tbuckley/cabot-search huggingface dataset:
Determination of a treatment response threshold for the Eosinophilic Esophagitis Endoscopic Reference Score
Authors: Cary C. Cotton, John T. Woosley, Susan E. Moist, Sarah J. McGee, Alina Iuga, Nicholas J. Shaheen, Evan S. Dellon
Journal: Endoscopy (2021)

Background Endoscopic features of eosinophilic esophagitis (EoE) are measured using the validated EoE Endoscopic Reference Score (EREFS); however, a threshold for treatment response has not been defined. We aimed to determine a cut-point for endoscopic response as measured by EREFS. Methods We performed a secondary analysis of a randomized clinical trial comparing budesonide slurry with swallowed fluticasone multidose inhaler for initial treatment of EoE. In the parent trial, EREFS was determined before and after treatment (score range 0–9), as were histologic findings and dysphagia symptoms. We performed tabular, flexible trend, and dependent mixture analyses of measures of treatment response to select the best clinical EREFS threshold. Results In the 111 included patients (mean age 39 years; 67 % male; 96 % white), an EREFS threshold of ≤ 2 was 80 % sensitive (95 % confidence interval [CI] 69 % to 88 %) and 83 % specific (95 %CI 67 % to 94 %) for histologic response (peak of &lt; 15 eosinophils per high-power field). Flexible trend analysis and dependent mixture modeling similarly suggested that a threshold of ≤ 2 best captured the correlation of EREFS with histologic and symptomatic measures. Dependent mixture modeling found near-total membership in the response class at EREFS of 0 or 1 and &gt; 75 % at EREFS of 2 or 3. Conclusions An EREFS of ≤ 2 was the best clinical threshold for endoscopic response to topical steroid treatment, and was consistent with clinical and histologic response. Therefore, future studies can report a binary outcome of endoscopic response when EREFS is 2 or less.
Efficacy and Safety of CyberKnife Stereotactic Radiosurgery in Acromegaly
Authors: Desiree Seguna, Scott Akker, James Ahlquist, Aparna Pal, Antonia Brooke, Rachel Lewis, P N Plowman, Jane Evanson, Pratistha Panday, William Martyn Drake
Journal: Neuro-Oncology (2021)

Abstract Aims Objective: Active acromegaly is associated with increased mortality. While surgery is the mainstay of treatment, it is not always curative. In selected cases, CyberKnife stereotactic radiosurgery (CK SRS) can be used as adjuvant treatment in patients with persistent disease. Method Methodology: Biochemical response was measured using serum IGF-1 levels, calculated as a percentage of the upper limit of normal (% ULN). Levels were recorded prior to treatment, at 6-12 months post-treatment and at the most recent follow-up. Anterior pituitary hormone deficits were assessed before and after treatment. Tumour size was followed-up using MRI. Results 10 patients (7 male, mean age 36 yrs [+/- 12.6, SD]) with acromegaly were treated with CK SRS. 9 were treated following failure to attain biochemical remission with TSS. 1 had primary CK SRS. 2 had previous conventional fractionated external beam radiotherapy. Median tumour diameter was 6 mm (IQR 5.2-10.5 mm), with cavernous sinus invasion in 2 cases. The dose was 20-24Gy/1#. 4 patients were on dopamine agonist, 4 on somatostatin analogue and 2 on pegvisomant. Mean follow-up 31.6 months (+/- 13.5 months, SD). Median IGF-1 % ULN was 146% pre-treatment (IQR 126.5-208.5), 109% at 6-12 months (IQR 76.5-131%) and 71% (IQR 59-91%) at last follow-up. Mean radiological follow-up 16.6 months (+/- 15.9 months, SD). No cases showed tumour enlargement. One patient developed secondary hypothyroidism. Side-effects: headache (7 patients), blurred vision (1 patient), fatigue/nausea (1 patient). No new visual fields defects, cranial nerve palsies, cerebrovascular events or secondary tumours. Conclusion Conclusions: CK SRS appears safe and effective in selected patients with acromegaly, when there is failure to attain biochemical cure with surgery and in patients intolerant or resistant to medical treatment.
Myofilament Phosphorylation in Stem Cell Treated Diastolic Heart Failure
Authors: Daniel Soetkamp, Romain Gallet, Sarah J. Parker, Ronald Holewinski, Vidya Venkatraman, Kiel Peck, Joshua I. Goldhaber, Eduardo Marbán, Jennifer E. Van Eyk
Journal: Circulation Research (2021)

Rationale: Phosphorylation of sarcomeric proteins has been implicated in heart failure with preserved ejection fraction (HFpEF); such changes may contribute to diastolic dysfunction by altering contractility, cardiac stiffness, Ca 2+ -sensitivity, and mechanosensing. Treatment with cardiosphere-derived cells (CDCs) restores normal diastolic function, attenuates fibrosis and inflammation, and improves survival in a rat HFpEF model. Objective: Phosphorylation changes that underlie HFpEF and those reversed by CDC therapy, with a focus on the sarcomeric subproteome were analyzed. Methods and Results: Dahl salt–sensitive rats fed a high-salt diet, with echocardiographically verified diastolic dysfunction, were randomly assigned to either intracoronary CDCs or placebo. Dahl salt–sensitive rats receiving low salt diet served as controls. Protein and phosphorylated Ser, Thr, and Tyr residues from left ventricular tissue were quantified by mass spectrometry. HFpEF hearts exhibited extensive hyperphosphorylation with 98% of the 529 significantly changed phospho-sites increased compared with control. Of those, 39% were located within the sarcomeric subproteome, with a large group of proteins located or associated with the Z-disk. CDC treatment partially reverted the hyperphosphorylation, with 85% of the significantly altered 76 residues hypophosphorylated. Bioinformatic upstream analysis of the differentially phosphorylated protein residues revealed PKC as the dominant putative regulatory kinase. PKC isoform analysis indicated increases in PKC α, β, and δ concentration, whereas CDC treatment led to a reversion of PKCβ. Use of PKC isoform specific inhibition and overexpression of various PKC isoforms strongly suggests that PKCβ is the dominant kinase involved in hyperphosphorylation in HFpEF and is altered with CDC treatment. Conclusions: Increased protein phosphorylation at the Z-disk is associated with diastolic dysfunction, with PKC isoforms driving most quantified phosphorylation changes. Because CDCs reverse the key abnormalities in HFpEF and selectively reverse PKCβ upregulation, PKCβ merits being classified as a potential therapeutic target in HFpEF, a disease notoriously refractory to medical intervention.
Ambulances queue outside A&amp;Es as 999 calls pile up
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Ambulance services in England are struggling to cope with huge numbers of calls, as crowded hospitals are unable to take patients and queues of ambulances waiting outside emergency departments have become an everyday occurrence.

The Association of Ambulance Chief Executives has said that every ambulance service in England is now at the highest level of alert, and paramedics have warned that services are regularly holding up to 300 calls at a time when no ambulances are available.

In September, 2.1 million people attended emergency departments—the highest figure ever recorded for that month—and calls to ambulance services for category one incidents (life threatening injuries and illnesses, such as cardiac arrest) increased by 36.5% compared with September 2019.1

Under this pressure, ambulance services missed the average …
P62.06 A Radiomics Nomogram for Preoperative Prediction of Occult Lymph Node Metastasis in Early-Stage Solid Lung Adenocarcinoma
Authors: R. Zhang, R. Zhang, T. Luan, B. Liu, Y. Zhang, Y. Xu, X. Sun, L. Xing
Journal: Journal of Thoracic Oncology (2021)
P60.09 Real-World Readiness of US Laboratories to Test Metastatic NSCLC Patients for Rare Actionable Genomic Variants by NGS
Authors: J. Sornkom, P. Cirillo, M. Hoefsmit, D. Keeling, L. Replogle, S. Munksted, J. Clark, R. Keeling, P. Riccelli
Journal: Journal of Thoracic Oncology (2021)
P47.05 A Phase 2 Study of Datopotamab Deruxtecan (Dato-DXd) in Advanced NSCLC With Actionable Genomic Alterations (TROPION-Lung05)
Authors: M. Johnson, A. Spira, K. Yoh, R. Heist, A. Lisberg, J. Greenberg, P. Phillips, F. Guevara, W. Gu, Y. Zhang, J. Sands
Journal: Journal of Thoracic Oncology (2021)
MA09.01 LCMC3: Immune Cell Subtypes Predict Nodal Status and Pathologic Response After Neoadjuvant Atezolizumab in Resectable NSCLC
Authors: F. Oezkan, M. Seweryn, M. Pietrzak, W.Y. Byun, D. Owen, K. Schulze, A. Nicholas, S. Hilz, J. Grindheim, A. Johnson, D. Kwiatkowski, I. Wistuba, B. Johnson, M. Kris, V. Rusch, J. Lee, G. Lozanski, D. Carbone
Journal: Journal of Thoracic Oncology (2021)
Maternal SARS-CoV-2 infection elicits sexually dimorphic placental immune responses
Authors: Evan A. Bordt, Lydia L. Shook, Caroline Atyeo, Krista M. Pullen, Rose M. De Guzman, Marie-Charlotte Meinsohn, Maeva Chauvin, Stephanie Fischinger, Laura J. Yockey, Kaitlyn James, Rosiane Lima, Lael M. Yonker, Alessio Fasano, Sara Brigida, Lisa M. Bebell, Drucilla J. Roberts, David Pépin, Jun R. Huh, Staci D. Bilbo, Jonathan Z. Li, Anjali Kaimal, Danny J. Schust, Kathryn J. Gray, Douglas Lauffenburger, Galit Alter, Andrea G. Edlow
Journal: Science Translational Medicine (2021)

Maternal SARS-CoV-2 infection drives sexually dimorphic placental immune responses and reduces SARS-CoV-2–specific antibody transfer to male fetuses.
Green space and mortality in European cities: a health impact assessment study
Authors: Evelise Pereira Barboza, Marta Cirach, Sasha Khomenko, Tamara Iungman, Natalie Mueller, Jose Barrera-Gómez, David Rojas-Rueda, Michelle Kondo, Mark Nieuwenhuijsen
Journal: The Lancet Planetary Health (2021)

Natural outdoor environments including green spaces play an important role in preserving population health and wellbeing in cities, but the number of deaths that could be prevented by increasing green space in European cities is not known. We aimed to estimate the number of natural-cause deaths among adult residents that could be prevented in cities in 31 European countries, if the WHO recommendation for universal access to green space was achieved.In this health impact assessment study we focused on adult residents (aged ≥20 years; n=169 134 322) in 978 cities and 49 greater cities, in 31 European countries. We used two green space proxies: normalised difference vegetation index (NDVI), and percentage of green area (%GA). The exposure was estimated at a fine grid-cell level (250 m × 250 m) and the preventable mortality burden for 2015 was estimated at the local city-level.For 2015 we found that meeting the WHO recommendation of access to green space could prevent 42 968 (95% CI 32 296-64 177) deaths annually using the NDVI proxy (ie, 20% [95% CI 15-30] of deaths per 100 000 inhabitants-year), which represents 2·3% (95% CI 1·7-3·4) of the total natural-cause mortality and 245 (95% CI 184-366) years of life lost per 100 000 inhabitants-year. For the %GA proxy 17 947 (95%CI 0-35 747) deaths could be prevented annually. For %GA the number of attributable deaths were half of that of the NDVI and results were non-significant due to the exposure response function considered. The distribution of NDVI and %GA varied between cities and was not equally distributed within cities. Among European capitals, Athens, Brussels, Budapest, Copenhagen, and Riga showed some of the highest mortality burdens due to the lack of green space. The main source of uncertainty for our results was the choice of the age-structures of the population for the NDVI analysis, and exposure-response function for the %GA analysis.A large number of premature deaths in European cities could be prevented by increasing exposure to green space, while contributing to sustainable, liveable and healthy cities.GoGreenRoutes, Internal ISGlobal fund, and the United States Department of Agriculture Forest Service.
Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial
Authors: Joël Guigay, Keun-Wook Lee, Manish R Patel, Amaury Daste, Deborah J Wong, Sanjay Goel, Michael S Gordon, Martin Gutierrez, Ani Balmanoukian, Christophe Le Tourneau, Alain Mita, Damien Vansteene, Ulrich Keilholz, Patrick Schöffski, Hans Juergen Grote, Dongli Zhou, Marcis Bajars, Nicolas Penel
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial ( NCT01772004 ). Methods Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. Results Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0–6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. Conclusion Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.
Temozolomide hypersensitivity – A story of success
Authors: Lanka Alagiyawanna, Stephanie Prince, Debbie Wright, Enrico Clarke, Jeng Ching
Journal: Neuro-Oncology (2021)

Abstract Aims Background: Temozolomide is an oral chemotherapy drug widely used in the treatment of glial tumours. This is generally well tolerated however, immediate and delayed hypersensitivity reactions have been described, necessitating treatment interruption that could significantly impact survival. Method Case description: We report a case of a 39-year-old young woman with WHO grade 2 IDH1mutant diffuse astrocytoma (MGMT promoter methylated) of the left temporal lobe. She had tumour resection in 2012 followed by radical radiotherapy. Afterwards, she had close surveillance with regular brain imaging. The tumour started to progress in early 2020. We agreed to commence on temozolomide to control tumour growth. She developed an itchy rash with easy bruising towards the end of the first cycle. It responded to a course of prednisolone. We proceeded with the second cycle and she developed a worsening rash on the third day. However she did not have signs or symptoms of anaphylaxis. This episode was again managed by a course of steroids and oral antibiotics. Since Temozolomide was the optimal treatment to control the disease progression at this stage, we agreed to persevere with temozolomide using a rapid desensitisation protocol. Results On the first day of third cycle, she was brought to the day chemotherapy unit and given prednisolone 30mg, fexofenadine 180mg and ondansetron 8mg, 30 minutes before the treatment. Our protocol was as follows; 5mg, 10mg, 20mg, 30mg, 50mg and 90mg of temozolomide at an interval of 30 minutes between the doses. She was advised to follow the same regime for the next four days of the third cycle. On days 6 -28, she has been advised to take fexofenadine 180mg once daily. Although there was a minor rash appeared on days 6/7, they subsided gradually. She tolerated the treatment without sinister symptoms or signs. We proceeded with the next 4 chemotherapy cycles adhering to the same protocol. The intensity of the rash gradually improved, and she became almost completely asymptomatic by the 7th cycle. It was also encouraging to see the radiological response of the tumour with the treatment. Conclusion Although the published literature is minimal, rapid desensitisation is shown to be a safe and effective method to counteract temozolomide hypersensitivity. In an era where there is still a paucity of systemic treatment options for primary brain tumours, adopting rapid desensitisation to induce tolerability to temozolomide, a drug which has shown to improve survival, would be a valuable addition in managing our patients. Further, our experience suggests that this protocol is safe, effective, and does not necessitate inpatient admission.
MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas
Authors: Qiang-Wei Wang, Li-Hua Sun, Ying Zhang, Zheng Wang, Zheng Zhao, Zhi-Liang Wang, Kuan-Yu Wang, Guan-Zhang Li, Jian-Bao Xu, Chang-Yuan Ren, Wen-Ping Ma, Hong-Jun Wang, Shou-Wei Li, Yong-Jian Zhu, Tao Jiang, Zhao-Shi Bao
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background Dysregulated receptor tyrosine kinases, such as the mesenchymal-epidermal transition factor (MET), have pivotal role in gliomas. MET and its interaction with the tumor microenvironment have been previously implicated in secondary gliomas. However, the contribution of MET gene to tumor cells’ ability to escape immunosurveillance checkpoints in primary gliomas, especially in glioblastoma (GBM), which is a WHO grade 4 glioma with the worst overall survival, is still poorly understood. Methods We investigated the relationship between MET expression and glioma microenvironment by using multiomics data and aimed to understand the potential implications of MET in clinical practice through survival analysis. RNA expression data from a total of 1243 primary glioma samples (WHO grades 2–4) were assembled, incorporating The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and GSE16011 data sets. Results Pearson’s correlation test from the three data sets indicated that MET showed a robust correlation with programmed death-ligand 1 ( PD-L1 ) and STAT pathways. Western blot analysis revealed that in GBM cell lines (N33 and LN229), PD-L1 and phosphorylated STAT4 were upregulated by MET activation treatment with hepatocyte growth factor and were downregulated on MET suppression by PLB-1001. Tumor tissue microarray analysis indicated a positive correlation between MET and PD-L1 and macrophage-associated markers. Chromatin immunoprecipitation-PCR assay showed enrichment of STAT4 in the PD-L1 DNA. Transwell co-culture and chemotaxis assays revealed that knockdown of MET in GBM cells inhibited macrophage chemotaxis. Moreover, we performed CIBERSORTx and single-cell RNA sequencing data analysis which revealed an elevated number of macrophages in glioma samples with MET overexpression. Kaplan-Meier survival analysis indicated that activation of the MET/STAT4/PD-L1 pathway and upregulation of macrophages were associated with shorter survival time in patients with primary GBM. Conclusions These data indicated that the MET-STAT4-PD-L1 axis and tumor-associated macrophages might enforce glioma immune evasion and were associated with poor prognosis in GBM samples, suggesting potential clinical strategies for targeted therapy combined with immunotherapy in patients with primary GBM.
Targeting KDM6A Suppresses SREBP1c-Dependent Lipid Metabolism and Prostate Tumorigenesis
Authors: Donge Tang, Yong Dai, Songhui Xu
Journal: Cancer Research (2021)

The histone demethylase KDM6A controls gene expression by the epigenetic regulation of H3K27 methylation and functions in diverse processes, including differentiation, development, and cancer. Here, we investigated the role of KDM6A in prostate cancer. Specific deletion of KDM6A in the adult mouse prostate epithelium strongly inhibited tumor progression initiated by the loss of PTEN. Mechanistically, KDM6A promoted prostate tumorigenesis and lipid metabolism by binding to the SREBP1c promoter to increase SREBP1c transcription. USP7 deubiquitinated KDM6A to increase its expression. KDM6A was significantly upregulated in prostate cancer and positively associated with USP7 expression. Furthermore, targeting KDM6A stability by inhibiting USP7 in conditional knockout mice and xenograft models markedly suppressed prostate cancer growth and significantly enhanced KDM6A inhibitor efficacy. Collectively, these findings indicate that KDM6A regulates prostate lipid metabolism and is essential for prostate tumorigenesis initiated by PTEN loss. Targeting USP7/KDM6A could be a valuable strategy to ameliorate prostate cancer progression and therapeutic resistance. SIGNIFICANCE: These findings show that KDM6A supports prostate tumorigenesis by promoting SREBP1c-mediated lipid metabolism, proposing targeting the USP7/KDM6A axis as a therapeutic strategy for treating prostate cancer.
Lymph node–resident dendritic cells drive T <sub>H</sub> 2 cell development involving MARCH1
Authors: Carlos A. Castellanos, Xin Ren, Steven Lomeli Gonzalez, Hong Kun Li, Andrew W. Schroeder, Hong-Erh Liang, Brian J. Laidlaw, Donglei Hu, Angel C.Y. Mak, Celeste Eng, José R. Rodríguez-Santana, Michael LeNoir, Qi Yan, Juan C. Celedón, Esteban G. Burchard, Scott S. Zamvil, Satoshi Ishido, Richard M. Locksley, Jason G. Cyster, Xiaozhu Huang, Jeoung-Sook Shin
Journal: Science Immunology (2021)

Type 2 T helper (T
Abstract 11200: Caregivers Experience With Difficult Decision Making in End-of-life Care of Patients Admitted for Cardiovascular Diseases
Authors: Shinada Keitaro, Takashi Kohno, Keiichi Fukuda, Michiaki Higashitani, Naoto Kawamatsu, Takeshi Kitai, Tatsuhiro Shibata, Makoto Takei, Kotaro Nochioka, Gaku Nakazawa, Hiroki Shiomi, Mitsunori Miyashita, Atsushi Mizuno
Journal: Circulation (2019)

Introduction: The difficult decisions encountered by caregivers in the end-of-life care of patients with cardiovascular diseases (CVD) are rarely studied. The aims of this study were 1) to evaluate...