Partners In Crime Research Articles

EP08.02-022 Investigating Partners in Crime: Osimertinib Resistance Mechanisms in Non-small Cell Lung Cancer Using Focused CRISPR Screen

Non-small cell lung cancer (NSCLC) is the most prevalent and detrimental cancer type, accounting for 85% of all lung cancer cases. EGFR mutations, which can be targeted by tyrosine kinase inhibitors (TKIs), have been addressed as one of the cancer driving mechanisms in NSCLC adenocarcinomas. Osimertinib, a third generation EGFR-TKI, has been recently approved for clinical use in the first-line treatment of advanced NSCLC. Unfortunately, the long-standing obstacle in EGFR-TKI treatments, including Osimertinib, is the inevitable resistance.

Longitudinal associations between Mexican-origin youth’s relationships with parents, siblings, and friends and individual adjustment

Across adolescence and into young adulthood, as youth experience both normative developmental and stressful life changes, close and supportive relationships are essential for healthy adjustment. Supportive relationships may be especially important for protecting Mexican-origin youth from developing depressive symptoms and engaging in risky behaviors given the emphasis within Mexican culture on close relationships, especially in families. With longitudinal data, we examined the associations between Mexican-origin youth’s relationships with mothers, fathers, siblings, and best friends and their adjustment across adolescence and into young adulthood. Participants were 246 Mexican-origin families with a 7th grader (younger sibling) and at least one older sibling, a mother, and a father at Time 1 (T1). Youth participated in home interviews at T1 and again five (T2) and eight (T3) years later. At T1, younger siblings were 12.55 (SD = .60) and older siblings were 15.48 (SD = 1.57) years old. Findings indicated that, with sibling and friend characteristics in the models, mother and father acceptance and conflict were significantly linked to youth positive and negative adjustment, respectively. Both sibling conflict and, consistent with a “partners in crime” process (Slomkowski et al., 2001; p. 273), sibling intimacy (of younger adolescents only), were linked to risky behavior. Same-gender friend conflict also was linked to risky behavior, but neither sibling nor friend relationships were linked to depressive symptoms. Some relationship effects were moderated by gender and age. Together, our findings have implications for programs aimed at preventing adjustment problems.

Banting memorial lecture 2022: 'Type 2 diabetes and nonalcoholic fatty liver disease: Partners in crime'.

Nonalcoholic fatty liver disease (NAFLD) was first described in the 1980s, but in the 21st century, NAFLD has become a very common condition. The explanation for this relatively recent problem is in large part due to the recent epidemic of obesity and type 2 diabetes (T2DM) increasing the risk of NAFLD. NAFLD is a silent condition that may not become manifest until severe liver damage (fibrosis or cirrhosis) has occurred. Consequently, NAFLD and its complications often remain undiagnosed. Research evidence shows that NAFLD is extremely common and some estimates suggest that it occurs in up to 70% of people with T2DM. In the last 5 years, it has become evident that NAFLD not only increases the risk of cirrhosis, primary liver cancer and end‐stage liver disease, but NAFLD is also an important multisystem disease that has major implications beyond the liver. NAFLD increases the risk of incident T2DM, cardiovascular disease, chronic kidney disease and certain extra‐hepatic cancers, and NAFLD and T2DM form part of a vicious spiral of worsening diseases, where one condition affects the other and vice versa. Diabetes markedly increases the risk of liver fibrosis and liver fibrosis is the most important risk factor for hepatocellular carcinoma. It is now possible to diagnose liver fibrosis with non‐invasive tools and therefore it is important to have clear care pathways for the management of NAFLD in patients with T2DM. This review summarises key recent research that was discussed as part of the Banting lecture at the annual scientific conference in 2022.

Partners in crime: Tbf1 and Vid22 promote expansions of long human telomeric repeats at an interstitial chromosome position in yeast.

In humans, telomeric repeats (TTAGGG)n are known to be present at internal chromosomal sites. These interstitial telomeric sequences (ITSs) are an important source of genomic instability, including repeat length polymorphism, but the molecular mechanisms responsible for this instability remain to be understood. Here, we studied the mechanisms responsible for expansions of human telomeric (Htel) repeats that were artificially inserted inside a yeast chromosome. We found that Htel repeats in an interstitial chromosome position are prone to expansions. The propensity of Htel repeats to expand depends on the presence of a complex of two yeast proteins: Tbf1 and Vid22. These two proteins are physically bound to an interstitial Htel repeat, and together they slow replication fork progression through it. We propose that slow progression of the replication fork through the protein complex formed by the Tbf1 and Vid22 partners at the Htel repeat cause DNA strand slippage, ultimately resulting in repeat expansions.

Shifting normative beliefs: On why groups behave more antisocially than individuals

A growing body of research shows that people tend to act more antisocially in groups than alone. However, little is known about why having “partners in crime” has such an effect. We run an experiment using sender–receiver games in which we elicit subjects’ normative and empirical beliefs to shed light on potential driving factors of this phenomenon. We find that the involvement of an additional sender makes the antisocial actions of senders more normatively acceptable to all parties, including receivers. By contrast, empirical beliefs are unaffected by the additional sender, suggesting that antisocial behavior increases in groups because antisocial actions become more acceptable and not because acceptable behavior is expected less often. We identify a necessary condition for this effect: the additional sender has to actively participate in the decision-making.

Familial Hypercholesterolemia and Lipoprotein(a): Two Partners in Crime?

Familial hypercholesterolemia is a high cardiovascular risk disorder. We will review the role of lipoprotein(a) in cardiovascular risk and in aortic valve stenosis in familial hypercholesterolemia, as well as its association with their phenotype, and strategies to identify this high-risk population. Patients with familial hypercholesterolemia have higher lipoprotein(a) levels mainly due to an increased frequency of LPA variants, and the cardiovascular risk is increased twofolds when both conditions coexist. Also, an increased risk for aortic valve stenosis and valve replacement has been observed with high lipoprotein(a) levels. Assessment of lipoprotein(a) during the cascade screening for familial hypercholesterolemia is a good opportunity to identify this high-risk population. High cardiovascular risk in familial hypercholesterolemia is increased even more when lipoprotein(a) is also elevated. Measurement of lipoprotein(a) in these patients is crucial to identify those subjects who need to intensify LDL-cholesterol reduction pending availability of lipoprotein(a)-specific treatments.

Hyperphosphorylation tunes TDP-43 solubility.

Post-translational modifications of intrinsically disordered regions (IDRs) enable changes in sequence chemistry, which in turn can tune conformational behavior and molecular interactions. In this issue of The EMBO Journal, Gruijs da Silva et al disentangle the effect of hyperphosphorylation on the C-terminal domain of TDP-43, a key IDR implicated in Amyotrophic Lateral Sclerosis (ALS).

Stem cells "aclymatise" to regenerate the blood system.

How blood stem cells balance fate decisions between quiescence maintenance and differentiation during recovery from cancer treatment remains poorly understood. A recent study by Umemoto etal (2022) uncovers an unexpected linkage between metabolic and epigenetic regulation of haematopoiesis, suggesting new targets in haematopoietic regeneration, with possible implications in leukaemogenesis and therapy resistance.

Partners in crime: Proteins implicated in RNA repeat expansion diseases.

Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X‐associated tremor/ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNAexp) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNAexp molecules and multiple protein partners, in this review, we discuss the roles of selected RNA‐binding proteins (RBPs) that interact with RNAexp and thus act as “partners in crime” in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNAexp life cycle, such as transcription, splicing, transport, and AUG‐independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNAexp within nuclear foci and those which participate in RNAexp‐dependent innate immunity activation. Moreover, we discuss the utility of selected RBPs as targets in the development of therapeutic strategies.This article is categorized under:RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional ImplicationsRNA in Disease and Development > RNA in Disease

Disabling partners in crime: Gold nanoparticles disrupt multicellular communications within the tumor microenvironment to inhibit ovarian tumor aggressiveness

The tumor microenvironment (TME) plays a key role in the poor prognosis of many cancers. However, there is a knowledge gap concerning how multicellular communication among the critical players within the TME contributes to such poor outcomes. Using epithelial ovarian cancer (EOC) as a model, we show how crosstalk among cancer cells (CC), cancer associated fibroblasts (CAF), and endothelial cells (EC) promotes EOC growth. We demonstrate here that co-culturing CC with CAF and EC promotes CC proliferation, migration, and invasion in vitro and that co-implantation of the three cell types facilitates tumor growthin vivo. We further demonstrate that disruption of this multicellular crosstalk using gold nanoparticles (GNP) inhibits these pro-tumorigenic phenotypesin vitroas well as tumor growthin vivo. Mechanistically, GNP treatment reduces expression of several tumor-promoting cytokines and growth factors, resulting in inhibition of MAPK and PI3K-AKT activation and epithelial-mesenchymal transition - three key oncogenic signaling pathways responsible for the aggressiveness of EOC.The current work highlights the importance of multicellular crosstalk within the TME and its role for the aggressive nature of EOC, and demonstrates the disruption of these multicellular communications by self-therapeutic GNP, thus providing new avenues to interrogate the crosstalk and identify key perpetrators responsible for poor prognosis of this intractable malignancy.

PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II.

SUMMARYIntrahepatic cholangiocarcinoma (ICC) contains abundant myofibroblasts derived from hepatic stellate cells (HSCs) through an activation process mediated by TGF-β. To determine the role of programmed death-ligand 1 (PD-L1) in myofibroblastic activation of HSCs, we disrupted PD-L1 of HSCs by shRNA or anti-PD-L1 antibody. We find that PD-L1, produced by HSCs, is required for HSC activation by stabilizing TGF-β receptors I (TβRI) and II (TβRII). While the extracellular domain of PD-L1 (amino acids 19–238) targets TβRII protein to the plasma membrane and protects it from lysosomal degradation, a C-terminal 260-RLRKGR-265 motif on PD-L1 protects TβRI mRNA from degradation by the RNA exosome complex. PD-L1 is required for HSC expression of tumor-promoting factors, and targeting HSC PD-L1 by shRNA or Cre/loxP recombination suppresses HSC activation and ICC growth in mice. Thus, myofibroblast PD-L1 can modulate the tumor microenvironment and tumor growth by a mechanism independent of immune suppression.

Brain-derived neurotrophic factor and inflammation in depression: Pathogenic partners in crime?

Major depressive disorder is a debilitating disorder affecting millions of people each year. Brain-derived neurotrophic factor (BDNF) and inflammation are two prominent biologic risk factors in the pathogenesis of depression that have received considerable attention. Many clinical and animal studies have highlighted associations between low levels of BDNF or high levels of inflammatory markers and the development of behavioral symptoms of depression. However, less is known about potential interaction between BDNF and inflammation, particularly within the central nervous system. Emerging evidence suggests that there is bidirectional regulation between these factors with important implications for the development of depressive symptoms and anti-depressant response. Elevated levels of inflammatory mediators have been shown to reduce expression of BDNF, and BDNF may play an important negative regulatory role on inflammation within the brain. Understanding this interaction more fully within the context of neuropsychiatric disease is important for both developing a fuller understanding of biological pathogenesis of depression and for identifying novel therapeutic opportunities. Here we review these two prominent risk factors for depression with a particular focus on pathogenic implications of their interaction.

Comrades-in-Arms and Partners in Crime: The German Democratic Republic (GDR) and China in the 1950s and 1960s

This article analyzes the quality of selected aspects and issues regarding relations between the German Democratic Republic (GDR) and China in the 1950s and early 1960s. How was Chinese dictator Mao Zedong’s Hundred Flowers Campaign perceived and interpreted in East Berlin, and why and until when was GDR leader Walter Ulbricht enthusiastic about Mao’s disastrous Great Leap Forward are among the questions this article will seek to answer. As it turned out, East German leaders’ assessments and newspaper reporting on Mao’s domestic and foreign policy and government propaganda did not in any way correspond with China’s on the ground realities. The East German authorities took Chinese propaganda and entirely false statistics and data on steel and agricultural production at face value and ordered its mouthpiece newspapers to do the same. The same was true for Chinese reporting and propaganda on Ulbricht’s decision to divide Berlin with a wall in 1961: misleading and nonsensical reporting in support of a fair-weather friendship, which in the wake of the Sino-Soviet Split in the early 1960s would turn into enmity (as ordered by Moscow).

Partners in Crime: Beta-Cells and Autoimmune Responses Complicit in Type 1 Diabetes Pathogenesis.

Type 1 diabetes (T1D) is an autoimmune disease characterized by autoreactive T cell-mediated destruction of insulin-producing pancreatic beta-cells. Loss of beta-cells leads to insulin insufficiency and hyperglycemia, with patients eventually requiring lifelong insulin therapy to maintain normal glycemic control. Since T1D has been historically defined as a disease of immune system dysregulation, there has been little focus on the state and response of beta-cells and how they may also contribute to their own demise. Major hurdles to identifying a cure for T1D include a limited understanding of disease etiology and how functional and transcriptional beta-cell heterogeneity may be involved in disease progression. Recent studies indicate that the beta-cell response is not simply a passive aspect of T1D pathogenesis, but rather an interplay between the beta-cell and the immune system actively contributing to disease. Here, we comprehensively review the current literature describing beta-cell vulnerability, heterogeneity, and contributions to pathophysiology of T1D, how these responses are influenced by autoimmunity, and describe pathways that can potentially be exploited to delay T1D.

COVID-19 INFECTION AND STEVENS-JOHNSON SYNDROME/TOXIC EPIDERMAL NECROLYSIS: ONE MORE THING TO WORRY ABOUT?

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Stevens-Johnson Syndrome/Toxic epidermal necrolysis (SJS/TEN) are fatal cutaneous side effects occasionally seen in the ICU. Although HIV is a known risk factor for SJS/TEN, we yet do not know the relation of COVID-19 infection to these severe cutaneous adverse reactions (SCAR) [1]. Here we present a case of a young man with COVID-19 and HIV infection who developed SCAR. CASE PRESENTATION: 40-year-old male with past medical history of substance abuse, HCV, HIV infection (not on ART) presented with odynophagia, voice change and drooling. COVID-19 testing in ED was positive. Head and neck CT scan revealed retropharyngeal abscess. He was intubated emergently due to inability to manage secretions and increased work of breathing. Abscess was managed conservatively with Ampicillin/Sulbactam and methylprednisone. On antibiotic day #3, he developed purple rashes with dark brown vesicles on his face, neck and anterior chest (Image 1). The following day, this evolved into an extensive bullous eruption with de-epithelization and epithelial loss, with lesions including face, eye lids, eyes, neck, upper trunk, bilateral upper extremities, back, genitalia and bilateral lower extremities (Image 2,3). Dermatology was consulted with concern for SJS/TEN and Ampicillin/Sulbactam was discontinued. His skin biopsy demonstrated full thickness epidermal necrosis. He was managed with pain medication, IV fluids, wound care and intravenous immunoglobulin.Meanwhile, his CD4 count was 65 with viral load of 174,000 which he was started on Atovaquone for PJP prophylaxis. COVID-19 markers were elevated on admission (CRP 2.49, Ferritin 546, D-dimer 0.69 LDH 299), and remained elevated throughout his hospital stay. Chest X-ray showed bibasilar hypoventilatory change with bilateral pleural effusions. Prophylactic low molecular weight heparin and methylprednisone were initiated.Patient was transferred to other facility burn ICU for further management. Despite full care, his skin lesions worsened, and patient passed away on hospital day 15. DISCUSSION: It has been reported that concomitant HIV and viral infections can precipitate SCAR [2]. However, we know little about COVID-19 infection and its relation to SCAR. There are few documented cases of COVID-19 associated SCAR but like other viral infections, SARS-COV-2 may be another risk factor for SCAR [3]. CONCLUSIONS: This case may lead clinicians to include SCAR as a differential when evaluating newly developed cutaneous lesions in COVID-19 patients. It is also essential to monitor the skin when COVID-19 patients are being treated with possible culprits. REFERENCE #1: Incidence of Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome in an HIV Cohort. AM J Clin Dermatol. 2012 Feb 1;13(1):49-54. REFERENCE #2: Nonimmediate Allergic Reactions Induced by Drugs: Pathogenesis and Diagnostic Tests. J Investig Allergol Clin Immununol. 2009;19(2):80-90. REFERENCE #3: A case report of toxic epidermal necrolysis (TEN) in a patient with COVID-19 treated with hydroxychloroquine: are these two partners in crime? Clin Mol Allergy. 2020 Oct 6;18:19. DISCLOSURES: No relevant relationships by Gregory Bassmann, source=Web Response No relevant relationships by Vignesh Harish, source=Web Response No relevant relationships by Kyunghoon Rhee, source=Web Response No relevant relationships by Zainab Shafi, source=Web Response

Prostate Health Index and Multiparametric MRI: Partners in Crime Fighting Overdiagnosis and Overtreatment in Prostate Cancer.

Simple SummaryIn the last decades, the widespread use of PSA as the standard tool for prostate cancer diagnosis led to a high rate of overdiagnosis and overtreatment. More recently, multiparametric magnetic resonance imaging (mpMRI) became part of the diagnostic pathway, and several next-generation PSA-based tests (PHI, PHI density, 4Kscore, STHLM3) have been proposed. The multivariable approach promises to help with a better stratification of PCa patients at initial diagnosis. In this study, we evaluated the performance of the prostate health index (PHI) and mpMRI for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). Our findings suggested that PHI had a better ability than mpMRI to predict positive biopsy, whereas a comparable performance in the identification of pathological aggressive PCa was pointed out. Notably, PHI and PHI density might represent useful biomarkers to recognize high-grade PCa in patients with low or uncertain PI-RADS scores on mpMRI.Widespread use of PSA as the standard tool for prostate cancer (PCa) diagnosis led to a high rate of overdiagnosis and overtreatment. In this study, we evaluated the performance of the prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). To this end, we prospectively enrolled 196 biopsy-naïve patients who underwent mpMRI. A subgroup of 116 subjects with biopsy-proven PCa underwent surgery. We found that PHI significantly outperformed both PI-RADS score (difference in AUC: 0.14; p < 0.001) and PHI density (difference in AUC: 0.08; p = 0.002) in the ability to predict positive biopsy with a cut-off value of 42.7 as the best threshold. Conversely, comparing the performance in the identification of clinically significant prostate cancer (csPCa) at RP, we found that PHI ≥ 61.68 and PI-RADS score ≥ 4 were able to identify csPCa (Gleason score ≥ 7 (3 + 4)) both alone and added to a base model including age, PSA, fPSA-to-tPSA ratio and prostate volume. In conclusion, PHI had a better ability than PI-RADS score to predict positive biopsy, whereas it had a comparable performance in the identification of pathological csPCa.

Reactive Oxygen Species and Endothelial Ca2+ Signaling: Brothers in Arms or Partners in Crime?

An increase in intracellular Ca2+ concentration ([Ca2+]i) controls virtually all endothelial cell functions and is, therefore, crucial to maintain cardiovascular homeostasis. An aberrant elevation in endothelial can indeed lead to severe cardiovascular disorders. Likewise, moderate amounts of reactive oxygen species (ROS) induce intracellular Ca2+ signals to regulate vascular functions, while excessive ROS production may exploit dysregulated Ca2+ dynamics to induce endothelial injury. Herein, we survey how ROS induce endothelial Ca2+ signals to regulate vascular functions and, vice versa, how aberrant ROS generation may exploit the Ca2+ handling machinery to promote endothelial dysfunction. ROS elicit endothelial Ca2+ signals by regulating inositol-1,4,5-trisphosphate receptors, sarco-endoplasmic reticulum Ca2+-ATPase 2B, two-pore channels, store-operated Ca2+ entry (SOCE), and multiple isoforms of transient receptor potential (TRP) channels. ROS-induced endothelial Ca2+ signals regulate endothelial permeability, angiogenesis, and generation of vasorelaxing mediators and can be exploited to induce therapeutic angiogenesis, rescue neurovascular coupling, and induce cancer regression. However, an increase in endothelial [Ca2+]i induced by aberrant ROS formation may result in endothelial dysfunction, inflammatory diseases, metabolic disorders, and pulmonary artery hypertension. This information could pave the way to design alternative treatments to interfere with the life-threatening interconnection between endothelial ROS and Ca2+ signaling under multiple pathological conditions.

Finding partners in crime? How transparency about managers’ behavior affects employee collusion

In this paper, we investigate how increasing transparency about managers' treatment of their employees affects the tendency of employees to initiate collusion. Building on behavioral economics theory, we argue that employees who are treated less kindly by their managers are more willing to initiate or join a collusive agreement. We hypothesize that internal transparency affects collusion in two ways. First, by revealing how kindly employees are treated by their managers, transparency increases or decreases the probability that individuals are singled out as potential “partners in crime.” Second, increasing transparency incentivizes managers to treat employees more kindly, which in turn reduces employees’ inclination to initiate collusion. The results of two experiments generally support the theory. We discuss the implications of our study for research and practice.

IPSCs and Exosomes: Partners in Crime Fighting Cardiovascular Diseases.

Cardiovascular diseases are the leading cause of mortality worldwide. Understanding the mechanisms at the basis of these diseases is necessary in order to generate therapeutic approaches. Recently, cardiac tissue engineering and induced pluripotent stem cell (iPSC) reprogramming has led to a skyrocketing number of publications describing cardiovascular regeneration as a promising option for cardiovascular disease treatment. Generation of artificial tissue and organoids derived from induced pluripotent stem cells is in the pipeline for regenerative medicine. The present review summarizes the multiple approaches of heart regeneration with a special focus on iPSC application. In particular, we describe the strength of iPSCs as a tool to study the molecular mechanisms driving cardiovascular pathologies, as well as their potential in drug discovery. Moreover, we will describe some insights into novel discoveries of how stem-cell-secreted biomolecules, such as exosomes, could affect cardiac regeneration, and how the fine tuning of the immune system could be a revolutionary tool in the modulation of heart regeneration.

Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.