tbuckley/cabot-search huggingface dataset:
Germline mutations in DNA damage repair genes and <i>HOXB13</i> among African American men diagnosed with early-onset prostate cancer.
Authors: Jennifer Lynn Beebe-Dimmer, Christopher Sample, Tara Baird, Azita Sadeghpour, Julie J. Ruterbusch, Kathleen A. Cooney
Journal: Journal of Clinical Oncology (2021)

10505 Background: Inherited defects in DNA damage repair (DDR) genes (e.g. ATM, BRCA1/2) and the tumor suppresser gene HOXB13 are rare in the general population, but have been observed at a higher rate among men with early-onset and advanced prostate cancer. However, most studies include few, if any, African American men, highlighting the need to understand the contribution of mutations in these genes in this high-risk population. Methods: A population-based cohort of 757 African American men diagnosed with prostate cancer at age 62 years or younger were identified and enrolled through the Metropolitan Detroit Cancer Surveillance System (MDCSS), one of NCI’s founding members of the SEER program. Participants completed a short survey to collect information on family history, medical history (including cancer-related treatment), surveillance, and health behaviors. Each participant submitted a saliva or blood sample for genetic analyses and consent for tumor tissue if available. All clinical data were collected through linkage with the MDCSS registry. Full exome sequencing was performed and herein, we report the mutation patterns observed in a panel of DNA repair genes and HOXB13. All variants were ranked according to frequency (MAF &lt; 1%); REVEL, SIFT and PolyPhen scores for pathogenic potential; evidence from existing literature; and prevalence in the cohort. Results: Among the 744 African American prostate cancer cases with adequate DNA for sequencing and thus included in this analysis, the mean age at diagnosis was 55.6 years, 29% reported a family history of prostate cancer in a first degree family member, and 40% were initially diagnosed with intermediate- to high-risk disease (stage T3/T4 and/or Gleason 4+3 and higher at diagnosis). We identified 20 variants that were either known or predicted to be pathogenic in 11 candidate genes ( ATM, ATR, BRCA1/2, BRIP1, CHEK2, FANCA, HOXB13, MSH2, PALB2, and PMS2). These particular variants were more common among men diagnosed before age 55 and in men with high grade cancer in this cohort. Conclusions: Our results suggest that mutations in DDR genes and HOXB13 may be important cancer risk factors for African American men diagnosed with early-onset and intermediate- to high-risk disease. Further study is necessary to describe the spectrum and prevalence of genetic mutations in this population including the characterization of variants of unknown significance.
Retraction Note to: Differential modulatory effects of GSK-3b and HDM2 on sorafenib-induced AIF nuclear translocation (programmed necrosis) in melanoma
Authors: Qingjun Liu, James W. Mier, David J. Panka
Journal: Molecular Cancer (2021)

GSK-3β phosphorylates numerous substrates that govern cell survival. It
                  phosphorylates p53, for example, and induces its nuclear export, HDM2-dependent
                  ubiquitination, and proteasomal degradation. GSK-3β can either enhance or inhibit
                  programmed cell death, depending on the nature of the pro-apoptotic stimulus. We
                  previously showed that the multikinase inhibitor sorafenib activated GSK-3β and
                  that this activation attenuated the cytotoxic effects of the drug in various
                  BRAF-mutant melanoma cell lines. In this report, we describe the results of
                  studies exploring the effects of GSK-3β on the cytotoxicity and antitumor activity
                  of sorafenib combined with the HDM2 antagonist MI-319. MI-319 alone increased p53 levels and p53-dependent gene expression in
                  melanoma cells but did not induce programmed cell death. Its cytotoxicity,
                  however, was augmented in some melanoma cell lines by the addition of sorafenib.
                  In responsive cell lines, the MI-319/sorafenib combination induced the
                  disappearance of p53 from the nucleus, the down modulation of Bcl-2 and
                    Bcl-xL, the translocation of p53 to the mitochondria and
                  that of AIF to the nuclei. These events were all GSK-3β-dependent in that they
                  were blocked with a GSK-3β shRNA and facilitated in otherwise unresponsive
                  melanoma cell lines by the introduction of a constitutively active form of the
                  kinase (GSK-3β-S9A). These modulatory effects of GSK-3β on the activities of the
                  sorafenib/MI-319 combination were the exact reverse of its effects on the
                  activities of sorafenib alone, which induced the down modulation of Bcl-2 and
                    Bcl-xL and the nuclear translocation of AIF only in cells
                  in which GSK-3β activity was either down modulated or constitutively low. In A375
                  xenografts, the antitumor effects of sorafenib and MI-319 were additive and
                  associated with the down modulation of Bcl-2 and Bcl-xL,
                  the nuclear translocation of AIF, and increased suppression of tumor
                  angiogenesis. Our data demonstrate a complex partnership between GSK-3β and HDM2 in the
                  regulation of p53 function in the nucleus and mitochondria. The data suggest that
                  the ability of sorafenib to activate GSK-3β and alter the intracellular
                  distribution of p53 may be exploitable as an adjunct to agents that prevent the
                  HDM2-dependent degradation of p53 in the treatment of melanoma.
Light‐Regulated Angiogenesis via a Phototriggerable VEGF Peptidomimetic
Authors: Roshna V. Nair, Aleeza Farrukh, Aránzazu del Campo
Journal: Advanced Healthcare Materials (2021)

Abstract The application of growth factor based therapies in regenerative medicine is limited by the high cost, fast degradation kinetics, and the multiple functions of these molecules in the cell, which requires regulated delivery to minimize side effects. Here a photoactivatable peptidomimetic of the vascular endothelial growth factor (VEGF) that allows the light‐controlled presentation of angiogenic signals to endothelial cells embedded in hydrogel matrices is presented. A photoresponsive analog of the 15‐mer peptidomimetic Ac‐KLTWQELYQLKYKGI‐NH 2 (abbreviated P QK ) is prepared by introducing a 3‐(4,5‐dimethoxy‐2‐nitrophenyl)‐2‐butyl (DMNPB) photoremovable protecting group at the Trp4 residue. This modification inhibits the angiogenic potential of the peptide temporally. Light exposure of P QK modified hydrogels provide instructive cues to embedded endothelial cells and promote angiogenesis at the illuminated sites of the 3D culture, with the possibility of spatial control. P QK modified photoresponsive biomaterials offer an attractive approach for the dosed delivery and spatial control of pro‐angiogenic factors to support regulated vascular growth by just using light as an external trigger.
Bioinspired supramolecular nanofiber hydrogel through self-assembly of biphenyl-tripeptide for tissue engineering
Authors: Yong Sun, Xing Li, Mingda Zhao, Yafang Chen, Yang Xu, Kefeng Wang, Shaoquan Bian, Qing Jiang, Yujiang Fan, Xingdong Zhang
Journal: Bioactive Materials (2021)

Supramolecular nanofiber peptide assemblies had been used to construct functional hydrogel biomaterials and achieved great progress. Here, a new class of biphenyl-tripeptides with different C-terminal amino acids sequences transposition were developed, which could self-assemble to form robust supramolecular nanofiber hydrogels from 0.7 to 13.8 kPa at ultra-low weight percent (about 0.27 wt%). Using molecular dynamics simulations to interrogate the physicochemical properties of designed biphenyl-tripeptide sequences in atomic detail, reasonable hydrogen bond interactions and "FF" brick (phenylalanine-phenylalanine) promoted the formation of supramolecular fibrous hydrogels. The biomechanical properties and intermolecular interactions were also analyzed by rheology and spectroscopy analysis to optimize amino acid sequence. Enhanced L929 cells adhesion and proliferation demonstrated good biocompatibility of the hydrogels. The storage modulus of BPAA-AFF with 10 nm nanofibers self-assembling was around 13.8 kPa, and the morphology was similar to natural extracellular matrix. These supramolecular nanofiber hydrogels could effectively support chondrocytes spreading and proliferation, and specifically enhance chondrogenic related genes expression and chondrogenic matrix secretion. Such biomimetic supramolecular short peptide biomaterials hold great potential in regenerative medicine as promising innovative matrices because of their simple and regular molecular structure and excellent biological performance.
Niraparib efficacy and safety in patients with <i>BRCA</i> mutated (<i>BRCA</i>m) ovarian cancer: Results from three phase 3 niraparib trials.
Authors: Antonio Gonzalez Martin, Ursula A. Matulonis, Jacob Korach, Mansoor Raza Mirza, Kathleen N. Moore, Divya Gupta, Stanislav Lechpammer, Bradley J. Monk
Journal: Journal of Clinical Oncology (2021)

5518 Background: Niraparib has been approved for the maintenance treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer after front-line chemotherapy (CT) and in the recurrent setting. Here, we summarize niraparib efficacy and safety in patients with BRCAm OC across three phase 3 trials: PRIMA/ENGOT-OV26/GOG-3012 (PRIMA; NCT02655016), ENGOT-OV16/NOVA (NOVA; NCT01847274), and NORA (NCT03705156). Methods: Patients enrolled in the PRIMA trial had newly diagnosed advanced ovarian, fallopian tube, or primary peritoneal cancer. All patients had stage III or IV high-grade serous or endometrioid tumors and had a complete or partial response to their first-line platinum-based CT treatment. Subgroup analysis by tumor BRCAm status was prespecified. Patients enrolled in the NOVA and NORA studies had platinum-sensitive, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Patients had already received at least 2 lines of platinum-based CT regimens. In both studies, subgroup analysis by germline BRCAm status was prespecified. The primary endpoint in all trials was progression-free survival (PFS) by blinded independent central review. Results: The BRCAm populations from each trial are as follows: 223 (148 BRCA1m and 75 BRCA2m) from the PRIMA trial, 203 (128 BRCA1m, 69 BRCA2m, and 13 BRCA1/2m) from the NOVA trial, and 100 (78 BRCA1m, 21 BRCA2m, and 1 BRCA1/2m) from the NORA trial. PFS results are shown in the Table. Across the 3 trials, the most common treatment-emergent adverse events were thrombocytopenia, anemia, neutropenia, and hypertension. Conclusions: Patients with BRCAm OC derived a significant PFS benefit from niraparib maintenance treatment across all 3 trials. No new safety signals were identified. Clinical trial information: NCT02655016, NCT01847274, NCT03705156. [Table: see text]
Breast cancer after IVF: Can ovary stimulation and follicular response affect prognostic factors?
Authors: Maxim Izquierdo, Sonia Baulies, Marta Devesa, Fransec Tresserra, Carmen Ara, Ignacio Rodriguez, Rafael Fabregas, Buenaventura Coroleu, Pedro S Barri, Pere Barri
Journal: Journal of Clinical Oncology (2021)

e12538 Background: The ovary stimulation and the follicular response is related with estradiol level. Study in breast cancer patients after IVF if ovarian response or number of IVF cycles affects the prognostic factors. Methods: Patients with breast cancer who underwent IVF are studied the prognostic factors (Ki67, HER2, estrogen receptor (ER), progesterone receptor (PR), oncogene p53, histologic grade) in relation to the ovary response and number of IVF cycles. Results: 73 patients with breast cancer after IVF are studied. They performed 135 cycles of IVF, 36 (49’3%) with 1 IVF and 37 (50’7%) with more than one IVF. Hyper response was present in at least one IVF in 24 (32.9%) patients and there was no hyper response in any IVF in 49 (67.1%) patients. The prognostic factors were: Ki 67&gt; 20 in 31'91% (15/47) Ki 67 &lt;20 in 68'08% (32/47), HER2 + 31'94% (23/72) HER2- 68'05% (49/72), p53 + 45'09% (23/51), p53-54'90% (28/51), HG II-III 56'36% (31/55), HG I 43'63% ( 24/55), RE + 87'5% (63/72), RE- 12'5% (9/72), RP + 76'38% (55/72), RP- 23'61% (17/72). None of prognostic factors varied with the ovary response (hyper response in at least one IVF cycle, normal response, normal or low response) (p=ns). The only prognostic factor that varied with the IVF number was p53 +. Patients with p53 + (23/51), 7 (30’43%) has one IVF, and 16 (69’53%) have more one IVF (p&lt;0’05). Conclusions: In breast cancer after IVF, the ovary stimulation and the follicular response not affect Ki67, HER2, estrogen receptor, progesterone receptor, p53, and histologic grade. p53 positive is more frequent in patients with more than one IVF.
Assessment of low-intensity transcranial magnetic stimulation (TMS) in treatment for high-grade glioma (HGG).
Authors: Ivan A. Popov, Oleg I. Kit, Alla I. Shikhlyarova, Elena M. Frantsiyants, Eduard E. Rostorguev, Marina A. Engibaryan, Natalya N. Timoshkina, Marina A. Gusareva, Dmitrii S. Potemkin, Vitaliy V. Stasov, Yulia Yu. Arapova, Galina V. Zhukova, Dmitriy P. Atmachidi, Emzari S. Nikitin, Natalya S. Kuznetsova, Olga V. Pandova, Vladislav E. Khatyushin
Journal: Journal of Clinical Oncology (2021)

e14027 Background: The existing modern standards of combination treatment of HGG patients do not provide recovery and a long-term favorable prognosis, and the increasong incidence of HGG determines the need for additional effective technologies for anticancer and decongestant therapy. One of such methods involves TMS, and we have reported its preliminary assessment earlier (DOI: 10.1200/JCO.2020.38.15_suppl.2545). In this study, we continued the observation to examine the survival of patients. Methods: Patients with HGG received combination treatment: stage 1 – surgical removal of tumors within visible unaltered tissues; stage 2 – radiation therapy (the Varian Novalis linear accelerator) to the bed of the removed tumor, single boost dose 2 Gy, total boost dose 60 Gy; stage 3 – multi-course chemotherapy: temozolomide 150 mg/m² on days 1-5 with a 23-day interval. Starting from the second day after surgery, patients of group 1 (n = 25) received 10 TMS sessions, and during radiotherapy – 15 TMS sessions. Patients of group 2 (n = 25) received combination treatment without TMS. 6 and 12 months after the surgery, survival of patients was assessed with the Kaplan-Meier method and the Log-Rank test. Results: After 6 months of the follow-up, the survival of patients in group 1 remained at 100%, while in the control group it decreased to 88.8±8.7%. The difference in the 1-year overall survival was even more pronounced: in group 1, it was 68.5±10.4%, exceeding the value in group 2 (52.0±7.5%.) The differences were statistically significant (Log-Rank test p = 0.001). Conclusions: The results confirm the effectiveness of accompanying TMS in the early postoperative period, as well as at the stage of radiation therapy. The undoubted effectiveness of the considered techniques makes it expedient to include this type of treatment in the combination therapy for HGG patients. The reported study was funded by RFBR, project number № 19-315-90082\19.
EPEN-07. SINGLE-CELL RNA SEQUENCING IDENTIFIES A UNIQUE MYELOID SUBPOPULATION ASSOCIATED WITH MESENCHYMAL TUMOR SUBPOPULATION IN POOR OUTCOME PEDIATRIC EPENDYMOMA
Authors: Andrea Griesinger, Kent Riemondy, Andrew Donson, Nicholas Willard, Eric Prince, Faith Harris, Vladimir Amani, Enrique Grimaldo, Todd Hankinson, Richard Grundy, Andrew Jackson, Nicholas Foreman, Timothy Ritzmann
Journal: Neuro-Oncology (2021)

Abstract We have previously shown immune gene phenotype variations between posterior fossa ependymoma subgroups. PFA1 tumors chronically secrete IL-6, which induces secretion of myeloid cell IL-8 and pushes the infiltrating myeloid cells to an immune suppressive function. In contrast, PFA2 tumors have a more immune activated phenotype associated with a better prognosis. The objective of this study was to use single-cell(sc) RNAseq to descriptively characterize the infiltrating myeloid cells. We analyzed approximately 8500 cells from 21 PFA patient samples. Using advanced machine learning, we identified eight myeloid cell subpopulations with unique gene expression profiles. Interestingly, only one subpopulation was significantly enriched in PFA1 tumors. This subpopulation, denoted as the hypoxia myeloid subpopulation, was defined by genes associated with angiogenesis, response to hypoxia, wound healing, cell migration, neutrophil activation and response to oxygen levels. These myeloid cells also share similar gene expression profile to a mesenchymal tumor subpopulation (MEC) enriched in PFA1 and associated with poor outcome in EPN patients. This tumor subpopulation was the only population expressing IL-6. Using immunohistochemistry, we found the hypoxia myeloid located in regions of tumor necrosis and perivascular niches. The MEC cells were also more abundant in these regions. In an independent single-cell cytokine release assay, we identified eight subpopulations of functional myeloid cells. One subpopulation significantly secreted IL-8, which represented the hypoxia subpopulation based on IL-8 gene expression in the scRNAseq dataset. This data suggests the tumor necrosis resulting in the development of MEC tumor subpopulation is driving the immune suppressive myeloid phenotype in PFA1 tumors through polarization of myeloid cells to the hypoxia subpopulation. Further studies are needed to determine how these myeloid cells interact with the lymphocyte subpopulations and whether they contribute to the progression of PFA1 EPN.
Anterior cruciate ligament reconstruction is not for all—a need for improved patient selection
Authors: Gilbert Moatshe, Christopher Y Kweon, Albert O Gee, Lars Engebretsen
Journal: British Journal of Sports Medicine (2021)

In an interesting article by Eggerding et al ,1 the authors conducted a cost-utility analysis for two treatment strategies for patients who sustain an anterior cruciate ligament (ACL) tear; early ACL reconstruction versus rehabilitation plus an optional reconstruction in case of persistent instability. The randomised controlled study included patients with ACL tear aged 18–65 years. The authors found that it takes 48460 € from a healthcare perspective and 78179 € from a societal perspective to gain a quality-adjusted life year (QALY) when performing early surgery compared with rehabilitation plus optional reconstruction. How much are we willing to pay to gain a QALY, and what is the best way to use limited resources? Most previous studies have focused on patient function and satisfaction, and with increasing economic burden in most countries, studies such as this one evaluating cost-utility are necessary.

Anterior cruciate ligament reconstruction (ACL-R) is one of the most commonly performed procedures in orthopaedic sports medicine. Increased sports participation and training load in the youth, and the desire to stay active into old age are among the factors that have contributed to the increased injury burden. The number of ACL-R procedures has increased in the last two decades in most countries in the western world. It is also possible that advances in surgical techniques have led to an increased number of ACL-R. The …
EPEN-11. TUMOR DIFFERENTIATION IMPACTS THE BIOLOGY OF RECURRENCE IN CHILDHOOD POSTERIOR FOSSA EPENDYMOMA
Authors: Andrew Donson, Timothy Ritzmann, Nicholas Willard, Andrea Griesinger, Vladimir Amani, Faith Harris, Enrique Grimaldo, Bridget Sanford, Kent Riemondy, Todd Hankinson, Richard Grundy, Nicholas Foreman
Journal: Neuro-Oncology (2021)

Abstract Ependymoma (EPN) of childhood is curable in only 50% of cases, with recurrences in the remainder that are refractory to treatment. In recent years significant advances have been made in understanding the molecular and cellular biology of EPN. Recent studies show that PFA subgroup EPN are comprised of multiple neoplastic subpopulations that show undifferentiated, differentiated and mesenchymal characteristics. These studies focused on tumor at presentation, with recurrent EPN being less well understood. In the present longitudinal study we examine changes in neoplastic cell heterogeneity in serial presentations of PFA EPN using deconvolution (Cibersort) of bulk RNAseq data. Analysis of a cohort of 48 PFA EPN presenting at Children’s Colorado showed survival and PFA1/PFA2 subtype assignment was associated with the proportion of individual neoplastic subpopulations as determined by deconvolution. Tumors that subsequently regrew had a significantly higher estimated proportion of undifferentiated EPN cells (UEC) at presentation, than those that were non-recurrent after 5 years follow-up. This outcome association potentially age related, as UEC proportions are significantly higher in PFA arising in children &amp;lt; 1 year old who have a particularly poor prognosis. Changes in PFA neoplastic subpopulations at recurrence was performed in two cohorts of patients from Children’s Colorado (n=23) and Nottingham, UK (n=15). As a whole, no subpopulation proportion was significantly changed at recurrence. However, separation of PFA into subtypes PFA1 and PFA2 revealed an increase in the proportion of the cilia-differentiated EPN cell subpopulation is more frequent event in PFA1 (15/24), and rare in PFA2 (2/11). Changes in other neoplastic subpopulations at recurrence were smaller and only seen in PFA1, both UEC and mesenchymal subpopulations being lower at recurrence. In summary, only PFA1 showed dynamic changes in neoplastic subpopulation proportions at recurrence, with potential impacts on transcriptomic based-subgroup assignment, whereas PFA2 proportions remained largely stable.
Loss of SDHB Promotes Dysregulated Iron Homeostasis, Oxidative Stress, and Sensitivity to Ascorbate
Authors: Judith Goncalves, Sophie Moog, Aurélie Morin, Géraldine Gentric, Sebastian Müller, Alexander P. Morrell, Katarina Kluckova, Theodora J. Stewart, Cynthia L. Andoniadou, Charlotte Lussey-Lepoutre, Paule Bénit, Alpesh Thakker, Lisa Vettore, Jennie Roberts, Raphaël Rodriguez, Fatima Mechta-Grigoriou, Anne-Paule Gimenez-Roqueplo, Eric Letouzé, Daniel A. Tennant, Judith Favier
Journal: Cancer Research (2021)

Succinate dehydrogenase is a key enzyme in the tricarboxylic acid cycle and the electron transport chain. All four subunits of succinate dehydrogenase are tumor suppressor genes predisposing to paraganglioma, but only mutations in the SDHB subunit are associated with increased risk of metastasis. Here we generated an
HIPAA at 25 — A Work in Progress
Authors: Anita L. Allen
Journal: New England Journal of Medicine (2021)

Interview with Dr. Anita Allen on progress in protecting health information privacy and the current direction of regulatory momentum. (13:14)Download HIPAA is best viewed as a framework of evolving regulation that's revised periodically in response to demands of biomedical innovation and public health in the digital age. That capacity for adaptive modification is among the greatest strengths of HIPAA and its rules.