CIS Cells Research Articles

Human/mouse CD137 agonist, JNU-0921, effectively shrinks tumors through enhancing the cytotoxicity of CD8+ T cells in cis and in trans.

Agonistic antibodies against CD137 have been demonstrated to completely regress established tumors through activating T cell immunity. Unfortunately, current CD137 antibodies failed to benefit patients with cancer. Moreover, their antitumor mechanisms in vivo remain to be determined. Here, we report the development of a small molecular CD137 agonist, JNU-0921. JNU-0921 effectively activates both human and mouse CD137 through direct binding their extracellular domains to induce oligomerization and signaling and effectively shrinks tumors in vivo. Mechanistically, JNU-0921 enhances effector and memory function of cytotoxic CD8+ T cells (CTLs) and alleviates their exhaustion. JNU-0921 also skews polarization of helper T cells toward T helper 1 type and enhances their activity to boost CTL function. Meanwhile, JNU-0921 attenuates the inhibitory function of regulatory T cells on CTLs. Our current work shows that JNU-0921 shrinks tumors by enhancing the cytotoxicity of CTLs in cis and in trans and sheds light on strategy for developing CD137 small molecular agonists.

Abstract 4071: The first-in-class PD1-IL18 conjugate BPT567 induces potent anti-tumor immunity by preferentially activating PD1+IL18R+ intratumoral effector T cells in cis

Abstract Antibody-cytokine conjugates leverage orthogonal mechanisms of action (MoA) in one molecule to induce potent antitumor immune responses. PD-1-targeting conjugates are of particular interest since they preferentially target antigen-experienced PD-1+ CD8+ T cells enriched in the tumor microenvironment (TME) while simultaneously blocking the PD-(L)1 pathway and inducing potent cytokine receptor stimulation in the same CD8+ T cell in cis (cis-signaling). Interleukin 18 (IL-18) is a proinflammatory cytokine able to integrate both innate and adaptive immunity resulting in profound anti-tumor immune responses mediated by T effector and NK cells. BPT567 has been generated via chemical conjugation of the anti-PD-1 Ab LipustobartTM to an enhanced human IL-18 variant of increased potency and reduced sensitivity to IL-18 binding protein (IL-18BP). BPT567 is designed to specifically target and activate a subset of tumor-infiltrating PD-1+ IL18R+ CD8+ T effector cells recently described to exhibit superior cytotoxic and proliferative activity (Codarri Deak et al., Nature 2022). Due to its ability to signal in cis, BPT567 shows enhanced potency as well as increased resistance to IL-18BP when analyzing IFNγ release in vitro in PD-1+ cells. Subsequent PD-1 receptor occupancy analyses showed that it is fully sufficient for BPT567 to engage a low number of PD-1 receptors to induce maximum IFNγ release in NK92 cells expressing human PD-1. Strikingly, despite addressing overlapping epitopes in PD-1, even a 200-fold excess of pembrolizumab has no impact on the in vitro potency of BPT567. In vivo, BPT567 exhibits strong anti-tumor efficacy at significantly lower IL-18 doses compared to the combination of an untargeted antibody-IL-18 conjugate and an anti-PD1 Ab further corroborating the importance of cis-signaling as a unique MoA of this PD1-IL18 conjugate. Detailed analyses of tumor-infiltrating immune leukocytes (TIL) revealed that BPT567 triggers a preferential expansion of CD8+ T effector memory cells within the TME. In line with this finding, activity in the MC38 tumor model is dependent on the presence of CD8+ T cells while depletion of other immune cell subsets (e.g. NK cells, CD4+ T cells, macrophages) had no impact on efficacy. Although not required for anti-tumor efficacy, CD4+ T cells are essential for proficient formation of an immunological memory. In an effort to confirm findings generated in murine models in relevant human ex vivo systems, we analyzed the release of cytokines and chemokines in dissociated cells isolated from primary human tumor explants. Also in this human model, BPT567 is able to induce significantly stronger IFNγ release compared to either single agents or the combination of untargeted IL-18 and an anti-PD1 Ab, thus confirming the unique MoA of the PD1-IL18 conjugate triggering superior TIL activation in cis. Citation Format: Kea Martin, Thuy Luu, Jean-Philippe Carralot, Lilian Gremlich, Petra Herzig, Caoimhe Herr, Roy Meoded, Philipp Moosmann, Arnaud Goepfert, Alfred Zippelius, Vijaya Pattabiraman, Bertolt Kreft. The first-in-class PD1-IL18 conjugate BPT567 induces potent anti-tumor immunity by preferentially activating PD1+IL18R+ intratumoral effector T cells in cis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4071.

Abstract 719: A tumor-activated PD1/IL2 bispecific molecule, designed to overcome IL-2 receptor-mediated clearance, improve tolerability and stimulate antigen-experienced CD8+ T cells in the tumor microenvironment of murine models

Abstract PD-1/PD-L1 therapies have shown significant activity across a range of tumor types, however, 70-90% of patients do not derive durable benefit. In preclinical settings, delivery of PD-1 blockade and IL-2 agonism in cis via a bispecific molecule, comprising a PD-1 antibody fused to IL-2, has demonstrated superior activity compared to delivery of individual components or their combination. Targeting of IL-2 to PD-1+ cells in cis has been shown to drive a unique differentiation path endowing CD8+ T cells with enhanced functionality. However, we show that the IL-2 component in an unmasked PD1/IL2 bispecific molecule dominates its pharmacology, driving marked peripheral activation of immune cells, rapid IL-2 receptor-mediated clearance and systemic toxicity. To address these challenges and enable tumor-specific activity, we designed a PD1/IL2 bispecific molecule that incorporates a single domain antibody-based mask to bind to the IL-2 component and maintain it in a quiescent state until activated by prevalent and dysregulated proteases in the tumor microenvironment (TME). In preclinical models, the affinity-optimized mask prevented peripheral IL-2 receptor binding, associated toxicity and receptor-mediated clearance. Improved pharmacokinetics of our tumor-activated PD1/IL2 enabled PD1 antibody-like exposures and is projected to achieve complete blockade of PD1 signaling. Tumor-activated PD1/IL2 significantly inhibited tumor growth compared to anti-PD-1 alone or vehicle and demonstrated improved tolerability compared to an unmasked PD1/IL2 bispecific in mouse models. In addition, pharmacodynamic activity of tumor-activated PD1/IL2 was restricted to the TME. Consistent with the masked design, we observed no significant change in CD8+ T cells in the periphery and significant increases in antigen specific CD8+ T cells, memory CD8+ T cells and TCF1+ stem-like CD8+ T cells in the TME. Ex vivo protease cleavage assays performed in human samples demonstrated efficient activation of tumor-activated PD1/IL2 by multiple tumor types and minimal activation in human plasma. In non-human primates, tumor-activated PD1/IL2 achieved tolerable exposures that were comparable to those of existing PD-1 blocking immunotherapies. Taken together, these preclinical data suggest that tumor-activated PD1/IL2 has the potential to improve upon existing PD-1/PD-L1 immunotherapies by inhibiting PD-1/PD-L1 axis and simultaneously directing immunostimulatory IL-2 to antigen-experienced effector cell populations in the TME. Citation Format: Ertan Eryilmaz, Wilson Guzman, Stephanie Hsiao, Parker Johnson, Lisa Quinn, Jimit Lakhani, Brendan Whalen, Rosa Quiroz, Kurt Jenkins, Bernard Lanter, Oleg Yerov, Will Scott, Justin Greene, Zhen Liu, Jason Hedges, Megan McLaughlin, Sallyann Vu, Chelsea Turcotte, Jacob Taylor, Caitlin O'Toole, Magali Pederzoli-Ribeil, Haley Duprey, Natalia Malkova, Damiano Fantini, David Crowe, Kyle Smith, Joseph Card, Janice Lee, Kerri Smith, Benjamin Nicholson, Jennifer O'Neil, Carl U. Bialucha. A tumor-activated PD1/IL2 bispecific molecule, designed to overcome IL-2 receptor-mediated clearance, improve tolerability and stimulate antigen-experienced CD8+ T cells in the tumor microenvironment of murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 719.

Abstract 4223: Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform

Abstract Immunocytokines (IC) provide the opportunity for targeted delivery of cytokines as payloads to tissues and cells to improve safety and efficacy of cytokine-based therapies. ICs have gained significant interest in recent years and several antibody-cytokine fusion proteins have entered clinical trials. Compared to recombinant fusion proteins, we have developed an entirely different approach to IC generation based on the site-specific, chemical conjugation of synthetic cytokines to antibodies. Bright Peak generates enhanced and conjugatable cytokines using a novel protein engineering platform based on solid-phase peptide synthesis and subsequent chemical ligation of protein segments. Our synthetic cytokines can then be readily chemically conjugated to specific lysine residues in the Fc region of an existing IgG1, IgG2 or IgG4 antibody without the need for prior antibody engineering. Chemical conjugation of cytokine payloads is rapid, enabling the flexible generation of ICs based on different antibodies and payloads within weeks. We applied our technology to more than 10 antibodies and found that neither antigen binding nor payload potency and selectivity are affected by chemical conjugation. Importantly, binding of the Fc domain of ICs to Fc gamma receptors or FcRn is not significantly affected. We are initially focusing on the development of PD-1-targeted ICs to achieve dual-targeting of PD-1+ effector T cells (cis-signaling). Using several anti-PD-1 antibodies and various synthetic IL-2 variants as payloads, we created ICs with different drug-antibody ratios and explored alternative conjugation sites within the Fc region. Resulting PD-1/IL-2 ICs are highly active showing significantly enhanced potency due to avidity resulting from binding of the cytokine to PD-1+ effector T cells in cis. Our PD-1/IL-2 ICs induce strong pharmacodynamic effects in vivo, and we are currently optimizing the pharmacological profiles of PD-1-targeted ICs for clinical application. In addition, we are actively exploring cis-signaling ICs targeting different surface receptors and immune cells. Citation Format: Jean-Philippe Carralot, Matilde Arévalo Ruiz, Robert Tam, Eric Armentani, Vijaya R. Pattabiraman, Bertolt Kreft. Cis-activation of PD-1+ effector T cells with dual-targeting immunocytokines generated using a novel chemical conjugation platform [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 4223.

PD53-01 MOLECULAR SUBTYPING OF N-METHYL-N-NITROSOUREA (MNU) RAT MODEL OF UROTHELIAL CARCINOMA REVEALS BOTH LUMINAL AND BASAL SIGNATURES

You have accessJournal of UrologyCME1 May 2022PD53-01 MOLECULAR SUBTYPING OF N-METHYL-N-NITROSOUREA (MNU) RAT MODEL OF UROTHELIAL CARCINOMA REVEALS BOTH LUMINAL AND BASAL SIGNATURES Kara Lombardo, Takahiro Yoshida, Kate Fitzgerald, Kate Johnson, David McConkey, Alok Singh, Ridwan Alam, Max Kates, Alex Baras, and Trinity Bivalacqua Kara LombardoKara Lombardo More articles by this author , Takahiro YoshidaTakahiro Yoshida More articles by this author , Kate FitzgeraldKate Fitzgerald More articles by this author , Kate JohnsonKate Johnson More articles by this author , David McConkeyDavid McConkey More articles by this author , Alok SinghAlok Singh More articles by this author , Ridwan AlamRidwan Alam More articles by this author , Max KatesMax Kates More articles by this author , Alex BarasAlex Baras More articles by this author , and Trinity BivalacquaTrinity Bivalacqua More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002630.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intrinsic subtypes of urothelial carcinoma have been identified with relevant genetic alterations and distinct clinical behavior. Carcinogen induced rodent models are clinically relevant to study urothelial carcinogenesis. In the present study, we sought to identify molecular profiles of the MNU-tumor induced rat model of urothelial carcinoma and provide additional insight into how experimental pre-clinical models may parallel human non-muscle invasive bladder cancer (NMIBC). METHODS: Intravesical MNU instillations were administered in 16 Fisher female rats every other week for a total of 4 instillations. Rats were sacrificed at either 16 (n=10) or 30 (n=6) weeks after initial instillation and bladders were harvested for analysis. Pathologic staging was assessed on H&E, and IHC was performed for basal (KRT5, KRT14, p63) and luminal (CK20, FOXA1, Pparg, Gata3) markers. Bulk RNA sequencing was performed on fresh whole bladders using an Illumina Sequencing platform and cluster analyses were performed for luminal and basal markers using Rstudio. RESULTS: MNU induced development of non-invasive tumors in 10/10 (100%,3 CIS, 3 Ta, 4 T1) bladders at week 16 and 3/6 (50%,3 T1) at week 30, while 3/6 (50%, 3 T2) progressed to muscle invasive disease at week 30. IHC analysis showed retention of luminal markers CK20, FOXA1, Pparg, and Gata3 in CIS, Ta and T1 tumor cells but loss of CDK20, Pparg and Gata3 expression in T2 disease. Basal IHC markers KRT5, KRT14 and p63 were highly expressed in all stages of MNU tumors. Sequencing data show MNU tumors cluster separately from basal-like BBN murine tumors and are more closely clustered with luminal-like UPPL mice tumors when looking at luminal signature markers KRT8 and KRT18 as well as with BASE47 subtype classifier. Cluster analysis including human tumors show MNU clusters more closely with urobasal A and B subtypes which have features including elevated expression of FGFR3, CCND1, and TP63 as well as KRT5 expression (Figure 1). CONCLUSIONS: This study is the first to characterize molecular subtype of the MNU-carcinogen induced rat model of urothelial cancer revealing a complex signature of both basal and luminal markers and provides insight into guiding clinically relevant investigations aimed at improving therapies for urothelial carcinoma. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e910 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kara Lombardo More articles by this author Takahiro Yoshida More articles by this author Kate Fitzgerald More articles by this author Kate Johnson More articles by this author David McConkey More articles by this author Alok Singh More articles by this author Ridwan Alam More articles by this author Max Kates More articles by this author Alex Baras More articles by this author Trinity Bivalacqua More articles by this author Expand All Advertisement PDF DownloadLoading ...

Studies on copper indium selenide/Zinc sulphide semiconductor quantum dots for solar cell applications

Despite dedicated efforts to develop efficient quantum dot sensitized (QDS) photovoltaic cells, the efficiency of these cells still lags behind their theoretical value. In order to increase photo conversion efficiency, the extant methods are predominantly focus on modifying the band gaps of quantum dots and optimizing the interfaces of cell components to increase light utilization capacity. In this study, we have designed and investigated QDS solar cells using Copper Indium Selenide (CuInSe2 or simply CIS) as a quantum dot absorber. In order to achieve tunable bandgap, increased photoluminescence, reduced density of surface defect state and higher light-harvesting efficiency, the CuInSe2 is alloying with Zinc sulfide (ZnS) to design Copper Indium Selenide-Zinc sulfide (CISZS) quantum dots. The resulting CISZS sensitizer exhibits improved photoelectric characteristics and greater chemical stability. The performance of the CIS and CISZS solar cells is evaluated individually through Silvaco-Atlas simulation software in terms of measures such as power conversion efficiency, open-circuit voltage (Voc), the density of short-circuit current (Jsc) and fill-factor (FF). The CISZS-based solar cells show an average conversion efficiency of 23.5% (i.e., 4.94% higher than the efficiency of CIS solar cell) with Voc = 0.596V, Jsc = 23.61mA/cm2 and FF = 0.84 under AM 1.5G with a power density of 100mW/cm2 . The achieved power conversion efficiency indicates the greatest performances of the QDS solar cells. These non-toxic photovoltaic devices reveal better optical and electrical properties than toxic lead and cadmium chalcogenide quantum dots absorbers.

Optimization of simulations of thickness layers, temperature and defect density of CIS based solar cells, with SCAPS-1D software, for photovoltaic application

In this paper, the performance of CIS Based solar cells was investigated, using a simulation program named SCAPS-1D Software (Solar Cells Capacitance Simulator). CIS cell structure is based on Cu(In, Ga), (Se,S)2; which is a semiconductor compound as an absorber layer; un-doped Zinc Oxyd (i) ZnO as a window layer, and Sulfide Cadmium CdS as a Buffer layer, with an efficiency of ƞ=15%. We studied the influence of different layers’ thickness and their defect densities, working temperature and absorber carrier density on the CIS based solar cells. The photovoltaic parameters have been calculated, and we have obtained the optimal values of every constraint cited above. As a result, we obtained a new high efficiency value of 19.71%, under air mass (AM) 1.5 and 100 mW/cm2 illumination and the area of this device was 0.15 cm2 .

Changes in gene expression in human skeletal stem cells transduced with constitutively active Gsα correlates with hallmark histopathological changes seen in fibrous dysplastic bone.

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the α subunit of the G protein-coupled receptor complex (Gsα). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (GsαR201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the GsαR201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets.

Incorporation of an efficient β-In2S3 thin film as window material into CdTe photovoltaic devices

Polycrystalline thin film CdS has been used as window material in photovoltaic solar cells. Its ideal band gap (2.45 eV), low resistivity and electron affinity made this material the most used in photovoltaic engineering; However, nowadays a cadmium free material with similar properties is necessary. β-In2S3 has shown adequate physical properties to be applied on CdTe, CIGS, CIS and CZTS solar cells. β-In2S3 thin films were grown by chemical bath deposition technique and thermally treated under different conditions. Their structural, optical, morphological and electrical properties were studied, and efficient cadmium free window layer was obtained and implemented on CdTe solar cells. The presented results are discussed.

Design of thin film solar cells based on a unified simple analytical model

Polycrystalline thin film solar cells made with absorber materials such as CdTe, CIGS, CZTS and metalorganic halides (perovskites) are currently important alternatives for the silicon solar cell technology, which still dominates the photovoltaic market. Then, it is important to have tools which can be used to design this kind of solar cells. For this purpose, we have developed a unified simple analytical model that can be applied to thin film solar cells. The model is based on the basic physics of hetero-junction devices, but it takes into consideration that the space charge region can extend along the major part of the cell length, particularly for very thin cells, causing important effects that typically are not observed in conventional junction devices. Photo-generated carriers are collected by electric field-drift instead of diffusion, and simultaneously strong recombination at this region may dominate the electrical I–V characteristic of the cell. Since the space-charge region width varies with the applied voltage, the illumination current density and the saturation dark current density are no longer independent of the voltage as is assumed for conventional solar cells. When the model is applied to CIS and CdTe solar cells as examples, it is found that it is possible to design very thin film solar cells (absorber less than 1 μm thick) with high efficiencies, whenever the recombination velocity at the back surface becomes small (102 cm/s), instead of the highrecombination velocities present at ohmic contacts (107 cm/s). This fact implies the cost reduction of thin film solar cells by reducing absorber material thickness, and therefore it poses a challenge to develop deposition methods for very thin CdTe and CIGS absorber materials without pinholes, so that improved efficiencies are obtained when the surface recombination velocity is made small at the back by having a p+ or an electron blocking region before the ohmic contact. This result also explains the high efficiencies achieved by very thin perovskite solar cells.

Effects of secondary EGFR mutations on resistance against upfront osimertinib in cells with EGFR-activating mutations in vitro

ObjectivesNon-small cell lung cancers (NSCLCs) that harbor activating mutations for epidermal growth factor receptor (EGFR) show remarkable initial response to EGFR-tyrosine kinase inhibitors (TKIs), but inevitably acquire resistance, half of which are due to a T790 M secondary mutation when first-generation (1 G) or 2 G EGFR-TKIs are used. Osimertinib, a 3 G EGFR-TKI, is a standard of care in this situation, but eventually also evokes resistance, reportedly due to some tertiary EGFR mutations. However, the FLAURA trial showed the superiority of osimertinib over 1 G EGFR-TKIs in treatment-naïve patients, thus providing an option of first-line osimertinib treatment. Resistance in this setting is also inevitable, but its mechanism is unclear. We investigated whether resistance mutations that emerged with T790 M were responsible for the osimertinib resistance in the first-line setting; i.e. without T790 M, and if so, what treatment option was available. Materials and MethodsWe used literature search to identify EGFR mutations at codons L718, G724, L792, G796, and C797 as mechanisms of osimertinib resistance in the presence of T790 M. These mutations were introduced into Ba/F3 cells in cis with activating EGFR mutations but not with T790 M; inhibitory effects of five EGFR-TKIs were evaluated. ResultsOnly C797S conferred significant resistance against osimertinib when exon 19 deletion was the activating mutation. However, co-existence of L858R with C797S, C797 G, L718Q, or L718 V mutations all conferred resistance to osimertinib. Erlotinib showed the greatest activity for C797S-mediated resistance. However, 2 G EGFR-TKIs (afatinib or dacomitinib) were effective for other resistance mutations. ConclusionAfter first-line osimertinib failure, 1 G or 2 G EGFR-TKIs are effective, depending on combinations of secondary and activating mutations.

The role of protein disulphide isomerase AGR2 in the tumour niche.

In recent years, the discovery of 'tumour niche', a microenvironment that favours tumour development has changed our perspective of cancer. This microenvironment generated by the tumour cells itself and surrounding cells is capable of providing essential elements for its growth. Consequently, the homoeostasis of the secretory pathway (SP) has become an essential player in cancer development. The SP not only promotes cellular adaptation to protein misfolding due to oncogenic transformation or challenging tumour niche but also allows tumour cells to produce specific secretomes. This impacts tumour cells in cis- or trans- as well as stromal cells in the tumour niche. In this context, the Anterior GRadient 2 (AGR2) protein has been identified as a key player. AGR2 is a protein disulphide isomerase that resides in the endoplasmic reticulum (ER) and mediates the formation of disulphide bonds, catalyses the cysteine-based redox reactions and assists the quality control of proteins. AGR2 not only plays an essential role in the homoeostasis of the SP but also exerts pro-oncogenic gain-of-function due to its reported mislocalisation in the tumour niche microenvironment. In this review, we summarise the dual role of AGR2, inside and outside the ER, on the tumour niche and its microenvironment.

Physical exercise contributes to cisplatin-induced nephrotoxicity protection with decreased CD4+ T cells activation

Cisplatin is a chemotherapy used to treat different types of cancer, such as testicular, bladder and head and neck. Physical exercise has been shown to improve cancer therapy and recently, it was demonstrated to be able to diminish side effects such as acute kidney injury (AKI), a common side effect in cisplatin treatment. In both cases, the modulation of inflammatory cytokines seems to be one of the mechanisms, but little is known about the immune cells in this process. Here, we investigated the role of CD4 + T cells in the AKI protection by physical exercise. We subjected C57Bl6 mice to long-term physical exercise (EX) before cisplatin treatment. Sedentary groups were used as control (CT). We confirmed that physical exercise decreased AKI by evaluating creatinine and Kim-1 levels, in the serum and kidney respectively. Analyzing the organs weight, we noticed a decrease in sedentary (CIS) and exercised (CIS-EX) cisplatin treated groups. Epididymal and brown adipose tissue weight were decreased in cisplatin treated subjects in comparison to untreated groups, as well as liver and spleen. We then investigated the profile of CD4 + T cells in the spleen and we observed increased levels of Tregs and CD4+CD25+ cells in CIS group, while CIS-EX presented similar amounts as control groups. Analyzing the kidney lymph nodes, we noticed a decrease of CD4+ cells in both CIS and CIS-EX group. However, a more activated phenotype (CD69+ and CD25+) was observed in CIS groups in comparison to CIS-EX group, as well as the presence of Tregs. We then investigated the production of cytokines by these cells and no difference among the groups was observed in cytokines production in splenic CD4 + T cells. However, a clear increase in TNF and IL-10 production was observed in CD4 + T cells from lymph nodes, while CIS-EX group presented similar levels as the control groups. We confirmed that physical exercise was able to diminish cisplatin-induced AKI with concomitant decrease in CD4 + T cell activation.

Design of thin film solar cells based on a unified simple analytical model

Abstract Polycrystalline thin film solar cells made with absorber materials such as CdTe, CIGS, CZTS and metalorganic halides (perovskites) are currently important alternatives for the silicon solar cell technology, which still dominates the photovoltaic market. Then, it is important to have tools which can be used to design this kind of solar cells. For this purpose, we have developed a unified simple analytical model that can be applied to thin film solar cells. The model is based on the basic physics of hetero-junction devices, but it takes into consideration that the space charge region can extend along the major part of the cell length, particularly for very thin cells, causing important effects that typically are not observed in conventional junction devices. Photo-generated carriers are collected by electric field-drift instead of diffusion, and simultaneously strong recombination at this region may dominate the electrical I–V characteristic of the cell. Since the space-charge region width varies with the applied voltage, the illumination current density and the saturation dark current density are no longer independent of the voltage as is assumed for conventional solar cells. When the model is applied to CIS and CdTe solar cells as examples, it is found that it is possible to design very thin film solar cells (absorber less than 1 μm thick) with high efficiencies, whenever the recombination velocity at the back surface becomes small (102 cm/s), instead of the high recombination velocities present at ohmic contacts (107 cm/s). This fact implies the cost reduction of thin film solar cells by reducing absorber material thickness, and therefore it poses a challenge to develop deposition methods for very thin CdTe and CIGS absorber materials without pinholes, so that improved efficiencies are obtained when the surface recombination velocity is made small at the back by having a p+ or an electron blocking region before the ohmic contact. This result also explains the high efficiencies achieved by very thin perovskite solar cells.

Abstract P3-07-16: ZBTB2 is a novel therapeutic target for cisplatin-resistance in metastatic breast cancer

Abstract Background: Zinc finger and BTB/POZ domain containing proteins (ZBTB) belong to a class of DNA-binding proteins that involved in development, differentiation and carcinogenesis. Our earlier findings showed that ZBTB2 expression was upregulated in cisplatin-resistant cells when compared with naïve cells. Increase in ZBTB2 expression was associated with ABCG2 drug transporter in drug resistance. However, the molecular mechanism of ZBTB2 in drug resistance and breast cancer metastasis remain largely unclear. Methods: A cisplatin-resistant triple-negative breast cancer (TNBC) cell line, MDA-MB-231/cis, was used to examine the involvement of drug transporter genes and the drug resistance pathway. Stem cell related genes were studied by RNA-sequencing. Characterization of ZBTB2 on cell proliferation, invasion and epithelial-mesenchymal transition (EMT) process were performed in ZBTB2 siRNA transfected cells. Stem-like cells properties were validated using aldehyde dehydrogenase (ALDH) activity, tumorsphere formation ability and stem cell markers. Metastatic animal model was used to study the genetic changes during metastasis and associated with the findings in clinical samples. Results: ZBTB2 has a higher expression in TNBC than other breast cancer subtypes. Also, the ZBTB2 expression is more prominent in primary breast tumor tissues when compared with non-tumor counterparts from TNBC patients. Silencing of ZBTB2 significantly reduced cell proliferation, invasion and sensitized cells to cisplatin through induction of apoptosis. Induction of ZBTB2 has been associated with breast cancer metastasis in mice model, where higher expression was seen in metastatic tumors when compared with primary tumors from tumor xenografts. ABCG2 and some epithelial-mesenchymal transition (EMT) markers (Twist 1, Snai2 and MMP-9) have been increased in metastatic tumors. Further, RNA sequencing analysis showed that ABCG2, IL6ST and FGFR1 were upregulated in MDA-MB-231/cis cells and downregulated in ZBTB2 siRNA transfected cells. Silencing of ZBTB2 reduced ALDH activity and tumorsphere formation ability. Treatment with inhibitor of NFkB (Bay11-7085) further decreased cell proliferation in cisplatin-resistant cells when compared with siZBTB2 alone. Expression of Stat3 and b-catenin were reduced upon knockdown of ZBTB2. Conclusion: Taken together, silencing of ZBTB2 sensitize cancer cells to cisplatin through regulation of EMT markers and stem-like cell properties in TNBC. These findings suggest a novel molecular pathway targeting ZBTB2/stat3/NFkB signaling to combat drug resistance in metastatic TNBC. Citation Format: Shin V, Siu MT, Cheuk I, Ho J, Chen J, Kwong A. ZBTB2 is a novel therapeutic target for cisplatin-resistance in metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-07-16.

CIS, CIGS and CIBS thin film solar cells and possibilities of their application in BIPV

CIS, CIGS and CIBS thin film solar cells and possibilities of their application in BIPV

Involvement of epigenetic modifiers in the pathogenesis of testicular dysgenesis and germ cell cancer.

Testicular germ cell cancer manifests mainly in young adults as a seminoma or non-seminoma. The solid tumors are preceded by the presence of a non-invasive precursor cell, the carcinoma in situ cell (CIS), which shows great similarity to fetal germ cells. It is therefore hypothesized that the CIS cell is a fetal germ cell that has been arrested during development due to testicular dysgenesis. CIS cells retain a fetal and open chromatin structure, and recently several epigenetic modifiers have been suggested to be involved in testicular dysgenesis in mice. We here review the possible involvement of epigenetic modifiers with a focus on jumonji C enzymes in the development of testicular dysgenesis and germ cell cancer in men.

Cytomegalovirus immune evasion of myeloid lineage cells.

Cytomegalovirus (CMV) evades the immune system in many different ways, allowing the virus to grow and its progeny to spread in the face of an adverse environment. Mounting evidence about the antiviral role of myeloid immune cells has prompted the research of CMV immune evasion mechanisms targeting these cells. Several cells of the myeloid lineage, such as monocytes, dendritic cells and macrophages, play a role in viral control, but are also permissive for CMV and are naturally infected by it. Therefore, CMV evasion of myeloid cells involves mechanisms that qualitatively differ from the evasion of non-CMV-permissive immune cells of the lymphoid lineage. The evasion of myeloid cells includes effects in cis, where the virus modulates the immune signaling pathways within the infected myeloid cell, and those in trans, where the virus affects somatic cells targeted by cytokines released from myeloid cells. This review presents an overview of CMV strategies to modulate and evade the antiviral activity of myeloid cells in cis and in trans.

Human chimera-type galectin-3: defining the critical tail length for high-affinity glycoprotein/cell surface binding and functional competition with galectin-1 in neuroblastoma cell growth regulation.

Many human proteins have a modular design with receptor and structural domains. Using adhesion/growth-regulatory galectin-3 as model, we describe an interdisciplinary strategy to define the functional significance of its tail established by nine non-triple helical collagen-like repeats (I-IX) and the N-terminal peptide. Genetic engineering with sophisticated mass spectrometric product analysis provided the tools for biotesting, i.e. eight protein variants with different degrees of tail truncation. Evidently,various aspects of galectin-3 activity (cis binding and cell bridging) are affected by tail shortening in a different manner. Thus, this combined approach reveals an unsuspected complexity of structure-function relationship, encouraging further application beyond this chimera-type galectin.

Synthesis, spectroscopic characterization and anti-cancer properties of new gold(III)–alkanediamine complexes against gastric, prostate and ovarian cancer cells; crystal structure of [Au2(pn)2(Cl)2]Cl2·H2O

A new series of Au(III) diamine complexes, with the general formulae [LAuCl2]Cl and [Au(L)2]Cl3 [where L=ethylenediamine (en), propylenediamine (pn), butylenediamine (bn) and N-alkyl substituted ethylenediamine (N-R-en)] was initially synthesized by reacting trihydrate auric acid (HAuCl4·3H2O) with 1 or 2 equivalents of the diamine ligands. These complexes have subsequently been characterized by elemental analysis, IR spectroscopy and NMR measurements. The IR data shows complexation of the diamine ligands to the Au(III) metal centre via N donor atoms. The solution and solid-state NMR data confirm the stability of the complexes due to the chelating effect of the diamine ligands. The crystal structure of one complex shows a dinuclear ionic complex with two discrete [Au(pn)(Cl)]+ units bridged by two deprotonated pn ligands and a pseudo square planar coordination geometry of the Au(III) ion. In this paper, the anti-cancer properties of gold(III) diamine complexes have also been evaluated in vitro against prostate PC3, gastric SGC7901 and ovarian A2780/A2780 ciscancer cells. Generally, [Au(diamine)2]3+ complexes demonstrate better anticancer properties in PC3 cells, whereas [Au(diamine)Cl2]+ displays better anticancer properties in SGC7901 and A2780/A2780 cis cells. The complex [Au(en)2]Cl3 is recognized as a cytotoxic agent that is as effective as cis-platin on prostate PC3 cancer cells.