tbuckley/cabot-search huggingface dataset:
Is there value to routine oncologic surveillance after radical cystectomy? Comparative outcomes of symptomatic versus asymptomatic recurrence.
Authors: Abhinav Khanna, Andrew Zganjar, Paras Shah, Matthew K. Tollefson, Vidit Sharma, Robert F. Tarrell, Prabin Thapa, Lance C. Pagliaro, Brian Addis Costello, Igor Frank, Stephen A. Boorjian
Journal: Journal of Clinical Oncology (2021)

421 Background: Reported rates of adherence to post-radical cystectomy (RC) surveillance guidelines in real-world practice have been as low as 9%, in part reflecting a nihilistic view held by many of the value of routine follow-up. Indeed, conflicting data exist regarding the outcomes of patients with cancer recurrence detected by scheduled surveillance versus symptom-directed evaluation. Herein, we assessed comparative outcomes of patients with symptomatic recurrence (SR) versus asymptomatic recurrence (AR) after RC. Methods: We reviewed our Institutional Registry of RC patients to identify patients with cancer recurrence following RC. Presenting symptoms in the SR cohort included pain, constitutional symptoms, gastrointestinal symptoms, and hematuria/voiding symptoms, whereas AR was defined as recurrence detected on routine surveillance in the absence of symptoms. Baseline demographic and clinical characteristics were compared between study groups using chi-square and t-test. Kaplan-Meier and Cox survival analyses were performed to compare cancer-specific survival (CSS) and overall survival (OS) between AR and SR groups. Results: Of 3822 patients who underwent RC from 1980-2018 (with a median follow-up after RC of 2.4 years (IQR 1.1,5.5), a total of 1100 were subsequently diagnosed with recurrence, including 311 (28.3%) with AR and 789 (71.7%) with SR. Median time from RC to recurrence was longer in the AR group (13.2 months) than in the SR group (10.8 months; p = 0.01). Presenting symptoms included pain (70.2%), constitutional symptoms (50.7%), gastrointestinal symptoms (23.3%), and urinary symptoms (23.3%). Median follow-up after recurrence was 2.4 years (IQR 1.1-5.5), during which time 997 patients died, including 840 who died of bladder cancer. Compared to patients with SR, patients with AR had a longer median CSS (54.5 months vs 27.3 months, p &lt; 0.001) and OS (43.0 months vs 25.8 months, p &lt; 0.001). On multivariable Cox proportional hazards models adjusting for demographic and clinical factors, SR was associated with a significantly increased risk of cancer-specific (hazard ratio [HR] 1.66 [95% confidence interval 1.41-1.96], p &lt; 0.0001) and all-cause mortality (HR 1.48 [1.23-1.71], p &lt; 0.0001). Conclusions: SR after RC is associated with worse oncologic outcomes than post-RC recurrence detected by routine surveillance. As such, continued surveillance is warranted, while further study is needed to determine the optimal follow-up regimen balancing patient and disease risks.
Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia
Authors: Ishwarya Murali, Siddha Kasar, Aishath Naeem, Svitlana Tyekucheva, Jasneet K. Khalsa, Emily M. Thrash, Gilad Itchaki, Dimitri Livitz, Ignaty Leshchiner, Shuai Dong, Stacey M. Fernandes, Gad Getz, Amy Johnson, Jennifer R. Brown
Journal: Blood (2021)
Abstract 13711: Exercise Restriction Decreases Risk of Ventricular Arrhythmia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy
Authors: Weijia Wang, Gabriela Orgeron, Crystal Tichnell, Brittney Murray, Jane Crosson, Harikrishna Tandri, Hugh Calkins, Cynthia A James
Journal: Circulation (2017)

Background: Prior studies have shown a close link between exercise and development of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). This study examines 1) arrhythmic outcomes ...
Group 2 innate lymphoid cells support hematopoietic recovery under stress conditions
Authors: Takao Sudo, Yasutaka Motomura, Daisuke Okuzaki, Tetsuo Hasegawa, Takafumi Yokota, Junichi Kikuta, Tomoka Ao, Hiroki Mizuno, Takahiro Matsui, Daisuke Motooka, Ryosuke Yoshizawa, Takashi Nagasawa, Yuzuru Kanakura, Kazuyo Moro, Masaru Ishii
Journal: The Journal of Experimental Medicine (2021)

The cell-cycle status of hematopoietic stem and progenitor cells (HSPCs) becomes activated following chemotherapy-induced stress, promoting bone marrow (BM) regeneration; however, the underlying molecular mechanism remains elusive. Here we show that BM-resident group 2 innate lymphoid cells (ILC2s) support the recovery of HSPCs from 5-fluorouracil (5-FU)–induced stress by secreting granulocyte-macrophage colony-stimulating factor (GM-CSF). Mechanistically, IL-33 released from chemo-sensitive B cell progenitors activates MyD88-mediated secretion of GM-CSF in ILC2, suggesting the existence of a B cell–ILC2 axis for maintaining hematopoietic homeostasis. GM-CSF knockout mice treated with 5-FU showed severe loss of myeloid lineage cells, causing lethality, which was rescued by transferring BM ILC2s from wild-type mice. Further, the adoptive transfer of ILC2s to 5-FU–treated mice accelerates hematopoietic recovery, while the reduction of ILC2s results in the opposite effect. Thus, ILC2s may function by “sensing” the damaged BM spaces and subsequently support hematopoietic recovery under stress conditions.
Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial
Authors: Fabian Frontzek, Marita Ziepert, Maike Nickelsen, Bettina Altmann, Bertram Glass, Mathias Haenel, Lorenz Truemper, Gerhard Held, Martin Bentz, Peter Borchmann, Martin Dreyling, Andreas Viardot, Frank P Kroschinsky, Bernd Metzner, Annette M Staiger, Heike Horn, German Ott, Andreas Rosenwald, Markus Loeffler, Georg Lenz, Norbert Schmitz
Journal: The Lancet Haematology (2021)
Phase III randomized trial of PSMA PET prior to definitive radiation therapy for unfavorable intermediate-risk or high-risk prostate cancer [PSMA dRT]: Study protocol NCT04457245.
Authors: Jeremie Calais, Shaojun Zhu, Nader Hirmas, Matthias Eiber, Boris A. Hadaschik, Martin Stuschke, Ken Herrmann, Johannes Czernin, Amar Upadhyaya Kishan, Nicholas George Nickols, David Elashoff, Wolfgang Peter Fendler
Journal: Journal of Clinical Oncology (2021)

TPS172 Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). Positron emission tomography (PET) using small molecule probes targeting prostate-specific membrane antigen (PSMA PET) is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET thus has the potential to guide primary radiotherapy planning in patients and improve outcomes. The purpose of the present randomized trial is to evaluate the success rate of dRT for IR or HR PCa with and without planning based on PSMA PET. Methods: We will randomize 312 patients to proceed with standard dRT (control Arm 1, n=150), or undergo a PSMA PET scan prior to dRT planning (intervention arm 2, n = 162). In the control arm, dRT will be performed as routinely planned in accordance with initial stratification. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET findings into the RT planning. We assume that approximately 8% of subjects randomized to arm 2 will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the analysis of the primary endpoint. The primary endpoint is the success rate of dRT measured as PFS after initiation of dRT. Progression is defined as (whichever occurs first): biochemical recurrence defined as a rise by 2 ng/mL or more above the nadir PSA (defined as the lowest PSA achieved) after radiotherapy with or without short-term hormonal therapy; appearance of metastasis or loco-regional recurrence (diagnosed by any imaging or biopsy); initiation of any new salvage therapy, or death from any cause. Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection and to personalizes the radiotherapy plan. Clinical trial registration: IND#147591, UCLA IRB #20-000378, ClinicalTrials.gov Identifier NCT04457245. Clinical trial information: NCT04457245.
Absolute eosinophil count as predictive biomarker of irAEs in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs).
Authors: Roberta Giorgione, Serena Pillozzi, Marinella Micol Mela, Elisa Giommoni, Agnese Paderi, Laura Doni, Elisa Pellegrini, Alessandro Di Costanzo, Lorenzo Antonuzzo
Journal: Journal of Clinical Oncology (2021)

345 Background: Nivolumab and ipilimumab are associated with immune-related adverse events (irAEs) and, to date, few biomarkers predictive of ICIs toxicity are reported in mRCC. Methods: We conducted a single-center, observational, retrospective study at Clinical Oncology Unit, Careggi University Hospital, Florence, Italy. We evaluated 43 patients (pts) with mRCC treated with ICIs from April 2013 to May 2020. Absolute Eosinophil Counts (AEC, N°/μL) were registered at baseline and at time of occurrence of irAEs. This study aims to evaluate whether the AEC could be a predictive biomarker of irAEs in patients with mRCC treated with ICIs. Results: Median age was 65 years and males were 81.4%. 10 pts received Nivolumab+Ipilimumab, while 33 pts received Nivolumab single agent. 74.4% pts (32/43) developed at least 1 irAE, 11.6% with G3-G4 irAEs. The most frequent first irAE was endocrine event (40.6% pts; 37.5% with hypo-/hyper-thyroidism). The baseline mean AEC was 163.1/μL in our cohort, in particular 132.2/μL in pts who did not develop irAEs and 176.7/μL in pts who developed irAEs (p=0.134). Among the pts who developed irAEs, the mean AEC was lower in pts with G1-G2 (153.1/μL) than in those with G3-G4 (330/μL; p=0.0013) irAEs. At the time of onset of the first irAE, the mean AEC increased to 247/μL (Δ 140.1%). Analyzing the trend of AEC from baseline to time of occurrence of irAE for the 32 pts who had developed at least one irAE, 53.1% (17 pts) showed an increasing trend; among these pts, the most frequent irAEs were endocrine occurring in 4/17 pts (23.6%). An increasing trend was also observed in the majority of pts who developed G1-2 (14/27, 51.9%) and G3-4 (3/5, 60.0%) irAEs. Additional analyzes are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Conclusions: There is little evidence in the literature about the potential role of absolute eosinophil counts as a predictive biomarker of irAEs in patients with solid tumors treated with ICIs, and most refer to patients with melanoma. In this study we observed that the baseline AEC values in patients that will develop irAEs are higher than in those without irAEs and, among the former, the values are lower for patients with toxicity G1-G2 vs G3-G4. We also found an increase of the mean AEC from baseline to the onset of the first irAE. Of the patients who experience toxicity, most have an upward trend in AEC at the onset of the first irAE. Compatibly with all the limitations of a retrospective analysis, our is the first experience exploring the role of the eosinophil count in the development of irAEs in mRCC patients treated with ICIs, and a prospective study is ongoing in our Unit to confirm the role of the eosinophil count in patients treated with ICIs.
Microbial signatures of health, gingivitis, and periodontitis
Authors: Loreto Abusleme, Anilei Hoare, Bo‐Young Hong, Patricia I. Diaz
Journal: Periodontology 2000 (2021)

Abstract The subgingival crevice harbors diverse microbial communities. Shifts in the composition of these communities occur with the development of gingivitis and periodontitis, which are considered as successive stages of periodontal health deterioration. It is not clear, however, to what extent health‐ and gingivitis‐associated microbiota are protective, or whether these communities facilitate the successive growth of periodontitis‐associated taxa. To further our understanding of the dynamics of the microbial stimuli that trigger disruptions in periodontal homeostasis, we reviewed the available literature with the aim of defining specific microbial signatures associated with different stages of periodontal dysbiosis. Although several studies have evaluated the subgingival communities present in different periodontal conditions, we found limited evidence for the direct comparison of communities in health, gingivitis, and periodontitis. Therefore, we aimed to better define subgingival microbiome shifts by merging and reanalyzing, using unified bioinformatic processing strategies, publicly available 16S ribosomal RNA gene amplicon datasets of periodontal health, gingivitis, and periodontitis. Despite inherent methodological differences across studies, distinct community structures were found for health, gingivitis, and periodontitis, demonstrating the specific associations between gingival tissue status and the subgingival microbiome. Consistent with the concept that periodontal dysbiosis is the result of a process of microbial succession without replacement, more species were detected in disease than in health. However, gingivitis‐associated communities were more diverse than those from subjects with periodontitis, suggesting that certain species ultimately become dominant as dysbiosis progresses. We identified the bacterial species associated with each periodontal condition and prevalent species that do not change in abundance from one state to another (core species), and we also outlined species co‐occurrence patterns via network analysis. Most periodontitis‐associated species were rarely detected in health but were frequently detected, albeit in low abundance, in gingivitis, which suggests that gingivitis and periodontitis are a continuum. Overall, we provide a framework of subgingival microbiome shifts, which can be used to generate hypotheses with respect to community assembly processes and the emergence of periodontal dysbiosis.
Blood lead levels in low-income and middle-income countries: a systematic review
Authors: Bret Ericson, Howard Hu, Emily Nash, Greg Ferraro, Julia Sinitsky, Mark Patrick Taylor
Journal: The Lancet Planetary Health (2021)

BackgroundSince the global phase-out of leaded petrol, reports have suggested that lead exposure remains substantial or is increasing in some low-income and middle-income countries (LMICs). However, few studies have attempted to systematically assess blood lead levels over the full range of LMICs. We aimed to describe values for blood lead level in LMICs.MethodsIn this systematic review, we searched PubMed for studies published between Jan 1, 2010, and Oct 31, 2019, that reported blood lead levels in the 137 countries in World Bank LMIC groupings. Studies were reviewed for inclusion if they contained blood lead level data from human populations residing in any given country; comprised at least 30 participants; presented blood lead level data derived from venous, capillary, or umbilical cord samples of whole blood; had data that were collected after Dec 31, 2004; and were published in English. Data on blood lead level were extracted and pooled, as appropriate, to make country-specific estimates of the distribution of background blood lead levels among children and adults, along with information on specific sources of exposure where available. This study is registered with PROSPERO, number CRD42018108706.FindingsOur search yielded 12 695 studies, of which 520 were eligible for inclusion (1100 sampled populations from 49 countries comprising 1 003 455 individuals). Pooled mean blood lead concentrations in children ranged from 1·66 μg/dL (SD 3·31) in Ethiopia to 9·30 μg/dL (11·73) in Palestine, and in adults from 0·39 μg/dL (1·25) in Sudan to 11·36 μg/dL (5·20) in Pakistan. Background values for blood lead level in children could be pooled in 34 countries and were used to estimate background distributions for 1·30 billion of them. 632 million children (95% CI 394 million–780 million; 48·5%) were estimated to have a blood lead level exceeding the US Centers for Disease Control's reference value of 5 μg/dL. Major sources of lead exposure were informal lead acid battery recycling and manufacture, metal mining and processing, electronic waste, and the use of lead as a food adulterant, primarily in spices.InterpretationMany children have a blood lead level exceeding 5 μg/dL in LMICs, despite leaded petrol phase-outs. Given the toxicity of lead, even at low amounts of exposure, urgent attention is required to control exposures and to expand population-based sampling in countries with no or scant data.FundingThis work was supported by the United States Agency for International Development (Cooperative Agreement number AID-OAA-A-16-00019).
Characterization of <i>FOXF1</i> as a novel regulator of nodal metastasis in bladder cancer.
Authors: Anirban P Mitra, Andrea Kokorovic, Tanner Miest, Vikram M Narayan, Debasish Sundi, Amy Lim, Sharada Mokkapati, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2021)

480 Background: Members of the forkhead transcription factor (FOX) family are important mediators of embryonic development and are known to be altered in a variety of cancers. The functional role of FOXF1 in bladder tumorigenesis and progression has not been clearly characterized thus far. This study investigated the clinical implications of differential FOXF1 expression in bladder cancer, and potential mechanisms by which its alteration can lead to tumor metastasis. Methods: Whole genome expression profiling was performed on paired primary tumors and nodal metastases from a radical cystectomy discovery cohort using Illumina HT12 v3-4 BeadChip arrays to identify FOXF1 as a top differentially expressed gene. Prognostic role of differential FOXF1 expression was validated on two independent cystectomy cohorts. Differential FOXF1 expression was also evaluated in murine orthotopic xenografts. Small interfering RNA was used to knock down FOXF1 in RT112 and UC6 bladder cancer cell lines to develop an in vitro model for assessment of metastatic potential. Next-generation sequencing and hierarchical clustering analysis were used to identify differentially altered genes secondary to FOXF1 knockdown. 186 biologically curated pathways were interrogated with internal validation to elucidate the downstream biologic mechanisms of metastasis. Results: In the discovery cohort, FOXF1 was a top differentially expressed gene with 3.6-fold lower expression in nodal metastases than paired primary tumors (n = 33, p &lt; 0.001). Multivariable analyses in two validation cohorts (total n = 128) indicated that FOXF1 underexpression was associated with worse cancer-specific (p = 0.046) and overall survival (p = 0.006). Murine orthotopic xenografts (n = 13) established from human bladder cancer cell lines (UC3, UC6, UC14) showed FOXF1 underexpression in metastatic deposits compared with primary tumors (p = 0.004). Hierarchical clustering identified 40 differentially expressed genes between FOXF1-knockdown bladder cancer cell lines and their corresponding controls. Biological pathway interrogation showed differential enrichment for genes associated with mitogen-activated protein kinase signaling, focal adhesion and other carcinogenic pathways in FOXF1-knockdown cells compared with controls (normalized enrichment score ≥ 1.3). Conclusions: We identify and characterize FOXF1 as a novel regulatory molecule that potentially drives bladder cancer metastasis. This may be modulated through alterations in intracellular signaling and cellular adhesion. FOXF1 may serve as a prognostic biomarker that can identify patients at impending risk for metastasis who may benefit from more aggressive management.
From the gut to bone: connecting the gut microbiota with Th17 T lymphocytes and postmenopausal osteoporosis
Authors: Joseph Lorenzo
Journal: Journal of Clinical Investigation (2021)

Osteoporosis is a serious clinical problem that often follows the accelerated bone loss that occurs after the estrogen withdrawal of menopause. In order to better understand the mechanism that produces estrogen withdrawal-induced bone loss, Yu and Pal et al., as reported in this issue of the JCI, examined mice that underwent ovariectomy (OVX). In C57BL/6 mice with enhanced Th17 cells in gut tissue, the authors demonstrated that OVX increased migration of TNF-expressing Th17 cells from the gut to the bone marrow. Furthermore, they found that manipulation of the pathways by which lymphocytes migrate and home to bone marrow prevented the increase of TNF+, Th17 cells in bone marrow after OVX in mice and the trabecular, but not cortical, bone loss in this model. These results argue that interactions of the gut microbiota with the immune system are involved in the effects of estrogen withdrawal on trabecular bone.
Cancer‐Associated Fibroblast‐Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression
Authors: Mengjia Song, Junyi He, Qiu‐Zhong Pan, Jieying Yang, Jingjing Zhao, Yao‐Jun Zhang, Yue Huang, Yan Tang, Qijing Wang, Jia He, Jiamei Gu, Yongqiang Li, Shiping Chen, Jianxiong Zeng, Zi‐Qi Zhou, Chaopin Yang, Yulong Han, Hao Chen, Tong Xiang, De‐Sheng Weng, Jian‐Chuan Xia
Journal: Hepatology (2021)

Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis.In the HCC-TME, CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-β secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF-β secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1-CXCL6/TGF-β axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis.This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1-CXCL6/TGF-β axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.
A novel claudin-10 mutation with a unique mechanism in two unrelated families with HELIX syndrome
Authors: Ali S. Alzahrani, Maged Hussein, Meshael Alswailem, Ahmad Mouna, Lina Albalawi, Yosra Moria, Mai Abdel Jabbar, Yufei Shi, Dorothee Günzel, Majed Dasouki
Journal: Kidney International (2021)