Identification Of Potential Novel Targets Research Articles

JAK/STAT Pathway Targeting in Primary Sjögren Syndrome.

Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease mainly affecting exocrine glands and resulting in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modifications and the dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells. Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made in recent years in basic and translational research field, allowing the identification of potential novel targets for therapy development. Despite such promising novelties, however, none therapy has been specifically approved for pSS treatment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal transducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT pathway plays a crucial role in autoimmunity and systemic inflammation, being involved in signal pathways of many cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular focus on available research and clinical data regarding the use of JAK inhibitors in pSS.

Abstract 454: TumorMapr™ analytical software platform: Unbiased spatial analytics and explainable AI (xAI) platform for generating data, extracting information, and creating knowledge from multi to hyperplexed fluorescence and/or mass spectrometry image datasets

Abstract Background: The current computational analyses of multi to hyperplexed fluorescence and/or mass spectrometry image datasets from patient pathology samples are not powerful enough to extract the maximum amount of information or to create the detailed knowledge that is required to advance precision medicine in pathology, including the development of personalized therapeutic strategies, identification of potential novel targets for drug discovery, selection of optimal patient cohorts for clinical trials, and improvement of the predictive power of prognostics/diagnostics. Methods: TumorMapr harnesses the computational power of proprietary, unbiased spatial analytics, spatial systems pathology, and explainable artificial intelligence (xAI) to extract information and to create knowledge from patient primary disease pathology samples imaged on any of the existing fluorescence and/or mass spectrometry imaging platforms. Results: To demonstrate the generalizability and utility of the TumorMapr platform, we apply it on two different datasets: hyperplexed immunofluorescence-based colorectal cancer data (51 biomarkers, 431 patients) and imaging mass cytometry-based breast cancer data (35 biomarkers, 281 patients). The TumorMapr platform (i) unlike the biased intensity thresholding approaches, the unbiased and automated functional cell phenotyping discovers a continuum of cell types and cell states, including transitional, multi-transitional cell states and fusion cell types that are critical for disease progression; (ii) derives microdomains with tumor promoting and tumor suppressing properties that are highly predictive of disease progression and response to therapy; (iii) spatial systems pathology analysis taps into the current network biology knowledge databases to derive pathway interactions and signaling networks, identify novel biomarkers and potential molecular targets and drugs, in the spatial context of each microdomain; (iv) xAI application guide, for example, in the case of predicting 5-year risk of recurrence in CRC patients, provides explanations in the form of microdomain-specific networks that are driving disease progression. Using the TumorMapr pipeline we created a prognostic test that shows a vastly superior performance over current approaches in predicting 5-yr risk of recurrence in CRC patients. Further, the TumorMapr platform enables building a rich outcome-specific library of microdomains to directly apply on prospective tissue samples for a companion diagnostic test that predicts disease outcomes. Citation Format: Samantha Panakkal, Brian Falkenstein, Akif Burak Tosun, Bruce Campbell, Michael Becich, Jeffrey Fine, D. Lansing Taylor, S. Chakra Chennubhotla, Filippo Pullara. TumorMapr™ analytical software platform: Unbiased spatial analytics and explainable AI (xAI) platform for generating data, extracting information, and creating knowledge from multi to hyperplexed fluorescence and/or mass spectrometry image datasets [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 454.

Emerging Evidence for cAMP-calcium Cross Talk in Heart Atrial Nanodomains Where IP3-Evoked Calcium Release Stimulates Adenylyl Cyclases.

Calcium handling is vital to normal physiological function in the heart. Human atrial arrhythmias, eg. atrial fibrillation, are a major morbidity and mortality burden, yet major gaps remain in our understanding of how calcium signaling pathways function and interact. Inositol trisphosphate (IP3) is a calcium-mobilizing second messenger and its agonist-induced effects have been observed in many tissue types. In the atria IP3 receptors (IR3Rs) residing on junctional sarcoplasmic reticulum augment cellular calcium transients and, when over-stimulated, lead to arrhythmogenesis. Recent studies have demonstrated that the predominant pathway for IP3 actions in atrial myocytes depends on stimulation of calcium-dependent forms of adenylyl cyclase (AC8 and AC1) by IP3-evoked calcium release from the sarcoplasmic reticulum. AC8 shows co-localisation with IP3Rs and AC1 appears to be nearby. These observations support crosstalk between calcium and cAMP pathways in nanodomains in atria. Similar mechanisms also appear to operate in the pacemaker region of the sinoatrial node. Here we discuss these significant advances in our understanding of atrial physiology and pathology, together with implications for the identification of potential novel targets and modulators for the treatment of atrial arrhythmias.

Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

Update on scleroderma-associated interstitial lung disease.

Systemic sclerosis (SSc), or scleroderma, is a heterogeneous and complex autoimmune disease characterized by varying degrees of skin and organ fibrosis and obliterative vasculopathy. The disease results in significant morbidity and mortality, and to date, available treatments are limited. Lung involvement is the leading cause of death of patients with SSc. Over the past year, significant advances have been made in our understanding of SSc-associated lung disease, and this review attempts to encapsulate these most recent findings and place them in context. We divide our discussion of the most recent literature into the following: first, clinical aspects of SSc lung management, including classification, imaging, biomarkers, and treatment; second, promising new animal models that may improve our ability to accurately study this disease; and third, studies that advance or change our understanding of SSc lung disease pathogenesis, thereby raising the potential for new targets for therapeutic intervention. Recent advances have resulted in a better understanding of SSc-associated lung disease, the development of new in-vivo models for exploring disease pathogenesis, and the identification of potential novel targets for the development of therapies.

An Effective Personalized Approach to a Rare Tumor: Prolonged Survival in Metastatic Pancreatic Acinar Cell Carcinoma Based on Genetic Analysis and Cell Line Development

Acinar cell carcinoma of the pancreas is an uncommon malignancy, accounting for less than 1% of all pancreatic neoplasms. Because of its rarity, only a few retrospective studies are available to help guide management. We report the case of a patient with metastatic ACC who achieved prolonged survival as a result of personalized treatment designed in part on the basis of molecular and in-vitro data collected on analysis of the tumor and a cell line developed from the liver metastasis. To our knowledge, this represents the first human cell line of ACC. The molecular findings on this case and this patient's cell line may be of use in the management of future cases of this rare tumor and allow the identification of potential novel targets for the effective treatment of this disease.

Telomere biology in cardiovascular disease: the TERC-/- mouse as a model for heart failure and ageing

Atherosclerosis and heart failure are major causes of morbidity and mortality in Western countries. Recent studies are suggesting involvement of telomere biology in the development and progression of age-associated conditions, including hypertension, atherosclerosis, and heart failure. Whether any of these reported associations are based on causal relationships remains to be elucidated. The construction of telomerase-deficient (telomerase RNA component, TERC(-/-)) mice might provide a potential instrumental model to study the involvement of telomere biology in cardiovascular disease. Here, we review the current available information from all studies performed in TERC(-/-) mice providing information on the cardiovascular phenotypic characteristics. Although this mouse model has proven its value in the understanding of the role of telomere biology in cancer, stem cell, and basic telomere research, only few studies were specifically designed to answer cardiovascular-related questions. The TERC(-/-) mice provide exciting opportunities to expand our knowledge of telomere biology in cardiovascular disease and the potential identification of novel targets of treatment.