tbuckley/cabot-search huggingface dataset:
Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies
Authors: Antonella Padella, Andrea Ghelli Luserna Di Rorà, Giovanni Marconi, Martina Ghetti, Giovanni Martinelli, Giorgia Simonetti
Journal: Journal of Hematology & Oncology (2022)

Abstract The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes ( FLT3 -ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members ( STAG2 ), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.
Unique molecular and functional features of extramedullary hematopoietic stem and progenitor cell reservoirs in humans
Authors: Nicole Mende, Hugo P. Bastos, Antonella Santoro, Krishnaa T. Mahbubani, Valerio Ciaurro, Emily F. Calderbank, Mariana Quiroga Londoño, Kendig Sham, Giovanna Mantica, Tatsuya Morishima, Emily Mitchell, Maria Rosa Lidonnici, Fabienne Meier-Abt, Daniel Hayler, Laura Jardine, Abbie Curd, Muzlifah Haniffa, Giuliana Ferrari, Hitoshi Takizawa, Nicola K. Wilson, Berthold Göttgens, Kourosh Saeb-Parsy, Mattia Frontini, Elisa Laurenti
Journal: Blood (2022)

Rare hematopoietic stem and progenitor cell (HSPC) pools outside the bone marrow (BM) contribute to blood production in stress and disease but remain ill-defined. Although nonmobilized peripheral blood (PB) is routinely sampled for clinical management, the diagnosis and monitoring potential of PB HSPCs remain untapped, as no healthy PB HSPC baseline has been reported. Here we comprehensively delineate human extramedullary HSPC compartments comparing spleen, PB, and mobilized PB to BM using single-cell RNA-sequencing and/or functional assays. We uncovered HSPC features shared by extramedullary tissues and others unique to PB. First, in contrast to actively dividing BM HSPCs, we found no evidence of substantial ongoing hematopoiesis in extramedullary tissues at steady state but report increased splenic HSPC proliferative output during stress erythropoiesis. Second, extramedullary hematopoietic stem cells/multipotent progenitors (HSCs/MPPs) from spleen, PB, and mobilized PB share a common transcriptional signature and increased abundance of lineage-primed subsets compared with BM. Third, healthy PB HSPCs display a unique bias toward erythroid-megakaryocytic differentiation. At the HSC/MPP level, this is functionally imparted by a subset of phenotypic CD71+ HSCs/MPPs, exclusively producing erythrocytes and megakaryocytes, highly abundant in PB but rare in other adult tissues. Finally, the unique erythroid-megakaryocytic-skewing of PB is perturbed with age in essential thrombocythemia and β-thalassemia. Collectively, we identify extramedullary lineage-primed HSPC reservoirs that are nonproliferative in situ and report involvement of splenic HSPCs during demand-adapted hematopoiesis. Our data also establish aberrant composition and function of circulating HSPCs as potential clinical indicators of BM dysfunction.
Does intracytoplasmic morphologically selected sperm injection improve live birth rates compared to ICSI in men with infertility and raised sperm DNA fragmentation?
Authors: R. Chen, T. Tharakan, C.N. Jayasena, S. Lewis, J. Parikh, M-Y. Thum, J. Nicopoullos, T. Yap, S. Minhas
Journal: European Urology (2021)
Impact of non-targeted prostate sampling histology on the probability of receiving invasive local treatment in an mpMRI-targeted pathway – analysis of 1,719 men
Authors: M.J. Connor, M. Van Son, D. Eldred-Evans, E.J. Bass, M. Bertoncelli Tanaka, U. Walters, P. Sakar, F. Hosking-Jervis, H. Bhola-Stewart, E. Pegers, L. Powell, D. Leelamany, K. Wong, S. Ahmad, H. Tam, S. Mccracken, D. Hrouda, H. Qasi, S. Gordon, M. Winkler, H.U. Ahmed
Journal: European Urology (2021)
1316P Trial-based costs of all-cause adverse events in first-line therapy for advanced non-small cell lung cancer: Findings from CheckMate-9LA
Authors: D. Stenehjem, S.J. Lubinga, S.B. King, K.A. Betts, S. Rao, F. Castriota, M. Mahin, E. Orvis, S. Marathe, J. Ma
Journal: Annals of Oncology (2020)
Rectal indometacin to prevent pancreatitis after extracorporeal shock wave lithotripsy (RIPEP): a single-centre, double-blind, randomised, placebo-controlled trial
Authors: Yang-Yang Qian, Nan Ru, Hui Chen, Wen-Bin Zou, Hao Wu, Jun Pan, Bo Li, Lei Xin, Ji-Yao Guo, Xin-Ying Tang, Liang-Hao Hu, Zhen-Dong Jin, Dong Wang, Yi-Qi Du, Luo-Wei Wang, Zhao-Shen Li, Zhuan Liao
Journal: The Lancet. Gastroenterology & hepatology (2022)
在患有中度至重度特应性皮炎的日本成人中进行的 dupilumab 研究
Journal: British Journal of Dermatology (2020)

特应性皮炎 (AD) 是一种慢性皮肤病,表现为剧烈瘙痒和皮肤干燥、发红、肿胀和皲裂,影响 2% 至 10% 的日 本成人。在日本,中度至重度或极重度 AD 患者的治疗选择有限
Antibiotic prophylaxis for prevention of infectious complications after shockwave lithotripsy: A systematic review and meta-analysis
Authors: B. Tadayon Najafabadi, M. Kandi, M. Ding, T. Bladeh, K. Bausch, M. Briel, K.A.O. Tikkinen, T. Tailly, P.D. Violette
Journal: European Urology (2021)
Modified apical dissection and lateral prostatic fascia preservation: Preliminary analysis of the reproducibility of the novel technique
Authors: B.M.C. Rocco, L. Sarchi, S. Assumma, A. Cassani, F. Turri, C. De Carne, C. Bellorofonte, P. Marcangeli, C. Cesana, G. Bozzini, S. Micali, M.C. Sighinolfi
Journal: European Urology (2021)
Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process
Authors: Antero Salminen
Journal: Ageing Research Reviews (2022)

Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states, e.g., in the aging process and age-related diseases. IDO1 enzyme catabolizes L-tryptophan (L-Trp) into kynurenine (KYN) thus stimulating the KYN pathway. The depletion of L-Trp inhibits the proliferation of immune cells in inflamed tissues and it also reduces serotonin synthesis predisposing to psychiatric disorders. Interestingly, IDO1 protein contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which trigger suppressive signaling through the binding of PI3K p110 and SHP-1 proteins. This immunosuppressive activity is not dependent on the catalytic activity of IDO1. KYN and its metabolite, kynurenic acid (KYNA), are potent activators of the aryl hydrocarbon receptor (AhR) which can enhance immunosuppression. IDO1-KYN-AhR signaling counteracts excessive pro-inflammatory responses in acute inflammation but in chronic inflammatory states it has many harmful effects. A chronic low-grade inflammation is associated with the aging process, a state called inflammaging. There is substantial evidence that the activation of the IDO1-KYN-AhR pathway robustly increases with the aging process. The activation of IDO1-KYN-AhR signaling does not only suppress the functions of effector immune cells, probably promoting immunosenescence, but it also impairs autophagy, induces cellular senescence, and remodels the extracellular matrix as well as enhancing the development of osteoporosis and vascular diseases. I will review the function of IDO1-KYN-AhR signaling and discuss its activation with aging as an enhancer of the aging process.
Added value of radiological tumor stage in predicting early oncological outcomes in prostate cancer patients undergoing radical prostatectomy within clinical stage: A stage-by-stage analysis
Authors: G. Gandaglia, E. Mazzone, F. Barletta, G. Cirulli, S. Scuderi, L. Afferi, M. Moschini, M. Gacci, R. Campi, A. Mari, A. Berni, S. Serni, R. Rahota, G. Ploussard, M. Valerio, G. Marra, A. Marquis, J. Beauval, M. Roumiguié, P. Gontero, J. Zhuang, H. Tuo, N. Fossati, F. Montorsi, A. Briganti
Journal: European Urology (2021)
Correction: Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer
Authors: Carmine De Angelis, Xiaoyong Fu, Maria Letizia Cataldo, Agostina Nardone, Resel Pereira, Jamunarani Veeraraghavan, Sarmistha Nanda, Lanfang Qin, Vidyalakshmi Sethunath, Tao Wang, Susan G. Hilsenbeck, Matteo Benelli, Ilenia Migliaccio, Cristina Guarducci, Luca Malorni, Lacey M. Litchfield, Jiangang Liu, Joshua Donaldson, Pier Selenica, David N. Brown, Britta Weigelt, Jorge S. Reis-Filho, Ben H. Park, Sara A. Hurvitz, Dennis J. Slamon, Mothaffar F. Rimawi, Valerie M. Jansen, Rinath Jeselsohn, C. Kent Osborne, Rachel Schiff
Journal: Clinical Cancer Research (2021)

In earlier versions of this article (1) that were published online on February 3, 2021 and February 25, 2021, one of the paired cell line models (T47D P/PalboR) failed authentication. The authors replaced the original T47D P and its PalboR cell derivative with a parallel T47D model (T47D P-LM/PalboR-LM) and repeated the experiments. All the key results and conclusions have been confirmed using the new T47D P-LM models. To help address these errors, the authors added a new author to their article: Cristina Guarducci. All stated errors have been corrected in the text and figures in the printed version of the article and in the latest online HTML and PDF versions of the article and its supplementary data. The authors regret these errors and stand by the article's conclusions.
Cardiorespiratory fitness and mortality from all causes, cardiovascular disease and cancer: dose–response meta-analysis of cohort studies
Authors: Minghui Han, Ranran Qie, Xuezhong Shi, Yongli Yang, Jie Lu, Fulan Hu, Ming Zhang, Zhenzhong Zhang, Dongsheng Hu, Yang Zhao
Journal: British Journal of Sports Medicine (2022)

Objective Current evidence of the associations between cardiorespiratory fitness (CRF) and mortality is limited. We performed a meta-analysis to assess the dose–response association of CRF with mortality from all causes, cardiovascular disease (CVD) and cancer in healthy population. Methods PubMed, EMBASE and Web of Science were searched up to 26 December 2019 for reports of cohort studies giving risk estimates for all-cause, CVD and cancer mortality by level of CRF. Cohort studies were included if CRF was assessed by an exercise stress test and reported as at least three levels or per incremental increase, and the association of CRF with all-cause, CVD and cancer mortality was evaluated. Generalised least-squares regression models were used to assess the quantitative relation of CRF with all-cause, CVD and cancer mortality. Results 34 cohort studies were eligible for the meta-analysis. The pooled relative risks (RRs) for all-cause, CVD and cancer mortality per one-metabolic equivalent increase in CRF were 0.88 (95% CI 0.83 to 0.93), 0.87 (95% CI0.83 to 0.91) and 0.93 (95% CI 0.91 to 0.96), respectively. As compared with lowest CRF, with intermediate CRF, the summary RRs for all-cause, CVD and cancer mortality were 0.67 (95% CI 0.61 to 0.74), 0.60 (95% CI 0.51 to 0.69) and 0.76 (95% CI 0.69 to 0.84), respectively, and with highest CRF were 0.47 (95% CI 0.39 to 0.56), 0.49 (95% CI 0.42 to 0.56) and 0.57 (95% CI 0.46 to 0.70), respectively. Conclusion Our analysis showed inverse dose–response associations of CRF with all-cause, CVD and cancer mortality, which provides evidence for public health recommendations for preventing all-cause, CVD and cancer mortality. PROSPERO registration number CRD42020208883.
Secukinumab dosing every 2 weeks demonstrated superior efficacy compared with dosing every 4 weeks in patients with psoriasis weighing 90 kg or more: results of a randomized controlled trial*
Authors: Matthias Augustin, Kristian Reich, Paul Yamauchi, Andreas Pinter, Jerry Bagel, Swapnil Dahale, Ruquan You, Gerard Bruin, Jimena Djimopoulos, Bertrand Paguet, Pascal Charef, Manmath Patekar, Deborah Keefe
Journal: British Journal of Dermatology (2022)

Background Obesity is a common comorbidity of psoriasis and can attenuate response to biologic treatment. Objectives To investigate the efficacy, safety and tolerability of secukinumab 300 mg every 2 weeks (Q2W) vs. secukinumab 300 mg every 4 weeks (Q4W) in patients with a higher bodyweight. Methods In this multicentre, double-blind, parallel-group trial, 331 patients with moderate-to-severe chronic plaque psoriasis weighing ≥ 90 kg were randomized to receive secukinumab 300 mg Q2W or secukinumab 300 mg Q4W. Patients who did not achieve Psoriasis Area and Severity Index (PASI) 90 at week 16 on the Q4W regimen were reallocated to remain on the Q4W regimen or uptitrate to Q2W. Results At week 16, Q2W dosing (n = 165) led to significantly higher PASI 90 responses vs. Q4W [n = 166; 73.2% vs. 55.5%, one-sided P-value = 0.0003, odds ratio estimate (95% confidence intervals): 2.3 (1.4–3.8)]. At week 52, higher efficacy responses were maintained in the Q2W arm (n = 165) vs. Q4W (n = 83); PASI 75: 88.9% vs. 74.8%; PASI 90: 76.4% vs. 52.4%; PASI 100: 46.7% vs. 27.3%; Investigator's Global Assessment 0/1: 75.9% vs. 55.6% and Dermatology Life Quality Index 0/1: 66.1% vs. 48.8%. PASI 90 nonresponders at week 16 who uptitrated to Q2W (n = 31) showed higher efficacy responses at week 32 (16 weeks post-uptitration, PASI 90: 38.7% vs. 16.5%) vs. those who remained on Q4W (n = 40). Safety results were comparable across treatment arms and consistent with the established secukinumab safety profile. Conclusions Secukinumab 300 mg Q2W demonstrated superior and sustained efficacy compared with Q4W in patients with moderate-to-severe plaque psoriasis weighing ≥ 90 kg. PASI 90 nonresponders derived additional benefits from uptitration to a Q2W regimen (ClinicalTrials.gov identifier: NCT03504852).
Correlation between exposure of endourologists and patient exposure during fluoroscopy-guided endourological procedures
Authors: A. Skolarikos, J. Vassileva, A. Zagorska, D. Basic, A. Karagiannis, K. Petkova, K. Sabuncu, I. Saltirov, K. Sarica, S. Stavridis, A. Trinchieri, L. Tzelves, I. Ulus, E. Yuruk
Journal: European Urology (2021)
A population study of clinical trial accrual for women and minorities in neuro-oncology following the NIH Revitalization Act
Authors: Sheantel J Reihl, Nirav Patil, Ramin A Morshed, Mulki Mehari, Alexander Aabedi, Ugonma N Chukwueke, Alyx B Porter, Valy Fontil, Gino Cioffi, Kristin Waite, Carol Kruchko, Quinn Ostrom, Jill Barnholtz-Sloan, Shawn L Hervey-Jumper
Journal: Neuro-Oncology (2022)

The NIH Revitalization Act, implemented 29 years ago, set to improve the representation of women and minorities in clinical trials. In this study, we investigate progress made in all phase therapeutic clinical trials for neuroepithelial CNS tumors stratified by demographic-specific age-adjusted disease incidence and mortality. Additionally, we identify workforce characteristics associated with clinical trials meeting established accrual benchmarks.Registry study of published clinical trials for World Health Organization defined neuroepithelial CNS tumors between January 2000 and December 2019. Study participants were obtained from PubMed and ClinicalTrials.gov. Population-based data originated from the CBTRUS for incidence analyses. SEER-18 Incidence-Based Mortality data was used for mortality analysis. Descriptive statistics, Fisher exact, and χ 2 tests were used for data analysis.Among 662 published clinical trials representing 49 907 participants, 62.5% of participants were men and 37.5% women (P < .0001) representing a mortality specific over-accrual for men (P = .001). Whites, Asians, Blacks, and Hispanics represented 91.7%, 1.5%, 2.6%, and 1.7% of trial participants. Compared with mortality, Blacks (47% of expected mortality, P = .008), Hispanics (17% of expected mortality, P < .001) and Asians (33% of expected mortality, P < .001) were underrepresented compared with Whites (114% of expected mortality, P < .001). Clinical trials meeting accrual benchmarks for race included minority authorship.Following the Revitalization Act, minorities and women remain underrepresented in therapeutic clinical trials for neuroepithelial tumors, relative to disease incidence and mortality. Study accrual has improved with time. This study provides a framework for clinical trial accrual efforts and offers guidance regarding workforce considerations associated with enrollment of underserved patients.
Screening Linear and Circular RNA Transcripts from Stress Granules
Authors: Shuai Chen, Jinyang Zhang, Fangqing Zhao
Journal: Genomics Proteomics & Bioinformatics (2022)

Stress granules (SGs) are cytoplasmic ribonucleoprotein assemblies formed under stress conditions and are related to various biological processes and human diseases. Previous studies have reported the regulatory role of some proteins and linear RNAs in SG assembly. However, the relationship between circular RNAs (circRNAs) and SGs has not been discovered. Here, we screened both linear RNAs and circRNAs in SGs using improved total RNA sequencing of purified SG cores in mammalian cells and identified circular transcripts specifically localized in SGs. circRNAs with higher SG-related RNA-binding protein (RBP) binding abilities are more likely to be enriched in SGs. Furthermore, some SG-enriched circRNAs are differentially expressed in hepatocellular carcinoma (HCC) and adjacent tissues. These results suggest the regulatory role of circRNAs in SG formation and provide insights into the biological function of circRNAs and SGs in HCC.
P14.64 PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma
Authors: S Kebir, D Pierscianek, M Proescholdt, P Hau, A Grosu, D Krex, U Sure, B Scheffler, M Stuschke, M Glas
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). In preclinical studies, the combination of TTFields and radiotherapy synergistically impaired proliferation and growth of glioblastoma cells. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. MATERIAL AND METHODS Following surgery and complete wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. Concomitant and adjuvant chemotherapy follow institutional standards and interdisciplinary tumor conference recommendations. RESULTS The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with 20 patients enrolled. We will present initial practical experiences as well as preliminary safety and tolerance data. CONCLUSION There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.
Vaccine booster efficiently inhibits entry of SARS-CoV-2 omicron variant
Authors: Wei Zhang, Linfen Huang, Gang Ye, Qibin Geng, Nwando Ikeogu, Morgan Harris, Gayathri Dileepan, Kristina Burrack, Lanying Du, Anne Frosch, Fang Li
Journal: Cellular and Molecular Immunology (2022)