bluuebunny/crossref_metadata_2025_split huggingface dataset:
HIV, hypertension and diabetes care and all-cause mortality in rural South Africa in the HIV antiretroviral therapy era: a longitudinal cohort study
Authors: Chidumwa Glory , Mazibuko Lusanda , Olivier Stephen , Rahman Kashfia , Gareta Dickman , Aung Taing N , Busang Jacob , Herbst Kobus , Wong Emily , Baisley Kathy , Siedner Mark 
Published: December 2023

IntroductionSouth Africa is in the midst of rapid epidemiological transition from extremely high HIV and tuberculosis (TB) mortality to one characterised increasingly non-communicable disease-related deaths. However, longitudinal data linking modifiable risk factors and disease care indices to mortality in the country are extremely rare, and a prerequisite to appropriately prioritise health system responses.MethodsIndividuals in the Africa Health Research Institute Southern Demographic Health Surveillance area were invited to health fairs to collect data on modifiable risk factors and HIV, TB, diabetes and hypertension disease status and control. Individuals are then followed longitudinally through routine surveillance to detect deaths. We fit Cox proportional hazards models and estimated population-attributable fractions (PAFs) to identify modifiable risk factors and disease control indicators associated with all-cause mortality.ResultsA total of 18 041 individuals completed health screening and were followed for 114 692 person-years. Men had higher mortality rates than women across all age bands. The median follow-up time was 3.3 years (IQR: 3.0–3.5 years). For men, communicable diseases accounted for a higher PAF of mortality (PAF=13.7% for HIV and 8.3% for TB) than non-communicable diseases (6.6% for hypertension and 1.9% for diabetes). By contrast, despite extremely high HIV prevalence, non-communicable diseases with comorbid communicable disease accounted for the greatest share of deaths. In both sexes, having a chronic disease with poor control was most predictive of all-cause mortality. For example, among men, compared with those without each condition, adjusted HRs of all-cause mortality for people with uncontrolled disease were 3.47 (95% CI 2.10 to 5.72) for HIV, 1.52 (95% CI 1.05 to 2.20) for hypertension and 2.34 (95% CI 1.75 to 6.79) for diabetes. Among women, these same ratios were 5.32 (95% CI 3.54 to 7.99) for HIV, 1.73 (95% CI 1.31 to 2.28) for hypertension and 3.11 (95% CI 2.02 to 4.77) for diabetes.DiscussionPoor control of chronic, treatable diseases predicts all-cause mortality in rural South Africa in the HIV antiretroviral therapy era. Health system strengthening to improve chronic disease and multimorbidity care should be prioritised.
What factors are associated with paediatric admissions and their outcomes in a rural hospital in northern Sierra Leone? Insights from a pilot observational study
Authors: Afolabi Muhammed Olanrewaju , Ayieko Philip , Njie Yusupha , Kowuor Dickens , Adetola Hammed Hassan , Kamara Bomposseh , Jalloh Abdulai Berber , Sesay Francis , Swaray Ernest , Odeny Lazarus , Pearce Richmonda M , Samai Mohamed H , Deen Gibrilla Fadlu , Koedoyoma Songor , Sesay Isaac G , Ishola David , Leigh Bailah , Watson-Jones Deborah , Greenwood Brian 
Published: December 2023

IntroductionData on the pattern of admissions and causes of child death are crucial in informing priorities for improving child survival. In many health facilities in sub-Saharan Africa, understanding the pattern of paediatric admissions and their outcomes is constrained by poor documentation of these important features.MethodsWe developed and piloted a simple paper-based tool for documentation of basic, standardised patient-level information on causes of admissions, diagnoses, treatments and outcomes in children admitted to a rural hospital in Sierra Leone. The tool contained sections covering basic sociodemographic information about a patient, chief medical complaints, findings from clinical examinations and tests conducted at admission, results from subsequent clinical and laboratory investigations, working/definitive diagnoses, management and treatment outcomes.ResultsFrom 1 August 2019 to 31 July 2021, we used this tool to document the admissions, treatments and clinical outcomes of 1663 children admitted to Kambia district hospital in northern Sierra Leone. The majority of the children (1015, 62%) were aged 12–59 months, were boys (942, 57%), were wasted (516, 31%), stunted (238, 14%) or underweight (537, 32%). Above a half of the children lived more than 1 km distance from the hospital (876/1410, 62%). The highest number of admissions occurred in November 2019 and the lowest in April 2020. Severe malaria was the leading cause of admission. More than 80% of the children were successfully treated and discharged home (1356/1663, 81.5%) while 122/1663 (7.3%) died. Children aged under 5 years who were underweight, and those who presented with danger signs (eg, signs of breathing difficulty, dehydration, head injury or severe infections) had a higher risk of death than children without these features (p<0.01; p=0.03; p=0.011 and p=0.009, respectively).ConclusionLack of systematic documentation of medical histories and poor record keeping of hospital admissions and outcomes can be overcome by using a simple tool. Continuous use of the tool with regular audits could improve delivery of paediatric care in resource-limited settings.
Antibodies against advanced glycation end-products and malondialdehyde-acetaldehyde adducts identify a new specific subgroup of hitherto patients with seronegative arthritis with a distinct clinical phenotype and an HLA class II association
Authors: van den Beukel Michelle D , van Wesemael Tineke J , Hoogslag Anna Titia W , Borggreven Nicole V , Huizinga Tom WJ , van der Helm-van Mil Annette HM , Toes René EM , van der Woude Diane , Trouw Leendert A 
Published: December 2023

ObjectiveIn rheumatoid arthritis (RA) around two-thirds of patients are autoantibody positive for rheumatoid factor, anti-citrullinated protein antibodies and/or anti-carbamylated protein antibodies. The remaining seronegative subgroup of patients is clinically heterogeneous and thus far, biomarkers predicting the disease course are lacking. Therefore, we analysed the value of other autoantibodies in RA directed against malondialdehyde-acetaldehyde adducts (MAA) and advanced glycation end-products (AGE).MethodsIn sera of 648 patients with RA and 538 patients without RA from the Leiden Early Arthritis Clinic, anti-MAA and anti-AGE IgG antibody levels were measured using ELISA. Associations between genetic risk factors, acute phase reactants, radiological joint damage, remission and anti-PTM positivity were investigated using regression, correlation and survival analyses.ResultsAnti-AGE and anti-MAA were most prevalent in RA (44.6% and 46.1% respectively) but were also present in non-RA arthritis patients (32.9% and 30.3% respectively). Anti-AGE and anti-MAA antibodies were associated with HLA-DRB1*03 within seronegative RA (OR=1.98, p=0.003, and OR=2.37, p<0.001, respectively) and, for anti-AGE also in non-RA arthritis patients (OR=2.34, p<0.001). Presence of anti-MAA antibodies was associated significantly with markers of inflammation, erythrocyte sedimentation rate and C reactive protein, in all groups independent of anti-AGE. Interestingly, the presence of anti-AGE and anti-MAA antibodies was associated with radiological progression in patients with seronegative RA, but not evidently with sustained drug-free remission.ConclusionsAnti-AGE and anti-MAA were present in around 45% of RA patients and 30% of non-RA arthritis patients, and although not specific for RA, their presence associated with HLA, inflammation and, for RA, with clinical outcomes especially in patients with seronegative RA.
Abstract A037: Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer
Authors: Uzunbas Gizem Karsli , McVeigh Quinn , Gupta Akansha , Hoyt Stephanie , Doucette Kristen , Keshishian Hasmik , Carr Steven , Yang Xiaoping , Root David , Cherniack Andrew D , Siegel Franziska , Siegel Stephan , Meyerson Matthew , Greulich Heidi 
Published: December 2023

Abstract
Molecular therapies targeting EGFR-mutant non-small cell lung cancer (NSCLC) have dramatically improved prognosis for patients with the classical activating mutations, L858R and exon 19 deletion. However, tumors harboring EGFR exon 20 insertions have been historically more difficult to target. Agents such as amivantamab and mobocertinib have recently been granted accelerated approval for treatment of lung cancer patients with exon 20 insertions, but agents with an improved selectivity profile versus wild-type EGFR are still needed. BAY 2927088, currently in phase I clinical trials, is a novel reversible inhibitor that targets EGFR exon 20 insertion mutations with decreased activity towards wild-type EGFR. Although most patients with advanced EGFR-mutant NSCLC eventually progress due to acquired resistance to EGFR inhibitors, the mechanisms of resistance to BAY 2927088 are currently unknown. Using two different methods of in vitro resistance generation by inhibitor treatment of sensitive cell lines, we identified mechanisms of intrinsic and acquired resistance to BAY 2927088 and other EGFR inhibitors. Incubation with a high concentration of inhibitor selected for drug-tolerant persister cells that underwent a transcriptional state transition resembling EMT (epithelial-mesenchymal transition). Conversely, gradual escalation of inhibitor concentrations resulted in acquisition of oncogenic NRAS mutations. In a parallel approach, we performed a deep mutational scanning assay of the EGFR D770_N771insSVD kinase domain, replacing each amino acid with every other possible amino acid, identifying both known and novel mutations that cause resistance to BAY 2927088 and other EGFR inhibitors. As expected, the C797S mutation was enriched as a mechanism of acquired resistance only to irreversible EGFR exon 20 insertion inhibitors. Surprisingly, the T790M gatekeeper mutation was found to cause resistance to all EGFR exon 20 insertion inhibitors tested, including irreversible inhibitors. Several novel resistance mutations clustering predominantly in exons 20 and 21 were also identified.
Citation Format: Gizem Karsli Uzunbas, Quinn McVeigh, Akansha Gupta, Stephanie Hoyt, Kristen Doucette, Hasmik Keshishian, Steven Carr, Xiaoping Yang, David Root, Andrew D Cherniack, Franziska Siegel, Stephan Siegel, Matthew Meyerson, Heidi Greulich. Mechanisms of resistance to BAY 2927088, the first reversible inhibitor targeting EGFR exon 20 insertion mutations in non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A037.
Abstract A038: Selective therapeutic antibodies against oncogenic mutations of HER2 ectodomain
Authors: Bang Injin , Hattori Takamitsu , Leloup Nadia , Corrado Alexis , Nyamaa Atekana , Koide Akiko , Geles Ken , Buck Elizabeth , Koide Shohei 
Published: December 2023

Abstract
Dysregulation of HER2 is a well-established mechanism of oncogenesis. Small molecule drugs targeting its kinase domain, and antibody-based drugs such as trastuzumab and pertuzumab targeting its ectodomain have shown efficacy against HER2-overexpression tumors. Separately from HER2 overexpression, oncogenic mutations in the ectodomain in HER2 have been identified in several tumors. As disease drivers that are readily accessible to biologics, these mutants are potentially attractive but still unvalidated therapeutic targets. Current anti-HER2 therapeutic antibodies are indiscriminatory of the mutational state of HER2 and their cross-reactivity to wild-type HER2 can cause toxicity. Here, we have developed antibodies exquisitely selective to HER2 S310F and S310Y, two most common oncogenic mutations in the HER2 ectodomain. These antibodies bound to both HER2 S310F/Y with &gt;100-fold selectivity over the wild-type. Cryo-EM structures of the homodimer of HER2 S310F and an antibody bound to HER2 S310F revealed that these antibodies mimic the dimerization arm of HER2 and inhibit dimerization. The developed antibodies as T cell engagers selectively killed a HER2 S310F-driven cancer cell line in vitro. These results establish the feasibility of targeted therapy against S310F/Y-driven cancers and offer promising candidates toward clinical development.
Citation Format: Injin Bang, Takamitsu Hattori, Nadia Leloup, Alexis Corrado, Atekana Nyamaa, Akiko Koide, Ken Geles, Elizabeth Buck, Shohei Koide. Selective therapeutic antibodies against oncogenic mutations of HER2 ectodomain [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A038.
Abstract A048: Novel murine models of ARID1A and PBRM1-deficient cholangiocarcinoma for preclinical discovery and development
Authors: Conboy Caitlin B. , Tomlinson Jennifer L. , Watkins Ryan D. , Millender Jayla T. , Carlson Danielle M. , Smoot Rory L. , Robertson Keith D. , Gores Greg J. 
Published: December 2023

Abstract
Genes encoding SWI/SNF chromatin remodeling complex subunits are recurrently mutated across human cancers. In cholangiocarcinoma (CCA), AT-rich interaction domain-1A (ARID1A) and polybromo-1 (PBRM1) loss of function mutations occur in approximately 18 and 10% of cases respectively. Yet our mechanistic understanding and ability to therapeutically exploit ARID1A and PBRM1 deficiency are immature. Genetically accurate preclinical models are needed to define the role of ARID1A and PBRM1 and test therapeutic approaches in CCA. Analysis of human CCA tumors showed that loss of function mutations in ARID1A and PBRM1 frequently co-occur with each other and with PI3K/AKT pathway activation. Therefore, we developed novel murine models of cholangiocarcinoma initiated by Arid1a knockout or dual Arid1a/Pbrm1 knockout in the context of AKT activation, employing a surgical biliary transfection method for somatic gene editing with CRISPR/Cas9. Mice with cholangiocyte Arid1a knockout and AKT activation (AAC) or dual Arid1a/Pbrm1 knockout and AKT activation (APAC) formed numerous liver tumors within 8 months. Histologically, tumors were predominantly CCA and mixed HCC/CCA, with a similar spectrum of tumors across AAC and APAC mice. Gene editing with CRISPR/Cas9 was confirmed at the DNA level, and loss of protein expression was confirmed in tumor cells by immunohistochemistry. Similar to human CCA, many tumors were densely infiltrated with cancer-associated fibroblasts and a variable degree of CD45+ immune cells. To generate scalable models for preclinical testing, tumors from AAC and APAC mice were dissociated to create cell lines for in vitro studies and propagated by orthotopic transplantation for in vivo studies. Cell lines and orthotopic tumors were validated and retained the genetic features and histologic characteristics of the parental tumors. Collectively these studies have produced a suite of novel, well-characterized, genetically relevant mouse models of epigenetic dysregulation in CCA due to ARID1A and PBRM1 deficiency, which can be used broadly for discovery research and preclinical testing of novel treatment approaches.
Citation Format: Caitlin B. Conboy, Jennifer L. Tomlinson, Ryan D. Watkins, Jayla T. Millender, Danielle M. Carlson, Rory L. Smoot, Keith D. Robertson, Greg J. Gores. Novel murine models of ARID1A and PBRM1-deficient cholangiocarcinoma for preclinical discovery and development [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A048.
Abstract A108: Metabolic oriented treatment: efficacy of sr59230a 𝜷3-adrenergic receptor antagonist, and sr plus buformin® in Ewing sarcoma
Authors: Banella Cristina , Zocca Laura , Boaretto Alessia , Mattei Gianluca , Mola Marina , Ballerini Lara , Nicla Lorito , Tondo Annalisa , Calvani Maura 
Published: December 2023

Abstract
Purpose of study: Metabolic targeted therapies may represent an innovative strategy in Ewing sarcoma (ES).
Introduction: Ewing sarcoma (ES) is highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. Metabolic peculiarities of ES cells are indeed involved in tumor growth, survival and resistance to therapy. We have further investigated apoptotic role of 𝜷3-adrenergic receptor (𝜷3-AR) SR59230A (SR) antagonist for its ability to reduce cells viability due increased oxidative stress, now we underline the metabolic role of SR.
Materials & Methods: The metabolic profile after SR administration in A673 ES cell model was studied using the Seahorse XF Analyzer. Viability was evaluated with MTS. Changes in gene expression was evaluated with RNA sequencing. Western blot analysis and Immunofluorescence was performed for redox signature and metabolic alteration. Ros production was assessed by flow cytometry.
Results: Quantification of transcript abundance using Salmon in A673 after SR treatment showed decrease in response to reactive oxygen species, increase of Thioredoxin Interacting Protein (TXNIP) inhibits the antioxidative function of thioredoxin, moreover reduced glucose uptake, consequently decrease NADPH/NADP resulting in the accumulation of ROS coincident with a decrease of GLUT1, SOD2, TrDX an increase of LC3IIA protein expression. SR enhances A673 pyruvate dependency, and decrease glyco and mito ATP production rate, more over observed under glucose deprivation. To inibite mitochondrial ATP production rate we proposed the metabolic oriented treatment with Buformin® (BUF) an oral antidiabetic drug of the biguanide class. BUF completely shut down mitochondrial respiration acted on complex I of electron transport chain (ETC). Buf combined with SR decrease ATP production and up-regulated ROS production in ES cells.
Conclusion: SR antagonist of 𝜷3-AR and combination of SR with BUF could be an innovative therapeutic option to raise awareness ES.
Citation Format: Cristina Banella, Laura Zocca, Alessia Boaretto, Gianluca Mattei, Marina Mola, Lara Ballerini, Lorito Nicla, Annalisa Tondo, Maura Calvani. Metabolic oriented treatment: efficacy of sr59230a 𝜷3-adrenergic receptor antagonist, and sr plus buformin® in Ewing sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A108.
Abstract A132: Pathological analysis of a newly established immunocompetent mice with full Hpv16 genome integration
Authors: Li Xue , Kothari Aditi , Rehmani Hina , Yarbrough Wendell , Isaeva Natalia 
Published: December 2023

Abstract
Human papillomaviruses (HPV) are associated with both benign and malignant epithelial lesions. High-risk HPV subtype HPV 16 is the causative agent of cervical and the majority of oropharyngeal squamous cell carcinomas. Despite the continuous increase in the disease burden, mechanisms and pathways of HPV16-induced cancer growth are not fully understood, thus leading to suboptimal treatment. In last decades, several transgenic mouse models were developed, helped tremendously to study HPV-induced carcinogenesis. However, all existent HPV transgenic mice were targeted early genes expression driven by an artificial promoter and did not encompass the functionality of the whole HPV genome, including the upstream regulatory region (URR) that contains HPV promoters, regulatory elements, and a replication origin, limited our ability to investigate HPV-associated malignant transformation and the role of host factors in this process. Therefore, we generated HPV16 transgenic mouse by using CRISPR/Cas9-mediated genome editing to insert the full-length HPV16 genome into the Rosa26 locus. Two founder mice, with single HPV copy and with tandem HPV integration, were used to establish mouse colonies. Interestingly, regardless of HPV copy number, ~50% of the HPV knock-in mice exhibited early death during the first 2 weeks after birth, while survived pups were significantly smaller than the same age wild-type mice, and had severe hair loss. Intriguingly, the growth retardant and hair loss phenotype in the HPV16 knock-in mice disappeared in ~4 weeks, most likely indicating that viral genes compromise specific stages of mouse development. We evaluated the expression of HPV genes during development, in different mouse organs, and in established fibroblasts and epithelial cell cultures. Our newly established HPV16 knock-in mouse model provides viral gene expression from natural viral promoters offering an essential basis to explore the role of cellular factors in HPV-driven pathologies.
Citation Format: Xue Li, Aditi Kothari, Hina Rehmani, Wendell Yarbrough, Natalia Isaeva. Pathological analysis of a newly established immunocompetent mice with full Hpv16 genome integration [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A132.