tbuckley/cabot-search huggingface dataset:
Artificial intelligence-assisted immunohistochemical (IHC) evaluation of tumor amphiregulin (AREG) and epiregulin (EREG) expression as a combined predictive biomarker for panitumumab (Pan) therapy benefit in <i>RAS</i> wild-type (wt) metastatic colorectal cancer (mCRC): Analysis within the phase III PICCOLO trial.
Authors: Christopher Williams, Jenny F. Seligmann, Christoph Guetter, Liping Zhang, Dongyao Yan, Andrea Muranyi, Isaac Bai, Shalini Singh, Faye Elliott, Mike Shires, Susan Richman, Nicholas West, Jenny Barrett, Matthew T. Seymour, Philip Quirke, Kandavel Shanmugam
Journal: Journal of Clinical Oncology (2021)

111 Background: High tumor mRNA levels of the EGFR ligands, AREG and EREG are associated with anti-EGFR agent response in patients (pts) with RAS-wt mCRC, regardless of tumor location. However, ligand RNA assays have not been adopted into routine clinical practice due to issues with analytical precision and practicality. Here we test whether AREG and EREG expression assessed by IHC can predict benefit from Pan. Methods: A retrospective biomarker study within the PICCOLO trial (NCT00389870; irinotecan [Ir] ± Pan in fluoropyrimidine-resistant RAS-wt mCRC). AREG and EREG positive tumor cells were assessed by IHC in all RAS-wt patients with available tumor tissue. Pathologists annotated tumor areas on digital images of glass slides. Artificial intelligence (AI) algorithms calculated the percentage of tumor cells staining positive for AREG and EREG within the tumor areas. More than 50% AREG and/or EREG tumor cell positivity was regarded as high ligand expression. The primary endpoint was progression-free survival (PFS) and secondary endpoints were RECIST response rate (RR) and overall survival (OS). Results: 274 RAS-wt pts had available tumor tissue. High ligand expression (n = 132) was associated with significant PFS benefit from IrPan compared with Ir (8.0 vs 3.2 months; HR 0.54 [0.37-0.79]; p = 0.001); whereas low ligand expression (n = 142) was not (3.4 vs 4.4 months; HR 1.05 [95% CI, 0.74-1.49]; p = 0.78). The ligand-treatment interaction was significant (p = 0.02) and independent of BRAF-mutation status and primary tumor location. Likewise RR was significantly improved in pts with high ligand expression (IrPan vs Ir: 48% vs 6%; risk ratio, 7.8 [2.90-20.69]; p &lt; 0.0001) but not those with low ligand expression (IrPan vs Ir: 25% vs 14%; risk ratio, 1.8 [95% CI, 0.89-3.65]; p = 0.10) (interaction p = 0.01). Lesser effect was seen on OS. Conclusions: IHC assessment of AREG and EREG identified pts who did or did not benefit from Pan, as has been previously demonstrated through mRNA quantification. IHC represents a more practicable technique as it can be provided at the point of care and is associated with shorter turn-around times. AREG and EREG IHC may be of use in routine practice to identify patients who would benefit from anti-EGFR therapy and those for whom alternative treatment strategies should be explored.
The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities
Authors: Paz Nombela, Borja Miguel-López, Sandra Blanco
Journal: Molecular Cancer (2021)

Abstract RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N 6 -methyladenosine (m 6 A), 5-methylcytosine (m 5 C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
THU0048 Addition of the rgd motif in the fibre knob of an adenoviral vector improved the transfection efficiency and when used for overexpression of il-1ra resulted in a more effective inhibition of arthritis
Authors: FA Van de Loo, AC Bakker, LA Joosten, V Krasnykh, DT Curiel, WB Van den Berg
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Adenoviral (Ad) vectors expressing anti-inflammatory cytokines are used for therapy in experimental arthritis. Cell recognition and entry is dependent on the initial recognition of the coxsackievirus and adenovirus receptor (CAR) on cells. Recently introducing an Arg-Gly-Asp (RGD) motif in the HI loop of the fibre knob modified the tropism of the virus.<sup>1</sup> The RGD motif is capable of mediating a CAR-independent cell entry via interactions with the αvb3 and αvb5 integrins. <h3>Objectives</h3> In this study we explored the transfection efficiency of the RGD modified viruses and investigated the effectiveness of intra-articular IL-1Ra overexpression in the collagen-induced arthritis (CIA) model mediated by the RGD modified vector compared to wildtype viruses. <h3>Methods</h3> 10e7 pfu of the AdLuc, AdLucRGD, AdmIL-1Ra, or AdmIL-1RaRGD were intra-articularly injected in all experiments. The CIA model was used to compare the wild type and the RGD viruses on their ability to downregulate arthritis. DBA/1 mice were immunised with collagen type II, and boostered 22 days later. Four days after the booster the adenoviral vectors were injected into both knee joints of the mice. Clinical scores of the knee joints were on a scale of 0–3. <h3>Results</h3> Twenty-four hours after intra-articular injection of 10e7 pfu virus into normal knee joints, luciferase production in AdlucRGD injected joints was around 22 times higher than in Adluc injected joints. On day 26 of the CIA model, 10e7 pfu of AdLuc, AdLucRGD, AdmIL-1Ra, or AdmIL-1RaRGD were injected into the knee joints. Onset of the CIA was significantly inhibited in the AdmIL-1RaRGD group (clinical score in the knee joints at day 38 was 0.82 ± 0.24) compared to the other groups (clinical scores were 1.57 ± 0.24 for the AdmIL-1Ra group and 1.86 ± 0.21 for the AdLucRGD group). <h3>Conclusion</h3> Transduction of the synovial lining cells in normal knee joints was up to 30 times more efficient when the RGD mediated pathway was used. CIA was significantly better inhibited when mIL-1Ra was overexpressed using the RGD adenoviruses for infection compared to the wild type adenovirus. <h3>Reference</h3> Dmitriev I, Krasnykh V, Miller CR, Wang M, Kashentseva E, Mikheeva G, Belousova N, Curiel DT. An adenovirus vector with genetically modified fibers demonstrates expanded tropism via utilization of a coxsackievirus and adenovirus receptor-independent cell entry mechanism. J Virol. 1998;72(12):9706–13
Patient characteristics and survival outcomes in gastrointestinal cancers harboring <i>RNF43 </i>mutations or <i>RSPO3 </i>fusions: a retrospective analysis.
Authors: Paul Sackstein, Garrett Buechner, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2021)

473 Background: The growth of intestinal epithelium is dependent on the Wnt/β-catenin signaling pathway. The R-Spondin (RSPO) family of proteins form complexes with Wnt ligand and RNF43 protein, which promote ubiquitination and degradation of Wnt receptors. Patients with gastrointestinal cancers harboring RSPO3 gene fusions or RNF43 gene mutations may benefit from Wnt pathway inhibitors. Methods: We retrospectively studied 51 patients at our institution diagnosed with gastrointestinal cancers with RSPO3 gene fusions or RNF43 gene mutations identified using Caris Life Sciences next-generation sequencing (NGS). Microsatellite-instability (MSI) was evaluated using NGS. Tumor mutational burden (TMB) was estimated from 592 genes by counting all nonsynonymous missense mutations not previously defined as germline mutations, expressed as mutations per megabase. First-line median progression-free survival (PFS) and median overall survival (mOS) were estimated using the Kaplan-Meier method. Results: Of the 51 patients in our study, 44 (86.3%) had RNF43 mutations and 7 (13.7%) had RSPO3 fusions, 6 of whom had colorectal cancer (CRC) and had PTPRK as the fusion partner, 1 case of small bowel cancer had a RSPO3: IFNGR1 fusion. Median age at diagnosis was 64.0 ± 12.0 years. The most common primary tumors were CRC in 23 patients (45.1%) and pancreas in 12 patients (23.5%). Co-occurring mutations in CRC patients with RSPO3 fusions included KRAS (50%, Q61H, G12C, and G12V), BRAF V600E (50%), and TP53 (100%), none were MSI-H, median TMB (mTMB) was 9.5 (range 7-11). Sixty-seven percent of RNF43-mutated CRC patients had the G659fs mutation. Co-occurring findings in RNF43-mutated CRC patients included 67% MSI-H, median TMB 27 (range 6-123), KRAS (28%), BRAF V600E (28%), and TP53 mutations (33%). Twenty-two patients (43.1%) had stage IV disease, 18 (35.3%) had stage III disease and 11 (21.6%) had stage II disease. Thirty RNF43-mutated patients (58.8%) underwent definitive surgical resection, with a mean time to recurrence of 22.2 months and mOS of 43.0 months (95% CI, 15.6-70.4). Among RNF43-mutated stage IV CRC (mCRC) patients, median PFS was 8.0 months (95% CI, 5.9-10.1). Stratified by stage, mOS was 111.0 months for stage II disease, 72.0 months for stage III disease, and 37.0 months for stage IV disease (95% CI, 14.7-59.3). Conclusions: RNF43 correlates with overall favorable mOS in patients with mCRC. mOS in RNF43-mutated mCRC is similar to those of RAS and BRAF wild-type subgroups as reported in the TRIBE study (Cremolini et al. 2015). Therefore, RNF43 mutational status appears to be useful in predicting clinical outcomes for patients with stage IV CRC and overlaps significantly with MSI-H. RSPO3 fusions are rare events and the clinical outcomes of this subset of patients with tumors with RSPO3 fusions remains largely unknown.
Is shift-work associated with increased risk of esophageal cancer for males? A meta-analysis.
Authors: Chenyu Sun, Ce Cheng
Journal: Journal of Clinical Oncology (2021)

190 Background: Globally, more than 570,000 people are diagnosed of esophageal cancer each year. Shift-work involving circadian disruption was designated as a probable cause of cancer by The International Agency for Research on Cancer. Previous studies investigating the relationship between shift-work and esophageal cancer among showed controversial results. Thus, this meta-analysis was conducted. Methods: A comprehensive literature search on PubMed was conducted to identify all relevant studies published prior to September 2020 according to the established inclusion criteria. The quality assessment was performed by the Newcastle-Ottawa Scale (NOS). The pooled odds risk (OR) and 95% confidence intervals (CI) were calculated to estimate the association between the shift-work and esophageal cancer risk. Random-effect or fixed-effect model was used to calculate the pooled OR, based on heterogeneity significance. Subgroup analyses were conducted based on night-shift versus rotating-shift. Sensitivity analysis and publication bias detection were also performed. All statistical analyses were performed using RevMan software (version 5.3; Cochrane library) and STATA 12.0 statistical software (Stata Corp., College Station, TX), and all P values were two-tailed, the test level was 0.05. Results: 21 articles were obtained from database searching, and 9 articles were obtained from other sources. 3 articles involving 52,098 participants were included. All studies were considered moderate to high quality. All included studies investigated only males on the association between shift-work and esophageal cancer risk. A statistically significant association between shift-work and increased esophageal cancer risk among males was found (OR 2.09, 95%CI: 1.48, 2.94, P&lt; 0.0001, I 2 = 29%). In subgroup analyses, night-shift work was associated with a non-statistically significant increased risk of esophageal cancer (OR 1.56, 95%CI: 0.96, 2.53, P= 0.07, I 2 = 0%). In contrast, Rotating-shift was associated with increased esophageal cancer risk (OR 2.80, 95%CI: 1.72, 4.57, P &lt; 0.0001, I 2 = 0%). Sensitivity analysis confirmed the stability of the result. Funnel plot, Egger's test, and Begg's test found no publication bias of analysis (P = 0.572). Conclusions: The current meta-analysis demonstrates that shift-work is associated with increased esophageal cancer risk for males. However, no association between night-shift work and esophageal cancer risk was found. In contrast, association between rotating-shift work and increased esophageal cancer risk was found. Original studies on females regarding shift-work and esophageal cancer risk are lacking. More original studies on this topic for both male and female are needed to further explore shift-work impacts on esophageal cancer risk.
Use of machine learning to identify a T cell response to SARS-CoV-2
Authors: M. Saad Shoukat, Andrew D. Foers, Stephen Woodmansey, Shelley C. Evans, Anna Fowler, Elizabeth J. Soilleux
Journal: Cell Reports Medicine (2021)

The identification of SARS-CoV-2-specific T cell receptor (TCR) sequences is critical for understanding T cell responses to SARS-CoV-2. Accordingly, we reanalyze publicly available data from SARS-CoV-2-recovered patients who had low-severity disease (n = 17) and SARS-CoV-2 infection-naive (control) individuals (n = 39). Applying a machine learning approach to TCR beta (TRB) repertoire data, we can classify patient/control samples with a training sensitivity, specificity, and accuracy of 88.2%, 100%, and 96.4% and a testing sensitivity, specificity, and accuracy of 82.4%, 97.4%, and 92.9%, respectively. Interestingly, the same machine learning approach cannot separate SARS-CoV-2 recovered from SARS-CoV-2 infection-naive individual samples on the basis of B cell receptor (immunoglobulin heavy chain; IGH) repertoire data, suggesting that the T cell response to SARS-CoV-2 may be more stereotyped and longer lived. Following validation in larger cohorts, our method may be useful in detecting protective immunity acquired through natural infection or in determining the longevity of vaccine-induced immunity.
Abstract 11: Beneficial Effects of Hcn Inhibitor on Post-Resuscitation Myocardial Dysfunction in a Porcine Model of Cardiac Arrest
Authors: Min Yang, Tianfeng Hua, Limin Chen, Yangyang Zou
Journal: Circulation (2018)

Introduction: Previous studies have demonstrated that β-adrenergic blocking agents improved neurologic function and the rate of survival. However, its negative inotrope effects that increased the severity of PRMD (post-resuscitation myocardial dysfunction). We studied whether ivabradine (IVA) improves PRMD in a cardiac arrest model. Hypothesis: we hypothesized that the rational use of IVA would improve severity of PRMD and prognosis in a porcine model of CA. Methods: Ventricular fibrillation was induced and untreated for 8 minutes in anesthetized domestic swine while defibrillation was attempted after 6 minutes of cardiopulmonary resuscitation. Hemodynamic parameters were monitored continuously after ROSC. Mitral E/A ratio and E/e′ velocity ratio were assessed by echocardiography at Baseline, PR 1, 2, 4, 8 and 24hours after ROSC. The levels of cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured by ELISA method at Baseline, PR 1, 4 and 24hours. The animals were euthanized 24h after ROSC, and the cardiac tissue was removed for histopathological analysis. Results: Heart rate in the IVA group reduced significantly compared with the control group (all P &lt; 0.05) at PR 1, 2, 4, 8hours. Animals subjected to IVA groups presented significantly better post-resuscitation relaxation function (E/A, E/e′) than those in the Placebo groups (all P &lt; 0.05) (Figure1). IVA group had a lower cTnI and NT-proBNP levels than Placebo group at PR 1, 4 and 24hours (all P &lt; 0.05) (Figure1). Biopsy score in the IVA group was significantly lower at PR 24hours when compared with the Placebo group (all P &lt; 0.05) (Figure2). Conclusions: Heart rate reduction with IVA, improved left ventricular diastolic function and reduced myocardial injury.
Management of breast cancer surgeryduring de-escalation of COVID-19 infection
Authors: J. M. B. Sanchez, A. L. Picado, M. E. O. Crespo, J. A. G. Saenz, R. M. De La Plata Merlo, M. H. De La Muela
Journal: Clinical Cancer Research (2020)

Purpose: Spain has been one of the countries most severely affected by the Covid-19 pandemic, and Madrid hasreported the highest number of cases and deaths  A safe management of breast cancer (BC) surgery in the de-escalation is a priority  Patients and Methods: Surgery was considered depending on the epidemic trend  28 BC surgeries wereperformed in our BC Unit inside San Carlos Clinical Hospital, from 23rd April-4th June, with a reduction of 25-50-75% surgical resources until availability of complete resources  We created a practical tool based on a “traffic light” system to prioritize surgical time  Every patient was evaluated according to the different stages (comorbidities, tumorbiology, and cancer treatments): Red = Surgical procedures in maximum two weeks;Amber = Surgical proceduresin maximum four weeks;Green = Surgical procedures in more than four weeks  All benign, cosmetic, and risk-reducing procedures was deferred, and microsurgeries were not performed because high levels of resources areneeded  Every patient was checked by a telephone call with our hospital preoperative COVID-19 protocol  Allpatients were screened for symptoms and PCR test prior to surgery  Results: Minimal surgical procedures (including patient preferences) were performed, avoiding surgicalcomplications and reducing hospital stay to minimize the risk of occupational exposure  2 asymptomatic patientswho underwent chemotherapy were delayed by positive COVID-19 test and were referred for further evaluation  Surgical procedures were performed in 28 patients with a negative COVID-19 PCR test  4/18 conservative surgeriesrequired minimal use of oncoplastic procedures and in 3/10 mastectomies, an immediate breast reconstruction withan implant were considered  The surgery was more minor than planned in 3 patients, and due to the reduced risksurgery was deferred  20 surgical procedures were performed in patients who received neoadjuvant chemotherapyand in 4 patients with endocrine therapy and with low 21 gene recurrence score (RS) (<25)  Sentinel lymph nodebiopsy was performed in 14 patients with clinically node-negative BC, and axillary lymph node dissection wasnecessary in 10 patients who underwent neoadjuvant chemotherapy  We also performed this surgical treatment in 6patients with in situ ductal carcinoma along usual production was establishment  After the surgery, the patients werehospitalized in COVID-19-free areas, and no perioperative complications or COVID-19 infection were reported  Conclusions: In the de-escalation period, an expert committee evaluation case by case must be performed forsurgical procedures  Treatment decision-making should balance risk and benefits of the surgical treatment, and a traffic light” scale could be a useful tool for the medical team  A preoperative COVID-19 protocol is necessary for asafe surgical procedure
A CHecklist for statistical Assessment of Medical Papers (the CHAMP statement): explanation and elaboration
Authors: Mohammad Ali Mansournia, Gary S Collins, Rasmus Oestergaard Nielsen, Maryam Nazemipour, Nicholas P Jewell, Douglas G Altman, Michael J Campbell
Journal: British Journal of Sports Medicine (2021)

Misuse of statistics in medical and sports science research is common and may lead to detrimental consequences to healthcare. Many authors, editors and peer reviewers of medical papers will not have expert knowledge of statistics or may be unconvinced about the importance of applying correct statistics in medical research. Although there are guidelines on reporting statistics in medical papers, a checklist on the more general and commonly seen aspects of statistics to assess when peer-reviewing an article is needed. In this article, we propose a CHecklist for statistical Assessment of Medical Papers (CHAMP) comprising 30 items related to the design and conduct, data analysis, reporting and presentation, and interpretation of a research paper. While CHAMP is primarily aimed at editors and peer reviewers during the statistical assessment of a medical paper, we believe it will serve as a useful reference to improve authors' and readers' practice in their use of statistics in medical research. We strongly encourage editors and peer reviewers to consult CHAMP when assessing manuscripts for potential publication. Authors also may apply CHAMP to ensure the validity of their statistical approach and reporting of medical research, and readers may consider using CHAMP to enhance their statistical assessment of a paper.
AB0034 The distribution of hla-drb1 alleles in the russian population with protracted rheumatoid arthritis (ra)
Authors: LA Taukumova, IA Gousseva
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The objective was to assess the distribution and possible associations of HLA-DRB1 alleles in the Russian population with long standing rheumatoid arthritis. <h3>Methods</h3> Forty four patients (pts) with RA (2 males, 42 females, mean age 53.3 ± 10.85 yr. and mean disease duration 12.9 ± 7.71 yr. and 135 controls were typed for HLA-DRB1 alleles using PCR based molecular techniques. Radiological outcome was measured by scoring X-rays of the hands and feet using the standard radiographs of Larsen (Larsen score). Patients were stratified by RF status and the results were analysed using the Fisher exact test. <h3>Results</h3> The frequency of individuals with DRB1*04 (p &lt; 0.00001) was significantly higher, DRB1*05 (p &lt; 0.04) and *07 (p &lt; 0.006) were lower in the pts in compare with the controls. HLA-DRB1*04 proved to be significantly increased in seropositive pts (p &lt; 0.038). RF(+) pts with homozygous status for HLA-DRB1*04 (p &lt; 0.04) had significantly higher radiological score (p &lt; 0.05). <h3>Conclusion</h3> Protracted RA in the Russian population is characterised by high frequency HLA-DRB1*04 and low distribution DRB1*05 and DRB1*07. In RF(+) RA pts there was association between the presence DR4 and radiological severity.
Epidemiology of Coronavirus Disease 2019 in US Immigration and Customs Enforcement Detention Facilities
Authors: Felicia O. Casanova, Alice Hamblett, Lauren Brinkley-Rubinstein, Kathryn M. Nowotny
Journal: JAMA Network Open (2021)

This cohort study describes the burden of coronavirus disease 2019 among people detained by US Immigration and Customs Enforcement compared with the US population.