bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection of Somatic Copy Number Deletion of the CDKN2A Gene by Quantitative Multiplex PCR for Clinical Practice
Authors: Tian Yuan , Zhou Jing , Qiao Juanli , Liu Zhaojun , Gu Liankun , Zhang Baozhen , Lu Youyong , Xing Rui , Deng Dajun 
Published: September 2021

AbstractBackgroundWhile the amplification of oncogenes (such as EGFR, c-ERBB2, c-MYC, and c-MET) are increasingly driving decision-making for precise cancer treatments, a feasible method to detect somatic copy number deletion (SCND) of tumor suppressor genes is still absent to date.MethodsThe genomic coordinates of gene deletion fragments were analyzed using the Catalogue Of Somatic Mutation In Cancer (COSMIC) datasets. Interstitial base-resolution deletion/fusion coordinates for CDKN2A were extracted from published articles and our whole genome sequencing (WGS) datasets. The copy number of the CDKN2A gene was measured with a multiplex quantitative PCR assay P16-Light and confirmed with whole genome sequencing (WGS).ResultsEstimated common deletion regions (CDRs) were observed in many tumor suppressor genes, such as ATM, CDKN2A, FAT1, miR31HG, PTEN, and RB1, in the SNP array-based COSMIC datasets. A 5.1-kb base-resolution CDR could be identified in >90% of cancer samples with CDKN2A deletion by sequencing. The CDKN2A CDR covers exon-2, which is essential for P16INK4A and P14ARF synthesis. Using the true CDKN2A CDR as a PCR target, a multiplex quantitative PCR assay P16-Light was programmed to detect CDKN2A gene copy number with a lower detection limit of 20%. P16-Light was further confirmed with WGS as the gold standard among cancer tissue samples from 139 patients.ConclusionCDRs are common in many tumor suppressor genes. The 5.1-kb CDKN2A CDR was found in >90% of cancers containing CDKN2A deletion. The CDKN2A CDR was used as a potential target for developing the P16-Light assay to detect CDKN2A SCND and amplification for routine clinical practices.
The Kinetics of COVID-19 Vaccine Response in a Community Vaccinated Population
Authors: Tu Michael , Chiang Samantha , Bender Richard , Wong David T.W. , Strom Charles 
Published: September 2021

AbstractWe used a noninvasive electrochemical quantitative assay for IgG antibodies to SARS-CoV-2 S1 in saliva to investigate the kinetics of antibody response in a community-based population who had received either the Pfizer or Moderna mRNA-based vaccines. Samples were received from a total of 97 individuals including a subset of 42 individuals who collected samples twice-weekly for 3 months or longer. In all, 840 samples were collected and analyzed. In all individuals, salivary antibody levels rose sharply in the 2-week period following their second vaccination, with peak antibody levels being at 10-20 days post-vaccination. We observed that 20%, 10% and 2.4% of individuals providing serial samples had a 90%, 95%, and 99% drop respectively from peak levels during the duration of monitoring and two patients fell to pre-vaccination levels (5%). The use of non-invasive quantitative salivary antibody measurement can allow widespread, cost-effective monitoring of vaccine response.Article Summary LineCOVID-19 antibodies were measured in saliva and 20% of vaccinated subjects experienced a 90% drop in peak antibody levels over the course of monitoring.
Unrecognized introductions of SARS-CoV-2 into the state of Georgia shaped the early epidemic
Authors: Babiker Ahmed , Martin Michael A. , Marvil Charles E. , Bellman Stephanie , Petit Robert A. , Bradley Heath L. , Stittleburg Victoria D. , Ingersoll Jessica M. , Kraft Colleen S. , Read Timothy D. , Waggoner Jesse J. , Koelle Katia , Piantadosi Anne 
Published: September 2021

AbstractIn early 2020, as SARS-CoV-2 diagnostic and surveillance responses ramped up, attention focused primarily on returning international travelers. Here, we build on existing studies characterizing early patterns of SARS-CoV-2 spread within the U.S. by analyzing detailed clinical, molecular, and viral genomic data from the state of Georgia through March 2020. We find evidence for multiple early introductions into Georgia, despite relatively sparse sampling. Most sampled sequences likely stemmed from a single introduction from Asia at least two weeks prior to the state’s first detected infection. Our analysis of sequences from domestic travelers demonstrates widespread circulation of closely-related viruses in multiple U.S. states by the end of March 2020. Our findings indicate that the early attention directed towards identifying SARS-CoV-2 in returning international travelers may have led to a failure to recognize locally circulating infections for several weeks, and points towards a critical need for rapid and broadly-targeted surveillance efforts in the future.
Basal cell carcinoma treated with HeberFERON. A real world retrospective study
Authors: Martínez-Suárez C , Roben-Aguilar Y , Reyes-Acosta O , Garcia-Vega Y , Vega-Abascal J , Sánchez-Linares V , Sotolongo-Díaz D , Piña-Rodriguez Y , Fernández-Martori M , Betancourt-Pérez A , Jimenez-Lamas M , Ballester-Caballero Y , Pérez-Morgado R , Curbelo-Alonso M , Molina-Abad A , Martínez-Borrego R , Maturell-Peraza J , Pulido-Garcia L , López-Pupo N , Ramírez-Hidalgo Y , Ramos-Trujillo M , Fernández-Ramirez I , Hernández-Colina M , Perez-Lopez A , Leon-Garcia Y , Chaya-Salgado S , La O-Ayala Y , Hernández-Rodriguez R , Duncan-Roberts Y , Bello-Rivero I 
Published: September 2021

AbstractBackgroundBasal cell carcinoma is the most common type of skin cancer with major impact in health-related quality of life. The use of the formulation based on the combination of IFN-alpha 2b and IFN-gamma (HeberFERON) is an effective alternative in the treatment of basal cell carcinoma, immunogenic tumor, potentially responsible to immunotherapies. The aim of this report is to record, retrospectively, the effect of HeberFERON patients with BCC in the Cuban real word condition.MethodsThis is a retrospectively study of the use of HeberFERON in real world conditions. Eligible patients were adults with histologic diagnosis of single or multiple basal cell carcinoma of any skin phototype, lesions of any size, subtype, location, recurrent or not, with or without specific prior treatments. Adult patients, who signed the informed consent to receive the treatment with HeberFERON, were identified from the data bases. The evaluation of clinical effectiveness was carried out according to RECIST 1.1. Ethical committee of participating institutions approved the study.ResultsIn clinical practice evaluated patients the nose was the region of higher frequency of tumors (36.3%) and the nodular clinical subtype was the predominant (45.3%). Clinical response rate differences (p=0. 000) were found, with complete response of 61.9%, and partial response of 32.7%; with an overall response rate of 94.2% The HeberFERON exerted a 100% disease control, with no progression reported in 640 treated patients. The best responder tumor subtypes to HeberFERON were the more aggressive tumors, morpheaform with complete response of 72% (overall response=96%), followed by the infiltrative with complete response of 66.7% (overall response=100%). Tumor with larger size and patients with more than four tumors had lesser response to the anti-tumor effect of HeberFERON.ConclusionsHeberFERON was highly effective in basal cell carcinomas in real world conditions. In the context of resistance of skin tumors to hedgehog and immune check point inhibitors the combination of IFNs alpha 2b and IFN gamma appears as a plausible therapeutic option for a wide number of basal cell carcinomas.
PathProfiler: Automated Quality Assessment of Retrospective Histopathology Whole-Slide Image Cohorts by Artificial Intelligence – A Case Study for Prostate Cancer Research
Authors: Haghighat Maryam , Browning Lisa , Sirinukunwattana Korsuk , Malacrino Stefano , Alham Nasullah Khalid , Colling Richard , Cui Ying , Rakha Emad , Hamdy Freddie C. , Verrill Clare , Rittscher Jens 
Published: September 2021

ABSTRACTResearch using whole slide images (WSIs) of scanned histopathology slides for the development of artificial intelligence (AI) algorithms has increased exponentially over recent years. Glass slides from large retrospective cohorts with patient follow-up data are digitised for the development and validation of AI tools. Such resources, therefore, become very important, with the need to ensure that their quality is of the standard necessary for downstream AI development. However, manual quality control of such large cohorts of WSIs by visual assessment is unfeasible, and whilst quality control AI algorithms exist, these focus on bespoke aspects of image quality, e.g. focus, or use traditional machine-learning methods such as hand-crafted features, which are unable to classify the range of potential image artefacts that should be considered.In this study, we have trained and validated a multi-task deep neural network to automate the process of quality control of a large retrospective cohort of prostate cases from which glass slides have been scanned several years after production, to determine both the usability of the images for research and the common image artefacts present.Using a two-layer approach, quality overlays of WSIs were generated from a quality assessment undertaken at patch-level at 5X magnification. From these quality overlays the slide-level quality scores were predicted and then compared to those generated by three specialist urological pathologists, with a Pearson correlation of 0.89 for overall ‘usability’ (at a diagnostic level), and 0.87 and 0.82 for focus and H&E staining quality scores respectively. We subsequently applied our quality assessment pipeline to the TCGA prostate cancer cohort and to a colorectal cancer cohort, for comparison.Our model, designated as PathProfiler, indicates comparable predicted usability of images from the cohorts assessed (86-90%), and perhaps more significantly is able to predicts WSIs that could benefit from re-scanning or re-staining for quality improvement.We have shown in this study that AI can be used to automate the process of quality control of large retrospective cohorts to maximise research outputs and conclusions.
Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa
Authors: Frings VG , Jopp L , Srivastava M , Presser D , Goebeler M , Schmidt M 
Published: September 2021

ABSTRACTBackgroundThe underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.ObjectivesTo elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.MethodsLesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.ResultsWe show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.ConclusionsTaken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.
Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19
Authors: Sacco Keith , Castagnoli Riccardo , Vakkilainen Svetlana , Liu Can , Delmonte Ottavia M. , Oguz Cihan , Kaplan Ian M. , Alehashemi Sara , Burbelo Peter D. , Bhuyan Farzana , de Jesus Adriana A. , Dobbs Kerry , Rosen Lindsey B. , Cheng Aristine , Shaw Elana , Vakkilainen Mikko S. , Pala Francesca , Lack Justin , Zhang Yu , Fink Danielle L. , Oikonomou Vasileios , Snow Andrew L. , Dalgard Clifton L. , Chen Jinguo , Sellers Brian A. , Montealegre Sanchez Gina A. , Barron Karyl , Rey Emma , Vial Cecilia , Poli Maria Cecilia , Licari Amelia , Montagna Daniela , Marseglia Gian Luigi , Licciardi Francesco , Ramenghi Ugo , Discepolo Valentina , Vecchio Andrea Lo , Guarino Alfredo , Eisenstein Eli M. , Imberti Luisa , Sottini Alessandra , Biondi Andrea , Mató Sayonara , Gerstbacher Dana , Truong Meng , Stack Michael A. , Magliocco Mary , Bosticardo Marita , Kawai Tomoki , Danielson Jeffrey J. , Hulett Tyler , Askenazi Manor ,   NIAID Immune Response to COVID Group,   Chile MIS-C Group,   Pavia Pediatric COVID-19 Group, Cohen Jeffrey I. , Su Helen C. , Kuhns Douglas B. , Lionakis Michail S. , Snyder Thomas M. , Holland Steven M. , Goldbach-Mansky Raphaela , Tsang John S. , Notarangelo Luigi D. ,   Members of the NIAID Immune Response to COVID Group, Barnett Jason , Cheng Xi , Kaladi Krishnaveni , Kuram Vasu , Mackey Joseph , Bansal Neha M. , Martins Andrew J. , Palterer Boaz , Matthews Helen , Mudunuri Uma , Nambiar Marshall , Oler Andrew , Rastegar Andre , Samuel Smilee , Shyu Conrad , Waingankar Varsha , Weber Sarah , Xirasagar Sandhya ,   Members of the Chile MIS-C Group, Espinosa Yazmin , Astudillo Camila ,   Members of the Pavia Pediatric COVID-19 Group, De Filippo Maria , Votto Martina , Montagna Lorenza 
Published: September 2021

AbstractPediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-κB dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.
Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children <5 years of age
Authors: Hetzel Manuel W. , Okitawutshu Jean , Tshefu Antoinette , Omoluabi Elizabeth , Awor Phyllis , Signorell Aita , Brunner Nina C. , Kalenga Jean-Claude , Akano Babatunde , Ayodeji Kazeem , Okon Charles , Yusuf Ocheche , Athieno Proscovia , Kimera Joseph , Tumukunde Gloria , Angiro Irene , Delvento Giulia , Lee Tristan , Lambiris Mark , Kwiatkowski Marek , Cereghetti Nadja , Visser Theodoor , Napier Harriet G. , Cohen Justin M. , Buj Valentina , Burri Christian , Lengeler Christian 
Published: September 2021

AbstractBackgroundTo prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems.MethodsAn observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment.FindingsPost-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent.InterpretationRAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.
Prediction of Life-threatening and Disabling Bleeding in Patients with Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy
Authors: Versluis Jurjen , Pandey Manu , Flamand Yael , Haydu J. Erika , Belizaire Roger , Vedula Rahul S. , Charles Anne , Copson Kevin M. , Shimony Shai , Rozental Alon , Bendapudi Pavan K. , Wolach Ofir , Griffiths Elizabeth A. , Thompson James E. , Stone Richard M. , DeAngelo Daniel J. , Neuberg Donna , Luskin Marlise R. , Wang Eunice S. , Lindsley R. Coleman 
Published: September 2021

ABSTRACTBleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were assessed according to the WHO bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n=341), which were tested in an independent cohort (n=143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count ≤40 ×109/L compared with >40 ×109/L, and baseline PT-INR >1.5 or >1.3-1.5 compared with ≤1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- versus low-risk (development: 31±7% vs. 2±1%, P<0.001, validation: 25±9% vs. 7±2%, P=0.008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.KEY POINTSRisk factors predicting grade 4 bleeding were consistent with DIC-like coagulopathy, including prolonged PT-INR and thrombocytopenia.The grade 4 bleeding score was externally validated and allows for preventive strategies to improve early mortality in high-risk patients.
Non-invasive Vagus Nerve Stimulation for Respiratory Symptoms of COVID-19: Results From a Randomized Controlled Trial (SAVIOR I)
Authors: Tornero Carlos , Pastor Ernesto , del Mar Garzando María , Orduña Jorge , Forner MJ , Bocigas Irene , Cedeño David L. , Vallejo Ricardo , Staats Peter , Liebler Eric J. 
Published: September 2021

ABSTRACTBackgroundSevere coronavirus disease 2019 (COVID-19) is characterized, in part, by an excessive inflammatory response. Evidence from animal and human studies suggests that vagus nerve stimulation can lead to reduced levels of various pro-inflammatory cytokines. We conducted a prospective randomized controlled study (SAVIOR-I) to assess the feasibility, efficacy, and safety of non-invasive vagus nerve stimulation (nVNS) for the treatment of respiratory symptoms and inflammatory markers among patients who were hospitalized for COVID-19 (ClinicalTrials.gov identifier: NCT04368156).MethodsParticipants were randomly assigned in a 1:1 allocation to receive either the standard of care (SoC) alone or nVNS therapy plus the SoC. The nVNS group received 2 consecutive 2-minute doses of nVNS 3 times daily as prophylaxis. Efficacy and safety were evaluated via the incidence of specific clinical events, inflammatory biomarker levels, and the occurrence of adverse events.ResultsOf the 110 participants who were enrolled and randomly assigned, 97 (nVNS, n=47; SoC, n=50) had sufficient available data and comprised the evaluable population. C-reactive protein (CRP) levels decreased from baseline to a significantly greater degree in the nVNS group than in the SoC group at day 5 and overall (ie, all postbaseline data points collected through day 5, combined). Procalcitonin level also showed significantly greater decreases from baseline to day 5 in the nVNS group than in the SoC group. D-dimer levels were decreased from baseline for the nVNS group and increased from baseline for the SoC group at day 5 and overall, although the difference between the treatment groups did not reach statistical significance. No significant treatment differences were seen for clinical respiratory outcomes or any of the other biochemical markers evaluated. No serious nVNS-related adverse events occurred during the study.ConclusionsnVNS therapy led to significant reductions in levels of inflammatory markers, specifically CRP and procalcitonin. Because nVNS has multiple mechanisms of action that may be relevant to COVID-19, additional research into its potential to be used earlier in the course of COVID-19 and possibly mitigate some of the symptoms associated with post-acute COVID-19 syndrome is warranted.