Conditions For Progression Research Articles

Current Insights into the Role of UV Radiation-Induced Oxidative Stress in Melanoma Pathogenesis.

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies.

Targeting the Hippo- Yes-Associated Protein/Transcriptional Coactivator with PDZ-Binding Motif Signaling Pathway in Primary Liver Cancer Therapy

Liver cancer imposes a pervasive global health challenge, ranking among the most prevalent cancers worldwide. Its prevalence and mortality rates are on a concerning upward trajectory and exacerbated by the dearth of efficacious treatment options. The Hippo signaling pathway, originally discovered in Drosophila, comprises the following four core components: MST1/2, WW45, MOB1A/B, and LATS1/2. This pathway regulates the cellular localization of the transcriptional coactivator Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) through a series of enzymatic reactions. The Hippo-YAP/TAZ pathway maintains a balance between cell proliferation and apoptosis, regulates tissue and organ sizes, and stabilizes the internal environment. Abnormalities of any genes within the Hippo signaling pathway, such as deletion or mutation, disturb the delicate balance between cell proliferation and apoptosis, creating a favorable condition for tumor initiation and progression. Mutations or epigenetic alterations in the Hippo signaling pathway components can lead to its inactivation. Consequently, YAP/TAZ becomes overexpressed and activated, promoting excessive cell proliferation and inhibiting apoptosis. This dysregulation is closely associated with the development of liver cancer. This review discusses the pivotal role of the Hippo signaling pathway in the pathogenesis and progression of liver cancer. By elucidating its mechanisms, we aim to offer new insights into potential therapeutic targets for effectively combating liver cancer.

Diabetes compromises tight junction protein claudin 14 in the urinary bladder.

Infections are common in patients with diabetes. Moreover, increasing incidence of antibiotic resistance impedes the complete bacterial clearance and calls for alternative treatment strategies. Along with antibacterial resistance, compromised host conditions create a favorable condition for the disease progression. In particular, cell junction proteins are of major importance as they contribute to a tight cell barrier, protecting against invading pathogens. However, the impact of high glucose on cell junction proteins has received little attention in the urinary bladder but merits closer investigation. Here, we report that during diabetes the expression of cell junction protein, claudin 14 is compromised in the human urine exfoliated cells and in the urinary bladder of type 2 diabetic mouse. Further in vitro analysis confirmed a direct correlation of lower intracellular calcium levels with claudin 14 expression in high glucose-treated human uroepithelial cells. Moreover, external calcium supplementation in high glucose-treated cells significantly affected the cell migration and restored the claudin 14 expression through focal adhesion and β-1 integrins. Strengthening the epithelial barrier is essential, especially in individuals with diabetes where basal calcium levels could contribute.

Singlet Fission as the Gateway to Triplet Generation in Heavy Atom-Free Organic Molecules.

Triplet generations in heavy atom-free organic molecules are primarily revealed to proceed through singlet fissions (SFs) by investigating the contributions of SFs and intersystem crossings to the generation rates. The spin-flip long-range corrected time-dependent density functional theory calculations on 11 organic molecules known for triplet generation under photoirradiation are performed. The correlation between the descriptors for SF and the experimental singlet-to-triplet conversion rates strongly supports the predominance of SF progressions in all these molecules, corroborated by experimental observations of their triplet-triplet annihilations. Based on these findings, we propose updated conditions for SF progression: There is a high-absorption singlet state just above the triplet-triplet excitation of the chromophore dimer, or the singlet (triplet-triplet) excitation itself is responsible for photoabsorption. To the best of our knowledge, all organic molecules known for rapid triplet state generation fulfill these conditions.

High Level of Adropin Promotes the Progression of Pancreatic Ductal Adenocarcinoma.

Preliminary experiments have revealed the abnormally high expression level of adropin in pancreatic ductal adenocarcinoma (PDA). This study investigated the role of adropin in the progression of PDA. The paraffin-embedded samples of 20 patients with PDA were obtained from the hospital biobank, and immunohistochemistry was used to evaluate adropin expression. PDA cell lines were cultured and treated with recombinant adropin or adropin knockdown. Cell behavior was assessed, and the expression of phospho-vascular endothelial growth factor receptor (p-VEGFR2) and other related proteins was detected. The cell-derived xenograft (CDX) of PDA was established, and the effects of adropin or adropin knockdown on tumor growth were observed. The PDA cancer tissues exhibited elevated adropin protein expression compared with the paracancerous tissues, and the expression was positively correlated with carbohydrate antigen 19-9 levels in patients. Adropin significantly promoted the proliferation and migration of PDA cells and upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and matrix metalloprotein 2 (MMP2). After the knockdown of adropin expression or blockade of VEGFR2, the above effects of adropin were significantly reversed. Adropin supplementation significantly accelerated tumor growth in PDA CDX; upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and MMP2; and promoted angiogenesis in tumor tissue microenvironment. However, CDX inoculated with adropin knockdown cells produced the opposite results. Adropin overexpression in PDA promotes cancer cell proliferation and angiogenesis in tumor microenvironment by continuously activating VEGFR2 signaling, thereby creating conditions for tumor progression. Thus, targeting adropin may be an effective anti-PDA strategy.

Metabolic connectivity of resting-state networks in alpha synucleinopathies, from prodromal to dementia phase.

Previous evidence suggests that the derangement of large-scale brain networks reflects structural, molecular, and functional mechanisms underlying neurodegenerative diseases. Although the alterations of multiple large-scale brain networks in Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are reported, a comprehensive study on connectivity reconfiguration starting from the preclinical phase is still lacking. We aimed to investigate shared and disease-specific changes in the large-scale networks across the Lewy Bodies (LB) disorders spectrum using a brain metabolic connectivity approach. We included 30 patients with isolated REM sleep behavior disorder (iRBD), 28 with stable PD, 30 with DLB, and 30 healthy controls for comparison. We applied seed-based interregional correlation analyses (IRCA) to evaluate the metabolic connectivity in the large-scale resting-state networks, as assessed by [18F]FDG-PET, in each clinical group compared to controls. We assessed metabolic connectivity changes by applying the IRCA and specific connectivity metrics, such as the weighted and unweighted Dice similarity coefficients (DC), for the topographical similarities. All the investigated large-scale brain resting-state networks showed metabolic connectivity alterations, supporting the widespread involvement of brain connectivity within the alpha-synuclein spectrum. Connectivity alterations were already evident in iRBD, severely affecting the posterior default mode, attentive and limbic networks. Strong similarities emerged in iRBD and DLB that showed comparable connectivity alterations in most large-scale networks, particularly in the posterior default mode and attentive networks. Contrarily, PD showed the main connectivity alterations limited to motor and somatosensory networks. The present findings reveal that metabolic connectivity alterations in the large-scale networks are already present in the early iRBD phase, resembling the DLB metabolic connectivity changes. This suggests and confirms iRBD as a risk condition for progression to the severe LB disease phenotype. Of note, the neurobiology of stable PD supports its more benign phenotype.

Competition of SARS-CoV-2 Variants in Cell Culture and Tissue: Wins the Fastest Viral Autowave.

Replication of viruses in living tissues and cell cultures is a “number game” involving complex biological processes (cell infection, virus replication inside infected cell, cell death, viral degradation) as well as transport processes limiting virus spatial propagation. In epithelial tissues and immovable cell cultures, viral particles are basically transported via Brownian diffusion. Highly non-linear kinetics of viral replication combined with diffusion limitation lead to spatial propagation of infection as a moving front switching from zero to high local viral concentration, the behavior typical of spatially distributed excitable media. We propose a mathematical model of viral infection propagation in cell cultures and tissues under the diffusion limitation. The model is based on the reaction–diffusion equations describing the concentration of uninfected cells, exposed cells (infected but still not shedding the virus), virus-shedding cells, and free virus. We obtain the expressions for the viral replication number, which determines the condition for spatial infection progression, and for the final concentration of uninfected cells. We determine analytically the speed of spatial infection propagation and validate it numerically. We calibrate the model to recent experimental data on SARS-CoV-2 Delta and Omicron variant replication in human nasal epithelial cells. In the case of competition of two virus variants in the same cell culture, the variant with larger individual spreading speed wins the competition and eliminates another one. These results give new insights concerning the emergence of new variants and their spread in the population.

Influence of environmental viral load, interpersonal contact and infected rodents on Lassa fever transmission dynamics: Perspectives from fractional-order dynamic modelling

<abstract><p>Lassa fever is a fatal zoonotic hemorrhagic disease caused by Lassa virus carried by multimammate rats, which are widely spread in West Africa. In this work, a fractional-order model for Lassa fever transmission dynamics is developed and analysed. The model involves transmissions from rodents-to-human, person-to-person, as well as from Lassa virus infested environment/surfaces. The basic properties of the model such as positivity of solutions, and local stability of the disease-free equilibrium are determined. The reproduction number, $ \mathcal{R}_0 $, of the model is determined using the next generation method and it is used to determine the suitable conditions for disease progression as well as its containment. In addition, we performed sensitivity analysis of the model parameters using the Latin Hypercube Sampling (LHS) scheme to determine the most influential processes on the disease threshold, and determined the key processes to be focused on if the infection is to be curtailed. Moreover, fixed point theory was used to prove the existence and uniqueness of non-trivial solutions of the model. We used the Adams-Bashforth Moulton method to solve the model system numerically for different orders of the fractional derivative. Our results show that using various interventions and control measures such as controlling environmental contamination, reducing rodents-to-humans transmission and interpersonal contact, can significantly help in curbing new infections. Morestill, we observe that an increase in the memory effect, i.e. dependence on future values of the model on the previous states predicts lower peak values of infection cases in the short term, but higher equilibrium values in the long term.</p></abstract>

Number of pustules of garlic rust under different temperatures and leaf wetness

Puccinia porri is an etiological agent of garlic rust. The disease symptoms are characterized by leaf lesions that initially appear as whitish spots. With the disruption of the leaf cuticle, yelloworange uredospores are exposed. These signs are commonly known as pustules. Bulb production is affected by the reduction of photosynthetically active leaf area. The decrease in production is most pronounced when the attack occurs before bulb formation. The objective of this work was to quantify the latency periods of garlic rust and the number of pustules formed under the influence of temperature (10, 15, 20 and 25ºC) and leaf wetness period (6, 12, 18 and 24h). The latent period for this pathosystem varied between 10 and 12 days when the plants were subjected to temperatures of 10, 15 and 20°C after inoculation. The number of rust pustules was higher in garlic plants subjected to a temperature of 15°C. However, there were also a significant number of lesions at temperatures of 10ºC, especially when the leaf wetness period was 24 hours. At temperatures above 20°C, the number of pustules was less expressive. The results are important to perform fungicide efficacy tests in optimal conditions for disease progression and epidemiological studies.

Transition Therapy: Tackling the Ecology of Tumor Phenotypic Plasticity

Phenotypic switching in cancer cells has been found to be present across tumor types. Recent studies on Glioblastoma report a remarkably common architecture of four well-defined phenotypes coexisting within high levels of intra-tumor genetic heterogeneity. Similar dynamics have been shown to occur in breast cancer and melanoma and are likely to be found across cancer types. Given the adaptive potential of phenotypic switching (PHS) strategies, understanding how it drives tumor evolution and therapy resistance is a major priority. Here we present a mathematical framework uncovering the ecological dynamics behind PHS. The model is able to reproduce experimental results, and mathematical conditions for cancer progression reveal PHS-specific features of tumors with direct consequences on therapy resistance. In particular, our model reveals a threshold for the resistant-to-sensitive phenotype transition rate, below which any cytotoxic or switch-inhibition therapy is likely to fail. The model is able to capture therapeutic success thresholds for cancers where nonlinear growth dynamics or larger PHS architectures are in place, such as glioblastoma or melanoma. By doing so, the model presents a novel set of conditions for the success of combination therapies able to target replication and phenotypic transitions at once. Following our results, we discuss transition therapy as a novel scheme to target not only combined cytotoxicity but also the rates of phenotypic switching.

Herd immunity to SARS-CoV-2 among the population of the Republic of Belarus amid the COVID-19 pandemic

Objective was to investigate the SARS-CoV-2 collective immunity status of the population of Belarus within the context of the COVID-19 pandemic. Materials and methods. The work was carried out according to the methodology for assessing SARS-CoV-2 population immunity, developed by Rospotrebnadzor Russia and the Ministry of Health of Belarus with the participation of the St. Petersburg Pasteur Institute, taking into account WHO recommendations. The Bioethics Committee of Belarus and the local ethics committee of the St. Petersburg Pasteur Institute approved the study. Selection of participants was carried out using a questionnaire method and online technology (internet, cloud server). Volunteers were randomized into seven age groups (years of age): 1–17; 18–29; 30–39; 40–49; 50–59; 60–69; and 70+. Regional randomization ensured proportional representation of volunteers from each region, and no more than 30 people were included from one enterprise. In accordance with manufacturer instructions, blood plasma samples were analyzed for: IgG antibodies (Abs) to the SARS-CoV-2 nucleocapsid (Nc) using a quantitative ELISA test system; and IgG Abs to the receptor binding domain (RBD) of the SARS-CoV-2 S (spike) surface glycoprotein using a qualitative ELISA test system. Statistical processing was carried out using Excel 2010 and other software. Statistical differences were designated as significant when p 0.05, unless otherwise indicated. Results. The level of seroprevalence, in terms of Abs to Nc among the Belarusian population, was 38.4% (95% CI 37.6–45.4). The highest Ab levels were found among individuals in older age groups (50-70+ years old). The lowest were found in children 1–17 years old and in young people 18–39 years old The distribution of seroprevalence across Belarusian regions was relatively homogeneous, with the exception of the Minsk Region, where a statistically significant decrease in the indicator was noted. In terms of profession, the largest share of seropositive individuals was found among transportation workers; the smallest was found in business. The moderate COVID-19 incidence has not led to a dramatic increase in the number of contacts. The base reproduction number (R0) was 1.3. In the Republic of Belarus, there was a moderate level of asymptomatic COVID-19 among seropositive individuals (45.3% [95% CI 44.0–46.7]). This form of infection was observed most often among children aged 1–17 years old (65.0% [95% CI 61.3–68.6]). In parallel with seroprevalence assessment, SARS-CoV-2 vaccination was carried out. We used two vaccines: Gam-COVID-Vac (also known as Sputnik V, developed by Gamaleya National Center for Epidemiology and Microbiology, Russia); and BBIBP-CorV (Sinopharm, PRC). Vaccination against SARS-CoV-2 was accompanied by an increase in the level of anti-RBD Abs (95% [95% CI 94.7–96.7]). Taking into account the vaccination of a subset of the population with BBIBP-CorV, the overall herd immunity, inferred from the analyzed indicators (presence of anti-Nc or anti-RBD Abs), was 47.1% (95% CI 46.3–48.0). Conclusion. COVID-19 in Belarus was characterized by a moderately pronounced course of the epidemic process. The threshold level of herd immunity to SARS-CoV-2 has not yet been reached, as a result of which the conditions for progression of the epidemic remain.

3D Printing and Bioprinting to Model Bone Cancer: The Role of Materials and Nanoscale Cues in Directing Cell Behavior.

Simple SummaryThree-dimensional bioprinting is a promising tool for the study of cancer development and progression in bone, as it permits modeling the complexity of the microenvironment and cell-to-cell interactions. To this aim, an ideal model should combine a proper structure design, biomaterials selection, and the cellular counterpart. In this review, 3D-bioprinted bone systems obtained by different bioinks, and strategies, are discussed, aimed at mimicking the bone cancer microenvironment. The main challenges and unmet needs to reach perfect biomimicry are highlighted.Bone cancer, both primary and metastatic, is characterized by a low survival rate. Currently, available models lack in mimicking the complexity of bone, of cancer, and of their microenvironment, leading to poor predictivity. Three-dimensional technologies can help address this need, by developing predictive models that can recapitulate the conditions for cancer development and progression. Among the existing tools to obtain suitable 3D models of bone cancer, 3D printing and bioprinting appear very promising, as they enable combining cells, biomolecules, and biomaterials into organized and complex structures that can reproduce the main characteristic of bone. The challenge is to recapitulate a bone-like microenvironment for analysis of stromal–cancer cell interactions and biological mechanics leading to tumor progression. In this review, existing approaches to obtain in vitro 3D-printed and -bioprinted bone models are discussed, with a focus on the role of biomaterials selection in determining the behavior of the models and its degree of customization. To obtain a reliable 3D bone model, the evaluation of different polymeric matrices and the inclusion of ceramic fillers is of paramount importance, as they help reproduce the behavior of both normal and cancer cells in the bone microenvironment. Open challenges and future perspectives are discussed to solve existing shortcomings and to pave the way for potential development strategies.

Oncogenic and tumor suppressor pathways in subchronic aflatoxicosis in rats: Association with serum and urinary aflatoxin exposure biomarkers

In this study, the changes in oncogenic and tumor suppressor signaling pathways in liver and their association with serum and urinary biomarkers of aflatoxin exposure were evaluated in Wistar rats fed diets containing aflatoxin B1 (AFB1) for 90 days. Rats were divided into four groups (n = 15 per group) and assigned to dietary treatments containing 0 (control), 50 (AFB50), 100 (AFB100) and 200 μg AFB1 kg−1 diet (AFB200). Multiple preneoplastic foci of hepatocytes marked with glutathione-S-transferase-placental form (GST-P) were identified in AFB100 and AFB200 groups. Hepatocellular damage induced by AFB1 resulted in overexpression of cyclin D1 and β-catenin. The liver expression of retinoblastoma (Rb) and p27Kip1 decreased in AFB100 and AFB200 groups, confirming the favorable conditions for neoplastic progression to hepatocellular carcinoma. All samples from rats fed AFB1-contaminated diets had quantifiable AFB1-lysine in serum or urinary AFM1 and AFB1-N7-guanine, with mean levels of 20.42–50.34 ng mL−1, 5.31–37.68 and 39.15–126.37 ng mg−1 creatinine, respectively. Positive correlations were found between AFB1-lysine, AFM1 or AFB1-N7-guanine and GST-P+, β-catenin+ and cyclin D1+ hepatocytes, while Rb + cells negatively correlated with those AFB1 exposure biomarkers. The pathways evaluated are critical molecular mechanisms of AFB1-induced hepatocarcinogenesis in rats.

An Experimental Investigation on the Mechanism of Contact Erosion in Levee Foundations Considering the Characteristics of Particle Shape and Flow Field

Abstract Internal erosion is one of the most critical contributing factors for levee failures. Contact erosion, as a type of internal erosion, dominants when the seepage flow direction is parallel with the interface between coarse and fine soil layers. As is often the case beneath the foundation of a levee or at the top of clay core in an embankment dam, contact erosion can induce continuous transport of fine particles. Consequently, these water-retaining structures may collapse. To mitigate such potential hazards, the condition for initiation and progression of contact erosion should be investigated. In this research, the characteristics of contact erosion within cohesionless soils are presented visually by means of a newly devised apparatus. Two types of transparent coarse particles, namely quartz rubble and glass bead, are incorporated in two tests to study the effect of hydraulic conditions and particle shape on the initiation of contact erosion. The occurrence of contact erosion is captured qualitatively by snapshots, and the variation of soil sample configuration and flow lines are monitored by a stationary camera. Quantitative measurements are also conducted. Hydraulic gradients, turbidity, eroded mass, and inlet water pressure are recorded. The results provide insight into the influence of flow condition and particle shape on the occurence of contact erosion. The initiation and progression of contact erosion are governed by both hydraulic conditions and pore morphology. The latter is more crucial.

Third position repair for resolving troubles in understanding teacher instructions

Teachers’ instruction-giving practices in classrooms are largely recognized as the primary condition for the smooth progression of pedagogical activities. Following the formulation of the instruction by teachers, students are expected to perform preferred actions in the next relevant place in interaction. It is also likely that potential troubles in understanding teacher instructions might arise, which leads to delays of activity completion. Such troubles are made visible in interaction through two ways: (1) students’ explicit claims of non-understanding and (2) teachers’ identification of trouble in understanding without students’ explicit claims. Using multimodal conversation analysis for the examination of video-recorded higher education English as a foreign language classroom interactions (25h), this study mainly deals with the latter in response to gaps in the literature and sets out to describe a method in particular deployed by an L2 teacher for the identification and resolution of understanding troubles in instruction-giving sequences, namely third position repairs. The findings provide insights into L2 classroom discourse.

The disproportions of personnel support of medical sphere

The article discusses such issues of current state of staffing in medical sector as availability of health care system specialists, training programs for applicants to medical educational organizations and post-graduate programs for specialists, professional motivation and job prospects for graduates, prospects for development of medical education and training. In addition to professional sphere, modern health care system is also a market for medical services, which, according to expert estimates, is about 10 trillion US dollars per year. The participants in the field of medical services are not only organizations that provide medical care, but also manufacturers of medical equipment and medications. The medical sphere can't to effectively develop isolated from social structure. The staffing in medical field requires, along with professional motivation and job prospects in order to attract specialists in the field of medicine, and provide social support for their retention. The students entering medical university need decent salary after graduation and favorable conditions for further progression in professional field.

Tumour Microenvironment in Skin Carcinogenesis.

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.

Abstract C082: AGX-73, a novel small molecule multi-immunokinase inhibitor, has robust antitumor activity in murine syngeneic tumor models as a single agent and in combination with anti-PD1 checkpoint inhibitor

Abstract One of the central hypotheses of modern targeted cancer treatment paradigm is that aberrant activation and/or over-expression of oncogenic kinases drive intrinsic cancer cell proliferation and survival and is the causative event in cancer initiation and progression. The numerous examples of effective cancer therapies targeting specific kinases are testaments to its validity. In recent years, the demonstrations of profound and broad antitumor responses to immune checkpoint inhibitors, such as anti-PD1/PD-L1 or anti-CTLA-4, have confirmed and emphasized the crucial role immune evasion plays in creating a permissive condition for disease progression. Because protein kinases are known to regulate the majority of cellular functions, we hypothesize that Just as cancer cells frequently usurp the kinase signaling machinery to promote uncontrolled proliferation and survival, they may similarly hijack key immunokinase signaling machinery to suppress immune detection and elimination. We prioritized 6 key kinases that play profound roles in sustaining immunosuppressive cells in the tumor microenvironment (AXL, DDR1, DDR2, FMS, KIT and MER) and design inhibitors that potently, selectively and collectively counteract their action. AGX-73, optimized for drug-like properties, is a small molecule compound currently undergoing IND evaluation as potential clinical candidate for first-in-human trial. In in vitro assay, carried out at high ATP concentration (100 μM), AGX-73 inhibited the activity of recombinant human AXL, DDR1, DDR2, FMS, KIT and MER with IC50 values of 30, 12, 0.63, 96, 54, and 40 nM, respectively, but was highly selective against a panel of 374 kinases. Importantly, in in vitro primary macrophage assays, AGX-73 promoted M1 macrophage polarization and increased the secretion of IL-6 and TNFα. In contrast, AGX-73 suppressed the activation of M2 macrophages and decreased the secretion of IL-10. In vivo, in the MC38 colon carcinoma model, AGX-73 treatment reduced the number of tumor-associated macrophages (TAMs), from 46 to 22% of the total CD45+ cells in the tumors. Moreover, the M1/M2 ratio was favorably increased, from 1.3 to 1.8. AGX-73 demonstrated robust antitumor activity in multiple syngeneic tumor models. In the MC38 model, AGX-73 administered orally was active at multiple dose levels, from 30-150 mg/kg, QDx14, yielding %TGI that ranged from 55-92%. Importantly, AGX-73 treatment produced greater antitumor effects in immunocompetent mice than in immunodeficient mice (88 vs. 65% TGI at 90 mg/kg), suggesting the involvement of a functional immune system in its optimal antitumor activity. Of the 13 syngeneic tumor models tested in immunocompetent mice (150 mg/kg, QDx14), eleven were sensitive with TGI>50% (range 45-122%). In combination with anti-PD1 (10 mg/kg) in the MC38 model, AGX-73 produced synergistic activity at multiple dose levels evaluated when compared with either single agent alone. In nonclinical ADME studies, AGX-73 demonstrated favorable drug-like properties: including good bioavailability (F>50% in mouse, rat and monkey) and systemic exposure following oral administration in multiple species, acceptable metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction). IND toxicologic studies are currently in progress. Citation Format: Francis Y.F. Lee, Wen-Lian Wu, Zhi-Qiang Yang, John Tan. AGX-73, a novel small molecule multi-immunokinase inhibitor, has robust antitumor activity in murine syngeneic tumor models as a single agent and in combination with anti-PD1 checkpoint inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C082. doi:10.1158/1535-7163.TARG-19-C082

Comparative gene expression analysis in melanocytes driven by tumor cell-derived exosomes

Abundant with organelle-like membranous structures, the tumor microenvironment is composed of cancer cells that secrete exosomes. Studies have shown that these secreted exosomes transport RNA and active molecules to other cells to reshape the tumor microenvironment and promote tumor growth. In fact, we found that exosomes derived from melanoma cells drive pre-malignant transition in primary melanocytes. However, there is little available in the scientific literature on how exosomes modulate melanocytes in the microenvironment to optimize conditions for tumor progression and metastasis. We therefore focused this current study on identifying these conditions genetically. Through RNA sequencing, we analyzed gene expression levels of melanocytes driven by exosomes derived from melanoma and lung cancer cells compared with those without exosome controls. Significant differences were found in gene expression patterns of melanocytes driven by exosomes derived from melanoma and lung cancer cells. In the melanocytes responding to exosomes derived from melanoma cells, genes of lipopolysaccharide and regulation of leukocyte chemotaxis were predominant. In the melanocytes responding to exosomes derived from lung cancer cells, genes of DNA replication and mitotic nuclear division played an important role. These results provide further mechanistic understanding of tumor progression promoted by tumor-derived exosomes. This will also help identify potential therapeutic targets for melanoma progression.

Dual role of Endoplasmic Reticulum Stress-Mediated Unfolded Protein Response Signaling Pathway in Carcinogenesis.

Cancer constitutes a grave problem nowadays in view of the fact that it has become one of the main causes of death worldwide. Poor clinical prognosis is presumably due to cancer cells metabolism as tumor microenvironment is affected by oxidative stress. This event triggers adequate cellular response and thereby creates appropriate conditions for further cancer progression. Endoplasmic reticulum (ER) stress occurs when the balance between an ability of the ER to fold and transfer proteins and the degradation of the misfolded ones become distorted. Since ER is an organelle relatively sensitive to oxidative damage, aforementioned conditions swiftly cause the activation of the unfolded protein response (UPR) signaling pathway. The output of the UPR, depending on numerous factors, may vary and switch between the pro-survival and the pro-apoptotic branch, and hence it displays opposing effects in deciding the fate of the cancer cell. The role of UPR-related proteins in tumorigenesis, such as binding the immunoglobulin protein (BiP) and inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6) or the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), has already been specifically described so far. Nevertheless, due to the paradoxical outcomes of the UPR activation as well as gaps in current knowledge, it still needs to be further investigated. Herein we would like to elicit the actual link between neoplastic diseases and the UPR signaling pathway, considering its major branches and discussing its potential use in the development of a novel, anti-cancer, targeted therapy.