Venous thromboembolism (VTE), a common condition in Western countries, is a cardiovascular disorder that arises due to haemostatic irregularities, which lead to thrombus generation inside veins. Even ...with successful treatment, the resulting disease spectrum of complications considerably affects the patient's quality of life, potentially leading to death. Cumulative data indicate that long non-coding RNAs (lncRNAs) may have a role in VTE pathogenesis. However, the clinical usefulness of these RNAs as biomarkers and potential therapeutic targets for VTE management is yet unclear. Thus, this article reviewed the emerging evidence on lncRNAs associated with VTE and with the activity of the coagulation system, which has a central role in disease pathogenesis. Until now, ten lncRNAs have been implicated in VTE pathogenesis, among which MALAT1 is the one with more evidence. Meanwhile, five lncRNAs have been reported to affect the expression of TFPI2, an important anticoagulant protein, but none with a described role in VTE development. More investigation in this field is needed as lncRNAs may help dissect VTE pathways, aiding in disease prediction, prevention and treatment.
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•Oxidized kraft liquor was purified by chromatographic processes after membrane treatment.•SP700 resin can be used at least up to 4–5 times (cycle adsorption studies).•Maximum ...adsorption capacity for phenolic monomers (TP) of 0.251 g/g obtained.•TP were recovered and concentrated with ethanol/water.•The enriched ethanolic solution in vanillin and syringaldehyde pursued with SFC.
In this study the purification of an oxidized industrial kraft liquor (IKL) by chromatographic processes is addressed after being submitted to a three stage membrane fractionation aiming the recovery of high added value phenolic monomers.
The IKL final permeates obtained from the second and third membrane separation stages (P5kDa and P1kDa, respectively) were loaded onto a bed packed with nonpolar SP700 resin and were readily eluted with an ethanol:water (90:10, % V/V) solution. Each stream was characterized regarding the total non-volatile solids, ashes and total phenolic compounds of interest quantified by HPLC-UV. Maximum adsorption capacities for vanillin and syringaldehyde of 0.0797 and 0.0673 g g−1dry resin, respectively, were obtained after loading the P1kDa permeate. Cycle adsorption studies performed with P5kDa and P1kDa permeates showed that the SP700 resin can be reutilized up to 4–5 adsorption/desorption cycles and no major differences regarding the performance of the adsorption process were observed employing both permeates.
Lastly, a final separation step of the ethanolic eluate by supercritical fluid chromatography (SFC) technology was successfully accomplished employing a silica column at 150 bar and 40 °C and a gradient of the co-solvent methanol.
BackgroundOvarian cancer is one of the leading cause of cancer-related mortality in women worldwide.1 Due to its frequent late-stage diagnosis, effective treatment remains challenging, underscoring ...the urgency for novel therapeutic strategies.2 While multiple immunotherapeutic interventions have been explored, their outcomes remain poor, and their efficacy is most likely hampered by the immunosuppressive nature of the ovarian cancer tumor microenvironment, characterized by limited tumor infiltration.3 Understanding and targeting this microenvironment is crucial for the success of immunotherapies. A promising area of interest is the role of endogenous retroviruses (ERVs). Recent evidence suggests transcriptional reactivation of ERVs in different types of cancers, leading to retroviral RNA and protein expression.4 5 Methods and ResultsHerein, by using the ERVmap tool, we identified, in a large cohort of public available data, a distinct ERV signature in ovarian cancer, which included both ovary-specific and cancer-specific profile. Predictive analysis showed that this mRNA ERV signature could originate thousands of peptides with a spectrum of affinities, ranging from weak to strong, for multiple HLA class I molecules. The functional translation capability of this RNA fragments was then proven by the presence of a small fraction of these peptides on the cell surface bound to HLA class I molecules. HLA class I elution and consequent mass spectrometry analysis of 42 ovarian cancer samples revealed the presence of these ERV-derived peptides, conspicuously absent in normal ovarian tissue (n=15), and with predicted immunogenic properties. Importantly, the promiscuous nature of these peptides, predicted to be presented across diverse HLA class I molecules, augments their application for T-cell based therapies.ConclusionsThe identification of immunogenic ERV-derived tumor specific peptides as potential targets offers a promising and exploitable vulnerability in ovarian cancer, opening new avenues for targeted immunotherapy.ReferencesSiegel RL, Miller KM, Wagle NS, et al. Cancer Statistics, 2023. A Cancer Journal for Clinicians. 2023;73:17–48.Matulonis UA, Sood AK, Fallowfield L, et al. Ovarian Cancer. Nat Rev Dis Primers. 2016;2:16061Hu X, Bian C, Zhao X, Yi t. Efficacy evaluation of multi-immunotherapy in ovarian cancer: From bench to bed. Front Immunol. 2022;6(13):1034903,Jansz N, Faulkner GJ. Endogenous retroviruses in the origins and treatment of cancer. Genome Biol. 2021;22:147.Tokuyama M, Kong Y, Song E, et al. ERVmap analysis reveals genome-wide transcription of human endogenous retroviruses. PNAS. 2018;115(50):12565Ethics ApprovalAll human data analyzed in this study is publicly available at TCGA, GTEX, and PRIDE databases.
BackgroundNon-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide.1 Despite the promise shown by immune checkpoint inhibitors (ICIs) in enhancing survival and ...tumor control for a subset of patients, a significant portion remains non-responsive, which may be attributed to a deficiency in CD8 T-cell tumor infiltration. The presence of pre-existing tumor-reactive T-cell infiltration is, in fact, a crucial determinant of ICI efficacy. Interestingly, despite NSCLC tumors with KRAS and TP53 mutations showcasing pronounced T-cell infiltration, ICI response rates stand at about 35%, pointing to varied tumor-reactive T-cell functionalities. This inconsistency suggests that the functional states of tumor-reactive T-cells vary considerably among patients. Central to these challenges is the immunosuppressive milieu of the lung tumor microenvironment that can be attributed to impaired peptide presentation in the tumor-draining lymph nodes together with a persistent IFN-γ activation signature.2–6 Methods and ResultsIn this study, we spotlight the role of transcription factor EB (TFEB), crucial for autophagy and MHC-II peptide presentation.7 Specifically, TFEB exhibited consistent overexpression in lung tissue-draining mediastinal lymph nodes, contrasting other lymphatic regions. Notably, overexpressing TFEB in CD11c+ dendritic cells augmented tumor-specific CD4 T-cell responses, yet reduced CD8 T-cell activities, suggesting a potential shift towards a tolerogenic immune environment in NSCLC.ConclusionsConclusively, our insights into TFEB’s function in NSCLC highlight the complex relationship between tissue-specific elements and tumor immunogenicity, offering avenues for refining immunotherapeutic strategies.ReferencesSiegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin 2023; 73 (1):17–48. DOI: 10.3322/caac.21763.Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature 2018; 553 (7689):446–454. DOI: 10.1038/nature25183.Network CGAR. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012; 489 (7417):519–525. DOI: 10.1038/nature11404.Garon EB, Hellmann MD, Rizvi NA, Carcereny E, Leighl NB, Ahn MJ, Eder JP, Balmanoukian AS, Aggarwal C, Horn L, et al. Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: results from the phase I KEYNOTE-001 study. J Clin Oncol 2019; 37 (28):2518–2527. DOI: 10.1200/JCO.19.00934.Horton BL, Morgan DM, Momin N, Zagorulya M, Torres-Mejia E, Bhandarkar V, Wittrup KD, Love JC, Spranger S. Lack of CD8+ T cell effector differentiation during priming mediates checkpoint blockade resistance in non-small cell lung cancer. Sci Immunol 2021; 6 (64):eabi8800. DOI: 10.1126/sciimmunol.abi8800.Zagorulya M, Yim L, Morgan DM, Edwards A, Torres-Mejia E, Momin N, McCreery CV, Zamora IL, Horton BL, Fox JG, et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity 2023; 56 (2):386–405.e310. DOI: 10.1016/j.immuni.2023.01.010.Samie M, Cresswell P. The transcription factor TFEB acts as a molecular switch that regulates exogenous antigen-presentation pathways. Nat Immunol 2015; 16 (7):729–736. DOI: 10.1038/ni.3196.Ethics ApprovalThe mouse protocol has been approved by Weill Cornell Medicine committee: 2020-0017
The risk factors for coronavirus disease 2019 (COVID-19) severity are still poorly understood. Considering the pivotal role of the gut microbiota on host immune and inflammatory functions, we ...investigated the association between changes in the gut microbiota composition and the clinical severity of COVID-19. We conducted a multicenter cross-sectional study prospectively enrolling 115 COVID-19 patients categorized according to: (1) the WHO Clinical Progression Scale—mild, 19 (16.5%); moderate, 37 (32.2%); or severe, 59 (51.3%), and (2) the location of recovery from COVID-19—ambulatory, 14 (household isolation, 12.2%); hospitalized in ward, 40 (34.8%); or hospitalized in the intensive care unit, 61 (53.0%). Gut microbiota analysis was performed through 16S rRNA gene sequencing, and the data obtained were further related to the clinical parameters of COVID-19 patients. The risk factors for COVID-19 severity were identified by univariate and multivariable logistic regression models. In comparison to mild COVID-19 patients, the gut microbiota of moderate and severe patients have: (a) lower Firmicutes/Bacteroidetes ratio; (b) higher abundance of Proteobacteria; and (c) lower abundance of beneficial butyrate-producing bacteria such as the genera
Roseburia
and
Lachnospira
. Multivariable regression analysis showed that the Shannon diversity index odds ratio (OR) = 2.85, 95% CI = 1.09–7.41,
p
= 0.032) and C-reactive protein (OR = 3.45, 95% CI = 1.33–8.91,
p
= 0.011) are risk factors for severe COVID-19 (a score of 6 or higher in the WHO Clinical Progression Scale). In conclusion, our results demonstrated that hospitalized patients with moderate and severe COVID-19 have microbial signatures of gut dysbiosis; for the first time, the gut microbiota diversity is pointed out as a prognostic biomarker of COVID-19 severity.
Lignin is an underexploited side-stream of pulp and paper industry and biorefineries, being used for energy production at mill site or as low value material for dispersants or binding applications. ...However, an integrated process of reaction and separation can be implemented for the production of high added-value monomeric phenolic chemicals such as vanillin and syringaldehyde. In this review, the main research advances in the recovery of vanillin and syringaldehyde resulting from oxidation of lignin are addressed, covering various separation methodologies namely liquid-liquid extraction, supercritical fluid extraction, distillation, crystallization, membrane separation, and adsorption. Studies in this area started in the early years of the 20
th
century, but in the last decades several processes have been suggested, mainly for vanillin separation. Finding the ultimate industrially feasible process is still a necessary task and this review points out the most promising technologies and sequence of processes.
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest ...and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.
Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic ...option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
•Genome-wide screening identifies PTPN1 and PTPN2 as phosphatases involved in ALK inhibitor resistance in lymphoma.•PTPN1 and PTPN2 regulate ALK and SHP2 phosphorylation, and combined inhibition of ALK and SHP2 is an effective approach to treat ALCL.
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Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological ...features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characteristics as well as the circadian distribution of CTCs vs paired bone marrow (BM) clonal PCs from MM patients. Our results show that CTCs typically represent a unique subpopulation of all BM clonal PCs, characterized by downregulation (P < .05) of integrins (CD11a/CD11c/CD29/CD49d/CD49e), adhesion (CD33/CD56/CD117/CD138), and activation molecules (CD28/CD38/CD81). Fluorescence in situ hybridization analysis of fluorescence-activated cell sorter–sorted CTCs also unraveled different cytogenetic profiles vs paired BM clonal PCs. Moreover, CTCs were mostly quiescent and associated with higher clonogenic potential when cocultured with BM stromal cells. Most interestingly, CTCs showed a circadian distribution which fluctuates in a similar pattern to that of CD34+ cells, and opposite to stromal cell–derived factor 1 plasma levels and corresponding surface expression of CXC chemokine receptor 4 on clonal PCs, suggesting that in MM, CTCs may egress to PB to colonize/metastasize other sites in the BM during the patients' resting period.
•Detailed characterization of myeloma circulating tumor cells shows that these represent a unique subpopulation of BM clonal PCs.•Myeloma CTCs are clonogenic, quiescent, and may represent an ancestral clone potentially driven by circadian rhythms.
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•SP700 is a nonpolar resin suitable for vanillin (V) and syringaldehyde (S) adsorption.•Batch experiments were successfully fitted with Langmuir and Freundlich models.•Maximum ...adsorption capacities obtained: 0.663 (V) and 0.707 (S) gg−1dry_resin.•SP700 showed 46% more capacity for V than reported in literature for other resins.•Fixed bed experiments were described with the axially dispersed plug flow model.
Pulp and paper mill and biorefinery side-streams are rich in lignin which can be partially converted to vanillin and syringaldehyde through an oxidation process. These value-added compounds can be recovered with an integrated separation process encompassing an adsorption step. In this work the potential of a macroporous polymeric resin, Sepabeads SP700, was assessed.
The resin was characterized regarding particle size, solid density, apparent density and particle porosity by means of laser dispersion, helium pycnometry and mercury intrusion porosimetry, respectively. Values within the ranges given by supplier were achieved: solid density, apparent density, particle size and particle porosity were 1294gL−1, 1012gL−1, 483μm and 0.73mLporesmL−1particle, respectively.
Batch equilibrium isotherms for three different temperatures 283/288, 298 and 333K were found for vanillin and syringaldehyde in aqueous solutions. Experimental results were fitted to Langmuir and Freundlich isotherm models. Equilibrium isotherms were validated by fixed bed studies at different temperatures and feed concentrations. A mathematical model comprising the equilibrium isotherms, linear driving force approximation, and intraparticle mass transfer resistances was used to describe the adsorption/desorption histories of concentration at the outlet of the fixed bed experiments. Although Langmuir model reasonably fit to the experimental results, the empirical Freundlich model was best to describe the experimental results for equilibrium concentrations bellow 1gL−1.
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