tbuckley/cabot-search huggingface dataset:
Rituximab or Cyclophosphamide in the Treatment of Membranous Nephropathy: The RI-CYCLO Randomized Trial
Authors: Francesco Scolari, Elisa Delbarba, Domenico Santoro, Loreto Gesualdo, Antonello Pani, Nadia Dallera, Laila-Yasmin Mani, Marisa Santostefano, Sandro Feriozzi, Marco Quaglia, Giuliano Boscutti, Angelo Ferrantelli, Carmelita Marcantoni, Patrizia Passerini, Riccardo Magistroni, Federico Alberici, Gian Marco Ghiggeri, Claudio Ponticelli, Pietro Ravani
Journal: Journal of the American Society of Nephrology (2021)

A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking.We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events.At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen.This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial.Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.
Association between tumor mutational burden (TMB) and immune-related adverse events (irAEs) in patients (pts) with metastatic urothelial carcinoma (mUC) during checkpoint immunotherapy.
Authors: Elie W. Akl, Pier Vitale Nuzzo, Elio Adib, Amin Nassar, Sarah Abou Alaiwi, Praful Ravi, Charlene Mantia, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

489 Background: Immune checkpoint inhibition (ICI) has greatly improved clinical outcomes for pts with mUC and other cancers. ICI is associated with a class of AEs, deemed irAEs due to immune activation. Nonetheless, biomarkers associated with irAE are still lacking. We hypothesized that the immune response against neoantigens is partly responsible for irAEs and investigated the association between irAEs, TMB and response to ICI. Methods: We identified patients with mUC at Dana Farber Cancer Institute who were treated with ICI (monotherapy or combination) and had available tumor sequencing data through Oncopanel. TMB was calculated using the number of non-synonymous exonic mutations per megabase. The severity of irAEs was graded using CTCAE v.5.0. Mann-Whitney U test was performed to identify association between TMB, incidence and grade of irAEs. A cut-off of 10/mb was assigned for TMB. Fisher’s exact test was used to evaluate the radiologic response between pts with and without irAEs and low vs. high TMB. Multivariable linear regression was used to assess the relationship between TMB, irAEs and response. p-values were adjusted using Benjamini-Hochberg method. Results: Of 101 pts with mUC who met the inclusion criteria, 32 (32%) reported irAEs. 6 (6%) were grade (G)1, 20 (20%) were G2, and 6 (6%) were G3. Median(m) time on therapy was 84 days for pts without irAEs and 88 days for pts with irAEs. Pts with irAEs had higher mTMB (15.4/mb) compared to pts with no irAEs (9.8) ( p = 0.01). In pts on monotherapy (93), those with irAEs (n=27) had a higher mTMB (15.13/mb) compared to pts with no irAEs (n=66) (mTMB = 10.20/mb) ( p = 0.01). Out of 94 pts with radiological data, response was achieved in 16 (50%) pts with irAE vs 10 (16%) pts with no irAE ( p &lt; 0.001). When both irAE and response were included in a multivariable regression, the association between irAE and TMB was not significant ( p = 0.4). Pts with both irAE and high TMB had a response rate of 56% which was significantly higher than those with either irAE but low TMB (28.6%) or high TMB but no irAE (21.2 %) or low TMB and no irAE (10.3%) (Chi-square test p = 0.002; FDR corrected p-values for individual comparisons in Table). There was no association between TMB and irAE grade. Conclusions: Higher TMB was associated with higher incidence of irAEs in pts with mUC on ICIs. Moreover, pts with both high TMB and irAEs exhibited better response rates than those with only high TMB or irAEs, suggesting that they may provide complementary tumor and host characteristics. Further evaluation in mUC is needed to confirm this relationship between TMB, irAEs and response in a larger cohort and explore specific mutational signatures that may be associated with irAEs. [Table: see text]
Abstract PO046: Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis
Authors: Wendy W. Hwang-Verslues, Po-Hao Chang
Journal: Cancer Research (2021)

Abstract Breast cancer is the most common cancer of women worldwide. Although the 5-year survival rate has greatly improved due to early detection and advance in therapeutic strategies, metastasis remains the major cause of breast cancer death. Metastatic cancer cells which formed clusters of circulating tumor cells (CTCs) are particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and CTC clustering remain elusive. We found that Desmoglein2 (DSG2), a cell adhesion molecule involved in desmosome mediated intercellular adhesion, promoted tumor growth, increased the prevalence of CTC clusters and facilitated distant organ colonization. Importantly, regulation of DSG2 by hypoxia was a key to this process. Hypoxia-induced DSG2 downregulation led to elevated epithelial-mesenchymal transition (EMT) gene expression allowing cells to detach from the primary tumor and undergo intravasation. Subsequent reactivation of DSG2 expression after release of hypoxic stress in the circulation allowed CTCs to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to activate expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the Polycomb Repressive Complex 2 components, EZH2 and SUZ12, to the DSG2 promoter. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a new mechanism by which hypoxia drives metastasis. Citation Format: Wendy W. Hwang-Verslues, Po-Hao Chang. Interaction between Desmoglein2 and hypoxia controls breast cancer metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO046.
Toward More Complete Prognostication for Patients with Clonal Hematopoiesis
Authors: Barbara Spitzer, Ross L. Levine
Journal: Blood Cancer Discovery (2021)

Abstract Summary: The study of clonal hematopoiesis is rapidly evolving, with the highest prevalence in aging populations and wide-ranging implications for health and disease, including an increased risk of subsequent myeloid malignancies and cardiovascular disease. In their article, Feusier and colleagues report on an expanded driver mutation list for capture of higher-risk clonal hematopoiesis mutations implicated in leukemia transformation. They also describe the prevalence of clonal hematopoiesis in several additional large studies, including, most importantly, in the pediatric context, which has not yet been extensively studied with respect to clonal hematopoiesis and clonal hematopoiesis–related sequelae. See related article by Feusier et al., p. 226.
Immunoglobulin Heavy Chain Variable Region (IgHV) Unmutated, but Not Mutated, Chronic Lymphocytic Leukemia (CLL) Arises in a CD34+ Progenitor
Authors: Brandy Perkins, Margaret M. Showel, Laura Schoch, Philip Imus, Gabriel Ghiaur, Douglas E. Gladstone, Richard J. Jones
Journal: Blood (2017)
inGAP-Family: Accurate Detection of Meiotic Recombination Loci and Causal Mutations by Filtering Out Artificial Variants due to Genome Complexities
Authors: Qichao Lian, Yamao Chen, Fang Chang, Ying Fu, Ji Qi
Journal: Genomics Proteomics & Bioinformatics (2021)

Accurately identifying DNA polymorphisms can bridge the gap between phenotypes and genotypes and is essential for molecular marker assisted genetic studies. Genome complexities, including large-scale structural variations, bring great challenges to bioinformatic analysis for obtaining high-confidence genomic variants, as sequence differences between non-allelic loci of two or more genomes can be misinterpreted as polymorphisms. It is important to correctly filter out artificial variants to avoid false genotyping or estimation of allele frequencies. Here, we present an efficient and effective framework, inGAP-family, to discover, filter, and visualize DNA polymorphisms and structural variants (SVs) from alignment of short reads. Applying this method to polymorphism detection on real datasets shows that elimination of artificial variants greatly facilitates the precise identification of meiotic recombination points as well as causal mutations in mutant genomes or quantitative trait loci. In addition, inGAP-family provides a user-friendly graphical interface for detecting polymorphisms and SVs, further evaluating predicted variants and identifying mutations related to genotypes. It is accessible at https://sourceforge.net/projects/ingap-family/.
Abstract PO-003: Deep learning identifies conserved pan-cancer tumor features
Authors: Javad Noorbakhsh, Saman Farahmand, Ali Foroughi pour, Sandeep Namburi, Dennis Caruana, David Rimm, Mohammad Soltanieh-ha, Kourosh Zarringhalam, Jeffrey H. Chuang
Journal: Clinical Cancer Research (2021)

Abstract Histopathological images are an integral data type for studying cancer. We show pre-trained convolutional neural networks (CNNs) can be systematically applied across cancer types, enabling comparisons to reveal shared spatial behaviors. We develop CNNs with a common architecture trained on 19 cancer types of The Cancer Genome Atlas (TCGA), analyzing 14459 hematoxylin and eosin scanned frozen tissue images. Our CNNs are based on the Inception-V3 network and classify TCGA pathologist-annotated tumor/normal status of whole slide images in all 19 cancer types with consistently high AUCs (0.995±0.008). Remarkably, CNNs trained on one tissue are effective in others (AUC 0.88±0.11), with classifier relationships recapitulating known adenocarcinoma, carcinoma, and developmental biology. Moreover, classifier comparisons reveal intra-slide spatial similarities, with an average tile-level correlation of 0.45±0.16 between classifier pairs on the TCGA test sets. In particular, the TCGA-trained classifiers had average tile-level correlation of 0.52±0.09 and 0.58±0.08 on hold-out TCGA lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) test sets, respectively. These relations are reflected on two external datasets, i.e., LUAD and LUSC whole slide images of Clinical Proteomic Tumor Analysis Consortium. The CNNs trained on TCGA achieved cross-classification AUCs of 0.75±0.12 and 0.73±0.13 on LUAD and LUSC external validation sets, respectively. These CNNs had average tile-level correlations of 0.38±0.09 and 0.39±0.08 on LUAD and LUSC validation sets, respectively. Breast cancers, bladder cancers, and uterine cancers have spatial patterns that are particularly easy to detect, suggesting these cancers can be canonical types for image analysis. This study illustrates pre-trained CNNs can detect tumor features across a wide range of cancers, suggesting presence of pan-cancer tumor features. These shared features allow combining datasets when analyzing small samples to narrow down the parameter search space of CNN models. Citation Format: Javad Noorbakhsh, Saman Farahmand, Ali Foroughi pour, Sandeep Namburi, Dennis Caruana, David Rimm, Mohammad Soltanieh-ha, Kourosh Zarringhalam, Jeffrey H. Chuang. Deep learning identifies conserved pan-cancer tumor features [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-003.
Covid-19: US Catholics split after bishops’ conference recommends against Johnson and Johnson vaccine
Authors: Owen Dyer
Journal: BMJ (2021)

Although abundant structural plasticity in the form of axonal retraction, neurite extension, and formation of presynaptic varicosities is displayed by photoreceptors after retinal detachment and during genetic and age-related retinal degeneration, the mechanisms involved are mostly unknown. We demonstrated recently that Ca<sup>2+</sup> influx through cGMP-gated channels in cones and voltage-gated L-type channels in rods is required for neurite extension <i>in vitro</i> (Zhang and Townes-Anderson, 2002). Here, we report that the nitric oxide (NO)-cGMP signaling pathway is active in photoreceptors and that its manipulation differentially regulates the structural plasticity of cone and rod cells. The NO receptor soluble guanylyl cyclase (sGC) was detected immunocytochemically in both cone and rod cells. Stimulation of sGC increased cGMP production in retinal cultures. In cone cells, quantitative analysis showed that NO or cGMP stimulated neuritic sprouting; this stimulatory effect was dependent on both Ca<sup>2+</sup> influx through cGMP-gated channels and phosphorylation by protein kinase G (PKG). At the highest levels of cGMP, however, cone outgrowth was no longer increased. In rod photoreceptors, NO or cGMP consistently inhibited neuritic growth in a dose-dependent manner; this inhibitory effect required PKG. When NO-cGMP signaling was inhibited, changes in the neuritic development of cone and rod cells were also observed but in the opposite direction. These results expand the role of cGMP in axonal activity to adult neuritogenesis and suggest an explanation for the neurite sprouting observed in an autosomal recessive form of retinitis pigmentosa that is characterized by high cGMP levels in photoreceptor layers.
35MO Discovery and characterization of selective, FGFR1-sparing, inhibitors of FGFR2/3 oncogenic mutations for the treatment of cancers
Authors: E. Dardenne, F. Padilla, S. Rasmussen, S.N. Yang, A. Mentes, L.S. Ogawa, R. Fiorenza, A. Trombino, S. Smith, D. Romashko, N. Ishiyama, M. Chevtsova, S. Thakur, E. Rosfjord, E. Buck, C. Roberts, M. Lucas, T-A. Lin
Journal: Annals of Oncology (2021)
Immunodominant antibody germlines in COVID-19
Authors: Emanuele Andreano, Rino Rappuoli
Journal: The Journal of Experimental Medicine (2021)

The neutralizing antibody response to SARS-CoV-2 is dominated by antibodies deriving from germlines IGHV3-53/IGHV3-66, which are also associated with self-reacting antibodies. Could vaccines avoid the expansion of this immunodominant response, decrease the risk of autoimmunity, and still protect against emerging SARS-CoV-2 variants?
Development of novel gene carrier using modified nano hydroxyapatite derived from equine bone for osteogenic differentiation of dental pulp stem cells
Authors: Myung Chul Lee, Hoon Seonwoo, Kyoung Je Jang, Shambhavi Pandey, Jaewoon Lim, Sangbae Park, Jae Eun Kim, Yun-Hoon Choung, Pankaj Garg, Jong Hoon Chung
Journal: Bioactive Materials (2021)

Hydroxyapatite (HA) is a representative substance that induces bone regeneration. Our research team extracted nanohydroxyapatite (EH) from natural resources, especially equine bones, and developed it as a molecular biological tool. Polyethylenimine (PEI) was used to coat the EH to develop a gene carrier. To verify that PEI is well coated in the EH, we first observed the morphology and dispersity of PEI-coated EH (pEH) by electron microscopy. The pEH particles were well distributed, while only the EH particles were not distributed and aggregated. Then, the existence of nitrogen elements of PEI on the surface of the pEH was confirmed by EDS, calcium concentration measurement and fourier transform infrared spectroscopy (FT-IR). Additionally, the pEH was confirmed to have a more positive charge than the 25 kD PEI by comparing the zeta potentials. As a result of pGL3 transfection, pEH was better able to transport genes to cells than 25 kD PEI. After verification as a gene carrier for pEH, we induced osteogenic differentiation of DPSCs by loading the BMP-2 gene in pEH (BMP-2/pEH) and delivering it to the cells. As a result, it was confirmed that osteogenic differentiation was promoted by showing that the expression of osteopontin (OPN), osteocalcin (OCN), and runt-related transcription factor 2 (RUNX2) was significantly increased in the group treated with BMP-2/pEH. In conclusion, we have not only developed a novel nonviral gene carrier that is better performing and less toxic than 25 kD PEI by modifying natural HA (the agricultural byproduct) but also proved that bone differentiation can be effectively promoted by delivering BMP-2 with pEH to stem cells.
Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease
Authors: Yilin Yang, Panjamaporn Sangwung, Reiichiro Kondo, Yirang Jung, Matthew J. McConnell, Jain Jeong, Teruo Utsumi, William C. Sessa, Yasuko Iwakiri
Journal: Journal of Hepatology (2021)
Association of health-related quality of life (HRQOL) variations with biological biomarkers for patients with metastatic castrate-resistant prostate cancer (MCRPC) treated by abiraterone/prednisone combination or prednisone.
Authors: Morgan Goujon, Amelie Anota, Alexandre Frontczak, Emilie Charton, Tristan Maurina, Hamadi Almotlak, Thierry Nguyen, Calcagno Fabien, Ulrich Stein, Guillaume Mouillet, Antoine Thiery-Vuillemin
Journal: Journal of Clinical Oncology (2021)

54 Background: A potential link between Health-Related Quality of life (HRQoL) and oncologic outcomes such as overall survival or progression-free survival has been underlined for endocrine therapies in patients with metastatic castrate resistant prostate cancer (mCRPC). Other surrogates such as circulating tumor cells (CTCs) or PSA can be used to evaluate disease control. This study explored the associations between HRQoL and biological biomarkers for patients with mCRPC treated by abiraterone / prednisone or prednisone within registration phase III trial COU-AA-301. Methods: Baseline differences of HRQoL evaluated with FACT-P total score (FACT-P TS) according to biological parameters (including CTCs and PSA) and links between HRQoL's change and variations of these parameters were assessed. The primary objective was to estimate the association between improvement or deterioration in FACT-P TS and the variations of CTCs and PSA. All analyses were conducted using clinically meaningful improvement and deterioration in FACT-P TS and subscales. Results: Among 1130 patients enrolled, 1111 (98.3%) had a baseline FACT-P TS available. At baseline, a favorable CTCs count was associated with higher FACT-P TS compared to unfavorable CTCs (difference in means 8 points, [95% CI, 4 to 12] p &lt; 0.001). At 3 months, there were differences in mean change from baseline FACT-P TS favoring patients with biomarkers response, with clinically meaningful difference for CTCs (12.7 points, [95% CI, 6 to 19.5%] p &lt; 0.001) and PSA (11.64 points, [95% CI, 9.3 to 14] p &lt; 0.0001). Biological progression was associated with higher risk of FACT-P TS worsening for PSA (Odds Ratio (OR) 2.8 [95% CI, 1.9 to 4.2]) with more frequent FACT-P TS improvement in case of response for CTCs (OR 3.14 [95% CI, 1.3 to 7.7]) and PSA (OR 2.9 [95% CI 2.1 to 4]). Significantly longer time until definitive deterioration was observed for patients with CTCs or PSA response (p &lt; 0.001) and shorter time in case of progression (p &lt; 0.001). Conclusions: QUA-lify is the first study to show an association between HRQoL and biomarkers outcomes in patients with mCRPC treated with endocrine therapy in a post-taxane setting. This concept is reinforced by the consistency of the association for all analyses carried out.
18F-Fluorothymidine PET for Functional Response Assessment Following Radiation Therapy for Extramedullary Hematopoiesis
Authors: Belinda A. Campbell, Jason Callahan, Merrole Cole-Sinclair, Michael MacManus, Michael S. Hofman
Journal: Clinical Nuclear Medicine (2021)

As a marker of cellular proliferation, 18F-fluorothymidine (FLT) PET can detect the distribution of proliferating hematopoiesis and has an emerging role in the investigation of hematopoietic disorders. These images demonstrate the novel utility of 18F-FLT PET for imaging sites of extramedullary hematopoiesis (EMH) in a patient with Chuvash-type polycythemia and suggest a role for 18F-FLT PET in response assessment following radiotherapy. Further, the discordant response observed in the irradiated marrow and sites of EMH is a unique discovery, possibly suggesting the influence of the microenvironment favoring more rapid recovery of proliferative function within EMH sites.