On iterated minimization in nonconvex optimization

In dynamic programming and decomposition methods one often applies an iterated minimization procedure. The problem variables are partitioned into several blocks, say x and y. Treating y as a parameter, the first phase consists of minimization with respect to the variable x. In a second phase the minimization of the resulting optimal value function depending on y is considered. In this paper we treat this basic idea on a local level. It turns out that strong stability (in the sense of Kojima) in the first phase is a natural assumption. In order to show that the iterated local minima of the parametric problem lead to a local minimum for the whole problem, we use a generalized version of a positive definiteness criterion of Fujiwara-Han-Mangasarian

Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

Biomarkers; Proteomics; Urothelial bladder cancerBiomarcadores; Proteómica; Cáncer de vejiga urotelialBiomarcadors; Proteòmica; Càncer de bufeta urotelialBackground Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12. Conclusions The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification. As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.Open access funding provided by Uppsala University. This work was supported by the Swedish Society for Medical Research (S15-0065) to S.M. and the Swedish Cancer Foundation (CAN 2017/199) to P-U. M. The funding bodies did not influence the research performed

Elevated levels of MMP12 sourced from macrophages are associated with poor prognosis in urothelial bladder cancer

Abstract Background Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required. Methods In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings. Results Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3–2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12. Conclusions The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification. As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment

Set optimization - a rather short introduction

Recent developments in set optimization are surveyed and extended including various set relations as well as fundamental constructions of a convex analysis for set- and vector-valued functions, and duality for set optimization problems. Extensive sections with bibliographical comments summarize the state of the art. Applications to vector optimization and financial risk measures are discussed along with algorithmic approaches to set optimization problems

Toksični učinci patulina na timus mužjaka štakora u razvoju

Patulin is a mycotoxin produced by several Penicillium, Aspergillus, and Byssachlamys species growing on food products. In this study, we investigated the effects of patulin on the thymus of growing male rats aged fi ve to six weeks. The rats were receiving it orally at a dose of 0.1 mg kg-1 bw a day for either 60 or 90 days. At the end of the experiment, the thymus was examined for histopathology by light microscopy and for epidermal growth factor (EGF) and its receptor (EGFR) by immunolocalisation. For morphometry we used the Bs200prop program to analyse images obtained with the Olympus BX51 light microscope. Cell ultrastructure was studied by electron microscopy. In rats treated with patulin, the thymus showed haemorrhage, plasma cell hyperplasia, a dilation and fi brosis in the cortex, enlarged interstitial tissue between the thymic lobules, enlarged fat tissue, thinning of the cortex, and blurring of the cortico-medullary demarcation. Electron microscopy showed signs of cell destruction, abnormalities of the nucleus and organelles, and loss of mitochondrial cristae. However, no differences were observed in thymus EGF and EGFR immunoreactivity between treated and control rats.Patulin je mikotoksin koji proizvode plijesni sojeva Penicillium, Aspergillus i Byssachlamys na različitim prehrambenim proizvodima kao podlozi. Učinke patulina istražili smo na timusu mužjaka štakora u razvoju (dobi 5 do 6 tjedana). Mikotoksin je životinjama davan per os u dnevnoj dozi 0,1 mg kg-1 tj. t. 60 odnosno 90 dana. Na kraju pokusa štakori su žrtvovani, timus je podvrgnut histološkim analizama s pomoću svjetlosne mikroskopije, a imunocitokemijskim je metodama istražena stanična lokalizacija epidermalnog faktora rasta (EGF) i njegova receptora (EGFR). Morfometrijska analiza provedena je s pomoću računalnog programa Bs200prop povezanog u sustav sa svjetlosnim mikroskopom Olympus BX51. Elektronskomikroskopski je istražena ultrastruktura stanica timusa. Utvrđeno je da patulin izaziva krvaranja u timusu, hiperplaziju plazma-stanica, dilataciju i fi brozu u kortikalnoj regiji timusa, širenje intersticijskog tkiva između režnjeva timusa, povećanje masnih stanica, smanjenje debljine kore timusa te nestanak kortiko-medularne demarkacije. Elektronskomikroskopski u tkivu timusa štakora tretiranih patulinom uočeni su znakovi raspadanja stanica, abnormalnosti jezgre i organela te gubitak mitohondrijskih krista. Unatoč navedenomu, na presjecima tkiva kontrolnih štakora i štakora tretiranih patulinom nismo utvrdili razlike u imunoreaktivnosti EGF i EGFR, što bi trebalo dodatno istražiti osjetljivijim molekularnim metodama

Antimicrobial resistance (AMR) nanomachines: mechanisms for fluoroquinolone and glycopeptide recognition, efflux and/or deactivation

In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics—the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins. Expression of efflux systems is regulated by GntR-like (S. aureus NorG), MarR-like (MgrA, MepR) regulators or a two-component signal transduction system (TCS) (S. aureus ArlSR). Resistance to the glycopeptide antibiotic teicoplanin occurs via efflux regulated by the TcaR regulator in S. aureus. Resistance to vancomycin occurs through modification of the D-Ala-D-Ala target in the cell wall peptidoglycan and removal of high affinity precursors, or by target protection via cell wall thickening. Of the six Van resistance types (VanA-E, VanG), the VanA resistance type is considered in this review, including its regulation by the VanSR TCS. We describe the recent application of biophysical approaches such as the hydrodynamic technique of analytical ultracentrifugation and circular dichroism spectroscopy to identify the possible molecular effector of the VanS receptor that activates expression of the Van resistance genes; both approaches demonstrated that vancomycin interacts with VanS, suggesting that vancomycin itself (or vancomycin with an accessory factor) may be an effector of vancomycin resistance. With 16 and 19 proteins or protein complexes involved in fluoroquinolone and glycopeptide resistances, respectively, and the complexities of bacterial sensing mechanisms that trigger and regulate a wide variety of possible resistance mechanisms, we propose that these antimicrobial resistance mechanisms might be considered complex ‘nanomachines’ that drive survival of bacterial cells in antibiotic environments

Helicobacter pylori Perturbs Iron Trafficking in the Epithelium to Grow on the Cell Surface

Helicobacter pylori (Hp) injects the CagA effector protein into host epithelial cells and induces growth factor-like signaling, perturbs cell-cell junctions, and alters host cell polarity. This enables Hp to grow as microcolonies adhered to the host cell surface even in conditions that do not support growth of free-swimming bacteria. We hypothesized that CagA alters host cell physiology to allow Hp to obtain specific nutrients from or across the epithelial barrier. Using a polarized epithelium model system, we find that isogenic ΔcagA mutants are defective in cell surface microcolony formation, but exogenous addition of iron to the apical medium partially rescues this defect, suggesting that one of CagA's effects on host cells is to facilitate iron acquisition from the host. Hp adhered to the apical epithelial surface increase basolateral uptake of transferrin and induce its transcytosis in a CagA-dependent manner. Both CagA and VacA contribute to the perturbation of transferrin recycling, since VacA is involved in apical mislocalization of the transferrin receptor to sites of bacterial attachment. To determine if the transferrin recycling pathway is involved in Hp colonization of the cell surface, we silenced transferrin receptor expression during infection. This resulted in a reduced ability of Hp to colonize the polarized epithelium. To test whether CagA is important in promoting iron acquisition in vivo, we compared colonization of Hp in iron-replete vs. iron-deficient Mongolian gerbils. While wild type Hp and ΔcagA mutants colonized iron-replete gerbils at similar levels, ΔcagA mutants are markedly impaired in colonizing iron-deficient gerbils. Our study indicates that CagA and VacA act in concert to usurp the polarized process of host cell iron uptake, allowing Hp to use the cell surface as a replicative niche