Biological Evidence Research Articles

Exploring the research needs, barriers and facilitators to the collection of biological data in adolescence for mental health research: a scoping review protocol paper

IntroductionWhile research into adolescent mental health has developed a considerable understanding of environmental and psychosocial risk factors, equivalent biological evidence is lacking and is not representative of economic, social and...

The Neuroscience of Motivated Memory

Motivation is essential to memory because it ensures important memories are prioritized for future behavior. Recent studies have looked into the multi-faceted relationship between motivation and memory; other biological evidence which links motivation and memory has given rise to an examination of the underlying neurobiological basis that facilitates this connection. The neurotransmitter dopamine is strongly associated with motivation. Particularly, midbrain dopamine neurons in the reward-regulating ventral tegmental area which project to the hippocampus are well-positioned to enable a motivational influence on memory formation. This prompts an examination of the differing effects of extrinsic and intrinsic motivation on memory encoding and consolidation, as well evidence supporting the crucial role of coordinated activity between the mesolimbic pathway and the hippocampus. In this review, we first look into hypotheses about the biological processes through which dopamine is associated with reward motivation and memory. We then examine and summarize the neurobiologic hypotheses and recent evidence on the interplay between motivation and declarative memory with a focus on dopamine as the linking mechanism.

DNA profiling in India: Addressing issues of sample preservation, databasing, marker selection, & statistical approaches

DNA technology is the gold standard with respect to the identification of individuals from biological evidence. The technology offers the convenience of a universally similar approach and methodology for analysis across the globe. However, the technology has not realised its full potential in India due to the lack of a DNA database and lacunae in sample collection and preservation from the scene of crime and victims (especially those of sexual assault). Further, statistical interpretation of DNA results is non-existent in the majority of cases. Though the latest technologies and developments in the field of DNA analysis are being adopted and implemented,very little has been enacted practically to improve optimise sample collection and preservation. This article discusses current casework scenarios that highlight the pitfalls and ambiguous areas in the field of DNA analysis, especially with respect DNA databases, sampling, andstatistical approaches to genetic data analysis. Possible solutions and mitigation measures are suggested.

Regeneration niche of Cortaderia selloana in an invaded region: Flower predation, environmental stress, and transgenerational effects

Background and aimsBiological invasions are causing massive environmental, social, and economic impacts worldwide. Understanding the ecological factors that affect the regeneration of invasive plants is critical to develop action plans based on empirical biological evidence. In this study, we investigate ecological limits in the regeneration of Cortaderia selloana, an invasive species with a strong impact in temperate regions. MethodsWe sampled 22 sites invaded by C. selloana along an environmental gradient in northern Spain to evaluate the influence of flower predation, environmental stress, and transgenerational effects on the performance of C. selloana offspring. Key resultsWe found that over half of the sampled flowers per individual contained larvae of Spanolepis selloanae, a recently discovered predator of C. selloana. This finding suggests that the presence of this natural enemy extends over a larger area than previously thought, which might drastically reduce seed production. A common-garden experiment conducted with over 5,200 seeds revealed that seed germination is significantly enhanced with increasing temperatures (with an optimum temperature of 22/12 °C day/night temperatures), and that seedling survival and growth are highest under waterlogged soil conditions. Our experiments also suggest that the minimum temperature for germination of C. selloana is 10 °C, and that seedlings can survive up to one month without water. These findings can improve management programs by delineating which areas are at high risk of invasion and which ones are unsuitable for the regeneration of C. selloana. We also found that seed mass and maternal plant size are positively correlated with seed germination and early seedling growth. Progeny from dry maternal environments performed better under continuous drought conditions and the opposite was found under wet conditions. ConclusionsOverall, our results suggest that flower predators, environmental stress, and transgenerational effects have complex and profound effects on early demographic stages of C. selloana, influencing seed production, seed germination, seedling growth, and seedling survival.

Evaluasi Protokol Pengumpulan Bukti Forensik Dalam Kasus Pemerkosaan: Meningkatkan Kualitas Bukti dan Akurasi Identifikasi Pelaku

Handling rape cases requires effective forensic evidence collection to ensure justice for victims and truth disclosure in court. This study aims to evaluate protocols for collecting forensic evidence in rape cases, focusing on enhancing evidence quality and perpetrator identification accuracy. The evaluation method involves analyzing the implementation of existing protocols, including procedures for collecting and analyzing relevant physical, biological, and digital evidence in the context of sexual crimes. The study's findings indicate that increasing training and awareness of updated protocols can significantly improve the quality of collected evidence and the accuracy of perpetrator identification. These findings highlight the importance of collaboration among investigators, forensic experts, and other authorities in improving and implementing effective protocols for handling rape cases. This research provides a foundation for ongoing improvements in forensic procedures to enhance justice for victims of sexual crimes and overall community safety.

Functional study of a rare L1CAM gene c.1759G>C variant prove its pathogenicity.

L1 syndrome, a neurological disorder with an X-linked inheritance pattern, mainly results from mutations occurring in the L1 cell adhesion molecule (L1CAM) gene. The L1CAM molecule, belonging to the immunoglobulin (Ig) superfamily of neurocyte adhesion molecules, plays a pivotal role in facilitating intercellular signal transmission across membranes and is indispensable for proper neuronal development and function. This study identified a rare missense variant (c.1759G>C; p.G587R) in the L1CAM gene within a male fetus presenting with hydrocephalus. Due to a lack of functional analysis, the significance of the L1CAM mutation c.1759G>C (p.G587R) remains unknown. We aimed to perform further verification for its pathogenicity. Blood samples were obtained from the proband and his parents for trio clinical exome sequencing and mutation analysis. Expression level analysis was conducted using western blot techniques. Immunofluorescence was employed to investigate L1CAM subcellular localization, while cell aggregation and cell scratch assays were utilized to assess protein function. The study showed that the mutation (c.1759G>C; p.G587R) affected posttranslational glycosylation modification and induced alterations in the subcellular localization of L1-G587R in the cells. It resulted in the diminished expression of L1CAM on the cell surface and accumulation in the endoplasmic reticulum. The p.G587R altered the function of L1CAM protein and reduced homophilic adhesion capacity of proteins, leading to impaired adhesion and migration of proteins between cells. Our findings provide first biological evidence for the association between the missense mutation (c.1759G>c; p.G587R) in the L1CAM gene and L1 syndrome, confirming the pathogenicity of this missense mutation.

Enzymatic removal of Numts from Panthera tigris DNA samples

Forensic mitochondrial DNA analysis is a vital investigative tool for wildlife casework, but numts continue to complicate DNA analysis. A major goal of wildlife forensic DNA analysis is to identify non-human biological evidence to its taxonomic source. Species identification is accomplished by sequencing genetic markers on the mitochondrial genome and comparing evidentiary sequence data to published reference sequences. Due to the high level of sequence similarity between mitochondrial genes and numts, current sequencing methods result in co-amplification of the target gene marker and non-target numt. Co-amplification of target and non-target loci results in ambiguous nucleotide calls in sequence data. Reducing the influence of numts during sequence analysis will provide a technique that will maximize accuracy and minimize error in taxonomic identifications. To overcome the analytical burden of numts, we studied the enzymatic removal of numts using exonuclease V. To evaluate the feasibility of exonuclease V as a numt removal method, total Panthera tigris DNA was extracted from blood and liver and divided into three treatment groups: untreated, 1st digest, and 2nd digest. For the untreated sample, 7.6 % of the 620 bp sequence data was classified as ambiguous. Following treatment, all samples demonstrated a reduction in ambiguous calls: liver-1st digest (48 h): 6.6 %, liver-2nd digest (48 h + 16 h): 1.8 %, and blood-1st digest (48 h): 0 %. Based on this preliminary study, exonuclease V treatment effectively removed numts before sequencing analysis. While exonuclease V treatment has demonstrated potential, additional studies are required to optimize the reaction and fully validate the methodology.

Metabolomic and transcriptomic reveal flavonoid biosynthesis and regulation mechanism in Phlomoides rotata from different habitats

Phlomoides rotata is a traditional medical plant at 3100–5200 m altitude in the Tibet Plateau. In this study, flavonoid metabolites were investigated in P. rotata from Henan County (HN), Guoluo County (GL), Yushu County (YS), and Chengduo County (CD) habitats in Qinghai. The level of kaempferol 3-neohesperidoside, sakuranetin, and biochanin A was high in HN. The content of limocitrin and isoquercetin was high in YS. The levels of ikarisoside A and chrysosplenol D in GL were high. Schaftoside, miquelianin, malvidin chloride, and glabrene in CD exhibited high levels. The results showed a significant correlation between 59 flavonoids and 29 DEGs. Eleven flavonoids increased with altitude. PAL2, UFGT6, COMT1, HCT2, 4CL4, and HCT3 genes were crucial in regulating flavonoid biosynthesis. Three enzymes CHS, 4CL, and UFGT, were crucial in regulating flavonoid biosynthesis. This study provided biological and chemical evidence for the different uses of various regional plants of P. rotata.

The antiquity and ancestral origin of humans in the americas: a five hundred year inquiry from a biological anthropology perspective.

The questions -When did humans arrive in the Americas? Who were they, or from where did they come from? -are enduring and fascinating inquiries that have been approached from different perspectives, thanks to the contributions of archaeology, biological anthropology, and linguistics, among other disciplines. As a result, and after several centuries of studies, this body of research inspired several proposed models on the peopling of the Americas. These models are not only equally unique from each other but also distinct from the current themes in recent literature. However, there is a limited and occasionally inaccurate reference to the knowledge produced in the peripheral countries. This may be attributed to differences in language, academic traditions, as well as the consequences of geopolitics and neocolonialism in science. By reviewing both the old and recent literature, my aim is to present a historical account of how biological evidence has contributed to supporting and discussing some of the broad models that were proposed to explain the peopling of the Americas. Instead of providing an exhaustive account on the models, herein I focus on critically linking evidence and discussions ranging from the early skeletal discoveries at Lagoa Santa in Brazil in the 1830s to the current challenges of integrating a large amount of disparate data and collaborating with indigenous communities in the "omics" era. Far from being fully understood, investigations into the antiquity and the ancestral origin of Native Americans are revealing that these complex questions should be addressed by combining diverse data, articulating information at finer and larger grain scales, and adopting a sensitive and respectful approach by engaging with the views of indigenous communities.

Forensic Discrimination of condom lubricants using ATR-FTIR spectroscopy in combination with chemometrics- effect of matrices, pre-coital and post-coital conditions.

The escalating rates of rape and sexual assault cases underscore the essential need to analyze associative evidence of sexual assault to ensure justice. The condom, when used during the act of sexual assault/rape, leaves behind traces of lubricant that could be instrumental in establishing the link between the victim and perpetrator. This leading evidence is crucial especially when the traditional DNA analysis is challenging owing to the lack of biological evidence. The present study employs the use of ATR FTIR spectroscopy coupled with the chemometric, to discern the chemical discrimination of condom lubricants. The study also aimed to investigate simulated real-case scenarios by analysing the effect of different matrices such as vaginal fluid, menstrual blood, and undergarment substrates (cotton, polyester and nylon) on condom traces. The difference in the spectral profile of pre-coitus and post-coitus samples was also investigated. The results of the present study are noteworthy, unveiling the efficacy of discriminating the condom lubricants of different brands and other frequently used household lubricants with 100% sensitivity, specificity, and accuracy. Condom lubricants are detected despite the presence of contaminants such as menstrual blood, and vaginal fluid, across different substrates and, in post-coital conditions. In conclusion, this study presents a comprehensive approach to analysing condom lubricants, offering a potential breakthrough in the investigation of sexual assault cases, coupled with the ability to counter false accusations.

Simultaneous identification and differentiation of human fingernails and hair from different regions by Terahertz time-domain spectroscopy and chemometrics for forensic purpose

Hair and fingernails, emerging as crucial biological physical evidence, play a prominent role in geographical traceability studies within the forensic anthropology. This study explored the potential of terahertz spectroscopy and chemometrics techniques in identifying hair and fingernail samples from various geographical regions. A total of 196 hair and fingernail samples underwent scanning with terahertz time-domain spectroscopy. Different chemometric tools, including multilayer perceptron, support vector machine, and Fisher discriminant analysis, were employed for model building on fingernail dataset, hair dataset, and fusion data, respectively. The performance of models constructed based on different datasets was compared and evaluated using metrics such as accuracy, precision, recall, and F-score. Results revealed that the fusion data, employing the Fisher discriminant analysis (FDA) algorithm, exhibited the best recognition ability, achieving a 100 % accuracy rate and F-value. Terahertz spectroscopy combined with FDA algorithm emerged as an effective and convenient tool for differentiating hair and fingernail samples from diverse geographical regions. This innovative technique boasts environmental friendliness, rapid analyses, and minimal sample preparation requirements compared to traditional methods.

Identifying Drug-Drug Interactions in Spontaneous Reports Utilizing Signal Detection and Biological Plausibility Aspects.

Translational approaches can benefit post-marketing drug safety surveillance through the growing availability of systems pharmacology data. Here, we propose a novel Bayesian framework for identifying drug-drug interaction (DDI) signals and differentiating between individual drug and drug combination signals. This framework is coupled with a systems pharmacology approach for automated biological plausibility assessment. Integrating statistical and biological evidence, our method achieves a 16.5% improvement (AUC: from 0.620 to 0.722) with drug-target-adverse event associations, 16.0% (AUC: from 0.580 to 0.673) with drug enzyme, and 15.0% (AUC: from 0.568 to 0.653) with drug transporter information. Applying this approach to detect potential DDI signals of QT prolongation and rhabdomyolysis within the FDA Adverse Event Reporting System (FAERS), we emphasize the significance of systems pharmacology in enhancing statistical signal detection in pharmacovigilance. Our study showcases the promise of data-driven biological plausibility assessment in the context of challenging post-marketing DDI surveillance.

A Case of Post Viral Acute Longitudinal Extensive Transverse Myelitis (LETM): MOGAD- A New Horizon

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children. It is a group of central nervous system demyelinating diseases caused by auto antibodies against myelin oligosaccharide protein, a myelin sheath component protein, and present with a variety of symptoms, including optic neuritis, longitudinal extensive transverse myelitis (LETM), acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, and corticobasal encephalitis. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Here, we present a case of a young male with acute onset of spastic paraplegia with sphincters involvement and patchy loss of pinprick sensation with positive Anti-MOG Antibody shortly after viral febrile illness. Bangladesh Crit Care J March 2024; 12 (1): 62-67

Holme I (Seahenge) and Holme II: ritual responses to climate change in Early Bronze Age Britain

Holme I and II were contemporary, adjacent Early Bronze Age (EBA) oak-timber enclosures exposed intertidally at Holme-next-the-sea, Norfolk, England, in 1998. Holme I enclosed a central upturned tree-stump, its function and intent unknown. Holme II is thought a mortuary structure. Both are proposed here best explained as independent ritual responses to reverse a period of severe climate deterioration recorded before 2049 BC when their timbers were felled. Holme I is thought erected on the summer-solstice, when the cuckoo traditionally stopped singing, departing to the ‘Otherworld’. It replicated the cuckoo’s supposed overwintering quarters: a tree-hole or the ‘bowers of the Otherworld’ represented by the tree-stump, remembered in folklore as ‘penning-the-cuckoo’ where a cuckoo is confined to keep singing and maintain summer. The cuckoo symbolised male-fertility being associated with several Indo-European goddesses of fertility that deified Venus - one previously identified in EBA Britain. Some mortal consorts of these goddesses appear to have been ritually sacrificed at Samhain. Holme II may be an enclosure for the body of one such ‘sacral king’. These hypotheses are considered, using abductive reasoning, as ‘inferences to the best explanations’ from the available evidence. They are supported with environmental data, astronomic and biological evidence, regional folklore, toponymy, and an ethnographic analogy with indigenous Late Iron Age practices that indirect evidence indicates were undertaken in EBA Britain. Cultural and religious continuity is supported by textual sources, the material record and ancient DNA (aDNA) studies.

Motion Learning and Generalization of Musculoskeletal Robot Using Gain Primitives

Organisms have an innate ability to rapidly produce diverse and flexible movement. Biological motor systems are composed of highly redundant muscle actuators and have strongly nonlinear dynamic characteristics. How organisms cope with such complex system is still an open question. Motor primitive theory proposed by neuroscientists has provided a convincing explanation for this extraordinary ability and have supported by several biological evidence. In this paper, based on the gain primitive model of cortical network proposed by neuroscientists, new algorithms for learning and combining gain primitives were designed to control musculoskeletal and robotic system with highly redundant actuators. It can realize dimensionality reduction of controll from the number of actuators to the number of primitives. A parameter adaptation algorithm inspired by monoamines modulation mechanism was applied to improve the learning efficiency of gain primitive. Learned motion experiences and primitives were introduced to effectively generate new movements. Validation experiments were carried out on a musculoskeletal model with 9 muscles and an articulated robot Baxter with redundant actuators. The experimental results demonstrated that the recurrent neural network modulated by gain primitives can generate high-dimensional control signals and realize efficient motion generalization for practical systems. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Note to Practitioners</i> —This paper applied a biologically plausible control method with gain primitive to practical systems with highly redundant actuators. To reduce the cumulative error occurring in learning gain primitive for control networks with high dimensional output, a bioinspired Hebbian learning rule was applied to train a recurrent neural network for optimizing the gain primitive. During the training process, systematic entropy was introduced as an index to adaptively adjust learning parameters, so as to reduce the exploration cost and improve the learning stability of the system. To realize easy implementation and generalization, prior motion experiences were introduced into the initialization of the optimization algorithm, and motion generalization was realized by using the particle swarm optimization algorithm. The algorithms designed in this paper are applicable to complex systems with highly redundant actuators such as humanoid robots.

Biological and physical studies on the protective and therapeutic roles of ashwagandha seed extract against the potential toxic effect of amoxicillin in rats

Background Ashwagandha plant enhances the body’s defense against toxicants through improving the cell-mediated immunity. Objective The present work was performed to assess the protective and therapeutic efficiencies of ashwagandha seed extract (ASE) against the harmful effects of amoxicillin (AM) treatment on biological and physical parameters in the brain, liver, and testes tissues of rats. Materials and methods Total RNA was isolated from brain, liver, and testes tissues to assess the gene expression of steroid 5 alpha-reductase 1 (5α-R1), multidrug resistant 1b (mdr1b), and luteinizing hormone receptor (LHR) genes, respectively. The cDNA was synthesized and real-time polymerase chain reaction (Real-time PCR) was performed, total antioxidant capacity (TAC) was measured. Histological examination and physiological tests for the cerebral cortex of brain tissue were recorded. Results and conclusion Our findings revealed that AM treatment (90 mg/kg. b.wt.) caused detrimental effects in all biological parameters, including up-regulation of gene expressions and reduction of TAC values in brain, liver, and testes tissues, in addition to severe damage to histological architectures in the cerebral cortex, including hemorrhage and neurodegeneration. ASE treatment at different doses (100, 200, and 300 mg/kg) significantly enhanced the biological and physical parameters. As the ASE dose level increased, it was observed that these improvements in gene expressions and TAC also increased. Gene expression enhancements were more pronounced in the therapeutic efficacy of ASE, whereas TAC enhancements were more pronounced in the protective efficacy of this medicinal plant extract, particularly in brain and liver tissues. In terms of histopathological parameters, the damage caused by AM was reduced by using 300 mg/kg of protective ASE than 200 mg/kg of therapeutic ASE. Biophysical investigation indicated that relaxation time and enthalpy were restored and improved, while DC conductivity was not recovered by ASE use against AM damages. The present investigation provided biological and physical evidence for protective and therapeutic efficiencies of ASE against lesion effects of AM in the previously mentioned tissues of rats.

An Architectural Solution to a Biological Problem: A Systematic Review of Lighting Designs in Healthcare Environments

Neuroscience and biological evidence emphasizes the profound influence of natural light on human health, offering benefits such as reducing fatigue, heightened alertness in healthcare providers, and improving patient outcomes. The objective of this review is to identify scientific studies and research to evaluate and report evidence of indoor lighting conditions’ influence on health outcomes, which can be used to develop lighting designs that align circadian rhythms in healthcare settings. A comprehensive search was conducted to identify rigorous empirical studies focused on the link between interior lighting conditions with health outcomes in the healthcare environment. For a comprehensive review of the existing literature, a four-phased methodology was employed including literature search, screening, and selection. Literature appraisals were conducted to determine the relevance and quality of evidence for each study identified. In addition, using a thematic analysis, patterns were identified, analyzed, and interpreted within the literature review. Accordingly, the results were organized into two main groups interventional human subjects and simulation-based studies. Despite evidence that natural light influences human health and happiness, a synthesis of reviewed studies suggests that the evidence for the benefits of artificial lighting in healthcare settings is less conclusive, with potential factors including variations in lighting design, inconsistent implementation of lighting interventions, and differing sample populations across studies. We conclude with an executive summary suggesting that future research should use standardized metrics and methods to focus on bridging the gap between theoretical understanding and practical application in lighting design for healthcare environments. Collaboration among architects, designers, lighting experts, and healthcare professionals can address these factors contributing to building a stronger evidence-based design for the benefits of artificial lighting in healthcare settings.

Dissecting the colocalized GWAS and eQTLs with mediation analysis for high-dimensional exposures and confounders.

To leverage the advancements in genome-wide association studies (GWAS) and quantitative trait loci (QTL) mapping for traits and molecular phenotypes to gain mechanistic understanding of the genetic regulation, biological researchers often investigate the expression QTLs (eQTLs) that colocalize with QTL or GWAS peaks. Our research is inspired by 2 such studies. One aims to identify the causal single nucleotide polymorphisms that are responsible for the phenotypic variation and whose effects can be explained by their impacts at the transcriptomic level in maize. The other study in mouse focuses on uncovering the cis-driver genes that induce phenotypic changes by regulating trans-regulated genes. Both studies can be formulated as mediation problems with potentially high-dimensional exposures, confounders, and mediators that seek to estimate the overall indirect effect (IE) for each exposure. In this paper, we propose MedDiC, a novel procedure to estimate the overall IE based on difference-in-coefficients approach. Our simulation studies find that MedDiC offers valid inference for the IE with higher power, shorter confidence intervals, and faster computing time than competing methods. We apply MedDiC to the 2 aforementioned motivating datasets and find that MedDiC yields reproducible outputs across the analysis of closely related traits, with results supported by external biological evidence. The code and additional information are available on our GitHub page (https://github.com/QiZhangStat/MedDiC).

Abstract 1846: Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell carcinoma

Abstract Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conduct comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. RCC tumors are distinctly separated from corresponding normal tissues through multi-omics clustering, a distinction further supported by pathway analysis. In addition, various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest adaptive immune response and angiogenesis with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways and alteration in VHL (100.0%) along with BAP1 (24.0%) genes. C3 (N=19) was associated with enrichment in inflammatory response with dismal prognosis and therapeutic resistance to tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. Transglutaminase 2 (TGM2), a crosslinking enzyme, is identified as a potential marker with therapeutic implication for ccRCC. Collectively, this study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Citation Format: Woo Sun Kwon, Chang Gon Kim, Harim Koo, Woo Kyun Bae, Eu Chang Hwang, Won Sik Ham, Nam Hoon Cho, Jason K. Sa, Jong Bae Park, Sun Young Rha. Integrative histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic characterization of renal cell 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 1846.

Abstract 4627: Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment

Abstract Background: Cancers of unknown primary (CUP) is a heterogenous group of malignancies characterized by distant metastases in the absence of detectable primary. Specifics subgroups of CUP that share similarities with cancers of known primary beneficiate from tissue-tailored therapeutic strategies. The objective of this study was to characterize the clinical and biological presentation of a cohort of patients with suspected CUP of renal origin (rCUP) and to evaluate their optimal therapeutic management. Methods: All Patients with rCUP identified prospectively between 2020 and 2023 within the French National Multidisciplinary Tumor Board for CUP were included. Centralized pathological review and immunohistochemical stainings were performed. Whole Exome Sequencing (WES), whole transcriptomic sequencing (RNAseq) and application of the deep-learning based algorithm TransCUPtomics for prediction of tissue of origin, and DNA methylation analysis were performed and compared to public renal cell carcinomas (RCC). Progression Free Survival (PFS) and Overall Survival (OS) were calculated using Kaplan-Meier estimates. Results: 23 patients were included. The median age at diagnosis was 57 yo and 17/23 were male. The most common metastatic sites were the bones (N=17) and the lymph nodes (N=14). 19/23 patients presented with at least two distinct distant metastatic sites. Genomic analyses performed in 10 patients led to the identification of recurrent inactivating mutations in genes commonly altered in RCC, including NF2 (N=7), SETD2 (N=3), or VHL (N=1). 10/11 samples analyzed by RNAseq were predicted as RCC by the TransCUPtomics classifier based on their gene expression profiles. DNA methylation profiling performed in 7 samples showed major similarity with known RCC subtypes.Centralized pathological review and integration of molecular characteristics led to the final diagnoses of papillary RCC (N=2), clear cell RCC (N=7), renal medullary carcinoma (N=1), TFEB-amplified RCC (N=1) and unclassified RCC (N=12). 20/23 patients received at least one line of systemic treatment based on the renal origin, including anti-angiogenic TKI, anti-PD1/PDL1 antibody, anti-CTLA4 antibody or mTOR inhibitor. The median PFS under the first renal-oriented systemic treatment was 5 months and 10 patients remained progression-free for more than 6 months under tailored-treatment. The median OS was 31 months, and 11 patients are still alive in October 2023. Conclusions: This study shows that rCUP represent a new entity within CUPs that shares major similarities with classical RCC despite the more frequent presentation of unfavorable prognostic factors. Prolonged survival can be observed with renal-tailored systemic treatment, supporting the individualization of these patients within CUP. Citation Format: Nicolas Jacquin, Julien Masliah-Planchon, Guillaume Grisay, Ronan Flippot, Riwan Brillet, Célia Dupain, Maud Kamal, Isabelle Guillou, Nadège Gruel, Nicolas Servant, Pierre Gestraud, Jennifer Wong, Vincent Cockenpot, Andreia Goncalves, Janick Selves, Hélène Blons, Etienne Rouleau, Oliver Delattre, Christophe Le Tourneau, Ivan Bièche, Yves Allory, Laurence Albigès, Sarah Watson. Metastatic renal cell carcinoma with occult primary: Clinical and biological evidence for a new entity of cancers of unknown primary that beneficiates from tissue-tailored treatment [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 4627.