tbuckley/cabot-search huggingface dataset:
Asymmetric Hapln1a drives regionalized cardiac ECM expansion and promotes heart morphogenesis in zebrafish development
Authors: Christopher J Derrick, Juliana Sánchez-Posada, Farah Hussein, Federico Tessadori, Eric J G Pollitt, Aaron M Savage, Robert N Wilkinson, Timothy J Chico, Fredericus J van Eeden, Jeroen Bakkers, Emily S Noël
Journal: Cardiovascular Research (2021)

Vertebrate heart development requires the complex morphogenesis of a linear tube to form the mature organ, a process essential for correct cardiac form and function, requiring coordination of embryonic laterality, cardiac growth, and regionalized cellular changes. While previous studies have demonstrated broad requirements for extracellular matrix (ECM) components in cardiac morphogenesis, we hypothesized that ECM regionalization may fine tune cardiac shape during heart development.Using live in vivo light sheet imaging of zebrafish embryos, we describe a left-sided expansion of the ECM between the myocardium and endocardium prior to the onset of heart looping and chamber ballooning. Analysis using an ECM sensor revealed the cardiac ECM is further regionalized along the atrioventricular axis. Spatial transcriptomic analysis of gene expression in the heart tube identified candidate genes that may drive ECM expansion. This approach identified regionalized expression of hapln1a, encoding an ECM cross-linking protein. Validation of transcriptomic data by in situ hybridization confirmed regionalized hapln1a expression in the heart, with highest levels of expression in the future atrium and on the left side of the tube, overlapping with the observed ECM expansion. Analysis of CRISPR-Cas9-generated hapln1a mutants revealed a reduction in atrial size and reduced chamber ballooning. Loss-of-function analysis demonstrated that ECM expansion is dependent upon Hapln1a, together supporting a role for Hapln1a in regionalized ECM modulation and cardiac morphogenesis. Analysis of hapln1a expression in zebrafish mutants with randomized or absent embryonic left-right asymmetry revealed that laterality cues position hapln1a-expressing cells asymmetrically in the left side of the heart tube.We identify a regionalized ECM expansion in the heart tube which promotes correct heart development, and propose a novel model whereby embryonic laterality cues orient the axis of ECM asymmetry in the heart, suggesting these two pathways interact to promote robust cardiac morphogenesis.
Mobocertinib (TAK-788): A Targeted Inhibitor of<i>EGFR</i>Exon 20 Insertion Mutants in Non–Small Cell Lung Cancer
Authors: Francois Gonzalvez, Sylvie Vincent, Theresa E. Baker, Alexandra E. Gould, Shuai Li, Scott D. Wardwell, Sara Nadworny, Yaoyu Ning, Sen Zhang, Wei-Sheng Huang, Yongbo Hu, Feng Li, Matthew T. Greenfield, Stephan G. Zech, Biplab Das, Narayana I. Narasimhan, Tim Clackson, David Dalgarno, William C. Shakespeare, Michael Fitzgerald, Johara Chouitar, Robert J. Griffin, Shengwu Liu, Kwok-kin Wong, Xiaotian Zhu, Victor M. Rivera
Journal: Cancer Discovery (2021)

Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non-small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC. SIGNIFICANCE: No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601.
Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology
Authors: Martin Hoenigl, Jon Salmanton-García, Thomas J Walsh, Marcio Nucci, Chin Fen Neoh, Jeffrey D Jenks, Michaela Lackner, Rosanne Sprute, Abdullah M S Al-Hatmi, Matteo Bassetti, Fabianne Carlesse, Tomas Freiberger, Philipp Koehler, Thomas Lehrnbecher, Anil Kumar, Juergen Prattes, Malcolm Richardson, Sanjay Revankar, Monica A Slavin, Jannik Stemler, Birgit Spiess, Saad J Taj-Aldeen, Adilia Warris, Patrick C Y Woo, Jo-Anne H Young, Kerstin Albus, Dorothee Arenz, Valentina Arsic-Arsenijevic, Jean-Philippe Bouchara, Terrence Rohan Chinniah, Anuradha Chowdhary, G Sybren de Hoog, George Dimopoulos, Rafael F Duarte, Petr Hamal, Jacques F Meis, Sayoki Mfinanga, Flavio Queiroz-Telles, Thomas F Patterson, Galia Rahav, Thomas R Rogers, Coleman Rotstein, Retno Wahyuningsih, Danila Seidel, Oliver A Cornely
Journal: The Lancet Infectious Diseases (2021)
A quality improvement project evaluating patient and clinician experience of video consultations in outpatient dermatology
Authors: R. Ramessur, R. Singh-Raghunath, A. Brown, D. Brazil, B. DeSilva
Journal: British Journal of Dermatology (2020)

The COVID-19 pandemic has brought about unprecedented changes to healthcare delivery  Balancing infection-control practices with the provision of safe specialist care has led to the introduction of video consultations (VCs)  Consequently, NHS England has collaborated with Attend Anywhere® (AA) to offer a VC platform to National Health Service trusts  We present the first evaluation of a VC platform in dermatology, at a time when minimizing the substantial indirect impact of the pandemic on patients' lives is vitally important in improving long-term accessibility to dermatology care for vulnerable groups  We are performing a quality-improvement project to evaluate patient and clinician experience of using AA in a U K  dermatology secondary care outpatient centre during the current pandemic (at the time of writing, June 2020)  The clinician survey and final outcomes will be assessed in September 2020  Prospective online surveys for patients and clinicians were designed  The patient survey was integrated into the platform to initiate automatically at the end of each VC  Seventeen questions qualitatively and quantitatively assessed several domains, including patient satisfaction and views on potential long-term use of the platform  Similarly, 12 questions were designed to evaluate clinicians' opinions about the platform, its use for training, ease of organizing prescriptions and potential future use  Data were recorded using a 5-point scoring system (ranging from 'strongly agree' to 'strongly disagree')  Key themes from patient and clinician free-text responses were categorized according to common properties  In total, 149 patient responses have been collected over a 4-week period to date  Patients included were of all ages:  70 years (14%)  Fifty-five per cent of consultations were first attendances (45% follow-ups), 31% for a lesional skin problem and 33% for systemic treatment monitoring  The main findings were that 91% had a 'very good' or 'good' overall experience of AA, with 90% feeling that they were able to communicate everything they wanted and 87% feeling comfortable being examined over a VC  Eighty-seven per cent would choose VC over telephone consultation during the current pandemic  Sixty per cent would choose VC over face-toface consultation after the pandemic  A common theme from free-text responses was that subgroups of patients who would find hospital attendances difficult had greater satisfaction with AA, including patients with physical or cognitive impairment, on long-term systemic/biological medication and who are carers for family members  We demonstrate that AA is a patientfriendly platform that can have a pivotal role in the short and long term in the dermatology outpatient setting
SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic <i>PTP4A3</i> through Chromatin Remodeling in t(4;14) Multiple Myeloma
Authors: Phyllis S.Y. Chong, Jing Yuan Chooi, Julia S.L. Lim, Sabrina Hui Min Toh, Tuan Zea Tan, Wee-Joo Chng
Journal: Cancer Research (2021)

Abstract NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2–SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. Significance: This study uncovers a novel, SWI/SNF–independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.
Current treatment and recent progress in gastric cancer
Authors: Smita S. Joshi, Brian D. Badgwell
Journal: CA A Cancer Journal for Clinicians (2021)

Abstract Gastric cancer is not a top‐10 malignancy in the United States but represents one of the most common causes of cancer death worldwide. Biological differences between tumors from Eastern and Western countries add to the complexity of identifying standard‐of‐care therapy based on international trials. Systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy all have proven efficacy in gastric adenocarcinoma; therefore, multidisciplinary treatment is paramount to treatment selection. Triplet chemotherapy for resectable gastric cancer is now accepted and could represent a plateau of standard cytotoxic chemotherapy for localized disease. Classification of gastric cancer based on molecular subtypes is providing an opportunity for personalized therapy. Biomarkers, in particular microsatellite instability (MSI), programmed cell death ligand 1 (PD‐L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein‐Barr virus, are increasingly driving systemic therapy approaches and allowing for the identification of populations most likely to benefit from immunotherapy and targeted therapy. Significant research opportunities remain for the less differentiated histologic subtypes of gastric adenocarcinoma and those without markers of immunotherapy activity.
Abstract #2916: Pharmacokinetics, tissue distribution and anticancer activity of eicosapentaenoic acid and docosahexaenoic acid, two cancer chemopreventive omega-3 fatty acids
Authors: Kisung Kang, Pan Wang, Bao Ting Zhu
Journal: Cancer Research (2009)

Background: Recent studies have shown that omega-3 fatty acids can inhibit tumorigenesis. In the present study, we determined in rats the pharmacokinetics and tissue distribution of two major omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), following oral administration of fish oil. In addition, we have also evaluated their anticancer activity against the growth of human MCF-7 breast cancer cells in vitro and also the underlying mechanism. Methods: Male Sprague-Dawley rats (300 g) were used for the pharmacokinetic study. Commercially-available fish oil (2 mL, containing 180 mg/mL EPA and 120 mg/mL DHA) was orally administered to the animals following overnight fasting. Blood was drawn at 1, 2, 3, 4, 5, 8, 12 and 24 h following the fish oil administration. Levels of DHA and EPA in the blood and various tissues (brain, heart, lung, liver, kidney, pancreas, spleen, small intestine and adipose) were determined by using GC-MS. Their anti-breast cancer activity was determined in cultured cells. Results: Brain showed the highest levels of endogenously-produced DHA, and its levels in several other tissues were also higher than EPA. After a single oral administration of fish oil containing both EPA and DHA to rats, the serum levels of EPA and DHA reached its maximum concentrations at 5 h, and the levels were gradually decreased to the original endogenous levels at 12 h after administration. The levels of EPA in the small intestinal tissue were increased by 13-fold, whereas the levels of DHA were increased by 3.4-fold. Similarly, the increase of EPA levels in heart, lung, liver, kidney, pancreas and spleen was also higher than the increase of DHA levels. Anticancer experiments showed that EPA and DHA, when present at endogenously-achievable tissue concentrations, exerted a strong growth-inhibitory effect in MCF-7 human breast cancer cells in culture. Mechanistic studies revealed that an increased formation of reactive free radicals contributed importantly to the anticancer activity of EPA and DHA since the presence of vitamin E strongly protected these cells from undergoing apoptosis. Interestingly, the anticancer effects of EPA and DHA were much weaker in MDA-MB-435s human breast cancer cells under the same conditions. Conclusion:Administration of DHA and EPA through oral intake of fish oil has a relatively short half-life in circulation but favorable distribution in a number of tissues. In addition, both EPA and DHA are highly efficacious in suppressing the growth of certain types of human breast cancer in vitro. More studies are warranted to further explore their potential anticancer and chemopreventive effects in animal models and human subjects.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2916.
Response to: ‘Correspondence on ‘Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment’’ by Pamuk and Hasni
Authors: Lyna Kamintsky, Steven D Beyea, John D Fisk, Javeria A Hashmi, Antonina Omisade, Cynthia Calkin, Tim Bardouille, Chris Bowen, Maher Quraan, Arnold Mitnitski, Kara Matheson, Alon Friedman, John G Hanly
Journal: Annals of the Rheumatic Diseases (2021)

Response to: 'Correspondence on 'Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment'' by Pamuk and Hasni We thank Dr Pamuk et al 1 for their interest in our work, 2 and for providing insights regarding mechanisms that may help explain our findings.Their correspondence highlights the importance of further understanding the processes underlying our main finding: extensive blood-brain barrier (BBB) leakage affects ~25% of patients with systemic lupus erythematosus (SLE) and is linked to smaller grey matter volume and cognitive impairment.We agree that the mechanisms resulting in BBB leakage in SLE remain poorly understood, and that a neuroinflammatory response mediated through the lymphatic system may contribute to BBB pathology.There is a growing consensus regarding the link between BBB pathology and neuroinflammation, 3 and several hypotheses regarding causality have been proposed.Some experimental evidence suggests that autoimmune-inflammatory mechanisms may interact with the BBB through the systemic circulation at the capillary lumen, causing BBB injury that triggers downstream neuroinflammation. 4Acting in an amplification loop, neuroinflammation, in turn, further exacerbates BBB injury. 5s reviewed by Pamuk et al, autoimmune-inflammatory mechanisms may also involve the lymphatic system.Animal data suggest that immune cells from lymphoid structures in the neck may migrate into cerebrospinal fluid (CSF) via lymphatics 6 or through the choroid plexus, 7 and trigger neuroinflammation from the space surrounding the BBB.According to this hypothesis, injury to the BBB occurs not at the capillary lumen, but at the network of glial lymphatic (glymphatic) clearance channels surrounding medium-sized brain vessels. 7e agree that further research is needed for elucidating the role of the lymphatic system in neuroinflammation, BBB permeability, and neuropsychiatric SLE (NPSLE).One of the major challenges in such research is the lack of established clinical tools for assessing the function of the CNS lymphatic system in living patients.Until such methods are available, we would like to highlight that quantitative assessment of BBB permeabilityusing dynamic contrast-enhanced MRI-offers an important tool for clinical diagnosis of BBB leakage and for gaining further insight into the role of BBB pathology in NPSLE.
Serum fibrosis index-based risk score predicts hepatocellular carcinoma in untreated patients with chronic hepatitis B
Authors: Lilian Yan Liang, Hye Won Lee, Vincent Wai-Sun Wong, Terry Cheuk-Fung Yip, Yee-Kit Tse, Vicki Wing-Ki Hui, Grace Chung-Yan Lui, Henry Lik-Yuen Chan, Grace Lai-Hung Wong
Journal: Clinical and Molecular Hepatology (2021)

Background/Aims: Serum fibrosis scores comprised of common laboratory tests have high utility to assess severity of liver fibrosis. We aimed to derive and validate a hepatocellular carcinoma (HCC) risk score based on serum fibrosis scores to predict HCC in treatment-naïve chronic hepatitis B (CHB) patients.Methods: Fifteen thousand one hundred eighty-seven treatment-naïve adult CHB patients were identified to form the training cohort in this retrospective study. Individual fibrosis score was included to construct a new HCC prediction score. The score was externally validated in an independent treatment-naïve Korean CHB cohort.Results: 180/15,187 patients (1.2%) in training cohort and 47/4,286 patients (1.1%) in validation cohort developed HCC during a mean follow-up of 52 and 50 months, respectively. The newly developed HCC risk score, Liang score, is composed of gender, age, hepatitis B virus DNA, fibrosis-4 (FIB-4) index, and ranges from 0 to 22. Area under the time-dependent receiver operating characteristic curve of Liang score was 0.79 (95% confidence interval, 0.70–0.89). A cutoff value of nine provided an extremely high negative predictive value of 99.9% and high sensitivity of 90.0% at 5 years in the validation cohort. Patients with Liang score ≤9 had HCC incidence &lt;0.2% per year in both training and validation cohorts, in whom HCC surveillance might be exempted.Conclusion: A novel HCC risk score, Liang score, based on FIB-4 index, is applicable and accurate to identify treatment-naïve CHB patients with very low risk of HCC to be exempted from HCC surveillance.
Abstract 10588: Double Trouble: A Case of St-segment-elevation Myocardial Infarction in a Patient With Vasculitis
Authors: Mohsin Chowdhury, David Dobroski, Diana E Litmanovich, Brett Carroll
Journal: Circulation (2019)

A 47-year-old woman with multiple risk factors for coronary disease presented with acute onset substernal chest pain at rest. Initial exam was notable for heart rate of 109 bpm, right arm blood pre...
Home testing HPV kits will be offered to women in England as part of screening trial
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Women in areas of London where screening attendance is low will be offered smear test kits that can be self-administered at home, as part of an NHS England trial.

The scheme will see more than 19 000 women aged 25 to 64 and who are 15 months overdue for a check sent a kit, while 12 000 women who attend a GP appointment for another reason and are at least six months overdue will also be offered a kit. The rollout will begin …
Immune-related Gene Expression Predicts Response to Neoadjuvant Chemotherapy but not Additional Benefit from PD-L1 Inhibition in Women with Early Triple-negative Breast Cancer
Authors: Bruno V. Sinn, Sibylle Loibl, Claus A. Hanusch, Dirk-Michael Zahm, Hans-Peter Sinn, Michael Untch, Karsten Weber, Thomas Karn, Clemens Becker, Frederik Marmé, Wolfgang D. Schmitt, Volkmar Müller, Christian Schem, Denise Treue, Elmar Stickeler, Frederik Klauschen, Nicole Burchardi, Jenny Furlanetto, Marion van Mackelenbergh, Peter A. Fasching, Andreas Schneeweiss, Carsten Denkert
Journal: Clinical Cancer Research (2021)

Abstract Purpose: We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer. Experimental Design: Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers. Results: Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130–2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234–2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling. Conclusions: Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.