Personalized Medicine Strategies Research Articles

Decoding the heterogeneous landscape in the development prostate cancer.

Prostate cancer (PCa) is characterized as being histologically and molecularly heterogeneous; however, this is not only incorrect among individuals, but also at the multiple foci level, which originates in the prostate gland itself. The reasons for such heterogeneity have not been fully elucidated; however, understanding these may be crucial in determining the course of the disease. PCa is characterized by a complex network of chromosomal rearrangements, which simultaneously deregulate multiple genes; this could explain the appearance of exclusive events associated with molecular subtypes, which have been extensively investigated to establish clinical management and the development of therapies targeted to this type of cancer. From a clinical aspect, the prognosis of the patient has focused on the characteristics of the index lesion (the largest focus in PCa); however, a significant percentage of patients (11%) also exhibit an aggressive secondary foci, which may determine the prognosis of the disease, and could be the determining factor of why, in different studies, the classification of the subtypes does not have an association with prognosis. Due to the aforementioned reasons, the analysis of molecular subtypes in several foci, from the same individual could assist in determining the association between clinical evolution and management of patients with PCa. Castration-resistant PCa (CRPC) has the worst prognosis and develops following androgen ablation therapy. Currently, there are two models to explain the development of CRPC: i) The selection model and ii) the adaptation model; both of which, have been found to include alterations described in the molecular subtypes, such as Enhancer of zeste 2 polycomb repressive complex 2 subunit overexpression, isocitrate dehydrogenase (NAPD+)1 and forkhead box A1 mutations, suggesting that the presence of specific molecular alterations could predict the development of CRPC. This type of analysis could lead to a biological understanding of PCa, to develop personalized medicine strategies, which could improve the response to treatment thus, avoiding the development of resistance. Therefore, the present review discusses the primary molecular factors, to which variable heterogeneity in PCa progress has been attributed.

Closed-Loop Transcranial Alternating Current Stimulation: Towards Personalized Non-invasive Brain Stimulation for the Treatment of Psychiatric Illnesses

This review introduces closed-loop transcranial alternating current stimulation (tACS), which has the potential to become an effective and safe treatment modality for psychiatric illnesses such as schizophrenia and depression. The weak electric fields delivered to the brain by transcranial current stimulation interact in a synergistic manner with endogenous rhythmic brain activity patterns. As a result, the effect of stimulation on neuronal network dynamics is state dependent. Therefore, closed-loop paradigms that measure brain activity and apply targeted stimulation based on these measurements may allow effective modulation by targeted low-amplitude stimulation that is tuned to modulate the measured activity. Few initial studies of such closed-loop tACS have recently documented successful target engagement, mostly for applications that target specific activity patterns during sleep. Given the urgent need of novel therapeutic interventions for psychiatric disorders and the recent promising data from initial tACS clinical trials in psychiatry, we propose that closed-loop tACS deserves attention as a promising personalized medicine strategy in psychiatry.

Vitamin D Status, Bone Mineral Density, and VDR Gene Polymorphism in a Cohort of Belarusian Postmenopausal Women.

Vitamin D plays an important role in bone metabolism and is important for the prevention of multifactorial pathologies, including osteoporosis (OP). The biological action of vitamin is realized through its receptor, which is coded by the VDR gene. VDR gene polymorphism can influence individual predisposition to OP and response to vitamin D supplementation. The aim of this work was to reveal the effects of VDR gene ApaI rs7975232, BsmI rs1544410, TaqI rs731236, FokI rs2228570, and Cdx2 rs11568820 variants on bone mineral density (BMD), 25-hydroxyvitamin D level, and OP risk in Belarusian women. Methods. The case group included 355 women with postmenopausal OP, and the control group comprised 247 women who met the inclusion criteria. TaqMan genotyping assay was used to determine VDR gene variants. Results. Rs7975232 A/A, rs1544410 T/T, and rs731236 G/G single variants and their A-T-G haplotype showed a significant association with increased OP risk (for A-T-G, OR = 1.8, p = 0.0001) and decreased BMD (A-T-G, −0.09 g/cm2, p = 0.0001). The rs11568820 A-allele showed a protective effect on BMD (+0.22 g/cm2, p = 0.027). A significant dose effect with 25(OH)D was found for rs1544410, rs731236, and rs11568820 genotypes. Rs731236 A/A was associated with the 25(OH)D deficiency state. Conclusion. Our novel data on the relationship between VDR gene variants and BMD, 25(OH)D level, and OP risk highlights the importance of genetic markers for personalized medicine strategy.

Radiogenomics of gastroenterological cancer: The dawn of personalized medicine with artificial intelligence-based image analysis.

Radiogenomics is a new field of medical science that integrates two omics, radiomics and genomics, and may bring a major paradigm shift in traditional personalized medicine strategies that require tumor tissue samples. In addition, the acquisition of the data does not require special imaging equipment or special imaging conditions, and it is possible to use image information from computed tomography, magnetic resonance imaging, positron emission tomography‐computed tomography in clinical practice, so the versatility and cost‐effectiveness of radiogenomics are expected. So far, the field of radiogenomics has developed, especially in the fields of brain tumors and breast cancer, but recently, reports of radiogenomic research on gastroenterological cancer are increasing. This review provides an overview of radiogenomic research methods and summarizes the current radiogenomic research in gastroenterological cancer. In addition, the application of artificial intelligence is considered to be indispensable for the integrated analysis of enormous omics information in the future, and the future direction of this research, including the latest technologies, will be discussed.

Predictors of self-perceived health worsening over COVID-19 emergency in ALS.

IntroductionFactors influencing self-perceived health status over Corona Virus Disease 2019 (COVID-19) emergency in vulnerable populations, such as patients with chronic neurological diseases, are still unknown. In this work, we aimed at testing whether clinical care changes imposed by the quarantine, together with certain demographic and disease-specific features, might have determined a self-perceived worsening of health status in patients with amyotrophic lateral sclerosis (ALS).MethodsA brief web-based questionnaire investigating self-perceived anxiety, depression, and motor worsening, as well as clinical care changes over COVID-19 emergency, was administered to ALS patients currently followed at San Martino Hospital. Ordinal and logistic regression analyses were applied to identify significant predictors of health status.ResultsFifty-seven ALS patients completed the questionnaire. A total of 35.08% of cases reported anxiety symptoms, 36.84% depressive symptoms, and 35.08% reported worsening of motor symptoms. Significant predictors of anxiety symptoms severity included female gender, greater motor impairment, more aggressive disease course, and rehabilitation therapy suspension. The only significant predictor of depressive symptoms severity was a more aggressive disease course. Significant predictors of motor worsening were shorter disease duration and exams/visits cancelation.DiscussionCOVID-19 emergency and its management exerted a significant impact on self-perceived health status in patients with ALS, particularly in those cases in the earliest disease phases and with a more aggressive disease course. These findings have potential to improve personalized medicine strategies in the next phase.

Metabolic and lifestyle risk factors for chemotherapy-induced peripheral neuropathy in taxane and platinum-treated patients: a systematic review.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN. Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included. Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk. Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors. Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection.

The Repertoire of Glycan Alterations and Glycoproteins in Human Cancers.

Cancer as the leading cause of death worldwide has many issues that still need to be addressed. Since the alterations on the glycan compositions or/and structures (i.e., glycosylation, sialylation, and fucosylation) are common features of tumorigenesis, glycomics becomes an emerging field examining the structure and function of glycans. In the past, cancer studies heavily relied on genomics and transcriptomics with relatively little exploration of the glycan alterations and glycoprotein biomarkers among individuals and populations. Since glycosylation of proteins increases their structural complexity by several orders of magnitude, glycome studies resulted in highly dynamic biomarkers that can be evaluated for cancer diagnosis, prognosis, and therapy. Glycome not only integrates our genetic background with past and present environmental factors but also offers a promise of more efficient patient stratification compared with genetic variations. Therefore, studying glycans holds great potential for better diagnostic markers as well as developing more efficient treatment strategies in human cancers. While recent developments in glycomics and associated technologies now offer new possibilities to achieve a high-throughput profiling of glycan diversity, we aim to give an overview of the current status of glycan research and the potential applications of the glycans in the scope of the personalized medicine strategies for cancer.

Ліпосоми per se: фармакотерапевтичний статус

Сучасне переважне сприйняття нанорозмірних ліпідних артефактів – ліпосом як систем транспорту ліків (DDS), що ґрунтується на здатності до універсальної інкорпорації активних фармацевтичних інгредієнтів, сформувалось у процесі створення та клінічного застосування в світі понад 50інноваційних ліпосомальних препаратів для лікування онкологічних, інфекційних, запальних та інших важких захворювань. Серед них – створені в Україні оригінальні засоби Ліпін, Ліподокс, Ліолів і Ліпофлавон.Поряд із визнанням ролі ліпосом як провайдера активних фармацевтичних інгредієнтів переконливо підтверджена концепція фармакотерапевтичної самодостатності ліпосом per se («порожніх» ліпосом), що вперше запропонована академіком НАМНУ О. В. Стефановим. Відповідно до варіабельності фосфоліпідного складу для порожніх ліпосом встановлені антимікробні, противірусні, протизапальні, імуномодулюючі та інші прояви фармакологічної активності.До найважливіших доказів ефективності та широти спектра клінічного застосування порожніх ліпосом належить лікарський засіб «Ліпін». Наведено показову експериментальну й клінічну інформацію щодо фармакотерапевтичного застосування Ліпіну в пульмонології, кардіології, нефрології,гінекології та акушерстві. Зазначено можливість клінічного позиціонування Ліпіну для стоматології, дерматології та радіаційної медицини. Ефективність і безпечність системного застосування Ліпіну в різних клінічних галузях відображають універсальність механізму дії порожніх фосфоліпідних ліпосом з акцентом на антиоксидантну, антигіпоксичну, мембранопротекторну, імуномодулюючу дію, просурфактантну активність.Звернуто увагу на потенціал ліпосом per se для реалізації стратегії персоналізованої медицини та клінічні переваги алгоритму сумісного використання порожніх ліпосом із DDS з можливістю оптимізації клінічного ефекту за цілеспрямованої диференціації фосфоліпідного складу ліпосомальних партнерів.

The combination of an inflammatory peripheral blood gene expression and imaging biomarkers enhance prediction of radiographic progression in knee osteoarthritis

ObjectivePredictive biomarkers of progression in knee osteoarthritis are sought to enable clinical trials of structure-modifying drugs. A peripheral blood leukocyte (PBL) inflammatory gene signature, MRI-based bone marrow lesions (BML) and meniscus extrusion scores, meniscal lesions, and osteophytes on X-ray each have been shown separately to predict radiographic joint space narrowing (JSN) in subjects with symptomatic knee osteoarthritis (SKOA). In these studies, we determined whether the combination of the PBL inflammatory gene expression and these imaging findings at baseline enhanced the prognostic value of either alone.MethodsPBL inflammatory gene expression (increased mRNA for IL-1β, TNFα, and COX-2), routine radiographs, and 3T knee MRI were assessed in two independent populations with SKOA: an NYU cohort and the Osteoarthritis Initiative (OAI). At baseline and 24 months, subjects underwent standardized fixed-flexion knee radiographs and knee MRI. Medial JSN (mJSN) was determined as the change in medial JSW. Progressors were defined by an mJSN cut-point (≥ 0.5 mm/24 months). Models were evaluated by odds ratios (OR) and area under the receiver operating characteristic curve (AUC).ResultsWe validated our prior finding in these two independent (NYU and OAI) cohorts, individually and combined, that an inflammatory PBL inflammatory gene expression predicted radiographic progression of SKOA after adjustment for age, sex, and BMI. Similarly, the presence of baseline BML and meniscal lesions by MRI or semiquantitative osteophyte score on X-ray each predicted radiographic medial JSN at 24 months. The combination of the PBL inflammatory gene expression and medial BML increased the AUC from 0.66 (p = 0.004) to 0.75 (p < 0.0001) and the odds ratio from 6.31 to 19.10 (p < 0.0001) in the combined cohort of 473 subjects. The addition of osteophyte score to BML and PBL inflammatory gene expression further increased the predictive value of any single biomarker. A causal analysis demonstrated that the PBL inflammatory gene expression and BML independently influenced mJSN.ConclusionThe use of the PBL inflammatory gene expression together with imaging biomarkers as combinatorial predictive biomarkers, markedly enhances the identification of radiographic progressors. The identification of the SKOA population at risk for progression will help in the future design of disease-modifying OA drug trials and personalized medicine strategies.

What's Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses.

The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.

An Intelligent DNA Nanorobot for Autonomous Anticoagulation

AbstractArtificial nanorobots that can recognize molecular triggers and respond with programable operations provide an inspiring proof‐of‐principle for personalized theragnostic applications. We have constructed an intelligent DNA nanorobot for autonomous blood anticoagulation in human plasma. The DNA nanorobot comprises a barrel‐shaped DNA nanostructure as the framework and molecular reaction cascades embedded as the computing core. This nanorobot can intelligently sense the concentration of thrombin in the local environment and trigger an autonomous anticoagulation when excess thrombin is present. The triggering concentration of thrombin at which the nanorobot responds can be tuned arbitrarily to avoid possible side effects induced by excess thrombin. This makes the nanorobot useful for autonomous anticoagulation in various medical scenarios and inspires a more efficient and safer strategy for future personalized medicine.

An Intelligent DNA Nanorobot for Autonomous Anticoagulation.

Artificial nanorobots that can recognize molecular triggers and respond with programable operations provide an inspiring proof-of-principle for personalized theragnostic applications. We have constructed an intelligent DNA nanorobot for autonomous blood anticoagulation in human plasma. The DNA nanorobot comprises a barrel-shaped DNA nanostructure as the framework and molecular reaction cascades embedded as the computing core. This nanorobot can intelligently sense the concentration of thrombin in the local environment and trigger an autonomous anticoagulation when excess thrombin is present. The triggering concentration of thrombin at which the nanorobot responds can be tuned arbitrarily to avoid possible side effects induced by excess thrombin. This makes the nanorobot useful for autonomous anticoagulation in various medical scenarios and inspires a more efficient and safer strategy for future personalized medicine.

Adipose-Derived Stem Cells Reduce Lipopolysaccharide-Induced Myelin Degradation and Neuroinflammatory Responses of Glial Cells in Mice.

Brain inflammation is a key event triggering the pathological process associated with many neurodegenerative diseases. Current personalized medicine and translational research in neurodegenerative diseases focus on adipose-derived stem cells (ASCs), because they are patient-specific, thereby reducing the risk of immune rejection. ASCs have been shown to exert a therapeutic effect following transplantation in animal models of neuroinflammation. However, the mechanisms by which transplanted ASCs promote cell survival and/or functional recovery are not fully understood. We investigated the effects of ASCs in in vivo and in vitro lipopolysaccharide (LPS)-induced neuroinflammatory models. Brain damage was evaluated immunohistochemically using specific antibody markers of microglia, astroglia and oligodendrocytes. ASCs were used for intracerebral transplantation, as well as for non-contact co-culture with brain slices. In both in vivo and in vitro models, we found that LPS caused micro- and astroglial activation and oligodendrocyte degradation, whereas the presence of ASCs significantly reduced the damaging effects. It should be noted that the observed ASCs protection in a non-contact co-culture suggested that this effect was due to humoral factors via ASC-released biomodulatory molecules. However, further clinical studies are required to establish the therapeutic mechanisms of ASCs, and optimize their use as a part of a personalized medicine strategy.

Microenvironment Molecular Profile Combining Glycation Adducts and Cytokines Patterns on Secretome of Short-term Blood-derived Cultures during Tumour Progression.

Cancer cells are known to secrete many bioactive factors acting both with paracrine and autocrine mechanisms by which they condition the surrounding microenvironment. At the same time, the intracytoplasmic metabolic activities microenvironment influences the profile of this secretion. It is well known that cancer cells exhibit prevalent glycolytic metabolism and a more oxidative atmosphere compared to their healthy counterparts; this metabolic phenotype promotes glycate adducts formation and secretion. Considering the exacerbation of metabolic changes during the cancer progression, it is suggestive to explore the potential correlation between the increasing rate of glycan adducts and the specific pattern of secreted cytokines in different phases of cancer disease. We analyzed the secretomes of blood-derived cancer cell cultures from cancer patients and healthy subjects. The relative glycate adducts content in cancer secretomes was higher in comparison to that of healthy samples. Moreover, the stratification based on different phases of cancer disease correlated with a specific cytokines panel. The results obtained open a new perspective of observation of the intricate relationship between metabolome and inflammation in cancer. By using the analysis of secretome combined with a standardized protocol of liquid biopsy, it would be possible to identify specific profiles of molecular markers useful to arrange alternative and personalized medicine strategies.

Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance.

Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in-vivo molecular mechanisms of brain IR until recently has proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared to age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared to age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.

Abstract A21: Utilizing endoscopic-derived gastric cancer organoids for personalized neoadjuvant chemotherapy

Abstract Introduction: Patient-derived organoids (PDOs) have become attractive tools for genetic studies, biomarker identification, drug screening, and preclinical evaluation of personalized medicine strategies. Previously, we created gastric cancer PDOs from esophagogastroduodenoscopy (EGD) biopsy specimens. As a continuation of our previous work, we sought to optimize methods for creating EGD-derived PDOs for drug sensitivity testing within clinically actionable time constraints. Methods: We previously established a standard operating protocol for creating PDOs from EGD specimens of patients with gastric cancer. To optimize the development of PDOs, we enrolled patients with gastric adenocarcinoma undergoing EGD at Markey Cancer Center. During diagnostic EGDs, additional research biopsies were collected for creation of gastric cancer PDOs and placed in ice-cold organoid medium. We employed different dissociation methods based on the texture of the biopsy tissues. Briefly, soft tissues were washed and isolated in a chelating solution to release the glands, while the hard tissues were digested with collagenase and dispase to release epithelium. Glands or epithelia cells were collected, resuspended in BME (basement membrane extract), and plated in 2 wells of 24-well chambers. On day 4-6, PDOs were dissociated and passaged using manual pipetting. For passage 2 on day 9-11, PDOs were isolated into smaller and uniform-sized PDOs or single cells with both mechanical and enzymatic (TripLE Express) dissociation and plated in a 96-well plate at 10uL (500-1000 cells)/well. To test drug sensitivities, PDOs were treated on day 12 with current standard-of-care cytotoxic combination chemotherapies (e.g., FLOT, ECF, FOLFIRI, and FOLFOX) or solvent control. We tested concentrations determined by the Cmax and AUC of each drug associated with a single highest recommended dose in drug product label. We performed LIVE/DEAD assay on CellInsight CX7 High-Content Screening (HCS) Platform (ThermoFisher) and CellTiter Glo luminescent cell viability assay consecutively to measure response of PDOs to chemotherapy regimens. Result: Consistent with our prior experience, we successfully developed EGD-derived gastric cancer PDOs from patients undergoing diagnostic EGD. Using our modified technique for PDO creation and expansion, we obtained sufficient and uniform-sized PDOs at the second passage on day 10 and then treated these PDOs with current standard-of-care chemotherapy regimens to predict in vivo drug response. Creation of EGD-derived PDOs and drug sensitivity testing was feasible within two weeks of tissue collection. Conclusions: We have optimized methods to create, grow, and test EGD-derived PDOs within a clinically actionable time period. Our modified technique yielded higher concentration and more uniform-sized PDOs, providing sufficient biologic material for future implementation of rapid and comprehensive drug testing for neoadjuvant chemotherapy trials. Citation Format: Mei Gao, Miranda Lin, Wesam M Frandah, Moamen Gabr, Houssam E. Mardini, Michael Cavnar, Joseph Kim. Utilizing endoscopic-derived gastric cancer organoids for personalized neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A21.

Inflammation and depression treatment response to electroconvulsive therapy: Sex-specific role of interleukin-8

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: β = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (β = -0.458, p = 0.03), but not in males (β = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies.

High-Content Phenotypic Profiling in Esophageal Adenocarcinoma Identifies Selectively Active Pharmacological Classes of Drugs for Repurposing and Chemical Starting Points for Novel Drug Discovery.

Esophageal adenocarcinoma (EAC) is a highly heterogeneous disease, dominated by large-scale genomic rearrangements and copy number alterations. Such characteristics have hampered conventional target-directed drug discovery and personalized medicine strategies, contributing to poor outcomes for patients. We describe the application of a high-content Cell Painting assay to profile the phenotypic response of 19,555 compounds across a panel of six EAC cell lines and two tissue-matched control lines. We built an automated high-content image analysis pipeline to identify compounds that selectively modified the phenotype of EAC cell lines. We further trained a machine-learning model to predict the mechanism of action of EAC selective compounds using phenotypic fingerprints from a library of reference compounds. We identified a number of phenotypic clusters enriched with similar pharmacological classes, including methotrexate and three other antimetabolites that are highly selective for EAC cell lines. We further identify a small number of hits from our diverse chemical library that show potent and selective activity for EAC cell lines and that do not cluster with the reference library of compounds, indicating they may be selectively targeting novel esophageal cancer biology. Overall, our results demonstrate that our EAC phenotypic screening platform can identify existing pharmacologic classes and novel compounds with selective activity for EAC cell phenotypes.

The Expression and Polymorphism of Entry Machinery for COVID-19 in Human: Juxtaposing Population Groups, Gender, and Different Tissues.

(1) Background: Combating viral disease outbreaks has doubtlessly been one of the major public health challenges for the 21st century. (2) Methods: The host entry machinery required for COVID-19 (SARS-CoV-2) infection was examined for the gene expression profiles and polymorphism. (3) Results: Lung, kidney, small intestine, and salivary glands were among the tissues which expressed the entry machinery coding genes Ace2, Tmprss2, CtsB, and CtsL. The genes had no significant expression changes between males and females. The four human population groups of Europeans, Africans, Asians, and Americans had specific and also a common pool of rare variants for the X-linked locus of ACE2 receptor. Several specific and common ACE2 variants including S19P, I21T/V, E23K, A25T, K26R, T27A, E35D/K, E37K, Y50F, N51D/S, M62V, N64K, K68E, F72V, E75G, M82I, T92I, Q102P, G220S, H239Q, G326E, E329G, G352V, D355N, H378R, Q388L, P389H, E467K, H505R, R514G/*, and Y515C were of the utmost importance to the viral entry and infection. The variants of S19P, I21T, K26R, T27A, E37K, N51D, N64K, K68E, F72V, M82I, G326E, H378R, Q388L, and P389H also had significant differences in frequencies among the population groups. Most interestingly, the analyses revealed that more than half of the variants can exist in males, i.e., as hemizygous. (4) Conclusions: The rare variants of human ACE2 seem to be one of the determinant factors associated with fitness in the battle against SARS viruses. The hemizygous viral-entry booster variants of ACE2 describe the higher SARS-CoV-2 mortality rate in males. This is also supported by the lack of gender bias for the gene expression profiles of entry machinery. A personalized medicine strategy is conceived for isolating high-risk individuals in epidemic circumstances.

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.