Impact of intensity modulated radiation therapy on the salivary glands function and saliva flow rate

In patients with head and neck cancer, the most common issue after radiation treatment is xerostomia and the consequences of that, which are affecting the quality of everyday life of the patient. Subjectively xerostomia is manifested as dryness in the oral cavity, followed with obstructed chewing and swallowing of the food. Mostly it happens because of the death of the cells in the gland that are supposed to be dividing, caused by the radiation. To improve patients’ life after treatment, IMRT approach has been considered to be a better solution for the gland tissue sparing during the radiation treatment, therefore, to decrease the severity and the intensity of the following xerostomia. The IMRT technique allows the chosen dose of radiation to be applied specifically on the tissue where it is supposed to be, sparing the surrounding healthy parts from the unnecessary radiation. The aim of this study was to evaluate the influence of the Intensity Modulated Radiation therapy (IMRT), with different intensity and dosage, on the function of salivary glands. For this study were analyzed total number of 87 surveys, 41 of them were used for detail analysis. This study is based on narrative review on published articles written in English language, reporting results related to the use of Intensity modulated radiation therapy treatment in patients with head and neck cancer. The wide research was done using the data bases of PubMed (Medline), NCBI (US National Library of Medicine), Medscape, Webmd, Mdconsult, Emedicine, Google scholar, and Cochrane Library. The gathered results have shown that the function of the salivary glands after radiation treatment can be in many cases protected during the treatment, or even restored to some level, therefore the resulting xerostomia can be reduced and its’ following negative effects affecting the patients’ life could be minimized by using the improved technique IMRT. In many studies the evaluated levels of xerostomia have been found to be significantly lower in the groups of patients treated with IMRT technique, compared with the other group of patients treated with conventional radiation therapy. Also, a big influence has the dosage of the radiation beams, on what depends on the outcome of the salivation function in patients treated with radiation therapy

Elevated Autotaxin and LPA Levels during Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation

Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid (LPA) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC)

Variable Normalization of Naïve CD4+ Lymphopenia and Markers of Monocyte and T Cell Activation over the Course of Direct-Acting Anti-Viral Treatment of Chronic Hepatitis C Virus Infection

Chronic hepatitis C virus (HCV) infection is associated with naïve CD4+ T cell lymphopenia and long-standing/persistent elevation of cellular and soluble immune activation parameters, the latter heightened in the setting of HIV co-infection. The underlying mechanisms are not completely understood. However, we recently reported that accelerated peripheral cell death may contribute to naïve CD4+ T cell loss and that mechanistic relationships between monocyte activation, T cell activation, and soluble inflammatory mediators may also contribute. Chronic HCV infection can be cured by direct-acting anti-viral (DAA) therapy, and success is defined as sustained virological response (SVR, undetectable HCV RNA (ribonucleic acid) at 12 weeks after DAA treatment completion). However, there is no general consensus on the short-term and long-term immunological outcomes of DAA therapy. Here, we consolidate previous reports on the partial normalization of naïve CD4+ lymphopenia and T cell immune activation and the apparent irreversibility of monocyte activation following DAA therapy in HCV infected and HCV/HIV co-infected individuals. Further, advanced age and cirrhosis are associated with delayed or abrogation of immune reconstitution after DAA therapy, an indication that non-viral factors also likely contribute to host immune dysregulation in HCV infection

Regulation of Interferon-stimulated gene BST2 by a lncRNA transcribed from a shared bidirectional promoter

Recent genome-wide studies have revealed the presence of thousands of long non-coding RNAs (lncRNAs), some of which may play critical roles in the cell. We have previously shown that a large number of lncRNAs show differential expression in response to IFNα stimulation in primary human cells. Here we show that a subset of IFN-induced lncRNAs are positioned in proximity of IFN-stimulated protein-coding genes (ISGs). The majority of gene pairs originated from bidirectional promoters and showed positively correlated expression. We focused our analysis on a pair consisting of the known protein-coding ISG, BST2, and an unstudied putative lncRNA originating from the promoter region of BST2 in a divergent orientation. We showed that this transcript was a multi-exonic, polyadenylated long RNA which lacked protein-coding capacity. BST2 and the lncRNA were both induced in response to IFNα in diverse cell types. The induction of both genes was mediated through the JAK-STAT pathway, suggesting that IFN-stimulated response elements within the shared promoter activated the transcription of both genes. RNAi-mediated knockdown of the lncRNA resulted in downregulation of BST2, and we could show that this downregulation occurred at the level of transcription. Forced overexpression of this lncRNA, which we named BST2 IFN-Stimulated Positive Regulator (BISPR), resulted in upregulation of BST2, indicating that the regulation of expression of BST2 by BISPR is mediated through interactions involving BISPR RNA itself, rather than the impact of its transcription from an adjacent locus. Importantly, upon IFN stimulation, transcriptional activation of BISPR preceded the induction of BST2, suggesting that expression of BISPR facilitated the initiation of transcription in its paired protein-coding gene. The lncRNA-mediated transcriptional regulation described in this study may help govern the expression of additional protein-coding RNAs involved in IFN response and other cellular processes

Presence of Rheumatoid Factor during Chronic HCV Infection Is Associated with Expansion of Mature Activated Memory B-Cells that Are Hypo-Responsive to B-Cell Receptor Stimulation and Persist during the Early Stage of IFN Free Therapy

<div><p>Approximately half of those with chronic hepatitis C virus (HCV) infection have circulating rheumatoid factor (RF), and a portion of these individuals develop cryoglobulinemic vasculitis. B cell phenotype/function in relation to RF in serum has been unclear. We examined B cell subset distribution, activation state (CD86), cell cycle state (Ki67), and ex-vivo response to BCR, TLR9 and TLR7/8 stimulation, in chronic HCV-infected donors with or without RF, and uninfected donors. Mature-activated B-cells of HCV-infected donors had lower CD86 expression compared to uninfected donors, and in the presence of RF they also showed reduced CD86 expression in response to BCR and TLR9 stimulation. Additionally, mature activated memory B cells of HCV RF+ donors less commonly expressed Ki67⁺ than HCV RF- donors, and did not proliferate as well in response to BCR stimulation. Proportions of mature-activated B cells were enhanced, while naïve B-cells were lower in the peripheral blood of HCV-RF+ compared to RF- and uninfected donors. None of these parameters normalize by week 8 of IFN free direct acting antiviral (DAA) therapy in HCV RF+ donors, while in RF- donors, mature activated B cell proportions did normalize. These data indicate that while chronic HCV infection alone results in a lower state of activation in mature activated memory B cells, the presence of RF in serum is associated with a more pronounced state of unresponsiveness and an overrepresentation of these B cells in the blood. This phenotype persists at least during the early time window after removal of HCV from the host.</p></div

Untreated study donor characteristics.

<p>Values are expressed as median (range) for age, HCV RNA level, albumin, platelet, AST level, ALT level, APRI score, calculated as described previously [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144629#pone.0144629.ref047" target="_blank">47</a>], and absolute CD19+ count. Numbers and proportions of subjects within each category are given for HCV genotype, duration of HCV infection, sex, ethnicity and RF. Abbreviations: ALT, alanine aminotransferase; APRI, AST-to-Platelet ratio index; AST, aspartate aminotransferase; HCV, hepatitis C virus, and RF, rheumatoid factor. ^a p< .05 compared with uninfected donors; ^b p< .05 compared between HCV RF- and HCV RF+</p><p>Untreated study donor characteristics.</p

Mature activated memory B cells of HCV RF+ donors have decreased ki-67 and are less likely to proliferate in response to BCR stimulation.

<p><b>(</b>A-B) Representative and summary for Ki-67expression in whole blood of uninfected donors (UD <b>▄</b> n = 23), HCV RF- (<b>●</b> n = 20) and HCV RF+ (<b>▼</b> n = 20). (C-D) Representative and summary data of CFSE dye dilution of ex vivo experiments, where peripheral blood mononuclear cells were cultured for 6 days in medium alone, anti BCR (anti IgG F(ab’)² fragment, 4ug/mL), CpG 2006 (1ug/mL), R848 (Iug/mL) and cells were stained for B cell subset markers. UD(▄, n = 11), HCV RF- (●, n = 11), HCV RF+ (▼, n = 10). Kruskal- Wallis was used to analyzed differences among the three groups (*) of donors and Mann-Whitney U test (p≤0.05) was used between two groups of donors.</p

HCV RF+ (donors have greater proportions of mature activated memory B cells and reduced proportions of naïve B cells in comparison to uninfected donors and HCV RF- donors.

<p><b>(</b>A) Absolute count of CD19+ B cell per uL of whole blood. (B) Representative flow plot of altered B cell subset distribution in whole blood from Uninfected donor, HCV RF-, and HCV RF+ donors. (C) Summary data of Proportion of mature activated memory B cells (%) in whole blood (CD19+CD20+CD10-CD21-/loCD27+) for Uninfected donors (<b>▄ n = 23)</b>, HCV RF- <b>(● n = 23)</b>, and HCV RF+ donors (<b>▼, n = 20).</b> (D). Summary data of Proportion of naïve B cells (CD19+CD20+CD10-CD21+CD27-) in whole blood for Uninfected donors (<b>▄ n = 23)</b>, HCV RF- <b>(● n = 23)</b>, and HCV RF+ donors (<b>▼, n = 20)</b>. Kruskal- Wallis was used to analyzed differences among the three groups of donors and Mann-Whitney U test was used between two groups of donors (p≤0.05)</p

Increased viral load in HCV RF+ donors and gating strategy to enumerate B cell subset frequencies from whole blood.

<p><b>(</b>A), HCV RNA copies IU/mL HCV RF- (●, n = 23) and HCV RF+ (▼, n = 23). <b>(</b>B) Shown an uninfected donor sample for total immature transitional B cells (CD19+CD20+CD10+) and its differentiation stages: T1 stage (CD19⁺CD20⁺CD10⁺CD21-) and T2 stage (CD19⁺CD20⁺CD10⁺CD21⁺). Mature activated B cells(CD19⁺CD20⁺CD10^-CD21^-CD27⁺), resting memory B cells (CD19⁺CD20⁺CD21⁺CD27⁺), naïve (CD19⁺CD20⁺CD21⁺CD27^-),Tissue like memory B cells (CD19⁺CD20⁺CD10^-CD21^-CD27^-) and Plasmablast cells (CD19⁺CD20^-CD38⁺)</p