tbuckley/cabot-search huggingface dataset:
Progress in cardiac research: from rebooting cardiac regeneration to a complete cell atlas of the heart
Authors: Sean M Davidson, Teresa Padró, Sveva Bollini, Gemma Vilahur, Dirk J Duncker, Paul C Evans, Tomasz Guzik, Imo E Hoefer, Johannes Waltenberger, Johann Wojta, Christian Weber
Journal: Cardiovascular Research (2021)

Abstract We review some of the important discoveries and advances made in basic and translational cardiac research in 2020. For example, in the field of myocardial infarction (MI), new aspects of autophagy and the importance of eosinophils were described. Novel approaches, such as a glycocalyx mimetic, were used to improve cardiac recovery following MI. The strategy of 3D bio-printing was shown to allow the fabrication of a chambered cardiac organoid. The benefit of combining tissue engineering with paracrine therapy to heal injured myocardium is discussed. We highlight the importance of cell-to-cell communication, in particular, the relevance of extracellular vesicles, such as exosomes, which transport proteins, lipids, non-coding RNAs, and mRNAs and actively contribute to angiogenesis and myocardial regeneration. In this rapidly growing field, new strategies were developed to stimulate the release of reparative exosomes in ischaemic myocardium. Single-cell sequencing technology is causing a revolution in the study of transcriptional expression at cellular resolution, revealing unanticipated heterogeneity within cardiomyocytes, pericytes and fibroblasts, and revealing a unique subpopulation of cardiac fibroblasts. Several studies demonstrated that exosome- and non-coding RNA-mediated approaches can enhance human induced pluripotent stem cell (iPSC) viability and differentiation into mature cardiomyocytes. Important details of the mitochondrial Ca2+ uniporter and its relevance were elucidated. Novel aspects of cancer therapeutic-induced cardiotoxicity were described, such as the novel circular RNA circITCH, which may lead to novel treatments. Finally, we provide some insights into the effects of SARS-CoV-2 on the heart.
HGG-21. MALIGNANT SYNAPTIC PLASTICITY IN PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Kathryn Taylor, Tara Barron, Griffin Hartmann, Helena Zhang, Alexa Hui, Shawn Gillespie, Michelle Monje
Journal: Neuro-Oncology (2021)

Abstract Pediatric high-grade gliomas (pHGG) are a devastating group of diseases that urgently require novel therapeutic options. We have previously demonstrated that pHGGs directly synapse onto neurons and the subsequent tumor cell depolarization, mediated by calcium-permeable AMPA channels, promotes their proliferation. The regulatory mechanisms governing these postsynaptic connections are unknown. Here, we investigated the role of BDNF-TrkB signaling in modulating the plasticity of the malignant synapse. BDNF ligand activation of its canonical receptor, TrkB (which is encoded for by the gene NTRK2), has been shown to be one important modulator of synaptic regulation in the normal setting. Electrophysiological recordings of glioma cell membrane properties, in response to acute neurotransmitter stimulation, demonstrate in an inward current resembling AMPA receptor (AMPAR) mediated excitatory neurotransmission. Extracellular BDNF increases the amplitude of this glutamate-induced tumor cell depolarization and this effect is abrogated in NTRK2 knockout glioma cells. Upon examining tumor cell excitability using in situ calcium imaging, we found that BDNF increases the intensity of glutamate-evoked calcium transients in GCaMP6s expressing glioma cells. Western blot analysis indicates the tumors AMPAR properties are altered downstream of BDNF induced TrkB activation in glioma. We find that BDNF-TrkB signaling promotes neuron-to-glioma synaptogenesis as measured by high-resolution confocal and electron microscopy in culture and tumor xenografts. Our analysis of published pHGG transcriptomic datasets, together with brain slice conditioned medium experiments in culture, indicate the tumor microenvironment as the chief source of BDNF ligand. Disruption of the BDNF-TrkB pathway in patient-derived orthotopic glioma xenograft models, both genetically and pharmacologically, results in an increased overall survival and reduced tumor proliferation rate. These findings suggest that gliomas leverage mechanisms of plasticity to modulate the excitatory channels involved in synaptic neurotransmission and they reveal the potential to target the regulatory components of glioma circuit dynamics as a therapeutic strategy for these lethal cancers.
Can radiomics combined with clinical data predict checkpoint inhibitor pneumonitis?
Authors: Christopher Montoya, Benjamin Spieler, Alan Dal Pra, Tejan Diwanji, Raphael Yechieli, Gilberto Lopes, Ivaylo Mihaylov
Journal: Journal of Clinical Oncology (2021)

e14555 Background: Immunotherapy (ImT) is increasingly utilized in patients with advanced non-small cell lung cancer (aNSCLC). Checkpoint-inhibitor pneumonitis (CIP) is an uncommon and potentially life-threatening adverse event (AE) associated with ImT. For patients with aNSCLC, CIP signs and symptoms can be misclassified in the setting of underlying lung disease and incidence may be underreported. The ability to identify patients at risk for CIP prior to ImT could prevent significant morbidity. Previously, we reported that radiomics, a datamining technique that extracts patterns from medical imaging, had identified texture features on pre-ImT CT that correlate with CIP. In this study, we hypothesized that such features combined with clinical data can predict CIP. Methods: In an IRB-approved database of 129 patients with aNSCLC treated with nivolumab, 9 controls were identified with clinical diagnosis of CIP. For all patients, uninvolved lung in the last pre-ImT CT was mined for textures associated with CIP. In the 9 controls, 3 features were identified that correlated with CIP. Imaging and patient charts were reviewed for signs and symptoms of CIP within the first 6 months after ImT administration. Non-controls with progressive clinical symptoms or radiographic findings consistent with CIP and unexplained by disease progression, infection or other medical interventions were treated as CIP-positives. Lastly, the area under the receiver operating curve (AUC) for predicting CIP was built progressively combining uncorrelated laboratory, imaging, and clinical data. Results: In all, 25 patients (19%) were identified with any-grade CIP. A model based on pre-ImT platelets (PLT) and neutrophil-to-lymphocyte ratio (NLR) had an AUC for predicting CIP of 0.648. The radiomics features associated with CIP were average gray value (p = .002), 3D normalized entropy (p = 0.022), and kurtosis (p = 0.011). When combined these 3 features had an AUC of 0.735. Combining both radiomics and laboratory data produced an AUC of 0.779. This increased to 0.793 with the addition of ECOG performance status and sex. Finally, incorporating smoking status yielded an AUC of 0.802. Paired sample difference in AUC between the final model and that including only PLT and NLR was significant (p = 0.003). Conclusions: In patients with aNSCLC treated with ImT, CIP is an uncommon but potentially serious AE. The ability to identify patients at higher risk for CIP could prevent significant morbidity. A model combining radiomics of pre-ImT imaging, laboratory, and clinical data showed better prediction for CIP than laboratory data alone. Future directions include validation of this model on an external cohort and with patients on different ImT regimens.
The upper temperature thresholds of life
Authors: Senthold Asseng, Dietrich Spänkuch, Ixchel M Hernandez-Ochoa, Jimena Laporta
Journal: The Lancet Planetary Health (2021)

Temperature affects many life processes, but its effect might be expected to differ among eukaryotic organisms inhabiting similar environments. We reviewed literature on temperature thresholds of humans, livestock, poultry, agricultural crops, and sparse examples of fisheries. We found that preferable and harmful temperatures are similar for humans, cattle, pigs, poultry, fish, and agricultural crops. Preferable temperatures range from 17°C to 24°C. Stress temperature thresholds are lower when humidity is higher. However, extended exposure to temperatures above 25°C with high humidity can cause heat stress in many organisms. Short exposures to temperatures above 35°C with high humidity, or above 40°C with low humidity, can be lethal. Increases in exposure, frequency, and duration of stressful and lethal temperatures increase the physiological stress and bodily damage suffered by humans, livestock, poultry, fish, and agricultural crops.
Analysis of RNA editing enzymes in malignancy.
Authors: A. Samee, A. Joseph, S. Pountain, I. Siddiqui, M. Deakin, J. Elder, P. Hoban
Journal: Cancer Research (2007)

5350  Introduction:   Genetic aberration to tumour suppressor genes and oncogenes, that regulate cellular proliferation, differentiation and apoptosis, is a key step in cancer progression. It is becoming increasingly evident however that disruption to processes involved in post-transcriptional modification of genes (mRNA splicing and RNA editing) may also contribute to tumourigenisis. The RNA editing enzymes ADAR, ADAR2 and ADAT1 are involved in site-specific base modification of Adenosine to Inosine (A-I) in primary mRNA transcripts and contribute to the fidelity of protein translation. Alterations in A-I editing have been demonstrated in peripheral nerve sheath tumours and malignant gliomas, however its role in cancer progression remains poorly studied. In this study, we have investigated the expression of the RNA editing enzymes ADAR, ADAR2 and ADAT1 in cancer.  Methods:  ADAR, ADAR2 (ADARB1) and ADAT1 expression was determined in 10 cancer cell lines and a panel of colorectal tumours and normal colon mucosa from 50 colorectal cancer patients (recruited under the LREC approval). RNA was extracted from snap-frozen tissue and RT- PCR was used to determine relative expression compared to a housekeeping gene. Real-time PCR was then used to quantitate expression levels of the genes.  Results:  RNA editing enzymes were found to be expressed to different levels in the cancer cell lines examined including those derived from gastrointestinal, ovarian, and vulval carcinoma, a leukaemia, osteosarcoma and a fibrosarcoma cell line. In these cell lines, real time PCR analysis using a relative quantification method, in which expression was normalised to normal colon tissue, revealed from 2-40 fold increase in the quantity of mRNA for ADAR and ADAT1 enzymes in 7 out of 10 cell lines. In contrast the expression of ADAR2 was comparatively lower, up to 12- fold increase in expression in 5 out of 10 of the cell lines examined.  We further found that while the levels of ADAT1 in normal colonic mucosa were low, it was found to be over expressed in 32% of the tumour samples (n=16/50). Real time PCR demonstrated a range of over expression from 2-26-fold increase of ADAT1 expression in tumour when compared to corresponding matched normal tissue in these 16 pairs.  Conclusion:  Our preliminary data suggest a role for deregulated expression of some of the RNA editing enzymes during tumourigenisis. Our future work will focus in investigating the mechanisms and consequences of such deregulated expression of these genes in cancer and examine whether such deregulated expression contributes to the development of malignant phenotype.
David Bruce Bamber
Authors: H G C Bradfield
Journal: BMJ (2021)

David Bamber was an anaesthetist at Charing Cross Hospital, later part of the Imperial College Healthcare NHS Trust, for more than 30 years.

He was born in Preston, the only child of William Gardner Bamber and Ada Margaret Jackson, who married in 1937. His father served in the Royal Navy during the second world war, on minesweepers as part of the “Russian Run” convoys. He was discharged because of ill health in 1942 and died in 1945 from tuberculosis.

David was educated as a boarder from the age of 8 at the Royal Masonic School in Bushey, Hertfordshire, gaining the necessary examination results for entry to medical school, as well as excelling in sport. He …
A phase II study of anlotinib plus whole brain radiation therapy (WBRT) for advanced non-small cell lung cancer with multiple brain metastases.
Authors: Xiangzhi Zhu, Hua Tao, Ming Jiang, Meiqi Shi, Cheng Kong, Xue Song, Nan Zhang, Cheng Chen, Ning Jiang, Lijun Zhao, Pengwei Yan, Xia He
Journal: Journal of Clinical Oncology (2021)

e21063 Background: The prognosis of non-small-cell lung cancer (NSCLC) patients(pts) with multiple brain metastases is poor. WBRT is the main treatment for the pts, but QUARTZ study showed that the efficacy of WBRT is unsatisfactory. The synergistic effect of the antiangiogenic therapy with radiation therapy has been well established. Anlotinib, an antiangiogenic multi-target TKI, had significantly improved progression-free survival (PFS) of advanced NSCLC with Brain Metastases. This study aimed to evaluate the efficacy and safety of anlotinib combined with WBRT in pts with brain metastases ( &gt; 3) from advanced NSCLC. Methods: Advanced NSCLC pts with brain metastases ( &gt; 3) who were histologically confirmed to be driver gene wild type or positive and pts who had received two or more previous treatments were eligible. Pts with meningeal metastasis were excluded. All pts were treated with anlotinib (12 mg, QD, day 1 to 14 of a 21-day cycle) combined with WBRT (DT 30Gy/12f), followed by maintenance therapy with anlotinib until disease progression or treatment intolerance. The primary endpoint was intracranial progression-free survival (iPFS). Secondary endpoints were extracranial PFS (ePFS), OS and toxicity. Results: As of 25 Jan 2021, 28 pts were enrolled. The median age was 57.5 years with 46.4% male. 89.3% of pts with adenocarcinoma. 21.4% pts harbored EGFR mutation. A total of 25 pts were included in efficacy analysis. In intracranial evaluation, ORR was 64.0%, DCR was 88.0%, median iPFS was 11.1 months (95% CI 5.9 to 12.1). In extracranial evaluation, ORR was 12.0%, DCR was 84.0%, median ePFS was 6.0months (95% CI 3.2 to 8.8). Most common grade 1-2 adverse events (AEs) were hypertension (67.8%), fatigue (64.2%)，anorexia (46.4%) and hand and foot skin reaction (37.5%). The most common grade 3-4 AEs were hypertension (12.5%), hand and foot skin reaction (10.7%) and fatigue (7.2%). No intracranial hemorrhage occurred during treatment. Dose adjustment due to AE occurred in 21.4% patients. Conclusions: This prospective study shows that the combination of anlotinib and WBRT for patients with multiple brain metastases after standard treatment resistance exhibited an effective therapeutic approach and manageable AEs. For further investigation, large sample and additional clinical trials are warranted. Clinical trial information: ChiCTR1900022093.
Cost-efficiency analysis of conversion from reference pegfilgrastim to its biosimilar (pegfilgrastim-jmdb) and expanded access to food and transportation support for Medicare/Medicaid patients within the CMS Oncology Care Model.
Authors: Karen MacDonald, Neda AlRawashdh, Ali McBride, Ivo Abraham
Journal: Journal of Clinical Oncology (2021)

e18837 Background: The CMS Oncology Care Model (OCM) aims to improve quality of care and health outcomes in cancer centers at the same or lower cost. We performed cost-efficiency analyses of converting selected cancer patients (pts) from reference pegfilgrastim (PFG) to its biosimilar (PFG-jmdb); and simulated re-allocating savings to provide nutrition and transportation support to CMS beneficiaries within OCM. Methods: Incidence rates for breast, ovarian, lung, colorectal cancers and non-Hodgkin lymphoma were extracted from SEER, further stratified by age &lt;65 (commercial insurance) or &gt;65 (Medicare) adjusted for Medicare/Medicaid mix. Chemotherapy (CTX) rates were matched to tumor type; of these 19.4% were assumed to require PFG prophylaxis (PPX). Two models compared respectively prefilled syringe (PFS) and on-body injector (OBI) reference PFG to PFS PFG-jmdb. Cost inputs included Average Sales Price (ASP) 3Q20 for Medicare and National Average Drug Acquisition Cost (NADAC, estimated by wholesale acquisition cost (WAC)-3.9%) for Medicaid pts plus medication administration. Cost savings across various biosimilar conversion rates for CTX cycles 1-6 were translated into $100 units of healthy food or medical transportation. Results: In 2020, biosimilar conversion for the estimated 31,210 Medicare and 1,722 Medicaid pts in the 5 tumor types needing PFG PPX yielded savings of up to ̃$19M (Medicare) and ̃$20M (Medicaid). These savings could have provided a monthly $100 food or transportation check to at least 24,716 Medicare or 33,630 Medicaid pts for 6 months. Conclusions: Savings from biosimilar conversion can be re-allocated on a budget neutral basis to food and transportation support to pts with such needs. This achieves the dual OCM aim of reducing drug budgets while enhancing patient-centric support services.[Table: see text]
Efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCH-P) in HER2-positive breast cancer: An Indian experience.
Authors: Ajay Gogia, Shalabh Arora, SVS Deo, Sandeep Mathur, Dayanand Sharma
Journal: Journal of Clinical Oncology (2021)

e12619 Background: Dual targeted therapy with chemotherapy is one of the therapeutic approaches as neoadjuvant treatment in HER2/neu positive breast cancer (BC). However the safety and efficacy data of dual-targeted, chemotherapy regimen (docetaxel, carboplatin, trastuzumab, &amp; pertuzumab [TCH-P] is limited from the Indian subcontinent. Methods: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH-P regimen in early, locally advanced, and oligometastatic (OM) HER2-positive BC, at All India Institute of Medical Sciences, New Delhi, India, in between the period 2015-2020. Total 6 cycles of 3-weekly neoadjuvant chemotherapy (NACT) protocol containing docetaxel (75 mg/m2), carboplatin (AUC = 6), trastuzumab (8 mg/kg loading followed by 6 mg/kg) and pertuzumab ( 840 mg loading followed by 420 mg) were planned. Subcutaneous peg-filgrastim was prophylactically administered on day 2 of each cycle. The primary outcome was the pathological complete response (pCR), which was defined as an absence of invasive and noninvasive cancer in breast or lymph node and secondary outcome were clinical overall response rate (ORR), rate of breast conservation surgery( BCS) for patients for whom modified radical mastectomy( MRM)was planned and toxicity. Results: Forty-five patients with a median age of 48 years (31-65) were included in this study. The TNM (AJCC-7th edition) stage distribution was stage II, 14 (31.1%); stage III, 29 (64.5%); and stage IV (OM), 2 (4.4%). Clinical node positivity disease was found in 26 (57.8%) cases. Nineteen (42.2%) patients had hormone-positive and 26(57.8%) cases were premenopausal. The clinically ORR and CR were seen in 100% and 60% respectively. Overall pCR rate was observed in 25 (55.6%) patients (70% in stage II). BCS was performed in 23(51.1%) cases. In 12(26.6%) cases, planned MRM was changed to BCS following NACT. Grade 3 and 4 toxicities were diarrhea 7 cases, thrombocytopenia in 6, neutropenia in 4, febrile neutropenia in 1, and anemia in 2 cases. Ten patients required dose modification and interruption. No patient had congestive heart failure or induction death. Conclusions: This is the first study of the non-anthracycline-based neoadjuvant protocol in HER2 positive BC from India. The TCH-P is an effective, safe, and well-tolerated, protocol with a path CR rate of 55.6% and 26.6% BCS conversion rate from planned MRM.
Development and characterization of a HCMV multiantigen therapeutic vaccine for GBM using the UNITE platform.
Authors: Amit Adhikari, Juliete Macauley, Yoshimi Johnson, Mike Connolly, Tim Coleman, Teri Heiland
Journal: Journal of Clinical Oncology (2021)

e14565 Background: Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months which has remained unchanged despite technological advances in the standard of care. GBM cells specifically express human cytomegalovirus (HCMV) proteins providing a unique opportunity for targeted therapy. Methods: We utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to develop a multi-antigen DNA vaccine (ITI-1001) that codes for the HCMV proteins- pp65, gB and IE-1. The UNITE platform involves lysosomal targeting technology, fusing lysosome-associated protein 1 (LAMP1) with target antigens resulting in increased antigen presentation by MHC-I and II. ELISpot, flow cytometry and ELISA techniques were used to evaluate the vaccine immunogenicity and a syngeneic, orthotopic GBM mouse model that expresses HCMV proteins was used for efficacy studies. The tumor microenvironment studies were done using flow cytometry and MSD assay. Results: ITI-1001 vaccination showed a robust antigen-specific CD4 and CD8 T cell response in addition to a strong humoral response. Using GBM mouse model, therapeutic treatment of ITI-1001 vaccine resulted in ̃56% survival with subsequent long-term immunity. Investigating the tumor microenvironment showed significant CD4 T cell infiltration as well as enhanced Th1 and CD8 T cell activation. Regulatory T cells were also upregulated upon ITI-1001 vaccination and would be an attractive target to further improve this therapy. In addition, tumor burden negatively correlated with number of activated CD4 T cells (CD4 IFNγ+) reiterating the importance of CD4 activation in ITI-1001 efficacy and potentially identifying treatment responders and non-responders. Further characterization of these two groups showed high infiltration of CD3+, CD4+ and CD8+ T cells in responders compared with non- responders along with higher CD8 T cell activation. Conclusions: Thus, we show that vaccination with HCMV antigens using the ITI-1001-UNITE platform generates strong cellular and humoral immune responses, triggering significant anti-tumor activity that leads to enhanced survival in mice with GBM.
Renal Regeneration: The Role of Extracellular Matrix and Current ECM‐Based Tissue Engineered Strategies
Authors: Rita Sobreiro‐Almeida, Rita Quinteira, Nuno M. Neves
Journal: Advanced Healthcare Materials (2021)

Abstract Natural extracellular matrices (ECM) are currently being studied as an alternative source for organ transplantation or as new solutions to treat kidney injuries, which can evolve to end‐stage renal disease, a life devastating condition. This paper provides an overview on the current knowledge in kidney ECM and its usefulness on future investigations. The composition and structure of kidney ECM is herein associated with its intrinsic capacity of remodeling and repair after insult. Moreover, it provides a deeper insight on altered ECM components during disease. The use of decellularized kidney matrices is discussed in the second part of the review, with emphasis on how these matrices contribute to tissue‐specific differentiation of embryonic, pluripotent, and other stem cells. The evolution on the field toward different uses of xenogeneic ECM as a biological scaffold material is discussed, namely the major outcomes on whole kidney recellularization and its in vivo implantation. At last, the recent literature on the use of processed kidney decellularized ECM to produce diverse biomaterial substrates, such as hydrogels, membranes, and bioinks are reviewed, with emphasis on future perspectives of its translation into the clinic.