tbuckley/cabot-search huggingface dataset:
A novel combination score based on early serum tumor markers and neutrophil-to-lymphocyte ratio dynamics predicts response to PD-1/PD-L1 inhibitors in advanced non-small cell lung cancer.
Authors: Jun Wang, Yin Tang, Yahong Sun, Beibei Yin, Yaping Guan, Dongfeng Feng
Journal: Journal of Clinical Oncology (2021)

e21095 Background: Serum tumor markers (STM) are viewed as surrogate indicators of tumor burden, and neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with the systematic inflammation and immunity status of the host. The present study was designed to evaluate early STM and NLR dynamics as combined biomarkers to predict efficacy and prognosis for advanced non-small cell lung cancer (NSCLC) patients who received immunotherapy with PD-1/PD-L1 inhibitors. Methods: We retrospectively reviewed patients with advanced NSCLC who were treated with PD-1/PD-L1 inhibitors. Several STM, including carcinoembryonic antigen (CEA), cytokeratin-19 fragments (CYFRA 21–1), neuron specific enolase (NSE), carbohydrate antigen 19–9 (CA19–9), and carbohydrate antigen 125 (CA125), and NLR were routinely measured or calculated at NSCLC diagnosis. Early leading STM and NLR change were evaluated between immunotherapy initiation and the first subsequent restaging. At least 20% decreases of the leading STM were considered as leading STM decrease after immunotherapy. Both pretreatment and posttreatment NLR &lt; 5 were considered as continuous low NLR. A combination score based on the leading STM and NLR dynamics was calculated. The effects of leading STM change, NLR change, and the combination score on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed in a training cohort (n = 79) and confirmed in a validation cohort (n = 35). Results: A total of 120 patients were included in this retrospective cohort study. The median age was 63.0 years and 71.0% was male. Overall, ORR was 20.0%, and median OS and PFS were 6.2 and 4.6 months, respectively. Patients with low combination score had a significantly improved ORR (15/60) compared to those with intermediate (0/11), or high score (0/4) ( P = 0.032). In the training cohort, the combination score was significantly associated with OS ( P &lt; 0.001) and PFS ( P &lt; 0.001) for all patients, as well as for those with stable and progressive disease ( P &lt; 0.001 for OS; P &lt; 0.001 for PFS). This combination score was also further confirmed to stratify patients with different prognosis in terms of OS ( P &lt; 0.001) and PFS ( P &lt; 0.001) in the validation cohort. In a multivariable model, the combination score was an independent indicator for predicting OS ( P &lt; 0.001) and PFS ( P &lt; 0.001). Conclusions: A simple and novel combination score based on early STM and NLR dynamics representing surrogate indicators of tumor burden, and immunity status, respectively, can accurately predict efficacy and prognosis for advanced NSCLC patients with PD-1/PD-L1 blockade.
Prevalence and Characterization of Itch in Pachyonychia Congenita
Authors: Lloyd Steele, Janice Schwartz, C. David Hansen, Edel A. O’Toole
Journal: JAMA Dermatology (2021)

Prevalence and Characterization of Itch in Pachyonychia CongenitaPachyonychia congenita (PC) is a group of autosomal dominant disorders that are caused by variants in 1 of 5 keratin genes.Itch is not well recognized as a clinical finding of PC 1 but is anecdotally reported by patients.To assess the prevalence and characteristics of itch in PC, we surveyed participants from the International Pachyonychia Congenita Research Registry (IPCRR).
The 2021‐2024 Work Plan of WPA Collaborating Centres
Authors: Andrea Fiorillo, Kamaldeep S. Bhui, Dan J. Stein, Tarek Okasha, David Ndetei, Linda C.W. Lam, Pratima Murthy, Muhammad Waqar Azeem, Afzal Javed
Journal: World Psychiatry (2021)

The network of WPA Collaborating Centres was established in 2016 with the aim to provide practical
Recovering genotypes and phenotypes using allele-specific genes
Authors: Gamze Gürsoy, Nancy Lu, Sarah Wagner, Mark Gerstein
Journal: Genome biology (2021)

Abstract With the recent increase in RNA sequencing efforts using large cohorts of individuals, surveying allele-specific gene expression is becoming increasingly frequent. Here, we report that, despite not containing explicit variant information, a list of genes known to be allele-specific in an individual is enough to recover key variants and link the individuals back to their genotypes and phenotypes. This creates a privacy conundrum.
A Comprehensive Assessment of Associations between Prenatal Phthalate Exposure and the Placental Transcriptomic Landscape
Authors: Alison G. Paquette, James MacDonald, Samantha Lapehn, Theo Bammler, Laken Kruger, Drew B. Day, Nathan D. Price, Christine Loftus, Kurunthachalam Kannan, Carmen Marsit, W. Alex Mason, Nicole R. Bush, Kaja Z. LeWinn, Daniel A. Enquobahrie, Bhagwat Prasad, Catherine J. Karr, Sheela Sathyanarayana
Journal: Environmental Health Perspectives (2021)

BACKGROUND: Phthalates are commonly used endocrine-disrupting chemicals that are ubiquitous in the general population.Prenatal phthalate exposure may alter placental physiology and fetal development, leading to adverse perinatal and childhood health outcomes.OBJECTIVE: We examined associations between prenatal phthalate exposure in the second and third trimesters and the placental transcriptome at birth, including genes and long noncoding RNAs (lncRNAs), to gain insight into potential mechanisms of action during fetal development. METHODS:The ECHO PATHWAYs consortium quantified 21 urinary phthalate metabolites from 760 women enrolled in the CANDLE study (Shelby County, TN) using high-performance liquid chromatography-tandem mass spectrometry.Placental transcriptomic data were obtained using paired-end RNA sequencing.Linear models were fitted to estimate separate associations between maternal urinary phthalate metabolite concentration during the second and third trimester and placental gene expression at birth, adjusted for confounding variables.Genes were considered differentially expressed at a Benjamini-Hochberg false discovery rate (FDR) p < 0:05.Associations between phthalate metabolites and biological pathways were identified using self-contained gene set testing and considered significantly altered with an FDR-adjusted p < 0:2.RESULTS: We observed significant associations between second-trimester phthalate metabolites mono (carboxyisooctyl) phthalate (MCIOP), mono-2ethyl-5-carboxypentyl phthalate, and mono-2-ethyl-5-oxohexyl phthalate and 18 genes in total, including four lncRNAs.Specifically, placental expression of NEAT1 was associated with multiple phthalate metabolites.Third-trimester MCIOP and mono-isobutyl phthalate concentrations were significantly associated with placental expression of 18 genes and two genes, respectively.Expression of genes within 27 biological pathways was associated with mono-methyl phthalate, MCIOP, and monoethyl phthalate concentrations.DISCUSSION: To our knowledge, this is the first genome-wide assessment of the relationship between the placental transcriptome at birth and prenatal phthalate exposure in a large and diverse birth cohort.We identified numerous genes and lncRNAs associated with prenatal phthalate exposure.These associations mirror findings from other epidemiological and in vitro analyses and may provide insight into biological pathways affected in utero by phthalate exposure.
Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB
Authors: Stanislav Fridland, Jaeyoun Choi, Myungwoo Nam, Samuel Joseph Schellenberg, Eugene Kim, Grace Lee, Nathaniel Yoon, Young Kwang Chae
Journal: Journal for ImmunoTherapy of Cancer (2021)

Tissue tumor mutational burden (tTMB) is calculated to aid in cancer treatment selection. High tTMB predicts a favorable response to immunotherapy in patients with non-small cell lung cancer. Blood TMB (bTMB) from circulating tumor DNA is reported to have similar predictive power and has been proposed as an alternative to tTMB. Across many studies not only are tTMB and bTMB not concordant but also as reported previously by our group predict conflicting outcomes. This implies that bTMB is not a substitute for tTMB, but rather a composite index that may encompass tumor heterogeneity. Here, we provide a thorough overview of the predictive power of TMB, discuss the use of tumor heterogeneity alongside TMB to predict treatment response and review several methods of tumor heterogeneity assessment. Furthermore, we propose a hypothetical method of estimating tumor heterogeneity and touch on its clinical implications.
In de novo Ph+ALL Imatinib, given intermittently or simultaneously with chemotherapy, can effectively reduce the leukemic cell burden but induces molecular remissions in only a subset of patients
Authors: H. Pfeifer, B. Wassmann, U. J. Scheming, P. Brueck, N. Goekbuget, A. Binckebanck, B. Gehrke, H. Gschaidmeier, D. Hoelzer, O. G. Ottmann
Journal: Blood (2003)
Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection
Authors: Alida L.P. Caforio, Anna Baritussio, Cristina Basso, Renzo Marcolongo
Journal: Annual Review of Medicine (2021)

We review current data on clinically suspected [European Society of Cardiology (ESC) 2013 criteria] and biopsy-proven [ESC and World Health Organization (WHO) criteria] myocarditis that is temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ESC/WHO etiological diagnosis of viral myocarditis is based on histological and immunohistological evidence of nonischemic myocyte necrosis and monolymphocytic infiltration, i.e., myocarditis, plus the identification of a specific cardiotropic virus by molecular techniques, in particular polymerase chain reaction (PCR)/in-situ hybridization, on endomyocardial biopsy (EMB)/autopsy tissue. There is not yet definitive EMB/autopsy proof that SARS-CoV-2 causes direct cardiomyocyte damage in association with histological myocarditis. Clinical epidemiology data suggest that myocarditis is uncommon for both SARS-CoV-2-positive and -negative PCR cases. We hypothesize that the rare virus-negative biopsy-proven cases may represent new-onset immune-mediated or latent pre-existing autoimmune forms,triggered or fostered by the hyperinflammatory state of severe COVID-19. We recommend the application of the ESC/WHO definitions and diagnostic criteria in future reports to avoid low-quality scientific information leading to an inaccurate estimate of myocarditis incidence based on misdiagnosis.
Abstract 11454: Diagnostic Performance of 37 Electrocardiographic Criteria for Detecting Left Ventricular Hypertrophy or a Concentric Cardiac Phenotype in Athletes
Authors: Kristofer Hedman, Kegan J Moneghetti, David Hsu, Jeffrey Christle, Alessandro Patti, Euan A Ashley, Francois Haddad, Victor Froelicher
Journal: Circulation (2019)

Introduction: Electrocardiography (ECG) is used to screen for left ventricular hypertrophy (LVH), but common ECG-LVH criteria have been found less effective in athletes. We aimed to evaluate the va...
A novel intronic circular RNA, circGNG7, inhibits head and neck squamous cell carcinoma progression by blocking the phosphorylation of heat shock protein 27 at Ser78 and Ser82
Authors: Houyu Ju, Zhenrong Hu, Dongliang Wei, Jinyun Huang, Xinyi Zhang, Mengyu Rui, Zhi Li, Xiaomeng Zhang, Jingzhou Hu, Wei Guo, Guoxin Ren
Journal: Cancer Communications (2021)

Abstract Background There is increasing evidence that circular RNAs (circRNAs) play a significant role in pathological processes including tumorigenesis. In contrast to exonic circRNAs, which are the most frequently reported circRNAs in cancer so far, the studies of intronic circRNAs have been greatly lagged behind. Here, we aimed to investigate the regulatory role of intronic circRNAs in head and neck squamous cell carcinoma (HNSCC). Methods We conducted whole‐transcriptome sequencing with four pairs of primary tumor tissues and adjacent normal tissues from HNSCC patients. Then, we characterized circGNG7 expression in HNSCC tissues and cell lines and explored its association with the prognosis of HNSCC patients. We also identified interactions between circGNG7 and functional proteins, which alter downstream signaling that regulate HNSCC progression. Results In this study, we identified a new intronic circRNA, circGNG7, and validated its functional roles in HNSCC progression. CircGNG7 was predominately localized to the cytoplasm, and its expression was downregulated in both HNSCC tissues andCAL27, CAL33, SCC4, SCC9, HN6, and HN30 cells. Low expression of circGNG7 was significantly correlated with poor prognosis in HNSCC patients. Consistent with this finding, overexpression of circGNG7 strongly inhibited tumor cell proliferation, colony formation, in vitro migration, and in vivo tumor growth. Mechanistically, the expression of circGNG7 in HNSCC cells was regulated by the transcription factor SMAD family member 4 (SMAD4). Importantly, we discovered that circGNG7 could bind to serine residues 78 and 82 of the functional heat shock protein 27 (HSP27), occupying its phosphorylation sites and hindering its phosphorylation, which reduced HSP27‐JNK/P38 mitogen‐activated protein kinase (MAPK) oncogenic signaling. Downregulation of circGNG7 expression in HNSCC increased HSP27‐JNK/P38 MAPK signaling and promoted tumor progression. Conclusions Our results revealed that a new intronic circRNA, circGNG7, functions as a strong tumor suppressor and that circGNG7/HSP27‐JNK/P38 MAPK signaling is a novel mechanism by which HNSCC progression can be controlled.
Phase II Trial of the Combination of Temsirolimus and Sorafenib in Advanced Hepatocellular Carcinoma with Tumor Mutation Profiling
Authors: Robin K. Kelley, Nancy M. Joseph, Halla S. Nimeiri, Jimmy Hwang, Laura M. Kulik, Zoe Ngo, Spencer C. Behr, Courtney Onodera, Karen Zhang, Andrea G. Bocobo, Al B. Benson, Alan P. Venook, John D. Gordan
Journal: Liver Cancer (2021)

The mammalian target of rapamycin (mTOR) pathway is upregulated in nearly half of hepatocellular carcinoma (HCC) tumors and is associated with poor prognosis. In preclinical models of HCC, the combination of mTOR pathway inhibition with the multikinase inhibitor sorafenib improves treatment efficacy. A prior phase I study of the allosteric mTOR inhibitor temsirolimus combined with sorafenib demonstrated acceptable safety at the recommended phase II dose.We conducted a single-arm, multicenter phase II trial of the combination of temsirolimus 10 mg intravenously weekly plus sorafenib 200 mg b.i.d. The primary endpoint was time to progression (TTP) with efficacy target of median TTP of at least 6 months; secondary endpoints included overall survival (OS), objective response rate, safety, and alpha-fetoprotein (AFP) tumor marker response. Next-generation tumor sequencing was performed as an exploratory endpoint.Twenty-nine patients were enrolled, including 48% with hepatitis C virus infection and 28% with hepatitis B virus; 86% had Barcelona clinic liver cancer stage C disease. Among 28 patients evaluable for efficacy, the median TTP was 3.7 (95% confidence interval [CI]: 2.2, 5.3) months, with 14% of patients achieving TTP of at least 6 months. The median OS was 8.8 (95% CI: 6.8, 14.8) months. There were no complete or partial responses; 75% of patients had stable disease as best response. AFP decline by at least 50% was associated with prolonged TTP and OS. Serious adverse events occurred in 21%; the most common treatment-related adverse events of CTCAE grade 3 or higher were hypophosphatemia (36%), thrombocytopenia (14%), and rash (11%). There were no grade 5 events attributed to sorafenib or temsirolimus. Tumor next-generation sequencing (NGS) was performed in a subgroup of 24 patients with adequate tumor samples. Tumor mTOR pathway mutations were identified in 42%. There was no association between tumor mutation profile and OS or TTP.The combination of temsirolimus and sorafenib demonstrated acceptable safety but did not achieve the target threshold for efficacy in this phase II study. Tumor NGS including the presence of mTOR pathway mutations was not associated with treatment response in an exploratory subgroup analysis.
Intracellular delivery of anti-BCR/ABL antibody by PLGA nanoparticles suppresses the oncogenesis of chronic myeloid leukemia cells
Authors: Guoyun Jiang, Zhenglan Huang, Ying Yuan, Kun Tao, Wenli Feng
Journal: Journal of Hematology & Oncology (2021)

Abstract Background The pathogenesis of chronic myeloid leukemia (CML) is the formation of the BCR/ABL protein, which is encoded by the bcr/abl fusion gene, possessing abnormal tyrosine kinase activity. Despite the wide application of tyrosine kinase inhibitors (TKIs) in CML treatment, TKIs drug resistance or intolerance limits their further usage in a subset of patients. Furthermore, TKIs inhibit the tyrosine kinase activity of the BCR/ABL oncoprotein while failing to eliminate the pathologenic oncoprotein. To develop alternative strategies for CML treatment using therapeutic antibodies, and to address the issue that antibodies cannot pass through cell membranes, we have established a novel intracellular delivery of anti-BCR/ABL antibodies, which serves as a prerequisite for CML therapy. Methods Anti-BCR/ABL antibodies were encapsulated in poly( d , l -lactide- co -glycolide) nanoparticles (PLGA NPs) by a double emulsion method, and transferrin was labeled on the surface of the nanoparticles (Ab@Tf-Cou6-PLGA NPs). The characteristics of nanoparticles were measured by dynamic light scattering (DLS) and transmission electron microscopy (TEM). Cellular uptake of nanoparticles was measured by flow cytometry (FCM). The effect of nanoparticles on the apoptosis and proliferation of CML cells was testified by FCM and CCK-8 assay. In addition, the anti-cancer impact of nanoparticles was evaluated in mouse models of CML. Results The results demonstrated that the Ab@Tf-Cou6-PLGA NPs functioned as an intracellular deliverer of antibodies, and exhibited an excellent effect on degrading BCR/ABL oncoprotein in CML cells via the Trim-Away pathway. Treatment with Ab@Tf-Cou6-PLGA NPs inhibited the proliferation and induced the apoptosis of CML cells in vitro as well as impaired the oncogenesis ability of CML cells in vivo. Conclusions In conclusion, our study indicated that this approach achieved safe and efficient intracellular delivery of antibodies and degraded BCR/ABL oncoprotein via the Trim-Away pathway, which provides a promising therapeutic strategy for CML patients, particularly those with TKI resistance.
Deciphering the vedolizumab dosing conundrum in IBD: when less is more
Authors: Timon Erik Adolph, Britta Siegmund
Journal: Gut (2021)

Already in the 1990s, the integrin α4β7, expressed on innate and adaptive immune cells, has been implicated in the control of lymphocyte recruitment to the intestinal mucosa.1 Pharmacological blockade of α4β7 with a monoclonal antibody, later termed vedolizumab, protected against spontaneous chronic colitis in the cotton-top tamarin model.2 Almost two decades later, phase III clinical trials in patients with IBDs proved vedolizumab efficacious for induction and maintenance of remission in UC3 as well as Crohn’s disease (CD),4 which led to the drug approval by the European Medicines Agency in 2014. Only recently, the VARSITY trial indicated superiority of vedolizumab compared with adalimumab in UC with respect to clinical remission and endoscopic improvement,5 6 while at the same time displaying a favourable safety profile7 and the potential to predict treatment response (in CD) by a clinical scoring system.8 Notably, the initial reasoning for this therapeutic concept appeared rather clear; however, we are only beginning to appreciate its mechanisms of action. For example, characterisation of the mucosal and systemic immune cell compartment before and during vedolizumab treatment of 18 patients with IBD did reveal neither alterations in the abundance nor the receptor repertoire of mucosal T cells. Unexpectedly, vedolizumab rather resulted in profound effects on the innate immune system.9 A second study corroborated this notion by demonstrating that vedolizumab affected mucosal homing of non-classical monocytes,10 indicating that the immunomodulatory actions of vedolizumab are more diverse than previously anticipated. These findings were paralleled by the observation that vedolizumab efficacy is counterintuitively affected by dosing, in that higher trough concentrations appear to confer an unfavourable clinical response.11 12 More specifically, these studies reported worse clinical outcomes in …
Treatment planning considerations in the older adult with periodontal disease
Authors: Donald A. Curtis, Guo‐Hao Lin, Yogalakshmi Rajendran, Tsegazeab Gessese, Jyotirmaie Suryadevara, Yvonne L. Kapila
Journal: Periodontology 2000 (2021)

Periodontal health in the elderly is influenced by numerous factors, including systemic conditions, patient compliance, age-associated changes, and restorative procedures. The numerous comorbidities seen in the elderly necessitate individualized approaches for treatment planning. In this paper, we review how age, comorbidities, oral hygiene, and restorative dental procedures collectively influence the treatment and management of the periodontium in the elderly. The elderly population is predicted to double in 30 years, which will have an economic impact the dental profession needs to plan for. Preventative and noninvasive treatment, supportive periodontal therapy, and patient-specific maintenance plans are imperative to maintaining oral health in the older population. Multiple coexisting changes, including xerostomia, altered wound healing, altered bone physiology, altered microbiome, and diminished plaque control, can add complexity to periodontal management. Considerations of the patient's general health, the selected periodontal treatment plan, and the selected completed restorative procedures need to be considered. The influence of caries, fixed prosthodontics, partial dentures, shortened dental arch, and implant therapy can have unintended impacts on periodontal health in the elderly. Adverse periodontal outcomes in the elderly can be minimized by carefully assessing the patient's medical history, impact of medications, functional needs, properly finishing and contouring restorations to avoid plaque accumulation, and designing restorations to allow access for hygiene. Partial dentures can be a source of plaque accumulation leading to periodontal disease, caries, and recession around abutment teeth. A shortened dental arch should be considered as a functional and cost-effective alternative to partial dentures. With dental implants, the patient's tissue phenotype, keratinized tissue quantity, risk of peri-implantitis, and patient access for maintaining adequate oral hygiene are all important to consider. Implant risk-assessment tools show promise by providing a systematic approach for early diagnosis to avoid future complications.
Erratum: A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis
Authors: Tony Muchamuel, Michael Basler, Monette A Aujay, Erika Suzuki, Khalid W Kalim, Christoph Lauer, Catherine Sylvain, Eileen R Ring, Jamie Shields, Jing Jiang, Peter Shwonek, Francesco Parlati, Susan D Demo, Mark K Bennett, Christopher J Kirk, Marcus Groettrup
Journal: Nature Medicine (2009)