Background: Tumor microenvironment (TME) plays a crucial role in virtually every aspect of tumorigenesis of glioblastoma multiforme (GBM). The dysfunctional TME promotes drug resistance, disease recurrence and distant metastasis. Recent evidence indicates that exosomes released by stromal cells within TME may promote oncogenic phenotypes via transferring signaling molecules such as cytokines, proteins and microRNAs. Results: In this study, clinical GBM samples were collected and analyzed. We found that GBM-associated macrophages (GAMs) secreted exosomes which were enriched with oncomiR-21. Co-culture of GAMs (and GAM derived exosomes) and GBM cell lines resulted in the increased GBM cells’ resistance against temozolomide (TMZ) by upregulating pro-survival gene, PDCD4 and stemness markers Sox2, STAT3, Nestin and miR-21-5p and increased M2 cytokines, IL-6 and TGF-β1 secreted by GBM cells, promoting the M2 polarization of GAMs. Subsequently, pacritinib treatment suppressed GBM tumorigenesis and stemness; more importantly, pacritinib-treated GBM cells showed markedly reduced ability to secret M2 cytokines and reduced miR-21 enriched exosomes secreted by GAMs. Pacritinib-mediated effects were accompanied by a reduction of oncomiR miR-21-5p, by which tumor suppressor PDCD4 was targeted. We subsequently established a patient-derived xenograft models where mice bore patient GBM and GAMs. The treatment of pacritinib, and the combination of pacritinib/TMZ appeared to significantly reduce tumorigenesis of GBM/GAM PDX mice, overcome TMZ-resistance, and M2 polarization of GAMs. Conclusion: In summation, we showed that potential of pacritinib alone or in combination with TMZ for suppressing GBM tumorigenesis via modulating STAT3/miR-21/PDCD4 signaling. Further investigations are warranted for adopting pacritinib for the treatment of TMZ-resistant GBM in the clinical settings.

Due to its aggressive and invasive nature glioblastoma (GBM), the most common and aggressive primary brain tumour in adults, remains almost invariably lethal. Significant advances in the last several years have elucidated much of the molecular and genetic complexities of GBM. However, GBM exhibits a vast genetic variation and a wide diversity of phenotypes that has complicated the development of effective therapeutic strategies. This complex pathogenesis makes it necessary the development of experimental models that could be used to further understand the disease, and also to provide a more realistic testing ground for potential therapies. In this report, we describe the process of transformation of primary mouse embryo astrocytes into immortalized cultures with neural stem cell characteristics, that are able to generate of GBM when injected in the brain of C57BL/6 mice, or heterotopic tumours when injected iv. Overall, our results show that oncogenic transformation is a fate for NSC if cultured for long periods in vitro. In addition, since no additional hit is necessary to induce the oncogenic transformation, our model may be used to investigate the pathogenesis of gliomagenesis and to test the effectiveness of different drugs throughout the natural history of GBM.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intra-cranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2 treated NK cells as compared to those subjected to non-treated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2 treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Background: Glioblastoma (GBM), a malignant grade IV tumor, is the most malignant brain tumor due to its hyper-proliferative and apoptosis-evading characteristics. The signal transducer and activators of transcription (STAT) family genes, including STAT3 and STAT5A, have been indicated to play important roles in GBM progression. Increasing number of reports suggest that Garcinol, a polyisoprenylated benzophenone and major bioactive component of Garcinia indica contains potent anti-cancer activities. Material & Methods: The present study investigated the anti-GBM effects of garcinol, focusing on the STAT3/STAT5A activation, using a combination of bioinformatics, in vitro, and ex vivo assays. Results: Our bioinformatics analysis of TCGA - GBM cohort (n=173) showed that STAT3 and STAT5A are preferentially elevated in primary and recurrent GBM, compared to non-tumor brain tissues, and is significantly correlated with reduced overall survival. In support, our immunohistochemical staining of a GBM cohort (n=30) showed an estimated 5.3-fold (p<0.001) elevation in STAT3 and STAT5A protein expression in primary and recurrent GBM versus the non-tumor group. In vitro, garcinol treatment significantly suppressed the proliferative, invasive, and migratory potential of U87MG or GBM8401 cells, dose-dependently. In addition, garcinol anticancer effect significantly attenuated the GBM stem cell-like phenotypes, as reflected by diminished ability of U87MG or GBM8401 to form colonies and tumorspheres and suppressed expression of OCT4 and SOX2. Furthermore, analysis on GBM transcriptome revealed an inverse correlation between the level of STAT3/5A and hsa-miR-181d. Garcinol-mediated anti-GBM effects were associated with an increased hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratio. Conclusion: We present evidence of anti-GBM efficacy of garcinol mediated by enhancing the hsa-miR-181d/STAT3 and hsa-miR-181d/5A ratios in GBM cells. Our findings suggest a potential new therapeutic agent for combating aggressive GBM.

Glioblastoma (GBM) is the most common and aggressive adult brain cancer with an average survival rate of around 15 months in patients receiving standard treatment. Oncolytic adenovirus expressing therapeutic transgenes represent a promising alternative treatment for GBM. Of the many human adenoviral serotypes described to date, adenovirus 5 (Ad5) has been most utilized clinically and experimentally. However, the use of Ad5 as an anti-cancer agent may be hampered by naturally high seroprevalence rates to Ad5 coupled with infection of healthy cells via native receptors. To explore whether alternative natural adenoviral tropisms are better suited to GBM therapeutics, we pseudotyped an Ad5 based platform with the fiber knob protein from alternative serotypes. We demonstrate that the adenoviral entry receptors coxsackie and adenovirus receptor (CAR) and CD46 are highly expressed by both GBM and healthy brain tissue, whereas Desmoglein 2 (DSG2) is expressed at low level in GBM. We demonstrate that adenoviral pseudotypes, engaging CAR, CD46 and DSG2, effectively transduce GBM cells. However, the presence of these receptors on non-transformed cells presents the possibility of off-target effects and therapeutic transgene expression in healthy cells. To enhance specificity of transgene expression to GBM, we assessed the potential for tumour specific promoters hTERT and survivin to drive reporter gene expression selectively in GBM cell lines. We demonstrate tightly GBM specific transgene expression using these constructs, indicating that the combination of pseudotyping and tumour specific promoters approaches may enable the development of efficacious therapies better suited to GBM.

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopic analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol. Moreover, IQGAP1 positive staining was found in podosome/invadopodia-like structures. IQGAP1⁺ staining was observed in neurons (Map2⁺ cells), in cancer stem cells (CSC; nestin⁺) and in several macrophages (CD31⁺ or Iba1⁺). Our results indicate that the IQGAP1 protein is involved in normal cell physiology as well as oncologic processes.

As renewable energy generation prediction system has been introduced into the energy trading market, making a model to accurately predict the quantity of solar photovoltaic (PV) energy generation has become a significant problem. Moreover, to encourage an accurate prediction of the quantity of energy generation, an incentive system has been implemented for those who predict the quantity of solar PV energy under the error rate of 8%. Therefore, it has become more important to investigate and analyze current prediction technology numerically and develop more advanced prediction system. In this study, we tried to develop a better model to improve the accuracy of solar PV energy generation quantity by comparing three models made with gradient boosting machine (GBM), Model 1, Model 2, Model 3 respectively. Model 1 was built with the whole training data set without any additional preprocessing. After conducting some additional preprocessing procedure to predict solar energy generation more accurately, we made Model 2 with the whole training data set and Model 3 with only upper 10% of energy generation capacity. To compare the accuracy of three models, normalized mean absolute error (nMAE) was used as an evaluation index. The nMAE of Model 1 was 9.64% while the Model 2 showed 8.41%. Also, Model 3, which was constructed with the training set of upper 10% energy generation capacity, outperformed with the nMAE of 8.08%. For further study, to check the effectiveness of models constructed with GBM, a time series model, autoregressive integrated moving average (ARIMA), was also built and the nMAE was compared.

Current therapeutic strategies targeting cancer cells within solid tumors have displayed limited success owing to the presence of non-cancer components referred to as the tumor stroma within the tumor microenvironment (TM). These stromal cells, extracellular matrix and blood vessels influence cancer cell response to therapy and play key roles in tumor relapse and resistance. Of the stromal cells present in the TM, a lot of attention has been given to cancer-associated fibroblasts (CAFs) as they are the most abundant and are important in cancer initiation, progression and therapy resistance. In this updated review I emphasize the role of CAFs in the regulation of tumor cell behaviour and reveal how CAF-derived factors and signaling influence tumor cell heterogeneity and development of novel strategies to combat cancer. To investigate the expression of CAF markers in tumor tissues versus normal tissues, transcriptomic data from The Cancer Genome Atlas (TCGA) and the Gene Expression Profiling Interactive Analysis (GEPIA) databases was used. Bioinformatic analysis reveals differential expression of CAF markers in several cancer types, underscoring the need for further multiomics and biochemical studies on CAFs, CAF subsets and markers. Differences in CAF markers’ expression could be due to different cellular origins as well as the effect of cancer-specific tumor microenvironmental effect on CAFs. Lastly, I present recent advances in therapeutic targeting of CAFs and the success of such endeavours or its lack thereof. It is recommended that for patients’ outcomes to improve, cancer treatment be combinatorial in nature, targeting both cancer cells and stromal cells and interactions.

Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of TMZ and cholesterol lowering medications (statins) is currently under investigation in in vivo and clinical trials. In our current investigation, we have used a triple combination therapy of TMZ, Simvastatin (Simva), and Acetylshikonin (ASH) and investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used viability, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. Our results showed that TMZ/Simva/ASH combination therapy significantly induced more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage (increase of ROS, decrease of MMP) and induced caspase-3/7 activation in both GBM cell lines. Compared to all single treatments and the TMZ/Simva treatment, TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment was due to partial inhibition of autophagy flux (accumulation of LC3β-II and decrease in p62 degradation) in GBM cells. Our investigation also showed that TMZ/Simva/ASH-induced cell death was depended on autophagy flux as further inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially depends on an increase of Bax expression in GBM cells. Our current investigation might open new avenues for more effective treatment of GBM but further investigations are required for better identification of the mechanisms.

Aim: Glioblastoma multiform (GBM) is a prevalent brain cancer which accounts for 80% of cases globally with a noticeably short life expectancy subsequent diagnosis. There are several factors associated with GBM including alterations and over expressions of oncoproteins. Analysis of SEC61G expression in GBM patient’s favor tumour progression, which promotes an environment of oxidative stress, while preventing apoptosis. Methods: In this article using in silico tools including GEPIA2, ULCAN, LinkedOmics, Gene MANIA and mirTEd, we observed the role of SEC61G gene in GBM progression by analyzing the expression, positive correlation associated with metabolic, mitochondrial gene, immune cell infiltration level, gene interaction networks, miRNA association as well as survival analysis. Results: The expression of the mitochondrial, metabolic genes PGLS, PGK1, EIF6, and EIF3K which are involved in redox metabolism and CD63 immunoregulation, as well as other genes that promote tumour progression and invasion, including EGFR, LANCL2, BCL2L12, SEC61G-DT, KDELR1, CDKN2A, IFNA16, IFNA10, and BCL7C were positively correlated with the increased/high expression of SEC61G.We also found hsa-mir-380-5p to be unregulated in glioblastoma phenotypes. Conclusion: Our findings suggest that SEC61G associated redox metabolism, complement system and immunoregulation, as well as miRNA expression can be targeted to develop a potential therapeutic approach for GBM patients.

The Energy Performance of Buildings Directive 2010 calls for the Nearly Zero Energy Standard for new buildings from 2021 onwards: Buildings using “almost no energy” are powered by renewable sources or energy produced by the building itself. For residential buildings, this ambitious new standard has already been reached. But for other building types this goal is still far away. The potential of these buildings to meet a Nearly Zero Energy Standard was investigated by analyzing ten case studies representing non-residential buildings with different uses. The analysis shows that the primary characteristics common to critical building types are a dense building context with a very high degree of technical installation (such as hospital, research and laboratory buildings). The large primary energy demand of these types of buildings cannot be compensated by building and property-related energy generation including off-site renewables. If the future Nearly Zero Energy Standard were to be defined with lower requirements because of this, the state related properties of Bavaria suggest that the real potential energy savings available in at least 85% of all new buildings would be insufficiently exploited. Therefore, it would be useful to instead individualize the legal energy verification process for new buildings to distinguish critical building types such as laboratories and hospitals.

P-glycoprotein (Pgp) determines resistance to a broad spectrum of drugs in glioblastoma multiforme (GB) because it is highly expressed in GB stem cells and in brain-blood barrier (BBB), the peculiar endothelium surrounding brain. Inhibiting Pgp activity in BBB and GB is still an open challenge. Here, we tested the efficacy of a small library of tetrahydroisoquinoline derivatives with an EC₅₀ for Pgp < 50 nM, in primary human BBB cells and in patients-derived GB, from which we isolated differentiated/adherent cells (AC, i.e. Pgp-negative/doxorubicin-sensitive cells) and stem cells (neurospheres, NS, i.e. Pgp-positive/doxorubicin-resistant cells). At 1 nM, 3 compounds increased the delivery of doxorubicin, a typical substrate of Pgp, across BBB monolayer, without altering expression and activity of other transporters. The compounds increased the drug accumulation within NS, restoring necrosis, apoptosis and reduction in cell viability induced by doxorubicin. In co-culture systems, the compounds added to the luminal face of BBB increased the delivery of doxorubicin to NS growing under BBB and rescued the drug’s cytotoxicity. Our work identified new ligands of Pgp active at low nanomolar concentrations, that effectively reduce Pgp activity in BBB and GB, and can improve chemotherapy efficacy in this tumor.

Although most people are infected with Epstein-Barr Virus (EBV) during their lifetime, only a minority of them develop an EBV-associated malignancy. EBV acts in both direct and indirect ways to transform infected cells into tumor cells. There are multiple ways in which the EBV, host, and tumor environment interact to promote malignant transformation. This paper focuses on some of the mechanisms that EBV uses to transform the tumor microenvironment (TME) of EBV-associated gastric cancer (EBVaGC) for its benefit, including overexpression of IDO1, synergism between H pylori and EBV coinfection, and M1 to M2 switch. In this review, we expand on different modalities and combinatorial approaches to therapeutically target this mechanism.

Tumor-associated macrophages (TAMs) play critical roles in the tumor microenvironment (TME), where they are recruited by signals released by cancer cells. Although they have great potential as therapeutic targets for cancer treatment, the dual roles of TAMs in promoting or inhibiting tumor growth, invasion, and metastasis make their function in cancer progression complex. In this review, we provide an overview of the current understanding of TAMs, including their phenotypic diversity, regulatory signaling pathways, and interactions with other cells in the TME. We also discuss the challenges related to the standard isolation protocols of TAMs, inconsistent research results, and translation of TAM knowledge into clinical applications. Additionally, we review the status of clinical trials involving TAMs and potential strategies to overcome the limitations. The future direction of TAM research should focus on developing more targeted therapies that specifically regulate TAM function and non-invasive methods for monitoring TAM activity in cancer patients. A comprehensive understanding of the complex role of TAMs in cancer may lead to the development of more effective treatments and improved outcomes for cancer patients.

Similarly to our healthy organs, tumor tissue also generates an ecosystem. This implies that stromal cells acquire an altered phenotype in tandem with tumor cells, thereby promoting tumor survival. Cancer cells are fueled by abnormal blood vessels, allowing them to develop and proliferate. Tumor-associated fibroblasts adapt their cytokine and chemokine production to the needs of tumor cells, alter the peritumoral stroma by generating more collagen, thereby stiffening the matrix, all promoting the epithelial-mesenchymal transition and tumor cell invasion. Chronic inflammation and the mobilization of pro-tumorigenic inflammatory cells further facilitate tumor expansion. All of these events can impede the effective administration of tumor treatment, so the successful inhibition of tumorous matrix remodeling could further enhance the success of tumor treatment. Numerous publications describe efforts to inhibit tumor matrix components, but the true breakthrough has yet to be achieved. If, on the other hand, we assume that tumorous blood vessels and inflammatory cells are residents of the tumorous stroma, then two steps forward have occurred.

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. Especially MGMT promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor was used to inhibit MGMT protein expression in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein expression and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect.

Glioblastoma multiforme (GBM) is the most common high-grade intracranial tumor in adults. It is characterized by uncontrolled proliferation, diffuse infiltration due to high invasive and migratory capacities, as well as intense resistance to chemo- and radiotherapy. With a five-year survival of less than 3% and an average survival rate of 12 months after diagnosis, GBM has become a focus of current research to urgently develop new therapeutic approaches in order to prolong survival of GBM patients. The methylation status of the promoter region of the O6-methylguanine–DNA methyltransferase (MGMT) is nowadays routinely analyzed, since a methylated promoter region is beneficial for an effective response to temozolomide-based chemotherapy. Furthermore, several miRNAs were identified regulating MGMT expression, apart from promoter methylation, by degrading MGMT mRNA before protein translation. These miRNAs could be a promising innovative treatment approach to enhance Temozolomide (TMZ) sensitivity in MGMT unmethylated patients and to increase progression-free survival as well as long-term survival. In this review, the relevant miRNAs are systematically reviewed.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 hours in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.

Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n=18) and IDH1 mutant (IDH1-mt) astrocytoma (n=12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical mem-braneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vascula-ture are shown to have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Overproduction of lipids by the tumor is suspected to be due to a combination of two processes: i) dysfunctional oxidative phosphorylation in mitochondria that causes metabolic backup and ac-cumulation of acetyl-CoA, as well as ii) the overproduction of pyruvate due to the tumor cell reli-ance on overactive glycolysis. Tumor cells use lipids for structural components but cannot use them for energy if their oxidative phosphorylation is dysfunctional, which seems to be the case in the tumor cells we examined. This lipid-rich environment, however, offers tumor cells certain advantages: protection from the immune system, non-lipophilic drugs, and oxidative stress. Our research highlights the significant presence of lipid overproduction in both IDH1-wild type glio-blastoma and IDH1-mutant astrocytoma tumors, leading to diverse lipid accumulations in var-ious cellular compartments and structures. This lipid excess stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune re-sponses, non-lipophilic drugs, and free radicals.

Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis and highlight various ways through which tumor cells reprogram normal cells including into phenotypes that are pro-tumorigenic including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to formation of new vascular networks in order to actively promote and sustain tumor growth via supply of oxygen and nutrients whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to targeting of tumor cells. Re-programming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centred therapies under investigations.

Tumor growth, progression, and therapy resistance are crucial factors in the prognosis of cancer. Properties of three-dimensional tumor-like organoids (tumoroids) more closely resemble in vivo tumors compared to two-dimensionally cultured cells and are therefore effectively used for assays and drug screening. We here established a repurposed drug for novel anticancer research and therapeutics using a tumoroid-based screening system. We screened 6 pharmacologically active compounds by using an original tumoroid-based multiplex phenotypic screening system with matrix metalloproteinase 9 (MMP9) promoter-driven fluorescence reporter for the evaluation of both tumoroid formation and progression. The effects of one of the hit compounds were examined on tumor formation and progression in vitro and in vivo. Antiparkinson drug benztropine was the most effective compound uncovered by the screen. Benztropine significantly inhibited in vitro tumoroid formation, cancer cell survival, and MMP9 promoter activity. Benztropine also reduced the activity of oncogenic signaling transducers and trans-activators for MMP9, including STAT3, NF-κB, and β-catenin, and properties of cancer stem cells / cancer-initiating cells. Benztropine and GBR-12935 directly targeted the dopamine transporter DAT/SLC6A3, whose genetic alterations such as amplification were correlated with poor prognosis for cancer patients. Benztropine also inhibited tumor growth, circulating tumor cell (CTC) number, and rate of metastasis in a tumor allograft model in mice. In conclusion, we propose the repurposing of benztropine for anticancer research and therapeutics that can suppress tumor progression, CTC, and metastasis of aggressive cancers by reducing key pro-tumorigenic factors.

Long gone was the time when tumors were thought to be insular masses of cells, residing independently at specific sites in an organ. Now, researchers gradually realize that tumors interact with the extracellular matrix (ECM), blood vessels, connective tissues and immune cells in their environment, which is now known as the tumor microenvironment (TME). It is found that the interactions between tumors and their surrounding promote tumor growth, invasion and metastasis. The dynamics and diversity of TME cause the tumors to be heterogeneous and thus pose a challenge for cancer diagnosis, drug design and therapy. As TME is significant in enhancing tumor progression, it is vital to identify the different components in the TME. This review explores how different factors in the TME supply tumors with the required growth factors and signaling molecules to proliferate, invade and metastasis. We also examine the development of TME-targeted nanotheranostics over the recent years for cancer therapy, diagnosis and anticancer drug delivery system. This review further discusses the limitations and future perspective of nanoparticle based theranostics when used in combination with current imaging modalities like Optical Imaging, Magnetic Resonance Imaging (MRI) and Nuclear Imaging (PET and SPECT).

Background: Glioblastomas (GBM) is generally burdened, to date, by a dismal prognosis, although Long Term Survivors have a relatively significant incidence. Our specific aim was to determine the exact impact of many surgery-, patient- and tumor-related variable on Survival parameters. Methods: The surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All the patients have been operated on in our Institution and classified according their Overall Survival in LTS (Long Term Survivors) and STS (Short Term Survivors). A thorough Review of our surgical series was conducted to compare the oncologic results of the patients in regards to 1. Surgical , 2. Molecular, and 3.Treatment related features. Results: A total of 177 patients were included in the final cohort. Extensive statistical analysis by means of univariate, multivariate and survival analyses disclosed a survival advantage for patients presenting a younger age, a smaller lesion and a better functional status at presentation. From the Histochemical point of view, Ki67(%) was the strongest predictor of better oncologic outcomes. A stepwise analysis of variance outlines the existence of 8 prognostic subgroups according to the molecular patterns of Ki67 overexpression and EGFR, p53 and IDH mutations. Conclusions: On the ground of our statistical analyses we can affirm that the following factors were significant predictors of survival advantage: KPS, Age, Volume of the lesion, Motor disorder at presentation, a Ki67 overexpression. A fine molecular profiling is feasible to precisely stratify the prognosis of GBM patients.

The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

Some tumors occur in anatomical regions that are hard to biopsy with a needle. Such regions include the brain, spinal cord, liver, and lungs. For the latter two, magnetic nanoparticle-loaded macrophages could be intravenously infused and driven via an MRI machine into the tumor or tumors. Once there, they can be induced to phagocytose whole tumor cells. They would keep their target in a non-digested form by inhibiting phagosome maturation - and be directed via magnetotaxis or chemotaxis to an extraction point in the body where they can be more easily collected via needle.

Our previous studies demonstrated that quercetin (Q) could be ingested and metabolized by macrophages and exerted prophylactic immuno-stimulatory activity and therapeutic anti-inflammatory effects on lipopolysaccharide (LPS)-treated macrophages ex vivo. To further clarify its possible anti-inflammatory mechanism, Q was selected to treat mouse peritoneal macrophages that obtained from female BALB/c mice exposed to LPS i.p. for 12 h. Relative gene expression of pro-/anti-inflammatory (TNF-α/IL-10) cytokines and components of inflammation-related intracellular signaling pathways (TLR2, TLR4, NF-κB, JAK2 and STAT3) was analyzed using two-step reverse transcription (RT) and real-time quantitative polymerase chain reaction (qPCR). STAT3 protein phosphorylation was determined using an in-cell ELISA method. As a result, Q and its metabolite quercetin-3-O-β-D-glucuronide (Q3G) decreased TNF-α gene expression amounts and ratios of pro-/anti-inflammatory (TNF-α/IL-10) cytokine gene expressions, but increased IL-10 gene expression amounts in activated inflammatory macrophages, supporting a substantial anti-inflammatory potential of Q and Q3G treatments. However, Q3G had lower effects than those of Q. Importantly, Q inhibited TLR2 gene expression and phosphorylation of STAT3 protein in the inflamed cells. Our results are the first report to suggest that Q inhibits LPS-induced inflammation ex vivo through suppressing TLR2 gene expression and STAT3 protein phosphorylation in activated inflammatory macrophages. Q has potential to further apply for treating inflammation-associated diseases.

Tumor-associated microbiota refers to the community of microorganisms found in tumors and is part of the larger tumor microenvironment (TME). The discovery of the complex relationship between these microbial populations and the growth of cancer has prompted the creation of cutting-edge tailored methods to cancer treatment. In recent years, microbiota profiling's potential as a diagnostic, prognostic, and therapeutic optimization tool has been increasingly apparent. The diagnostic and prognostic use of microbiota profiling is explored in this abstract. Microbiota profiling shows potential for early cancer detection, improved risk stratification, and greater prediction of treatment outcomes by identifying different microbial signatures associated with early-stage tumors, aggressive characteristics, and responses to treatment. In addition, this method provides the way for individualized medicinal approaches based on an individual's specific microbiome.Microbiota profiling is investigated as a means of customizing treatment plans, illuminating how knowledge of an individual's microbiome might direct the development of individualized treatments and multimodal approaches. These kind of interventions have the potential to herald in a new era of patient-centered oncology care by increasing treatment efficacy while decreasing side effects. Despite significant promise, microbiota profiling has obstacles that must be overcome before it can be successfully translated into therapeutic practice. This abstract highlights the revolutionary potential of microbiota-based approaches in cancer care and the need for ongoing research and technology improvements to harness the power of the tumor-associated microbiome for improved patient outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a ravaging disease whose poor prognosis requires a more detailed understanding of its biology to foster the development of effective therapies. The unsatisfactory results of treatments targeting cell proliferation and its related mechanisms suggested to rather focus on the inflammatory tumor microenvironment (TME). Here, we discuss the role of cancer secreted proteins in the complex TME tumor-stroma crosstalk, to sched lights on druggable molecular targets for the development of innovative, safer and more efficient therapeutic strategies.

Epigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage. Combining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy. Thus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in-depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.

Only two percent of Glioblastoma multiforme (GBM) patients respond to standard care and survive beyond 36 months (long-term survivors, LTS) while the majority survive less than 12 months (short-term survivors, STS). To understand the mechanism leading to poor survival, we analyzed publicly available datasets of 113 STS and 58 LTS. This analysis revealed 198 differentially expressed genes (DEGs) that characterize aggressive tumor growth and may be responsible for the poor prognosis. These genes belong largely to the GO-categories “epithelial to mesenchymal transition” and “response to hypoxia”. In this paper we applied upstream analysis approach which involves state-of-art promoter analysis and network analysis of the dysregulated genes potentially responsible for short survival in GBM. Binding sites for transcription factors associated with GBM pathology like NANOG, NF-κB, REST, FRA-1, PPARG and seven others were found enriched in the promoters of the dysregulated genes. We reconstructed the gene regulatory network with several positive feedback loops controlled by five master regulators – IGFBP2, VEGFA, VEGF165, PDGFA, AEBP1 and OSMR which can be proposed as biomarkers and as therapeutic targets for enhancing GBM prognosis. Critical analysis of this gene regulatory network gives insights on mechanism of gene regulation by IGFBP2 via several transcription factors including the key molecule of GBM tumor invasiveness and progression, FRA-1. All the observations are validated in independent cohorts and their impact on overall survival is studied.

Protein phosphatase 2A (PP2A) is a ubiquitous serine/threonine phosphatase implicated in a wide variety of regulatory cellular functions. PP2A is abundant in the mammalian nervous system and dysregulation of its cellular functions are associated with myriad neurodegenerative disorders. Additionally, PP2A has oncologic implications, recently garnering attention and emerging as a therapeutic target because of the antitumor effects of a potent PP2A inhibitor, LB100. LB100 abrogation of PP2A is believed to exert its inhibitory effects on tumor progression through cellular chemo- and radio-sensitization to adjuvant agents. An updated and unifying review of PP2A biology and inhibition with LB100 as a therapeutic strategy for targeting cancers of the nervous system is needed, as other reviews have mainly covered broader applications of LB100. In this review, we discuss the role of PP2A in normal cells and tumor cells of the nervous system. Further, we summarize current evidence regarding the therapeutic potential of LB100 for treating solid tumors of the nervous system.

Here we report a comparative study of the pyhtochemical profile and a biological activity of the two onion extracts, namely A. cepa L. and A. × cornutum (Clementi ex Visiani 1842). Identification of flavonoids and anthocyanins and their individual quantities were determined by high performance liquid chromatography (HPLC). The potency of both extracts to scavenge free radicals was determined by DPPH (2,2'-diphenyl-1-picrylhydrazyl) radical-scavenging activity and oxygen radical absorbance capacity (ORAC) methods. DNA protective role was further tested by single-cell gel electrophoresis (COMET) assay and by Fenton’s reagent causing double strand brakes on pUC19 plasmid. In the presence of both extracts, a significant decrease in the DNA damage was observed, which indicates a protective role of A. cepa and A. × cornutum on the DNA strand brakes. Additionally, cytotoxicity was tested on glioblastoma and breast cancer cell lines. The results showed that both extracts had antiproliferative effect, but the most prominent decrease in cellular growth was observed with glioblastoma cells

The key challenges to treating glioblastoma multiforme (GBM) are the heterogenous and complex nature of the GBM tumour microenvironment (TME) and difficulty of drug delivery across the blood-brain barrier (BBB). The TME is composed of various neuronal and immune cells, as well as non-cellular components including metabolic products, cellular interactions, and chemical compositions, all of which play a critical role in GBM development and therapeutic resistance. In this review, we aim to unravel the complexity of the GBM TME, evaluate current therapeutics targeting this microenvironment, and lastly identify potential targets and therapeutic delivery vehicles for the treatment of GBM. Specifically, we explore the potential of aptamer-targeted delivery as a successful approach to treating brain cancers. Aptamers have emerged as promising therapeutic drug delivery vehicles with the potential to cross the BBB and deliver payloads to GBM and brain metastases. By targeting specific ligands within the TME, aptamers could potentially improve treatment outcomes and overcome the challenges associated with larger therapies such as antibodies.

STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation and loading as S3I-NP. The release of S3I-1757 at 24 hours was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p<0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p<0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4 folds compared to S3I-NP on day 12 after drug administration (p=0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM.

The central reason behind emergence of clinically-detectable tumors is evasion from immune surveillance due to lack of cancer cells surface membrane expression of tumor-specific peptides in association with MHC class I molecules, concealment of natural killer cells-activating molecules, and absence of inflammation resulting from inefficient stimulation of innate immunity receptors and co-stimulatory molecules. The tumor microenvironment (TME) also contributes to tumor initiation, progression and resistance to therapeutic interventions because of its dense, fibrogenic, barrier-like composition, aberrant vasculature, and production of cytokines and chemokines responsible for recruitment of immune suppressive cells, notably myeloid-derived suppressor cells, M2 macrophages, regulatory T cells, extracellular trap-forming neutrophils, and cancer-associated fibroblasts. We herein show that the relentless efforts and strategies to overcome the TME elusive tumor-promoting impact produced contrasting, opposed, controversial effects, characterized by limited efficacy and proven adversity, and most importantly deterred from attempts to discover and counteract the fundamental inherent mechanisms initiating, and not consequent to, carcinogenesis.

ABSTRACT: Recurrent glioblastoma (rGBM) is a highly aggressive form of brain cancer that poses a significant challenge for treatment in neurooncology, and the survival status of patients after relapse usually means rapid deterioration, and also the leading cause of death among patients. In recent years, immunotherapy has emerged as a promising strategy for the treatment of recurrent glioblastoma by stimulate the body's immune system to recognize and attack cancer cells , which could be used as a in combination with other treatments such as surgery, radiation, and chemotherapy to improve outcomes for patients with recurrent glioblastoma, This therapy combines several key methods such as the use of monoclonal antibodies, chimeric antigen receptor T cell (CAR-T) therapy, checkpoint inhibitors, oncolytic viral therapy cancer vaccines, and combination strategies. In this review, we mainly document the latest immunotherapies for the treatment of glioblastoma and focus on the rGBM especially.

Previous research has shown that propolis has immunomodulatory activity. Extracts from two UK propolis samples were assessed for their anti-inflammatory activities by investigating their ability to alter the production of the cytokines tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6 and IL-10 from mouse bone marrow derived macrophages co-stimulated with lipopolysaccharide (LPS). The propolis extracts suppressed secretion of IL-1β and IL-6 with less effect on TNFα. In addition, propolis reduced the levels of nitric oxide formed by LPS-stimulated macrophages. Metabolomic profiling was carried out by liquid chromatography (LC) coupled with mass spectrometry (MS) on a ZIC-pHILIC column. LPS increased the levels of intermediates involved in nitric oxide biosynthesis; propolis lowered many of these. Also, LPS produced an increase in itaconate and citrate and propolis treatment increased itaconate still further while greatly reducing citrate levels. Moreover, LPS treatment increased levels of GSH and intermediates in its biosynthesis while propolis treatment boosted these still further. In addition, propolis treatment greatly increased levels of UDP-sugar conjugates. Overall, the results showed that propolis extracts exert an anti-inflammatory effect by inhibition of pro-inflammatory cytokines and by metabolic reprogramming of LPS activity in macrophages.

PHLNs (polymeric lipid hybrid nanoparticles) are core–shell nanoparticle structures made up of polymer cores and lipid shells that have properties similar to both polymeric nanoparticles and liposomes. Methotrexate (MTX) loaded PLHNPs containing tween 80, phosphatidylcholine, poly D, L-lactic-co-glycolic acid (PLGA) & glyceryl tripalmitate prepared using solvent injection & homogenization method for glioblastoma treatment option. The MTX loaded PLHNPs optimized by Box–Behnken design to minimize particle size, higher entrapment efficacy, and maximize MTX concentration in the brain at 4h. The particle size, entrapment efficacy, concentration of drug in brain at 4h, zeta potential and AUC(Brain)/AUC(Plasma) ratio were in the range of 173.51-233.37nm, 70.56-86.34%, 6.38-12.38 μg/mL, 25.78-36.31mV & 1.02-5.32. in-vitro drug release studies, cellular internalization of optimized formulation against U-87 MG shows good anticancer effects.

Many cellular functions important for tumor initiation and progression are mediated by members of the integrin family, a diverse family of cell adhesion receptors. With recent studies emphasising on the role of the tumor microenvironment (TME) in tumor initiation and progression, it is not surprising that a lot of attention is being given to integrins. Several integrins are under trial with many demonstrating appealing activity in patients with different cancers. A deeper knowledge of the functions of integrins within the tumor microenvironment is still required, and might lead to better inhibitors being discovered. Integrin expression is commonly dysregulated in many tumors with integrins playing key roles in signaling as well as promotion of tumor cell invasion and migration. This review report new data on the differential expression of integrins within solid tumors using two publicly available resources: The Cancer Genomic Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA). In this analysis, I investigated the expression of integrin alpha 2 (ITGα2), ITGα3, ITGβ4 and ITGβ6 in tumor tissues versus adjacent normal tissues. This analysis showed that integrins were differentially expressed in cervical squamous cell carcinoma (CESC), head and neck squamous cell carcinoma (HNSC), esophageal carcinoma (ESCA) and lung adenocarcinoma (LUAD). This analysis showed that ITGα2 and ITGβ6 expression are upregulated in CESC and ESCA, ITGα3 is upregulated in HNSC and ESCA whilst ITGβ4 is highly expressed in CESC, HNSC, ESCA and LUAD tumor tissues compared to adjacent normal tissues. Integrins also play a major role in adhesion of circulating tumor cells to new sites and the resulting formation of secondary tumors. Furthermore, integrins have demonstrated the ability to promoting stem cell-like properties in tumor cells as well as drug resistance. Anti-integrin therapies rely heavily on the doses or concentrations used as these determine whether the drugs act as antagonists or as integrin agonists. This review offers the latest synthesis in terms of current knowledge of integrins functions within the tumor microenvironment and potential targets for different cancers.

The tumor microenvironment plays a pivotal role in the behavior and development of solid tumors as well as shaping the immune response against them. As the tumor cells proliferate, the space they occupy and their physical interactions with the surrounding tissue increases. The growing tumor tissue becomes a complex dynamic structure, containing connective tissue, vascular structures, and extracellular matrix that facilitates stimulation, oxygenation, and nutrition, necessary for its fast growth. Mechanical cues such as stiffness, solid stress, interstitial fluid pressure, matrix density, and microarchitecture influence cellular functions and ultimately tumor progression and metastasis. In this fight, our body is equipped with T cells as its spearhead against tumors. However, the altered biochemical and mechanical environment of the tumor niche affects T cell efficacy and leads to their exhaustion. Understanding the mechanobiological properties of the tumor microenvironment and their effects on T cells is key for developing novel adoptive tumor immunotherapies.

Progression of oral squamous cell carcinoma (OSCC) has been associated with an escape of tumor cells from the host immune surveillance due to an increased knowledge of its underlying molecular mechanisms and its modulation by the tumor microenvironment and immune cell repertoire. In this study the expression of HLA class I (HLA-I) antigens and of components of the antigen processing machinery (APM) was analyzed in 160 pathologically classified human papilloma virus (HPV)-negative OSCC lesions and correlated to the intra-tumoral immune cell response, IFN- signaling and to the patients outcome. A heterogeneous, but predominantly lower constitutive protein expression of HLA-I APM components was found in OSCC sections when compared to non-neoplastic cells. Tumoral HLA-I APM component expression was further categorized into the three major phenotypes HLA-Ihigh/APMhigh, HLA-Ilow/APMlow and HLA-Idiscordant high/low/APMhigh. In the HLA-Ihigh/APMhigh group, the highest frequency of intra-tumoral CD8+ T cells and lowest number of CD8+ T cells close to FoxP3+ cells was found. Patients within this group presented the most unfavorable survival, which was significantly evident in stage T2 tumors. Despite a correlation with the number of intra-tumoral CD8+ T cells, tumoral JAK1 expression as a surrogate marker for IFN- signaling was not associated with HLA-I/APM expression. Thus, the presented findings strongly indicate the presence of additional factors involved in the immunomodulatory process of HPV-negative OSCC with a possible tumor-burden-dependent complex network of immune escape mechanisms beyond HLA-I/APM components and T cell infiltration in this tumor entity.

Considering tumors from an evolucionary perspective, successive tumor cells undergo turnover in response to stressful conditions which pressures tumor cells to adapt to a new environment. Tumor cells uses parts of themselves to communicate and share biological information, known as extracellular vesicles (EV) secretion to promote their survival and “survive to each and every metabolic cost”. Tumor microenvironment (TME) is a miscellaneous of cells, factors, extracellular matrix proteins and EVs. EVs include smalls (<160nm, exosomes) and larger (100-1,000nm, microvesicles) lipid bilayer enclosed packages of biomolecules that are shed by tumors to TME. Tumor-derived extracellular vesicles transfer adaptative stress signaling to recipient cells, reprograming these cells. Heat Shock Proteins (HSP) are more prominent stress response regulators found in exosomes. HSP-loaded exosomes actively reprogram tumor and TME cells to acquire mechanisms that contribute to tumor progression and therapy resistance. The intercellular communication mediated by HSP-loaded EVs favors the escape of tumor cells from, endoplasmic reticulum (ER) stress, hypoxia, apoptosis and anti-cancer therapies. Extracellular HSPs activate and deactivate immune response, induce cell differentiation, changes vascular homeostasis, and help to augment the pre-metastatic niche formation. Here we will explore the EV mechanism of HSP transmission among TME cells and the relevance of these intercellular communications for resistance to therapies in cancer.

Glioblastoma multiforme (GBM) is a highly heterogeneous brain tumor with limited treatment options and a poor prognosis. Cancer stem cells (CSCs) have emerged as a critical factor in GBM resistance and management, contributing to tumor growth, heterogeneity, and immunosuppression. The transcription factor FOXM1 has been identified as a key player in the progression, spread, and therapy resistance of various cancers, including GBM. In this study, researchers conducted structure-based in silico screening to identify natural compounds that could target the DNA-binding domain (DBD) of the FOXM1 protein. Through molecular docking analyses, identified Silybin B as a potential inhibitor of FOXM1, exhibiting strong interaction with the protein. MD simulations were performed to validate the binding stability of the FOXM1-Silybin B complex. The study provides valuable insights into the potential of Silybin B as a FOXM1 inhibitor and its ability to induce senescence in GBM stem cells. These findings contribute to the development of structure-based design strategies for FOXM1 inhibitors and innovative therapeutic approaches for the treatment of Glioblastoma.

Background: Diffuse glioma is a malignant human brain cancer that is hard to overcome. This represents a high risk of mortality. The current challenge is limited to the control of tumor progression and survival improvement. Immunotherapy consists of stimulating the immune system in order to eliminate the non-self-elements that damage the human body, including cancer cells. However, in human glioma, the current immunotherapeutic targets did not show significant benefit. In this study, we aimed at evaluating the expression and potential role of a new immunosuppressive molecule, TIGIT in glioma patients. Methods: A cohort of 667 patients from the TCGA database along with a cohort of 53 Moroccan patients, were analyzed in order to assess the role of TIGIT in human glioma progression and to estimate whether blocking this immune checkpoint molecule would be of a potential therapeutic benefit. Real time RT-PCR from fresh human biopsies and RNAseq data analysis were performed in this study. Results: Our results showed that high expression of TIGIT had prognostic value with some known clinical glioma risk factors such as sex, age and IDH mutation status. High expression of TIGIT was positively associated with advanced grades of glioma. Interestingly, elevated rates of TIGIT were significantly associated to elevated levels of other inhibitory immune checkpoint molecules (PD-1, VISTA and Tim-3) in human glioma patients, also TIGIT showed strong association with Treg cell-secreted cytokines (TGF-beta and IL-10), indicating the high potential involvement of TIGIT in immunosuppression in human glioma. Moreover, we reported that high TIGIT expressing CD8 T-cells displayed more surface inhibitory molecules and, elevated levels of Treg cells and FoxP3 were linked to higher rates of TIGIT, supporting the likely involvement of TIGIT in the suppression of the intra-tumoral immune cells. Finally, high expression of TIGIT was significantly linked to advanced histological subtypes of glioma and was associated with poor overall survival in human glioma. Conclusion: TIGIT blockade might be of valuable therapeutic benefit in patients with advanced glioma.

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

Background: Disulfidptosis, a recently identified form of cell death triggered by excessive cysteine accumulation and subsequent disulfide stress, has emerged as a novel mechanism of cell death. Despite its significance, the role of disulfidptosis in the tumor microenvironment (TME) remains poorly understood. Methods: In this study, we employed single-cell RNA sequencing data from 100,987 cells of 11 osteosarcoma (OS) patients. Using the non-negative matrix factorization (NMF) algorithm, we performed dimensionality reduction analysis to identify distinct subtypes characterized by 14 disulfidptosis-related genes across major cell types within the TME. Subsequently, we assessed the prognosis and immunotherapy response associated with each disulfidptosis-related subtype, leveraging publicly available databases comprising osteosarcoma data and immunotherapy cohorts. Results: We identified distinct subtypes within tumor-associated fibroblasts, tumor-infiltrating lymphocytes, and macrophages, which we named and annotated based on their characteristic genes. Furthermore, we observed a close association between disulfidptosis-related genes and key biological features of immune cells within the TME, elucidating inferred pseudotime trajectories. Notably, integrating bulk-seq data of osteosarcoma patients, we observed significant differences in overall survival rates among the disulfidptosis-related subtypes. Particularly, the disulfidptosis-related subtype within tumor-associated fibroblasts exhibited superior discriminatory ability in predicting the response of patients undergoing immunotherapy, surpassing other cell subtypes. Our cell-cell communication analysis highlighted extensive and specific interactions between disulfidptosis-related subtypes and osteosarcoma cells. Furthermore, we confirmed the histological localization of the CAPZB+CAF subtype within osteosarcoma tissue and osteoclastoma using immunofluorescence (IF) techniques. Conclusions: Collectively, our study sheds light on the intercellular communication facilitated by disulfidptosis in the TME, underscoring its involvement in the biological functions and immunotherapy response of osteosarcoma.

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance, culminating in relapse and metastatic disease continue to be associated with fatal disease. Cancer stem cells (CSCs) are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterised in many cancers with data illustrating that CSCs display great abilities to self-renew, withstand therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ABC membrane transporters, activation of several survival signaling pathways and increased immune evasion DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we re-visit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

With increasing constraints on energy and resource markets and the non-decreasing trend in energy demand, the need for relevant clean energy generation and storage solutions is growing and is gradually reaching the individual home. But small-scale energy storage is still an expensive investment in 2022 and the risk/reward ratio is not yet attractive enough for individual homeowners. One solution is for homeowners not to store excess clean energy individually but to produce hydrogen for mutual use. In this paper a collective production of hydrogen for a daily filling of a bus is considered. Following our previous work on the subject, the investigation consists of finding an optimal buy/sell rule to the grid, and the use of the energy with an additional objective: mobility. The dominant technique in the energy community is reinforcement learning, which is however difficult to use when the learning data is limited as in our study. We chose a less data-intensive and yet technically well-documented approach. Our results show that rulebooks, different but more interesting than the usual robust rule, exist and can be cost-effective. But they require fine-tuning as to not deteriorate system performance. In some cases, it is worth missing the H2 production requirement in exchange for higher economic performance.

Glioblastoma multiforme (GBM) and malignant gliomas are the most common primary malignant brain tumors. Temozolomide (TMZ) chemotherapy plus radiation therapy (RT), admi-nistered after debulking surgery, increased median survival time (MST) from 12.1 months with RT alone merely to 14.6 months. In this study, the action of deuterium-depleted water (DDW) on the survival of GBM patients who also received conventional therapies was investigated. Without changing the conventional treatment, the daily fluid intake of the patients was wholly replaced with DDW in 1.5-2 liters per day volume to reduce D concentration in their bodies. The primary endpoint was MST. The 55 patients involved, receiving conventional treatment and consuming DDW, showed longer MST (30 months) compared to the historical control (12.1-14.6 months). There was a massive difference between the two genders in the calculated MST values; it was 25 months in the male subgroup (n=33) and 42 months in the female subgroup (n=22). MST was 27 months without TMZ treatment (38 patients) and 42 months in the TMZ-treated group (17 patients). For the selected 31 patients, who consumed DDW in the correct way in addition to conventional treatments, MST was 30 months. Within this group, the 20 subjects who had relapsed before DDW treatment had 30 months of MST, but in those 10 subjects who were in remission when DDW treatment started, MST was 47 months. In the subgroup of patients who started DDW treatment parallel with radiotherapy, MST was 47 months again, and it was 25 months when DDW treatment started 8 weeks or later after the completion of radiotherapy. Altogether, survival times were substantially prolonged, compared to prospective clinical data of patients with primary GBM. Consequently, if conventional therapies are supplemented with D depletion, better survival is achieved in advanced stage of GBM than with the known targeted or combination therapies. Application of DDW is recommended in all stages of the disease, before surgery, parallel with radiotherapy, and repeated DDW courses are advised when remission has been achieved.

Ral-interacting protein 76 (RLIP76) is a potential factor with vascular endothelial growth factor (VEGF) in the corpus luteum and tumor angiogenesis. RLIP76, VEGF, and hypoxia-inducible factor-1 (HIF-1) are proteins that activate angiogenic functions in tumor and endothelial cells. RLIP76 is a main factor in tumor growth, and VEGF is a major endothelial cell protein for angiogenesis. Also, RLIP76 regulates a small GTPase (R-Ras, oncogene) in cell survival, spreading, and migration. HIF-1 is important in the corpus luteum, tumor angiogenesis, and tumor growth. VEGF and HIF-1 regulate the angiogenic function of RLIP76, and RLIP76 controls vascular growth in endothelial and tumor cells. RLIP76, R-Ras, VEGF, and HIF-1 may be useful in the research of corpus luteum and cancer therapy and the study of mechanisms of tumor angiogenesis. This review will help to elucidate the roles of RLIP76/R-Ras and VEGF via HIF-1 in corpus luteum and tumor angiogenesis, tumorigenesis, and the specific regulation of RLIP76 in luteal, tumor, and endothelial cells. Thus, we reviewed the angiogenesis of the corpus luteum and tumor in the ovarian and tumor microenvironment.

Background: Recent researches have investigated the biological importance of RNA N1-methyladenosine (m1A) modifications in oncogenesis and progression of head and neck squamous cell carcinoma (HNSCC). However, whether m1A modifications also have latent effect in tumor microenvironment (TME) generation and immune regulation in HNSCC is unknown. Methods: We evaluated the m1A modification patterns and related to these modification patterns with TME cell infiltration features in 1041 HNSCC samples by bioinformatics approach. Results: The m1A score is an independent prognostic indicator. HNSCC patients with low m1A score group with poor overall survival (OS) was mainly characterized by stroma activation, lack of sufficient immune infiltration, and exhibited an immune- desert TME phenotype. Low m1A scores were also correlated with increased tumor mutation burden (TMB), and HNSCC patients with high TMB and low m1A scores had the worst OS. In addition, anti-CTLA-4 combined with anti-PD1 treatment was more effective in the high m1A score subgroup than in the low m1A score subgroup. Conclusions: This study revealed that m1A modifications play a non-negligible role in developing the TME versatility and complexity of HNSCC. Assessing m1A modification patterns in HNSCC helps improve our comprehension of its TME infiltration profile and guides more effective immunotherapeutic approaches.

The Na+/K+ ATPase is a protein involved in the active transport of ions across the cellular membrane. Ouabain is a cardiotonic glycoside that, by inhibiting the Na+/K+ pump, interferes with cell processes mediated directly by the pump, but also indirectly influences other cellular processes, such as cellular cycle and proliferation, growth, cell differentiation, angiogenesis, migration, adhesion and invasion. We used the SK-BR-3 breast cancer cell line, mesenchymal stem cells (MSCs), and tumor-associated fibroblasts (TAFs) in vitro for determining the changes induced by Ouabain in concentration of 10-5 M, 10-6 M, 10-8 M, 10-9 M on these cellular types, employing specific methods: SEM for morphological evaluation; immunocytochemistry, flowcytometry to assess immunophenotypical markers expression, cell cycle and Annexin V/PI assay for cellular proliferation and viability testing; flowchamber assay to evaluate functional adhesion behavior; RT-PCR for Na+/K+ ATPase subunits molecular expression. Being indicative of the pro-apoptotic and inhibitory effect of Ouabain on tumor invasion and metastasis, the results support the addition of Ouabain to the oncological therapeutic arsenal, trailing the “repurposing drugs” approach.

With the rapid and continuous advancement and deployment of advanced energy storage de-vices, there has been significant interest in aqueous capacitors that possess non-flammable properties and high safety features. Consequently, extensive research efforts have focused on investigating zinc anodes and low-cost carbonaceous cathode materials. Despite these efforts, the development of high-performance zinc-ion capacitors (ZICs) still faces challenges such as limited cycling stability and low energy densities. In this study, we present a novel approach to address these challenges. We demonstrate the utilization of a three-dimensionally (3D) grown conductive porous carbon framework cathode coupled with zinc anode cells, which exhibit exceptional sta-bility and durability in ZICs. Our experiments reveal a remarkable cycling performance, with a capacity retention of approximately 97.3% and a coulombic efficiency of nearly 100% even after 10,000 charge-discharge cycles. These findings signify significant progress in enhancing the performance of ZICs.

Uveal melanoma (UM) is the most common primary cancer of the eye and is associated with a high rate of metastatic death. UM can be stratified into two main classes based on metastatic risk, with class 1 UM having a low metastatic risk and class 2 UM having a high metastatic risk. Class 2 UM have a distinctive genomic, transcriptomic, histopathologic, and clinical phenotype characterized by biallelic inactivation of the BAP1 tumor suppressor gene, an immune suppressive microenvironment enriched for M2-polarized macrophages, and poor response to checkpoint inhibitor immunotherapy. To identify potential mechanistic links between BAP1 loss and immune suppression in class 2 UM, we performed an integrated analysis of UM samples, as well as genetically engineered UM cell lines and uveal melanocytes (UMC). Using RNA sequencing (RNA-seq), we found that the most highly up-regulated gene associated with BAP1 loss across these datasets was PROS1, which encodes a ligand that triggers phosphorylation and activation of the immunosuppressive macrophage receptor MERTK. The inverse association between BAP1 and PROS1 in class 2 UM was confirmed by single-cell RNA-seq, which also revealed that MERTK was up-regulated in CD163+ macrophages in class 2 UM. Using ChIP-seq, BAP1 knockdown in UM cells resulted in an accumulation of H3K27ac at the PROS1 locus, suggesting epigenetic regulation of PROS1 by BAP1. Phosphorylation of MERTK in RAW 264.7 monocyte-macrophage cells was increased upon co-culture with BAP1-/- UMCs, and this phosphorylation was blocked by depletion of PROS1 in the UMCs. These findings were corroborated by multi-color immunohistochemistry, where class 2/BAP1-mutant UMs demonstrated increased PROS1 expression in tumor cells and increased MERTK phosphorylation in CD163+ macrophages compared to class 1/BAP1-wildtype UMs. Taken together, these findings provide a mechanistic link between BAP1 loss and suppression of the tumor immune microenvironment in class 2 UMs, and they implicate the PROS1-MERTK pathway as a potential target for immunotherapy in UM.

Research on fall and movement detection with wearable devices has witnessed promising growth. However, there are few publicly available datasets, all recorded with smartphones, that prevent authors to evenly compare their new proposals. Here, we present a dataset of falls and activities of daily living (ADL) acquired with a self-developed device composed of two types of accelerometer and one gyroscope. It consists of 19 ADL and 15 fall types performed by 23 young adults, 15 ADL types performed by 14 healthy and independent participants over 62 years old, and data from one participant of 60 years old that performed all ADL and falls. These activities were selected based on a survey and a literature analysis. We test the dataset with widely used feature extraction and a simple to implement threshold based classification, achieving up to 96~\% of accuracy in fall detection. An individual activity analysis demonstrates that most errors coincide in a few number of activities where algorithms could be focused on. Finally, validation tests with elderly people significantly reduced the fall detection performance of the tested features. This validates findings of other authors and encourages to develop new strategies with this new dataset as benchmark.

The apicomplexan parasite, Sarcocystis neurona causes the degenerative neurological equine protozoal myeloencephalitis (EPM) disease of horses. Due to its host range expansion, S. neurona is an emerging threat that requires close monitoring. In apicomplexans, protein kinases (PKs) have been implicated in a myriad of critical functions such as host cell invasion, cell cycle progression and host immune responses evasion. Here, we used various bioinformatics methods to define the kinome of S. neurona and phylogenetic relatedness of its PKs to other apicomplexans. Further, three-dimensional (3D) homology models for selected S. neurona putative PKs were constructed and evaluated for inhibitor docking. We identified 92 putative PKs clustering within the AGC, CAMK, CK1, CMGC, STE, TKL, aPK and OPK groups. Although containing the universally conserved PKA (AGC group), S. neurona kinome was devoid of PKB and PKC, but contained the six apicomplexan conserved CDPKs (CAMK group). The OPK group was represented by ROPKs 19A, 27, 30, 33, 35 and 37, but was devoid of the virulence-associated ROPKs 5, 6, 18 and 38. Two out of the three S. neurona CK1 enzymes had high sequence similarities to T. gondii TgCK1-α and TgCK1-β and the Plasmodium PfCK1. Docking of four inhibitors onto homology models of putative ROP27 and PKA indicated that inhibition of S. neurona PKs is feasible, but needs to be experimentally tested. The essentiality of apicomplexan PKs makes the elucidation of S. neurona kinome a key milestone for development of novel therapeutics for EPM.

Despite the numerous advances in target therapy for the treatment of colorectal cancer, aggressive colorectal cancer remains an incurable disease whose negative modulation of the immune system in the tumor microenvironment is still critical for improving the patient's prognosis. Extracellular vesicles (EVs) have received attention for their use as cell-membrane-camouflaged nanoparticles and drug delivery systems in nanomedicine derived by nearly all cell types for intercellular communication and regulation in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), or combined together with retinoic acid and Libidibia ferrea (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines, as well as their capacity to prevent metastases in mouse models of colorectal cancer such as allographic and peritoneal. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or especially combined (M1EV4) downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastases in peritoneum, liver and lungs. STAT3, NF-kB and AKT were the major genes downregulated by systems of M1EVs. Tumor-associated macrophages (TAM) switched M2 phenotype (CD163) towards M1 (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR-1, survivin, vimentin, CXCR4, and PD-L1 after treatment with systems of M1EVs. The results obtained in this study provided evidence that EVs from M1 antitumor macrophages can transport drugs and increase their immunomodulatory and antitumor activity by stimulating activation or blockage of pathways involved in cell proliferation, migration, cell survival, and drug resistance processes.

Central adiposity is one of the significant determinants of obesity-related hypertension risk, which may arise due to the abdominal fat depot's pathogenic inflammatory nature. Pro-inflammatory cytokines and adipokines up-regulation through nuclear factor-kappa B (NF-κB) activation in adipose tissue has been considered an essential function in the pathogenesis of obesity-related hypertension. This study aimed to ascertain the NF-κB inhibitor (SN50) effect on TNF-α and angiotensinogen (AGT) secretion and expression in mediating the anti-inflammatory effect through its impact on NF-κB activity in humans adipose tissue. Primary human adipocytes were isolated from 20 subjects among 10 overweight and 10 obese with and without hypertension and treated with 10ng/ml LPS in the presence and absence of NF-κB inhibitor, SN50 (50μg/ml). TNF-α secretion and NF-κB p65 activity were detected in supernatants extracted from cultured cells treated and untreated with LPS (10ng/ml) and SN50 (50μg/ml) using enzyme-linked immunosorbent assay (ELISA). The western blot technique detected the protein of NF-κB p65 and AGT. Gene expression of TNF-α and AGT was detected in cells and performed using quantitative real-time polymerase chain reaction (RT-PCR). Treatment of AbdSc adipocytes with LPS (10ng/ml) caused a significant increase in NF-κB p65 among overweight and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. In contrast, SN50-NF-κB inhibitor causes a reduction of NF-κB p65 in overweight (P= <0.001) and obese subjects with and without hypertension (P= 0.001) at 24 hours incubation. Treatment of AbdSc adipocytes with 10ng/ml LPS caused a significant increase in TNF-α secretion in overweight and obese subjects at all-time points (P= <0.001), whereas SN50 leads to a decrease in TNF-α secretion at 3 and 12 hours incubation. Treatment of AbdSc adipocytes with LPS (10ng/ml) caused increased TNF-α and AGT gene expression twofold compared with untreated cells, whereas, in the presence of SN50, it reduces mRNA AGT levels in both groups. Taken together, these adipokines with NF-κB activation may represent essential biomarkers to evaluate hypertension risk and to provide insight into the pathogenesis of obesity-related hypertension.

The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and non-tumoral cells. The success of TME-targeted therapies highlights their potential in achieving better cancer control or even a cure.

The tumor microenvironment (TME) plays a critical role in cancer progression and treatment outcomes. Despite advances in cancer research, many therapeutic strategies have failed to provide the desired clinical outcomes. In this integrated review, aimed to explore the role of TME in cancer biology and develop novel therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Study conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases for articles published between 2016 and 2022. Inclusion of articles that discussed the impact of TME on cancer development and progression, as well as articles that proposed novel therapeutic strategies targeting the TME. The analysis of the literature revealed that the TME plays a crucial role in cancer development and progression by promoting cancer cell survival, angiogenesis, invasion, and metastasis, and by interfering with the efficacy of cancer therapies. The TME is composed of a complex network of non-cancerous cells, extracellular matrix components, and signaling molecules that interact with cancer cells. Several novel therapeutic strategies have been proposed based on the modulation of TME components. One of the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. These approaches have shown promising results in preclinical studies and clinical trials. The TME plays a critical role in cancer development and progression, and targeting its components represents a promising avenue for cancer therapy. Novel therapeutic strategies such as immunotherapy, extracellular matrix-targeting drugs, and nanoparticle-based therapies have shown promising results in preclinical studies and clinical trials. However, further research is needed to identify the most effective strategies and to overcome the challenges associated with TME targeting.

Background: Prostate cancer (PCa) is characterized by significant heterogeneity in its molecular, genomic, and immunologic characteristics. Methods: Whole transcriptome RNAseq data from The Cancer Genome Atlas of prostate adenocarcinomas (n=496) was utilized. The immune microenvironment was characterized using the CIBERSORTX tool to identify immune cell type composition. Unsupervised hierarchical clustering was performed based on immune cell type content. Analyses of progression-free survival (PFS), distant metastases, and overall survival (OS) were performed using Kaplan-Meier estimates and Cox-regression multivariable analyses. Results: Four immune clusters were identified, largely defined by plasma cell, CD4+ Memory Resting T Cells (CD4 MR), M0 and M2 macrophage content (CD4 MRHighPlasma CellHighM0LowM2Low, CD4 MRLowPlasma CellHighM0LowM2Low, CD4 MRHighPlasma CellLowM0HighM2Low, and CD4 MRHighPlasma CellLowM0LowM2High). The two macrophage-enriched/plasma cell non-enriched clusters (3&4) demonstrated worse PFS (HR 2.24, 95% CI 1.46–3.45, p=0.0002) than the clusters 1&2. No metastatic events occurred in the non-macrophage-enriched clusters. Comparing clusters 3 vs 4, in patients treated by surgery alone, cluster 3 had zero progression events (p<0.0001). However, cluster 3 patients had worse outcomes after post-operative radiotherapy (p=0.018). Conclusion: Distinct tumor immune clusters with a macrophage-enriched phenotype and reduced plasma cell enrichment independently characterize an aggressive phenotype in localized prostate cancer that may differentially respond to treatment.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association to survival in cancer patients. The molecular mechanisms that underpins the oncogenic activity of STAT3/5 signaling includes the regulation of genes that control cell cycle, cell death, inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling including the p19ARF/p53 pathway, tyrosine phosphatases, suppressor of cytokine signaling 1 and 3, the sumo ligase PIAS3, the E3 ubiquitin ligase TMF/ARA160 and the miRNAs miR-124 and miR-1181. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated to STAT3/5 signaling explaining their context dependent association to tumor progression both in human cancers and animal models.

Marine renewable energy is emerging as one of the fast-growing industry in the last decades, as modern society pushes for technologies that can convert energy contained from winds, waves, tides and stream flows. The implementation of renewable energy technologies impose high demands on both structural and environmental engineering, as the energy converters have to work under extreme conditions where parameters such as sea-bottom configuration, water transparency and depth, sea-states and prevailing winds are harsh. Constant monitoring of the marine environment is crucial in order to keep this sector reliable. Active acoustics is becoming a standard tool to collect multi-dimensional data from physical, geological and biological properties of the marine environment. The Div. of Electricity of Uppsala University have been developing an environmental monitoring platform based on sonar (Sound Navigation And Raging) systems. This platform aims to monitor the installation, operation and decommissioning of marine renewable energy converters. The focus will be given the observations of behaviours of marine animals in vicinity of energy converters but also structural inspection and monitoring of MRETs. This paper describes how this multifunctional environmental monitoring platform come to existence from the design to the deployment phase.

The objective of this study is to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the equivalence ratio distributions and the injected fuel droplet behavior in the cylinder of the RCCI engine. The spray simulation was conducted by dividing two-part. First, the spray validation simulations progressed to find the spray-influenced factor of the test injector. Next, the engine simulations were performed with the spray-influenced factor obtained from spray validation simulations to investigate the effect of the premixed ethanol ratio based on the same total heating value in-cylinder on the injected fuel atomization and the equivalence ratio distributions. The introduced total heating value was fixed at 595J based on the lower heating value of diesel 14mg. The heating value of the premixed ethanol ratio varied from 0% to 40% based on the same total heating value in-cylinder in steps of 10%. It was revealed that when the premixed ethanol ratio based on the same total heating value in-cylinder was increased, the spray tip penetration value was reduced from the time after 4deg of diesel injection start because of the short injection duration by the small amount of diesel fuel. The SMD value was also more enormous up to 32.58% with increasing the premixed ethanol ratio because of the low kinetic energy of the injected fuel by the short injection duration and the slow evaporation of the injected fuel by the low cylinder temperature.

Small and micro hydropower represents an attractive solution for electricity generation, with low cost and low environmental impact. The pump-as-turbine (PAT) approach has promise in this application owing to its low purchase and maintenance costs. In this paper, a new method to predict the inverse characteristic of industrial centrifugal pumps is presented. This method is based on results of simulations performed with commercial three-dimensional CFD software. Model results have been first validated in pumping mode using data supplied by pump manufacturers. Then, results have been compared to experimental data for a pump running in reverse condition. Experimentation has been performed on a dedicated test bench installed in the Department of Civil Construction and Environmental Engineering of the University of Naples Federico II. Three different pumps, with different specific speeds, have been analyzed. Using the model results, the inverse characteristic and the best efficiency point have been evaluated. Finally, results of this methodology have been compared to prediction methods available in the literature.

Glioblastoma (GBM) is the most common primary brain tumor in adults, with few available therapies and a 5-year survival rate of 7.2%. Hence, strategies for improving GBM prognosis are urgently needed. The translocator protein 18kDa (TSPO) plays crucial roles in essential mito-chondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide pol-ymorphism, rs6971, which is the most common SNP in the Caucasian population. High TSPO gene expression is associated with reduced survival in GBM patients; however, the relation between the most frequent TSPO genetic variant and GBM pathogenesis is not known. The present study ret-rospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. TSPO rs6971 poly-morphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort of 441 patients. We observed similar trends in two other independent cohorts. These observations suggest that the TSPO rs6971 pol-ymorphism could be a significant predictor of poor prognosis in GBM, with a potential for use as a prognosis biomarker in GBM patients. These results reveal for the first time a biological sex-specific relation between rs6971 TSPO polymorphism and GBM.

Glioblastoma is the most common and malignant primary brain tumor. Despite a century of research efforts, the survival of patients has not significantly improved. Currently, diagnosis is based on neuroimaging techniques followed by histopathological and molecular analysis of resected or biopsied tissue. A recent paradigm shift in diagnostics ranks the molecular analysis of tissue samples as the new gold standard over classical histopathology, thus correlating better with the biological behavior of glioblastoma and clinical prediction, especially when a tumor lacks the typical hallmarks for glioblastoma. Liquid biopsy aims to detect and quantify tumor-derived content, such as nucleic acids (DNA/RNA), circulating tumor cells (CTC), or extracellular vesicles (EV) in biofluids, mainly blood, cerebrospinal fluid (CSF), or urine. Liquid biopsy has the potential to overcome the limitations of both neuroimaging and tissue-based methods to identify early recurrence and to differentiate tumor progression from pseudoprogression, without the risks of repeated surgical biopsies. This review highlights the origins and time-frame of liquid biopsy in glioblastoma and points to recent developments, limitations and challenges of adding liquid biopsy to support the clinical management of glioblastoma patients.

Abstract: Autophagy has a dual role in gliomagenesis in a microRNA-modulated environment. We investigated the potential relevance of autophagy in glioma development and survival by exploring the association of autophagy-associated genes and microRNAs in low- and high-grade gliomas. Real-time PCR (qPCR) was used to determine the expression of genes and microRNAs in 50 fresh glioma tissues while Formalin-fixed paraf-fin-embedded tissues of the same patients were used for immunohistochemistry. The Mann-Whitney U-test test, Spearman correlation test, and Kaplan-Meier survival analysis were performed to evaluate the expression, association, and overall survival in patients respectively. The expression of LC3, AKT, and miR-21 was increased in high-grade glioma compared to low-grade glioma while ULK2 expression was decreased in high-grade glioma. A strong positive correlation was observed for ULK2 with UVRAG, PTEN, miR-7, and miR-100, while the moderate correlation with mTOR, Beclin1, miR-30, miR-204, miR-374, miR-21 and miR-126 in low-grade glioma, while a moderate positive correlation between ULK2 and PI3K, PTEN, ULK1, VPS34, mTOR, Beclin1, UVRAG, AKT and miR-374, and between AKT and ULK1, VPS34, UVRAG, and miR-7 in high-grade gliomas. The low ULK2 and LC3 expression group was significantly associated with better overall survival in gliomas while miR-21 overexpression showed a poor prognosis in glioma patients. Therefore, miR-21, ULK2, and LC3 may serve as prognostic biomarkers for survival outcomes in glioblastoma.

Tocilizumab against interleukin-6 receptor (IL-6R) has been demonstrated to inhibit the progression of diverse cancers in vitro and in vivo. Nonetheless, evidence regarding the anti-tumor effects of Tocilizumab on human colorectal carcinoma (CRC) corresponding to IL-6R expression levels re-mains scarce. To investigate the influence of IL-6R expression, SW480 and HT-29 cells inoculated subcutaneously into NU/NU mice were used as our human CRC xenograft models with anti-IL-6R antibody (Tocilizumab) therapy. IL-6R expression levels, the histology of CRC growth/ invasiveness and tumor growth-related signaling pathway were estimated by H&E and immunohistochemical staining. SW480 tumor cells with higher IL-6R expression levels exerted better responsiveness in Tocilizumab therapy than the treated HT-29 group. Likewise, therapeutic effects of Tocilizumab on the proliferative ability with mitotic index and Ki-67 expressions, the invasiveness with MMP-9 proteinase expressions, ERK 1/2 and STAT3 signaling transduction in SW480 treatment group were superior to HT-29 treatment group. In light of our results, IL-6R is the key indicator for the efficacy of Tocilizumab treatment in CRC xenografts. From the perspective of precision medicine, tumor response to anti-IL-6R antibody therapy could be predicted on the basis of IL-6R expression levels. In this manner, Tocilizumab may serve as a targeted and promising anti-CRC therapy.

There is a relationship between systemic sarcoidosis (SS) and malignancy. Sarcoidosis results from an exaggerated immune response in genetically susceptible individuals. In oncologic pa-tients with sarcoidosis, tumoral antigens and antineoplastic treatment are considered potential triggering factors. The observation of a patient with granulomas in a parotid carcinoma that later developed SS led us to review previous tumors of patients with SS. The aim of the study is to see if granulomas were already present in the tumors that preceded sarcoidosis. We identified 196 sarcoidosis patients, 47 of which had a previous tumor. We were able to review 29 cases 12 of which showed tumor associated granulomas (TAGs)(41.4%). This ratio is much higher than that of the normal population. We analyzed five control patients without sarcoidosis for each tumor. In conclusion, we have observed TAGs in patients who later develop SS. In our series, the ratio of TAGs in patients with SS was significantly greater than in the normal population. To prove our findings, we suggest reviewing the history of patients with SS in search of previous tumors. The histology of such tumors should be reviewed in an attempt to identify granulomas.

The paper presents the findings of research on companies in the early stage of development based on the concept of ensuring their sustainability. The starting point is attributes shaping a sustainable model of start-ups. A solution has been proposed and examined that identifies the factors dynamising a business model, which give the company the ability to make fast changes in the configuration of the business model, and that applies stabilizing factors based on the concept of the Triple Bottom Line. The research problem is a response to the phenomena of the bankruptcy of many start-ups that cannot find a way to survive in the long term. The business models of companies in the early stage of development should be designed taking into account the possibility of their dynamic and iterative changes when the earlier assumptions do not work when implemented in practice. A cognitive gap has been observed as the relevant literature does not propose a systemic solution to the problem of instability of the startups viewed from the perspective of the business model concept. The research problem, therefore, is to identify potential new methods to ensure the sustainability of young companies trying to combine aspects dynamising changes in business models, taking into account economic, environmental and social aspects. The findings of research on companies in the early stage of development show that when the methods of increasing the flexibility of the business model are applied and attention is drawn to environmental and social activities and a strong emphasis is put on financial performance, reflecting the expectations of shareholders, the concept of ensuring the sustainability of young companies from the point of view of sustainable business model attributes emerges.

The precise molecular basis of anti-tumor immunity is not yet fully understood, although commensal Bifidobacterium (c-BIF) is expected to be one of the key players in cancer control via antigenic mimicry. We investigated the sequence similarity between c-BIF and cytotoxic T lymphocyte (CTL) epitope peptides against human tumor-associated antigens to better understand the molecular basis of antigenic mimicry. We used two different similarity analyses for this purpose, a linear sequence analysis and a similarity analysis of T cell receptor (TCR)-mediated recognition of CTL epitope peptides on antigen-presenting cells. The linear sequence analysis revealed 3,900 positive numbers of similarity sites between them with 126 mean per peptide and 107 median per peptide, while the TCR-mediated recognition analysis revealed 5,018 positive numbers with a mean of 162 and median of 132 per peptide. These results demonstrated the existence of durable and abundant sequence similarities between c-BIF and CTL epitope peptides, suggesting that the former play a pivotal in inducing cellular and humoral immunity against the latter in the absence of cancer cells via antigenic mimicry.

More than 1 million women are diagnosed annually worldwide with a gynecological cancer. Most gynecological cancers are diagnosed at late stage, either because lack of symptoms such as in ovarian cancer or limited accessibility to primary prevention in low-resource countries such as in cervical cancer. Here, we extend the studies of AR2011, a stroma-targeted and tumor microenvironment responsive oncolytic adenovirus (OAdV) whose replication is driven by a triple hybrid promoter. We show that AR2011 was able to replicate and lyse in vitro fresh explants obtained from human ovarian cancer. uterine cancer, and cervical cancer. AR2011 was also able to strongly inhibit the in vitro growth of ovarian malignant cells obtained from human ascites fluid. The virus could synergize in vitro with cisplatin even on ascites-derived cells obtained from patients heavily pretreated with neoadjuvant chemotherapy. AR2011(h404) a dual transcriptionally targeted derived virus armed with hCD40L and h41BBL under the regulation of the hTERT promoter, showed a strong efficacy in vivo both on subcutaneous and intraperitoneally established human ovarian cancer in nude mice. Preliminary studies in an immunocompetent murine tumor model showed that AR2011(m404) expressing the murine cytokines was able to induce an abscopal effect. The present studies suggest that AR2011(h404) is a likely candidate as a novel medicine for intraperitoneal disseminated ovarian cancer.

Papillary thyroid cancer (PTC) is the most common endocrine malignancy which diagnosis and recurrences still challenge clinicians. New perspectives to overcome those issues could come from the study of extracellular vesicles (EVs) populations and content. Here, we aimed to elucidate the heterogeneity of EVs circulating in tumor and the changes in their microRNA content during cancer progression. Using a mouse model expressing BRAF^V600E, we isolated and characterized EVs from thyroid tissue by ultracentrifugations and elucidated their microRNA content by small RNA sequencing. Cellular origin of EVs was investigated by ExoView and that of deregulated EV-microRNA by qPCR on FACS-sorted cell populations. We found that PTC released more EVs bearing epithelial and immune markers, as compared to healthy thyroid, and that changes in EV-microRNAs abundance were mainly due to their deregulated expression in thyrocytes. Pathway analysis showed that the more abundant EV-microRNAs could impact on immune processes. Altogether, our work provides a full description of in vivo-derived EVs produced by, and within, normal and cancerous thyroid. We elucidated the global EV-microRNAs signature, the dynamic loading of microRNAs in EVs upon BRAF^V600E induction, and their cellular origin. Thyroid tumor-derived EV-microRNAs could support the establishment of a permissive immune microenvironment.

Extracellular vesicles (EV), including exosomes and microvesicles, are released from various cells and alter recipient cell phenotypes and fates by their biomolecules. Here we review current knowledge about tumor EVs and how they prompt malignant cell communication with tumor-associated cells, such as cancer-associated fibroblasts, tumor endothelial cells, and immune cells. We delineate the major pathways and molecular players that influence each step of cancer initiation, progression, and resistance. Of note, cancer exosomes involve immunosuppression by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells. Moreover, tumor exosomes can induce the apoptosis of killer T cells and immune checkpoint of dendritic cells and attenuate natural killer cells. An in-depth understanding of EV biology is essential to ensure the clinical development of exosome/EV-based therapeutic products, which will be of benefit to exosome manipulation in cancer management.

The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges identified up-to-date in this field are summarized.

Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.

As a fundamental, overall, and strategic issue facing human society, human migration is a key factor affecting the development of countries and cities given constantly changing population numbers. The fuzziness of the spatiotemporal attributes of human migration limits the pool of open-source data for human migration prediction, leading to a relative lag in human migration prediction algorithm research. This study expands the definition of human migration research, reviews the progress of research into human migration prediction, and classifies and compares human migration algorithms based on open-source data. It also explores the critical uncertainty factors restricting the development of human migration prediction. Given the effect of human migration prediction, in combination with artificial intelligence and big data technology, the paper concludes with specific suggestions and countermeasures aimed at enhancing human migration prediction research results to serve economic and social development and national strategy.

Remote sensing datasets are increasingly being used to provide spatially explicit large scale evapotranspiration (ET) estimates. The focus of this study was to estimate and thematically map on a pixel-by-pixel basis, the actual evapotranspiration (ET_a) of the Wonji Shoa Sugarcane Estate using the Surface Energy Balance Algorithm for Land (SEBAL), Simplified Surface Energy Balance (SSEB) and Operational Simplified Surface Energy Balance (SSEBop) algorithms. The results obtained revealed that the ranges of the daily ETa estimated on January 25, February 26, September 06 and October 08, 2002 using SEBAL were 0.0 - 6.85, 0.0 – 9.36, 0.0 – 3.61, 0.0 – 6.83 mm/day; using SSEB 0.0 - 6.78, 0.0 – 7.81, 0.0 – 3.65, 0.0 – 6.46 mm/day, and SSEBop were 0.05 - 8.25, 0.0 – 8.82, 0.2 – 4.0, 0.0 – 7.40 mm/day, respectively. The Root Mean Square Error (RMSE) values between SSEB and SEBAL, SSEBop and SEBAL, and SSEB and SSEBop were 0.548, 0.548, and 0.99 for January 25, 2002; 0.739, 0.753, and 0.994 for February 26, 2002;0.847, 0.846, and 0.999 for September 06, 2002; 0.573, 0.573, and 1.00 for October 08, 2002, respectively. The standard deviation of ET_a over the sugarcane estate showed high spatio-temporal variability perhaps due to soil moisture variability and surface cover. The three algorithm results showed that well watered sugarcane fields in the mid-season growing stage of the crop had higher ET_a values compared with the other dry agricultural fields confirming that they consumptively use more water. Generally during the dry season, ET_a is limited to water surplus areas only and in wet season, ET_a was high throughout the entire sugarcane estate. The evaporation fraction (ETrF) results also followed the same pattern as the daily ET_a over the sugarcane estate. The total crop and irrigation water requirement and effective rainfall estimated using the Cropwat model were 2468.8, 2061.6 and 423.8 mm/yr for January 2001 planted and 2281.9, 1851.0 and 437.8 mm/yr for March 2001 planted sugarcanes, respectively. The mean annual ET_a estimated for the whole estate were 107 Mm³, 140 Mm³, and 178 Mm³ using SEBAL, SSEB, and SSEBop, respectively. Even though the algorithms should be validated through field observation, they have potential to be used for effective estimation of ET in the sugarcane estate.

Caveolin-1 (Cav-1) is 22 kDa caveolae protein, acts as a scaffold within caveolar membranes. It interacts with alpha subunits of G-protein and thereby regulates their activity. Earlier studies reported elevated or up-regulated levels of caveolin-1 in the serum of prostate cancer patients. Secreted Cav-1 promotes angiogenesis, cell proliferation and anti-apoptotic activities in prostate cancer patients. Cav-1 upregulation is mainly related to prostate cancer metastasis. Keeping above facts in view, the present study was designed to explore Cav-1 as a target for prostate cancer therapy using computational approach. Molecular docking, structural base molecular modelling and molecular dynamics simulations were performed to investigate Cav-1 inhibitors. A predictive model was generated and validated to establish a stable structure. ZINC database of biogenic compounds was used for induced fit docking (IFD) and high throughput virtual screening. The H-bond interactions of the compounds with active site residues of Cav-1 were estimated by IFD and 100 ns long molecular dynamic simulations. The reported compounds showed significant binding and thus can be considered as potent therapeutic inhibitors of Cav-1. This study provides a valuable insight into biochemical interactions of Cav-1 for therapeutic applications and warrants for experimental validation of the predicted ‘active(s)’.

Macrophages serve as vital defenders, protecting the body by exhibiting remarkable cellular adaptability in response to invading pathogens and various stimuli. These cells express nicotinic acetylcholine receptors, with the α7-nAChR being extensively studied due to its involvement in activating the cholinergic anti-inflammatory pathway. Activation of this pathway plays a crucial role in suppressing macrophages' production of proinflammatory cytokines, thus mitigating excessive inflammation and maintaining host homeostasis. Macrophage polarization, which occurs in response to specific pathogens or insults, is a process that has received limited attention concerning the activation of the cholinergic anti-inflammatory pathway and the contributions of the α7-nAChR in this context. This review aims to present evidence highlighting how the cholinergic machinery in macrophages, led by the α7-nAChR, facilitates the polarization of macrophages towards anti-inflammatory phenotypes. Additionally, we explore the influence of viral infections on macrophage inflammatory phenotypes, taking into account cholinergic mechanisms. We also review the current understanding of macrophage polarization in response to these infections. Finally, we provide insights into the relatively unexplored partial duplication of the α7-nAChR, known as dup α7, which is emerging as a significant factor in macrophage polarization and inflammation scenarios.

Allergic diseases represent a global health and economic burden of increasing significance. The lack of disease-modifying therapies besides specific allergen immunotherapy (AIT) which is not available for all types of allergies, necessitates the study of novel therapeutic approaches. Exosomes are small endosome-derived vesicles delivering cargo between cells and thus allowing inter-cellular communication. Since immune cells make use of exosomes to boost, deviate, or suppress immune responses, exosomes are intriguing candidates for immunotherapy. Here, we review the role of exosomes in allergic sensitization and inflammation and we discuss the mechanisms by which exosomes could be used in immunotherapeutic approaches for the treatment of allergic diseases. We propose the following approaches: a) Mast cell derived exosomes expressing IgE receptor FcεRI could absorb IgE and down-regulate systemic IgE levels. b) Tolerogenic exosomes could suppress allergic immune responses via induction of regulatory T cells. c) Exosomes could promote TH1-like responses towards an allergen. d) Exosomes could modulate IgE-facilitated antigen presentation.

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder that poses a significant public health challenge. Prioritising its prevention is essential for enhancing health at both individual and community levels. With the burgeoning interest in wearable health technologies and individualised nutrition, continuous glucose monitoring systems (CGMs) have expanded their scope, transitioning from exclusive use in diabetes management to lifestyle enhancement for individuals without diabetes (PNLD). While CGMs primarily target glycaemic stabilization, their potential role in mitigating noncommunicable conditions, including T2DM, warrants exploration. This review examines the regulation of CGMs and critically assesses the purported benefits of CGMs for PNLD, as presented in the 'health and wellness' sector: (1) early dysglycaemia detection through glucose variability observation; (2) refining glycaemic control by tailoring nutrition according to postprandial glucose response; and (3) promoting and fine-tuning physical activity based on instantaneous data feedback. The current literature inadequately supports the clinical relevance and lasting impact of these interventions. Moreover, a glaring paucity of research exists on the potential negative consequences of CGM usage, such as obsessive symptom tracking and potential onset of disordered eating behaviours, like orthorexia. This highlights a pressing need to refine CGM regulation in the UK, especially concerning its 'off-label use'. Addressing these research gaps and regulatory issues may enhance the role of CGMs in T2DM prevention strategies and non-communicable diseases among PNLD, ensuring a more unified and effective approach. Current evidence suggests caution in endorsing CGMs as a holistic instrument for T2DM prevention through lifestyle refinement is warranted.

Nowadays molecular research is essential for the better understanding of tumor cells pathophysiology. The increasing number of neoplasms is taken under ‘the molecular magnifying glass’ therefore it is possible to discover complex relationships between cytophysiology and tumor cells. Signal transducer and activator of transcription 3 (STAT3) belongs to the family of latent cytoplasmic transcription factors called STATs which comprises seven members: STAT1, STAT2, STAT3, STAT5A, STAT5B, STAT6. Those proteins play important role in cytokine-activated gene expression by transducing signals from the cell membrane to the nucleus. Abnormal prolonged activation results in tumorigenesis, metastasis, cell proliferation, invasion, migration and angiogenesis. Inhibition of this transcription factor inhibits previously mentioned effects in cancer cells whereas normal cells are not affected. Hence STAT3 might be a viable target for cancer therapy.

Poor survival of human pluripotent stem cells (hPSCs) following freezing, thawing, or passaging hinders maintenance and differentiation in stem cell research. Rho-associated kinases (ROCKs) play a crucial role in hPSC survival. To date, a typical ROCK inhibitor, Y-27632, has been the primary agent used in hPSC research. Here, we report that another ROCK inhibitor, fasudil, can be used as an alternative. Fasudil increased hPSC growth due to survival rather than proliferation following thawing and passaging, similar to Y-27632. It did not affect pluripotency and genetic integrity including mitochondrial genome (mtDNA). Notably, the genes related to metabolism, mTORC1, and TP53 have mainly displayed a faster recovery pattern with ROCK inhibitors than control. Furthermore, fasudil was confirmed as useful for the single dissociation of hPSCs and for aggregation. It also increased retinal pigment epithelium (RPE) differentiation and the survival of neural crest cells during differentiation. These findings suggest that fasudil can replace Y-27632 for use in stem cell research.

Extracellular vesicles (EV) are a very heterogeneous group of cell-derived vesicles released by almost all kind of living cells. EV are involved in intercellular communication, both locally and systemically, since they induce signals and transfer their contents (proteins, lipids, RNAs) to other cells, which subsequently trigger a wide variety of biological responses in the target cells. How-ever, cell surface receptor-induced EV release is limited to cells from the immune system, includ-ing T lymphocytes. T cell receptor activation of T lymphocytes induces secretion of EV containing T cell receptor for antigen and several bioactive molecules, including proapoptotic proteins. These EV are thus specific for antigen-bearing cells, which make them ideal candidates for a cell-free, EV-dependent cancer therapy. In this review we discuss the generation of EV by T lymphocytes and some potential therapeutic approaches of these EV.

Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, a number of mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation, and the impairment of mitochondrial functions has been probed in the pathogenesis of a wide range of illnesses including neurodegenerative diseases. Recently growing number of preclinical studies has revealed that animal behaviors are influenced by the impairment of mitochondrial functions and possibly by the loss of mitochondrial stress resilience. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms including cognitive impairment, mood disorder, anxiety, and psychosis. Mitochondria are multifunctional organelles which produce cellular energy and play a major role in other cellular functions including homeostasis, cellular signaling, and gene expression, among other. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Meanwhile, stress and inflammation have been linked to the activation of the tryptophan (Trp)-kynurenine (KYN) metabolic system, which observably contributes to development of pathological conditions including neurological and psychiatric disorders. This narrative review discusses the functions of mitochondria and the Trp-KYN system, the interaction of the Trp-KYN system with mitochondria, and the current understanding of the involvement of mitochondria and the Trp-KYN system in preclinical and clinical studies of major neurological and psychiatric diseases.

Knowledge on the function of Connexin-43 on macrophages is gradually increasing and recent studies show how macrophages utilise Connexin-43. Migration, antigen-presentation and some forms of intercellular communication in macrophages are Connexin-43-dependant. Delicate processes, such as electrochemical support in conduction of the heartbeat in the AV-node, immunomodulatory regulation in the lungs and macrophage-differentiation are performed using Connexin-43 in macrophages. The relevance on pathophysiology becomes evident in inflammatory bowel disease, tumour networks and HIV in which aberrant function of Connexin-43 has been observed. Although many physiological, as well as pathophysiological functions were found to be Connexin-43-dependant, some still remain debated: the involvement of Connexin-43 in phagocytosis and polarisation, as well as its involvement in the mortality in murine sepsis are still unclear. These functions as well as further involvement in increasingly complex functions of the macrophage pose possible fields of research.

Prostate cancer is a highly heterogeneous disease, and mortality is mainly due to metastases, but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3,929 primary tumors and 2,721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and find that mutations in EYA1 and CSMD3 are associated with poor outcome in prostate cancer.

Neutrophils are the most abundant immune cells and make up about 70% of white blood cells in human blood and play a critical role as the first line of defense in the innate immune response. They also help regulate the inflammatory environment to promote tissue repair. However, in cancer, neutrophils can be manipulated by tumors to either promote or hinder tumor growth depending on the cytokine pool. Studies have shown that tumor-bearing mice have increased levels of neutrophils in peripheral circulation, and that neutrophil-derived exosomes can deliver various cargos, including lncRNA and miRNA, which contribute to tumor growth and degradation of extracellular matrix. Exosomes derived from immune cells generally possess anti-tumor activities and induce tumor-cell apoptosis by delivering cytotoxic proteins, ROS generation, H2O2 or activation of Fas-mediated apoptosis in target cells. Engineered exosome-like nanovesicles have been developed to deliver chemotherapeutic drugs precisely to tumor cells. However, tumor-derived exosomes can aggravate cancer-associated thrombosis through the formation of neutrophil extracellular traps. Despite the advancements in neutrophil-related research, a detailed understanding of tumor-neutrophil crosstalk is still lacking and remains a major barrier in developing neutrophil-based or targeted therapy. This review will focus on the communication pathways between tumors and neutrophils, and the role of neutrophil-derived exosomes (NDEs) in tumor growth. Additionally, potential strategies to manipulate NDEs for therapeutic purposes will be discussed.

Tumor-associated macrophages are a key component in the tumor microenvironment, secreting extracellular vesicles (EVs) such as exosomes and other various factors for intercellular communication. However, macrophage-derived EVs heterogeneity and their cytotoxicity to cancer cells has not been well understood. Here, we aimed to separately isolate various types of macro-phage-EVs by size exclusion chromatography (SEC) method and investigate EV transmission and cytotoxicity to oral cancer cells. For fluorescence-labeling of cellular and EV membranes, palmitoylation signal-fused GFP and tdTomato were expressed in THP-1 monocytic cells and HSC-3 oral cancer cells, respectively. We found that fluorescence-labeled EVs secreted by macrophages were highly transmissive to oral cancer cells than those from parental monocytic cells. In a co-culture system and conditioned medium (CM), a macrophage-secreted unidentified factor was cytotoxic to oral cancer cells. We fractionated macrophage-derived EVs by the SEC method and performed western blotting to characterize various EV types. Three fractions were characterized: small exosomes (EXO-S: < 50 nm) fraction containing HSP90α, HSP90β, CD63 (EV marker) and β-actin; large exosomes (EXO-L: 50-200 nm) fraction containing CD9 (EV marker) and HSP90β; large EVs (100-500 nm) fraction. Notably, the macrophage-derived small exosomes fraction was cytotoxic to oral cancer cells, while large exosomes and large EVs were not. There-fore, it was implicated that macrophage-derived small exosomes are cytotoxic with high trans-mission potential to cancer cells.

Background: This study aimed to evaluate survival rate, marginal bone levels, and full arch prosthetic success on short implants when placed in areas of severely resorbed and edentulous mandibles. Methods: This is a systematic review of all randomized controlled trials of at least 10 patients with a control group in which bone augmentations were performed that were published between January 2010 and February 2023. Only 3 relevant studies met the inclusion criteria. Results: It obtained demonstrate that short-term dental implant survival rates ranged from 94.2% to 97.4% with a 5-year follow-up and the prosthetic success rate varied by 62% during the same follow-up. The mean marginal bone level values ​​of the affected short implants ranged from 0.2 mm to 0.6 mm. Conclusions: The data obtained demonstrated that short dental implants positioned with criterion and precision as a full-arch fixed support are a valid therapeutic choice for the medium-long term rehabilitation of severe edentulous mandibular atrophy.

Purpose Immune responses for cancer cells can be altered according to genetic variation of human leukocyte antigen (HLA). Association of HLA polymorphism with risk of various cancer types is well known. However, the association between HLA and glioblastoma (GBM) remains uncertain. We sought to evaluate the association of HLA polymorphism with risk of GBM development in Koreans. Materials and Methods A case-control study was performed to identify the odds ratios (OR) of HLA class I and II genes for GBM. The control group consisted of 142 healthy Korean volunteers, and the GBM group was 80 patients with newly diagnosed GBM at our institution. HLA class I (-A, -B, and –C) and class II (-DR, -DQ, and –DP) genotyping was performed by high-resolution polymerase chain reaction (PCR)-sequence-based typing (PCR-SBT) methods. Results There were significantly decreased frequencies of HLA-A*26:02 (OR 0.22 CI 0.05-0.98), HLA-C*08:01 (OR 0.29 CI 0.10-0.87), and HLA-DRB1*08:03 (OR 0.32 CI 0.11-0.98), while there was significantly increased frequency of HLA-C*04:01 (OR 2.29 CI 1.05-4.97). In analysis of haplotypes, the frequency of DRB1*14:05-DQB1*05:03 was significantly decreased (OR 0.22 CI 0.05-0.98). Conclusion This study suggests that genetic variations of HLA may affect GBM development in Koreans. Further investigations with larger sample sizes are needed to delineate any potential role of the HLA polymorphisms in the pathogenesis of GBM development.

Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery–Dreifuss muscular dystrophy (EDMD). There has been accumulating evidence that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has still less revealing. Here, we have shown that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus-kinase (JAK). Deletion mutation experiments showed that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacted directly and co-localized with STAT3 in the nuclear membrane. Emerin knockdown induced STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced apoptosis in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin by assembling with BAF and lamin A/C acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induced STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and could be a new therapeutic target for treatment.

Extracellular vesicles (EVs) are involved in intercellular communication during carcinogenesis and cancer cells are able to secrete EVs, in particular exosomes containing molecules, that can be transferred to recipient cells to induce pathological processes and significant modifications, as metastasis, increase of proliferation and carcinogenesis evolution. FZD proteins, a family of receptors comprised in the Wnt signaling pathway, play an important role in carcinogenesis of gastroenteric tract. Here, a still unrecognized role of Frizzled 10 (FZD10) protein was identified. In particular, the presence of FZD10 and FZD10-mRNA in exosomes extracted from culture medium of the untreated colorectal, gastric, hepatic and cholangio cancer cell lines, was detected. A substantial reduction in the FZD10 and FZD10-mRNA level was achieved in FZD10-mRNA silenced cells and in their corresponding exosomes and, concomitantly a significant decrease in viability of the silenced cells compared to their respective controls was observed. Interestingly, the incubation of silenced cells with exosomes extracted from culture medium of the same untreated cells promoted a remarkable restoration of the cell viability and, also, of the FZD10 and FZD10-mRNA level, thus indicating that the FZD10 and FZD10-mRNA delivering exosomes may be potential messengers of cancer reactivation and play an active role in long-distance metastatization

Inflammatory bowel diseases (IBD) includes Crohn's disease and ulcerative colitis, are idiopathic chronic relapsing inflammatory disorders of the intestinal tract. Different studies indicate that phytocanna-binoids, could play a possible role in the treatment of IBD by relieving the symptoms involved in the dis-ease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative-anti-inflammatory effect of nine-selected pure cannabinoids in J774A1 macrophages cells and enteric glial cells (EGC’s) triggered to undergo inflammation with lipopolysaccharide (LPS). The an-ti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNF tran-scription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and tran-scription in EGC’s. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti- inflammatory effect in both J774A1 macrophages and EGC’s compared to the other phy-tocannabinoids tested herein. We then performed RNA-seq analysis of EGC’s exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGC’s revealed 23 differ-entially expressed genes (DEG) compared to treatment with only LPS. Pretreatment with THC resulted in 26 DEG and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments we used the Ingenuity platform. We show that THC treatment affected the mTOR and RAR signaling pathway while THC-COOH affected mainly the IL6 signaling pathway.

Primary sclerosing cholangitis (PSC) is a cholestatic liver disorder frequently associated with ulcerative colitis (UC). Patients with PSC and UC have higher risk of colorectal neoplasia than patients with UC without PSC. Oncogenic properties of micro RNA 346 (miR-346) have been recently reported. In this study we investigated expressions of miR-346 and its two target genes i.e. the receptor of vitamin D (VDR) and the tumor necrosis factor α (TNF-α), which are known to modulate carcinogenesis. Biopsies from ascending and sigmoid colon were obtained from patients with PSC with and without UC, patients with UC and healthy controls. MiR-346 expression was increased in ascending but not sigmoid colon of patients with PSC and UC when compared to other analyzed groups (p<0.001 for all). In patients with UC an exceptionally low colonic expression of miRNA-346 was accompanied by the increase in VDR expression, and the extensive upregulation of TNF-α gene which protein product is known to be cytotoxic to tumor cells at high concentration. In summary, a substantial upregulation of miRNA-346 in ascending colon of patients with PSC and UC may be responsible for the inhibition of VDR and TNF-α signaling -pathway which may result in an inadequate suppression of neoplasia.

This comprehensive review delves into cancer's complexity, focusing on adhesion, metastasis, and inhibition. It explores the pivotal role of these factors in disease progression and therapeutic strategies. This review covers cancer cell migration, invasion, and colonization of distant organs, emphasizing the significance of cell adhesion and the intricate metastasis process. Inhibition approaches targeting adhesion molecules, such as integrins and cadherins, are discussed. Overall, this review contributes significantly to advancing cancer research and developing targeted therapies, holding promise for improving patient outcomes worldwide. Exploring different inhibition strategies revealed promising therapeutic targets to alleviate adhesion and metastasis of cancer cells. The effectiveness of integrin-blocking antibodies, small molecule inhibitors targeting FAK and the TGF-β pathway, and combination therapies underscores their potential to disrupt focal adhesions and control epithelial-mesenchymal transition processes. The identification of as FAK, Src, β-catenin and SMAD4 offers valuable starting points for further research and the development of targeted therapies. The complex interrelationships between adhesion and metastatic signaling networks will be relevant to the development of new treatment approaches.

The concept of targeted drug delivery can be described in terms of the drug’s ability to mimic the other biological objects’ property to localize to target cells or tissues. For example, drug delivery systems based on red blood cells or mimicking some of their useful features, such as long circulation in stealth mode, have been known for decades. On the contrary, therapeutic strategies based on macrophages have gained very limited attention until recently. Here we review two biomimetic strategies associated with macrophages, that can be used to develop new therapeutic modalities: First, the mimicry of certain types of macrophages (i.e., the use of macrophages, including tumor-associated, or macrophage-like particles as a carrier for targeted delivery of therapeutic agents); and Second, the mimicry of ligands, naturally absorbed by macrophages (i.e., the use of therapeutic agents specifically targeted at macrophages). We discuss potential applications of biomimetic systems involving macrophages for the new advancements in treatment of infections, inflammatory diseases, and cancer.