Common Type Research Articles

Morphological classification, anatomical variations, innervation patterns, musculocutaneous nerve relation of the coracobrachialis muscle: Anatomical study and clinical significance.

The anatomical variations of coracobrachialis muscle (CBM) are of great clinical importance. This study aimed to elucidate the morphological variations, innervation patterns and musculocutaneous nerve (MCN) relation to CBM. Upper limbs of fifty cadavers (30 males and 20 females) were examined for proximal and distal attachments, innervation pattern of CBM and its relation to MCN. Four morphological types of CBM were identified according to number of its heads. The commonest type was the two-headed (63.0%) followed by the single belly (22.0%), three-headed (12.0%) and lastly four-headed (3.0%) type. Moreover, an abnormal insertion of CBM was observed in four left limbs (4.0%); one inserting into the medial humeral epicondyle, the second into the upper third of humeral shaft, the third one in the common tendon of biceps, and the fourth one showing a bifurcated insertion. Also, four different innervation patterns of CBM were identified including MCN (80.0%), lateral cord (14.0%), lateral root of median nerve (4.0%), and median nerve itself (2.0%). The course of MCN was superficial to the single belly CBM (19.0%) and in-between the heads in the other types (71.0%). Measurements of the length and original distance of CBM muscular branches originating from MCN revealed no sex or side significant difference. Awareness of the anatomic variations, innervation patterns, and MCN relation of CBM is imperative in recent diagnostic and surgical procedures to obtain definite diagnosis, effective management and good outcome.

Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation.

Colorectal cancer (CRC) is one of the world's most common types of malignancy. The proliferation of precancerous lesions causes this type of cancer. Two distinct pathways for CRC carcinogenesis have been identified: the conventional adenoma-carcinoma pathway and the serrated neoplasia pathway. Recently, evidence has demonstrated the regulatory roles of noncoding RNAs (ncRNAs) in the initiation and progression of precancerous lesions, especially in the adenoma-carcinoma pathway and serrated neoplasia pathway. By expanding the science of molecular genetics and bioinformatics, several studies have identified dysregulated ncRNAs that function as oncogenes or tumor suppressors in cancer initiation and formation by diverse mechanisms via intracellular signaling pathways known to act on tumor cells. However, many of their roles are still unclear. This review summarizes the functions and mechanisms of ncRNAs (such as long non-coding RNAs, microRNAs, long intergenic non-coding RNAs, small interfering RNAs, and circRNAs) in the initiation and formation of precancerous lesions.

A Common Arts Instructional Method and the Logic of Design

Abstract For almost 300 years, five different art forms have used the same instructional method. This Common Arts Instructional Method (CAIM) can be explained using a variety of theories. The CAIM also offers the opportunity to understand instructional methods under the banner of design: instances of types rather than applications of laws or principles. The differences between theory and design are explored, and some recommendations are offered for striking new instances of this common type.

Determining the Performance Limits of LDMOS With Three Common Types of Field Oxides

Determining the Performance Limits of LDMOS With Three Common Types of Field Oxides

Recent Advances in Nanobiotechnology for the Treatment of Non-Hodgkin's Lymphoma.

Lymphoma is the eighth most common type of cancer worldwide. Currently, lymphoma is mainly classified into two main groups: Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with NHL accounting for 80% to 90% of the cases. NHL is primarily divided into B, T, and natural killer (NK) cell lymphoma. Nanotechnology is developing rapidly and has made significant contributions to the field of medicine. This review summarizes the advancements of nanobiotechnology in recent years and its applications in the treatment of NHL, especially in diffuse large B cell lymphoma (DLBCL), central nerve cell lymphoma, and follicular lymphoma. The technologies discussed include clinical imaging, targeted drug delivery, photodynamic therapy (PDT), and thermodynamic therapy for lymphoma. This review aims to provide a better understanding of the use of nanotechnology in the treatment of non-Hodgkin's lymphoma.

Experimental Analysis on Partial Replacement of Cement by Glass Powder and Using of Steel Fiber

Abstract: Concrete consists of fine aggregate, coarse aggregate, water, and optional admixtures, such as Portland cement or another hydraulic cement. Because of its massive resource consumption, the concrete industry poses a serious danger to the sector's long-term viability. The concrete industry is struggling in part because of concerns about the environment and the economy. Many studies are currently being conducted on the utilisation of waste materials like Pulverised Fly Ash (PFA) and Ground Granulated Blast Furnace Slag (GGBS) as supplemental cementitious materials. Similar to PFA and GGBS, waste glass powder can be used to partially substitute cement during the hydration reaction. To some extent, waste glass can substitute cement in concrete and contribute to strength development if it is ground to a very fine powder and demonstrates pozzolanic properties due to its high SiO2 content. This research examined the Compressive, Tensile, and Flexural strengths of concrete that had been aged for up to 60 days with concrete that had been partially replaced with Glass Powder at percentages ranging from 0% to 40%. The aggregate test findings suggest that Waste Glass Powder could be used as a suitable cement replacement in construction projects. Fibre reinforced concrete (FRC) is a composite building material made from small, discontinuous fibres that are randomly distributed throughout the concrete part. Steel, glass, and polymer fibres, as well as fibres originating from natural sources, are the most common types of fibre used in cement-based composites. The tendency of fibres to be more closely spaced than traditional reinforcing steel bars makes them more effective at preventing cracking. It's important to note that fibre is not a suitable replacement for steel bars when reinforcing concrete.

(PM-15) THE EFFECT OF A PELVIC FLOOR TRAINING PROGRAM APPLIED IN PREGNANT WOMEN WITH URINARY INCONTINENCE

Abstract Introduction Urinary incontinence is a common symptom during pregnancy, the most common type of incontinence in pregnant women is SUI. Stress urinary incontinence affects 54% of all pregnant women. These symptoms are usually experienced during pregnancy and postpartum and can negatively affect quality of life, interfering with social, professional and family activities. Pelvic floor muscle training supervised by a therapist is an effective treatment for UI in women and has been shown to be effective; However, there is still clinical uncertainty about the application of these exercises in pregnant women. Objective The objective of this study is to conduct a review of the literature and present the effect of pelvic floor exercise in pregnant women with urinary incontinence, in order to validate whether there are benefits or not. Methods An integrative review of the literature was carried out, surveys were carried out in the electronic databases PubMed and PEDro, using the descriptors “Exercise”, “Physical Activities”, “Urinary Incontinence” and “Pregnant Women”. Only randomized clinical trials were selected and the search was carried out between April and May 2022. Results 71 studies were found, only 10 met the established criteria and agreed with the objective of the present review. Conclusion An integrative review of the literature was carried out and it was observed that pelvic muscle training helps reduce urinary incontinence in pregnant women and promotes a better quality of life, without associated risks. Financing No conflict.

Impact of Sexual Abuse on Post-Traumatic Stress Disorder in Children and Adolescents: A Systematic Review

Child sexual abuse (CSA), the most common type of maltreatment, is any action of a sexual nature by one or more adults towards a minor without the minor’s consent. This abuse represents one of the most damaging forms of trauma, has a severe impact on mental health and psychopathology, and can lead to several disorders, including post-traumatic stress disorder (PTSD). PTSD is characterized as a disorder that encompasses physical symptoms resulting from traumatic experiences that are experienced or witnessed by the victim. This systematic review aims to understand the impact of sexual abuse on post-traumatic stress disorder in children and adolescents. Studies focusing on the relationship between these two variables were obtained through multiple databases. Of the 940 documents collected, 24 were retained for further analysis and the objectives, methodologies, results, and main conclusions were registered. One of the main conclusions was that the earlier the abuse starts and the more severe and long-lasting it is, the symptomatology of PTSD will be aggravated and remain in the long term.

Registration, incidence patterns, and survival trends of central nervous system tumors among children in Germany 1980-2019: An analysis of 40years based on data from the German Childhood Cancer Registry.

Tumors of the central nervous system (CNS) are the second most common type of pediatric cancer in Germany. We aimed to describe registration practice, incidence, and survival patterns for childhood CNS tumors in Germany for the past 40years. Including all CNS tumor cases in children diagnosed at ages 0-14years registered at the German Childhood Cancer Registry (GCCR) in 1980-2019 (for survival analysis 1980-2016), we calculated age-specific and age-standardized incidence rates (ASIR) over time, average annual percentage changes (AAPC), and 1- and 5-year overall survival. While we observed a pronounced increase in ASIR after the establishment of the GCCR during the 1980s, ASIR for all pediatric CNS tumors combined continued to increase markedly from 28.6 per million in 1990-1999 to 43.3 in 2010-2019 (AAPC=2.7% in 1991-2010, AAPC=0.3% in 2010-2019). The 5-year overall survival from CNS tumors improved from 63% in the 1980s, 70% in the 1990s to 79% in 2010-2016. These improvements have occurred across all age groups. Children diagnosed with ependymomas and choroid plexus tumors experienced the strongest increase (from 54% to 81%). Observed increases in incidence rates for pediatric CNS tumors are likely only partially caused by actual increasing case numbers. The majority is a function of improved registration and, to a minor extent, improvements in diagnostics. Survival from pediatric CNS tumors has, by and large, improved consistently, leading to a growing population of childhood cancer survivors with diverse health biographies and risk of lifelong adverse impact on health and wellbeing.

Investigation of Fourier Transform Infrared (FT-IR) Spectroscopy and Chemometric Analysis Method as an Alternative Method in the Diagnosis of Prostate Cancer

Prostate cancer is one of the most common types of cancer in men. It usually grows slowly and may not show obvious symptoms at first. Prostate cancer can be diagnosed by symptoms or by a doctor performing certain tests during routine health checkups. These tests include physical examination, PSA (Prostate Specific Antigen) Test, biopsy, imaging techniques, and Gleason score. In addition, Fourier transform infrared spectroscopy (FT-IR) is an analysis method used for prostate cancer diagnosis. This study aims to demonstrate FT-IR spectroscopy as an alternative method to other diagnostic methods in the diagnosis of prostate cancer. The FT-IR spectroscopy method is used to examine the molecular structure of samples. For prostate cancer diagnosis, FT-IR spectroscopy can be used to identify molecular changes in prostate tissue and identify characteristics by which cancerous cells differ from healthy cells. FT-IR spectroscopy is based on spectral data obtained by exposing samples to infrared radiation. These spectral data are based on properties associated with the movements of the molecules contained in the samples, such as vibration, rotation and bending. Molecular changes caused by diseases such as prostate cancer may be evident in these spectral data. These changes can provide information about the presence or stage of cancerous cells. Data obtained using FT-IR spectroscopy is processed with statistical analysis methods. These analyses are used to identify molecular differences between cancerous and healthy prostate tissues. In this way, FTIR spectroscopy can help obtain sensitive and accurate results in the diagnosis of prostate cancer.

Mining Gaze for Contrastive Learning toward Computer-Assisted Diagnosis

Obtaining large-scale radiology reports can be difficult for medical images due to ethical concerns, limiting the effectiveness of contrastive pre-training in the medical image domain and underscoring the need for alternative methods. In this paper, we propose eye-tracking as an alternative to text reports, as it allows for the passive collection of gaze signals without ethical issues. By tracking the gaze of radiologists as they read and diagnose medical images, we can understand their visual attention and clinical reasoning. When a radiologist has similar gazes for two medical images, it may indicate semantic similarity for diagnosis, and these images should be treated as positive pairs when pre-training a computer-assisted diagnosis (CAD) network through contrastive learning. Accordingly, we introduce the Medical contrastive Gaze Image Pre-training (McGIP) as a plug-and-play module for contrastive learning frameworks. McGIP uses radiologist gaze to guide contrastive pre-training. We evaluate our method using two representative types of medical images and two common types of gaze data. The experimental results demonstrate the practicality of McGIP, indicating its high potential for various clinical scenarios and applications.

Abstract 2552: Real-world analysis of biomarker testing and use of targeted therapies in metastatic non-small cell lung cancer (mNSCLC) in the United States (US)

Abstract Background: Between 1998 and 2022, over 40% of new oncology drugs approved by the US FDA were precision therapies. In nonsquamous mNSCLC, detecting biomarkers where targeted therapies exist (EGFR, ALK, ROS1, BRAF V600E variant, MET exon 14 skipping variant, RET and PD-L1) has become essential for adequate clinical care. This study investigated real-world use of these biomarker tests, their characteristics, and associated use of targeted therapies in mNSCLC patients in the US. Methods: Adults ≥18 years old with stage IV mNSCLC from the nationwide Flatiron Health electronic health record-derived de identified database (01/2011 - 04/2023). The proportion of patients receiving biomarker tests, timing, characteristics, test type (single, multiple or next-generation sequencing), and proportion of patients receiving guideline recommended associated targeted therapies (i.e. actionable treatment) was assessed. Actionable treatment was defined in study years where at least one actionable therapy was FDA approved (biomarker, therapy, date: ALK, crizotinib, Aug 2011; BRAF V600E, dabrafenib+trametinib, Jul 2015; EGFR, afatinib, Jul 2013; MET exon 14 skipping, capmatinib, May 2020; PD-L1, pembrolizumab, Oct 2015; RET, pralsetinib, Sep 2020; ROS-1, crizotinib, Mar 2016). Results: In 42,037 patients with mNSCLC, the proportion of patients receiving each test were: ALK: 71.6%, BRAF: 48.8%, EGFR: 74.9%, MET: 41.4%, PD-L1: 49.3%, RET: 42.3%, and ROS1: 54.2%. Median (Q1, Q3) time from mNSCLC diagnosis to first biomarker result was 21 (12, 37) days. Tissue was the most common sample type for biomarker testing, although sampling by blood has increased in recent years. Multiple testing methods were more common in ALK and PD-L1 (48.1% and 50.3%, respectively) and next generation sequencing was more common in the other biomarkers (BRAF: 77.7%, EGFR: 57.1%, MET: 74.1%, RET: 70.7%, ROS1: 54.0%). Testing rates increased from 2011 through 2023 for each biomarker, with the highest rates in 2023: ALK (87.7%), BRAF (85.2%), EGFR (88.7%), MET (85.7%), PDL1 (78.7%), RET (84.8%), and ROS1 (86.9%). Testing rates were similar when timing was restricted to a 1-year window from mNSCLC diagnosis. Receipt of actionable treatment varied by biomarker, in order of increasing frequency: RET+ (23.0%), MET+ (34.0%), BRAF+ (42.7%), PDL1+ (56.3%), ROS1+ (59.8%), EGFR+ (70.6%), and ALK+ (89.0%). Generally, across all biomarkers, receipt of actionable therapy increased in more recent years. Conclusion: Current real-world biomarker testing rates and use of actionable treatments may reflect increased adoption of clinical guideline recommendations. Despite increased testing, use of actionable therapy remains low for certain biomarkers. Further improvements in the implementation of robust biomarker testing to use appropriate therapies are needed, which can lead to better patient outcomes. Citation Format: Michael J. Dennis, Devin Abrahami, Maria Cecilia Vieira, Darrin Benjumea, Marley Boyd, Anran Shao, Kirsten Duncan, John Kelton, Sandip P. Patel. Real-world analysis of biomarker testing and use of targeted therapies in metastatic non-small cell lung cancer (mNSCLC) in the United States (US) [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 2552.

Abstract 3433: Characterization of co-occurring clonal hematopoiesis to identify high risk clones associated with hematologic cancer risk

Abstract Clonal hematopoiesis (CH) is the age-related clonal expansion of hematopoietic cells as a result of acquired mutations in driver genes, commonly referred to as clonal hematopoiesis of indeterminate potential (CHIP), or due to large-scale mosaic chromosomal alterations (mCAs). While the type and genomic location of CH exhibits varying associations with hematological parameters as well as lymphoid and myeloid malignancy risk, few studies have examined the co-occurrence of CH types. We characterized the frequency of co-occurring CH and examined the association of co-occurring CH with various cancer-related phenotypes to identify potential high-risk clones associated with hematologic cancer risk. We analyzed sequencing and genotyping array data from 453,807 participants in the UK Biobank to detect CHIP and mCAs. In total, 83,240 (18.3%) individuals had at least one detectable type of CH, with increasing age strongly associated with increasing frequency of CH (P < 2 × 10−16). The most common type of CH was mCAs (N= 67,081 (14.7%)), with mosaic loss of the Y (mLOY) and X (mLOX) chromosomes being most frequently observed in males and females, respectively. We noted inverse associations between mLOY or mLOX with autosomal mCAs, but positive associations between some autosomal mCAs (e.g., chr3 and chr18 mCAs). CHIP was detected in 20,354 (4.5%) individuals, with mutations in DNMT3A, TET2, and ASXL1 most common. Similar to mCAs, some forms of CHIP were inversely associated (e.g., DNMT3A CHIP with most other CHIP mutations) while others displayed positive associations (e.g., JAK2 CHIP with NFE2 CHIP), suggesting both instances of mutual exclusivity as well as cooperation. We likewise noted several instances of CHIP and mCAs co-occurring (e.g., MYD88 and chr18 mCAs) and overlapping (e.g., JAK2 and 9p24 mCAs) more frequently than expected. Compared to those with no CH, participants with CH had notable alterations in blood cell counts, leukocyte telomere length (LTL), and elevated hematologic cancer risk even after adjusting for age, sex, smoking, and genetic ancestry. Furthermore, co-occurring CH had more pronounced associations, with the greatest alterations and hematologic cancer risk generally noted in participants with overlapping CHIP and mCAs (e.g., MYD88 and 3p22 mCAs). These findings highlight substantial enrichment in CH co-occurrences, particularly in the positional overlap of CHIP and mCAs, and indicate an increased risk of hematological malignancies when CH types overlap (HR = 29.5, 95% CI [24.0, 36.3], P < 2 × 10−16). Overall, this study details the landscape of co-occurring CH and nominates high risk co-occurrences with strong implications for future hematological malignancy risk. Citation Format: Kara M. Barnao, Aubrey K. Hubbard, Weiyin Zhou, Irenaeus Chan, Duc Tran, Yin Cao, Stephen J. Chanock, Kelly L. Bolton, Mitchell J. Machiela. Characterization of co-occurring clonal hematopoiesis to identify high risk clones associated with hematologic cancer risk [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 3433.

Abstract 5431: Identification of serine/threonine kinase 39 (STK39) as a driver for multidrug resistance in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is a common type of cancer globally and is associated with a poor prognosis due to its high recurrence rate and resistance to treatment. Solid evidence showed the existence of cancer stem cells (CSCs) that are crucial for therapeutic resistance. However, there are only a few kinase inhibitors that have been found to specifically target liver T-ICs for the HCC treatment. To understand the regulatory mechanism of liver CSCs, we employed RNA-Seq analysis to compare the gene expression profiles, with a particular focus on protein kinases, between (1) sorted CD133+ liver CSCs and CD133- differentiated cells extracted from two HCC cell lines (Huh7 and PLC8024), as well as cultured hepatospheres and adherent differentiated cells of HCC cell line PLC/PRF/5. Our analysis identified Serine/Threonine kinase 39 (STK39) as a commonly up-regulated protein kinase in both CD133+ liver CSCs and CSC-enriched hepatospheres. Based on our analysis of the TCGA data, a positive correlation has consistently been observed between STK39 mRNA expression and the expression of liver CSC markers, including CD24, CD133, and CD47. Utilizing publicly available transcriptome datasets from the NCBI Gene Expression Omnibus (GEO), including GSE14520 and GSE25097, we found that overexpression of STK39 is detected in HCC tumor tissues (p<0.001) and is significantly associated with poorer overall survival and disease-free survival. Through the use of lentiviral based overexpression and knockdown approaches, we have demonstrated the role of STK39 in regulating liver CSC properties, including self-renewal, tumorigenicity, cell invasiveness, and the expression of liver CSC markers. STK39 expression was found to be significantly elevated in in HCC cells that were resistant to both sorafenib and lenvatinib, and its inhibition resulted in increased sensitivity of HCC cells to these treatments. To identify the downstream target of STK39 for regulation of cancer stemness, tandem affinity purification coupled with mass spectrometry was employed. The analysis led to the identification of PARP1 as a novel protein binding partner of STK39. Upon suppression of STK39 in HCC cells, it was observed that the phosphorylation of PARP1 at Threonine 368 (T368) was significantly inhibited, indicating its role as a downstream effector of STK39-mediated liver CSC functions. Interestingly, STK39-mediated PARP1 phosphorylation led to development of resistance to PARP1 inhibitor, rucaparib. Additionally, STK39 plays a critical role in regulating PARP1-mediated chromatin decondensation, which enables it to open chromatin structure at the promoter regions of SOX2/OCT4. In summary, treatment of molecular targeted drugs including rucaparib and lenvatinib with STK39 inhibitor may be a potential therapeutic strategy for treatment of this deadly disease. Citation Format: Carmen Oi Ning Leung, Terence Kin-Wah Lee. Identification of serine/threonine kinase 39 (STK39) as a driver for multidrug resistance in hepatocellular carcinoma [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 5431.

Abstract 5411: Effect of different fatty acids on ccRCC behavior and metabolism

Abstract Introduction: Clear Cell Renal Cell Carcinoma (ccRCC) is the most common type of kidney cancer, presenting with defining characteristics of increased lipid droplets formation, loss of the VHL tumor suppressor, and low levels of fatty acid oxidation (FAO). Obesity is associated with an increase in ccRCC incidence, although obese patients respond better to different therapies, a phenomenon called as obesity paradox. The consumption of diets rich in lipids and leading to obesity has been increasing, but how the dietary composition affects ccRCC progression, or could be modulated in combination with other therapies for better responses is still unclear. In the present study, we aimed to evaluate how different fatty acids (FAs) affect ccRCC behavior and metabolism. Methods: We used 786-O and 769-P ccRCC cell lines. Palmitic acid (PA), oleic acid (OA), and linoleic acid (LA), which are saturated, monounsaturated, and polyunsaturated fatty acids, respectively were used as stimuli for the cells at 50 or 200µM. All stimuli were diluted in culture media with 5% FBS. Lipid droplets were evaluated by Oil Red O staining; viability was assessed by MTT; protein expression was tested by Western Blotting; Oxygen Consumption rate (OCR) by Seahorse; survival was quantified by clonogenic assay; and mRNA was measured by RT-qPCR. Results: All FAs increased the amount of lipid droplets compared to the control, but OA was the most potent. PA impaired the growth rate for cells compared to control, and other FAs in both cell lines, and did not increase the expression of cleaved caspase-3. PA, even in a lower concentration [50µM], impaired the formation of colonies for both cell lines compared to control and other FAs. LA impaired colony formation only in the higher concentration [200µM], while OA only induced a difference for 769-P cells at the smaller concentration, increasing the number of colonies. OA, and mainly PA, decreased 769-P cells migration, at the time of 6 and 12 h, while only PA decreased migration for 786-O cells, at the time of 12 h. LA, and mainly PA, increased CPT1a mRNA levels in 786-O cells but did not induce a significant difference to 769-P, and all FAs decreased FASN in both cell lines. Conclusion: It was demonstrated that OA was a potent inducer of lipid droplet formation, which can be protective in avoiding lipid peroxidation. On the other hand, PA and LA induced fewer lipid droplets probably because they are going to FAO, as we observed increased mRNA CPT1a levels, which is the rate-limiting enzyme in FAO. PA impaired potentially the formation of colonies and growth rate, and it is important to highlight that it was without inducing caspase 3-dependent programmed cell death. Taken together our data suggest that PA could be a target therapy for ccRCC, but it is still necessary for more studies in vitro and in vivo to evaluate how PA and enriched lipid diet can impact a better outcome for patients. Citation Format: Isadora Ramos de Andrade, Dazhi Wang, Scott Welford. Effect of different fatty acids on ccRCC behavior and metabolism [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 5411.

Abstract 2583: [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging

Abstract Introduction & Purpose: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. To date, the imaging of HCC is difficult, insufficient for disease staging and barely improved over the past decades. Glypican-3 (GPC3) is a cell-surface receptor highly expressed by HCC and of diagnostic and prognostic value. GPC3 has been reported as potential target for diagnosis and treatment of HCC for nuclear theranostics. RYZ-GPC3 is a DOTA modified macrocyclic peptide with high affinity for GPC3, which may allow PET imaging or nuclear therapy. Here we report the first clinical results of [68Ga]Ga-RYZ-GPC3 PET-imaging in patients with known or suspected HCC. Methods: [68Ga]Ga-RYZ-GPC3 was obtained upon labeling the peptide precursor with 68Ga from a 68Ge/68Ga-generator and heating till 90⁰C for 10 min followed by sterile filtration. After administration of 2 MBq/kg [68Ga]Ga-RYZ-GPC3, a 60 min dynamic PET scan was acquired or multiple static PET/CT were acquired at 20 min, 1, 2 and 4 hours. Besides qualitative interpretation, standardized uptake values (SUVmax, SUVmean) were measured in various compartments; HCC lesions, healthy liver (HL), kidneys, blood pool activity in the left ventricle (BP) and gastric fundus. Additionally, tumor-to-healthy liver ratios (TLR) were calculated: SUVmean,HCC divided by SUVmean,HL. Results: Radiolabeling to obtain [68Ga]Ga-RYZ-GPC3 was near quantitative, making the production highly reliable. Eleven patients (4 patients dynamic; 7 patients static protocol) were scanned. One patient did not have an HCC. Another patient had a concurrent metastatic prostate adenocarcinoma, which did not show uptake, both qualitatively and quantitatively. All HCC lesions showed uptake in qualitative assessment, even in immunohistochemistry confirmed GPC3-negative HCC lesions (3 lesions). In 23 HCC lesions, including the aforementioned GPC3-negative lesions, mean SUVmax was 17.9 (range 2.7-95.3) and mean SUVmean was 10.2 (range 1.0-49.2) at 60 minutes. Uptake in HL and BP decrease over time and become negligible 45 minutes after administration (SUVmean <1.5). The opposite occurs for HCC and TLR, which continuously increase up to 4 hours after administration (TLR 4.4 to 19.2, at 18 minutes and 4 hours respectively). In individual lesion analysis, TLR was the highest at 60 or 120 minutes post-injection scans. Uptake in the gastric fundus, gradually increases in the first hour, and decreases gradually afterwards (SUVmean from 4.0 to 12.7, back to 10.1). Conclusions: [68Ga]Ga-RYZ-GPC3 is the first peptide based PET tracer that allows the high quality molecular imaging of HCC. Thereby [68Ga]Ga-RYZ-GPC3 is suitable for the selective diagnosis of HCC. In addition, based on the biodistribution and in vivo dynamics on these diagnostic images, RYZ-GPC3 is very likely to hold therapeutic potential upon labeling with a therapeutic isotope (e.g 177Lu or 225Ac). Citation Format: Arthur J.A.T. Braat, Alex J. Poot, Constantin Lapa, Marnix G.E.H. Lam, Wolfgang A. Weber, Anna Karmann, Ye Yuan, Jessica Rearden, Ken Song, Ralph A. Bundschuh. [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging [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 2583.

Abstract 631: Functional genetics of APR-246 rescuable TP53 mutants

Abstract TP53, often referred to as the guardian of the genome, encodes for the p53 tumor suppressor protein, and is one of the most frequently mutated genes in human cancers. Some cancer sub-types, such as non-small cell lung carcinoma (NSCLC) and high grade serous carcinoma (HGSC), have high TP53 mutation rates reaching up to 56% and 96%, respectively. Given its multi-faceted role in human cancers, there have been several emerging therapeutic approaches targeting mutant p53. APR-246 is a small molecule drug currently in clinical trials for the functional rescue of p53 missense mutants, the most common type of p53 mutant protein, across various cancer types. APR-246 is proposed to bind mutant p53 and promote thermodynamic stabilization of the protein allowing it to regain wild-type-like conformation and consequentially regain WT-like functionality. However, there has yet to be a functional genomic screening of p53 mutants to systematically catalog which mutants are rescuable by APR-246. To address this critical gap, we have performed functional genetic screenings using a TP53 mutagenesis library. This pooled lentiviral library contains ~8,000 amino acid variants, spanning the entirety of the TP53 gene. Following stable transduction of this library into p53-null NSCLC and HGSOC cell lines, we performed functional screenings against sublethal doses of APR-246. Next-generation sequencing of the untreated and treated cell population allows for comparison of variant representation and determination of APR-246-sensitivity of p53 mutants. Preliminary statistical analysis of our screens has identified a pool of 117 “hit” mutants which are significantly depleted following treatment, indicative of APR-246-sensitivity. Two of these mutants, C242F and G266V, are non-functional, damaging mutations which occur in patients. Identifying p53 mutants that can be rescued by APR-246 will help identify which patients may benefit most from treatment with the drug. Citation Format: Anais Saunders, Caili Tong, Anthony N. Karnezis, Gary S. Leiserowitz, Jeremy R. Chein. Functional genetics of APR-246 rescuable TP53 mutants [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 631.

Multiple Genomic Landscapes of Recombination and Genomic Divergence in Wild Populations of House Mice-The Role of Chromosomal Fusions and Prdm9.

Chromosomal fusions represent one of the most common types of chromosomal rearrangements found in nature. Yet, their role in shaping the genomic landscape of recombination and hence genome evolution remains largely unexplored. Here, we take advantage of wild mice populations with chromosomal fusions to evaluate the effect of this type of structural variant on genomic landscapes of recombination and divergence. To this aim, we combined cytological analysis of meiotic crossovers in primary spermatocytes with inferred analysis of recombination rates based on linkage disequilibrium using single nucleotide polymorphisms. Our results suggest the presence of a combined effect of Robertsonian fusions and Prdm9 allelic background, a gene involved in the formation of meiotic double strand breaks and postzygotic reproductive isolation, in reshaping genomic landscapes of recombination. We detected a chromosomal redistribution of meiotic recombination toward telomeric regions in metacentric chromosomes in mice with Robertsonian fusions when compared to nonfused mice. This repatterning was accompanied by increased levels of crossover interference and reduced levels of estimated recombination rates between populations, together with high levels of genomic divergence. Interestingly, we detected that Prdm9 allelic background was a major determinant of recombination rates at the population level, whereas Robertsonian fusions showed limited effects, restricted to centromeric regions of fused chromosomes. Altogether, our results provide new insights into the effect of Robertsonian fusions and Prdm9 background on meiotic recombination.

Systematic characterization of p53-regulated long non-coding RNAs across human cancers reveals remarkable heterogeneity among different tumor types.

The p53 tumor suppressor protein, a sequence specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. While the protein coding target genes of p53 have been well studied, less is known about its role in regulating long non-coding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1000) of long non-coding RNAs(lncRNAs) that are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, while others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 non-coding response. The newly identified non-coding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis. Implications: Our results not only identify myriad p53-regulated lncRNAs, they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.

Dosimetry of Large Field Valencia applicators for Cobalt-60-based brachytherapy.

Non-melanoma skin cancer is one of the most common types of cancer and one of the main approaches is brachytherapy. For small lesions, the treatment of this cancer with brachytherapy can be done with two commercial applicators, one of these is the Large Field Valencia Applicators (LFVA). The aim of this study is to test the capabilities of the LFVA to use clinically 60Co sources instead of the 192Ir ones. This study was designed for the same dwell positions and weights for both sources. The Penelope Monte Carlo code was used to evaluate dose distribution in a water phantom when a 60Co source is considered. The LFVA design and the optimized dwell weights reported for the case of 192Ir are maintained with the only exception of the dwell weight of the central position, that was increased. 2D dose distributions, field flatness, symmetry and the leakage dose distribution around the applicator were calculated. When comparing the dose distributions of both sources, field flatness and symmetry remain unchanged. The only evident difference is an increase of the penumbra regions for all depths when using the 60Co source. Regarding leakage, the maximum dose within the air volume surrounding the applicator is in the order of 20% of the prescription dose for the 60Co source, but it decreases to less than 5% at about 1cm distance. Flatness and symmetry remains unaltered as compared with 192Ir sources, while an increase in leakage has been observed. This proves the feasibility of using the LFVA in a larger range of clinical applications.