Adult B-Cell Acute Lymphoblastic Leukemia Cells Display Decreased PTEN Activity and Constitutive Hyperactivation of PI3K/Akt Pathway Despite High PTEN Protein Levels

Adult B-cell acute lymphoblastic leukemia remains a major therapeutic challenge, requiring a better characterization of the molecular determinants underlying disease progression and resistance to treatment. Here, using a phospho-flow cytometry approach we show that adult diagnostic B-cell acute lymphoblastic leukemia specimens display PI3K/Akt pathway hyperactivation, irrespective of their BCR-ABL status and despite paradoxically high basal expression of PTEN, the major negative regulator of the pathway. Protein kinase CK2 is known to phosphorylate PTEN thereby driving PTEN protein stabilization and concomitant PTEN functional inactivation. In agreement, we found that adult B-cell acute lymphoblastic leukemia samples show significantly higher CK2 kinase activity and lower PTEN lipid phosphatase activity than healthy controls. Moreover, the clinical-grade CK2 inhibitor CX-4945 (Silmitasertib) reversed PTEN levels in leukemia cells to those observed in healthy controls, and promoted leukemia cell death without significantly affecting normal bone marrow cells. Our studies indicate that CK2-mediated PTEN posttranslational inactivation, associated with PI3K/Akt pathway hyperactivation, are a common event in adult B-cell acute lymphoblastic leukemia and suggest that CK2 inhibition may constitute a valid, novel therapeutic tool in this malignancy.

Degree of disability, pain levels, muscle strength, and electromyographic function in patients with Hansen's disease with common peroneal nerve damage

INTRODUCTION: This study evaluated the degree of disability, pain levels, muscle strength, and electromyographic function (RMS) in individuals with leprosy. METHODS: We assessed 29 individuals with leprosy showing common peroneal nerve damage and grade 1 or 2 disability who were referred for physiotherapeutic treatment, as well as a control group of 19 healthy participants without leprosy. All subjects underwent analyses of degree of disability, electromyographic tests, voluntary muscle force, and the Visual Analog Pain Scale. RESULTS: McNemar's test found higher levels of grade 2 of disability (Δ = 75.9%; p = 0.0001) among individuals with leprosy. The Mann-Whitney test showed greater pain levels (Δ = 5.0; p = 0.0001) in patients with leprosy who had less extension strength in the right and left extensor hallucis longus muscles (Δ = 1.28, p = 0.0001; Δ = 1.55, p = 0.0001, respectively) and dorsiflexion of the right and left feet (Δ = 1.24, p = 0.0001; Δ = 1.45, p = 0.0001, respectively) than control subjects. The Kruskal-Wallis test showed that the RMS score for dorsiflexion of the right (Δ = 181.66 m·s-2, p = 0.001) and left (Δ = 102.57m·s-2, p = 0.002) feet was lower in patients with leprosy than in control subjects, but intragroup comparisons showed no difference. CONCLUSIONS: Leprosy had a negative influence on all of the study variables, indicating the need for immediate physiotherapeutic intervention in individuals with leprosy. This investigation opens perspectives for future studies that analyze leprosy treatment with physical therapeutic intervention.

MMP-9/RECK imbalance: a mechanism associated with high-grade cervical lesions and genital infection by Human Papillomavirus (HPV) and Chlamydia trachomatis

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Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome.

For patients with brain tumors identification of diagnostic and prognostic markers in easy accessible biological material, such as plasma or cerebrospinal fluid (CSF), would greatly facilitate patient management. MIC-1/GDF15 (growth differentiation factor 15) is a secreted protein of the TGF-beta superfamily and emerged as a candidate marker exhibiting increasing mRNA expression during malignant progression of glioma. Determination of MIC-1/GDF15 protein levels by ELISA in the CSF of a cohort of 94 patients with intracranial tumors including gliomas, meningioma and metastasis revealed significantly increased concentrations in glioblastoma patients (median, 229 pg/ml) when compared with control cohort of patients treated for non-neoplastic diseases (median below limit of detection of 156 pg/ml, p < 0.0001, Mann-Whitney test). However, plasma MIC-1/GDF15 levels were not elevated in the matching plasma samples from these patients. Most interestingly, patients with glioblastoma and increased CSF MIC-1/GDF15 had a shorter survival (p = 0.007, log-rank test). In conclusion, MIC-1/GDF15 protein measured in the CSF may have diagnostic and prognostic value in patients with intracranial tumors.

CD30 in PTCLS: correlation between RNA and protein levels in a large european series from the LYSA

Introduction: CD22 is expressed on most B-non-Hodgkin lymphomas (NHL); inotuzumab ozogamicin (INO) is an anti-CD22 antibody conjugated to calicheamicin. This study evaluated the safety and tolerability of INO plus R-CVP in patients (pts) with relapsed/refractory CD22+ B-NHL. Efficacy data were also collected. Methods: Part 1 of this open-label study identified a maximum tolerated dose (MTD) of INO 0.8mg/m,2 on day 2 plus R-CVP (rituximab 375mg/m,2 cyclophosphamide 750mg/m,2 and vincristine 1.4mg/m,2 on day 1; prednisone 40mg/m,2 on days 1-5) every 21 days. Subsequently, pts were enrolled in the MTD confirmation cohort (part 2, n = 10), which required a dose-limiting toxicity rate of <33% in cycle 1 and <4 pts discontinuing prior to cycle 3 due to an adverse event (AE) in the MTD expansion cohort (part 3, n = 22), which explored preliminary activity. Results: Parts 2 and 3 enrolled 32 pts: 16 pts with diffuse large B-cell lymphoma, 15 with follicular lymphoma and one with mantle cell lymphoma. Median age was 64.5 years (range 44-81 years); 34% of pts had 1 prior regimen, 34% had 2, 28% had ≥3 and 3% had none (median 2; range 0-6).Median treatment duration was five cycles (range 1-6). Part 2 confirmed the MTD as standard dose R-CVP plus INO 0.8mg/m,2; 2/10 pts had a dose-limiting toxicity (grade 3 increased ALT/AST, grade 4 neutropenia requiring G-CSF). One pt discontinued because of an AE prior to cycle 3. Common treatment-related AEs were thrombocytopenia (78%), neutropenia (66%), fatigue (50%), leukopenia (50%), nausea (41%) and lymphopenia (38%); common grade 3/4 AEs were neutropenia (63%), thrombocytopenia (53%), leukopenia (38%) and lymphopenia (31%). There was one case of treatment-related fatal pneumonia with grade 4 neutropenia. Ten pts discontinued treatment due to AEs; thrombocytopenia/delayed platelet recovery was the leading cause (grade 1/2, n = 6; grade 3/4, n = 3). Objective response rate (ORR) was 77% (n = 24/31 evaluable pts), including 26% (n=8/31) with complete response (CR); three pts had stable disease. Of the pts with follicular lymphoma, ORR was 100% (n = 15/15), including seven pts with CR. Of the pts with diffuse large B-cell lymphoma, ORR was 60% (n = 9/16), including one pt with CR. Conclusions: Results suggest that INOplus R-CVP has acceptable toxicity and promising activity in relapsed/refractory CD22+ B-NHL. The most common grade 3/4 AEs were hematologic. Follow-up for progression-free and overall survival is ongoing.

Phase I study of sorafenib combined with radiation therapy and temozolomide as first-line treatment of high-grade glioma.

BACKGROUND: Sorafenib (Sb) is a multiple kinase inhibitor targeting both tumour cell proliferation and angiogenesis that may further act as a potent radiosensitizer by arresting cells in the most radiosensitive cell cycle phase. This phase I open-label, noncontrolled dose escalation study was performed to determine the safety and maximum tolerated dose (MTD) of Sb in combination with radiation therapy (RT) and temozolomide (TMZ) in 17 patients with newly diagnosed high-grade glioma. METHODS: Patients were treated with RT (60 Gy in 2 Gy fractions) combined with TMZ 75 mg m(-2) daily, and Sb administered at three dose levels (200 mg daily, 200 mg BID, and 400 mg BID) starting on day 8 of RT. Thirty days after the end of RT, patients received monthly TMZ (150-200 mg m(-2) D1-5/28) and Sb (400 mg BID). Pharmacokinetic (PK) analyses were performed on day 8 (TMZ) and on day 21 (TMZ&Sb) (Clinicaltrials ID: NCT00884416). RESULTS: The MTD of Sb was established at 200 mg BID. Dose-limiting toxicities included thrombocytopenia (two patients), diarrhoea (one patient) and hypercholesterolaemia (one patient). Sb administration did not affect the mean area under the curve(0-24) and mean Cmax of TMZ and its metabolite 5-amino-imidazole-4-carboxamide (AIC). Tmax of both TMZ and AIC was delayed from 0.75 (TMZ alone) to 1.5 h (combined TMZ/Sb). The median progression-free survival was 7.9 months (95% confidence interval (CI): 5.4-14.55), and the median overall survival was 17.8 months (95% CI: 14.7-25.6). CONCLUSIONS: Although Sb can be combined with RT and TMZ, significant side effects and moderate outcome results do not support further clinical development in malignant gliomas. The robust PK data of the TMZ/Sb combination could be useful in other cancer settings.

Inverse metamorphic zonation in very low-grade Tibetan zone series of SE Zanskar and its tectonic consequences (NW India, Himalaya)

The metamorphism of the carbonate rocks of the SE Zanskar Tibetan zone has been studied by `'illite crystallinity'' and calcite-dolomite thermometry. The epizonal Zangla unit overlies the anchizonal Chumik unit. This discontinuous inverse zonation demonstrates a late to post-metamorphic thrust of the first unit over the second. The studied area underwent a complex tectonic history: - The tectonic units were stacked from the NE to the SW, generating recumbent folds, NE dipping thrusts and the regional metamorphism. The compressive movements were active under lower temperature conditions, resulting in late thrusts that disturbed the metamorphic zonation. The discontinuous inverse metamorphic zonation dates from this phase. - A NE vergent backfolding phase occurred at lower temperature conditions. It caused the uplift of more metamorphic levels. - A late extensional phase is revealed by the presence of NE dipping low angle normal faults, and a major high angle fault, the Sarchu fault. The low angle normal faults locally run along earlier thrusts (composite tectonic contacts). Their throw has been sufficient to reset a normal stratigraphic superposition (young layers overlying old ones), but insufficient to erase the inverse metamorphic relationship. However, the combined action of backfolding and normal faulting can locally lessen, or even cancel, the inverse metamorphic superposition. After deduction of the normal fault translation, the vertical component of the original thrust displacement through stratigraphy is 400 m, which is a value far too low to explain the temperature difference between the two units. The horizontal component of displacement is therefore far more important than the vertical one. The regional distribution of metamorphism within the Zangla unit points out to an anchizonal front and an epizonal inner part. This fact is in agreement with nappe tectonics.

Evidence for chronic low-grade systemic inflammation in individuals with agoraphobia from a population-based prospective study.

BACKGROUND: Anxiety disorders have been linked to an increased risk of incident coronary heart disease in which inflammation plays a key pathogenic role. To date, no studies have looked at the association between proinflammatory markers and agoraphobia. METHODS: In a random Swiss population sample of 2890 persons (35-67 years, 53% women), we diagnosed a total of 124 individuals (4.3%) with agoraphobia using a validated semi-structured psychiatric interview. We also assessed socioeconomic status, traditional cardiovascular risk factors (i.e., body mass index, hypertension, blood glucose levels, total cholesterol/high-density lipoprotein-cholesterol ratio), and health behaviors (i.e., smoking, alcohol consumption, and physical activity), and other major psychiatric diseases (other anxiety disorders, major depressive disorder, drug dependence) which were treated as covariates in linear regression models. Circulating levels of inflammatory markers, statistically controlled for the baseline demographic and health-related measures, were determined at a mean follow-up of 5.5 ± 0.4 years (range 4.7 - 8.5). RESULTS: Individuals with agoraphobia had significantly higher follow-up levels of C-reactive protein (p = 0.007) and tumor-necrosis-factor-α (p = 0.042) as well as lower levels of the cardioprotective marker adiponectin (p = 0.032) than their non-agoraphobic counterparts. Follow-up levels of interleukin (IL)-1β and IL-6 did not significantly differ between the two groups. CONCLUSIONS: Our results suggest an increase in chronic low-grade inflammation in agoraphobia over time. Such a mechanism might link agoraphobia with an increased risk of atherosclerosis and coronary heart disease, and needs to be tested in longitudinal studies.

High Risk HPV E6/E7 Oncoprotein Expression in Women with High Grade Squamous Intraepithelial Lesion

Purpose To correlate the expression of high-risk HPV E6 mRNA with pap smear, colposcopy, and biopsy results in women with high grade squamous intraepithelial lesion (HSIL). Methods A cross-sectional study was performed on women referred for primary care services after cytological diagnosis of HSIL. We evaluated the expression of E6/E7 mRNA of HPV types 16,18,31,33, and 45 and correlated the results with those of Pap smear, colposcopy, and biopsy. For amplification/detection of mRNA E6 / E7 we used NucliSENSEasyQ kit to detect HPV mRNA by polymerase chain reaction with primers/ probes for HPV types 16, 18, 31, 33, and 45. Results Out of 128 valid tests, the results of 30 (23.4%) tests were negative and 98 (70%) tests were positive. Only one type of HPV was detected in 87.7% of the E6/E7 mRNA positive cases. HPV16 was detected in 61.2% of the cases, followed by HPV33 (26.5%), HPV31 (17.3%), HPV18 (10%), and HPV45 (4.08%). Pap smear tests revealed that the E6/E7 test was positive in 107 (83.8%) women with atypical squamous cells - high grade (ASC-H), HSIL, or higher. The E6/E7 test was positive in 69 (57.5%) specimens presenting negative cytology results. When analyzing the association with colposcopy results, the frequency of positive E6/E7 results increased with the severity of the injury, ranging from 57.1% in women without colposcopy-detected injury to 86.5% in those with higher levels of colposcopy findings. Of the 111 women who underwent biopsy and E6/E7 testing, the E6/E7 test was positive in 84.7% of the women who presented with lesions of cervical intraepithelial neoplasia (CIN) grade 2 or higher. Finally, 41.2% of women with a negative biopsy presented a positive E6/E7 test. Conclusions E6/E7mRNA expression was higher in women with HSIL and CIN grade 2 or higher.

Cardiovascular health risk profiling of Niagara Region grade 9 students : implications for elementary curriculum /

The purpose of this study was to determine if Ontario's health and physical education curriculum contributes sufficiently to ensure the health of our children and young adults. To determine the curriculum effect, the health risk profile of Niagara Region's grade 9 students was compared to Canada's adolescent population. All subjects completed a "Heart Health Lifestyle" survey and were measured for height, weight, percent body fat, blood pressure, and total cholesterol and performed the 20-metre shuttle run test as part of their physical and health education classes. The Niagara Region grade 9 population had a healthy risk profile. Aerobic power was inversely related, and cholesterol levels were positively associated to body mass index and percent body fat in the whole group analysis. These results indicate that physical education can offer unique and essential aspects allowing individuals a means to learn and control body movements and keep physically fit while providing protection against modern disease. Ontario's health and physical education curriculum does contribute to the health of our children and adolescents; however, there is a need to implement a stronger mandate for daily vigorous physical activity.

A classroom-based investigation of reciprocal teaching at the grade seven level

This study assessed the effectiveness of a reciprocal teaching program as a method of teaching reading comprehension, using narrative text material in a t.ypical grade seven classroom. In order to determine the effectiveness of the reciprocal teaching program, this method was compared to two other reading instruction approaches that, unlike rcciprocal teaching, did not include social interaction components. Two intact grade scven classes, and a grade seven teacher, participated in this study. Students were appropriately assigned to three treatment groups by reading achievement level as determined from a norm-referenced test. Training proceeded for a five week intervention period during regularly scheduled English periods. Throughout the program curriculum-based tests were administered. These tests were designed to assess comprehension in two distinct ways; namely, character analysis components as they relate to narrative text, and strategy use components as they contribute to student understanding of narrative and expository text. Pre, post, and maintenance tests were administered to measure overall training effects. Moreover, during intervention, training probes were administered in the last period of each week to evaluate treatment group performance. AU curriculum-based tests were coded and comparisons of pre, post, maintenance tests and training probes were presented in graph form. Results showed that the reciprocal group achieved some improvement in reading comprehension scores in the strategy use component of the tests. No improvements were observed for the character analysis components of the curriculum-based tests and the norm-referenced tests. At pre and post intervention, interviews requiring students to respond to questions that addressed metacomprehension awareness of study strategies were administered. The intelviews were coded and comparisons were made between the two intelVicws. No significant improvements were observed regarding student awareness of ten identified study strategies . This study indicated that reciprocal teaching is a viable approach that can be utilized to help students acquire more effective comprehension strategies. However, the maximum utility of the technique when administered to a population of grade seven students performing at average to above average levels of reading achievement has yet to be determined. In order to explore this issue, the refinement of training materials and curriculum-based measurements need to be explored. As well, this study revealed that reciprocal teaching placed heavier demands on the classroom teacher when compared to other reading instruction methods. This may suggest that innovative and intensive teacher training techniques are required before it is feasible to use this method in the classroom.

Development of Techniques for the Automatic Extraction and Grade Detection of Glioma Tumors from Conventional Brain Magnetic Resonant Images

Cerebral glioma is the most prevalent primary brain tumor, which are classified broadly into low and high grades according to the degree of malignancy. High grade gliomas are highly malignant which possess a poor prognosis, and the patients survive less than eighteen months after diagnosis. Low grade gliomas are slow growing, least malignant and has better response to therapy. To date, histological grading is used as the standard technique for diagnosis, treatment planning and survival prediction. The main objective of this thesis is to propose novel methods for automatic extraction of low and high grade glioma and other brain tissues, grade detection techniques for glioma using conventional magnetic resonance imaging (MRI) modalities and 3D modelling of glioma from segmented tumor slices in order to assess the growth rate of tumors. Two new methods are developed for extracting tumor regions, of which the second method, named as Adaptive Gray level Algebraic set Segmentation Algorithm (AGASA) can also extract white matter and grey matter from T1 FLAIR an T2 weighted images. The methods were validated with manual Ground truth images, which showed promising results. The developed methods were compared with widely used Fuzzy c-means clustering technique and the robustness of the algorithm with respect to noise is also checked for different noise levels. Image texture can provide significant information on the (ab)normality of tissue, and this thesis expands this idea to tumour texture grading and detection. Based on the thresholds of discriminant first order and gray level cooccurrence matrix based second order statistical features three feature sets were formulated and a decision system was developed for grade detection of glioma from conventional T2 weighted MRI modality.The quantitative performance analysis using ROC curve showed 99.03% accuracy for distinguishing between advanced (aggressive) and early stage (non-aggressive) malignant glioma. The developed brain texture analysis techniques can improve the physician’s ability to detect and analyse pathologies leading to a more reliable diagnosis and treatment of disease. The segmented tumors were also used for volumetric modelling of tumors which can provide an idea of the growth rate of tumor; this can be used for assessing response to therapy and patient prognosis.

Chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and TLR4 mRNA in rat skeletal muscle

Skeletal muscle is the source of pro- and anti-inflammatory cytokines, and recently, it has been recognized as an important source of interleukin 6 (IL-6), a cytokine that exerts inhibitory effects on several pro-inflammatory cytokines. Although dynamic chronic resistance training has been shown to produce the known ""repeated bout effect"", which abolishes the acute muscle damage, performing of high-intensity resistance training has been regarded highly advisable, at least from the hypertrophy perspective. On the other hand, a more therapeutic, ""non-damaging"" resistance training program, mainly composed of concentric forces, low frequency/low volume of training, and the same exercise, could theoretically benefit the muscle when the main issue is to avoid muscle inflammation (as in the treatment of several ""low-grade"" inflammatory diseases) because the acute effect of each resistance exercise session could be diminished/avoided, at the same time that the muscle is still being overloaded in a concentric manner. However, the benefits of such ""less demanding"" resistance training schedule on the muscle inflammatory profile have never been investigated. Therefore, we assessed the protein expression of IL-6, TNF-alpha, IL-10, IL-10/TNF-alpha ratio, and HSP70 levels and mRNA expression of SCF(beta-TrCP), IL-15, and TLR-4 in the skeletal muscle of rats submitted to resistance training. Briefly, animals were randomly assigned to either a control group (S, n = 8) or a resistance-trained group (T, n = 7). Trained rats were exercised over a duration of 12 weeks (two times per day, two times per week). Detection of IL-6, TNF-alpha, IL-10, and HSP70 protein expression was carried out by western blotting and SCF(beta-TrCP) (SKP Cullin F-Box Protein Ligases), a class of enzymes involved in the ubiquitination of protein substrates to proteasomal degradation, IL-15, and TLR-4 by RT-PCR. Our results show a decreased expression of TNF-alpha and TLR4 mRNA (40 and 60%, respectively; p < 0.05) in the plantar muscle from trained, when compared with control rats. In conclusion, exercise training induced decreased TNF-alpha and TLR-4 expressions, resulting in a modified IL-10/TNF-alpha ratio in the skeletal muscle. These data show that, in healthy rats, 12-week resistance training, predominantly composed of concentric stimuli and low frequency/low volume schedule, down regulates skeletal muscle production of cytokines involved in the onset, maintenance, and regulation of inXammation.

Endotoxin levels correlate positively with a sedentary lifestyle and negatively with highly trained subjects

Introduction: A sedentary lifestyle increases the risk of developing cardiovascular disease, obesity, and diabetes. This phenomenon is supported by recent studies suggesting a chronic, low-grade inflammation status. Endotoxin derived from gut flora may be key to the development of inflammation by stimulating the secretion of inflammatory factors. This study aimed to examine plasma inflammatory markers and endotoxin levels in individuals with a sedentary lifestyle and/or in highly trained subjects at rest. Methods: Fourteen male subjects (sedentary lifestyle n = 7; highly trained subjects n = 7) were recruited. Blood samples were collected after an overnight fast (similar to 12 h). The plasmatic endotoxin, plasminogen activator inhibitor type-1 (PAI-1), monocyte chemotactic protein-1 (MCP1), ICAM/CD54, VCAM/CD106 and lipid profile levels were determined. Results: Endotoxinemia was lower in the highly trained subject group relative to the sedentary subjects (p < 0.002). In addition, we observed a positive correlation between endotoxin and PAI-1 (r = 0.85, p < 0.0001), endotoxin and total cholesterol (r = 0.65; p < 0.01), endotoxin and LDL-c (r = 0.55; p < 0.049) and endotoxin and TG levels (r = 0.90; p < 0.0001). The plasma levels of MCP-1, ICAM/CD54 and VCAM/CD106 did not differ. Conclusion: These results indicate that a lifestyle associated with high-intensity and high-volume exercise induces favorable changes in chronic low-grade inflammation markers and may reduce the risk for diseases such as obesity, diabetes and cardiovascular diseases.

Cathepsin S as a biomarker of low-grade inflammation, insulin resistance, and cardiometabolic disease risk

Cathepsin S is a protease important in major histocompatibility complex (MHC) class II antigen presentation and also in degrading the extracellular matrix. Studies, most of them experimental, have shown that cathepsin S is involved in different pathological conditions such as obesity, inflammation, atherosclerosis, diabetes, and cancer.    The overall hypothesis of this report is that high levels of circulating cathepsin S, is a biomarker that reflects pathology induced by inflammation and obesity. The overall aim of this report was to investigate possible associations between circulating cathepsin S, inflammation, glucometabolic disturbance, and its associated diseases in the community. As cathepsin S appears to be a novel risk marker for several pathological conditions, we also wanted to examine the effect of dietary intervention on circulating cathepsin S concentrations.    This thesis is based on data from three community-based cohorts, the Uppsala longitudinal study of adult men (ULSAM), the prospective investigation of the vasculature in Uppsala seniors (PIVUS), and a post-hoc study from the randomized controlled NORDIET trial.    In the first study, we identified a cross-sectional positive association between serum cathepsin S and two markers of cytokine-mediated inflammation, CRP and IL-6. These associations were similar in non-obese individuals. In longitudinal analyses, higher cathepsin S at baseline was associated with higher CRP and IL-6 levels after six years of follow-up. In the second study, we identified a cross-sectional association between increased serum levels of cathepsin S and reduced insulin sensitivity. These associations were similar in non-obese individuals. No significant association was observed between cathepsin S and insulin secretion. In longitudinal analysis, higher cathepsin S levels were associated with an increased risk of developing diabetes during the six-year follow-up. In the third study, we found that higher serum levels of cathepsin S were associated with increased mortality risk. Moreover, in the ULSAM cohort, serum cathepsin S was independently associated with cause-specific mortality from cardiovascular disease and cancer. In the fourth study, we identified that adherence to an ad libitum healthy Nordic diet for 6 weeks slightly decreased the levels of plasma cathepsin S in normal or marginally overweight individuals, relative to the control group. Changes in circulating cathepsin S concentrations were correlated with changes in body weight, LDL-C, and total cholesterol.    Conclusion: This thesis shows that circulating cathepsin S is a biomarker that independently reflects inflammation, insulin resistance, the risk of developing diabetes, and mortality risk. Furthermore, a Nordic diet moderately reduced cathepsin S levels in normal-weight and overweight men and women. This effect may be partially mediated by diet-induced weight loss and possibly by reduced LDL-C concentrations.