tbuckley/cabot-search huggingface dataset:
How to make the most of your ophthalmology placement
Authors: Ping Hei Alfie Lee, James Fisher, Daniela Vaideanu-Collins
Journal: BMJ (2024)

The demand for ophthalmology services in the UK is eye wateringly high. In the past decade, ophthalmology accounted for the largest number of outpatient appointments of any medical specialty in the UK,1 and in 2019 alone, more than 450 000 cataract operations were performed across England.2 Vision is so important that we devote over one third of our brain to processing visual information.3 Yet at medical school, students' exposure to ophthalmology is often limited, with little scope for clinical experience.4 To ensure that your ophthalmology placement doesn't go past in a blur, here are some pointers to help you make the most of the experience. Familiarise yourself with the basic anatomy of the eyeball, especially the cornea, lens, and retina. Without this knowledge it will be very hard to follow what is going on in the clinic or theatre. Review common causes of vision loss and red eye—this will give you greater insight into the clinical reasoning used by clinicians in eye clinics. Ophthalmology has a unique lexicon as well as a distinctive blend of biochemistry and physics. See box 1 for some useful resources, and box 2 for an approach to taking an eye focused history. Box 1 ### Key reading materials and toolkitsRETURN TO TEXT
Development and Validation of Staging Systems for AA Amyloidosis
Authors: Marco Basset, Stefan O. Schönland, Laura Obici, Janine Günther, Eloisa Riva, Tobias Dittrich, Paolo Milani, Virginia Valeria Ferretti, Ettore Pasquinucci, Andrea Foli, Christoph Kimmich, Martina Nanci, Claudia Bellofiore, Francesca Benigna, Jörg Beimler, Pietro Benvenuti, Francesca Fabris, Roberta Mussinelli, Mario Nuvolone, Catherine Klersy, Riccardo Albertini, Giampaolo Merlini, Ute Hegenbart, Giovanni Palladini, Norbert Blank
Journal: Journal of the American Society of Nephrology (2024)

Key Points Patients with AA amyloidosis and age ≥65 years, eGFR &lt;45 ml/min per 1.73 m 2 , and N -terminal type-B natriuretic peptide &gt;1000 ng/L and/or type-B natriuretic peptide &gt;130 ng/L at diagnosis have poorer survival. Proteinuria &gt;3.0 g/24 hours and eGFR &lt;35 ml/min per 1.73 m 2 identify patients at high risk of progression to end-stage kidney failure. Prognostic stratification in AA amyloidosis can be easily made by staging systems, similarly to AL and transthyretin amyloidosis. Background The kidney is involved in almost 100% of cases of AA amyloidosis, a rare disease caused by persistent inflammation with long overall survival but frequent progression to kidney failure. Identification of patients with advanced disease at diagnosis is difficult, given the absence of validated staging systems. Methods Patients with newly diagnosed AA amyloidosis from the Pavia ( n =233, testing cohort) and Heidelberg ( n =243, validation cohort) centers were included in this study. Cutoffs of continuous variables were determined by receiver operating characteristic analysis predicting death or dialysis at 24 months. Prognostic factors included in staging systems were identified by multivariable models in the testing cohort. Results Age ≥65 years, eGFR &lt;45 ml/min per 1.73 m 2 , and elevated natriuretic peptides (type-B natriuretic peptide &gt;130 ng/L and/or N -terminal type-B natriuretic peptide &gt;1000 ng/L) were associated with overall survival and included in the staging system (all with simplified coefficients 1). Mean 36-month overall survival was lower with higher staging system scores (score 0–1: 92%; score 2: 72%; score 3: 32%). These results were confirmed in the validation cohort. For kidney failure, variables selected to enter in the staging system model were proteinuria &gt;3 g/24 hour and eGFR &lt;35 ml/min per 1.73 m 2 (both with simplified coefficients 1). The 36-month cumulative incidence of kidney failure was higher with higher staging system scores (score 0: 0%; score 1: 24%; score 2: 51%). Again, similar results were obtained in validation cohort. Conclusions We identified and validated biomarker-based staging systems for overall survival and kidney failure in AA amyloidosis.
Abstract 3175: Dear ABBIE, edit that colon cancer
Authors: David C. Aguilar, Alfred Gallegos
Journal: Cancer Research (2024)

Abstract Genome editing has exciting potential for gene therapy of cancers. Colorectal cancer is the third most occurring cancer in both men and women. The current treatments for colon cancers include surgery, radiofrequency ablation, chemotherapies and immunotherapies. These either involve removal of intestinal tissue that can alter the quality of life of the patient, or require doses of drugs that generally result in various side effects. ABBIE (A Binding Based Integrase Enzyme) genome editing can insert operational gene sequences into a chosen site in the genomic DNA of cells via its targetability and integrase activity. The ABBIE system offers ease of use, faster time to a readout and decreased time per genome editing experiment. SW480 and Caco-2 colon adenocarcinoma cells were used with the ABBIE system to integrate a GFP donor sequence into a safe harbor locus of the genome. Integration is to be confirmed with fluorescence microscopy and DNA sequencing. The colon cancer cell line will then be edited with the ABBIE genome editing system to include a gene cassette that overexpresses caspase genes into the genomic DNA of these cells. ABBIE-Edited colon cancer cell lines are expected to exhibit increased apoptosis as compared to non-edited controls or controls edited with DNA that do not have the caspase genes. This strategy will help lead to novel and more targetable treatments for colon cancer. Citation Format: David C. Aguilar, Alfred Gallegos. Dear ABBIE, edit that colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3175.
Abstract 4337: Illuminating the complex rearrangement landscape of sarcoma
Authors: Sara Waise, Tom Lesluyes, Jonas Demeulemeester, Maxime Tarabichi, Adrienne Flanagan, Nischalan Pillay, Peter Van Loo
Journal: Cancer Research (2024)

Abstract Structural rearrangements and in particular, gene fusions, are key mutational processes in bone and soft tissue tumors, used for both disease classification and as biomarkers. However, the mutational processes and rearrangement processes underlying many of these events remain poorly characterized. Recent data indicate that sarcomas show particularly high frequencies of complex rearrangement events, including patterns which do not fit those of known mutational mechanisms. As the largest whole genome sequencing (WGS) cohort of sarcomas to date, the Genomics England (GE) 100,000 Genomes project represents a unique dataset in which to profile these events. Structural variants (SVs) were identified in whole genome sequencing data for 978 samples from the Genomics England 100,000 Genomes Project using an optimized approach based on 5 specialized SV callers. SVs identified by at least 2 callers were filtered to retain only those which passed the quality filter, and to remove variants present in either matched germline samples or &amp;gt;1% of a panel of normal variants. Chromothriptic events, extrachromosomal DNA (ecDNA) and genes enriched for SVs were identified using established algorithms. The prevalence of SVs varies across sarcoma, in keeping with previous reports, with particularly high rates observed in myxofibrosarcoma and liposarcoma. As described previously, liposarcomas showed the highest rates of chromothripsis. We have examined some tumor types at higher granularity than previously available, demonstrating directly that the rates of complex rearrangement events vary across subtypes. For example, chromothriptic events are identified in 100% of well-differentiated liposarcomas, but less than 10% of myxoid liposarcomas. Similarly, the presence of ecDNA varies by tumor type, with the novel observation of particularly high rates in angiosarcoma. Using these data, we have catalogued the rearrangement patterns generating canonical gene fusions in fusion-driven soft tissue tumor types. Despite more recent advances in histological classification, survival for patients with sarcoma has remained largely unchanged for 40 years. Characterization of the mutational processes underlying these rearrangements will shed light on the pathogenesis of these tumors. Citation Format: Sara Waise, Tom Lesluyes, Jonas Demeulemeester, Maxime Tarabichi, Adrienne Flanagan, Nischalan Pillay, Peter Van Loo. Illuminating the complex rearrangement landscape of sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4337.
Abstract 1337: Characterization of anti-AXL CAR-NK cell therapy for the treatment of melanoma
Authors: Winston Hibler, Glenn Merlino, Yan Lin Yu
Journal: Cancer Research (2024)

Abstract AXL is a receptor tyrosine kinase (RTK) that is commonly expressed in metastatic melanoma and several other forms of cancer. Activation of AXL signaling is linked to tumor cell growth, invasion, metastatic transformation, drug resistance, and immune response regulation. However, treatment of metastatic melanoma continues to present clinical challenges due to its capacity to rapidly develop drug resistance, which manifests under the influence of AXL signaling. As such, AXL may be a viable antigen target for immunotherapies. Despite their successes in hematological malignancies, chimeric antigen receptor (CAR)-T cell therapies remain limited by their susceptibility to causing off-target toxicity. In contrast, natural killer (NK) cells are not associated with such risks, which makes them clinically appealing as an alternative to T cells. However, studies on the application of CAR-NK cells to treat solid tumors remain acutely scarce. To explore the clinical viability of CAR-NK cells for the treatment of metastatic melanoma, AXL-specific CAR-NK cells were generated by transfecting NK cells obtained from NK cell lines. Preliminary data from a cytotoxicity assay indicated that the cytotoxicity of CAR-NK92-MI cells against AXL-positive melanoma cell lines was significantly stronger (up to a 10-fold difference) than the corresponding parental cells. Further in vitro characterization of this CAR-NK cell line and other CAR-NK cell lines, as well as in vivo evaluation of their efficacy in a mouse xenograft model of melanoma metastasis, is underway. Citation Format: Winston Hibler, Glenn Merlino, Yan Lin Yu. Characterization of anti-AXL CAR-NK cell therapy for the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1337.
Abstract 3178: Vitamin B1 derivative, fursultiamine, prevents colon cancer growth
Authors: Sudeep Poludasu, Christian Pompoco, Kota Ramana
Journal: Cancer Research (2024)

Abstract Colon cancer is the second deadliest type of cancer in the United States, with surgical resection being the primary treatment modality for localized early-stage colon cancer. Still, more treatment and prevention options are needed to help improve the outcomes for colon cancer as they are currently limited to invasive procedures. One promising option is fursultiamine, a disulfide lipid-soluble vitamin B1 derivative, which has anti-oxidative and anti-inflammatory activity that could aid in preventing colon cancer. We hypothesize that supplementation of fursultiamine could be an effective chemopreventive treatment to control the growth and spread of colon carcinogenesis. Human colorectal adenocarcinoma (SW480) cell lines were incubated with complete media (CM) or human recombinant endothelial growth factor (EGF 20 ng/ml) in the absence and presence of fursultiamine. The cell viability was examined by MTT assay in a concentration- (0-150 uM) and time (24 and 48 h) - dependent manner. Our results indicate that fursultiamine prevents SW480 cell death in a dose-dependent manner. Apoptosis was detected by using Annexin-V staining and live and death cell assay. Our results suggest that fursultiamine prevents SW480 cell proliferation by inducing apoptotic cell death. The production of reactive oxygen species (ROS) and activation of caspase-3 were examined by specific assay kits. Treatment with fursultiamine resulted in the decreased production of ROS and activation of caspase-3. The expression of anti-apoptotic, pro-apoptotic, and pro-inflammatory factors was analyzed using antibody arrays. The results demonstrated that treatment with fursultiamine increased the expression of pro-apoptotic factors such as Bad, Bax, cleaved caspase 3, Fas/CD95, and FADD. Further, fursultiamine increased expression of the tumor suppressor genes p53, p27, and p21. We next planned to examine this vitamin B1 derivative's effect in preventing cancer growth in nude mice xenograft models. In conclusion, our in vitro results indicate that fursultiamine, a vitamin B1 derivative, prevents colon cancer growth through increased regulation of pro-apoptotic pathways and tumor suppressor proteins and thus has the potential for further development as a chemopreventative agent. Citation Format: Sudeep Poludasu, Christian Pompoco, Kota Ramana. Vitamin B1 derivative, fursultiamine, prevents colon cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3178.
Abstract 3177: Angiopoietin-like 4 suppress clear cell renal cell carcinoma via inhibition lysosomal acid lipase
Authors: Zeng Jin, Umasankar De, Tanzia Tithi, Jeremy Kleberg, Akhila Nataraj, Elena Jolley, Brandon Davies, Weizhou Zhang, Ryan Kolb
Journal: Cancer Research (2024)

Abstract Renal cell carcinomas(RCC) account for about 76,000 new cancer cases annually in the U.S. and 403,000 cases world wide. Clear cell RCC (ccRCC) is both the most common and aggressive subtype, accounting for 75-85% of cases with a 5-year survival rate of 50-69% for all cases and only 10% for metastatic disease. In our study, we report thatANGPTL4 is highly upregulated in ccRCC compared to other types of cancers and normal kidney tissues. However, we identified a cohort of patients with significantly lower expression of ANGPTL4 which had a worse prognosis compared to rest of the patients with higher expression of ANGPTL4. This subset of patients had a lower frequency of mutated VHL and were enriched for genes related to lipid metabolism. In transplant tumor models using RCC cell lines with wild-type VHL, we found that ANGPTL4 suppresses tumor growth. Moreover, loss of ANGPTL4 in ccRCC cell lines reduces colony formation in a lysosomal acid lipase (LAL) dependent manner, a phenotype that is rescued by expression of nANGPTL4. This data indicates that ANGPTL4 suppresses ccRCC tumors in a cancer cell intrinsic manner via regulation of LAL activity. This cohort of patients with low ANGPTL4 may be more dependent on lipid metabolism and less likely to respond to anti-angiogenic TKI plus immune checkpoint inhibitor therapy. Citation Format: Zeng Jin, Umasankar De, Tanzia Tithi, Jeremy Kleberg, Akhila Nataraj, Elena Jolley, Brandon Davies, Weizhou Zhang, Ryan Kolb. Angiopoietin-like 4 suppress clear cell renal cell carcinoma via inhibition lysosomal acid lipase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3177.
Abstract 3960: Establishment of humanized mouse models engrafted with luciferase-expressing acute myeloid leukemia cell lines
Authors: Emilie Bayon, Arije Mersni, Audrey Wetzel, Jade Villé, Kiave Yune Ho Wang Yin
Journal: Cancer Research (2024)

Abstract Introduction: Because acute myeloid leukemia (AML) is a very aggressive and quickly developing cancer, for which actual treatments are either inefficient, poorly tolerated, or leading to resistance, there is a strong need for an effective platform to evaluate novel therapies. Our aim is to provide a relevant humanized mouse model as a precious tool to evaluate innovated treatments to cure AML. Methods: Mice were humanized with CD34+ hematopoietic stem cells to reconstitute a complete human immune system. Three AML cell lines, namely OCI-AML2, OCI-AML3 and MOLM-14, all expressing mCherry and luciferase, were intravenously engrafted at different doses in non-humanized and CD34-humanized mice. Tumor proliferation was monitored by bioluminescence imaging (BLI) thanks to luciferase expression on tumor cells. Their expression of mCherry was also exploited to determine the presence of tumor cells in blood and tissues using flow cytometry. Results: All AML cell lines engrafted in mice, but we observed different growth kinetics and homogeneity depending on the humanization of mice and the dose injected. Indeed, tumor grew more slowly and heterogeneously in humanized mice, which underlines the role of human immune cells reconstituted in mice. This was improved by increasing the number of tumor cells injected. Tumor cells were found in femurs, spleen, kidneys, ovary, lungs, and uterus depending on the cell line. Mice survival was also highly affected by the tumor cell line engrafted. We observed that MOLM14 was the most aggressive model, while OCI-AML3 reached a steady state and were tolerated by mice over a long period. Conclusion: We established 3 different AML cell lines in a model of humanized mice which nicely recapitulates the growth of tumor cells in target organs. These 3 models behave differently in terms of growth kinetic, tolerability by mice, and organs infiltrated, which gives plenty of opportunities to evaluate novel therapies designed to cure AML. Citation Format: Emilie Bayon, Arije Mersni, Audrey Wetzel, Jade Villé, Kiave Yune Ho Wang Yin. Establishment of humanized mouse models engrafted with luciferase-expressing acute myeloid leukemia cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3960.
Abstract 3173: Impact of hypoxia on the integrated stress response activated by imipridones ONC201 and ONC206 in pediatric diffuse midline glioma cells
Authors: Tyler J. Roady, Nolan Stubbs, Josephine Chen, Yutong Xia, Ashley Sanchez Sevilla Uruchurtu, Xiaobing Tian, Lanlan Zhou, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Diffuse midline gliomas (DMGs) are highly aggressive, high-grade gliomas which typically arise in children and young adults. With currently approved treatments the median survival from time of diagnosis for pediatric DMG is 8-10 months with only 10% of children living to 2 years post diagnosis. Despite being only 15% of the cases it makes up 40% of the pediatric brain cancer deaths making it the leading cause of death for all pediatric glioma cases. Two recent clinical studies, NCT03416530 and NCT03134131, have shown the clinical efficacy of Dordaviprone (ONC201/TIC10) for the treatment of DMG; increasing median survival to 22 months in patients following radiation treatment prior to recurrence. Imipridone ONC206, a chemical derivative of ONC201, is under clinical development for treatment of pediatric and adult patients with primary brain tumors (NCT04732065 and NCT04541082). To further improve treatment, we must continue to study how the tumor microenvironment impacts the efficacy of imipridones. One crucial aspect of all brain cancers is hypoxia, so the IC50s of the SU-DIGP-25, SU-DIPG-XIII and SU-DIPGIV pediatric DMG cell lines treated with ONC201 or ONC206 were measured using the CellTiter-Glo assay under conditions of hypoxia and normoxia. Imipridones mediate apoptosis through the upregulation of the TRAIL death receptor DR5 and the activation of the integrated stress response (ISR), so western blots were used to show changes in the ISR protein expression in ONC201 treated DMG cells at multiple different degrees of hypoxia. To understand how hypoxia inducible factors (HIFs) play a role in resistance and susceptibility to ONC201 or ONC206, HIF-1a, HIF-2a, and HIF-3a were knocked down showing altered ISR protein expression after treating with the imipridones under hypoxic and normoxic conditions. Citation Format: Tyler J. Roady, Nolan Stubbs, Josephine Chen, Yutong Xia, Ashley Sanchez Sevilla Uruchurtu, Xiaobing Tian, Lanlan Zhou, Wafik S. El-Deiry. Impact of hypoxia on the integrated stress response activated by imipridones ONC201 and ONC206 in pediatric diffuse midline glioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3173.
Abstract 134: ZEB2 as a therapeutic target in fusion-positive rhabdomyosarcoma
Authors: Assil Fahs, Aanandi Munshi, Leen Barbar, Seth Zimmerman, Chris Counter, Corinne Linardic
Journal: Cancer Research (2024)

Abstract Rhabdomyosarcoma (RMS) is a highly aggressive childhood soft tissue cancer with skeletal muscle histogenesis. It is classified at the molecular level into fusion-negative (FN) and fusion-positive (FP) subtypes, with FP subtypes being defined by their signature oncofusions between the transcription factors PAX3 (or PAX7) and a variety of 3’ partners. Patients with FP-RMS have a five-year survival of &amp;lt30%, and current treatments remain ineffective against the driving oncofusions. To address this challenge, we are interested in identifying proteins that interact with the oncofusions as alternate therapeutic targets, and conducted an unbiased proximity labeling screen for seven of the known RMS oncofusions. This approach revealed that ZEB2 is a common member of the interactome for all seven FP-RMS subtypes. ZEB2 is a DNA-binding transcriptional repressor that interacts with SMAD proteins and is known to be important for coordinating muscle and nerve development during embryogenesis. ZEB2 has been identified as an oncogene in various cancer types such as leukemia, glioblastoma, lung, and breast cancers. Further analysis of ZEB2's expression in FP-RMS cell lines, compared to skeletal muscle and other cancer cell lines, showed significantly higher levels of expression. In silico analyses of genomic CRISPR and RNAi screens in DepMap suggested a strong dependency of FP-RMS on ZEB2, with ZEB2 being one of the top four differential CRISPR dependencies in RMS cell lines compared to all other cancer cell lines. To investigate the functional consequences of ZEB2 suppression, we employed a loss-of-function approach using RNAi (siRNA and shRNA) in human FP-RMS cells. Our experiments confirmed the knockdown of ZEB2 through qRT-PCR and immunoblotting. Interestingly, the extent of ZEB2 knockdown determined whether FP-RMS cells underwent apoptosis or differentiation, potentially towards a neurodifferentiation pathway. We hypothesize that ZEB2 holds potential as a therapeutic target for FP-RMS patients. We aim to elucidate ZEB2's phenotypic role and mechanism of action in FP-RMS tumorigenesis, and assess its value as a therapeutic target in vivo. Our long-term goals for this project are to contribute to the development of innovative therapies that can mitigate the oncogenic activity driven by oncofusions in FP-RMS. Citation Format: Assil Fahs, Aanandi Munshi, Leen Barbar, Seth Zimmerman, Chris Counter, Corinne Linardic. ZEB2 as a therapeutic target in fusion-positive rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 134.