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(1) CD8 cytotoxic T cell responses to dominant tumor-associated antigens are profoundly weakened by aging yet subdominant responses retain functionality and expand in response to chemotherapy.[TOP]

Pubmed ID :30906657
Publication Date : //
Increasing life expectancy is associated with increased cancer incidence, yet the effect of cancer and anti-cancer treatment on elderly patients and their immune systems is not well understood. Declining T cell function with aging in response to infection and vaccination is well documented, however little is known about aged T cell responses to tumor antigens during cancer progression or how these responses are modulated by standard chemotherapy. We examined T cell responses to cancer in aged mice using AE17sOVA mesothelioma in which ovalbumin (OVA) becomes a 'spy' tumor antigen containing one dominant (SIINFEKL) and two subdominant (KVVRFDKL and NAIVFKGL) epitopes. Faster progressing tumors in elderly (22-24 months, cf. 60-70 human years) relative to young (2-3 months, human 15-18 years) mice were associated with increased pro-inflammatory cytokines and worsened cancer cachexia. Pentamer staining and an cytotoxic T lymphocyte (CTL) assay showed that whilst elderly mice generated a greater number of CD8 T cells recognizing all epitopes, they exhibited a profound loss of function in their ability to lyse targets expressing the dominant, but not subdominant, epitopes compared to young mice. Chemotherapy was less effective and more toxic in elderly mice however, similar to young mice, chemotherapy expanded CTLs recognizing at least one subdominant epitope in tumors and draining lymph nodes, yet treatment efficacy still required CD8 T cells. Given the significant dysfunction associated with elderly CTLs recognizing dominant epitopes, our data suggest that responses to subdominant tumor epitopes may become important when elderly hosts with cancer are treated with chemotherapy.

Authors : Jackaman Connie, Gardner Joanne K, Tomay Federica, Spowart Joshua, Crabb Hannah, Dye Danielle E, Fox Simon, Proksch Stephen, Metharom Pat, Dhaliwal Satvinder S, Nelson Delia J,

(2) Implantable pre-metastatic niches for the study of the microenvironmental regulation of disseminated human tumour cells.[TOP]

Pubmed ID :30906645
Publication Date : //
Cancer survivors often carry disseminated tumour cells (DTCs), yet owing to DTC dormancy they do not relapse from treatment. Understanding how the local microenvironment regulates the transition of DTCs from a quiescent state to active proliferation could suggest new therapeutic strategies to prevent or delay the formation of metastases. Here, we show that implantable biomaterial microenvironments incorporating human stromal cells, immune cells and cancer cells can be used to examine the post-dissemination phase of the evolution of the tumour microenvironment. After subdermal implantation in mice, porous hydrogel scaffolds seeded with human bone marrow stromal cells form a vascularized niche and recruit human circulating tumour cells released from an orthotopic prostate tumour xenograft. Systemic injection of human peripheral blood mononuclear cells slowed the evolution of the active metastatic niches but did not change the rate of overt metastases, as the ensuing inflammation promoted the formation of DTC colonies. Implantable pre-metastatic niches might enable the study of DTC colonization and proliferation, and facilitate the development of effective anti-metastatic therapies.

Authors : Carpenter Ryan A, Kwak Jun-Goo, Peyton Shelly R, Lee Jungwoo,

(3) Inhibition of invasive pancreatic cancer: restoring cell apoptosis by activating mitochondrial p53.[TOP]

Pubmed ID :30906636
Publication Date : //
Pancreatic ductal adenocarcinoma (PDAC), constitutes >90% of pancreatic cancers (PC) and is one of the most aggressive human tumors. Standard chemotherapies for PDAC (e.g., gemcitabine, FOLFIRINOX, etc.) has proven to be largely ineffective. Herein, we report a novel molecule (i.e., compound ) that potently inhibits proliferation and induces apoptosis of PDAC cells. As we observed in other cancer types (i.e., colorectal, breast cancer), the effect of against PDAC cells is also related to microtubule destabilization and DNA damage checkpoint activation. However, in PDAC cells, the inhibitory effect of was mainly controlled by mitochondrial p53-dependent apoptosis. Compound worked with cells of different p53 mutant status and affected p53 activation/phosphorylation not simply by stabilizing p53 protein but through antagonizing anti-apoptotic effects of Bcl-xL and restoring p53 to activate mitochondrial-apoptotic pathways (i.e., cytochrome c release, caspase activation and PARP cleavage). Compound was more efficient than a typical PDAC combination therapy (i.e., gemcitabine with paclitaxel) and showed synergism in inhibiting PDAC cell proliferation with gemcitabine (or gemcitabine with paclitaxel). This synergism varied between different types of PDAC cells and was partially controlled by the phosphorylation of p53 on Serine15 (phospho-Ser15-p53). In vivo studies in an orthotopic syngeneic murine model showed that (20 mg/kg/day, 28 days, i.p.) inhibited tumor growth by 65% compared to vehicle-treated mice. No apparent acute or chronic toxicity was observed. Thus, compound utilizes a distinct mechanism of action to inhibit PC growth in vitro and in vivo and is a novel anti-PDAC compound.

Authors : Cheng Jiongjia, Okolotowicz Karl J, Ryan Daniel, Mose Evangeline, Lowy Andrew M, Cashman John R,

(4) Anti- antibodies attach to mouse cancer cell lines but not normal mouse lymphocytes.[TOP]

Pubmed ID :30906547
Publication Date : //
is prevalent intracellular parasite and a cause of worldwide infection in the human population. An inhibitory effect of this parasite on cancer growth has been demonstrated in cell culture and animal models. To determine whether the anticancer activities of are associated with host immune response, in the current study the reactivity of anti- antiserum with the surface of cancer cell lines was investigated. Anti- antibodies were raised in rabbit and the reaction of this antiserum in comparison with other anti-parasite antisera (anti-, anti-hydatid cyst fluid, anti-protoscolices antigens) with mouse melanoma or breast cancer cells lines was investigated using flow cytometry. Anti- antiserum reacted markedly with the surface of mouse melanoma and breast cancer cells, and less so with the normal mouse spleen lymphocytes. Meanwhile, the other anti-parasite antisera did not react strongly with the surface of cancer cells compared with normal mouse spleen lymphocytes. In summary, it has been demonstrated herein that anti- antiserum may selectively react with the surface of mouse cancer cells but not with normal mouse spleen lymphocytes. Therefore, further study on anti- antibodies may be useful for directing the application of selective drug delivery in cancer treatment.

Authors : Mohamadi Fereshteh, Shakibapour Mahshid, Sharafi Seyedeh Maryam, Reza Ali Andalib, Tolouei Sepideh, Darani Hossein Yousofi,

(5) Repression of Hexokinases II-Mediated Glycolysis Contributes to Piperlongumine-Induced Tumor Suppression in Non-Small Cell Lung Cancer Cells.[TOP]

Pubmed ID :30906213
Publication Date : //
Deregulation of glycolysis is a common phenomenon in human non-small cell lung cancer (NSCLC). In the present study, we reported the natural compound, piperlongumine, has a profound anti-tumor effect on NSCLC via regulation of glycolysis. Piperlongumine suppressed the proliferation, colony formation and HK2-mediated glycolysis in NSCLC cells. We demonstrated that exposure to piperlongumine disrupted the interaction between HK2 and VDAC1, induced the activation of the intrinsic apoptosis signaling pathway. Moreover, our results revealed that piperlongumine down-regulated the Akt signaling, exogenous overexpression of constitutively activated Akt1 in HCC827 and H1975 cells significantly rescued piperlongumine-induced glycolysis suppression and apoptosis. The xenograft mouse model data demonstrated the pivotal role of suppression of Akt activation and HK2-mediated glycolysis in mediating the antitumor effects of piperlongumine. The expression of HK2 was higher in malignant NSCLC tissues than that of the paired adjacent tissues, and was positively correlated with poor survival time. Our results suggest that HK2 could be used as a potential predictor of survival and targeting HK2 appears to be a new approach for clinical NSCLC prevention or treatment.

Authors : Zhou Li, Li Ming, Yu Xinyou, Gao Feng, Li Wei,

(6) The TNF-derived TIP peptide activates the epithelial sodium channel and ameliorates experimental nephrotoxic serum nephritis.[TOP]

Pubmed ID :30905471
Publication Date : //
In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation.

Authors : Madaio Michael P, Czikora Istvan, Kvirkvelia Nino, McMenamin Malgorzata, Yue Qiang, Liu Ting, Toque Haroldo A, Sridhar Supriya, Covington Katherine, Alaisami Rabei, O'Connor Paul M, Caldwell Robert W, Chen Jian-Kang, Clauss Matthias, Brands Michael W, Eaton Douglas C, Romero Maritza J, Lucas Rudolf,

(7) Current Status on Immunological Therapies for Type 1 Diabetes Mellitus.[TOP]

Pubmed ID :30905013
Publication Date : //
Type 1 diabetes (T1D) occurs when there is destruction of beta cells within the islets of Langerhans in the pancreas due to autoimmunity. It is considered a complex disease, and different complications can surface and worsen the condition if T1D is not managed well. Since it is an incurable disease, numerous treatments and therapies have been postulated in order to control T1D by balancing hyperglycemia control while minimizing hypoglycemic episodes. The purpose of this review is to primarily look into the current state of the available immunological therapies and their advantages for the treatment of T1D.

Authors : Xin Griselda Lim Loo, Khee Yap Pui, Ying Tan Yoke, Chellian Jestin, Gupta Gaurav, Kunnath Anil Philip, Nammi Srinivas, Collet Trudi, Hansbro Philip Michael, Dua Kamal, Chellappan Dinesh Kumar,

(8) Differential roles of microtubules in the two formation stages of membrane nanotubes between human mesenchymal stem cells and neonatal mouse cardiomyocytes.[TOP]

Pubmed ID :30904163
Publication Date : //
Membrane nanotubes (MNTs) are a kind of novel way for communication between two distant cells. It was recently shown that MNTs can be formed between distressed cardiomyocytes (CMs) and mesenchymal stem cells (MSCs). As a cytoskeleton-containing structure, the role of microtubules in MNTs is not fully understood. Here, we investigated this question. By membrane dye staining, we found that the numbers of MNTs between human MSCs (hMSCs) and distressed neonatal mouse CMs (NMCMs) increased gradually from 3 to 16 h and remained constant from 16 to 30 h, which were identified as active formation stage (the 1st stage, ≤16 h in coculture), and mature and stable stage (the 2nd stage, >16 h in coculture), respectively. In the 1st stage, more MNTs originated from hMSCs, whereas more MNTs originated from NMCMs in the 2nd stage. The formation of MNTs was affected when microtubules were disrupted by nocodazole in the 1st stage, but not in the 2nd stage. MNTs became shorter and thinner when microtubules were disrupted in the 2nd stage. Immunofluorescence staining and flow cytometry showed that mitochondria in hMSCs were transported into distressed NMCMs, which was suppressed by nocodazole in the 2nd stage. Tunnel staining showed that hypoxia/reoxygenation-induced apoptosis of NMCMs only in the 2nd stage could be rescued by direct, but not indirect, coculture with hMSCs. This rescue function was weakened when the mitochondrial functions of cocultured hMSCs were disrupted by EtBr or microtubules in cocultures were disrupted by nocodazole. All these results suggested that there are two stages for MNT formation, and microtubules played differential roles in the two stages: During the 1st stage, microtubules were required for MNT formation, whereas during the 2nd stage, microtubules were related to the morphological features of MNTs and played a key role in anti-apoptosis of MNTs by mitochondrial transfer.

Authors : Zhang Jianghui, Zhang Jing, Zhao Limin, Xin Yi, Liu Sa, Cui Wei,

(9) A novel interleukin-13 receptor alpha 2-targeted hybrid peptide for effective glioblastoma therapy.[TOP]

Pubmed ID :30903640
Publication Date : //
We previously designed and reported a novel class of drugs, namely, hybrid peptides, which are chemically synthesized and composed of a targeted-binding peptide and a lytic-type peptide containing cationic amino acid residues that cause cancer cell death. In the present study, we screened for peptides that bind to interleukin-13 receptor alpha 2 (IL13Rα2) by using a T7 random peptide phage display library system and isolated several positive phage clones. The A2b11 peptide, which was one of the positive clones, was shown to bind to IL13Rα2 protein by Biacore analysis and a binding assay using glioblastoma (GB) cell lines. This peptide was linked with a lytic peptide containing a linker sequence to form the IL13Rα2-lytic hybrid peptide. The IL13Rα2-lytic hybrid peptide showed cytotoxic activity against GB cell lines in vitro. The IL13Rα2-lytic hybrid peptide also affected Akt and Erk1/2 activation following treatment with interleukin-13 and induced rapid ATP dynamics in GB cells. Anti-tumor activity of the IL13Rα2-lytic hybrid peptide was observed in vivo after intratumoral injection in a mouse xenograft model of human GB cells. These results suggest that the IL13Rα2-hybird peptide might be a potent therapeutic option for patients with GB. This article is protected by copyright. All rights reserved.

Authors : Kurihara Ryohsuke, Horibe Tomohisa, Shimizu Eiko, Torisawa Aya, Gaowa Arong, Kohno Masayuki, Kawakami Koji,

(10) Ethyl pyruvate protects against Salmonella intestinal infection in mice through down-regulation of pro-inflammatory factors and inhibition of TLR4/MAPK pathway.[TOP]

Pubmed ID :30901678
Publication Date : //
Salmonella typhimurium is one of the main causes of intestinal diseases, affecting the health of humans and livestock. Ethyl pyruvate (EP), which is ordinarily an edible spice, has been indicated to exert anti-inflammatory effects and preserve intestinal barrier function. In this study, intestinal immune function and signaling pathways activated by EP were investigated in vivo in S. typhimurium-challenged BALB/c mice and in vitro in RAW264.7 cells. EP improved body weight loss and the organ index of the liver and spleen (p < 0.05). Serum IgA and IgM levels were significantly increased in EP-treated mice (p < 0.05). According to histopathological and immunohistochemical staining, EP significantly increased the villus height, reduced edema in the jejunum and increased the levels of claudin-1, occludin-1 and ZO-1 proteins compared to the Salmonella-treated group (p < 0.05). In addition, EP decreased the levels of the IL-6, IL-1β and TNF-α mRNA levels in jejunum, liver, spleen and RAW264.7 cells (p < 0.05). EP decreased the levels of TLR4, phosphorylated p38MAPK and ERK1/2 in mice infected with S. typhimurium (p < 0.05). In conclusion, EP effectively protected BALB/c mice from an intestinal S. typhimurium infection by improving the activity of the humoral immune system, reducing intestinal barrier damage, and inhibiting proinflammatory cytokine production in the jejunum by modulating the TLR4/MAPK signaling pathway. Based on these findings, EP has the potential to inhibit inflammation or to serve as an immune-enhancing adjuvant.

Authors : Dong Na, Xu Xinyao, Xue Chenyu, Wang Chensi, Li Xinran, Shan Anshan, Xu Li, Li Deshan,