Molecular Receptors Research Articles

Solution and Solid State Studies of Urea Derivatives of DITIPIRAM Acting as Powerful Anion Receptors.

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4–7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2′,3′-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO2, F, CF3, and Me). Solution, X-ray, and DFT studies reveal that the presented host–guest system offers a convergent array of four urea NH hydrogen bond donors to anions allowing the formation of remarkably stable complexes with carboxylates (acetate, benzoate) and chloride anions in solution, even in competitive solvent mixtures such as DMSO-d6/H2O 99.5/0.5 (v/v) and DMSO-d3/MeOH-d3 9:1 (v/v). The most effective derivatives among the series turned out to be receptors 5 and 6 containing electron-withdrawing F- and -CF3 para-substituents, respectively.

Unveiling the binding mode of perfluorooctanoic acid to human serum albumin.

Perfluorooctanoic acid (PFOA) is a toxic compound that is absorbed and distributed throughout the body by noncovalent binding to serum proteins such as human serum albumin (hSA). Though the interaction between PFOA and hSA has been already assessed using various analytical techniques, a high resolution and detailed analysis of the binding mode is still lacking. We report here the crystal structure of hSA in complex with PFOA and a medium-chain saturated fatty acid (FA). A total of eight distinct binding sites, four occupied by PFOAs and four by FAs, have been identified. In solution binding studies confirmed the 4:1 PFOA-hSA stoichiometry and revealed the presence of one high and three low affinity binding sites. Competition experiments with known hSA-binding drugs allowed locating the high affinity binding site in sub-domain IIIA. The elucidation of the molecular basis of the interaction between PFOA and hSA might provide not only a better assessment of the absorption and elimination mechanisms of these compounds in vivo but also have implications for the development of novel molecular receptors for diagnostic and biotechnological applications.

Differential expression of viral pathogen-associated molecular pattern receptors mRNA in Egyptian chronic hepatitis C virus patients

BackgroundOne possible mechanism utilized by hepatitis C virus (HCV) to escape from the host’s innate immune surveillance is modification of its pathogen-associated molecular patterns (PAMPs) by altering or hiding its RNA which interfering with toll-like receptors (TLRs) signaling and ultimately hindering the production of proinflammatory cytokines, chemokines, and interferons (IFNs). This study aimed to examine the expression levels of TLR3, TLR7, and IFN-α to investigate the correlated expression pattern among them in chronic HCV patients. Patients included in this study were categorized into two different groups, non-treated chronic HCV patients and treated chronic HCV patients, in addition to healthy volunteers as a control group. The blood samples were assessed for HCVAb, HCVRNA, HCV genotypes, and different biochemical analyses. The mRNA levels of TLR3, TLR7, and IFN-α in peripheral blood of chronic HCV patients were quantitatively measured in comparison to healthy controls.ResultsThe expression levels of TLR3, TLR7, and IFN-α were significantly downregulated in non-treated chronic HCV patients compared to both treated HCV patients and control subjects. On the other hand, treated HCV patients showed non-significant downregulation of the same three sensing receptors (TLR3, TLR7, and IFN-α) compared to control group. Obviously, the expression levels of IFN-α were positively correlated with the levels of both TLR3 and TLR7.ConclusionThe exhausted innate immunity against HCV may correlate to HCV downregulation of TLR3 and TLR7 expression on innate immune cells with a subsequent decrease in INF-α production and the possibility of targeting these receptors to enhance the immune response and clear the infection needs further studies.

Long-Term Liver Expression of an Apolipoprotein A-I Mimetic Peptide Attenuates Interferon-Alpha-Induced Inflammation and Promotes Antiviral Activity.

Apolipoprotein A-I mimetic peptides are amphipathic alpha-helix peptides that display similar functions to apolipoprotein A-I. Preclinical and clinical studies have demonstrated the safety and efficacy of apolipoprotein A-I mimetic peptides in multiple indications associated with inflammatory processes. In this study, we evaluated the effect of the long-term expression of L37pA in the liver by an adeno-associated virus (AAV-L37pA) on the expression of an adeno-associated virus encoding interferon-alpha (AAV-IFNα). Long-term IFNα expression in the liver leads to lethal hematological toxicity one month after AAV administration. Concomitant administration of AAV-L37pA prevented the lethal toxicity since the IFNα expression was reduced one month after AAV administration. To identify the mechanism of action of L37pA, a genomic and proteomic analysis was performed 15 days after AAV administration when a similar level of IFNα and interferon-stimulated genes were observed in mice treated with AAV-IFNα alone and in mice treated with AAV-IFNα and AAV-L37pA. The coexpression of the apolipoprotein A-I mimetic peptide L37pA with IFNα modulated the gene expression program of IFNα, inducing a significant reduction in inflammatory pathways affecting pathogen-associated molecular patterns receptor, dendritic cells, NK cells and Th1 immune response. The proteomic analysis confirmed the impact of the L37pA activity on several inflammatory pathways and indicated an activation of LXR/RXR and PPPARα/γ nuclear receptors. Thus, long-term expression of L37pA induces an anti-inflammatory effect in the liver that allows silencing of IFNα expression mediated by an adeno-associated virus.

Weakly Acidic Bile Is a Risk Factor for Hypopharyngeal Carcinogenesis Evidenced by DNA Damage, Antiapoptotic Function, and Premalignant Dysplastic Lesions In Vivo.

Simple SummaryThe etiologic role of biliary reflux in hypopharyngeal cancer is supported by clinical data. Although, reflux episodes often occur at pH 4.0, they can also occur at weakly acidic pH (5.5–6.0). The carcinogenic effect of bile at strongly acidic pH (pH 3.0) was recently documented in vivo. Here, we provide novel in vivo evidence that a weakly acidic pH of 5.5, similarly to a strongly acidic pH of 3.0, increases the risk of bile-related hypopharyngeal neoplasia. We document that chronic exposure of hypopharyngeal mucosa to bile at pH 5.5 promotes premalignant lesions with DNA damage, NF-κB activation, and deregulated mRNA and miRNA phenotypes, including Bcl-2 and miR-451a. The oncogenic effects of bile over a wider pH range suggests that antacid therapy may be insufficient to fully modify the effects of a bile induced oncogenic effect.Background: There is recent in vivo discovery documenting the carcinogenic effect of bile at strongly acidic pH 3.0 in hypopharynx, while in vitro data demonstrate that weakly acidic bile (pH 5.5) has a similar oncogenic effect. Because esophageal refluxate often occurs at pH > 4.0, here we aim to determine whether weakly acidic bile is also carcinogenic in vivo. Methods: Using 32 wild-type mice C57B16J, we performed topical application of conjugated primary bile acids with or without unconjugated secondary bile acid, deoxycholic acid (DCA), at pH 5.5 and controls, to hypopharyngeal mucosa (HM) twice per day, for 15 weeks. Results: Chronic exposure of HM to weakly acidic bile, promotes premalignant lesions with microinvasion, preceded by significant DNA/RNA oxidative damage, γH2AX (double strand breaks), NF-κB and p53 expression, overexpression of Bcl-2, and elevated Tnf and Il6 mRNAs, compared to controls. Weakly acidic bile, without DCA, upregulates the “oncomirs”, miR-21 and miR-155. The presence of DCA promotes Egfr, Wnt5a, and Rela overexpression, and a significant downregulation of “tumor suppressor” miR-451a. Conclusion: Weakly acidic pH increases the risk of bile-related hypopharyngeal neoplasia. The oncogenic properties of biliary esophageal reflux on the epithelium of the upper aerodigestive tract may not be fully modified when antacid therapy is applied. We believe that due to bile content, alternative therapeutic strategies using specific inhibitors of relevant molecular pathways or receptors may be considered in patients with refractory GERD.

Abstract PS14-27: Oncogenetic caracterization and imunohistochemistry patterns of male cancer breast diagnosticated in Haroldo JuaÇaba hospital, Northeast of Brazil

Abstract INTRODUCTION: The male breast cancer (MBC) is a rare disease, responsible for about 0.2% of all cancers and 0.1% of deaths for male cancer. Despite the rarity of the disease, statistics indicate that the incidence of MBC has been increasing significantly. The main risk factors for the development of MBC include old age, hormonal imbalance, radiation exposure, and family history of breast cancer. Hereditary breast and ovarian cancer (HBOC) is a syndrome associated with mutations in the BRCA1 and BRCA2 genes that have been related to MBC that as a rare disease, still poorly understood. METHODOLOGY: Family history analyzes, type and tumor staging, molecular markers expression, hormone receptors (RE, RP, and HER2), and cell proliferation marker (KI67) analysis were performed by immunohistochemistry. The presence of genetic mutations and the frequency of these mutations were evaluated in 31 genes of HBOC suspected patients treated at the Haroldo Juaçaba Hospital between the years 2009 to 2020. RESULTS: A total of 236 patients were diagnosed with breast cancer and submitted to a genetic test. Six of them were male patients aged between 54 and 73 years. His family history indicated that 83.3% had first-degree relatives affected by breast cancer. Different pathological staging was founded after tumors evaluation with the presence of micrometastases (P3) and higher levels of invasion in the lymph nodes. The expression of the cell proliferation marker (KI67) indicated low levels of expression except for patient P5. All patients presented expression of two hormone receptors (ER and RP) and no expression for HER2, except for one patient (P1), who had bilateral breast cancer, with HER2 expression (+2) on the right breast (first tumor) and no RP and HER2 expression in the left breast (second tumor), besides a moderate expression of KI67 (40%) (Table 1). The oncogenetic evaluation indicated that 83.33% of the patients had mutations described in the clinical database (ClinVar) 60% of them were pathogenic. The variants founded were in the PALB2 (16.66%), BRCA1 (33.33%), and BRCA2 (33.33%) genes (Table 1). The pathogenic mutations founded were located in the BRCA 1 and BRCA2 genes. One patient (P5) did not present mutations or VUS. The patient without the mutation (P5) presented a tumor with T3N1 pathological staging, low expression of estrogen (10%) and progesterone (10%) receptors, absence of HER2 expression, and high capacity of proliferation, indicated by the expression of KI67 (80%). The results indicate heterogeneity in the histological and molecular patterns of the patients evaluated, besides the oncogenetic patterns that may be associated with HBOC, especially those whose variants founded were pathogenic.CONCLUSION: Due to the low frequency of male breast cancer, the oncological data of these patients are relevant for epidemiological, pathological, and oncogenetic characterization, improving the characterization and identification of patterns for this pathology.Research Sponsor: Ministerio da Saude, Brasil (PRONON) Table 1. Histopathologic molecular markers and variation gene characterization of male breast cancer evaluated in Hospital Haroldo Juaçaba, Northest of Brazil, between 2009 and 2020. *VUS #Pathogenic variation.AgeFamiliar historyMolecular markersVariationPatientDiagnosticLast clinical evaluationBCOtherSubtype tumorPathological stagingRERPHER2KI67GeneSpecificityP14857YesPancreas; CCPLUMINAL A(R) pT1cpN1a(L) pT1B(R) 80%(L) 80%(R) 20%(L) negative(R) +2(L) negative(R) 18%(L) 40%PALB2*c. 3257G>A:Arg1086GlnP27274YesNoLUMINAL B(L)pT2 pN3a90%100%Negative20%BRCA1*c. 754C>T:Arg252CysP36466NoNoLUMINAL ApT2pN1mic90%70%Negative10%BRCA1#c. 5266dupC: p.Gln1756Pro fs74P45457YesNoLUMINAL A(L)T4bN290%90%Negative10%BRCA2#c. 4808delA: pAsn1603Thr fs14P55858YesProstaticLUMINAL A(R) T3N110%10%Negative80%Not detectedNot detectedP65858YesProstaticLUMINAL B(R) T4dN060%60%Negative30%BRCA2#c. 4808delA: pAsn1603Thr fs14 Citation Format: Maria Claudia dos Santos Luciano, Maria Júlia Barbosa Bezerra, Isabelle JoyceLima Silva-Fernandes, Paulo Goberlanio de Barros Silva, Clarissa Gondim Picanço-Albuquerque, Rosane Oliveira Sant´anna, Francisca Fernanda Barbosa Oliveira, Flavio Silveira Bitencourt, Marcos Venicio Alves Lima. Oncogenetic caracterization and imunohistochemistry patterns of male cancer breast diagnosticated in Haroldo JuaÇaba hospital, Northeast of Brazil [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-27.

In situ assembly of ZnO/graphene oxide on synthetic molecular receptors: Towards selective photoreduction of Cr(VI) via interfacial synergistic catalysis

Designing a novel type of imprinted photocatalysts for selective photoreduction of highly toxic pollutants is extremely needed in semiconductor photocatalysis. In this work, imprinted photocatalysts (named ZnO/GO-MIPs) were synthesized via Pickering emulsion polymerization by in situ assembling ZnO/GO composites on the synthetic molecular receptors (MIPs). The experimental data showed that the ZnO/GO-MIPs owned specific affinity towards the target Cr(VI) in aqueous solution with an imprinting factor (IF) of 1.6. Under the illumination of visible light, the ZnO/GO composites could selectively photoreduce the Cr(VI) adsorbed by the MIPs. In comparison with the ZnO/GO catalysts under light illumination, the ZnO/GO-MIPs showed a 15 fold increase in photoreduction of Cr(VI). Mechanism study indicates the photoreduction of Cr(VI) by the ZnO/GO composites was occurred at the interface between the solid MIP core and the aqueous solution. Compared to the ZnO-MIPs and the GO-MIPs, the ZnO/GO-MIPs clearly showed interfacial synergistic catalysis effect. To the best of our knowledge, this is first time that selective photoreduction of highly toxic pollutants at the solid-water interface by the ZnO/GO-MIPs was achieved. We believe the ZnO/GO-MIP catalysts have great potential in interfacial synergistic catalysis in environment and catalysis fields.

Supersensitive Detection of Anions in Pure Organic and Aqueous Media by Amino Acid Conjugated Ellman's Reagent.

The last few decades witnessed a remarkable advancement in the field of molecular anion receptors. A variety of anion binding motifs have been discovered, and large number of designer molecular anion receptors with high selectivity are being reported. However, anion detection in an aqueous medium is still a formidable challenge as evident from only a miniscule of synthetic systems available in the literature. We, herein, report 5,5'-dithio-bis(2-nitrobenzoic acid) (Ellman's reagent) appended with amino acids as supersensitive anion sensors that can detect F- and H2PO4- ions in both aqueous as well as organic media. Interestingly, the sensors showed a dual response to anions, viz., chromogenic response in organic medium and electrochemical response in aqueous solutions. Various spectroscopic techniques such as UV-vis and 1H NMR are used to investigate the binding studies in acetonitrile, whereas electrochemical methods such as cyclic voltammetry (CV) and differential pulse voltammetry (DPV) are employed to explore the anion binding in water. The host-guest complex stoichiometry and binding constants are calculated using the BindFit software. The geometry of host-guest complex has been optimized by the density functional theory (DFT) method. These molecules are versatile sensors since these function in both water and acetonitrile with extremely low limit of detection (LOD) up to 0.07 fM and limit of quantification (LOQ) up to 0.23 fM. To our knowledge, the present system is the first example of a sensor that can detect the lowest concentration of anions in water quantitatively. The minimalistic design strategy presented here opens up the innumerable possibilities for designing dual anion sensors in a one fell swoop.

5-Bromo-1H-indol based flexible molecular receptor possessing spectroscopic characteristics for detection of Sm(III) and Dy(III) ions

We have designed 1,3-bis(4-((E)-((Z)-((5-bromo-1H-indol-3-yl)methylene)hydrazono)methyl)-3-methoxyphenoxy)propane (BIHMPP) molecular receptor that posses π–π* and n–π* electronic transitions as well as PET (photo-induced electron transfer). When the receptor BIHMPP was tested with different metal ions under UV–visible and fluorescence techniques, only the introduction of Sm(III) and Dy(III) ions to the solution showed the change in spectra due to interactions between the receptor and metal ions (Sm(III) and Dy(III)). The quantum yields for BIHMPP is 0.29, Sm(III)-BIHMPP complex is 0.38, and Dy(III)-BIHMPP complex is 0.56. The ligand:metal binding stoichiometry observed is 2:1 (metal:BIHMPP) and maximum concentration that could be measured 1.2 nM and 0.7 nM for Sm(III) and Dy(III) ions respectively and with low detection limits. The cyclic voltammetric studies reveal the concomitant changes in electron transfer processes and support the complex formation.

Research Progress on the Mechanism and Clinical Data of Cereblon in Reversing the Resistance of Lung Cancer to PD-1 Antibody by T cells

程序性细胞死亡受体1（programmed cell death receptor 1, PD-1）是一种跨膜蛋白，主要表达于T细胞，并与靶细胞上的PD-1配体，即细胞程序性死亡配体1（programmed cell death ligand 1, PD-L1）结合。PD-1作为一种免疫抑制分子，当PD-1与肿瘤细胞上的配体PD-L1结合时，抑制了T细胞的免疫功能，从而发生肿瘤的免疫逃逸，如外周效应T细胞的耗竭导致效应T细胞向调节性T细胞（regulatory T cells, Tregs）转化。为解决这一问题，利用PD-1抗体与T细胞上的PD-1结合，从而抑制T细胞表面的PD-1与肿瘤细胞表面的PD-L1相互作用，进而恢复T细胞杀伤肿瘤细胞的功能。以Nivolumab和Pembrolizumab为代表的PD-1抗体现已被批准用于晚期非小细胞肺癌的一线治疗。但在部分患者中出现了由于肿瘤细胞、T细胞及细胞因子的相互作用导致的耐药，降低了免疫治疗的疗效。因此，如何克服患者的耐药成为了当前待解决的主要问题。研究发现，Cereblon（CRBN）作为DDB1泛素环E3泛素连接酶复合物的底物受体及免疫调节药物唯一已知的结合受体，与CRBN调节剂（cereblon modulatory agents, CMs）结合可以通过上调T细胞的增殖、激活和代谢，发挥T细胞的免疫功能从而逆转PD-1抗体耐药。本文就T细胞的下调导致PD-1抗体治疗肺癌耐药的机制、CRBN调节T细胞的机制及CRBN调节剂治疗肺癌的研究进展进行综述。

Investigating the Potential of Flexible and Pre-Organized Tetraamide Ligands to Encapsulate Anions in One-Dimensional Coordination Polymers: Synthesis, Spectroscopic Studies and Crystal Structures

The synthesis of amide-based molecules, possessing pre-organized structures, has received significant attention due to their potential applications as molecular receptors and as components of nanomaterials. In this study, four extended tetraamide ligands incorporating ethylene and propylene spacers, namely 1,2-bis[N,N′-6-(3-pyridylmethylamido)pyridyl-2-carboxyamido]ethane (L1), 1,2-bis[N,N′-6-(4-pyridylmethylamido)pyridyl-2-carboxyamido]ethane (L2), 1,2-bis[N,N′-6-(3-pyridylmethylamido)pyridyl-2-carboxyamido]propane (L3) and 1,2-bis[N,N′-6-(4-pyridylmethylamido)pyridyl-2-carboxyamido]propane (L4), were successfully synthesized. Further, reaction of L2 and L4, incorporating pendant 4-pyridyl donors as the metal coordinating sites, with cadmium salts, produced two close-packed one-dimensional coordination polymers, {[Cd3(L2)4(H2O)10](NO3)6·12H2O·CH3OH}n and {[Cd(SO4)(L4)(H2O)2]·4H2O·CH3OH}n. X-ray crystallography reveals that the flexible tetraamide ligands fold upon themselves in the coordination polymer structure. As a consequence, the anion pocket in {[Cd(SO4)(L4)(H2O)2]·4H2O·CH3OH}n incorporating the ligand with the propylene spacer was blocked from encapsulating charge-balancing anions, which were involved in bridging the di-cadmium units. Interestingly, a strong interaction between the 2,6-pyridine dicarboxamide moiety with the nitrate anions was found in {[Cd3(L2)4(H2O)10](NO3)6·12H2O·CH3OH}n, showing potential for materials made from these ligands to serve as anion receptors.

Absolute Stereochemical Determination of Organic Molecules through Induction of Helicity in Host-Guest Complexes.

Stereochemistry is a fundamental molecular property with important ramifications for structure, function, and activity of organic molecules. The basic building blocks of living organisms (amino acids and sugars) exhibit a precisely selected set of molecular handedness that has evolved over millions of years. The absolute stereochemistry of these building blocks is manifested in the structure and function of the cell machinery (e.g., enzymes, proteins, etc.), which are essential components of life. In the many chemical subdisciplines, molecular stereochemistry is exceedingly important and is often a strong determinant of structure and function. Besides its biological implications, the centrally important role of stereochemistry in many disciplines of chemistry and related fields has led to tremendous effort and activity, highlighted by the success in stereoselective syntheses of a host of functionalities. In the present climate, it is often the difficulty of assigning absolute stereochemistry as opposed to synthesis, which has become a nontrivial challenge, requiring the attention of the community. There will not be a general solution to this problem, as each system will have its own unique requirements and challenges; however, the need for rapid, routine, and microscale analysis is apparent. This is especially true with parallel and high-throughput arrays for screening conditions and catalysts, generating a large number of samples that require analysis.In this Account, we summarize our contribution to this field through the development of molecular receptors for sensing molecular asymmetry. These methodologies strive to unambiguously assign the absolute configuration of asymmetric center(s). To accomplish this task, our laboratory has designed a variety of host molecules, bearing various binding elements, to form stable complexes with chiral molecules (guests). During this complexation event, the stereochemistry of a target molecule induces a supramolecular chirality (i.e., helicity) within the host system. The design of the host system is such that the helicity of the host/guest complex can be observed and assigned via Exciton Coupled Circular Dichroism (ECCD), a nonempirical technique for identifying handedness, which is correlated back to the absolute stereochemistry of the bound chiral molecule. Taking advantage of the high sensitivity of chiroptical techniques (in terms of the required amount of sample for analysis) and fast response time, these methodologies offer a microscale, rapid, and nonempirical solution for assignment of absolute stereochemistry.The first part of this Account describes application of porphyrin tweezers as reporters of chirality for the absolute stereochemical determination of various classes of organic molecules. This methodology is suitable to report the absolute configuration of organic molecules that contain two binding elements (nitrogen or oxygen based functionalities). In the second part, host systems that do not require two sites of attachment to form ECCD active complexes will be described. This enables the absolute stereochemical assignment of challenging chiral molecules with functional groups lacking routine techniques for analysis.

Oncological Ligand-Target Binding Systems and Developmental Approaches for Cancer Theranostics.

Targeted treatment of cancer hinges on the identification of specific intracellular molecular receptors on cancer cells to stimulate apoptosis for eventually inhibiting growth; the development of novel ligands to target biomarkers expressed by the cancer cells; and the creation of novel multifunctional carrier systems for targeted delivery of anticancer drugs to specific malignant sites. There are numerous receptors, antigens, and biomarkers that have been discovered as oncological targets (oncotargets) for cancer diagnosis and treatment applications. Oncotargets are critically important to navigate active anticancer drug ingredients to specific disease sites with no/minimal effect on surrounding normal cells. In silico techniques relating to genomics, proteomics, and bioinformatics have catalyzed the discovery of oncotargets for various cancer types. Effective oncotargeting requires high-affinity probes engineered for specific binding of receptors associated with the malignancy. Computational methods such as structural modeling and molecular dynamic (MD) simulations offer opportunities to structurally design novel ligands and optimize binding affinity for specific oncotargets. This article proposes a streamlined approach for the development of ligand-oncotarget bioaffinity systems via integrated structural modeling and MD simulations, making use of proteomics, genomic, and X-ray crystallographic resources, to support targeted diagnosis and treatment of cancers and tumors.

A hybrid integro-differential model for the early development of the zebrafish posterior lateral line

The aim of this work is to provide a mathematical model to describe the early stages of the embryonic development of zebrafish posterior lateral line (PLL). In particular, we focus on evolution of PLL proto-organ (said primordium), from its formation to the beginning of the cyclical behavior that amounts in the assembly of immature proto-neuromasts towards its caudal edge accompanied by the deposition of mature proto-neuromasts at its rostral region. Our approach has an hybrid integro-differential nature, since it integrates a microscopic/discrete particle-based description for cell dynamics and a continuous description for the evolution of the spatial distribution of chemical substances (i.e., the stromal-derived factor SDF1a and the fibroblast growth factor FGF10). Boolean variables instead implement the expression of molecular receptors (i.e., Cxcr4/Cxcr7 and fgfr1). Cell phenotypic transitions and proliferation are included as well. The resulting numerical simulations show that the model is able to qualitatively and quantitatively capture the evolution of the wild-type (i.e., normal) embryos as well as the effect of known experimental manipulations. In particular, it is shown that cell proliferation, intercellular adhesion, FGF10-driven dynamics, and a polarized expression of SDF1a receptors are all fundamental for the correct development of the zebrafish posterior lateral line.

Harnessing selectivity in chemical sensing via supramolecular interactions: from functionalization of nanomaterials to device applications.

Chemical sensing is a strategic field of science and technology ultimately aiming at improving the quality of our lives and the sustainability of our Planet. Sensors bear a direct societal impact on well-being, which includes the quality and composition of the air we breathe, the water we drink, and the food we eat. Pristine low-dimensional materials are widely exploited as highly sensitive elements in chemical sensors, although they suffer from lack of intrinsic selectivity towards specific analytes. Here, we showcase the most recent strategies on the use of (supra)molecular interactions to harness the selectivity of suitably functionalized 0D, 1D, and 2D low-dimensional materials for chemical sensing. We discuss how the design and selection of receptors via machine learning and artificial intelligence hold a disruptive potential in chemical sensing, where selectivity is achieved by the design and high-throughput screening of large libraries of molecules exhibiting a set of affinity parameters that dictates the analyte specificity. We also discuss the importance of achieving selectivity along with other relevant characteristics in chemical sensing, such as high sensitivity, response speed, and reversibility, as milestones for true practical applications. Finally, for each distinct class of low-dimensional material, we present the most suitable functionalization strategies for their incorporation into efficient transducers for chemical sensing.

Expression of Human epidermal growth factor receptor 2, Survivin, Enhancer of zeste homolog -2, Cyclooxygenase-2, p53 and p16 molecular markers in Gall bladder carcinoma.

INTRODUCTION:Gallbladder cancer exhibits striking variability in the global rates, reaching epidemic levels for some regions and ethnicities. The basis of its variability resides in differences in environmental exposure and intrinsic genetic predisposition to carcinogenesis. There is little information present regarding genetic and molecular alterations in gall bladder cancer (GBC). We, therefore, have evaluated the molecular marker expression in GBC and studied their correlation with clinicopathological staging.MATERIALS AND METHODS:This prospective observational study was conducted on newly diagnosed GBC patients from July 2017 to July 2020. After complete staging workup, the GBC biopsy samples paraffin block was tested for molecular markers estrogen receptor (ER), progesterone receptor (PR), p53, p16, Human epidermal growth factor receptor 2 (HER 2-neu), Survivin, Enhancer of zeste homolog-2 (EZH2), and Cyclooxygenase-2 (COX-2) expression by immunohistochemistry.RESULTS:Fifty newly diagnosed patients of carcinoma gall bladder were included in the present study. Age was ranged from 29 – 69 years (mean 53.42). p53 was the most common positive marker in 74% of patients, survivin in 58%, COX-2 in 44%, and p16 in 42% whereas Her 2 neu and EZH-2 were positive in 16% of patients each. None of the patients of GBC were ER or PR positive. There was a significant difference between the various groups in terms of the distribution of histological grade and Her 2 neu (χ2 = 9.886, P = 0.014) but not with other markers. Furthermore, there was a significant difference in terms of distribution of p16 and p53 with stage (χ2 = 7.017, P = 0.037 and χ2 = 5.861, P = 0.033) respectively.CONCLUSIONS:The present study shows the expression of molecular markers Her2 neu, p53, p16, survivin, COX-2, and EZH-2 in GBC. Now the time has come, and it is also the need of the day to establish early biomarkers of this highly lethal malignancy. It can be used in future for the detection of disease in the early phase and targeted therapy.

Breast cancer molecular subtypes and receptor status among women at Potchefstroom Hospital: a cross-sectional study.

Introductionthis study aimed to determine the prevalence of receptor status and molecular subtypes in women with breast cancer treated at Potchefstroom Regional Hospital, South Africa and to analyze the association of molecular subtypes with some clinicopathologic characteristics of the tumor.Methodsthe study population for this cross-sectional study consisted of 116 women with primary invasive breast cancer, treated at the hospital from 1st January 2012 to 31st December 2018. Molecular subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor (ER) positive and/or progesterone receptor (PR) positive, HER2-; Ki-67 <30%), luminal B HER2- (ER+ and/or PR+, HER2-; Ki-67 ≥30%), luminal B HER2+ (ER+ and/or PR+, HER2+; any Ki-67), HER2 enriched (ER- and PR-, HER2+; any Ki-67), or triple-negative (ER-, PR-, HER2-, any Ki-67).Resultsthe proportions of breast cancer receptor status of ER+, PR+ and HER2-, were 71.6%, 64.7% and 75.9%, respectively. The molecular subtypes of 29.3% of patients were luminal A-type, 24.1% were luminal B HER2-, 22.4% were triple-negative, 18.1% were luminal B HER2+ and 6% were HER2-enriched. Molecular subtypes were significantly associated with tumor grade (p <0.001; Cramér's V=0.337), but independent of age (p=0.847), menopausal status (p=0.690), histology type (p=0.316), cancer stage (p=0.819), lymph node status (p=0.362), or tumor size (p=0.255).Conclusionthe study has revealed that most of the breast cancer in our setting was receptor-positive; approximately one-quarter were triple-negative. Furthermore, the study showed that luminal type A and B are the preponderant molecular subtypes. Molecular subtypes were associated with tumor grade but independent of age and menopausal status. The current study may assist in guiding the therapeutic strategy for patients with breast cancer in the Potchefstroom hospital catchment area.

A new class of fluorogenic thiazolo[2,3-b]quinazolinone receptor: selective detection towards mercury and hydrogen bisulfate ions in aqueous medium.

A series of fluorophoric and structurally diverse thiazoloquinazoline derivatives were synthesized in a one-pot multicomponent cascade reaction using a microwave irradiation technique. The unique structural arrangement of the synthesized compounds encouraged us to design a new type of bioactive molecular receptor. This receptor interacts with HSO4− in 1 : 1 and Hg2+ in 1 : 2 binding stoichiometric ratios resulting in a change in fluorescence as well as absorption spectra in aqueous medium. The ion bonded receptor complex possibly enhances the fluorescence signal of the receptor via H-bonded complex formation with HSO4− ions and co-ordinate complex formation with Hg2+ ions.

Copper(ii) complex of N-truncated amyloid-β peptide bearing a His-2 motif as a potential receptor for phosphate anions.

Electrochemical and spectroscopic studies demonstrated that the N-truncated amyloid β peptide Aβ5-9 (Arg-His-Asp-Ser-Gly-NH2) possessing histidine at position 2 (His-2) formed ternary complexes with copper(ii) and phosphate anions or phosphate groups of biomolecules. The recognition ability of Cu(ii)-Aβ5-9 toward phosphate species provided a new perspective on designing phosphate-selective molecular receptors.

Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment.

Simple SummaryDoublecortin-like kinase 1 (DCLK1) is a tumor stem cell marker in colon, pancreatic, and potentially other cancers that has received wide attention recently. Aside from its role as a tuft cell marker in normal tissue and as a tumor stem cell marker in cancer, previous studies have demonstrated that silencing DCLK1 functionally reduces stemness, epithelial mesenchymal transition (EMT), and tumorigenesis in cancers. More recently, DCLK1′s role in regulating the inflammatory, pre-cancer, and tumor microenvironment including its ability to modulate immune cell mechanisms has started to come into focus. Importantly, clinically viable therapeutic means of targeting DCLK1 have finally become available in the form of kinase inhibitors, monoclonal antibodies, and chimeric antigen receptor T cells (CAR-T). Herein, we comprehensively review the mechanistic role of DCLK1 in the tumor microenvironment, assess the potential for targeting DCLK1 in colon, pancreatic and renal cancer.Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.