tbuckley/cabot-search huggingface dataset:
CC16 Binding to α<sub>4</sub>β<sub>1</sub> Integrin Protects against <i>Mycoplasma pneumoniae</i> Infection
Authors: Michael D. L. Johnson, Usir S. Younis, Sanjay V. Menghani, Kenneth J. Addison, Michael Whalen, Aprile L. Pilon, Anne E. Cress, Francesca Polverino, Casey E. Romanoski, Monica Kraft, Fernando D. Martinez, Stefano Guerra, Julie G. Ledford
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases (asthma and chronic obstructive pulmonary disease). Objectives Although exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating antiinflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Methods Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, leucine-valine-aspartic acid (LVD), a known integrin-binding motif. Recombinant CC16 was generated with and without the putative integrin-binding site. A Mycoplasma pneumoniae mouse model and a fluorescent cellular adhesion assay were used to determine the impact of the LVD site regarding CC16 function during live infection and on cellular adhesion during inflammatory conditions. Measurements and Main Results CC16 bound to integrin α4β1), also known as the adhesion molecule VLA-4 (very late antigen 4), dependent on the presence of the LVD integrin-binding motif. During infection, recombinant CC16 rescued lung function parameters both when administered to the lung and intravenously but only when the LVD integrin-binding site was intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. Conclusions We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.
Dynamics and Correlation Among Viral Positivity, Seroconversion, and Disease Severity in COVID-19
Authors: Yu Fu, Yongsheng Li, Ensong Guo, Liang He, Jia Liu, Bin Yang, Fuxia Li, Zizhuo Wang, Yuan Li, Rourou Xiao, Chen Liu, Yuhan Huang, Xue Wu, Funian Lu, Lixin You, Tianyu Qin, Chaolong Wang, Kezhen Li, Peng Wu, Ding Ma, Chaoyang Sun, Gang Chen
Journal: Annals of Internal Medicine (2020)

The understanding of viral positivity and seroconversion during the course of coronavirus disease 2019 (COVID-19) is limited.To describe patterns of viral polymerase chain reaction (PCR) positivity and evaluate their correlations with seroconversion and disease severity.Retrospective cohort study.3 designated specialty care centers for COVID-19 in Wuhan, China.3192 adult patients with COVID-19.Demographic, clinical, and laboratory data.Among 12 780 reverse transcriptase PCR tests for severe acute respiratory syndrome coronavirus 2 that were done, 24.0% had positive results. In 2142 patients with laboratory-confirmed COVID-19, the viral positivity rate peaked within the first 3 days. The median duration of viral positivity was 24.0 days (95% CI, 18.9 to 29.1 days) in critically ill patients and 18.0 days (CI, 16.8 to 19.1 days) in noncritically ill patients. Being critically ill was an independent risk factor for longer viral positivity (hazard ratio, 0.700 [CI, 0.595 to 0.824]; P < 0.001). In patients with laboratory-confirmed COVID-19, the IgM-positive rate was 19.3% in the first week, peaked in the fifth week (81.5%), and then decreased steadily to around 55% within 9 to 10 weeks. The IgG-positive rate was 44.6% in the first week, reached 93.3% in the fourth week, and then remained high. Similar antibody responses were seen in clinically diagnosed cases. Serum inflammatory markers remained higher in critically ill patients. Among noncritically ill patients, a higher proportion of those with persistent viral positivity had low IgM titers (<100 AU/mL) during the entire course compared with those with short viral positivity.Retrospective study and irregular viral and serology testing.The rate of viral PCR positivity peaked within the initial few days. Seroconversion rates peaked within 4 to 5 weeks. Dynamic laboratory index changes corresponded well to clinical signs, the recovery process, and disease severity. Low IgM titers (<100 AU/mL) are an independent risk factor for persistent viral positivity.None.
Platelet Function Assessment to Predict Outcomes After Coronary Interventions: Hype or Hope?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Fernando Alfonso, Dominick J. Angiolillo
Journal: Journal of the American College of Cardiology (2006)
IMMU-04. IMMUNE-RELATED ADVERSE EVENTS STRONGLY PREDICT SUPERIOR OUTCOMES IN BRAIN METASTASES PATIENTS RECEIVING LOCAL TREATMENT AND IMMUNE CHECKPOINT INHIBITORS
Authors: Alexander Hulsbergen, Asad Lak, Yu Tung Lo, Nayan Lamba, Steven Nagtegaal, Arun Job, Joost Verhoeff, Timothy Smith, Marike Broekman, John Phillips
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION In several cancers treated with immune checkpoint inhibitors (ICIs), a remarkable association between the occurrence of immune-related adverse events (irAEs) and superior oncological outcomes has been reported. This effect has hitherto not been reported in the brain. This study aimed to investigate the relation between irAEs and outcomes in brain metastases (BM) patients treated with both local treatment to the brain (LT; i.e. surgery and/or radiation) and ICIs. METHODS This study is a retrospective cohort analysis of patients treated for non-small cell lung cancer (NSCLC) BMs in a tertiary institution in Boston, MA. Outcomes of interest were overall survival (OS) and intracranial progression-free survival (IC-PFS), measured from the time of LT. Sensitivity analyses were performed to account for immortal time bias (i.e., patients who live longer receive more cycles of ICIs and thus have more opportunity to develop an irAE). RESULTS A total of 184 patients were included; 62 (33.7%) were treated with neurosurgical resection and 122 (66.3%) with upfront brain radiation. irAEs occurred in 62 patients (33.7%). After adjusting for lung-Graded Prognostic Assessment, type of LT, type of ICI, newly diagnosed vs. recurrent BM, BM size and number, targetable mutations, and smoking status, irAEs were strongly associated with better OS (HR 0.33, 95% CI 0.19 – 0.58, p &amp;lt; 0.0001) and IC-PFS (HR 0.41; 95% CI 0.26 – 0.65; p = 0.0001). Landmark analysis including only patients who received more than 3 cycles of ICI (n = 133) demonstrated similar results for OS and IC-PFS, as did sensitivity analysis adjusting for the number of cycles administered (HR range 0.36 – 0.51, all p-values &amp;lt; 0.02). CONCLUSIONS After adjusting for known prognostic factors, irAEs strongly predict superior outcomes after LT in NSCLC BM patients. Sensitivity analysis suggests that this is unlikely due to immortal time bias.
GCT-50. LONG-TERM OUTCOMES OF INTRACRANIAL GERMINOMA IN A SINGLE INSTITUTION
Authors: Etsuko Yamamoto, Yoshiki Arakawa, Katsutsugu Umeda, Youhei Mineharu, Megumi Uto, Junko Takita, Takashi Mizowaki, Susumu Miyamoto
Journal: Neuro-Oncology (2020)

Abstract The treatment for intracranial germinoma has been well-established. Complete removal is not necessary, but radiation therapy is important. As the prognosis of patients with germinoma has become better, side effect of radiotherapy and chemotherapy must be well considered. The aim of this study was to evaluate the outcome of intracranial germinomas at Kyoto University Hospital from 1979 to 2019. 64 patients were diagnosed as intracranial germinoma. Patients with hCG &amp;gt; 100 IU/l and/or AFP &amp;gt; 10 ng/ml were excluded. Patients, who were histologically diagnosed as germinoma without information of hCG and AFP, were included. Follow-up time was from 2 to 486 months (median 136 months). Recently, germinoma patients were diagnosed with biopsy and received low dose whole-ventricle irradiation with intensity modulated radiation therapy (IMRT) (total 24-30Gy) and chemotherapy dominated by platinating agent. 10-year PFS was 80.21% (high dose radiation alone), 86.36% (high dose radiation with chemotherapy) and 100% (low dose radiation with chemotherapy). Many recurrent sites were out of irradiation areas. Late cognitive dysfunction was identified in 6 patients, and 5 of them were treated with high dose radiation. Patients with intracranial germinoma can obtain long-term survival. It is important to prevent recurrence without increasing late iatrogenic complications. Low dose radiotherapy and chemotherapy is highly effective, and it potentially reduces late adverse effects.
18F-FDG PET/CT in Anti–Leucine-Rich Glioma-Inactivated 1 Antibody Encephalitis
Authors: Pierre-Ambroise Caquot, Ghali Zizi, Maxime Lelièvre, Sébastien Dejust, David Morland
Journal: Clinical Nuclear Medicine (2020)

We report the case of a 55-year-old man presenting pseudopsychiatric behavior disorders of subacute-onset. MRI showed a FLAIR (fluid-attenuated inversion recovery) hyperintensity in the left hippocampus. The diagnosis of limbic encephalitis was raised, and the patient was referred for an 18F-FDG PET/CT. PET/CT depicted an increased uptake of the left mesiotemporal structures and also an increased uptake of both cerebellum and striatal areas. This pattern was compatible with an anti-leucine-rich glioma-inactivated 1 antibody encephalitis that was later confirmed.
Incident CKD in Diabetes, Hypertension, and Prediabetes
Authors: Cami R. Jones, Kenn B. Daratha, Susanne B. Nicholas, Radica Z. Alicic, Obidiugwu Duru, Keith C. Norris, Nilka Rios Burrows, Katherine R. Tuttle, Meda E. Pavkov
Journal: Journal of the American Society of Nephrology (2020)
LINC-05. PRIMARY CENTRAL NERVOUS SYSTEM EWING SARCOMA IN PEDIATRIC AND AYA PATIENTS: 2 INSTITUTIONS EXPERIENCE IN BUENOS AIRES ARGENTINA
Authors: Roberto Nicolas Palomar, Florencia Yorio, Lucas Alessandro, Naomi Arakaki, Alejandro Muggeri, Mercedes Garcia Lombardi, Blanca Diez
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Ewing Sarcoma (ES) is defined by molecular markers, being t(11;22)(q24;q12) the most frequent. Intracranial ES usually shows as metastases from extracranial sites. Primary central nervous system (CNS) lesions are extremely rare. MATERIAL AND METHODS Retrospective review of clinical records from patients with primary CNS ES, assessed at 2 institutions in Argentina between 2007–2019. Translocation was evidenced in all cases through molecular testing. Clinical characteristics, imaging, histopathology, and treatment response were evaluated. Extracranial and osseous lesions were excluded. RESULTS 15 patients. Median age at beginning of symptoms: 8 yo (2–20). Most patients had intracranial hypertension syndrome (14/15). In brain MRI, 5/15 supratentorial lesions, 4/15 posterior fosa, 1/15 medullary, 2/15 supra and infratentorial, and 3/15 lesions diffuse leptomeningeal infiltration. Histopathologic findings showed diffuse pattern with small round blue cells in most cases, other patterns were also described. CD99 marked positive in all cases. Misdiagnosis with glial tumors (4/15), medulloblastoma (6/15) and infectious diseases (3/15); led to median delay to accurate diagnosis of 3 months (range 0–67). After correct diagnosis patients were treated with standard ES treatment (6 VIDE cycles plus radiotherapy) in 14/15 patients. Vincristine, irinotecan and temozolamide was used as second line treatment in all relapse cases whenever possible. EFS was 22 months (2- 65). OS at 5 years of follow-up was 46,67% (mean OS 31 mo). CONCLUSION Even though molecular assessment led to accurate diagnosis in all cases, treatment response and outcome showed two different groups of patients with long and very short survival. Adaptative therapy should be considered.
RARE-46. A THIRTEEN YEAR PATIENT JOURNEY OF INFANT GIANT CLIVAL CHORDOMA: CASE REPORT AND LITERATURE REVIEW
Authors: John Apps, Eloise Neumann, Fardad Afshari, Guirish Solanki, Martin English
Journal: Neuro-Oncology (2020)

Abstract In 2006 we reported the youngest case of a large clival chordoma, a 15-week old baby, the second case to present without skull base involvement and the fourth case of chordoma in a patient with tuberous sclerosis. This unusually rare case (surgically un-resect able) underwent endoscopic skull-base diagnostic biopsy and a novel chemotherapy regime that aimed to control his disease[i]. Initial tumour control was achieved with chemotherapy (Ifosfamide, doxorubicin with dexrazonane, intrathecal hydrocortisone, methotrexate, cytarabine). Carboplatin and etoposide were later given for a further year. Following this, Sirolimus and imatinib were used for another twelve months due to primary tumour regrowth and three new skull-vault lesions. Sirolimus alone was continued for an additional year, but stopped due to optic neuritis. Imatinib was given until further progression two years later, leading to a change to everolimus. Surgery for the ventral foramen magnum was performed a year later. The patient received further surgery and radiotherapy for tumour recurrence. Sadly the tumour metastasised and he succumbed at age 13. Chordomas are aggressive and recur frequently. Complete primary resection followed by radiotherapy/proton beam therapy offers the best chance of cure but is not an option in infants with giant lesions, as in our case. We inform on alternative targeted treatment strategies and review the literature on these rare lesions. [i] Kambogiorgas D, St George EJ, Chapman S, English M, Solanki G: Infantile Clivus chordoma without clivus involvement: Case report and review of the literature, Childs Nerv System (2006) 22:1369–1374
CBIO-11. NOVEL THERAPY TO TARGET PR-RECURRENT GLIOMA
Authors: Masum Rahman, Ian E Olson, Rehan Saber, Jibo Zhang, Lucas P Carlstrom, Chen Sisi, Karishma Rajani, Desmond Brown, Ian Parney, Jann Sarkaria, Terry C Burns
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p&amp;lt; 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.
SURG-10. SPECTROSCOPIC MEASUREMENT OF 5-ALA-INDUCED INTRACELLULAR PROTOPORPHYRIN IX IN PEDIATRIC BRAIN TUMORS
Authors: Michael Schwake, Sadahiro Kaneko, Eric Suero Morina, Walter Stummer
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE 5-ALA guided resection of glioma in adults enables better delineation between tumor and normal brain, allowing improved resection and improved patients’ outcome. Recently, several reports were published regarding 5-ALA for resection of pediatric brain tumors. The aim of the study was to determine the intracellular fluorescence of PPIX in pediatric brain tumors by hyperspectral imaging and to compare it with visually observed intraoperative fluorescence. METHODS 5-ALA was administered orally four hours prior to surgery. During tumor resection the surgeon assessed the fluorescence signal to be strong, weak or absent. Subsequently, fluorescence intensity of samples was measured via spectroscopy. In addition, clinical data, imaging and laboratory data were analyzed. RESULTS Eleven children (1–16 years) were operated. Tumor entities included: three medulloblastomas, two pilocytic astrocytomas (PA), two anaplastic ependymomas and one diffuse astrocytoma, anaplastic astrocytoma, pilomyxoid astrocytoma and anaplastic pleomorphic xanthoastrocytoma. Strong fluorescence was visible in all anaplastic tumors and one PA; one PA demonstrated weak fluorescence. Visible fluorescence was strongly associated with intracellular fluorescence intensity and PPIX concentration (P&amp;lt;0.05). Within all tumors with visible fluorescence the intracellular PPIX concentration was greater than 4 µg/ml. Except for moderate and transient elevation of liver enzymes, no 5-ALA related adverse events were reported. CONCLUSION We demonstrate a strong association between intraoperative observations and spectrometric measurements of PPIX fluorescence in tumor tissue. As in former studies, fluorescence signal was more commonly observed in malignant glial tumors. Further prospective controlled trials should be conducted to investigate the feasibility of 5-ALA guided resection of pediatric brain tumors.
Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study
Authors: Josefin E. Löfvenborg, Sofia Carlsson, Tomas Andersson, Christiane S. Hampe, Albert Koulman, María Dolores Chirlaque Lopez, Paula Jakszyn, Verena A. Katzke, Tilman Kühn, Cecilie Kyrø, Giovanna Masala, Peter M. Nilsson, Kim Overvad, Salvatore Panico, Maria-Jose Sánchez, Yvonne van der Schouw, Matthias B. Schulze, Anne Tjønneland, Elisabete Weiderpass, Elio Riboli, Nita G. Forouhi, Stephen J. Sharp, Olov Rolandsson, Nicholas J. Wareham
Journal: Diabetes Care (2020)

OBJECTIVE Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes. RESEARCH DESIGN AND METHODS We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed. RESULTS The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76–3.63] and 2.48 [1.79–3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16–0.72] and 0.48 [0.24–0.72]) and multiplicative (P = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70–6.72]) and an AP of 0.46 (0.12–0.80) compared with antibody-negative individuals with high n-3 PUFAs. CONCLUSIONS High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.
Tony Gershlick: pioneering cardiologist
Authors: John Illman
Journal: BMJ (2020)

Photo credit: British Heart Foundation

Tony Gershlick, professor at the University of Leicester, was at the forefront of cardiology research for more than 30 years, despite struggling at school with undiagnosed dyslexia and nearly failing to get into medical school.

He was the first UK cardiologist to undertake clinical vascular brachytherapy, and the first to implant both a drug eluting stent and a bioabsorbable stent. The UK lead for more than 10 international trials, he generated more than £3m (€3.3m; $4m) of research funding from bodies such as the British Heart Foundation, the National Institute for Health Research, and the Medical Research Council.

His friend and colleague, Nick Curzen, professor of interventional cardiology at the University of Southampton and president of the British Cardiovascular Intervention Society, said, “Tony was an outstanding interventional cardiologist and original thinker. He was a pioneer, both in terms of clinical advancement of the specialty, but especially in the area of original research.”

In 2017 Gershlick received the inaugural lifetime achievement award of the British Cardiovascular Intervention Society. He carried on working until he …
Origin of a Giant Sex Chromosome
Authors: Matthew A Conte, Frances E Clark, Reade B Roberts, Luohao Xu, Wenjing Tao, Qi Zhou, Deshou Wang, Thomas D Kocher
Journal: Molecular Biology and Evolution (2020)

Chromosome size and morphology vary within and among species, but little is known about the proximate or ultimate causes of these differences. Cichlid fish species in the tribe Oreochromini share an unusual giant chromosome that is ∼3 times longer than the other chromosomes. This giant chromosome functions as a sex chromosome in some of these species. We test two hypotheses of how this giant sex chromosome may have evolved. The first hypothesis proposes that it evolved by accumulating repetitive elements as recombination was reduced around a dominant sex determination locus, as suggested by canonical models of sex chromosome evolution. An alternative hypothesis is that the giant sex chromosome originated via the fusion of an autosome with a highly repetitive B chromosome, one of which carried a sex determination locus. We test these hypotheses using comparative analysis of chromosome-scale cichlid and teleost genomes. We find that the giant sex chromosome consists of three distinct regions based on patterns of recombination, gene and transposable element content, and synteny to the ancestral autosome. The WZ sex determination locus encompasses the last ∼105 Mb of the 134-Mb giant chromosome. The last 47 Mb of the giant chromosome shares no obvious homology to any ancestral chromosome. Comparisons across 69 teleost genomes reveal that the giant sex chromosome contains unparalleled amounts of endogenous retroviral elements, immunoglobulin genes, and long noncoding RNAs. The results favor the B chromosome fusion hypothesis for the origin of the giant chromosome.