability to activate transcription of key antioxidants, suppress inflammation, and reduce proliferation. Here we describe our ongoing randomized, placebo-controlled, double-blind clinical trial to assess the effect of curcumin therapy on vascular function and kidney growth in 68 children and young adults age 6–25 years with ADPKD. Baseline demographic, vascular, and kidney volume data are provided. This study has the potential to establish a novel, safe, and facile therapy for the treatment of arterial dysfunction, and possibly renal cystic disease, in an understudied population of children and young adults with ADPKD.Item Efficacy and Failure Patterns of Early SBRT to the Primary Tumor in Advanced EGFR-Mutation-Positive Lung Cancer with EFGR-TKI Treatment: A Prospective, Single Arm, Phase II Study(MDPI, 2022-11-22) Shi, Yangyang; Xu, Hailing; Raynor, William Y.; Ding, Jiapei; Lin, Ling; Zhou, Chao; Wang, Wei; Meng, Yinnan; Wu, Xiaomai; Chen, Xiaofeng; Lv, Dongqing; Yang, Haihua; Radiation Oncology, School of MedicineEarly stereotactic body radiation therapy (SBRT) to the primary tumor combined with epidermal growth factor receptor tyrosine kinase inhibitor (EFGR-TKI) treatment may increase progression-free survival (PFS) by delaying resistance in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). In this prospective, single arm, phase II study, patients with advanced NSCLC were treated with EGFR-TKI (icotinib 125 mg tid or gefitinib 250 mg qd) for one month followed by SBRT (40-60 Gy/5-8 F/5-10 d) to the primary tumor with concurrent EGFR-TKI until disease progression. The primary endpoint was PFS and the patterns of failure. Overall survival (OS) and adverse effects (AEs) were secondary endpoints. Overall, 41 advanced NSCLC patients with EGFR mutations received treatment with 24.42 months of median follow-up time. On average, SBRT was initiated 1.49 months after EGFR-TKI administration. Tumors were found to have an average shrinkage rate of 42.50%. Median PFS was 15.23 months (95% CI 13.10-17.36), while median OS was 27.57 months (95% CI 23.05-32.09). Thirty-three patients were found to have disease progression, of which new site failure (NF) (22 patients, 66.66%) was the most common pattern, followed by original site failure (OF) (7 patients, 21.21%) and simultaneous OF/NF (ONF) (4 patients, 12.12%). There were no Aes equal to or greater than grade 3, with the most frequent AE being radiation pneumonitis. Therefore, administering therapy targeted at the primary tumor using early SBRT after EGFR-TKI initiation is a new potentially safe and effective approach to treat EGFR-mutant advanced NSCLC.Item Enhanced CT-Based Radiomics to Predict Micropapillary Pattern Within Lung Invasive Adenocarcinoma(Frontiers Media, 2021-08-27) Xu, Yunyu; Ji, Wenbin; Hou, Liqiao; Lin, Shuangxiang; Shi, Yangyang; Zhou, Chao; Meng, Yinnan; Wang, Wei; Chen, Xiaofeng; Wang, Meihao; Yang, Haihua; Radiation Oncology, School of MedicineObjective: We aimed to investigate whether enhanced CT-based radiomics can predict micropapillary pattern (MPP) of lung invasive adenocarcinoma (IAC) in the pre-op phase and to develop an individual diagnostic predictive model for MPP in IAC. Methods: 170 patients who underwent complete resection for pathologically confirmed lung IAC were included in our study. Of these 121 were used as a training cohort and the other 49 as a test cohort. Clinical features and enhanced CT images were collected and assessed. Quantitative CT analysis was performed based on feature types including first order, shape, gray-level co-occurrence matrix-based, gray-level size zone matrix-based, gray-level run length matrix-based, gray-level dependence matrix-based, neighboring gray tone difference matrix-based features and transform types including Log, wavelet and local binary pattern. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to value the ability to identify the lung IAC with MPP using these characteristics. Results: Using quantitative CT analysis, one thousand three hundred and seventeen radiomics features were deciphered from R (https://www.r-project.org/). Then these radiomic features were decreased to 14 features after dimension reduction using the least absolute shrinkage and selection operator (LASSO) method in R. After correlation analysis, 5 key features were obtained and used as signatures for predicting MPP within IAC. The individualized prediction model which included age, smoking, family tumor history and radiomics signature had better identification (AUC=0.739) in comparison with the model consisting only of radiomics features (AUC=0.722). DeLong test showed that the difference in AUC between the two models was statistically significant (P<0.01). Compared with the simple radiomics model, the more comprehensive individual prediction model has better prediction performance. Conclusion: The use of radiomics approach is of great value in the diagnosis of tumors by non-invasive means. The individualized prediction model in the study, when incorporated with age, smoking and radiomics signature, had effective predictive performance of lung IAC with MPP lesions. The combination of imaging features and clinical features can provide additional diagnostic value to identify the micropapillary pattern in IAC and can affect clinical diagnosis and treatment.
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