Detection of Novel Biomarkers in Pediatric Autoimmune Hepatitis by Proteomic Profiling.

Autoimmune hepatitis (AIH) is characterized by immune-mediated hepatocyte injury resulting in the destruction of liver cells, causing inflammation, liver failure, and fibrosis. Pediatric (AIH) is an autoimmune inflammatory disease that usually requires immunosuppression for an extended period. Frequent relapses after treatment discontinuation demonstrate that current therapies do not control intrahepatic immune processes. This study describes targeted proteomic profiling data in patients with AIH and controls. A total of 92 inflammatory and 92 cardiometabolic plasma markers were assessed for (i) pediatric AIH versus controls, (ii) AIH type 1 versus type 2, (iii) AIH and AIH-autoimmune sclerosing cholangitis overlapping syndrome and (iv) correlations with circulating vitamin D levels in AIH. A total of 16 proteins showed a nominally significant differential abundance in pediatric patients with AIH compared to controls. No clustering of AIH subphenotypes based on all protein data was observed, and no significant correlation of vitamin D levels was observed for the identified proteins. The proteins that showed variable expression include CA1, CA3, GAS6, FCGR2A, 4E-BP1 and CCL19, which may serve as potential biomarkers for patients with AIH. CX3CL1, CXCL10, CCL23, CSF1 and CCL19 showed homology to one another and may be coexpressed in AIH. CXCL10 seems to be the central intermediary link for the listed proteins. These proteins were involved in relevant mechanistic pathways for liver diseases and immune processes in AIH pathogenesis. This is the first report on the proteomic profile of pediatric AIH. The identified markers could potentially lead to new diagnostic and therapeutic tools. Nevertheless, considering the complex pathogenesis of AIH, more extensive studies are warranted to replicate and validate the present study's findings.

The Impact of Diet on the Involvement of Non-Coding RNAs, Extracellular Vesicles, and Gut Microbiome-Virome in Colorectal Cancer Initiation and Progression.

Cancer is the major cause of morbidity and mortality in the world today. The third most common cancer and which is most diet related is colorectal cancer (CRC). Although there is complexity and limited understanding in the link between diet and CRC, the advancement in research methods have demonstrated the involvement of non-coding RNAs (ncRNAs) as key regulators of gene expression. MicroRNAs (miRNAs) which are a class of ncRNAs are key players in cancer related pathways in the context of dietary modulation. The involvement of ncRNA in cancer progression has recently been clarified throughout the last decade. ncRNAs are involved in biological processes relating to tumor onset and progression. The advances in research have given insights into cell to cell communication, by highlighting the pivotal involvement of extracellular vesicle (EV) associated-ncRNAs in tumorigenesis. The abundance and stability of EV associated ncRNAs act as a new diagnostic and therapeutic target for cancer. The understanding of the deranging of these molecules in cancer can give access to modulating the expression of the ncRNAs, thereby influencing the cancer phenotype. Food derived exosomes/vesicles (FDE) are gaining interest in the implication of exosomes in cell-cell communication with little or no understanding to date on the role FDE plays. There are resident microbiota in the colon; to which the imbalance in the normal intestinal occurrence leads to chronic inflammation and the production of carcinogenic metabolites that lead to neoplasm. Limited studies have shown the implication of various types of microbiome in CRC incidence, without particular emphasis on fungi and protozoa. This review discusses important dietary factors in relation to the expression of EV-associated ncRNAs in CRC, the impact of diet on the colon ecosystem with particular emphasis on molecular mechanisms of interactions in the ecosystem, the influence of homeostasis regulators such as glutathione, and its conjugating enzyme-glutathione S-transferase (GST) polymorphism on intestinal ecosystem, oxidative stress response, and its relationship to DNA adduct fighting enzyme-0-6-methylguanine-DNA methyltransferase. The understanding of the molecular mechanisms and interaction in the intestinal ecosystem will inform on the diagnostic, preventive and prognosis as well as treatment of CRC.

Is type 2 diabetes related to leukoaraiosis? an updated review.

A significantly increased interest has been dedicated to the study of the effects of diabetes mellitus (DM) on the brain. DM is associated with an increased risk of stroke and cognitive decline. In patients with DM, neuroimaging discloses with high-frequency structural changes, such as cerebral atrophy, infarcts and white matter lesions, also called leukoaraiosis (LA), an expression of small vessel disease. A previous review showed a relation between DM and both cerebral atrophy and lacunar infarcts, while the question about the relation between DM and LA remained unanswered. In this review, we provide an update on data on this last association. In the reviewed studies, we examined the presence of DM, other disease characteristics, such as duration and complications, and laboratory markers of the disease such as blood glycated hemoglobin (HbA1c), insulin resistance, insulin concentrations and their association with LA. About 40% of the reviewed studies reported a statistically significant association between DM and LA. Long-standing DM and a poor glycemic control were associated with severe LA. Studies using innovative MRI techniques, such as diffusion tensor imaging (DTI), reported a significant association between microstructural white matter alterations and DM. This review highlights more firmly than previously reported the existence of a relation between DM and both presence and severity of LA. These results are possibly due to more sensitive and advanced imaging techniques recently used to study the extent of LA. However, because of the heterogeneous methodology used in the reviewed studies, a definitive conclusion cannot be drawn.

Predictors of progression in patients presenting with minor subcortical stroke.

OBJECTIVES: Early neurological worsening is common in minor subcortical strokes (SS) and may lead to a poor outcome. We aimed to describe clinical and imaging features associated with progression. MATERIAL AND METHODS: Consecutive patients with SS were divided into progressive and non-progressive. Progression was defined as an increase of NIHSS motor score ≥ 1 point within 72 h from onset. Vascular risk factors and imaging features (vascular territory, size and number of slices in which the lesion was visible, the presence of leukoaraiosis) were compared in the two groups. We investigated potential independent determinants of progression using stepwise logistic regression. RESULTS: Thirty of 94 patients (31.9%) underwent progression. The distribution of vascular risk factors did not differ significantly between the two groups. Increasing number of risk factors was associated with a higher risk of progression (OR 2.2; 95% CI 1.1-4.5). Patients who progressed were more likely to have a lesion ≥ 15 mm in diameter (P = 0.004) or a lesion visible ≥ 3 slices (P = 0.007). After logistic regression stepwise adjustment for all the considered potential determinants, diameter ≥ 15 mm and severe leukoaraiosis proved to be independently associated with neurological worsening (OR = 6.3, 95% CI 2.0-19.6 and OR = 5.9, 95% CI 1.3-25.7, respectively). CONCLUSION: In a series of consecutive SS, early neurological worsening was associated with a high vascular risk profile, a larger infarct size and the presence of severe leukoaraiosis. Based on the knowledge that extensive microvascular changes are a feature of severe leukoaraiosis, we hypothesize that stroke progression could be promoted through an impaired compensatory flow in the penumbral area.

Influence of vascular risk factors and neuropsychological profile on functional performances in CADASIL: results from the MIcrovascular LEukoencephalopathy Study (MILES).

BACKGROUND AND PURPOSE: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral small vessel disease that may lead to disability and whose phenotype modulators are still unknown. METHODS: In the MIcrovascular LEukoencephalopathy Study (MILES), we assessed the influence of vascular risk factors and the effect of different cognitive domains (memory, psychomotor speed and executive functions) performances on functional abilities in CADASIL in comparison with age-related leukoencephalopathy (ARL). RESULTS: We evaluated 51 CADASIL patients (mean age 50.3 ± 13.8 years, 47.1% males) and 68 ARL patients (70.6 ± 7.4 years, 58.8% males). Considering vascular risk factors, after adjustment for age, CADASIL patients had higher mean BMI values than ARL patients. Stroke history frequency was similar in the two groups. After adjustment for age, more CADASIL patients were disabled (impaired on ≥ 2 items of the Instrumental Activities of Daily Living scale) in comparison with ARL patients, and CADASIL patients had worse functional performances evaluated with the Disability Assessment for Dementia (DAD) scale. In CADASIL patients, hypertension was related to both DAD score and disability. The cognitive profile of CADASIL and ARL patients was similar, but on a stepwise linear regression analysis functional performances were mainly associated with the memory index (ß = -0.418, P < 0.003) in CADASIL patients and the executive function index (ß = -0.321, P = 0.028) in ARL. CONCLUSIONS: This study suggests that hypertension may contribute to functional impairment in CADASIL and that memory impairment has a large influence on functional decline in contrast with that observed in a sample of subjects with ARL.

Influence of 5-fluorouracil and folinic acid on interleukin-18 production in colorectal cancer patients.

AIMS AND BACKGROUND: This study was carried out to evaluate the IL-18 blood concentrations of operated colorectal cancer patients and their possible variation in response to combination chemotherapy with 5-fluorouracil (5-FU) and folinic acid. METHODS: IL-18 levels were assayed in sera of 18 healthy donors and 18 surgical colorectal cancer patients before and after adjuvant chemotherapy with 5-fluorouracil and folinic acid. An ELISA kit for human IL-18 was used for the assay. RESULTS: Colorectal cancer patients showed significantly higher baseline levels of IL-18 than healthy donors (p<0.005). Furthermore, serum IL-18 levels increased significantly with respect to baseline in patients receiving adjuvant chemotherapy (p<0.005). CONCLUSIONS: This study suggests that treatment with 5-fluorouracil and folinic acid may provoke an increase in IL-18 serum levels in colorectal cancer patients. This increase may help to explain the efficacy of adjuvant chemotherapy with 5-FU in colorectal cancer.

Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations.

Interleukin-18 (IL-18), a cytokine that plays an important role in the T-cell-helper type 1 response, acts as an angiogenesis and tumor suppressor. Intercellular adhesion molecule-1 (ICAM-1) has a potential role in immunoregulation by mediating immune cell infiltration into the tissue. The aim of this study was to evaluate IL-18 and soluble (s) ICAM-1 serum levels in breast cancer (BCa) patients with liver (BCaM1 h) or bone (BCaM1 b) metastases compared to BCa patients without metastases (BCaM0) and healthy donors (HDs). Furthermore, since IL-18 enhances ICAM-1 expression, we investigated whether there was a direct correlation between sICAM-1 and IL-18 serum levels. Serum IL-18 and sICAM-1 levels were assayed by immunoenzymatic methods. The serum sICAM-1 levels in the three groups of cancer patients were significantly higher (p<0.05) than those of HDs. Serum IL-18 levels were significantly higher (p<0.05) in BCaM1h and BCaM1b patients compared to BCaM0 patients and HDs. sICAM-1 proved to be closely correlated with serum IL-18 levels in HDs, whereas a weaker correlation was found in BCaM1h, BCaM1b and BCaM0 patients. The defective correlation between sICAM-1 and IL-18 found in cancer patients may contribute to our understanding of the immunity upset occurring in cancer. Our data suggest that IL-18, irrespective of its biological activity, could represent a marker for metastatic breast cancer.

In vitro effect of lithium chloride on interleukin-15 production by monocytes from IL-breast cancer patients.

Lithium salt compounds are used to limit the degree and duration of neutropenia in patients receiving chemotherapy for cancer. Interleukin-15 (IL-15) is a cytokine which possesses promoting activities on hematopoiesis and is also involved in antitumor response, activating NK, CTL and LAK cells. In this study we analyzed IL-15 production by monocyte cultures treated with lithium chloride (LiCl). Monocytes were obtained from patients affected by non-metastatic and metastatic breast cancer. LiCl treatment induced IL-15 production by monocytes mainly from non-metastatic patients. Combined lipopolysaccharide/LiCl treatment of monocyte cultures up-regulated IL-15 release compared to those treated with LPS alone (p<0.0001). The modulation of LiCl-induced IL-15 could counteract the immunosuppression state of cancer patients, which should be taken into account when developing new immunotherapeutic strategies.

In vitro interleukin-8 production by monocytes treated with lithium chloride from breast cancer patients.

AIMS AND BACKGROUND: Since interleukin-8 (IL-8) has a suppressive effect on hematopoiesis, lithium induces leukocytosis and granulocytosis and mononuclear cells are defective in patients affected by neoplastic disease, we analyzed IL-8 production by monocytes obtained from patients with nonmetastatic breast cancer (BCaM0) and metastatic breast cancer (BCaM1) and the effect of lithium chloride (LiCl) on these cells. Lithium salt compounds are used to limit the degree and duration of neutropenia in patients receiving chemotherapy for cancer and acute leukemia. Lithium influences the hematopoietic system, which is known to be regulated by numerous cytokines including IL-8. METHODS: We selected three groups of subjects (15 per group): patients affected by BCaM0, BCaM1 and healthy donors (HD) matched for sex and age. IL-8 release was assessed in supernatants of lipopolysaccharide (LPS) and/or LiCl-treated monocyte cultures. RESULTS: Monocytes from BCaM1 released higher IL-8 levels than monocytes from BCaM0 (P <0.0001); the IL-8 levels of both groups were significantly higher (P <0.0001) than those of HD. In vitro LiCl treatment reduced IL-8 production by monocytes obtained from all subjects compared to the same cells when untreated or LPS treated. The suppressive effect of LiCl on IL-8 production by monocytes from breast cancer patients was particularly marked in monocytes from BCaM0 with respect to those from BCaM1. LPS treatment increased the IL-8 production more in BCaM1 monocytes than in BCaM0 monocytes. Moreover, combined LPS/LiCl treatment of monocytes significantly (p <0.0001) downregulated the release of IL-8 compared to treatment with LPS alone. CONCLUSIONS: Our data demonstrate that monocytes from BCaM0 release larger amounts of IL-8 than monocytes from BCaM0 and from HD. Lithium was able to downregulate IL-8 production by monocytes from different subgroups. Further studies are needed to clarify if the improvement of the hematopoietic system in vivo observed following lithium therapy could reside, at least in part, in the ability of lithium to downregulate this chemokine.

Evaluation of interleukin-18 production by in vitro differentiated monocytes from breast cancer patients.

Interleukin-18 (IL-18) is a multifunctional cytokine which may play an important role in cancer. In previous studies it has been reported that mononuclear cells from breast cancer patients were defective in cytokine production. In this report we examined in vitro IL-18 release by monocytes (Mo) and differentiated monocytes (Mphi) for 6 or 12 days from healthy donors (HD) and nonmetastatic breast cancer (BCa) patients prior to chemo-, hormonal or radiotherapy. Our results show no production of this cytokine by Mo and Mphi for 6 days in all the experimental conditions. HD Mphi cultured for 12 days were responsive to lipopolysaccharides only after 24 h of treatment, while significantly (p<0.05) lower amounts of IL-18 were produced by BCa Mphi cultures in the same experimental conditions. Since BCa Mphi are defective in IL-18 production, and this cytokine elicits in vivo protective antitumor effects, we hypothesize a future possibility for the use of IL-18 in cancer therapy.

Gemcitabine as single agent in the treatment of elderly patients with advanced non small cell lung cancer.

BACKGROUND: In phase II trials gemicitabine proved to be an active agent in NSCLC, producing a clinical benefit, often higher than response rate. PATIENTS AND METHODS: We assessed the impact of gemcitabine treatment on response rate and quality of life in 21 untreated elderly patients (aged > 70 years) with NSCLC. Gemcitabine (1250 mg/sm) was administered days 1-8 every 21 days. Response and toxicity were analyzed according to WHO criteria. The assessment of quality of life was performed by analysing a disease symptom related questionnaire completed by the patient. RESULTS: All the patients were evaluable: we found 7 PR (33%), 5 SD (24%) and 9 PD; the median duration of response was 24 weeks; the median overall survival 32 weeks; WHO grade 2 leukopenia (in 4 patients) and thrombocytopenia (grade 3 in 1 patient and grade 2 in two patients) were the main toxic effects. A clinical benefit was demonstrated in all 12 patients with PR or SD and in 3 patients with PD. CONCLUSIONS: These data confirm that gemcitabine is a well tolerated and active therapeutic approach in elderly non small cell lung cancer patients.