tbuckley/cabot-search huggingface dataset:
<i>ERO1L</i> shapes the immune-suppressive tumor microenvironment and is a potential biomarker for immunotherapy response in lung adenocarcinoma.
Authors: Lihui Liu, Chao Wang, Sini Li, Pei Xue, Hua Bai, Jie Wang
Journal: Journal of Clinical Oncology (2021)

e21006 Background: Recently, immune checkpoint inhibitors have led to a paradigm shift in treatment for patients with lung adenocarcinoma (LUAD), however, the identification of biomarkers to enable patient selection is urgently required. The endoplasmic reticulum oxidoreductin-1-like ( ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia. The role of ERO1L in the crafting of the tumor immune microenvironment (TIME) is yet to be elucidated. Methods: In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of ERO1L in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy. Results: We identified ERO1L to be an oncogene, the mRNA expression of which is significantly higher in LUAD compared with normal tissues. High expression levels of ERO1L were associated with poor prognoses in terms of overall survival (HR: 1.52, 95% CI: 1.27-1.82) and progression-free survival (HR: 1.93, 95% CI: 1.47-2.53). This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Spearman’s ρ = 0.199, p &lt; 0.001) cancer associated fibroblasts (ρ = 0.286, p &lt; 0.001), and myeloid-derived suppressor cells (ρ = 0.423, p &lt; 0.001), and also indicated the polarization of M1-type to M2-type macrophage. On the contrary, overexpression of ERO1L was closely associated with deficiency of immune-active cells including B cells (ρ = -0.250, p &lt; 0.001), CD8 + T cells (ρ = -0.299, p &lt; 0.001), and NK cells (ρ = -0.258, p &lt; 0.001). Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1L high group possessed a significantly lower response rate (31.0%) to immunotherapy compared with the ERO1L low group (86.0%). Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT (NES = 1.65, FDR q-value = 0.0) and NF-κB (NES = 2.03, FDR q-value = 0.0) signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: Our study provides clear insight into the potential role of ERO1L in tumor immunology. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. ERO1L was shown to mediate cytokine and chemokine patterns in the TIME, which were resulted from activations of JAK-STAT and NF-κB signaling pathways.
Modeling cell-free DNA fragment size densities for non-invasive detection of cancer.
Authors: Jacob Carey, Bryan Chesnick, Denise Butler, Michael Rongione, Giovanni Parmigiani, Victor E. Velculescu, Nicholas C Dracopoli, Robert B. Scharpf
Journal: Journal of Clinical Oncology (2021)

3058 Background: Circulating cell-free DNA (cfDNA) is largely nucleosomal in origin with typical fragment lengths of 167 base-pairs reflecting the length of DNA wrapped around-the histone and H1 linker. Given the nucleosomal origin of cfDNA, we have previously used low coverage whole genome sequencing to evaluate DNA fragmentation profiles to sensitively and specifically detect tumor-derived DNA with altered fragment lengths or coverage. Methods: Here we evaluate the use of Bayesian finite mixtures to model the fragment length distribution and demonstrate how the parameters from these models can be useful to distinguish between individuals with and without cancer. We examined the number of cfDNA fragments by size ranging from 100-220bp and approximated the mixture component location, scale, and weight using Markov Chain Monte Carlo. The performance of the method was determined using a ten-fold, ten repeat cross-validation of Gradient Boosted Machine model using 1) our previously described genome-wide fragmentation profile approach, 2) the parameters from the mixture model and 3) a combination of approaches 1) and 2) as features. Results: In this study of 215 cancer patients and 208 cancer-free individuals, we observed cross-validated AUCs of 1) 0.94, 2) 0.95, and 3) 0.97 among the three approaches. Conclusions: Our findings indicate that parsimonious mixture models may improve detection of cancer in conjunction with fragmentation profile analyses across the genome.
High-dose lenalidomide and melphalan as conditioning for autologous stem cell transplantation in relapsed or refractory multiple myeloma.
Authors: Adriana C. Rossi, Jorge Monge, Ruben Niesvizky, Jing Mei Hsu, Tsiporah Shore, Koen Van Besien, Roger Pearse, Tomer Mark, David Jayabalan, Sebastian Alexander Mayer
Journal: Journal of Clinical Oncology (2021)

8021 Background: Autologous stem cell transplantation (ASCT) remains a standard of care of eligible patients with multiple myeloma, despite the many novel therapies introduced over the past decade. High dose melphalan (HDM) is the only approved regimen to date. Lenalidomide (LEN) is an oral immunomodulatory drug which has become the backbone of myeloma therapy from induction through salvage and maintenance. Early studies noted a dose response relationship, and found myelosuppression to be the dose limiting toxicity. We previously reported on our phase 1 study of high dose lenalidomide (HDLEN) with HDM in conditioning for ASCT, where no DLT was noted up to 350mg PO daily of LEN. Here we report the phase 2 data of patients undergoing ASCT with combination conditioning regimen. Methods: 50 patients with relapsed/refractory multiple myeloma (RRMM) underwent ASCT using HDLEN+HDM conditioning. HDLEN was dosed at 350mg PO daily from day -5 to day -1 and HDM was dosed 100mg/m2 on days -2 and -1. TPatients were heavily pre-treated: 32% had prior HDM-ASCT, 96% had received prior lenalidomide, and 42% prior pomalidomide; 40% prior anti-CD38 mAB. Of note, 68% entered the study with progressive disease at time of enrollment. Results: Overall response rate was 96%, with 80% being ≥VGPR. Median progression free survival (PFS) was noted at 14.3 months, while overall survival (OS) was 68.2 months. PFS was similar when patients were stratified by prior ASCT, depth of response at enrollment, or presence of high risk FISH. Toxicities were mostly hematologic (100% neutropenia and thrombocytopenia, 90% anemia), GI (88% diarrhea, 72% nausea, 42% vomiting) and metabolic (30-96% derangement in electrolytes), and similar to historical controls receiving HDM alone. Second malignancies were noted in 2 patients. Conclusions: HDLEN/HDM is a well tolerated and effective conditioning regimen for ASCT in patients with RRMM. This regimen merits further investigation as ASCT is likely to remain an integral part of the treatment of RRMM patients, yet few advancements have been made to this modality. HDLEN may be particularly useful in patients with high risk disease and those progressing after multiple lines of therapy. HDLEN added little toxicity to HDM and SPMs were not more frequent than expected per SEER database for patients in this age range. Clinical trial information: NCT01054196. [Table: see text]
Five‐year maintenance of clinical response and health‐related quality of life improvements in patients with moderate‐to‐severe psoriasis treated with guselkumab: results from VOYAGE 1 and VOYAGE 2*
Authors: K. Reich, K. B. Gordon, B. E. Strober, A. W. Armstrong, M. Miller, Y. K. Shen, Y. You, C. Han, Y. W. Yang, P. Foley, C. E. M. Griffiths
Journal: British Journal of Dermatology (2021)

Psoriasis is a chronic disease requiring long-term therapy.Physician- and patient-reported outcomes were evaluated through week 252 in VOYAGE 1 and VOYAGE 2.In total, 1829 patients were randomized at baseline to receive guselkumab 100 mg every 8 weeks, placebo or adalimumab. Patients receiving placebo crossed over to guselkumab at week 16. Patients receiving adalimumab crossed over to guselkumab at week 52 in VOYAGE 1, and randomized withdrawal and retreatment occurred at weeks 28-76 in VOYAGE 2; all patients then received open-label guselkumab through week 252. Efficacy and health-related quality of life (HRQoL) endpoints were analysed through week 252. Safety was monitored through week 264.The proportions of patients in the guselkumab group who achieved clinical responses at week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84·1% and 82·0% [≥ 90% improvement in Psoriasis Area and Severity Index (PASI)]; 82·4% and 85·0% [Investigator's Global Assessment (IGA) 0 or 1]; 52·7% and 53·0% (100% improvement in PASI) and 54·7% and 55·5% (IGA 0). HRQoL endpoints were achieved as follows: 72·7% and 71·1% of patients (Dermatology Life Quality Index 0 or 1: no effect on patient's life); 42·4% and 42·0% [Psoriasis Symptoms and Signs Diary (PSSD) symptom score = 0] and 33·0% and 31·0% (PSSD sign score = 0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥ 5-point reduction in Short Form-36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores < 8). Similar findings were reported for adalimumab crossovers. These effects were maintained from week 52 in VOYAGE 1 and week 100 in VOYAGE 2. No new safety signals were identified.Guselkumab maintains high levels of clinical response and improvement in patient-reported outcomes through 5 years in patients with moderate-to-severe psoriasis.
Abstract 17416: miR-1468-3p Regulates Development of Cardiac Fibrosis
Authors: Ruizhu Lin, Lea Rahtu-Korpela, Johanna Magga, Lasse Pakanen, Katja Porvari, Juhani Junttila, Heikki Huikuri, Risto Kerkelä
Journal: Circulation (2018)

Background: Accumulation of extracellular matrix disturbs the electrical conduction and stiffens myocardium, leading to higher risk for arrhythmias and diastolic dysfunction. MicroRNAs (miRNAs) function in post-translational gene regulation, and aberrant alteration of miRNAs level has been implicated in cardiac pathologies. Methods and Results: RNA sequencing of RNA samples of sudden cardiac death (SCD) victims with idiopathic myocardial fibrosis (IMF) for differentially expressed miRNAs identified miR-1468-3p. qPCR analysis validated that expression of miR-1468-3p is upregulated in hearts of SCD victims with IMF comparing to control subjects. However, the role and molecular function of miR-1468-3p in cardiac fibrosis are not known. We utilized human cardiac fibroblasts (hCFs) and gain- and loss-of-function approaches to study the role of miR-1468-3p in modulating fibroblast function. Overexpressing miR-1468-3p in hCFs resulted in an increase in expression of several fibrotic genes compared with hCFs transfected with control mir-mimic. Western blot analysis showed that miR-1468-3p mimic was sufficient to drive expression of collagen I and CTGF protein expression. Treatment of hCFs with miR-1468-3p antagomir did not alter expression of fibrosis-related gene at basal level, whereas miR-1468-3p inhibition significantly attenuated TGF-β1-induced collagen I and collagen III expression. Treatment of hCFs with miR-1468-3p antagomir blunted TGF-β1-induced collagen I and CTGF protein expression, but not TGF-β1-induced αSMA expression. Employing Sirius Red/Fast Green assay, we validated that depletion of miR-1468-3p antagonized both TGF-β1-triggered collagen and non-collagen protein production. Finally, we found that miR-1468-3p antagomir downregulated TGF-β1-induced collagen expression partially through the interference of TGF-β1/MAPK signals (p38 and JNK) and Integrin signaling. Conclusions: Our data indicate a pro-fibrotic role of miR-1468-3p in modulating cardiac fibrosis, and manipulating the expression of miR-1468-3p may provide a therapeutic strategy for treatment of cardiac fibrosis.
Association between primary care and acute care services utilization in the year following diagnosis of breast cancer.
Authors: Vincent Tran, Ruchi Hamal, Xiao Hu, Margaret Byrne, Yu Cao
Journal: Journal of Clinical Oncology (2021)

e13522 Background: Primary care physicians (PCPs) play a pivotal role during cancer diagnosis. Lack of access to primary care has been linked to worse outcomes including increased mortality in patients with cancer. Higher PCP continuity of care has been associated with lower likelihood of acute care services use among breast cancer survivors, however the impact of PCP utilization is not well studied in those newly diagnosed. This study examines the association between PCP visits and emergency department (ED) use and hospitalization in the year following diagnosis of breast cancer. Methods: Electronic medical records of women newly diagnosed with primary breast cancer from 2013 to 2019 at a single institution (Tufts Medical Center, Boston, Massachusetts) with an established PCP in the same system were retrospectively reviewed. Demographic (age at diagnosis, menopausal status, race/ethnicity), clinical (Charlson Comorbidity Index (CCI), Eastern Cooperative Oncology Group (ECOG) performance status, body mass index, mental health disorder, chronic pain syndrome), and tumor (histology, stage, grade, hormone receptor (HR) positivity, HER2 status) characteristics were extracted in addition to information on treatment modalities (if patient received surgery, radiation (RT), chemotherapy (CT), endocrine therapy (ET), ovarian suppression (OFS)). Univariate and multivariate logistic regression models were used to examine associations between frequency of PCP visits and ED use and hospitalizations within a year after diagnosis of breast cancer. Results: Of 182 women ages 33-93 (mean 60) years old, 131 (72%) were postmenopausal, 116 (64%) Caucasian; 176 (97%) had stages 1-3, and 157 (86%) had HR positivity. In the year following diagnosis, 178 (98%) received surgery, 127 (67%) RT, 142 (78%) ET, 19 (10%) OFS, 70 (39%) CT; 68 (37%) had ≤1 PCP visit, and 45 (25%) had 4-10 PCP visits. Increased PCP visits correlated with advancing age, increased BMI, greater mental health disorders and chronic pain syndromes, and increasing CCI and ECOG score. After adjusting for these confounders and tumor and treatment characteristics, logistic regressions showed that while frequency of PCP visits was not associated with hospitalizations (univariate: OR = 1.02, 95% CI [0.53, 1.62], p = 0.93; multivariate: OR = 0.35, 95% CI [0.05, 1.50], p = 0.184), increased PCP visits tended toward association with increased ED use (univariate: OR = 1.12, 95% CI [0.97,1.29], p = 0.124; multivariate: OR = 1.15, 95% CI [0.94, 1.41], p = 0.188), however did not demonstrate statistical significance. Conclusions: Primary care utilization was not associated with acute care services utilization in women newly diagnosed with breast cancer. Higher PCP utilization tended toward correlation with increased ED use. These findings may help in evaluating multidisciplinary care support in patients newly diagnosed with breast cancer.
Evaluation of pain in breast and prostate cancer bone metastasis rat models
Authors: Martine P. Roudier, Kimberley Haynes, Rachel Feldman, Karry Gilbraith, Eric Bell, Steve Bain
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2915 

Prostate cancer (CaP) and Breast Cancer (CaB) are the most common forms of malignancies diagnosed in the United States male and female population, accounting for approximately 40,000 deaths each per year. Bone metastases are observed in 100% and up to 85 % of patients dying of CaP and CaB, respectively. As bone metastases induce debilitating pain and fracture, development of effective pain therapies requires efficacy evaluation in animal models that emulate human disease. Accordingly, we have investigated and compared pain behaviors in a CaP and CaB bone metastasis model in the rat. Experimentally, MRMT-1 3 x 103 and MatLyLu 1 x 105 cells were injected in the right tibia of 12 female Sprague Dawley and Dunning rats, respectively. An additional 12-rat group was injected with media only to serve as a control for each model. At D3, D7 and D14 bone lesions were assessed using X-rays, micro-CT, and histology-histomorphometry. At D3, D7 and D14 bone mineral density (BMD) was determined using DXA scan and from D9 to D14, bone pain was evaluated using mechanical allodynia and weight bearing testing. In the CaP model, a progressive decrease of BMD from D3 to D14 was observed. However, there was no statistical difference in BMD between the normal and tumor groups at D3, D7 and D14. Statistical difference was found at D10 using mechanical allodynia (9.9g for media only and 1.35g for tumor). Statistical difference was found at D14 using weight-bearing differences between the 2 legs (2.7g for media only, and 101.8 for tumor). In the CaB model, affected tibias showed a progressive, radiographically visible lytic bone lesion. Furthermore, statistically significant increases in mechanical allodynia were observed on D9 (2.8g for media only and 0.4g for tumor). By D14, the weight-bearing differences between the normal and tumor-affected limbs were markedly increased as well (7.8g for media only and 55.9g for tumor). These finding suggest that CaP and CaB lesions, observed in different rodent strains, induced the same pain behaviors with the same window of treatment opportunity. Thus, the efficacy of selective pain drugs, chemotherapy, and/or anti-resorptive agents on pain behaviors can be evaluated in rat models of prostate and breast cancer.
Correction: CXCR4 in Tumor Epithelial Cells Mediates Desmoplastic Reaction in Pancreatic Ductal Adenocarcinoma
Authors: Toshihiro Morita, Yuzo Kodama, Masahiro Shiokawa, Katsutoshi Kuriyama, Saiko Marui, Takeshi Kuwada, Yuko Sogabe, Tomoaki Matsumori, Nobuyuki Kakiuchi, Teruko Tomono, Atsushi Mima, Tatsuki Ueda, Motoyuki Tsuda, Yuki Yamauchi, Yoshihiro Nishikawa, Yojiro Sakuma, Yuji Ota, Takahisa Maruno, Norimitsu Uza, Takashi Nagasawa, Tsutomu Chiba, Hiroshi Seno
Journal: Cancer Research (2021)

In the original version of this article (1), there were typographical errors in the Results sections describing the data presented in Figs. 2A, 3E, and 3K–3S. Likewise, the incorrect statistical analysis was indicated in the legend for Fig. 4D and E. The authors have revised the text to accurately reflect the data and statistical analyses performed. The authors also made an error when calculating and describing the error bars in Figs. 2A and 6Q. The authors have provided new images for these figures and updated the figure legends and Materials and Methods Statistical Analysis section. These errors have been corrected in the latest online HTML and PDF versions of the article. The authors regret this error.
Association of high level of plasma tissue factor activity with venous thromboembolism and early death in lung cancers.
Authors: Helene Doubre, Isabelle Monnet, Reza Azarian, Philippe Girard, Guy Meyer, Julie Trichereau, Philippe Devillier, Patrick Van Dreden, Louis-Jean Couderc, Christos Chouaid, Marc Vasse
Journal: Journal of Clinical Oncology (2021)

8532 Background: Venous thromboembolism (VTE) is associated with tumor aggressiveness and mortality in cancers. Tissue Factor is the main activator of the coagulation but its variations in lung cancers (LC) have been less studied than D-dimers (DDi). We assessed plasma Tissue Factor Activity (TFa) and DDi and VTE events and mortality in patients with LC. Methods: This prospective study included patients, from 5 hospitals, recently diagnosed LC, without prior VTE or anticoagulant therapy within the last 2 months. Clinical and tumor data, Khorana score (KS), VTE events and overall survival (OS) were assessed (follow up 2 years). Blood samples were collected before any cancer treatment (V1): DDi (HemosIL) and TFa (chromogenic assay, Diagnostica Stago) were analyzed in a central lab. Independent nonparametric tests were used for group comparisons. A relevant clinical threshold of both markers was determined :1500 μg/ml for DDi and 1.2 ng/ml for TFa. Early death was compared using Cox model and Kaplan Meier curves and logrank tests. All tests were two-tailed tests and 0.05 was considered as significant. Results: Between 12/2014 and 01/2017, 302 consecutive patients (pts) were included (mean age 64 years, 61% males, 89% smokers, 85% NSCLC, 67% stage IV). At V1, TFa levels increased with cancer stage (p = 0.004) but not DDi. VTE incidence was 13,9%: 39 events (62% incidental and 51% pulmonary embolism) with 33 events within 6 months. KS failed to predict VTE (KS &gt; 3 in 23% of the pts in VTE group vs 21% of the 302 pts, p = 0.42). DDi and TFa levels were not significantly different in VTE pts than in no VTE pts. But, a TFa &gt; 1.2 ng/ml was significantly predictive in occurrence of VTE within the first 6 months (57.6% of the VTE pts vs 38.8% of no VTE pts, p = 0.04), and also within the first year (p = 0.03). Median OS was 17,6 months (m) in VTE pts and 19.5 m in no VTE pts (p = 0,97). Compared to survivors, higher levels of DDi and TFa were observed for the 38 pts who died within 6 months : 1.82 vs 0.67 μg/ml (p &lt; 0.001) and 1.95 vs 0.33 ng/ml (p &lt; 0.001) respectively. These differences were observed for the 97 pts who died during the first year, too. With thresholds of TFa &gt; 1.2 ng/ml and DDi &gt; 1500 μg/ml, median OS was significantly shorter: 14.4 m vs &gt; 29.8 m ( p &lt; 0,001) and 13.8 m vs 22.6 m (p &lt; 0.001), respectively. Conclusions: High TFa level discriminates a population with high risk to VTE and early death in LC. This biomarker could take place in a predictive score. Clinical trial information: NCT02853188.