bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Self‐Monitoring Blood Glucose on Glycaemic Control Among Insulin‐Treated Patients With Diabetes Mellitus in Northeastern Tanzania: A Randomised Controlled Trial
Authors: Muhali Sophia S. , Muhali Fatma S. , Mfinanga Sayoki G. , Sadiq Abid M. , Marandu Annette A. , Kyala Norman J. , Said Fuad H. , Nziku Eliada B. , Mirai Tumaini E. , Ngocho James S. , Mlay Henry L. , Waria Gilbert G. , Chambega Angelina , Kessy Stella N. , Kilonzo Kajiru G. , Lyamuya Furaha S. , Mkwizu Elifuraha W. , Shao Elichilia R. , Chamba Nyasatu G. 
Published: June 2024

Introduction: Tracking of blood glucose levels by patients and care providers remains an integral component in the management of diabetes mellitus (DM). Evidence, primarily from high‐income countries, has illustrated the effectiveness of self‐monitoring of blood glucose (SMBG) in controlling DM. However, there is limited data on the feasibility and impact of SMBG among patients in the rural regions of sub‐Saharan Africa. This study is aimed at assessing SMBG, its adherence, and associated factors on the effect of glycaemic control among insulin‐treated patients with DM in northeastern Tanzania.Materials and Methods: This was a single‐blinded, randomised clinical trial conducted from December 2022 to May 2023. The study included patients with DM who had already been on insulin treatment for at least 3 months. A total of 85 participants were recruited into the study and categorised into the intervention and control groups by a simple randomization method using numbered envelopes. The intervention group received glucose metres, test strips, logbooks, and extensive SMBG training. The control group received the usual care at the outpatient clinic. Each participant was followed for a period of 12 weeks, with glycated haemoglobin (HbA1c) and fasting blood glucose (FBG) being checked both at the beginning and at the end of the study follow‐up. The primary and secondary outcomes were adherence to the SMBG schedule, barriers associated with the use of SMBG, and the ability to self‐manage DM, logbook data recording, and change in HbA1c. The analysis included descriptive statistics, paired t‐tests, and logistic regression.Results: Eighty participants were analysed: 39 in the intervention group and 41 in the control group. In the intervention group, 24 (61.5%) of patients displayed favourable adherence to SMBG, as evidenced by tests documented in the logbooks and glucometer readings. Education on SMBG was significantly associated with adherence. Structured SMBG improved glycaemic control with a HbA1c reduction of −1.01 (95% confidence interval (CI) −1.39, −0.63) in the intervention group within 3 months from baseline compared to controls of 0.18 (95% CI −0.07, 0.44) (p < 0.001).Conclusion: Structured SMBG positively impacted glycaemic control among insulin‐treated patients with DM in the outpatient clinic. The results suggest that implementing a structured testing programme can lead to significant reductions in HbA1c and FBG levels.Trial Registration: Pan African Clinical Trials Registry identifier: PACTR202402642155729.
Review and Evaluation of European National Clinical Practice Guidelines for the Treatment and Management of Active Charcot Neuro‐Osteoarthropathy in Diabetes Using the AGREE‐II Tool Identifies an Absence of Evidence‐Based Recommendations
Authors: Renwick Nichola , Pallin Jennifer , Bo Jansen Rasmus , Gooday Catherine , Tardáguila-Garcia Aroa , Sanz-Corbalán Irene , Tentolouris Anastasios , Jirkovská Alexandra , Koller Armin , Korzon-Burakowska Anna , Petrova Nina , Game Frances 
Published: June 2024

Background: Charcot neuro‐osteoarthropathy (CNO) is a rare but devastating complication of diabetes associated with high rates of morbidity; yet, many nonfoot specialists are unaware of it, resulting in missed and delayed diagnosis. Clinical practice guidelines (CPGs) have proven useful in improving quality of care and standardizing practice in diabetes and diabetic foot care. However, little is known about the consistency in recommendations for identification and management of active CNO.Aim: The aim of this study is to review European national diabetes CPGs for the diagnosis and management of active CNO and to assess their methodological rigor and transparency.Methods: A systematic search was performed to identify diabetes national CPGs across Europe. Guidelines in any language were reviewed to explore whether they provided a definition for active CNO and recommendations for diagnosis, monitoring, and management. Methodological rigor and transparency were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE‐II) tool, which comprises 23 key items organized within six domains with an overall guideline assessment score of ≥ 60% considered to be of adequate quality to recommend use. Each guideline was assessed by two reviewers, and inter‐rater agreement (Kendall’s W) was calculated for AGREE‐II scores.Results: Seventeen CPGs met the inclusion criteria. Breadth of CNO content varied across guidelines (median (IQR) word count: 327; Q1 = 151; Q3 = 790), and 53% provided a definition for active CNO. Recommendations for diagnosis and monitoring were provided by 82% and 53%, respectively, with offloading being the most common management recommendation (88%). Four guidelines (24%) reached threshold for recommendation for use in clinical practice (≥ 60%) with the scope and purpose domain scoring highest (mean (SD): 67%, ± 23%). The remaining domains had average scores ranging between 19% and 53%. Inter‐rater agreement was strong (W = 0.882; p < 0.001).Conclusions: European national CPGs for diabetes provide limited recommendations on active CNO. All guidelines showcased deficits in their methodology, suggesting that more rigorous methods should be employed for diabetes CPG development across Europe.
Abstract A007: Assessment of metabolic vulnerabilities of breast cancer brain metastasis
Authors: Abbott Keene L. , Subudhi Sonu , Ferreira Raphael , Gültekin Yetiş , Steinbuch Sophie C. , Honeder Sophie E. , Kumar Ashwin S , Wu Michelle , Ramesh Diya , Hansen Jacob , Riedmayr Lisa M. , Duquette Mark , Ali Ahmed , Henning Nicole , Sivanand Sharanya , Kunchok Tenzin , Waite Millenia , Do Brian T. , Spanoudaki Virginia , Sánchez-Rivera Francisco J. , Church George M. , Jain Rakesh K , Vander Heiden Matthew G. 
Published: June 2024

Abstract
The metastasis of cancer to the brain is a major contributor to patient morbidity and mortality. Prior work suggests that there is therapeutic potential in targeting metabolic processes within brain metastatic cancer, however how best to identify novel targets and select patient populations remains unclear. In this study, we determine what nutrients are available to breast cancer cells in the brain and how those nutrients are used. We also engineer breast cancer cells that are auxotrophic for specific nutrients and assess how this impacts tumor growth in the brain using various approaches. These methodologies include direct implantation into the brain and introduction into the circulation to evaluate tumor formation as brain metastases. Unexpectedly, we find that no single approach, including assessment of brain nutrient availability, tumor biosynthetic activity, and evaluation of genetic dependencies using in vivo CRISPR screens reliably predicts metabolic dependencies that broadly extend across models of breast cancer brain metastasis. Our findings underscore the necessity of a holistic approach in considering how best to identify and prioritize new targets for treating metastatic cancer.
Citation Format: Keene L. Abbott, Sonu Subudhi, Raphael Ferreira, Yetiş Gültekin, Sophie C. Steinbuch, Sophie E. Honeder, Ashwin S Kumar, Michelle Wu, Diya Ramesh, Jacob Hansen, Lisa M. Riedmayr, Mark Duquette, Ahmed Ali, Nicole Henning, Sharanya Sivanand, Tenzin Kunchok, Millenia Waite, Brian T. Do, Virginia Spanoudaki, Francisco J. Sánchez-Rivera, George M. Church, Rakesh K Jain, Matthew G. Vander Heiden. Assessment of metabolic vulnerabilities of breast cancer brain metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A007.
Abstract A010: Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis
Authors: Mukiza Tresor O , Enrique-Rodriguez Ricardo , Budhraja Amit , Brakefield Lauren , Moldoveanu Tudor , Opferman Joseph T 
Published: June 2024

Abstract
In the intrinsic pathway of apoptosis, death stimuli (including drugs, cellular stress, viral infections, etc.) trigger the oligomerization of BAX and BAK resulting in pore formation in the outer mitochondrial membrane to release cytochrome c from the intermembrane space. The released cytochrome c then activates APAF-1 and CASPASE9 to form a 1.4 MDa complex known as apoptosome, which recruits and activates downstream caspases that dismantle the cell. However, we have found that proteasome inhibition leads to a BAX and BAK independent apoptotic cell death. We show using immunofluorescence, fluorogenic assays, and flow cytometry that the proteasome inhibitors, bortezomib and MG-132, trigger a caspase dependent cell death that requires the apoptosome components APAF-1 and CASPASE9, but not cytochrome c. Furthermore, size exclusion chromatography revealed that unlike classical death stimuli, which induce the mega-dalton canonical apoptosome fomation, proteasome inhibitors induce a minor shift in APAF-1, forming a smaller, non-canonical apoptosome. Current efforts are focused on the identification of the APAF-1 activator. Our results indicate the existence of a non-canonical caspase-dependent cell death pathway, which could be a novel therapeutic target in malignancies by bypassing the BCL-2 family of apoptotic regulators.
Citation Format: Tresor O Mukiza, Ricardo Enrique-Rodriguez, Amit Budhraja, Lauren Brakefield, Tudor Moldoveanu, Joseph T Opferman. Proteasome inhibitors induce a BAX and BAK independent, non-canonical apoptosis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr A010.
Abstract B002: POLB knockout is synthetic lethal with PARP inhibition leading to complete and durable responses in BRCA-mutant tumor xenografts
Authors: Bandi Madhavi 
Published: June 2024

Abstract
Despite the clinical benefit of PARP1/2 inhibitors (PARPi), which are FDA-approved for the treatment of certain BRCA-mutant cancers, many patients achieve incomplete disease control and develop progressive disease. Motivated by this clinical need, we utilized our CRISPR target discovery screening platform to identify novel targets that synergize with PARP inhibitor treatment. By conducting parallel screens in both BRCA-mutant and wildtype cells, we identified DNA polymerase beta (POLB) as a novel target that - when combined with PARPi - selectively kills BRCA-mutant lines while sparing normal cells. POLB knockout and cDNA rescue experiments using both BRCA1 and BRCA2-mutant isogenic cell lines further demonstrated that the catalytic activity of POLB is required for synthetic lethality with PARPi. Most strikingly, POLB knockout combined with sub-therapeutic doses of PARPi, led to profound tumor regression and prevented in vivo tumor regrowth, even after cessation of drug treatment. Mechanistically, POLB knockout is associated with increased single and double strand DNA breaks, accumulation of poly-ADP-ribose polymers, cell cycle arrest and apoptosis. Together, these results suggest that POLB inhibitors in combination with PARPi have the potential to drive deep and durable responses providing a novel therapeutic option for cancer patients with BRCA1/2-mutations.
Citation Format: Madhavi Bandi. POLB knockout is synthetic lethal with PARP inhibition leading to complete and durable responses in BRCA-mutant tumor xenografts [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B002.
Abstract B006: Data-driven discoveries of molecular mechanism and therapeutic vulnerabilities of CDK12 mutant tumors
Authors: Yang Lixing 
Published: June 2024

Abstract
Somatic structural variations (SVs) are common in cancer. Although a small fraction of SVs in breast and ovarian cancers can be attributed to homologous recombination deficiency, the underlying molecular mechanisms for the vast majority of somatic SVs remain unclear. Here, we focus on the roles of transcription and DNA replication collisions in genomic instability in cancer. Such collisions are unavoidable in cells since both transcription and replication use the same DNA as template. We hypothesized that transcription replication collisions (TRCs), if not properly repaired, would lead to collapsed replication forks and result in SVs. To this end, we studied somatic SVs in 6193 high-coverage whole-genome sequenced primary and metastatic tumors from three independent pan-cancer cohorts. A total of 13 conserved SV signatures, representing independent molecular mechanisms, were deconvoluted from these cohorts using non-negative matrix factorization approach. We detected replicated-strand bias, the expected footprint of transcription-replication collision, in large tandem duplications (TDs) across multiple cohorts. This bias was only observed in expressed genes, consistent with TRCs depending on transcription activity. Large TDs were abundant in female-specific (breast, ovarian and uterus), upper gastric-intestinal tract, and prostate cancers. They were associated with CDK12 mutations and worse patient survival. CDK12 is a cyclin-dependent kinase, a key regulator of transcription elongation and termination. Deleting or suppressing CDK12 using CRISPR-Cas9 in prostate cell lines increased RNA:DNA hybrids (R-loops), promoted TRCs, and ultimately led to large TDs. Finally, we found that cells lacking CDK12 were sensitive to WEE1, CHK1 and ATR inhibitors. In summary, our data suggest that large TDs in cancer form due to impaired TRC repair and can be used as a biomarker for prognosis and treatment.
Citation Format: Lixing Yang. Data-driven discoveries of molecular mechanism and therapeutic vulnerabilities of CDK12 mutant tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B006.
Abstract B010: Drug tolerant persister cancer cells escape therapy-induced senescence
Authors: Fortier Anne-Marie , Topolski Jason , Alzial Gabriel , Monast Anie , Kuasne Hellen , Zuo Dongmei , Pacis Alain , Deblois Genevieve , Park Morag 
Published: June 2024

Abstract
Triple-negative breast cancer (TNBC) accounts for 15% of breast cancers and is the most aggressive subtype lacking precision oncology therapeutic strategies. Standard-of-care is predominantly chemotherapy in the neoadjuvant setting (NACT). Despite good responses, ∼40% of TNBC patients develop resistance and present residual disease at surgery. Overcoming resistance and implementing better therapeutic options is critical. Our objectives are to develop targeting opportunities for drug tolerant persister (DTP) cells which underlie residual disease. Using our unique biobank of patient derived xenografts from treatment naive as well as NACT resistant TNBC, we developed longitudinal in vivo models of residual and relapse tumors to standard-of-care therapy. Transcriptomic analysis revealed transient metabolic changes such as oxidative phosphorylation, starvation and autophagy, associated with hallmarks of senescence at residual disease. We demonstrated that therapy-induced senescent cells in vitro can escape cell cycle arrest and resume proliferation through autophagy. Interfering with autophagy impairs redox balance, promotes ferroptosis and delays tumor relapse. These results support that autophagy is a promising targetable vulnerability in TNBC residual disease.
Citation Format: Anne-Marie Fortier, Jason Topolski, Gabriel Alzial, Anie Monast, Hellen Kuasne, Dongmei Zuo, Alain Pacis, Genevieve Deblois, Morag Park. Drug tolerant persister cancer cells escape therapy-induced senescence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B010.
Abstract B016: Discovering novel synthetic lethal relationships with large-scale cellular simulations
Authors: Purcell Oliver , Lang Paul , Komianos James , Vashi Nimi 
Published: June 2024

Abstract
Synthetic Lethality (SL) is a compelling example of a large combinatorial space, with the number of (order-independent) pairwise combinations of human genes totaling approximately 400 million. When further considering higher-order combinations beyond pairs i.e. additional biomarkers that modulate the the efficacy of an SL pair, this space grows exponentially larger still. Understanding these higher-order combinations is crucial for the discovery of synthetic lethal pairs with better defined therapeutic windows and improved segmentation in clinical trials. As the size of this combinatorial space is far greater than can be searched by existing screening technologies, novel approaches are required to efficiently search this space and prioritize higher-order candidate SL combinations for screening. DeepOrigin is developing large-scale dynamical models of cellular systems to drive the in silico discovery of novel therapeutics across a range of diseases. These models can be simulated efficiently and in parallel, and are therefore ideally suited for searching large combinatorial spaces. We have applied our proprietary Cellular Simulation Pipeline to the problem of identifying higher-order combinations in Synthetic Lethality, so far predicting hundreds of novel synthetic lethal pairs. These pairs are currently being validated in vitro, and we present a selection of these results that demonstrate the utility of this approach. This approach could provide both novel therapeutic targets while providing additional stratification criteria for increased clinical study success.
Citation Format: Oliver Purcell, Paul Lang, James Komianos, Nimi Vashi. Discovering novel synthetic lethal relationships with large-scale cellular simulations [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B016.
Abstract B021: CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer
Authors: Quereda Victor , O'Brien Shane W. , Della Pietra Tony C. , Foley James J. , Fedoriw Andy 
Published: June 2024

Abstract
The extrinsic apoptotic pathway activates programmed cell death through the binding of extracellular death ligands, such as TNFα, to their cognate receptors. Although some death ligands are often upregulated in the tumor microenvironment, this pathway is subverted in cancer cells to instead favor growth and survival rather than the induction of apoptosis. Reflecting the strict control cancer cells exert over this pathway, functional genomics screens, such as DepMap, have identified several of the extrinsic apoptotic components as essential targets, with selective dependency in a subset of cancer cell lines. We have genetically validated that downregulation of CFLAR, a negative regulator of the extrinsic apoptosis pathway, causes apoptosis and cell growth inhibition alone, but specially in combination with TNFα signaling, across multiple cancer types, with increase prevalence in Triple-negative breast cancer. Furthermore, we have shown that in order to have maximal activity most cell lines require targeting of CFLAR short isoform splicing variant. Importantly, CFLAR downregulation in non-tumoral models presented much less activity than the observed in the sensitive cancer models supporting the selective activity of CFLAR in a subset of cancer cells.
Citation Format: Victor Quereda, Shane W. O'Brien, Tony C. Della Pietra, James J. Foley, Andy Fedoriw. CFLAR targeting selectively exploits extrinsic apoptosis signaling in triple-negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B021.
Abstract B024: Leveraging synthetic lethality across EP300-mutant solid cancers through selective CBP degradation
Authors: Sappal Darshan , Adam Ammar , Ahmad Hafiz , Adams Benjamin , Adhikari Ketaki , Austin Wesley , Bullock Breanna , Di Bernardo Julie , Dixon Thomas , Daniels Danette , Dominici Claudi , Elliott GiNell , Ethell Brian , Gervais Anais , Hossain Md Imran , Huang David , Lahr David , La Bonte Laura , Lin Mei Yun , Mayhew David , Mizeracka Karolina , Negretti Solymar , Nguyen Tyler , Prifti Olga , Schiller Shawn , Sherbanee Brenna , Terry David , Ucisik Nihan , Wittenborn Elizabeth , Wilson Molly M , Zhou Qianhe , Zimmerman Mark 
Published: June 2024

Abstract
CREB binding protein (CBP) and E1A binding protein P300 (EP300) are paralog histone acetyltransferases that can function as transcriptional coactivators to regulate diverse cellular processes. Mutations in CBP and EP300 have been implicated in the biology of various cancer types. Functional genomic screens have revealed a bidirectional synthetic lethal relationship between these paralogs in tumor cells, highlighting a therapeutic opportunity in targeting CBP selectively in EP300-mutant cancers while sparing other tissues in which EP300 is intact. This strategy would enable an improved therapeutic window beyond those observed with dual CBP/EP300 inhibitors, which exhibit hematological toxicities. However, due to the high degree of homology between the CBP and EP300 proteins, identifying chemical matter that selectively disrupts CBP activity has proven challenging. Here, we demonstrate selective and potent CBP degrader compounds that disrupt proliferation in EP300-mutant cancer cell line models. Notably, these degraders have little impact on cell lines with intact EP300. Moreover, in cell line-derived xenograft (CDX) tumor models, we achieve potent and sustained CBP degradation and associated tumor growth inhibition. Our CBP-selective protein degraders have the potential to be a first-in-class therapeutic option for patients with tumors harboring EP300 mutations.
Citation Format: Darshan Sappal, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudi Dominici, GiNell Elliott, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, David Lahr, Laura La Bonte, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Molly M Wilson, Qianhe Zhou, Mark Zimmerman. Leveraging synthetic lethality across EP300-mutant solid cancers through selective CBP degradation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B024.