The solution of nonlinear inverse problems is a challenging task in numerical analysis. In most cases, this kind of problems is solved by iterative procedures that, at each iteration, linearize the ...problem in a neighborhood of the currently available approximation of the solution. The linearized problem is then solved by a direct or iterative method. Among this class of solution methods, the Gauss–Newton method is one of the most popular ones. We propose an efficient implementation of this method for large-scale problems. Our implementation is based on projecting the nonlinear problem into a sequence of nested subspaces, referred to as Generalized Krylov Subspaces, whose dimension increases with the number of iterations, except for when restarts are carried out. When the computation of the Jacobian matrix is expensive, we combine our iterative method with secant (Broyden) updates to further reduce the computational cost. We show convergence of the proposed solution methods and provide a few numerical examples that illustrate their performance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
It is well known that interferon-α (IFN-α), used for long time as the main therapy for HCV-related disease, induces thyroid alterations, but the impact of the new direct-acting antivirals ...(DAAs) on thyroid is not established. Aim of this prospective study was to evaluate if DAAs therapy may induce thyroid alterations.
Methods
A total of 113 HCV patients, subdivided at the time of the enrollment in naïve group (
n
= 64) and in IFN-α group (
n
= 49) previously treated with pegylated interferon-α and ribavirin, were evaluated for thyroid function and autoimmunity before and after 20–32 weeks of DAAs.
Results
Before starting DAAs, a total of 8/113 (7.1%) patients showed Hashimoto's thyroiditis (HT) all belonging to IFN-α group (8/49, 16.3%), while no HT cases were found in the naïve group. Overall, 7/113 (6.2%) patients were hypothyroid: 3/64 (4.7%) belonging to naïve group and 4/49 (8.2%) to IFN-α group. Furthermore, a total of 8/113 patients (7.1%) showed subclinical hyperthyroidism: 2/64 (3.1%) were from naïve group and 6/49 (12.2%) from IFN-α group. Interestingly, after DAAs therapy, no new cases of HT, hypothyroidism and hyperthyroidism was found in all series, while 6/11 (54.5%) patients with non-autoimmune subclinical thyroid dysfunction became euthyroid. Finally, the only association between viral genotypes and thyroid alterations was genotype 1 and hypothyroidism.
Conclusions
This study supports evidence that DAAs have a limited or missing influence on thyroid in patients with HCV-related diseases. Moreover, it provides preliminary evidence that subclinical non-autoimmune thyroid dysfunction may improve after HCV infection resolution obtained by DAAs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
3.
Does HLA-G play a role in PBC? Miglianti, M.; Littera, R.; Mocci, S. ...
Digestive and liver disease,
02/2024, Volume:
56
Journal Article
Peer reviewed
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A healthy diet should balance caloric intake (quality calories) with a variety of foods poor in simple sugars, such as cereals and legumes, fruits and vegetables, nuts, low-fat dairy products, fish, ...meat, and eggs prepared with culinary skills and minimally processed. This paper investigates the eating habits of school children of Villagrande, Italy, a rural village characterized by the remarkable longevity of its inhabitants, and makes a comparison with a sample of school children of the same age from an urban setting in the island. A specific questionnaire was used to collect demographic data, meals structure and composition, frequency of food consumption, and characteristic of the usual diet. The frequency of healthy eating habits, according to the current standards, was superior in the rural compared to the urban setting. The consumption of vegetables was higher in rural than in urban students (≥ once a week, 94% vs 54%, p<0.01) whereas for fruit and legumes the percentages were comparable (≥ once a week, 97% vs 94% and 79% vs 71%, respectively). Cheese, which is a typical product of Sardinia and mostly homemade, was consumed more than once a week in 86% of rural compared to 73% of urban school children. Fish consumption was consistently higher in the rural compared to the urban area (more than once a week 81% vs 65% (p<0.001). Alcoholic beverages were consumed in small quantities in both cohorts surveyed, while soft drinks to a greater extent among urban school children. The overall nutrition pattern observed in the rural village could be considered the result of persistent traditional household influence and may prove useful to prevent early onset of obesity if extended to a broader school children population, although the implementation of such observations may be the biggest challenge
Conventional treatments of pediatric femoral shaft fractures may result in an unacceptable rate of complications, especially in complex fractures. These fractures include high-energy injuries ...resulting in unstable fracture patterns, fractures in the proximal or distal third, and fractures occurring in large or multiply injured children. Our goal was to evaluate whether a minimally invasive submuscular bridge plating technique provides stability for early functional treatment (without protective casting or bracing) and predictable healing. Fifty-one patients with an average age of 10 years were studied. Sixty-seven percent had high-energy injuries and 55% had unstable fracture patterns. With an average followup of 14.2 months, all fractures united with excellent clinical results. Two (4%) significant complications occurred: fracture of one 3.5-mm LC-DCP Ti plate, and refracture of a pathologic fracture after early plate removal. Four patients (8%) had a leg-length discrepancy ranging from 23-mm short to 10-mm long. The average operative time was 106 minutes, with average fluoroscopy time of 84 seconds. Procedures were done by 15 surgeons in five university medical centers. This technique offers the advantage of adequate stability for early functional treatment and predictable healing with maintenance of length and alignment for all pediatric femoral shaft fractures.
To discuss the use of renal mass biopsy (RMB) for small renal masses (SRMs), formulate technical aspects, outline potential pitfalls and provide recommendations for the practicing clinician.
The ...meeting was conducted as an informal consensus process and no scoring system was used to measure the levels of agreement on the different topics.
A moderated general discussion was used as the basis for consensus and arising issues were resolved at this point.
A consensus was established and lack of agreement to topics or specific items was noted at this point.
Recommended biopsy technique: at least two cores, sampling different tumour regions with ultrasonography being the preferred method of image guidance.
Pathological interpretation: ‘non‐diagnostic samples’ should refer to insufficient material, inconclusive and normal renal parenchyma. For non‐diagnostic samples, a repeat biopsy is recommended. Fine‐needle aspiration may provide additional information but cannot substitute for core biopsy.
Indications for RMB: biopsy is recommended in most cases except in patients with imaging or clinical characteristics indicative of pathology (syndromes, imaging characteristics) and cases whereby conservative management is not contemplated. RMB is recommended for active surveillance but not for watchful‐waiting candidates.
We report the results of an international consensus meeting on the use of RMB for SRMs, defining the technique, pathological interpretation and indications.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Amplification and/or activation of the c‐Myc proto‐oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the ...finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc‐dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c‐Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed up‐regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c‐Myc signaling. (Hepatology 2017;66:167–181).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is upregulated in many tumor types and is a promising target for cancer therapy. Herein, we elucidated the functional role of FAK in ...intrahepatic cholangiocarcinoma (iCCA) development and progression.
Expression levels and activation status of FAK were determined in human iCCA samples. The functional contribution of FAK to Akt/YAP murine iCCA initiation and progression was investigated using conditional Fak knockout mice and constitutive Cre or inducible Cre mice, respectively. The oncogenic potential of FAK was further examined via overexpression of FAK in mice. In vitro cell line studies and in vivo drug treatment were applied to address the therapeutic potential of targeting FAK for iCCA treatment.
FAK was ubiquitously upregulated and activated in iCCA lesions. Ablation of FAK strongly delayed Akt/YAP-driven mouse iCCA initiation. FAK overexpression synergized with activated AKT to promote iCCA development and accelerated Akt/Jag1-driven cholangiocarcinogenesis. Mechanistically, FAK was required for YAP(Y357) phosphorylation, supporting the role of FAK as a central YAP regulator in iCCA. Significantly, ablation of FAK after Akt/YAP-dependent iCCA formation strongly suppressed tumor progression in mice. Furthermore, a remarkable iCCA growth reduction was achieved when a FAK inhibitor and palbociclib, a CDK4/6 inhibitor, were administered simultaneously in human iCCA cell lines and Akt/YAP mice.
FAK activation contributes to the initiation and progression of iCCA by inducing the YAP proto-oncogene. Targeting FAK, either alone or in combination with anti-CDK4/6 inhibitors, may be an effective strategy for iCCA treatment.
We found that the protein FAK (focal adhesion kinase) is upregulated and activated in human and mouse intrahepatic cholangiocarcinoma samples. FAK promotes intrahepatic cholangiocarcinoma development, whereas deletion of FAK strongly suppresses its initiation and progression. Combined FAK and CDK4/6 inhibitor treatment had a strong anti-cancer effect in in vitro and in vivo models. This combination therapy might represent a valuable and novel treatment against human intrahepatic cholangiocarcinoma.
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•FAK is activated in human and mouse iCCA samples.•Overexpression of FAK promotes cholangiocarcinogenesis, whereas deletion of FAK strongly suppresses iCCA initiation and progression.•FAK modulates YAP nuclear localization by phosphorylating YAP at the Y357 residue to promote iCCA development.•FAK is a potential therapeutic target for human iCCA treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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