How do Regeneration status, Vegetation Diversity, Stand Structure, and Carbon Stock vary across Ecological Regions of Nepal?

This study compared the regeneration status, vegetation diversity, stand structure, and carbon stock of two community-managed forests located in different ecological regions of Nepal. A total of 61 concentric sample plots were investigated by using systematic random sampling with 1 % sampling intensity. The phytosociological parameters of trees and regeneration density were calculated using standard techniques. The aboveground tree carbon was estimated using a non-destructive method.  Correlation analysis was performed to assess the variation of carbon stock with biomass, stand density, tree diameter at breast height (DBH), tree height, basal area, and seedling density. Janata community forest had higher regeneration than the Hazare community forest, with a bell-shaped distribution of DBH in Janata and an interrupted curve in Hazare community forest. Both forests were dominated by Shorea robusta. Hazare had higher Shannon diversity index, Simpson\u27s index, and evenness index, while Janata community forest had higher carbon stock. The observed differences in the studied parameters between the two community forests can be attributed to the difference in ecological factors such as temperature, rainfall, soil nutrient availability, and management practices. Future studies focusing on investigating the underlying factors driving the observed patterns and relationships, such as the effects of disturbance, climate, and management practices on forest structure and function are also needed. These findings have important implications for forest management and conservation policies, especially in the context of climate change mitigation and biodiversity conservation

Oncolytic adenovirus decreases the proportion of TIM-3(+) subset of tumor-infiltrating CD8(+) T cells with correlation to improved survival in patients with cancer

Background Oncolytic viruses are a potent form of active immunotherapy, capable of invoking antitumor T-cell responses. Meanwhile, less is known about their effects on immune checkpoints, the main targets for passive immunotherapy of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3) is a coinhibitory checkpoint driving T-cell exhaustion in cancer. Here we investigated the effects of oncolytic adenovirus on the TIM-3 checkpoint on tumor-infiltrating immune cells and clinical impact in patients with cancer receiving oncolytic immunotherapy. Methods Modulation of TIM-3 expression on tumor-infiltrating immune cells was studied preclinically in B16 melanoma following intratumoral treatment with Ad5/3 increment 24-granulocyte-macrophage colony-stimulating factor oncolytic adenovirus. We conducted a retrospective longitudinal analysis of 15 patients with advanced-stage cancer with tumor-site biopsies before and after oncolytic immunotherapy, treated in the Advanced Therapy Access Program (ISRCTN10141600, April 5, 2011). Following patient stratification with regard to TIM-3 (increase vs decrease in tumors), overall survival and imaging/marker responses were evaluated by log-rank and Fisher's test, while coinhibitory receptors/ligands, transcriptomic changes and tumor-reactive and tumor-infltrating immune cells in biopsies and blood samples were studied by microarray rank-based statistics and immunoassays. Results Preclinically, TIM-3(+) tumor-infiltrating lymphocytes (TILs) in B16 melanoma showed an exhausted phenotype, whereas oncolytic adenovirus treatment significantly reduced the proportion of TIM-3(+) TIL subset through recruitment of less-exhausted CD8(+) TIL. Decrease of TIM-3 was observed in 60% of patients, which was associated with improved overall survival over TIM-3 increase patients (p=0.004), together with evidence of clinical benefit by imaging and blood analyses. Coinhibitory T-cell receptors and ligands were consistently associated with TIM-3 changes in gene expression data, while core transcriptional exhaustion programs and T-cell dysfunction were enriched in patients with TIM-3 increase, thus identifying patients potentially benefiting from checkpoint blockade. In striking contrast, patients with TIM-3 decrease displayed an acute inflammatory signature, redistribution of tumor-reactive CD8(+) lymphocytes and higher influx of CD8(+) TIL into tumors, which were associated with the longest overall survival, suggesting benefit from active immunotherapy. Conclusions Our results indicate a key role for the TIM-3 immune checkpoint in oncolytic adenoviral immunotherapy. Moreover, our results identify TIM-3 as a potential biomarker for oncolytic adenoviruses and create rationale for combination with passive immunotherapy for a subset of patients.Peer reviewe

Local therapy with an engineered oncolytic adenovirus enables antitumor response in non- injected melanoma tumors in mice treated with aPD-1

Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus"). Virus was given intratumorally (to one of the two tumors only) and aPD-1 monoclonal antibody systemically. We evaluated both tumors' response to treatment, overall survival, metastasis development, and immunological mechanisms involved with response. Consistent tumor control was observed in both injected and non-injected tumors, including complete response in all treated animals receiving aPD-1+ virus therapy. Mechanistically, virus injections enabled potent effector lymphocyte response locally, with systemic effects in non-injected tumors facilitated by aPD-1 treatment. Moreover, adenovirus therapy demonstrated immunological memory formation. Virus therapy was effective in preventing metastasis development. Local treatment with TNFa and IL-2 coding adenovirus enhanced systemic response to aPD-1 therapy, by re-shaping the microenvironment of both injected and non-injected tumors. Therefore, our pre-clinical data support the rationale for a trial utilizing a combination of aPD-1 plus virus for the treatment of human cancer.Peer reviewe

Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples

Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.Peer reviewe

Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNF alpha and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNF alpha and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naive and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNF alpha and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3(+) tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45(+) tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo, in both ICI naive and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNF alpha and mIL-2 compared to monotherapies. This observation was verified by striking CD3(+) TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNF alpha and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNF alpha and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1.Peer reviewe

Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNF alpha and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNF alpha and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes. The in vitro effect of Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 was characterized through analyses of virus replication, transgene expression and lytic activity using head and neck cancer patient derived cell lines. Mouse models of ICI naive and refractory oral cavity squamous cell carcinoma were established to evaluate the local and systemic anti-tumor immune response upon ICI treatment with or without the non-replicative adenovirus encoding mTNF alpha and mIL-2. We delineated the mechanism of action by measuring the metabolic activity and effector function of CD3(+) tumor infiltrating lymphocytes (TIL) and transcriptomic profile of the CD45(+) tumor immune compartment. Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 demonstrated robust replicative capability in vitro across all head and neck cell lines screened through potent lytic activity, E1a and transgene expression. In vivo, in both ICI naive and refractory models, we observed improvement to tumor growth control and long-term survival when combining anti-PD-1 or anti-PD-L1 with the non-replicative adenovirus encoding mTNF alpha and mIL-2 compared to monotherapies. This observation was verified by striking CD3(+) TIL derived mGranzyme b and interferon gamma production complemented by increased T cell bioenergetics. Notably, interrogation of the tumor immune transcriptome revealed the upregulation of a gene signature distinctive of tertiary lymphoid structure formation upon treatment of murine anti-PD-L1 refractory tumors with non-replicative adenovirus encoding mTNF alpha and mIL-2. In addition, we detected an increase in anti-tumor antibody production and expansion of the memory T cell compartment in the secondary lymphoid organs. In summary, a non-replicative adenovirus encoding mTNF alpha and mIL-2 potentiates ICI therapy, demonstrated by improved tumor growth control and survival in head and neck tumor-bearing mice. Moreover, the data reveals a potential approach for inducing tertiary lymphoid structure formation. Altogether our results support the clinical potential of combining this adenovirotherapy with anti-PD-1 or anti-PD-L1.Peer reviewe

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression

Cytokines have proven to be effective for cancer therapy, however whilst low-dose monotherapy with cytokines provides limited therapeutic benefit, high-dose treatment can lead to a number of adverse events. Interleukin 7 has shown promising results in clinical trials, but anti-cancer effect was limited, in part due to a low concentration of the cytokine within the tumor. We hypothesized that arming an oncolytic adenovirus with Interleukin 7, enabling high expression localized to the tumor microenvironment, would overcome systemic delivery issues and improve therapeutic efficacy. We evaluated the effects of Ad5/3-E2F-d24-hIL7 (TILT-517) on tumor growth, immune cell activation and cytokine profiles in the tumor microenvironment using three clinically relevant animal models and ex vivo tumor cultures. Our data showed that local treatment of tumor bearing animals with Ad5/3- E2F-d24-hIL7 significantly decreased cancer growth and increased frequency of tumor-infiltrating cells. Ad5/3-E2F-d24-hIL7 promoted notable upregulation of pro-inflammatory cytokines, and concomitant activation and migration of CD4+ and CD8 + T cells. Interleukin 7 expression within the tumor was positively correlated with increased number of cytotoxic CD4+ cells and IFNg-producing CD4+ and CD8+ cells. These findings offer an approach to overcome the current limitations of conventional IL7 therapy and could therefore be translated to the clinic.Peer reviewe

An oncolytic adenovirus coding for a variant interleukin 2 cytokine improves response to chemotherapy through enhancement of effector lymphocyte cytotoxicity, fibroblast compartment modulation and mitotic slippage

Pancreatic ductal adenocarcinoma (PDAC) is a highly treatment-resistant cancer. Currently, the only curative treatment for PDAC is surgery, but most patients are diagnosed with metastatic disease and thus outside the scope of surgery. The majority of metastatic patients receive chemotherapy, but responses are limited. New therapeutics are thus urgently needed for PDAC. One major limitation in treating PDAC has been the highly immunosuppressive tumor microenvironment (TME) which inhibits anti-cancer immune responses. We have constructed an oncolytic adenovirus coding for a variant the interleukin 2 molecule, Ad5/3-E2F-d24-vIL2 (also known as TILT-452, and “vIL-2 virus”), with preferential binding to IL-2 receptors on the surface of effector lymphocytes over T regulatory cells (T regs). In the present study this virus was evaluated in combination with nab-paclitaxel and gemcitabine chemotherapy in Panc02 mouse model. Ad5/3-E2F-d24-vIL2 showed marked PDAC cell killing in vitro, alongside induction of mitotic slippage and immunogenic cell death in PDAC cell lines, when combined with chemotherapy. Increased survival was seen in vivo with 80% of animals surviving long term, when compared to chemotherapy alone. Moreover, combination therapy mediated enhanced tumor growth control, without observable toxicities in internal organs or external features. Survival and tumor control benefits were associated with activation of tumor infiltrating immune cells, downregulation of inhibitory signals, change in fibroblast populations in the tumors and changes in intratumoral cytokines, with increased chemokine amounts (CCL2, CCL3, CCL4) and anti-tumor cytokines (IFN-γ and TNFα). Furthermore, vIL-2 virus in combination with chemotherapy efficiently induced tumor protection upon rechallenge, that was extended to a previously non-encountered cancer cell line. In conclusion, Ad5/3-E2F-d24-vIL2 is a promising immunotherapy candidate when combined with nab-paclitaxel and gemcitabine

Cancer immunotherapy with oncolytic viruses armed with cytokines and fusion proteins

Bispecific T cell engager (BsTe) therapy can harness the power of T cells and enhances antitumor activity. In a clinical setting, this therapy has proven efficacy in treating uveal and hematological malignancies. However, because of their short serum half-life and low tumor concentration, BsTes have limited anticancer effects in most solid tumors. A promising therapeutic strategy is needed to convert immunosuppressive cold tumors into immunologically hot tumors. Oncolytic viruses (OVs) are a promising class of therapeutic agents. Genetically modified OVs selectively replicate within tumor cells and lyse cancer cells without harming healthy cells. OVs induce immunogenic tumor cell death, direct tumor lysis and can control tumor growth. OV therapy serves as a versatile platform that can be engineered to carry therapeutic genes within their genome. OVs have shown positive synergistic effects when combined with other immunotherapies and result in improved antitumor control. However, OV monotherapy has shown limited antitumor efficacy when used in human clinical trials to treat solid tumors. This study aimed to improve OV efficacy in solid tumors through the utilization of oncolytic adenoviruses (OAds) coding for human Mucin1 (MUC1) T cell engager intending to increase T cell-mediated immune response in cancer treatment. The first study investigated the antitumor efficacy of a novel Ad5/3-E2F-d24-aMUC1aCD3 virus. The oncolytic potential of this virus and its ability to induce rapid tumor cell lysis was confirmed by in vitro assays. Infected tumor cells released functional aMUC1aCD3-BsTe, which bound to its target cells and enhanced T cell activation. In vivo studies demonstrated enhanced tumor growth control in an A549 mouse model and an ovarian cancer (OvCa) patient-derived xenograft (PDX) model. Immunological studies of virus-treated tumors showed increased T cell infiltration and longer in vivo persistence of aMUC1aCD3-BsTe molecules. Overall, these findings suggest that this therapy can serve as an effective strategy to enhance BsTe delivery in solid tumors by utilizing OV therapy. The second study interrogated another novel Ad5/3-E2F-d24-aMUC1aCD3-IL2 virus armed with human aMUC1aCD3-IL2 transgene. This study investigated the mechanism of action of this novel construct by utilizing a panel of different tumor cells in vitro and ovarian cancer ascites ex vivo models. In the virus-treated group, stimulated T cell cytotoxicity was detected followed by the presence of increased levels of granzymeB, perforin, and interferon-gamma (IFN-y). In addition to the activation of conventional lymphocytes, increased gamma delta T cell activation was evident with virus treatment. When ascites samples were treated with this virus, a reduction in T cell exhaustion was observed. The in vivo study performed in an immunodeficient mouse model using the PDX-OvCa xenograft resulted in a significantly improved antitumor response. Tumor control was superior when the virus was administered systemically or locally, compared to control groups. The presence of T cells in locally treated tumors was slightly elevated compared to systemically treated tumors, resulting in a better antitumor effect. The third study investigated fully chimeric Ad3-hTERT-CMV-CD40L virus and its synergistic effect in combination with dendritic cell (DC) therapy in prostate cancer. The in vivo study performed in a humanized mouse model bearing PC3MM2 tumor indicated greater antitumor immune response and improved cancer-specific survival with the CD40L-armed virus and DC combination therapy. The release of high levels of proinflammatory cytokines in addition to DC maturation was observed in patient prostate tumors treated with the virus. The fourth study discovered a key role of T cell immunoglobulin and mucin domain-3 (TIM-3) checkpoint in adenoviral immunotherapy. The preclinical study performed in B16 melanoma model revealed an association between TIM-3 and an exhausted T cell phenotype, and TIM-3 expression was reduced significantly by the OAd treatment. Decreased levels of TIM-3 with OAd treatment in different clinical samples resulted in prolonged survival. Overall, this study has successfully demonstrated that arming OAd with immunomodulatory genes can enhance their therapeutic efficacy by leveraging the immune system to mount potent antitumor responses.Bispesifinen T-solu sitoutuja (Bispecific T cell engager, BsTe) -hoito hyödyntää immuunisoluja – pääosin T soluja – ja tehostaa kasvaimen vastaista toimintaa. Kliinisesti terapia on osoittautunut tehokkaaksi suonikalvoston melanooman (uveal melanoma) ja hematologisten syöpien hoidossa. Kuitenkin johtuen näiden molekyylien lyhyestä seerumin puoliintumisajasta ja matalista kasvainpitoisuuksista, BsTe-hoidon teho useimmissa kiinteissä kasvaimissa on ollut matala. Uusia terapeuttisia keinoja tarvitaan ’kylmien’ immunosuppressiivisten kasvaimien muuttamiseksi immunoprevalenteiksi ’kuumiksi’ kasvaimiksi. Onkolyyttiset virukset (OV) ovat lupaava terapeuttisten tuotteiden luokka. Geneettisesti muokatut OV:t lisääntyvät valikoivasti kasvainsoluissa ja hajottavat ne vahingoittamatta terveitä soluja. OV:t saavat aikaan immunogeenistä solukuolemaa, suoraa kasvainsolujen hajoamista ja tehostettua kasvainkontrollia. OV-terapia on monipuolinen alusta, jota voidaan muokata kuljettamaan terapeuttisia geenejä. OV:t ovat osoittaneet positiivisia synergistisiä vaikutuksia muiden immunoterapioiden kanssa johtaen parempaan kasvainkontrolliin. OV-monoterapia on kuitenkin osoittanut rajallista tehoa ihmisten kiinteiden kasvainten hoidossa. Tässä väitöstutkimuksessa hyödynnettiin onkolyyttisiä adenoviruksia (OAd), jotka tuottavat bispesifistä T-solu sitoutujaa tunnistamaan ihmisen musiini-1 (Mucin 1, MUC1) proteiinia, tarkoituksena tehostaa T-soluvälitteisiä immuunivastetta syöpähoidoissa. Ensimmäinen osatyö selvitti uuden Ad5/3-E2F-d24-aMUC1aCD3 viruksen tehokkuutta syöpähoitona. Viruksen onkolyyttistä kykyä ja nopeaa kasvainsolujen hajoamista tutkittiin in vitro kokeilla. Infektoituneet kasvainsolut vapauttivat toiminnallista aMUC1aCD3-BsTe-molekyyliä, mikä sitoutui kohdesoluihin ja kykeni tehostamaan T-solujen aktivaatiota. In vivo tutkimukset hiirissä osoittivat tehostettua kasvainkontrollia A549-kasvainmallissa ja munasarjasyöpäpotilaan ksenograftimallissa (patient-derived xenograft, PDX). Immunologiset tutkimukset virushoidetuista kasvaimista osoittivat lisääntynyttä T-solujen määrää ja pidempää aMUC1aCD3-BsTe-molekyylien in vivo kestoaikaa. Yhdessä nämä tulokset osoittavat tämän hoidon olevan tehokas keino parantaa BsTe-molekyylien toimitusta kiinteisiin kasvaimiin käyttäen OV-terapiaa. Toinessa osatyössä tutkittiin toista uutta virusta, Ad5/3-E2F-d24-aMUC1aCD3-IL2, joka kantaa ihmisen aMUC1aCD3-IL2 transgeeniä. Tämä tutkimus selvitti viruksen vaikutusmekanismia käyttäen hyväkseen useiden kasvainsolujen paneelia in vitro ja munasarjasyövän askitesnäytteiden ex vivo-malleja. Viruksella hoidetussa ryhmässä stimuloitua T-solujen sytotoksisuutta mitattiin lisääntyneellä grantsyymi B:n, perforiinin ja interferoni gamman (IFN-y) määrällä. Tavanomaisten T-solujen aktivaation lisäksi gamma-delta-T-solut aktivoituivat virushoidon myötä. Askites-näytteiden virushoito johti vähentyneeseen T-solujen uupumistilaan. In vitro kokeet immuunipuutteisten hiirien PDX-OvCa-ksenografti mallissa osoittivat hoidon johtavan merkittävästi parempaan kasvainkontrolliin. Virushoidon kasvainkontrolli oli parempi sekä systeemisesti ja paikallisesti annosteltuna kontrolleihin verratessa. T-solujen määrä kasvaimissa oli hieman suurempi paikallisessa annostelureitissä johtaen myös parempaan kasvainkontrolliin systeemiseen reittiin verratessa. Kolmas osatyö tutki täysin kimeeristä Ad3-hTERT-CMV-CD40L virusta ja sen synergistisiä vaikutuksia dendriittisolujen (dendritic cells, DC) kanssa eturauhassyövän hoidossa. In vivo-koe humanisoitujen hiirien PC3MM2-kasvainmallissa osoitti parempia kasvaimen vastaisia immuunivasteita ja pidempää eloonjäämistä CD40L-virus ja DC-yhdistelmäterapialla. Korkeita määriä tulehdusta edistäviä sytokiineja ja dendriittisolujen kypsymistä havaittiin viruksella hoidetuissa potilaiden eturauhassyöpänäytteissä. Neljäs osatyö selvitti T cell immunoglobulin and mucin domain-3 (TIM-3) -proteiinin roolin adenovirusimmunoterapiassa. Pre-kliininen koe B16-melanoomamallissa havaitsi TIM-3 proteiinin ekspression liittyvän uupuneeseen T-solufenotyyppiin ja adenovirusterapia vähensi huomattavasti sen esiintymistä. Matalammat TIM-3 tasot adenovirusterapian kanssa johti pidempään selviytymiseen erilaisissa kliinisissä näytteissä. Tiivistettynä, nämä tutkimukset osoittavat kuinka onkolyyttisten adenovirusten terapeuttista tehoa voidaan parantaa lisäämällä niihin immunomodulatorisia geenejä, hyödyntäen täten immuunipuolustusta syöpää vastaan

Sustainability perceptions towards digitalization of maintenance services – A survey

Digital maintenance has the potential to leverage data and advanced analytics to forecast, prevent, diagnose, and rectify equipment problems. To better fulfill the maintenance objective, digital maintenance combines traditional maintenance functionalities with modern digital tools and techniques. It also serves as a sustainable and strategic component for achieving several corporate goals, including profitability and overall business performance. Despite the immense value of sustainable digital maintenance, only a few industries have adopted and started using it. Early adopters benefited greatly from the early and widespread transformation of their maintenance and reliability functions. However, adoption remains oppressive for most organizations. This survey focuses on maintenance users and their company's beliefs in the transformation of sustainable digital maintenance services by establishing a technology acceptance model and exploring different intent factors. According to the results and analysis, experienced users have a strong and positive attitude towards the adoption of sustainable digital maintenance. They feel hesitant towards their immediate use due to their non-readiness and the lack of facilitating conditions such as the resources and knowledge required for it. Additionally, digital maintenance services must be sustainable, with a prime focus on the environment, economy, and safety