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The present study reports a sustainable source of lignin, from termite frass. Lignin was extracted using Klason’s method and subjected to polarization studies to check the inhibition efficiency and measured the electrochemical performance of the coated sample on the carbon steel using electrochemical impedance spectroscopy. The anticorrosive property was determined in a simulated corrosive environment (0.1 M NaOH and 0.5 M NaOH). The morphological analysis of the surface of both bare metal and the lignin-coated ones, before and after exposure to the corrosive environment, was recorded using atomic force microscopy (AFM), scanning electron microscopy (SEM), and energy-dispersive X-Ray spectroscopy (EDX). The lignin showed maximum inhibition efficiency at 600 ppm in 0.5 M NaOH solution. Moreover, the lignin coated on carbon steel exhibited about 70% corrosion inhibition efficiency as recorded by potentiodynamic polarization studies and electrochemical impedance spectroscopy. The AFM and SEM analyses further corroborated the protection of the metal surface from corrosion when coated with lignin. Hence, the study suggests lignin from termite frass as a sustainable biological source suitable for anticorrosive applications. Graphic abstract

Studies in multiple species indicate that reducing growth hormone (GH) action enhances healthy lifespan. In fact, GH receptor knockout (GHRKO) mice hold the Methuselah prize for the world's longest‐lived laboratory mouse. We previously demonstrated that GHR ablation starting at puberty (1.5 months), improved insulin sensitivity and female lifespan but results in markedly reduced body size. In this study, we investigated the effects of GHR disruption in mature‐adult mice at 6 months old (6mGHRKO). These mice exhibited GH resistance (reduced IGF‐1 and elevated GH serum levels), increased body adiposity, reduced lean mass, and minimal effects on body length. Importantly, 6mGHRKO males have enhanced insulin sensitivity and reduced neoplasms while females exhibited increased median and maximal lifespan. Furthermore, fasting glucose and oxidative damage was reduced in females compared to males irrespective of Ghr deletion. Overall, disrupted GH action in adult mice resulted in sexual dimorphic effects suggesting that GH reduction at older ages may have gerotherapeutic effects., Attenuation of growth hormone action in mice at a mature adult age (6‐months) extends lifespan, reduces protein oxidation and glomerulonephritis in females while improving insulin sensitivity and decreasing lipid peroxidation, glomerulonephritis, and neoplasms in males.

Much of our understanding of GH’s action stems from animal models and the generation and characterization of genetically altered or modified mice. Manipulation of genes in the GH/IGF1 family in animals started in 1982 when the first GH transgenic mice were produced. Since then, multiple laboratories have altered mouse DNA to globally disrupt Gh, Ghr, and other genes upstream or downstream of GH or its receptor. The ability to stay current with the various genetically manipulated mouse lines within the realm of GH/IGF1 research has been daunting. As such, this review attempts to consolidate and summarize the literature related to the initial characterization of many of the known gene-manipulated mice relating to the actions of GH, PRL and IGF1. We have organized the mouse lines by modifications made to constituents of the GH/IGF1 family either upstream or downstream of GHR or to the GHR itself. Available data on the effect of altered gene expression on growth, GH/IGF1 levels, body composition, reproduction, diabetes, metabolism, cancer, and aging are summarized. For the ease of finding this information, key words are highlighted in bold throughout the main text for each mouse line and this information is summarized in Tables 1, 2, 3 and 4. Most importantly, the collective data derived from and reported for these mice have enhanced our understanding of GH action.

Pancreatic cancer is responsible for more than 48,000 deaths and 60,000 new cancer cases every year in the United States while the overall 5-year survival rate is only 10%. These numbers point towards an urgent need for new therapeutic approaches wherein therapy resistance poses a tremendous challenge. We and others have identified the role of growth hormone (GH) and its cognate receptor (GHR), overexpressed in pancreatic ductal adenocarcinoma patients (PDAC; >90% of pancreatic cancer cases), in driving therapy resistance by directly upregulating multidrug efflux, phenotype switch via epithelial-to-mesenchymal transition (EMT) and inhibition of apoptosis. Our laboratory had pioneered the discovery of pharmacologic GHR antagonists including the only approved and prescribed GHR antagonist, pegvisomant, and a new antagonist candidate named compound-G. Here, we used in vitro, in vivo and in silico analyses to assess the feasibility and efficacy of a treatment regimen including GHR antagonist and chemotherapy to manage PDAC. Both pegvisomant and compound-G exhibit significant suppression of cancer cellular viability, invasive potential, drug efflux rate and apoptosis in PDAC cell cultures. In male and female Nude mice with human PDAC xenografts, GHR inhibition by either pegvisomant or compound-G markedly re-sensitized the tumors towards both low and high doses of gemcitabine treatment. Compound G plus high doses of gemcitabine lead to almost complete tumor clearance in 40% of the mice. Also, tissue analyses reveal increased production of GH in tumors treated with chemotherapy. In the GHR antagonist treated tumors, significantly lower expression of ABC transporter (Abcb1, Abcg5, Abcc2, Abcg2), EMT mediator (Cdh2, Zeb1, Snai2, Epas1) and apoptosis marker (Bcl2) genes compared to control were observed - accounting for the observed sensitization to gemcitabine. In the human PDAC patient datasets, increased expression of GHR correlates strongly with increased expression of multidrug efflux transporters, anti-apoptotic markers, and EMT transcription factors. Therefore, we provide robust pre-clinical validation for a treatment regimen combining GHR antagonist and chemotherapy leading to highly efficacious tumor clearance. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute. Citation Format: Reetobrata Basu, Prateek Kulkarni, Emily Davis, Silvana Duran, John J. Kopchick. Combination of growth hormone receptor antagonist and gemcitabine leads to highly efficacious tumor clearance in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2620.

Knockdown of the growth hormone receptor (GHR) in melanoma cells downregulates ATP-binding cassette (ABC) transporters and sensitizes them to multiple drug treatments in vitro. The goal for this study is to understand whether a GHR antagonist (GHA) could suppress different types of cancers by sensitizing tumors to drug treatments in vivo through the downregulation of ABC transporters. Sera from GHA transgenic mice inhibited the proliferation of mouse melanoma cells (B16F10) in culture and suppressed expression of multiple ABC transporters. When B16-F10 cells were intradermally inoculated into GHA mice, tumor size was markedly reduced, as was STAT5 activation and ABCG1, ABCG2 levels. We then tested the effect of the GHA on the efficacy of cisplatin in vivo. GHA sensitized melanomas to cisplatin, leading to the smallest tumors among all groups. GHKO mice showed the same effect. We further extended this investigation to hepatocellular carcinoma (HCC). GHA mice were subcutaneously inoculated with mouse HCC (Hepa1 6 cells) and subsequently treated with sorafenib. The HCC tumors in GHA mice were markedly sensitive to sorafenib treatment compared to the same in wild-type mice. RNA analysis showed that when HCC was exposed to the combined treatment, relatively decreased ABC transporters expression was found. Immunohistochemical staining showed that phosphorylation of STAT5 and ABCB1 were downregulated in HCC tissues, suggesting that GHA in vivo downregulates ABC transporters in HCC, and therefore sensitizes them to sorafenib. Clinical data derived from HCC patients using the TCGA database showed that multiple ABC transporters in both types of cancer correlate with GHR levels; that is, when GHR levels are relatively high, patient survival is significantly decreased. Additionally, higher ABCC1 levels also lead to significantly decreased survival rate in HCC patients. Collectively, the results indicate that a GHA is effective in sensitizing both melanoma and HCC to available treatments in vivo and may be used as a therapeutic strategy for higher efficacy of tumor clearance. Citation Format: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick. Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2621.

Melanoma is the most aggressive form of skin cancer with a dismal 5-year survival rate of 16% at the metastatic stage of the disease. Exosomes have recently emerged as a critical mediator of cancer therapy resistance by regulating epithelial to mesenchymal transition (EMT) and drug efflux. Exosomes are extracellular vesicles (diameters 30-150nm) released from almost all types of cells including tumor cells which package and transfer proteins, RNA, and lipids (often called cargo) from one cell to another. This intercellular communication via exosomes has been reported to induce a drug-resistant phenotype across the tumor by transporting ABC multidrug transporters and mediators of EMT. Multiple studies have established that pituitary-, or tumor- or tumor microenvironment-derived growth hormone (GH) promotes EMT and drug resistance in cancer by binding to GHR-expressing tumor cells. A question arises: Does GH exert this effect across the tumor population via modulating tumor-derived exosomal cargo? No study has yet directly assessed the effect of GH on exosomes in terms of modulating EMT or drug resistance. We isolated exosomes from human melanoma cells with differential levels of GHR expression, following treatment with combinations of GH, anti-cancer drugs, and the GHR antagonist, pegvisomant. We observed no change in the quantity of tumor-derived exosomes with changes in GH action. However, we found significant upregulation of multidrug efflux pumps ABCB1, ABCC1, ABCC2, and ABCG2 in GH-treated tumor exosomes. Importantly, treatment of naïve melanoma cells with these exosomes increased their drug efflux rate and reduced drug retention. Exosomes derived from pegvisomant treated melanoma cells showed markedly reduced ABC transporter contents and did not increase the efflux rate of naïve tumor cells. A similar trend in matrix metalloproteinases (MMP2, MMP9) and TGFb levels in isolated exosomes as well as TGFb signaling and invasion capacity in naïve tumor cells treated with isolated exosomes were observed. These results present a unique effect of GH on tumor-derived exosomal content modulation towards propagating a drug-resistant tumor phenotype in naïve cancer cells. Acknowledgment: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute. Citation Format: Prateek Kulkarni, Reetobrata Basu, John J. Kopchick. Growth hormone upregulates tumor-derived exosomal distribution of EMT mediators and multi-drug efflux pumps in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1004.

A rare 20K isoform of GH-V (here abbreviated as GHv) was discovered in 1998. To date, only 1 research article has characterized this isoform in vivo, observing that GHv treatment in male high-fat fed rats had several GH-like activities, but unlike GH lacked diabetogenic and lactogenic activities and failed to increase IGF-1 or body length. Therefore, the current study was conducted to further characterize the in vivo activities of GHv in a separate species and in a GH-deficient model (GH-/- mice) and with both sexes represented. GHv-treated GH-/- mice had significant increases to serum IGF-1, femur length, body length, body weight, and lean body mass and reduced body fat mass similar to mice receiving GH treatment. GH treatment increased circulating insulin levels and impaired insulin sensitivity; in contrast, both measures were unchanged in GHv-treated mice. Since GHv lacks prolactin receptor (PRLR) binding activity, we tested the ability of GH and GHv to stimulate the proliferation of human cancer cell lines and found that GHv has a decreased proliferative response in cancers with high PRLR. Our findings demonstrate that GHv can stimulate insulin-like growth factor-1 and subsequent longitudinal body growth in GH-deficient mice similar to GH, but unlike GH, GHv promoted growth without inhibiting insulin action and without promoting the growth of PRLR-positive cancers in vitro. Thus, GHv may represent improvements to current GH therapies especially for individuals at risk for metabolic syndrome or PRLR-positive cancers.

Data is nowadays an invaluable resource; indeed, it guides all business decisions in most of the computer-aided human activities. Threats to data integrity are thus of paramount relevance, as tampering with data may maliciously affect crucial business decisions. This issue is especially true in cloud computing environments, where data owners cannot control fundamental data aspects, like the physical storage of data and the control of its accesses. Blockchain has recently emerged as a fascinating technology which, among others, provides compelling properties about data integrity. Using the Blockchain to face data integrity threats seems to be a natural choice, but its current limitations of low throughput, high latency, and weak stability hinder the practical feasibility of any Blockchain-based solutions. In this paper, by focusing on a case study from the European SUNFISH project, which concerns the design of a secure by-design cloud federation platform for the public sector, we precisely delineate the actual data integrity needs of cloud computing environments and the research questions to be tackled to adopt Blockchain-based databases. First, we detail the open research questions and the difficulties inherent in addressing them. Then, we outline a preliminary design of an effective Blockchain-based database for cloud computing environments.

Block chain and AI are the most well liked technology trends, even if the 2 technologies have extremely completely different developing parties and applications, researchers are discussing and exploring their combinational applications. With integrating these technologies we can enhance blockchain architect along with bosting potential of Ai, and these process knowledge takes the existing system to new higher levels. At a similar time, the combination of machine learning and blockchain can make AI more coherent and understandable by tracing all the datas which is stored in the form of ledger and there by building up the standard in the system. Hence we discuss further more in detail in the paper.

Human growth hormone (GH) and its cognate growth hormone receptor (GHR) have been established to have a distinct role in promoting the progression of several types of human cancers. We had earlier described a newfound role of the GH-GHR axis in driving chemoresistance in melanoma by upregulating drug efflux by ABC multidrug transporter expression and a phenotype switch by induction of epithelial-to-mesenchymal transition (EMT). Here we present an in-depth analysis of this role of GH-GHR in the highly therapy resistant human pancreatic cancer which has a 5-year survival rate of only 10% in 2020. Using human and mouse pancreatic cancer cells and RNA and protein expression analyses by RT-qPCR, ELISA, and western-blot, we identified that (i) GH upregulates specific ABC-transporter expressions in a drug-context specific manner, (ii) GH upregulates EMT transcription factors, (iii) GH activates specific oncogenic signaling pathways, and (iii) GH action increases cytochrome P450 members involved in hepatic drug metabolism. The GH antagonist, Pegvisomant, significantly inhibited these effects. Additionally, we confirmed the effects of these molecular changes by specific assays. For example, GH increases basement membrane invasion, viability of circulating tumor cells, and drug efflux; while inhibition of GHR by pegvisomant in pancreatic cancer cells reversed this aggressive tumor phenotype and sensitized the tumor cells to chemotherapy. Cell viability assays confirmed a decreased IC50 of gemcitabine, doxorubicin, and erlotinib in pancreatic cancer cells treated with pegvisomant and an increase in IC50 cells treated with GH. We further verified our results using in silico analyses of TCGA datasets for pancreatic cancer - which provided robust confirmation of our experimental findings. Presently we are validating our observation in nude mice with human pancreatic cancer cell xenografts. In conclusion, our in vitro results confirm that GHR antagonism can drastically sensitize human pancreatic cancer cells by blocking mechanisms of drug resistance, thus providing a valuable window for improved efficacy of available chemo- and targeted therapy.

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play important roles in different stages of progression and drug resistance in many types of cancers, including breast, colon, endometrial, liver cancer and melanoma. GH receptor (GHR) is highly expressed in melanoma and promotes cancer proliferation and multidrug efflux pumps mediated drug resistance. Knockdown of GHR in melanoma cells significantly increased their drug sensitivity in vitro. Thus, a GHR antagonist could become a therapeutic molecule in suppressing melanoma cancer growth and sensitizing the tumor to chemotherapy in vivo. Here, we used GHR antagonist (GHA) transgenic mice which constitutively express a GHA to specifically suppress GH/IGF-1 axis. We found have circulating IGF-1 level was significantly lowered in these mice as a result of GHR antagonism. Furthermore, the sera from the mice could inhibit the growth of melanoma cells in culture. Recombinant GHA produced in our laboratory was able to suppress the phosphorylation of STAT5, a well-established marker of GH action, and the phosphorylation of MAPK, a critical signaling component of cell growth. The GHA mice were intradermally inoculated with mouse melanoma cells (B16-F10) or subcutaneously inoculated with mouse liver cancer cells (Hepa1-6) to generate syngeneic mouse tumor models. We observed that tumor size and tumor weight were markedly reduced and that phosphorylation of STAT5 and MAPK was suppressed in the livers from these mice. In parallel, the activation of GH signaling and the expression level of various types of multidrug efflux pumps were reduced in these tumors. To test the effect of GHA on drug synergy, the GHA mice or WT controls with liver cancer cells were treated with sorafenib or vehicle. Sorafenib is an FDA-approved tyrosine kinase inhibitor, widely used to treat advanced hepatocarcinoma, but has a reduced efficacy in application due to the multidrug efflux pump ABCG2. In vitro, recombinant bovine GH increased the IC50 of sorafenib and the expression of ABCG2. In vivo, GHA mice treated with sorafenib had the smallest tumors compared with WT mice, or in mice treated with sorafenib or GHA alone. Furthermore, ABCG2 mRNA levels were also suppressed in the liver tumors from GHA mice. All these findings from functional and mechanistic investigations confirm that a GHA or Pegvisomant is effective in cancer treatment in vivo and may be a novel therapeutic strategy or molecule to suppress the tumor growth and to sensitize different types of cancers to anti-cancer therapies. Acknowledgments: This work was supported by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll to J.K.; NIH-R01AG059779, the AMVETS, Edison Biotechnology Institute and Diabetes Institute at Ohio University; OURC funding and Baker Fund to Y.Q.; the PURF Fund and the John J. Kopchick Molecular Cell Biology Undergraduate Student Fund to N.A and J.T.

In 2020, the National Cancer Institute (NCI) estimates 57,600 new cases and 47,050 deaths in the US due to pancreatic ductal adenocarcinoma (PDAC). A dismal 10% five-year overall survival rate in PDAC is attributed to late diagnosis, limited treatment options, a remarkably high metastasis rate, and resistance of this cancer to available therapies. Therefore, a better understanding of the mechanisms of how PDAC tumors acquire drug resistance and spread to distal parts of the body are necessary for developing novel therapeutic approaches. Exosomes, microscopic vesicles released from most cells (both tumor and non-tumor) have been recently established to play a significant role in cell to cell communication. Exosomes modulate their target cell responses systematically depending on the nature of exosomal cargoes (nucleic acids, proteins, and lipids). PDAC derived exosomes have been implicated to promote metastasis via forming a pre-metastatic niche of cells as well as enhancing drug resistance. Growth hormone (GH) secreted primarily by the pituitary gland promotes metastasis and drug resistance as shown by plethora of studies. No study has directly assessed the effect of GH on exosomal cargoes in terms of promoting metastases and drug resistance. In this report, we show that GH modulates various pancreatic cancer cell exosomal cargoes which in turn potentially amplifies tumor invasion and metastases. Our data shows that GH treatment on human and mouse PDAC cells increases the exosomal protein levels of TGFβ - a critical inducer of epithelial-to-mesenchymal transition (EMT, a process leading to metastasis). In addition, GH treatment also increases extracellular matrix-degrading enzymes, MMP2 and 9, as well as multi-drug efflux pump ABCC1, ABCB1, and ABCG2 in PDAC cells. These results strongly implicate GH action in driving EMT and chemoresistance via exosomes in pancreatic cancer. Exosomes have a crucial impact especially in the areas of diagnostics and therapeutics. This report is the first to show that GH modulates the effects of exosomes secreted by pancreatic cancer cells. Acknowledgement: This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and Ohio University’s Student Enhancement Award and Edison Biotechnology Institute.

In order to provide new insights into the various activities of GH in specific tissues, recent advances have allowed for the generation of tissue-specific GHR knockout mice. To date, 21 distinct tissue-specific mouse lines have been created and reported in 28 publications. Targeted tissues include liver, muscle, fat, brain, bone, heart, intestine, macrophage, pancreatic beta cells, hematopoietic stem cells, and multi-tissue “global”. In this review, we provide a brief history and description of the 21 tissue-specific GHR knockout mouse lines. Arch Endocrinol Metab. 2019;63(6):557-67

Exosomes, the extracellular vesicles originating from endosomes, modulate their target cell responses systematically by the nature of exosomal cargoes and their source tissues. The exosomes thus occupy a new-found critical role in the diagnoses of multiple pathologies especially cancer as well as in anti-cancer therapy. Growth hormone (GH) produced centrally by the pituitary gland or peripherally by several tissues, contributes to the regulation of growth and metabolism. We and others have shown that GH significantly promotes cancer progression, metastasis, and drug resistance- processes also regulated by exosomes from tumor tissues. In this report, we show for the first time that GH increases cancer cell exosome secretion as well as content which in turn potentially amplify tumor invasion and metastases. Our data show that GH treatment, significantly increases levels of exosomal markers in human melanoma SK-MEL-30 (skin cancer), PANC1 (pancreatic cancer) and H1299 (lung cancer) cell lines without a comparable increase in total cell numbers, indicating an increased exosome output. In addition, GH treatment induced changes in the tumor exosomal cargoes including Matrix Metalloproteinases (MMPs) and Transforming Growth Factor beta (TGFβ). Also, GHR as a hitherto unknown exosomal cargo was found in exosomes from H1299 and PANC1 cell lines. Exosomes are a hotbed of current biological research and have diverse potential as an indicator in diagnosis, as a drug target, or the drug itself. Our study identifies the previously unknown effects of GH on exosome secretion from cancer cells and the nature of the respective exosomal cargoes. Acknowledgement This work was supported in part by the State of Ohio’s Eminent Scholar Program that includes a gift from Milton and Lawrence Goll, by the AMVETS, and the Edison Biotechnology Institute at Ohio University. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

The credit card business has increased speedily over the last two decades. Corporations and establishments are moving towards various online services, which aims to permit their customers with high potency and accessibility. The evolution is a huge step towards potency, accessibility and profitableness of view. Nevertheless, it additionally has some downsides. These smart services are recently prone to significant security related vulnerabilities. Developing business through card depends on the fact that neither the card nor the user needs to be present at the point of transaction. Thus, it is impossible for merchandiser to check weather the cardholder is real or not. Companies’ loss in recent times are majorly due to the credit card fraud and the fraudsters who ceaselessly obtain new ways to commit the unlawful activities. As we know that Artificial Neural Network has the ability to work as a human brain when trained properly. We have also implemented SOM for accuracy purpose. In this paper, we discuss about the performance of the network and their accuracy.

Excess circulating human growth hormone (hGH) in vivo is linked to metabolic and growth disorders such as cancer, diabetes, and acromegaly. Consequently, there is considerable interest in developing antagonists of hGH action. Here, we present the design, synthesis, and characterization of a 16- residue peptide (site 1-binding helix [S1H]) that inhibits hGH-mediated STAT5 phosphorylation in cultured cells. S1H was designed as a direct sequence mimetic of the site 1 minihelix (residues 36-51) of wild-type hGH and acts by inhibiting the interaction of hGH with the human growth hormone receptor (hGHR). In vitro studies indicated that S1H is stable in human serum and can adopt an α-helix in solution. Our results also show that S1H mitigates phosphorylation of STAT5 in cells co-treated with hGH, reducing intracellular STAT5 phosphorylation levels to those observed in untreated controls. Furthermore, S1H was found to attenuate the activity of the hGHR and the human prolactin receptor, suggesting that this peptide acts as an antagonist of both lactogenic and somatotrophic hGH actions. Finally, we used alanine scanning to determine how discrete amino acids within the S1H sequence contribute to its structural organization and biological activity. We observed a strong correlation between helical propensity and inhibitory effect, indicating that S1H-mediated antagonism of the hGHR is largely dependent on the ability for S1H to adopt an α-helix. Taken together, these results show that S1H not only acts as a novel peptide-based antagonist of the hGHR but can also be applied as a chemical tool to study the molecular nature of hGH-hGHR interactions.

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH, high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO, high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

The Fourier series are, as we know, widely used in a number of mathematical problems arising in various topics of Communication systems, Signal Processing, Image processing and many more. The main contribution through these series is to analyze and build periodic functions in the form of infinite or finite sums of sines and cosines. In this paper, a new series representation like the Fourier series has been derived for every periodic function which can be represented by the Fourier series, thereby increasing the extent of applications of Fourier analysis in the related fields.

Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH&ndash, GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.