Biological Explanations Research Articles

Genetic overlap between Parkinson's disease and inflammatory bowel disease.

Parkinson's disease and inflammatory bowel disease have been increasingly associated, implying shared pathophysiology. To explore biological explanations for the reported connection, we leveraged summary statistics of updated genome-wide association studies and characterized the genetic overlap between the two diseases. Aggregated genetic association data were available for 37 688 cases versus 981 372 controls for Parkinson's disease and 25 042 cases versus 34 915 controls for inflammatory bowel disease. Genetic correlation was estimated with the high-definition likelihood method. Genetic variants with joint association to both diseases were identified by conditional false discovery rate framework and further annotated to reveal shared loci, genes, and enriched pathways. For both Crohn's disease and ulcerative colitis, the two main subtypes of inflammatory bowel disease, we detected weak but statistically significant genetic correlations with Parkinson's disease (Crohn's disease: rg = 0.06, P = 0.01; ulcerative colitis: rg = 0.06, P = 0.03). A total of 1290 variants in 27 independent genomic loci were detected to associate with Parkinson's disease and Crohn's disease at conjunctional false discovery rate under 0.01 and 1359 variants in 15 loci were pleiotropic to Parkinson's disease and ulcerative colitis. Among the identified pleiotropic loci, 23 are novel and have never been associated with both phenotypes. A mixture of loci conferring either same or opposing genetic effects on two phenotypes was also observed. Positional and expression quantitative trait loci mapping prioritized 296 and 253 genes for Parkinson's disease with Crohn's disease and ulcerative colitis, respectively, among which only <10% are differentially expressed in both colon and substantia nigra. These genes were identified to overrepresent in pathways regulating gene expression and post-translational modification beyond several immune-related pathways enriched by major histocompatibility complex genes. In conclusion, we found robust evidence for a genetic link between Parkinson's disease and inflammatory bowel disease. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both synergistic and antagonistic pleiotropy. At the functional level, our findings implied a role of immune-centered mechanisms in the reported gut-brain connection.

Belleza y elección de pareja: Lo que la biología evolutiva nos enseña

We tend to regard beauty as the product of our education, the quintessence of cultural refinement, and we often emphasise the relative nature of beauty. That is why many find it shocking that the perception of beauty, especially human beauty, has a clear biological explanation, one that is largely independent from our education and culture. People are surprised because not only do the characteristics that define beauty originate in biology, but they are also universal and common to all members of our species.

Factors Causing Infertility in Women Diagnosed with Endometriosis

Endometriosis is a pathology that commonly prevails in more than 50% of women as a cause of dysmenorrhea and infertility and we can define it as the presence of endometrial glands and stroma outside of it, that is, ectopic endometrial tissue that is mostly located in the ovaries, Douglas pouch, uterosacral ligaments and other anatomical sites. Infertility associated with endometriosis is a multifactorial disease and there is no certainty about the mechanisms by which it is developed, however there are several theories that could provide an explanation. Oxidative stress is one of the factors that contribute to infertility where a chain of events is created that culminates in the alteration of the number of oocyte recovery and the number of mature oocytes. Dysregulation of aromatase P450 production in steroidogenesis causes a decrease in estrogen production altering follicular and oocyte development. There are also interleukins associated with infertility of which TNF-α, interleukin-1β, IL-6, IL-8, IL-10 and others stand out. On the other hand, there are several biological explanations that are related to the causal link between endometriosis and infertility, some of them include factors of the pelvic cavity, ovarian and genetic factors.

Biological Explanations of Social Inequalities

AbstractInequalities of social goods between gender, racial, or other groups call out for explanation. Such inequalities might be explained by socialization and discrimination. But historically some have attributed these inequalities to biological differences between social groups. Such explanations are highly controversial: on the one hand, they have a very troubling racist and sexist history, but on the other hand, they are empirical claims, and so it seems inappropriate to rule them out a priori. I propose that the appropriate epistemic attitude toward biological explanations of social inequalities is a general but defeasible skepticism. I then turn to the appropriate moral attitude, arguing that when such explanations are inadequately supported, they are offensive.

Peripheral neuropathies associated with DNA repair disorders.

Repair of genomic DNA is a fundamental housekeeping process that quietly maintains the health of our genomes. The consequences of a genetic defect affecting a component of this delicate mechanism are quite harmful, characterized by a cascade of premature aging that injures a variety of organs, including the nervous system. One part of the nervous system that is impaired in certain DNA repair disorders is the peripheral nerve. Chronic motor, sensory, and sensorimotor polyneuropathies have all been observed in affected individuals, with specific physiologies associated with different categories of DNA repair disorders. Cockayne syndrome has classically been linked to demyelinating polyneuropathies, whereas xeroderma pigmentosum has long been associated with axonal polyneuropathies. Three additional recessive DNA repair disorders are associated with neuropathies, including trichothiodystrophy, Werner syndrome, and ataxia-telangiectasia. Although plausible biological explanations exist for why the peripheral nerves are specifically vulnerable to impairments of DNA repair, specific mechanisms such as oxidative stress remain largely unexplored in this context, and bear further study. It is also unclear why different DNA repair disorders manifest with different types of neuropathy, and why neuropathy is not universally present in those diseases. Longitudinal physiological monitoring of these neuropathies with serial electrodiagnostic studies may provide valuable noninvasive outcome data in the context of future natural history studies, and thus the responses of these neuropathies may become sentinel outcome measures for future clinical trials of treatments currently in development such as adeno-associated virus gene replacement therapies.

Complex effects of chytrid parasites on the growth of the cyanobacterium Planktothrix rubescens across interacting temperature and light gradients

Chytrids are important drivers of aquatic ecosystems as phytoplankton parasites. The interaction between these parasites and their hosts are shaped by abiotic factors such as temperature and light. Here, we performed a full-factorial experiment to study how temperature and light interact to affect the dynamics of the bloom-forming toxic cyanobacterium Planktothrix rubescens and its chytrid parasite. We used a dynamic host-parasite model to explore how temperature and light affect long term dynamics. At low temperatures, chytrids do not survive. Higher light and temperature levels stimulated both phytoplankton and chytrid growth, with complex effects on their dynamics. Model exploration indicates that increasing temperature and light shifts equilibrium outcomes from P. rubescens persisting alone to stable coexistence and then to limit cycles. This provides an alternative biological explanation for why P. rubescens is mainly found in the relatively cold and dark lake metalimnion – it may enable avoidance of its parasite. Our study emphasizes the importance of investigating how abiotic factors interact with biotic interactions to drive complex outcomes.

High-content phenotyping of Parkinson's disease patient stem cell-derived midbrain dopaminergic neurons using machine learning classification.

SummaryCombining multiple Parkinson's disease (PD) relevant cellular phenotypes might increase the accuracy of midbrain dopaminergic neuron (mDAN) in vitro models. We differentiated patient-derived induced pluripotent stem cells (iPSCs) with a LRRK2 G2019S mutation, isogenic control, and genetically unrelated iPSCs into mDANs. Using automated fluorescence microscopy in 384-well-plate format, we identified elevated levels of α-synuclein (αSyn) and serine 129 phosphorylation, reduced dendritic complexity, and mitochondrial dysfunction. Next, we measured additional image-based phenotypes and used machine learning (ML) to accurately classify mDANs according to their genotype. Additionally, we show that chemical compound treatments, targeting LRRK2 kinase activity or αSyn levels, are detectable when using ML classification based on multiple image-based phenotypes. We validated our approach using a second isogenic patient-derived SNCA gene triplication mDAN model which overexpresses αSyn. This phenotyping and classification strategy improves the practical exploitability of mDANs for disease modeling and the identification of novel LRRK2-associated drug targets.

Mild-to-moderate iodine deficiency and symptoms of emotional distress and depression in pregnancy and six months postpartum – Results from a large pregnancy cohort

BackgroundThe relationship between iodine intake and depression is unknown. The aim of the present study was to investigate whether iodine intake was associated with symptoms of perinatal emotional distress and depression in a mild- to moderately iodine deficient population. MethodsThe study population comprised 67,812 women with 77,927 pregnancies participating in the Norwegian Mother, Father and Child Cohort Study. Self-reported emotional distress and depressive symptoms were reported in pregnancy and at six months postpartum. Iodine intake was assessed by a food frequency questionnaire in mid-pregnancy. Urinary iodine concentration (UIC) was available for 2792 pregnancies. ResultsThe median iodine intake from food was 121 μg/day and the median UIC was 68 μg/L. The prevalence of high scores for emotional distress was 6.6 % in pregnancy and 5.8 % six months postpartum, and for high scores on postpartum depression it was 10.3 %. In non-users of iodine supplements (63 %), a low maternal iodine intake from food (lower than ~100–150 μg/day) was associated with increased risk of high scores of emotional distress and depression both in pregnancy and six months postpartum (p < 0.001). Iodine supplement use was associated with increased risk of high scores of emotional distress in pregnancy compared to no supplement use or use of supplements without iodine. LimitationsObservational design, self-report information, and short scales to assess symptoms of emotional distress and depression. ConclusionA low habitual iodine intake was associated with increased prevalence of perinatal emotional distress and depression. The potential non-beneficial effect of iodine supplements may have biological explanations. More studies are needed.

Neuroanatomical correlates of social approach in Williams Syndrome and down syndrome

Individuals with Williams Syndrome (WS) or Downs Syndrome (DS) are often described as hypersociable, friendly and overly trusting of others. This hypersociability is a major concern for parents/caregivers due to the associated increased risk of exploitation and victimisation. Two brain regions - the amygdala and the orbitofrontal cortex (OFC) - have been implicated in driving this hypersociability in WS, and in the general population and have associations with emotional evaluation, threat detection and social motivation. However, there has been little neuroimaging research on this topic, especially in DS, to date. The aim of the present study was to investigate the potential neuroanatomical and neuropsychological correlates of hypersociability in WS and DS. Twelve individuals with WS (M = 22 years of age) and eleven individuals with DS (M = 26 years of age) completed a neuropsychological battery of executive functioning and social measures, including informant ratings on an ecologically measure of social approach. Clinical groups and twelve typically developing controls (M = 23 years) underwent a magnetic resonance imaging scan to investigate volumetric differences in the OFC and the amygdala. As expected, WS individuals displayed the highest overall social approach, especially in relation to need to approach strangers and drive to interact with strangers, as well as inappropriate/overfriendly behaviours. Both groups rated similarly in terms of social trust and unconditional positive regard. Emotion recognition abilities were similar across groups, with the DS group displaying some difficulties with negative emotions (especially anger). Inhibition and flexibility were similarly impaired across WS and DS. Compared to neurotypical controls, the DS group showed increased amygdala volumes bilaterally, while the WS group showed an enlarged right medial OFC. Approach ratings were significantly correlated with left amygdala and medial and left lateral OFC volumes in WS, and with these same regions bilaterally in DS. Results provide potential biological explanations for the hypersociability seen in WS and DS. Future research should focus on other potential neural correlates, as well as potential genetic and hormonal contributions to approach.

Moving Beyond Religious Clichés: A Review

Abstract The article reviews the most recent systematic effort to correct some of the widespread misconceptions about religion: Brad Stoddard and Craig Martin’s edited volume Stereotyping Religion: Critiquing Clichés (2017) and Tenzan Eaghll’s article “Religious Clichés” (2015). It argues that the joint goal becomes problematic due to some empirical and logical distortions, which mainly result from the emphasis on the relativist message offsetting the impartial assessment of facts and their implications. It argues for integrating the biological and cultural explanations of religion and offers some proposals toward identifying the contemporary clichés that impede progress in our understanding of the phenomenon.

HER2-positive/ER-low breast carcinoma shows a response to neoadjuvant chemotherapy similar to that of HER2-positive/ER-negative breast carcinoma

Negative expression of estrogen receptor (ER) predicts response to chemotherapy in breast cancers (BCs). ER negative cancers are those with less than 1 % of nuclear staining. Tumors with 1–10 % staining are sub-classified as “low-positive” (ER-low). HER2 negative tumors with ER low staining are considered biologically and clinically equivalent to ER negative tumors. This study investigates whether ER low expression in HER2-positive (HER2+) BCs has different clinical behavior than ER negative HER2-positive tumors. We used a sample of 171 patients with HER2+ BCs to compare risk of residual cancer after neoadjuvant chemotherapy by different ER expression strength. Patients were classified into 3 groups: ER-negative (ER <1 %); ER-low (ER <10 %, any intensity or <33 % staining, weak intensity); and ER-high (ER = 10–33 %, moderate to strong intensity or >33 %, any intensity). The risk of residual cancer in patients with ER-low tumors was similar to the risk in patients with ER-negative tumors (RR = 0.76, 95 % CI: 0.30–1.93). Conversely, patients with ER-high tumors had twice the risk of residual cancer than patients with ER-negative tumors (RR = 2.20, 95 % CI: 1.46–3.31). These findings persisted after adjusting for tumor grade, clinical tumor and lymph node stage, chemotherapy regimen, and progesterone receptor status. In this cohort of patients with HER2+ BCs, ER-low tumors had a similar pathologic response to chemotherapy as ER-negative tumors suggesting similar clinical behavior. Future research should address biological explanations to these similarities between ER negative and ER low breast cancers such as HER2 enriched phenomenon.

Functional Biology and Evolutionary Biology: A Different View of the Origin of Living Things

The distinction proposed by Ernst Mayr and François Jacob between functional biology and evolutionary biology is a fundamental key for a clear and conclusive treatment of two problems that, recurrently, are placed in the field of the Philosophy of Biology: that which concerns the possible character teleological of biological explanations and that relative to the autonomy of Biology in relation to Physics and Chemistry. Without supporting an alternative solution for any of these problems, we present that opposition showing its relevance for the treatment of such issues. Our idea is that they should not be raised without specifying which of the two domains of life sciences we are referring to.

Transcription–replication conflicts in primordial germ cells necessitate the Fanconi anemia pathway to safeguard genome stability

Preserving a high degree of genome integrity and stability in germ cells is of utmost importance for reproduction and species propagation. However, the regulatory mechanisms of maintaining genome stability in the developing primordial germ cells (PGCs), in which rapid proliferation is coupled with global hypertranscription, remain largely unknown. Here, we find that mouse PGCs encounter a constitutively high frequency of transcription-replication conflicts (TRCs), which lead to R-loop accumulation and impose endogenous replication stress on PGCs. We further demonstrate that the Fanconi anemia (FA) pathway is activated by TRCs and has a central role in the coordination between replication and transcription in the rapidly proliferating PGCs, as disabling the FA pathway leads to TRC and R-loop accumulation, replication fork destabilization, increased DNA damage, dramatic loss of mitotically dividing mouse PGCs, and consequent sterility of both sexes. Overall, our findings uncover the unique source and resolving mechanism of endogenous replication stress during PGC proliferation, provide a biological explanation for reproductive defects in individuals with FA, and improve our understanding of the monitoring strategies for genome stability during germ cell development.

Serum 25-hydroxyvitamin D and cancer-related fatigue: associations and effects on depression, anxiety, functional capacity and health-related quality of Life in breast cancer survivors during adjuvant endocrine therapy

BackgroundThe adjuvant treatment with Aromatase Inhibitor (AI) is considered standard of care for postmenopausal breast cancer (BC) women with hormone receptor-positive (HR +), however, it often causes adverse effects such as cancer-related fatigue (CRF). The high prevalence of vitamin D deficiency in postmenopausal women who start adjuvant AI supports the hypothesis that hypovitaminosis D would be one of the biological explanations for toxicity of AI. This study aimed to identify the relationship between 25-hydroxyvitamin D [25(OH)D] and CRF, and to analyze their associations and effects on depression, anxiety, functional disability, muscle/joint aches and HRQL.MethodsThis prospective study included 89 postmenopausal women diagnosed with HR + early BC in adjuvant endocrine therapy with AI. Anthropometric and body composition assessments were performed, as well as dietary assessments by application of 24-h dietary recall, at three time points, totaling 24 months of follow-up. The women completed the Cervantes Scale (CS), Hospital Anxiety and Depression Scale (HADS) and Health Assessment Questionnaire (HAQ). The CRF was determined from the Functional Assessment of Chronic Illness Therapy-fatigue (FACIT-F). The serum 25(OH)D was determined by electrochemiluminescence, with cut-off point above 75 nmol/L adopted as sufficiency. Generalized Linear Model (GLzM) and Generalized Mixed Model (GMM) analysis were used.ResultsAt baseline, 36% (n = 32) of the women presented CRF and 39.3% (n = 35) had 25(OH)D below 75 nmol/L. None of the women reached the Estimated Average Requirements (EAR) of vitamin D. The causality between 25(OH)D and CRF was not significant. Longitudinally, lower levels of 25(OH)D had a negative effect on anxiety (p = 0.020), Menopause and Health (p = 0.033) and Vasomotor scores (p = 0.007). Also, the CRF had a negative effect on anxiety (p = 0.028); depression (p = 0.027); functional disability (p = 0.022); HRQL (p = 0.007); Menopause and Health (p = 0.042), Psychological (p = 0.008) and Couple Relations (p = 0.008) domains; and on Health (p = 0.019) and Aging (p = 0.036) subdomains. Vasomotor subdomain (β = -2.279, p = 0.045) and muscle/joint aches (β = -0.779, p = 0.013) were significant with CRF only at baseline.ConclusionsThis study found negative effect of body adiposity on CRF. Still, the clinical relevance of 25(OH)D and CRF is highlighted, especially that of CRF, considering the consistent impact on several adverse effects reported by BC survivors during adjuvant endocrine therapy.

Making Sense of Troubled Livelihoods: Gendered Expectations and Poor Health Narratives in Rural South Africa

When men and women cannot attain idealized gendered forms of economic provision and dependence, how do they make sense of this perceived failure? In this article, we posit that poor health narratives serve as a gendered tool to make sense of inadequate livelihoods, even when that inadequacy is attributable to structural conditions. We draw on survey and life-history interview data from middle-aged and older rural South Africans. The survey data show that even after adjusting for biometrically measured health differences, working-age (40–59 years) men report poorer health when they are unemployed, and women (age 40+) and pension-age men (age 60+) report poorer health when they live without household earners. Life-history interviews show parallel patterns: When their economic circumstance is not troubled, individuals regularly minimize health concerns; conversely, when they have a troubled livelihood, individuals draw on poor health to explain it. When women and men cannot perform idealized gendered practices in the family, poor health becomes a tool to reduce the resulting cognitive dissonance. Poor health narratives recast perceived gender failures to an individualized, biological explanation. Our study illustrates how the epidemiological context can be a resource that forestalls a redefinition of gender norms when the gender order is in crisis.

The sex and gender dimensions of COVID-19: A narrative review of the potential underlying factors.

Multiple lines of evidence indicate that the male sex is a significant risk factor for severe disease and mortality due to coronavirus disease 2019 (COVID-19). However, the precise explanation for the discrepancy is currently unclear. Immunologically, the female-biased protection against COVID-19 could presumably be due to a more rapid and robust immune response to viruses exhibited by males. The female hormones, e.g., estrogens and progesterone, may have protective roles against viral infections. In contrast, male hormones, e.g., testosterone, can act oppositely. Besides, the expression of the ACE-2 receptor in the lung and airway lining, which the SARS-CoV-2 uses to enter cells, is more pronounced in males. Estrogen potentially plays a role in downregulating the expression of ACE-2, which could be a plausible biological explanation for the reduced severity of COVID-19 in females. Comorbidities, e.g., cardiovascular diseases, diabetes, and kidney disorders, are considered significant risk factors for severe outcomes in COVID-19. Age-adjusted data shows that males are statistically more predisposed to these morbidities—amplifying risks for males with COVID-19. In addition, many sociocultural factors and gender-constructed behavior of men and women impact exposure to infections and outcomes. In many parts of the world, women are more likely to abide by health regulations, e.g., mask-wearing and handwashing, than men. In contrast, men, in general, are more involved with high-risk behaviors, e.g., smoking and alcohol consumption, and high-risk jobs that require admixing with people, which increases their risk of exposure to the infection. Overall, males and females suffer differently from COVID-19 due to a complex interplay between many biological and sociocultural factors.

On the nature, pathology, and etiology of delusions: comments on Miyazono’s delusions and beliefs

Kengo Miyazono’s (2019) Delusions and Beliefs: A Philosophical Inquiry is an attempt to provide a unified account of the nature, pathology, and etiology of delusions. The strength of his book resides in the clarity of arguments and its consistent adoption of a biological explanation of delusions, based on teleo-functionalism about mental states. However, there are some weaknesses in each of his arguments regarding the nature, pathology, and etiology of delusions. Regarding the nature of delusions, teleo-functionalism makes it difficult to confirm that delusions are beliefs. Regarding the pathology of delusions, I suggest that the existence of harmful malfunction is a necessary but not a sufficient condition for a belief to be considered pathological, and that additional evidence is needed to justify the separation of the belief and the holder’s personhood. Regarding the etiology, it is not reasonable to incorporate the prediction error theory into a kind of two-factor theory. Therefore, the details of his arguments require further modification.

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

Early detection of Alzheimer's diseases through IoT

In this article, we discuss a biological explanation of Alzheimer's disease by using IoT-enabled devices. Alzheimer's disease has different stages depending on risk factors, and it has no current cure. Today, Alzheimer's disease is a prominent issue among researchers. In order to provide better treatment, the investigation is updated for improved understanding of Alzheimer's disease (AD). In this research, we classify IoT implemented data to recognize and identify stages of Alzheimer's patients. Wearable assistive IoT with complicated embedded artificial perception utilizing deep learning is being developed in this paper and also represents the largest comprehensive study of AD approaches with helping the neurologist to make a better diagnosis.

Abstract 987: Proteomics identifies differences in the biological phenotype of tumor deposits and lymph node metastases in colorectal cancer

Abstract Background: Distant metastatic disease remains the main cause of colorectal cancer (CRC) mortality, but our knowledge on how cancer cells travel from the primary tumor to a secondary site is limited. Lymph node metastases (LNM) play a central role in the staging of CRC patients since they are currently viewed as the gateway to distant metastases. However, in recent years additional forms of locoregional spread with varying prognostic impact have been identified, with tumor deposits (TD) having significantly more impact than LNM. The biological explanation for the difference in prognostic impact between LNM and TD is lacking, while this is essential for a more comprehensive understanding of the role of these biomarkers CRC spread. Therefore, in this study, shotgun proteomics were used to compare the biological phenotype of TD and LNM. Methods: From 12 CRC patients, one TD and one LNM were included for paired protein analyses. Proteins were isolated from formalin-fixed paraffin-embedded tissue after which a filter aided sample preparation method was performed. Then, the samples were analyzed by liquid-chromatography tandem mass-spectrometry, and after data handling and filtering, 5578 differentially expressed proteins were used for downstream analyses. Differences in expression were visualized using heatmaps and volcano plots, and enrichment analyses as well as gene set enrichment was performed. All analyses were performed using R version 4.1.2. Results: Among the main findings was that the proteins ASPN, MRC2, SPON1, MXRA5, BGN, LUM, and PLOD2 were overexpressed in TD. These proteins play a role in stimulating pro-tumorigenic processes such as migration, invasion, and epithelial to mesenchymal transition. For the enrichment analyses all proteins with a Fold change of less than -1 and more than 1 were included. Enrichment analyses using the KEGG pathways showed more immune activity in the LNM, with upregulated B-cell and T-cell signaling (p&amp;lt;0.001), while TD showed more interaction with the extracellular matrix in the form of proteoglycans, focal adhesion, and ECM-receptor interaction (p&amp;lt;0.01). In addition, when hallmarks from the Molecular Signatures Database (MSigDB) were used for the enrichment analyses, TD showed the hallmark of epithelial mesenchymal transition (p &amp;lt;0.005). Conclusions: This study shows that TD have a more aggressive and invasive phenotype compared to LNM on protein level. TD had a higher expression of proteins that promote pro-tumorigenic processes and a more extensive interaction with the extracellular matrix. Furthermore, the hallmark of epithelial mesenchymal transition is enriched in TD compared to LNM. These findings form a possible explanation for the strong prognostic impact of TD, and give insight into the heterogeneity of different modes of locoregional spread in CRC. Citation Format: Nelleke P. Brouwer, Loth Webbink, Shannon Van Lent-Van Vliet, Pascal W. Jansen, Femke Simmer, Daniele V. Tauriello, Michiel Vermeulen, Iris D. Nagtegaal. Proteomics identifies differences in the biological phenotype of tumor deposits and lymph node metastases in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 987.