Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.

BACKGROUND: Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. METHODS: Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. RESULTS: TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. CONCLUSIONS: Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

A commentary on methodological aspects of hydrolysable tannins metabolism in ruminant: a perspective view.

Although, the application of tannic acid (TA), gallic acid (GA), natural hydrolysable tannins (HT)-rich ingredients, and HT-rich feeds in ruminant feeding have been explored in order to modify or manipulate microbial activities of digestive tract of animals, the interaction between HT and gastrointestinal microbiota and the fate of HT metabolites (GA, ellagic acid, pyrogallol, resorcinol, phloroglucinol, catechol and urolithin) derived from gastrointestinal microbial HT metabolism in the animal as a whole and animal products are missing. Incomplete biotransformation of HT and TA to GA, pyrogallol, resorcinol, phloroglucinol and other phenolic metabolites is a prevalent phenomenon discovered by researchers who examine the fate of HT metabolites in ruminant. While the rest of fellow researchers do not even examine the fate of HT metabolites and assume the complete biotransformation and fermentation of HT metabolites to volatile fatty acids (VFA). Only three studies have successfully identified the complete biotransformation and fermentation of HT metabolites to VFA in ruminant. The HT metabolites, mostly pyrogallol, produced through incomplete biotransformation of HT have adverse effects on gastrointestinal microbiota and host animal. Lack of awareness regarding the metabolism of HT metabolites and its consequences would compromise ruminant gastrointestinal microbiota, animal welfare, our environment and the power of research papers' findings. In this perspective paper, I will bring to attention a new angle on the biotransformation and fermentation of HT metabolites in gastrointestinal tract, the role of gastrointestinal microbiota and deficiency of current approach in isolating tannin-degrading bacteria from rumen. Also, suggestions for better monitoring and understanding HT metabolisms in ruminant are presented.

High mobility group box 1 is increased in the sera of psoriatic patients with disease progression.

BACKGROUND: Psoriasis vulgaris (PV) is an autoimmune-related chronic inflammatory disease, which appears mostly in skin, but also affects the vascular and metabolic system. The incidence of PV is 2-3% in the general population and there is still no possibility to cure. Trigger factors have been identified to initiate and maintain inflammation in the skin, which is characterized by Th1-, Th17- and Th22- cells. OBJECTIVE: We hypothesize that the damage-associated molecular pattern (DAMP) molecule high mobility group box 1 (HMGB1) plays a role in the pathogenesis of PV. HMGB1 is a DNA-binding protein located in the nucleus, which acquires cytokine-like properties once released from the cell upon necrotic cell death or actively secreted by immune cells in inflammation and cancer. METHODS: We recruited 90 psoriatic patients under and without therapy with mild, intermediate and severe progression of disease, defined by the Psoriasis Area Severity Index. Serum levels of HMGB1 in patients with PV were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our results show an increased level of HMGB1 in the sera of patients with PV in comparison to healthy donors. Furthermore, our analyses reveal that HMGB1 levels are significantly increased with disease progression and are downregulated after standard therapies for PV have been conducted. CONCLUSION: Our data provide insights into a possible role of HMGB1 for inflammation in PV.

Influence of photodynamic therapy on peripheral immune cell populations and cytokine concentrations in head and neck cancer.

BACKGROUND: Photodynamic therapy (PDT) represents a palliative treatment option for a selected group of patients with head and neck squamous cell carcinoma (HNSCC). PDT induces a local inflammatory reaction with the potential to initiate antitumor immune responses. However, the systemic impact on peripheral immune cells has not been described so far. METHODS: HNSCC patients (n=9) were treated with PDT in a palliative setting. All patients had previously undergone several oncologic treatment regimens. Blood samples were taken before, during and after PDT. Age-matched healthy donors served as control group (NC, n=15). The frequency and absolute number of T- and B-lymphocytes, CD4+CD39+ regulatory T-cells (Treg) and NK-cells were measured by 10-color flow cytometry. Serum concentrations of T cell related cytokine panel, including HMGB1, IL-6, IL-10 and perforin were measured by bead array and ELISA. RESULTS: In heavily pretreated HNSCC patients, the number and frequency of Treg and NK-cells were increased as compared to NC. PDT induced a further increase of the frequency of Treg and NK-cells in the peripheral blood. Additionally, the serum concentrations of HMGB1, IL-6 and IL-10 showed a significant elevation after treatment with simultaneously decreased perforin levels. CONCLUSION: Although PDT is a local treatment regimen, a systemic inflammatory response with altered peripheral immune cell populations and cytokine concentrations is visible. The increased Treg and NK cell numbers after PDT support the hypothesis that PDT may successfully be combined with NK cell or T cell activating immune checkpoint modulators in HNSCC patients to improve HNSCC specific immunity.

Analysis of respiratory events in obstructive sleep apnea syndrome: Inter-relations and association to simple nocturnal features.

OBJECTIVE: This study carefully evaluates the association of different respiration-related events to each other and to simple nocturnal features in obstructive sleep apnea-hypopnea syndrome (OSAS). The events include apneas, hypopneas, respiratory event-related arousals and snores. METHODS: We conducted a statistical study on 158 adults who underwent polysomnography between July 2012 and May 2014. To monitor relevance, along with linear statistical strategies like analysis of variance and bootstrapping a correlation coefficient standard error, the non-linear method of mutual information is also applied to illuminate vague results of linear techniques. RESULTS: Based on normalized mutual information weights (NMIW), indices of apnea are 1.3 times more relevant to AHI values than those of hypopnea. NMIW for the number of blood oxygen desaturation below 95% is considerable (0.531). The next relevant feature is "respiratory arousals index" with NMIW of 0.501. Snore indices (0.314), and BMI (0.203) take the next place. Based on NMIW values, snoring events are nearly one-third (29.9%) more dependent to hypopneas than RERAs. CONCLUSION: 1. The more sever the OSAS is, the more frequently the apneic events happen. 2. The association of snore with hypopnea/RERA revealed which is routinely ignored in regression-based OSAS modeling. 3. The statistical dependencies of oximetry features potentially can lead to home-based screening of OSAS. 4. Poor ESS-AHI relevance in the database under study indicates its disability for the OSA diagnosis compared to oximetry. 5. Based on poor RERA-snore/ESS relevance, detailed history of the symptoms plus polysomnography is suggested for accurate diagnosis of RERAs.

Comparing the effectiveness of mindfulness and emotion regulation training in reduction of marital conflicts.

Introduction:this study aimed to compare the effectiveness of mindfulness and emotion regulation training in the reduction of marital conflicts. Methodology:the present evaluation was a quasi-experimental study with a pretest-posttest design and a control group. The population consisted of all clients who referred to Moein Counseling Center in Alborz province (Spring 2014) due to marital problems. Using the simple random sampling method, 45 married people were selected as the sample and divided into two experimental groups (15 participants in each) and a control group (15 participants). Mindfulness training sessions were held for the first experimental group and emotion regulation training sessions were held for the second experimental group while, the participants in the control group did not receive any training. The Marital Conflicts Questionnaire was used for data collection and the obtained data were analyzed through descriptive statistics and analysis of covariance. Results: the results confirmed the main hypothesis of this study regarding the effectiveness of mindfulness and emotion regulation training in reduction of marital conflicts (p<0.001, F=43.41). Discussion and conclusion: there was a significant difference between mindfulness training and emotion regulation training in the reduction of marital conflicts; thus, compared to the mindfulness training, emotion regulation training can be considered a more effective treatment of marital conflicts.

Serum Th17 cytokines in leprosy: correlation with circulating CD4(+) CD25 (high)FoxP3 (+) T-regs cells, as well as down regulatory cytokines.

Leprosy is not only a bacteriological disease but also an immunological disease, in which T helper17 and CD4(+) CD25(high)FoxP3(+) regulatory T cells (T-regs), among others, may play a role. We aimed to evaluate serum levels of interleukin (IL)-17, IL-22 (Th17 cytokines), IL-10 and transforming growth factor (TGF)-ß (down regulatory cytokines) in 43 untreated leprosy patients and 40 controls by enzyme-linked immunosorbent assay, and to assess circulating CD4(+) CD25(high)FoxP3(+)T-regs in patients using flow cytometry. Patients were grouped into tuberculoid, pure neural, borderline, lepromatous, type 1 reactional leprosy, and erythema nodosum leprosum. IL-10 and TGF-ß were significantly higher in patients as compared to controls (p < 0.001), while IL-17, but not IL-22, was significantly lower (p < 0.001), with no significant difference comparing patients' subgroups. Significantly higher CD4(+) CD25(high)FoxP3(+)T-regs levels was detected in tuberculoid, type 1 reaction and pure neural leprosy, while the lowest levels in erythema nodosum leprosum (p < 0.001). TregsFoxP3 expression% was significantly lower in pure neural leprosy than other patients' subgroups (p < 0.05). T-regs/T-effs was lowest in erythema nodosum leprosum (p < 0.05). TGF-ß correlated negatively with TregsFoxP3 expression% and T-effs% (p = 0.009 and 0.018 respectively). Leprosy is associated with defective IL-17 and overproduction of IL-10 and TGF-ß. Tuberculoid, type 1 reaction and pure neural leprosy express significantly higher circulating T-regs, consistent with effector immune mechanisms activation, but with lower TregsFoxP3 expression (in pure neural leprosy). Erythema nodosum leprosum is characterized by deficient T-regs and increased TregsFoxP3 expression%. The present study pinpointed a potential role of Th17, CD4(+) CD25(high)FoxP3(+)T-regs, and probably CD4(+) CD25(+)IL-10(+) T regulatory cells 1 (Tr1), and Th3 in leprosy.

Cytolytic activity of NK cell clones against acute childhood precursor-B-cell leukaemia is influenced by HLA class I expression on blasts and the differential KIR phenotype of NK clones.

Relapse after allo-SCT in patients with acute leukaemia remains a major problem. A beneficial impact of alloreactive natural killer (NK) cells has been reported for myeloid malignancies, but has been questionable for B-lineage ALL. We analysed lysis of primary paediatric precursor-B-ALL blasts by 285 NK cell clones to investigate whether HLA class I expression on the blasts and phenotypic killer cell Ig-like receptor (KIR) expression on NK cells affect the lytic activity against ALL blasts. Precursor-B-ALL blasts with low HLA-I expression were lysed by a majority (79%) of NK cell clones, whereas those with high HLA-I expression showed low susceptibility to NK clones independent of their KIR expression patterns. NK cell activity against susceptible blasts was regulated by differential surface expression of the three major KIRs (CD158a, CD158b, CD158e). NK clones with none of these three KIRs or a single KIR that recognized no ligand, were not inhibited by the targets and exerted higher lysis (P = <0.0005) in comparison to NK clones expressing KIRs with a ligand on the ALL blasts. In conclusion, the quantity of HLA-I expression on precursor-B-ALL blast regulates overall NK cell susceptibility; in case of reduced HLA expression, differential surface expression of KIRs affects NK cell alloreactivity against those blasts.

Inhibition of growth and induction of differentiation of glioma cell lines by oncostatin M (OSM).

The neuropoietic cytokines of the interleukin-6 family are a group of structurally and functionally related polypeptides. We studied the effect of the multifunctional neuropoietic cytokines, including oncostatin M (OSM), leukemia inhibitory factor (LIF) and interleukin-6 (IL-6), on anaplastic glioma cell lines. Growth and morphology of the glioma cell lines were affected differently. While IL-6 and LIF exerted no or only small minor morphological changes and growth retardation, OSM induced a marked change in morphology and a strong suppression of growth. OSM treated cells were characterized by enlargement and the formation of multiple, thin processes thus resembling mature cultured astrocytes. The growth inhibitory effects were dose dependent with a maximum exerted by addition of 50 ng/ml OSM. The inhibition of DNA synthesis by OSM could be abolished by antibodies blocking either the activity of OSM or the OSM-receptor component, gp130.

Control of deaths from diarrheal disease in rural communities. I. Design of an intervention study and effects on child mortality.

From May through October 1980, the "Strengthening Rural Health Delivery" project (SRHD) under the Rural Health Department of the Ministry of Health of Egypt had conducted an investigation into prevention of child mortality from diarrheal disease through testing various modules of Oral Rehydration Therapy delivery mechanisms. In a six-cell design counting a total of almost 29,000 children, ORT was provided both as hypotonic sucrose/salt solution prepared and administered by mothers and normotonic, balanced electrolyte solution in the hands of both mothers and health care providers and the effects on child mortality during the peak season of diarrheal incidence were measured. In addition, utilization and effects of ORT when made readily available through commercial channels was similarly examined. A cost-benefit analysis was performed on the cost of the services as well as on the outcome for each of five study cells using the sixth, the control, as reference. Results showed that early rehydration with a sucrose/salt solution in the hands of mothers, backed by balanced oral rehydration solution in the hands of health care providers proved the most cost-effective means of reducing diarrhea-specific mortality as well as being as safe as prepackaged commercial preparations.

PIP: A study design consisting of 2 control and 4 treatment cells was used to compare the effectiveness of different compositions of oral rehydration fluids and preventing dehydration and ultimately child deaths from diarrheal disease. Specifically, the extent of reduction in child mortality among 3 groups was compared: 1 group used a combination of oral rehdration therapy (ORT) prepared from the home ingredients of sugar and salt and administered by the mother and ("Oralyte") placed in the hands of the health care providers only; and 1 group used "Oralyte" only administered by both mothers and health care providers. Several data collection processes were employed to collect data on both baseline, intermediate (process), and impact (outcome) variables, including household surveys on demographic composition, sources of (drinking) water, incidence of diarrheal disease, knowledge and practice (KP) of mothers on diarrheal disease (DD) recognition and treatment regimen, availability of utensils and supplies necessary for the preparation of rehydration fluid, sodium concentration of randomly selected samples of home prepared rehydration fluids. In all study villages, the clerk in each health station maintained a regular count of the number of preschool children who had died within the preceding week. Age, sex, house number, and father's name were reported for each death. 2760 children (12.1%) of the total population under care in egypt's "Strengthening Rural Health Delivery" project were seen in the course of outpatient clinics during the 6 months of the program, May through October 1980. Overall, the rate of referral to secondary levels of care was almost 11 times higher in the control than treatment villages. From an initial level of about 22/1000 children per 6 months (May through October) in 1976-77, mortality dropped sigififcantly to a mean of 17.5/1000 in 1978-79 and to a mean of a mean of 10.5 by 1980 in the 3 treatment cells. A most important finding was the demonstration that ordinary household sugar and salt together with potassium containing fruits and vegetables or, intheir absence, tea, may serve as the basic ingredients of an alternative to, and temporary replacement of, the more costly and less readily available prepackaged ORS. This is not to suggest that a simple oral rehydration solution made from sugar and salt is as effective as the balanced "Oralyte", yet this simple solution when backed with adeqate supplies of "Oralyte" in the hands of the health care provider becomes a more cost effective means of reducing high child mortality from diarrheal disease than the "Oralyte" alone.