tbuckley/cabot-search huggingface dataset:
The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma
Authors: Gajanan Kendre, Silke Marhenke, Georgina Lorz, Diana Becker, Tanja Reineke‐Plaaß, Tanja Poth, Karthikeyan Murugesan, Florian Kühnel, Norman Woller, Ralph M. Wirtz, Andreas Pich, Jens U. Marquardt, Michael Saborowski, Arndt Vogel, Anna Saborowski
Journal: Hepatology (2021)

Background and Aims Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion‐positive ICC. Response rates of up to 35% indicate that FGFR‐targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or response to FGFR‐targeted therapies in patients with ICC. Approach and Results In this study, we use an autochthonous murine model of ICC to demonstrate that FGFR2 fusions are potent drivers of malignant transformation. Furthermore, we provide preclinical evidence that the co‐mutational spectrum acts not only as an accelerator of tumor development, but also modifies the response to targeted FGFR inhibitors. Using pharmacologic approaches and RNA‐interference technology, we delineate that Kirsten rat sarcoma oncogene (KRAS)–activated mitogen‐activated protein kinase signaling causes primary resistance to FGFR inhibitors in FGFR2 fusion–positive ICC. The translational relevance is supported by the observation that a subset of human FGFR2 fusion patients exhibits transcriptome profiles reminiscent of KRAS mutant ICC. Moreover, we demonstrate that combination therapy has the potential to overcome primary resistance and to sensitize tumors to FGFR inhibition. Conclusions Our work highlights the importance of the co‐mutational spectrum as a significant modifier of response in tumors that harbor potent oncogenic drivers. A better understanding of the genetic underpinnings of resistance will be pivotal to improve biomarker‐guided patient selection and to design clinically relevant combination strategies.
Abstract IA-17: Plumbing the depths of the non-coding cancer genome
Authors: Lincoln D. Stein
Journal: Clinical Cancer Research (2021)

Abstract Cancer is driven by genomic mutations that alter common pathways that regulate cell growth and interaction with the microenvironment. More than 20,000 cancer genomes have been sequenced over the past decade, revealing multiple insights into the causes, evolution and consequences of cancer. However, almost everything we know about the cancer genome has been obtained using exome sequencing, which surveys the 2% of the genome that encodes protein coding genes. The 98% of the genome that is ignored by exome sequencing is the "dark matter" of the cancer genome and was until recently largely unexplored. In this talk, I will discuss highlights from the recently-published Pan-Cancer of Whole Genomes project (https://www.nature.com/articles/s41586-020-1969-6), in which an international team of researchers performed a comprehensive analysis of over 2,600 whole cancer genomes and matched normals, revealing new insights into origins, mechanisms and evolution of tumours. I'll also talk about how machine-learning techniques contributed to the Pan-Cancer project, including the development of an "electronic pathologist" that uses deep learning to accurately identify the tissue origins of tumours based on whole genome sequencing data. Citation Format: Lincoln D. Stein. Plumbing the depths of the non-coding cancer genome [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr IA-17.
NAFLD in lean individuals: not a benign disease
Authors: Sven Francque, Vincent Wai-Sun Wong
Journal: Gut (2021)

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide, affecting at least a quarter of the global adult population. It is rapidly becoming one of the most common indications for liver transplantation in Western countries. NAFLD is widely considered as the hepatic manifestation of the metabolic syndrome. It is particularly common among patients with type 2 diabetes and obesity. Nonetheless, emerging data suggest that NAFLD is present in a significant proportion of lean individuals. In a systematic review and meta-analysis of 93 studies (involving over 10 million individuals), Ye et al found that 19.2% and 40.8% of patients with NAFLD were lean and non-obese, respectively, according to ethnic-specific body mass index (BMI) cut-offs.1 However, over 80% of the studies included in this systematic review were from Asia, raising the suspicion that NAFLD in lean individuals is a unique phenomenon among Asians, especially as Asians are known to have more central fat deposition and develop NAFLD and metabolic complications at a lower BMI.2

In Gut , Younes et al now report a multicentre study on the clinical features, histological severity and clinical outcomes of 1339 Caucasian patients with biopsy-proven NAFLD from Italy, UK, Spain and Australia.3 Patients were grouped in lean and non-lean according to BMI<or ≥ 25 kg/m2. The first finding was the marked difference across the participating centres. Among the patients with NAFLD, 12.6%–41.7% of those from Italy were lean, compared with 13.5% in Australia, 3.2% in Spain, and 1.6% in the UK. While this may in part reflect a difference in patient selection for liver biopsy at the participating centres, there is likely considerable variability in the epidemiology of NAFLD in the lean population.

If a patient develops NAFLD despite being lean, this may represent the milder end of the …
Impact of concurrent ACE inhibitors and ARBs on outcomes with immune-checkpoint inhibitors (ICIs) for patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Pier Vitale Nuzzo, Catherine Curran, Elio Adib, Dory Freeman, Amin Nassar, Sarah Abou Alaiwi, Ziad Bakouny, Bradley Alexander McGregor, Toni K. Choueiri, Rakesh K. Jain, Rana R. McKay, Guru Sonpavde
Journal: Journal of Clinical Oncology (2021)

354 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis and cell proliferation and may improve drug delivery by enhancing tumor perfusion partly by downregulating transforming growth factor (TGF)-β. Since (TGF)-β appears to be associated with resistance in patients receiving immune checkpoint inhibitors (ICIs), we investigated whether angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) may enhance the outcomes of mRCC pts receiving ICI. Methods: Data from mRCC pts who received ICIs at the Dana-Farber Cancer Institute (DFCI) was obtained. Data for ACEI and ARB administration was collected with concurrent administration defined as ongoing therapy from the time of starting ICI . The Kaplan-Meier method and Cox were used to evaluate the impact of concurrent ACEI/ARB on overall survival (OS). Results: Data was available for 134 pts. The mean age was 63 years (Range 37-85)). 94 (70%) pts were male. The therapies included Nivolumab+/-Other (104), Atezolizumab+/-Other (21), Pembrolizumab+/-Other (8) and Durvalumab +Tremelimumab (1). 35 (25%) pts received ICI as first line treatment, 52 (39%) received as second line treatment, and 48 (36%) received as third line or higher. Out of the 134 pts, 39 (29%) had been treated with an ACEI or ARB during ICI treatment. Out of the 39 pts who had ACEI or ARB, 2 (5%) had complete response (CR) as best response, 11 (28%) had partial response (PR), 17 (46%) had stable disease (SD) and 9 (23%) had progressive disease (PD). Out of the 95 pts who did not receive ACEI or ARB, 3 pts (3%) had CR as their best response to ICI, 19 (21%) had PR, 39 (43%) had SD, and 29 (32%) had PD, (5 patients’ best response were unevaluable). The median OS for those who had ACEI/ARBs and did not have ACEI/ARBs was 32 months and 20 months respectively. Univariable analysis revealed that patients who received ACEI/ARBs had improved OS (Logrank p-value = 0.002; HR = 2.5 [95%CI: 1.4 - 4.5]). Conclusions: In this hypothesis-generating study, concurrent ACEI/ARBs are associated with better outcomes for mRCC pts receiving ICIs. Given the availability of ACEI/ARBs, it is important to validate this result in a larger dataset and after controlling for known prognostic factors.
Platelet TLR4-ERK5 Axis Facilitates NET-Mediated Capturing of Circulating Tumor Cells and Distant Metastasis after Surgical Stress
Authors: Jinghua Ren, Jiayi He, Hongji Zhang, Yujia Xia, Zhiwei Hu, Patricia Loughran, Timothy Billiar, Hai Huang, Allan Tsung
Journal: Cancer Research (2021)

Abstract Surgical removal of malignant tumors is a mainstay in controlling most solid cancers. However, surgical insult also increases the risk of tumor recurrence and metastasis. Tissue trauma activates the innate immune system locally and systemically, mounting an inflammatory response. Platelets and neutrophils are two crucial players in the early innate immune response that heals tissues, but their actions may also contribute to cancer cell dissemination and distant metastasis. Here we report that surgical stress–activated platelets enhance the formation of platelet-tumor cell aggregates, facilitating their entrapment by neutrophil extracellular traps (NET) and subsequent distant metastasis. A murine hepatic ischemia/reperfusion (I/R) injury model of localized surgical stress showed that I/R promotes capturing of aggregated circulating tumor cells (CTC) by NETs and eventual metastasis to the lungs, which are abrogated when platelets are depleted. Hepatic I/R also increased deposition of NETs within the lung microvasculature, but depletion of platelets had no effect. TLR4 was essential for platelet activation and platelet-tumor cell aggregate formation in an ERK5-GPIIb/IIIa integrin-dependent manner. Such aggregation facilitated NET-mediated capture of CTCs in vitro under static and dynamic conditions. Blocking platelet activation or knocking out TLR4 protected mice from hepatic I/R-induced metastasis with no CTC entrapment by NETs. These results uncover a novel mechanism where platelets and neutrophils contribute to metastasis in the setting of acute inflammation. Targeted disruption of the interaction between platelets and NETs holds therapeutic promise to prevent postoperative distant metastasis. Significance: Targeting platelet activation via TLR4/ERK5/integrin GPIIb/IIIa signaling shows potential for preventing NET-driven distant metastasis in patients post-resection.
Treatment effects in randomised trials using routinely collected data for outcome assessment versus traditional trials: meta-research study
Authors: Kimberly A Mc Cord, Hannah Ewald, Arnav Agarwal, Dominik Glinz, Soheila Aghlmandi, John P A Ioannidis, Lars G Hemkens
Journal: BMJ (2021)

Abstract Objective To compare effect estimates of randomised clinical trials that use routinely collected data (RCD-RCT) for outcome ascertainment with traditional trials not using routinely collected data. Design Meta-research study. Data source Studies included in the same meta-analysis in a Cochrane review. Eligibility criteria for study selection Randomised clinical trials using any type of routinely collected data for outcome ascertainment, including from registries, electronic health records, and administrative databases, that were included in a meta-analysis of a Cochrane review on any clinical question and any health outcome together with traditional trials not using routinely collected data for outcome measurement. Review methods Effect estimates from trials using or not using routinely collected data were summarised in random effects meta-analyses. Agreement of (summary) treatment effect estimates from trials using routinely collected data and those not using such data was expressed as the ratio of odds ratios. Subgroup analyses explored effects in trials based on different types of routinely collected data. Two investigators independently assessed the quality of each data source. Results 84 RCD-RCTs and 463 traditional trials on 22 clinical questions were included. Trials using routinely collected data for outcome ascertainment showed 20% less favourable treatment effect estimates than traditional trials (ratio of odds ratios 0.80, 95% confidence interval 0.70 to 0.91, I 2 =14%). Results were similar across various types of outcomes (mortality outcomes: 0.92, 0.74 to 1.15, I 2 =12%; non-mortality outcomes: 0.71, 0.60 to 0.84, I 2 =8%), data sources (electronic health records: 0.81, 0.59 to 1.11, I 2 =28%; registries: 0.86, 0.75 to 0.99, I 2 =20%; administrative data: 0.84, 0.72 to 0.99, I 2 =0%), and data quality (high data quality: 0.82, 0.72 to 0.93, I 2 =0%). Conclusions Randomised clinical trials using routinely collected data for outcome ascertainment show smaller treatment benefits than traditional trials not using routinely collected data. These differences could have implications for healthcare decision making and the application of real world evidence.
Nanomedicines for the treatment of rheumatoid arthritis: State of art and potential therapeutic strategies
Authors: Qin Wang, Xianyan Qin, Jiyu Fang, Xun Sun
Journal: Acta Pharmaceutica Sinica B (2021)

Increasing understanding of the pathogenesis of rheumatoid arthritis (RA) has remarkably promoted the development of effective therapeutic regimens of RA. Nevertheless, the inadequate response to current therapies in a proportion of patients, the systemic toxicity accompanied by long-term administration or distribution in non-targeted sites and the comprised efficacy caused by undesirable bioavailability, are still unsettled problems lying across the full remission of RA. So far, these existing limitations have inspired comprehensive academic researches on nanomedicines for RA treatment. A variety of versatile nanocarriers with controllable physicochemical properties, tailorable drug release pattern or active targeting ability were fabricated to enhance the drug delivery efficiency in RA treatment. This review aims to provide an up-to-date progress regarding to RA treatment using nanomedicines in the last 5 years and concisely discuss the potential application of several newly emerged therapeutic strategies such as inducing the antigen-specific tolerance, pro-resolving therapy or regulating the immunometabolism for RA treatments.
Ionic liquid-loaded microcapsules doped into dental resin infiltrants
Authors: Marla Cuppini, Isadora Martini Garcia, Virgínia Serra de Souza, Kelly Cristine Zatta, Fernanda Visioli, Vicente Castelo Branco Leitune, Sílvia Stanisçuazki Guterres, Jackson Damiani Scholten, Fabrício Mezzomo Collares
Journal: Bioactive Materials (2021)

Resin infiltrants have been effectively applied in dentistry to manage non-cavitated carious lesions in proximal dental surfaces. However, the common formulations are composed of inert methacrylate monomers. In this study, we developed a novel resin infiltrant with microcapsules loaded with an ionic liquid (MC-IL), and analyzed the physical properties and cytotoxicity of the dental resin. First, the ionic liquid 1-n-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (BMI.NTf2) was synthesized. BMI.NTf2 has previously shown antibacterial activity in a dental resin. Then, MC-IL were synthesized by the deposition of a preformed polymer. The MC-IL were analyzed for particle size and de-agglomeration effect via laser diffraction analysis and shape via scanning electron microscopy (SEM). The infiltrants were formulated, and the MC-IL were incorporated at 2.5%, 5%, and 10 wt%. A group without MC-IL was used as a control. The infiltrants were evaluated for ultimate tensile strength (UTS), contact angle, surface free energy (SFE), and cytotoxicity. The MC-IL showed a mean particle size of 1.64 (±0.08) μm, shriveled aspect, and a de-agglomeration profile suggestive of nanoparticles' presence in the synthesized powder. There were no differences in UTS among groups (p > 0.05). The incorporation of 10 wt% of MC-IL increased the contact angle (p < 0.05), while the addition from 5 wt% reduced the SFE in comparison to the control group (p < 0.05). The human cell viability was above 90% for all groups (p > 0.05). The incorporation of microcapsules as a drug-delivery system for ionic liquids may be a promising strategy to improve dental restorative materials.
Mutation in the basal core promoter in Lamivudine-refractory patients with chronic hepatitis B is a pardictor of viral breakthrough during sequential adefovir monotherapy
Authors: Byung Cheol Song, Xiu Ji Cui, Jung Woo Shin, Neung Hwa Park, Eun Kwang Choi, Heung Up Kim, Yoo Kyung Cho
Journal: Clinical and Molecular Hepatology (2008)
Single‐dose prolonged drug provocation test, without previous skin testing, is safe for diagnosing children with mild non‐immediate reactions to beta‐lactams
Authors: Ana Prieto, Candelaria Muñoz, Gádor Bogas, Rubén Fernández‐Santamaría, Francisca Palomares, Cristobalina Mayorga, Maria Salas, Inmaculada Doña, María José Torres
Journal: Allergy (2021)

Abstract Introduction Mild non‐immediate reactions (NIRs) to beta‐lactams (BLs) are the most frequent manifestation of drug allergy in children. The diagnostic approach is complex as the utility of skin tests (STs) and lymphocyte transformation tests (LTTs) is controversial. Drug provocation test (DPT) is the gold standard, although no standardized protocols exist. We aimed to investigate the utility of DPT in a unique dose without previous STs, and LTTs in the diagnosis of NIRs to BLs in children. Methods We prospectively evaluated children 0–14 years old referred to the Regional University Hospital of Málaga during 2017–2020 reporting NIRs to BLs. We performed a DPT with a unique dose followed by regular treatment at home. If positive, STs and LTTs were done after the reaction had disappeared. Results We included 194 children, having 24 (12.4%) a positive DPT. The main culprit was AX (70.1%) followed by AX‐clavulanic acid (CLV) (26.8%) and the main symptoms maculopapular exanthema (MPE) (49.5%) and delayed‐urticaria (48.5%). A decrease ( p = 0.013) in the interval of days between drug administration and onset of symptoms was observed in positive DPT compared with the original reaction (3.5 vs 6 days), with no differences in the overall percentage of MPE and delayed‐appearing urticaria ( p = 0.551). No severe reactions occurred during DPT. Moreover, STs were positive in 13.33% and LTTs in 52.9%. Conclusions Single‐dose DPT without previous STs is a safe and useful way to assess NIRs to BLs in children. LTT has shown to be useful, confirming a T‐cell mechanism involved in these reactions.
Localized activation of the metastatic phenotype within the perineural region in prostate cancer.
Authors: Mick D. Brown, Claire Alexandre Hart, Ashwin Sachdeva, Christian Faulkner, David Wedge, Noel W. Clarke
Journal: Journal of Clinical Oncology (2021)

253 Background: Perineural Invasion (PNI) is defined as malignant epithelial cell invasion of the perineural space and nerves. Despite widespread acknowledgement of the clinical significance of PNI as a PCa pathological finding associated with recurrence, increased risk of bone metastasis and poor survival, the molecular mechanism underlying this pathology is relatively unknown. The malignant epithelial cells within the PNI potentially provides a spatially defined “snapshot” of disease progression, as the cells switch to a more migrational phenotype associated with metastatic progression. Here we present the initial spatial PNI phenotypic characterisation in PCa. Methods: Archival FFPE blocks, with associated full clinical history, from patients who underwent a radical prostatectomy for prostate cancer were retrieved under research ethics REC#07/H1003/161+5 10_NOCL_02. Biomarkers EphA2, pEphA2 s897 , pMLC2, E-Cadherin, Vimentin, TOMM20, MTC01, NDUFB8, PTEN were assessed on 4µm serial sections stained using a multiplex TSA protocol, with S100, pan-cytokeratin and DAPI acting as landmarks, on a Ventana Discovery platform prior to scanning on a Versa 3 platform with Halo image analysis. Prostate zones were defined at 500µm intervals either side of the prostate capsule. Univariate and multivariate (hierarchical clustering, UMap clustering) expression analysis and correlation with clinic-pathological features was conducted within R. Results: The PNI epithelial cells within each spatial zone of the prostate are significantly different to each other (Kruskal-Wallis test p &lt; 2.2x10 −16 except for MTC01 p = 5.3x10 −10 ). In comparison with the local tumour lesion, PNI epithelial cells localised within 1000µm of the prostate edge and outside the tumour lesion, have undergone a migrational switch, gaining features associated with an activated metastatic phenotype, with increased expression of amoeboid signalling (EphA2, pEphA2 s897 , pMLC2) and mitochondrial defects (loss of Complex I and IV, gain of mitochondrial mass (TOMM20)). Patients clustering by multivariate expression trends across the prostate regions showed 4 distinct patient groups, with PNI epithelial cells in patient group 1 &amp; 2 displaying a more epithelial to mesenchymal (EMT) phenotype, especially in the first 1000µm inside the prostate organ. Conclusions: Cells within PNI close to the edge of the prostate have features consistent with a switch to migrational/metastatic activation in contrast to the more indolent cell type found deeper within the tumour. Further characterisation of this localised migrational upregulation will help in understanding the transition from a localised to a metastatic phenotype.