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Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases. Synopsis: The MondoA dependent relationship between TXNIP and GDF15 in response to oxaliplatin-induced ROS can be used to predict aggression and treatment sensitivity in colorectal adenocarcinoma. Non-lethal oxaliplatin treatment increases glucose update, oxidative phosphorylation and ROS in CRC models. The increase in the above drives MondoA to translocate to the nucleus and promote TXNIP expression which, amongst other impacts, inhibits GDF15 expression. GDF15 binds to CD48 on naïve CD4 T cells to induce Tregs which inhibit CD8 T cell activation. In aggressive or oxaliplatin-resistant cases, the inter-relationship between TXNIP and GDF15, and control of local Treg induction, is lost. The GDF15/TXNIP ratio can be used to predict aggression, sensitivity to oxaliplatin and highlight a population suitable for GDF15 targeting therapies. The MondoA dependent relationship between TXNIP and GDF15 in response to oxaliplatin-induced ROS can be used to predict aggression and treatment sensitivity in colorectal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Background and purpose: Loss of long‐term potentiation (LTP) expression has been associated with a worse disease course in relapsing–remitting multiple sclerosis (RR‐MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP‐like plasticity in patients with multiple sclerosis (MS). Methods: In 46 newly diagnosed RR‐MS patients, we explored the impact of preventive exercise on LTP‐like plasticity as assessed by intermittent theta‐burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8‐week inpatient neurorehabilitation program on clinical scores and LTP‐like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Results: Reduced LTP expression was found in RR‐MS patients compared with controls. Exercising RR‐MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Conclusions: Both preventive exercise and physical rehabilitation may enhance the expression of LTP‐like synaptic plasticity in MS, with potential beneficial effects on disability accumulation. [ABSTRACT FROM AUTHOR]

Treatment of melanomas with targeted and immunotherapies has proven effective, but resistance to both treatments is a common outcome leaving a high proportion of patients without effective alternative treatment options. Replication stress is a common feature of melanomas, and this is effectively targeted using a combination of checkpoint kinase 1 (CHK1) inhibitor and low‐dose hydroxyurea (LDHU). This combination also promotes inflammatory and anti‐tumour immune responses in vivo. Melanoma cell lines resistant to BRAF inhibitor (BRAFi) or immune checkpoint inhibitors (ICI) retain their sensitivity to CHK1i + LDHU, with sensitivity similar to that of parental tumours. In vivo, BRAFi‐resistant and BRAFi‐sensitive parental tumours produce an identical immune response with treatment. [ABSTRACT FROM AUTHOR]

Venn diagram comparing common and unique proteins identified in sEV samples derived from saliva (A) and plasma (B) isolated by UC, UCF, SEC and DG. In saliva sEVs, UC (63) and DG (54) showed a higher representation of the top 100 EV proteins when compared to UCF (45) and SEC (53). Seven micrograms of protein for each isolation method using saliva and plasma samples (N1, N2 and N3) was separated and then blotted in the presence of different antibodies. In contrast, for plasma-derived sEVs, UC, UCF and DG displayed 22, 21 and 20 common proteins, respectively, when compared to the top 100 EV proteins, whilst SEC showed 52 common proteins. [Extracted from the article]

The neuroinflammatory process characterizing multiple sclerosis (MS) is associated with changes in excitatory synaptic transmission and altered central concentrations of the primary excitatory amino acid, L‐glutamate (L‐Glu). Recent findings report that cerebrospinal fluid (CSF) levels of L‐Glu positively correlate with pro‐inflammatory cytokines in MS patients. However, to date, there is no evidence about the relationship between the other primary excitatory amino acid, L‐aspartate (L‐Asp), its derivative D‐enantiomer, D‐aspartate, and the levels of pro‐inflammatory and anti‐inflammatory cytokines in the CSF of MS. In the present study, we measured by HPLC the levels of these amino acids in the cortex, hippocampus, cerebellum, and spinal cord of mice affected by experimental autoimmune encephalomyelitis (EAE). Interestingly, in support of glutamatergic neurotransmission abnormalities in neuroinflammatory conditions, we showed reduced L‐Asp levels in the cortex and spinal cord of EAE mice and increased D‐aspartate/total aspartate ratio within the cerebellum and spinal cord of these animals. Additionally, we found significantly decreased CSF levels of L‐Asp in both relapsing–remitting (n = 157) MS (RR‐MS) and secondary progressive/primary progressive (n = 22) (SP/PP‐MS) patients, compared to control subjects with other neurological diseases (n = 40). Importantly, in RR‐MS patients, L‐Asp levels were correlated with the CSF concentrations of the inflammatory biomarkers G‐CSF, IL‐1ra, MIP‐1β, and Eotaxin, indicating that the central content of this excitatory amino acid, as previously reported for L‐Glu, reflects a neuroinflammatory environment in MS. In keeping with this, we revealed that CSF L‐Asp levels were positively correlated with those of L‐Glu, highlighting the convergent variation of these two excitatory amino acids under inflammatory synaptopathy occurring in MS. [ABSTRACT FROM AUTHOR]

Estimating river discharge requires simultaneous measurement of velocity and flow depth. While surface velocities are relatively easy to measure using noncontact techniques, depth measurement usually requires physically intrusive instrumentation. This limits our capability to remotely monitor discharge in natural rivers subject to bed level variations. This work tests the potential to estimate the surface velocity, the water depth, the depth average velocity, and then discharge of a river using only a sequence of images of the dynamic water surface. The method is based on a comparison between the spatiotemporal Fourier spectra of the pixel intensities of these images and the theoretical dispersion relations of turbulence‐generated surface fluctuations and gravity‐capillary waves. The method is validated through the analysis of water surface videos obtained with fixed cameras from two river sections equipped with conventional discharge gauging. The applicability of the approach is demonstrated and the measurement uncertainties are quantified. The method is affected by two main sources of uncertainty: one derives from the estimation of the velocity index and the other from the obtainable resolution of the Fourier analysis. This resolution strongly controls the observation of depth and/or velocity variations in space and in time. The technique has advantages over current approaches: it has clear physical foundations; the equipment is low cost and is highly mobile; it does not need artificial tracers or physical equipment to measure depth; and it can directly provide estimates of the key flow parameters just from time series of images of the water surface. Plain Language Summary: Continuous river flow discharge measurement is of great importance for managing natural water resources and flood risks. Current remote measurements that can be performed without immersing sensors only determine the velocity of the very upper surface layer of the river. River water surfaces have distinct patterns of waves. This work demonstrates that by remotely observing the dynamics of water surface waves using a low‐cost video camera and using wave theory, it is possible to estimate the surface water velocity, water depth, depth‐average velocity, and therefore the flow rate. Key Points: Water surface fluctuations of a river surface react systematically to changes in the flow depth and velocityDepth, velocity, and discharge are estimated remotely by fitting theoretical relations to the spectra of images of the water surfaceThe uncertainty of the estimates is governed by the size of river surface covered by the images, limiting the achievable spatial resolution [ABSTRACT FROM AUTHOR]

Background: Although the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV‐driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study was conducted to investigate such associations in head and neck cancer (HNC). Methods: In all, 192 patients with HNC and 384 controls were genotyped with the Infinium Global Screening Array (Illumina, Inc). HLA variants were imputed with SNP2HLA, and an association analysis was performed by logistic regression. Results: HPV‐positive HNCs were significantly associated with single‐nucleotide polymorphisms (SNPs) at DRB1_32660090 (P = 1.728 × 10–6) and DRB1_32660116 (P = 1.728 × 10–6) and with the amino acid variant DRB1_11_32660115 (P = 1.728 × 10–6). None of these associations were observed in the HPV‐negative cohort, and this suggested their specificity to convey risk for HPV‐associated HNCs. In general, associations observed for HPV‐negative HNC were relatively weak, and variants in the HLA‐DPA1 region were the strongest among them (P = 4.531 × 10–4). Several lead signals reported by previous HNC genome‐wide association studies, including SNPs rs3135001 (P =.012), rs1049055 (P =.012), and rs34518860 (P =.029) and allele HLA‐DQB1*06 (P =.009), were replicated in the current study. However, these associations were limited to the HPV‐positive HNC group. Several cervical cancer–associated HLA variants, including SNPs rs9272143 (P =.002) and rs9271858 (P =.002) and alleles HLA‐B‐1501 (P =.009) and HLA‐B‐15 (P =.015), were also exclusively associated with HPV‐positive HNC. Conclusions: HPV‐positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV‐positive HNC. Human papillomavirus (HPV)–positive head and neck cancer (HNC) risk is associated with distinct human leukocyte antigen variants, and some of them are shared by both cervical cancer and HPV‐positive HNC. Lay Summary: Cervical cancer studies highlight that human papillomavirus (HPV)–driven cancer risk is linked with human leukocyte antigen (HLA) polymorphism.Hence, the current study was designed to investigate the HLA associations in HPV‐positive and HPV‐negative head and neck cancer (HNC) and compare these associations with cervical cancer.Several lead signals reported by previous HNC and cervical genome‐wide association studies were replicated in the current study.However, these associations were limited to the HPV‐positive HNC group, and this suggests that HPV‐positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV‐positive HNC. [ABSTRACT FROM AUTHOR]

Aim: We recently proposed miR‐142‐3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR‐142‐3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR‐142‐3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs). Methods and Results: In a cohort of 151 MS patients, we found positive correlations between CSF miR‐142‐3p levels and clinical progression, IL‐1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with 'low miR‐142‐3p' to dimethyl fumarate (DMF), an established disease‐modifying treatment (DMT), was superior to that of patients with 'high miR‐142‐3p' levels. Accordingly, the EAE clinical course of heterozygous miR‐142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR‐142‐3p‐dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR‐142‐3p as a molecular target of DMF. Conclusion: MiR‐142‐3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies. [ABSTRACT FROM AUTHOR]

Background: Ultrasound is the main requested technique for the assessment of traumatic, vascular, neoplastic, and inflammatory testicular pathology. Moreover, the role of ultrasound has broadened over the years along with the introduction of new techniques, such as contrast enhanced ultrasound and ultrasound elastography. Objective: An updated representation of the pre‐existing Literature evidence for multiparametric ultrasound imaging with particular regard to elastography, in the evaluation of focal and diffuse testicular pathologies, has been presented. Methods: The search was performed in PubMed, Cochrane, EMBASE, Web of Science and Scopus databases from the earliest available article (1977) until January 2021. Based on the evidence of the Literature, the current role of US imaging for focal and diffuse testicular pathologies has been reported and illustrated, with emphasis on examination technique, classification, and pitfalls. Results: Multiparametric Ultrasound has a recognized role for testicle focal and diffuse disease. Elastography is nowadays recognized as an essential part of the multiparametric ultrasound examination. However, in the setting of testicular pathology this method showed some promising results in the setting of varicocoele and for focal lesions characterization. In the remaining field its role is still under debate. Discussion: B‐mode ultrasound and color Doppler ultrasound have been for a long time the diagnostic gold standard for testicular pathologies. The introduction of both contrast enhanced ultrasound and elastography in the last two decades has brought to the emergence of the multiparametric ultrasound concept. These methods are currently able to increase diagnostic confidence especially for testicular lesions characterization, with different relevance depending on the pathology under consideration. Conclusion: Multiparametric ultrasound testis assessment, with specific regard to elastography is nowadays recommended for focal and diffuse disease evaluation. Further and larger studies are however needed to validate these results and to understand if the role of elastography in testicular pathology may be broadened. [ABSTRACT FROM AUTHOR]

Background: Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV‐positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine the association of these genes with patient's outcome. Methods: Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD‐1 and its ligand PD‐L1. Results: The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV‐related diseases than blood donors (P <.0001). Patients expressing the IFNλ4 variant with one amino acid change that reduces IFNλ4 secretion was found increased in frequency in HCV‐related diseases compared to HCC PDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD‐1.3 A or the PD‐1.7 G allele (P =.0025 and P =.0167). Linkage disequilibrium (LD) between PD‐1.3 and IFNL4 was found in patients with mixed cryoglobulinaemia (MC) only (LD = 0 in HCC; LD = 72 in MC). PBMCs of MC patients expressed low levels of PD‐L1 in CD19+IgM+B cells and of PD‐1 in CD4+T cells suggesting the involvement of regulatory B cell‐T cell interaction to the pathogenesis of MC. Conclusion: Collectively, our data indicate an important contribution of IFNλ4 expression to the development of HCV‐related HCC and an epistatic contribution of IFNL4 and PDCD1 in MC. Lay summary: Studies of IFNL4 and PDCD1 genes are helpful to better understand the role of host genetic factors and immune antigens influencing the outcome of HCV‐related diseases. Our data support an association between the expression of IFNλ4, which prevents the expression of IFNλ3, with all the different HCV‐related diseases studied, and besides, evidence that a higher IFNλ4 expression is associated with hepatocellular at a younger age. The expression pattern of low PD‐L1 on B cells and high PD‐1 on CD4+T‐cells in patients with HCV‐positive cryoglobulinaemia suggests a critical role of the PD‐1/PD‐L1 signaling in modulating B cell‐T cell interaction in this lymphoproliferative disease. [ABSTRACT FROM AUTHOR]

The discovery of immune checkpoints and their role in modulating immune response have revolutionised cancer treatment in recent years. The immune checkpoints, cytotoxic T‐lymphocyte‐associated protein 4, programmed cell death protein 1 and its ligand, programmed cell death‐ligand 1, have been extensively studied. Currently 7 monoclonal antibodies targeting these immune checkpoints are approved for treatment of various cancers. Inhibiting immune checkpoints has shown some success in clinic, however, a proportion of patients do not benefit from this treatment. Several other inhibitory molecules, in addition to lymphocyte‐associated protein 4 and programmed cell death protein 1, are known to be involved in regulating immune response. To further improve patient outcomes, studies have examined targeting these inhibitory molecules through combination therapies. This review discusses the current landscape of combination therapies of checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

It is well‐established that females live longer than males. Paradoxically, women tend to have poorer health, a condition often named sex frailty. The aim of this study was to evaluate possible frailty predictors in older mice in a sex‐specific manner, in order to employ these predictors to follow‐up therapy efficiency. To further evaluate therapy effects, we also investigated the use of neurotrophic insulin‐like growth factor 1 (IGF‐1) gene therapy and its correlation with the expression of this frailty and emotional behaviour. In order to evaluate frailty, we employed two different approaches. We performed a frailty assessment through a 31‐Item Clinical Frailty Index and through a Performance‐Based 8‐Item Frailty Index. Our results show that both indexes are in concordance to evaluate sex differences, but they do not correlate when evaluating IGF‐1 therapy effects. Moreover, in order to reduce test‐to‐test variability for measures of dependent variables, we compared open field results across studies assessing sex and treatment by means of the z‐score normalization. The data show that regular open field parameters submitted to z‐score normalization analysis could be a useful tool to identify sex differences in ageing mice after growth factor therapies. Taking this into account, sex is a factor that influences the incidence and/or nature of all major complex diseases; the main outcome of our investigation is the development of an efficient tool that compares the use of different frailty index calculations. This represents an important strategy in order to identify sex differences and therapy efficiency in ageing models. [ABSTRACT FROM AUTHOR]

Objectives: Adoptive transfer of chimeric antigen receptor (CAR)‐modified T cells is a form of cancer immunotherapy that has achieved remarkable efficacy in patients with some haematological cancers. However, challenges remain in CAR T‐cell treatment of solid tumours because of tumour‐mediated immunosuppression. Methods: We have demonstrated that CAR T‐cell stimulation through T‐cell receptors (TCRs) in vivo can generate durable responses against solid tumours in a variety of murine models. Since Clec9A‐targeting tailored nanoemulsion (Clec9A‐TNE) vaccine enhances antitumour immune responses through selective activation of Clec9A+ cross‐presenting dendritic cells (DCs), we hypothesised that Clec9A‐TNE could prime DCs for antigen presentation to CAR T cells through TCRs and thus improve CAR T‐cell responses against solid tumours. To test this hypothesis, we used CAR T cells expressing transgenic TCRs specific for ovalbumin (OVA) peptides SIINFEKL (CAROTI) or OVA323‐339 (CAROTII). Results: We demonstrated that the Clec9A‐TNEs encapsulating full‐length recombinant OVA protein (OVA‐Clec9A‐TNE) improved CAROT T‐cell proliferation and inflammatory cytokine secretion in vitro. Combined treatment using the OVA‐Clec9A‐TNE and CAROT cells resulted in durable responses and some rejections of tumours in immunocompetent mice. Tumour regression was accompanied by enhanced CAROT cell proliferation and infiltration into the tumours. Conclusion: Our study presents Clec9A‐TNE as a prospective avenue to enhance CAR T‐cell efficacy for solid cancers. [ABSTRACT FROM AUTHOR]

The primary endpoint was met: 32 pts remain relapse-free at 2 years: 18 had a Cp-pos OAML, 7 were Cp-neg, and PCR results are pending in 7. B Introduction: b In geographical areas where ocular adnexal MALT lymphoma (OAML) is frequently associated with I Chlamydia psittaci i (Cp) infection, monotherapy with a 3-week regimen of doxycycline has been associated with an overall response rate (ORR) of 65% and a 2-year progression-free survival (PFS) of 60% (IELSG27 trial; Ferreri, I et al. i JCO 2012). THE IELSG39 TRIAL: EFFICACY OF FIRST-LINE CHLAMYDIA PSITTACI ERADICATION WITH A SIX-MONTH REGIMEN OF DOXYCYCLINE IN PATIENTS WITH STAGE-I MALT LYMPHOMA OF THE OCULAR ADNEXAE. [Extracted from the article]

Immune checkpoint‐blocking antibodies have therapeutic activity against relapsed or progressive classic Hodgkin lymphoma (cHL), but Hodgkin Reed‐Sternberg cells can develop resistance to this therapy via multiple mechanisms. To improve the efficacy of immune checkpoint blockade, we need a more precise understanding of the immune escape mechanisms active in individual cHL patients, and this requires a detailed characterization of immune cell populations in the tumor microenvironment. These cell‐cell interactions can now be studied by multiplex immunohistochemistry coupled to digital image analysis. This method should allow the identification of actionable target molecules mediating resistance to immune checkpoint inhibitors in individual cHL patients, thereby favoring the implementation of personalized therapies. [ABSTRACT FROM AUTHOR]

Despite antiretroviral therapy, HIV+ individuals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, which was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117 to 118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicated that HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected individuals where they may act as a local stimulus promoting the development of lymphomas. [ABSTRACT FROM AUTHOR]

The pathogenesis of classical Hodgkin lymphoma (cHL) is still enigmatic, largely because its tumor cells, the so-called Hodgkin and Reed-Stenberg (HRS) cells, invariably reside in a prominent reactive microenvironment, are rare and therefore difficult to analyze. On the other hand, the broadly investigated cHL-derived cell lines are not unequivocally considered as suitable and representative models for this puzzling disease. Based on current knowledge, it appears that the cross talk between the tumor cells and the reactive infiltrate of the microenvironment is complex and that multiple mechanisms occur, making cHL a very heterogeneous disease. In 20-40% of cHL cases, HRS cells carry a monoclonal infection by Epstein Barr virus (EBV), which is considered a tumor-initiating factor. In these cases, EBV shows a latency type II infection pattern with the expression of latent membrane protein-1 (LMP-1), a viral oncoprotein that mimics CD40 activation. This scenario is particularly intriguing for the pathogenesis of cHL arising in HIV-infected patients, which, for still obscure reasons, is invariably EBV-associated with LMP-1 expression in HRS cells. Recent evidences are consistent with the occurrence of different pathogenic pathways variably triggered by virus infections (EBV and HIV), genetic alterations, and interactions with critical microenvironmental components. This review focuses on the different microenvironmental niches that characterize cHL of the general population as well as cases of HIV-infected patients. A more comprehensive understanding of the complex interplay existing between HRS and tumor microenvironment is pivotal for the development of more effective treatments, particularly for relapsed or refractory diseases. [ABSTRACT FROM AUTHOR]

ABSTRACT Background The association between undifferentiated nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) is well established. Nevertheless, available evidence suggests that other cofactors are required for the development of undifferentiated NPC. Several investigations reported simian virus 40 (SV40) footprints in human tumors of different histotypes. Methods Serum samples from patients with undifferentiated NPC ( n = 64) and healthy subjects ( n = 130) were analyzed by an indirect enzyme-linked immunosorbent assay (ELISA) with SV40 synthetic peptides to detect antibodies against viral peptide (VP) capsid proteins VP1, 2, and 3. Results Immunologic data indicate that in sera from patients with undifferentiated NPC, the prevalence of SV40 antibodies was 25%, whereas in controls it was 16%. This difference is not statistically significant ( p > .05). Conclusion A similar prevalence of SV40 antibodies was detected in undifferentiated NPC and healthy subjects. Our serologic data suggest no association between undifferentiated NPC and SV40 infection. This investigation may stimulate further studies aimed at determining the possible contribution of other risk factors in the pathogenesis of undifferentiated NPC. © 2015 Wiley Periodicals, Inc. Head Neck 38: 232-236, 2016 [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV+ B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting. [ABSTRACT FROM AUTHOR]

Telomerase is a ribonucleoprotein complex critically involved in extending and maintaining telomeres. Unlike the majority of somatic cells, in which hTERT and telomerase activity are generally silent, normal lymphocytes show transient physiological hTERT expression and telomerase activity according to their differentiation/activation status. During lymphomagenesis, induction of persistent telomerase expression and activity may occur before or after telomere shortening, as a consequence of the different mechanisms through which transforming factors/agents may activate telomerase. Available data indicate that the timing of telomerase activation may allow the distinction of two different lymphomagenetic models: (i) an early activation of telomerase via exogenous regulators of hTERT, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies; (ii) a progressive shortening of telomeres, leading to genetic instability which favors a subsequent activation of telomerase via endogenous regulators may occur in most virus-unrelated lymphoid tumors. These models may have clinically relevant implications, particularly for the tailoring of therapeutic strategies targeting telomerase. © 2010 Wiley Periodicals, Inc. Med Res Rev [ABSTRACT FROM AUTHOR]

The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this strategy of intervention. In particular, clinical trials using adoptive T-cell therapies disclosed encouraging results, particularly in the context of Epstein-Barr-virus- (EBV-) related tumors. Nevertheless, the rate of complete clinical responses is still limited, thus stimulating the development of more effective therapeutic protocols. Considering the relevance of innate immunity in controlling both infections and cancers, innovative immunotherapeutic approaches should take into account also this compartment to improve clinical efficacy. Evidence accumulated so far indicates that innate immunity effectors, particularly NK cells, can be exploited with therapeutic purposes and new targets have been recently identified.We herein review the complex interactions between EBV and innate immunity and summarize the therapeutic strategies involving both adaptive and innate immune system, in the light of a fruitful integration between these immunotherapeutic modalities for a better control of EBVdriven tumors. [ABSTRACT FROM AUTHOR]

This investigation was focused on the contribution of individual human leukocyte antigen (HLA)-DR and -DQ alleles to the human hepatitis C virus (HCV)+ non-Hodgkin's lymphoma (NHL), with and without mixed cryoglobulinemia (MC), to study whether individual HLA class II alleles are expressed preferentially or equally in human HCV-specific NHL. For this purpose, peripheral blood mononuclear cells were obtained from two groups of patients with HCV+ NHL and with or without MC (70 and 71 cases, respectively), and from 4575 blood donors. Eighty-three subjects with HCV infection only, and 118 patients with MC, only without lymphoma, were added as additional control groups. Individual HLA-DR and -DQ alleles were determined using high-resolution sequence-based typing and then data were collected by considering the HLA-DRB1 and DQB1 supertypes on the basis of common structural and functional features, proposed by in silico Bioinformatic studies. From the data, it is evidenced that the DR5-DQ3 HLA combination was strongly associated with the HCV + MC + NHL group of patients compared with bone marrow donor population ( P≤ 0.001, RR = 2.498), while the contribution of DR1-DQ1 was higher in HCV + NHL without MC ( P≤ 0.001, RR = 2.519). Thus, cryoglobulinemia clinical manifestation was found to be correlated with the preferential use of HLA DR-DQ combination in HCV-associated NHL. These data provide new insight into HCV-associated lymphoproliferative pathogenesis. [ABSTRACT FROM AUTHOR]

CD11b [ABSTRACT FROM AUTHOR]

The role of genetic factors involved in the development of undifferentiated nasopharyngeal carcinoma (UNPC) in nonendemic areas has been poorly investigated. High-resolution human leukocyte antigen (HLA) class I genotyping carried out in 82 Italian UNPC patients and 286 bone marrow donors born in the same province showed that A*0201, B*1801, and B*3501, known to efficiently present Epstein-Barr virus (EBV)-derived epitopes, were significantly under-represented in UNPC patients. Moreover, the A*0201/B*1801 haplotype was significantly less frequent in UNPC cases, with a 90% reduced risk (odds ratio [OR] 0.1, 95% confidence interval [CI] = 0.0-0.5) to develop UNPC, suggesting an additive effect. Notably, all 5 BARF1 epitopes and 7 of the 8 LMP-2 epitopes known to bind A*0201 showed a fully conserved sequence in all the 31 Italian EBV isolates investigated. The 4 amino acid changes affecting the 436-447 LMP-2 epitope do not reduce, but rather increase in two cases, the predicted ability of 'variant' epitopes to bind the HLA-A*0201 allele, as shown by immunoinformatic analysis. Moreover, a significantly increased risk for UNPC was associated with A*2601 (OR 2.4, 95% CI = 1.1-4.9) and B*4101 (OR 9.2, 95% CI = 2.5-34.3). These findings indicate that Italian UNPC patients have a distinct HLA-A and -B genotypic profile and suggest that the decreased risk for UNPC conferred by definite HLA class I molecules is probably related to their ability to efficiently present LMP-2 and BARF1 epitopes that are highly conserved in EBV isolates from this geographic region. These results have practical implications for the immunotherapy of UNPC. © 2009 UICC [ABSTRACT FROM AUTHOR]

Autoimmune type-II cryoglobulinemia (II-MC) is sustained by hepatitis C virus (HCV) infection and B-cell (oligo)clones. This is the reason why the disease may be considered an “indolent B-cell lymphoma (NHL).” B clones show a restricted use of immunoglobulin variable genes (BCR), in particular in the use of the variable κ (VK)3–20/15 light chain, and show a homology between their BCR functional regions and those of autoimmune rheumatoid factors. We underlined the BCR unique repertoire with frequent rheumatoid factor activity also observed in other autoimmune disorders associated with NHL. The immunoglobulin idiotype is a clonal B-cell marker and an ideal target for immunotherapy. Five monoclonal antibodies were produced in our laboratory toward the VK3–20 of a subject with HCV infection and a II-MC-associated NHL. Epitope determination was performed using the epitope excision approach. Monoclonal antibody reactivity was tested in vitro in ELISA, Western blot, and cytofluorimetry. Data confirmed that a panel of antibodies, reactive against shared idiotypes, can be produced from patients with HCV-associated B-cell lymphoproliferative diseases, thus obviating the need to produce an anti-idiotype antibody for each patient. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that the Achilles' heel of cancer immunotherapies is often the complex interplay of tumor-derived factors and deviant host properties, which involve a wide range of immune elements in the lymphoid and myeloid compartments. Regulatory lymphocytes, tumor-conditioned myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, and dysfunctional and immature dendritic cells take part in a complex immunoregulatory network. Despite the fact that some mechanisms governing tumor-induced immune tolerance and suppression are starting to be better understood and their complexity dissected, little is known about the diachronic picture of immune tolerance. Based on observations of MDSCs, we present a time-structured and topologically consistent idea of tumor-dependent tolerance progression in tumor-bearing hosts. [ABSTRACT FROM AUTHOR]

One complication of celiac disease (CD) is refractory CD. These patients frequently show aberrant intraepithelial T cell clones and an increasing risk of evolution into enteropathy-associated T cell lymphoma (EATL). There is debate in the literature whether these cases are actually a smoldering lymphoma from the outset. The mechanism inducing T cell proliferation and prognosis remains unknown. Recently, alemtuzumab has been proposed as a promising new approach to treat these patients. Only few single cases have been tested presently, nevertheless, in all of them a clinical improvement has been observed, while intraepithelial lymphocytes (IELs) effectively targeted by alemtuzumab are still a debated issue. Using 2D-DIGE, we found hyperexpressed proteins specifically associated with aberrant T cell in a patient with CD by comparing the protein expression with that of patients with CD and polyclonal T cell or with that of control subjects (patients with polyclonal T cell and no CD). Proteins with a higher expression in duodenal biopsy of the patient with aberrant T cell were identified as IgM, apolipoprotein C-III, and Charcot–Leyden crystal proteins. These preliminary data allow hypothesizing different clinical effects of alemtuzumab in patients with CD, since besides the probable effect of alemtuzumab on T cell, it could effect inflammatory-associated CD52+ IgM+B cell and eosinophils cells, known to produce IgM and Charcot–Leyden crystal proteins, which we demonstrated to be altered in this patient. Results also emphasize the possible association of apolipoprotein with aberrant T cell proliferation. [ABSTRACT FROM AUTHOR]

Transformation of primary B lymphocytes by Epstein-Barr Virus (EBV) requires the establishment of a latent infection, the expression of several latent viral proteins and a sustained telomerase activity. We investigated the interplay between the activation of human telomerase reverse transcriptase (hTERT), the catalytic rate-limiting component of the telomerase complex, and the expression of latent/lytic EBV genes during the establishment of a stably latent EBV infection of normal B lymphocytes. Cell cultures at early passages after EBV infection greatly differed in their timing of hTERT expression and telomerase activation. Induction of hTERT was dependent on the balance between latent and lytic EBV gene expression, being positively associated with a high ratio of latent/lytic isoforms of latent membrane protein 1, and negatively associated with the expression of BZLF1 gene, the main activator of the viral lytic cycle. In turn, hTERT expression was followed by a decrease in EBV lytic gene expression and virus production. Ectopic expression of hTERT in BZLF1-positive B cell cultures resulted in BZLF1 down-regulation, increased resistance to lytic cycle induction, and enhanced in vitro growth properties, whereas hTERT inhibition by siRNA triggered the activation of the EBV lytic cycle. These findings indicate that hTERT contributes by multiple mechanisms to the EBV-driven transformation of B lymphocytes and suggest that hTERT may constitute a therapeutic target for EBV-associated B cell lymphomas. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, charateristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs. [ABSTRACT FROM AUTHOR]

Background The prevalence and the clinical impact of gastric Helicobacter pylori ( Hp) infection, as well as its possible correlation with Chlamydia psittaci ( Cps) infection and the lymphoma regression rate produced by Hp eradicating antibiotic therapy were investigated in patients with MALT-type lymphoma of the ocular adnexa (OAL). Methods During staging, the presence of gastric Hp infection was assessed by gastroscopy and multiple biopsies in 31 OAL patients. Immediately after, Hp-positive patients were treated with eradicating antibiotic therapy, alone or associated with other therapies. Results Gastric Hp infection was detected in 10 (32%) patients; this feature did not correlate with patients' characteristics and disease. Four Hp-positive patients were treated with Hp-eradicating antibiotics therapy as exclusive strategy (assessable for response), none of them showed lymphoma regression. Conversely, 6 Hp-positive patients were treated with antibiotic therapy concurrently with other therapies, achieving lymphoma regression in all cases. Three Hp-positive patients with Cps-positive lymphoma were treated with doxycycline at relapse, resulting in two CR and one PR, which lasted 24+, 20+, and 18+ months, respectively. One of these patients achieved a CR after doxycycline despite the chronic persistence of Hp infection, whereas Cps-eradication was confirmed in the analysis of PBMC samples. Conclusions Gastric Hp infection, even if common among OAL patients, does not influence clinical presentation. Hp-eradicating antibiotic therapy is not active against OAL. Cps-eradicating antibiotic therapy with doxycycline induces lymphoma remission irrespectively of the persistence of Hp infection. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Drinkable water supplied by aqueducts undergoes preliminar potabilization which, in Italy, is mainly accomplished by chlorine addition. The bactericidal action involved in this process is always accompanied by chlorination and oxidation of organic species (mainly humic and fulvic acids) naturally present in treated waters, so that many disinfection by-products (DBPs) are formed, such as trihalomethanes (THMs) and halo-acetic acids (HAA), which can represent a chemical risk for public health. The aim of this study was the monitoring of DBPs in drinking water disinfected by chlorination, supplied by four different aqueducts of Central Friuli (Italy). DBP evaluations were performed in water samples consisting of both input and output of disinfection plants. The results of analytical determinations were worked out to provide the THM and HAA parameters for disinfected waters, while in feeding waters the following different conventional parameters were adopted : (1) trihalomethanes formation potential (THMFP), (ii) halo-acetic acids formation potential (HAAFP) and (iii) UV absorbance at 254 nm (UV254). The quite moderate content of chlorinated products found in all samples considered highlighted the excellent quality of potabilized waters available in Central Friuli. Moreover, our results confirmed that the majority of DBPs formed when chlorine is used for water disinfection consists of THMs, while chlorites and chlorates prevailed when potabilization is accomplished by using chlorine dioxide. Finally, simple UV254 monitoring turned out to be a profitable approach for the determination of chlorinated by-products only when THMs prevail among DBPs. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV), a ubiquitous human herpes virus, is associated with an increasing number of lymphoid and epithelial malignancies. The ability of the virus to establish life-long persistent infections and induce growth transformation is related to the function of a set of viral proteins that are variously expressed in both normal and malignant cells. Recent evidence indicates that these viral proteins are able to usurp cellular pathways that promote the cell growth and survival, while impairing anti-viral immune responses. Elucidation of the mechanisms by which EBV induces cell transformation and escapes host immune control provides the rational background for the design of new strategies of intervention for EBV-related malignancies. J. Cell. Physiol. 196: 207–218, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]