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The Higgs doublet can mediate a long-range interaction between multi-TeV particles coupled to the Weak interactions of the Standard Model, while its emission can lead to very rapid bound-state formation processes and bound-to-bound transitions. Using the rates calculated in a companion paper, here we compute the thermal decoupling of multi-TeV WIMP dark matter coupled to the Higgs, and show that the formation of metastable dark matter bound states via Higgs-doublet emission and their decay decrease the relic density very significantly. This in turn implies that WIMP dark matter may be much heavier than previously anticipated, or conversely that for a given mass, the dark matter couplings to the Higgs may be much lower than previously predicted, thereby altering the dark matter phenomenology. While we focus on a minimal singlet-doublet model in the coannihilation regime, our calculations can be extended to larger multiplets where the effects under consideration are expected to be even more significant. [ABSTRACT FROM AUTHOR]

We investigate the role of the Higgs doublet in the thermal decoupling of multi-TeV dark matter coupled to the Weak interactions of the Standard Model and the Higgs. The Higgs doublet can mediate a long-range force that affects the annihilation processes and binds dark matter into bound states. More importantly, the emission of a Higgs doublet by a pair of dark matter particles can give rise to extremely rapid monopole bound-state formation processes and bound-to-bound transitions. We compute these effects in the unbroken electroweak phase. To this end, we consider the simplest renormalisable fermionic model, consisting of a singlet and a doublet under SUL(2) that are stabilised by a ℤ2 symmetry, in the regime where the two multiplets coannihilate. In a companion paper, we use the results to show that the formation of metastable bound states via Higgs-doublet emission and their decay decrease the relic density very significantly. [ABSTRACT FROM AUTHOR]

The formation of stable or meta-stable bound states can dramatically affect the phenomenology of dark matter (DM). Although the capture into bound states via emission of a vector is known to be significant, the capture via scalar emission suffers from cancellations that render it important only within narrow parameter space. While this is true for neutral scalar mediators, here we show that bound-state formation via emission of a charged scalar can be extremely significant. To this end, we consider DM charged under a dark U(1) force and coupled also to a light complex scalar that is charged under the same gauge symmetry. We compute the cross-sections for bound-state formation via emission of the charged scalar, and show that they can exceed those for capture via vector emission, as well as annihilation, by orders of magnitude. This holds even for very small values of the DM coupling to the charged scalar, and remains true in the limit of global symmetry. We then compute the DM thermal freeze-out, and find that the capture into meta-stable bound states via emission of a charged scalar can cause a late period of significant DM depletion. Our results include analytical expressions in the Coulomb limit, and are readily generalisable to non-Abelian interactions. We expect them to have implications for Higgs-portal scenarios of multi-TeV WIMP DM, as well as scenarios that feature dark Higgses or (darkly-)charged inert scalars, including models of self-interacting DM. [ABSTRACT FROM AUTHOR]

We compute the cross-sections for the radiative capture of non-relativistic particles into bound states, in unbroken perturbative non-Abelian theories. We find that the formation of bound states via emission of a gauge boson can be significant for a variety of dark matter models that feature non-Abelian long-range interactions, including multi-TeV scale WIMPs, dark matter co-annihilating with coloured partners and hidden-sector models. Our results disagree with previous computations, on the relative sign of the Abelian and non-Abelian contributions. In particular, in the case of capture of a particle-antiparticle pair into its tightest bound state, we find that these contributions add up, rather than partially canceling each other. We apply our results to dark matter co-annihilating with particles transforming in the (anti)fundamental of SU(3)c, as is the case in degenerate stop-neutralino scenarios in the MSSM. We show that the radiative formation and decay of particle-antiparticle bound states can deplete the dark matter density by (40 - 240)%, for dark matter heavier than 500 GeV. This implies a larger mass difference between the co-annihilating particles, and allows for the dark matter to be as heavy as 3.3TeV. [ABSTRACT FROM AUTHOR]

We calculate the cross-sections for the radiative formation of bound states by dark matter whose interactions are described in the non-relativistic regime by a Yukawa potential. These cross-sections are important for cosmological and phenomenological studies of dark matter with long-range interactions, residing in a hidden sector, as well as for TeV-scale WIMP dark matter. We provide the leading-order contributions to the cross-sections for the dominant capture processes occurring via emission of a vector or a scalar boson. We offer a detailed inspection of their features, including their velocity dependence within and outside the Coulomb regime, and their resonance structure. For pairs of annihilating particles, we compare bound-state formation with annihilation. [ABSTRACT FROM AUTHOR]

Asymmetric dark matter models are based on the hypothesis that the present-day abundance of dark matter has the same origin as the abundance of ordinary or "visible" matter: an asymmetry in the number densities of particles and antiparticles. They are largely motivated by the observed similarity in the mass densities of dark and visible matter, with the former observed to be about five times the latter. This review discusses the construction of asymmetric dark matter models, summarizes cosmological and astrophysical bounds, and touches on direct detection prospects and collider signatures. [ABSTRACT FROM AUTHOR]

The ultra-slow-roll (USR) inflation represents a class of single-field models with sharp deceleration of the rolling dynamics on small scales, leading to a significantly enhanced power spectrum of the curvature perturbations and primordial black hole (PBH) formation. Such a sharp transition of the inflationary background can trigger the coherent motion of scalar condensates with effective potentials governed by the rolling rate of the inflaton field. We show that a scalar condensate carrying (a combination of) baryon or lepton number can achieve successful baryogenesis through the Affleck-Dine mechanism from unconventional initial conditions excited by the USR transition. Viable parameter space for creating the correct baryon asymmetry of the Universe naturally incorporates the specific limit for PBHs to contribute significantly to dark matter, shedding light on the cosmic coincidence problem between the baryon and dark matter densities today. [ABSTRACT FROM AUTHOR]

A 20-year-old woman was admitted with iron deficiency anemia and history of melena. Upper endoscopy demonstrated normal esophagus, stomach and proximal duodenum. At colonoscopy, two bluish pedunculated angiectatic polypoid lesions (1 to 2 cm in diameter) were noted due to blue rubber bleb nevus syndrome (BRBNS). The small intestine was screened for further lesions with the use of capsule endoscopy. The capsule identified four more lesions at the proximal jejunum. The small bowel lesions were smaller, 0.5 to 1cm in diameter at their bases. We performed enteroscopy to approach the jejunal lesions. All lesions were ligated in one session using the band ligation technique with multi-band ligator device. A colonoscopy was performed and detachable snares - endoloops were inserted at the colonic lesions. Three weeks following the interventions further endoscopic evaluations were performed; they revealed scars at all sites treated with either technique. No bleeding or new venous malformations were observed. In conclusion, we report a dual technique resection method on a patient with BRBNS. The choice of resection technique depended on the lesion characteristics. Both band ligation and endoloop can be safely used for polypoid BRBNS lesions at the jejunum and colon respectively. [ABSTRACT FROM AUTHOR]

Background and Aims: Helicobacter pylori (H. pylori)‐induced gastric pathology involves remodeling of extracellular matrix mediated by aberrant activity of matrix metalloproteinases (MMPs). We have previously shown that in vitro H. pylori infection leads to MMP‐3 and MMP‐9 overexpression, associated with phosphorylation of bacterial oncoprotein CagA. We extended these findings in an in vivo model of H. pylori infection and further assessed the involvement of MAPK pathways in MMP expression. Materials and Methods: C57BL/6 mice were infected with H. pylori strains HPARE, HPARE ΔCagA, and SS1, for 6 and 9 months. Transcriptional expression of Mmp‐3 and Mmp‐9 was evaluated via qPCR while respective protein levels in the gastric mucosa were determined immunohistochemically. Epithelial cell lines AGS and GES‐1 were infected with H. pylori strain P12 in the presence of chemical inhibitors of JNK, ERK1/2, and p38 pathways, for 24 h. mRNA and protein expression of MMP‐3 and MMP‐9 were determined via qPCR and Western blot, respectively. Results: We observed transcriptional activation of Mmp‐3 and Mmp‐9 as well as aberrant MMP‐3 and MMP‐9 protein expression in murine gastric tissue following H. pylori infection. CagA expression was associated with MMP upregulation, particularly during the early time points of infection. We found that inhibition of ERK1/2 resulted in reduced mRNA and protein expression of MMP‐3 and MMP‐9 during H. pylori infection, in both cell lines. Expressed protein levels of both MMPs were also found reduced in the presence of JNK pathway inhibitors in both cell lines. However, p38 inhibition resulted in a more complex effect, probably attributed to the accumulation of phospho‐p38 and increased phospho‐ERK1/2 activity due to crosstalk between MAPK pathways. Conclusions: H. pylori colonization leads to the upregulation of MMP‐3 and MMP‐9 in vivo, which primarily involves ERK1/2 and JNK pathways. Therefore, their inhibition may potentially offer a protective effect against gastric carcinogenesis and metastasis. [ABSTRACT FROM AUTHOR]

The formation and decay of metastable bound states can significantly decrease the thermal-relic dark matter density, particularly for dark matter masses around and above the TeV scale. Incorporating bound-state effects in the dark matter thermal decoupling requires in principle a set of coupled Boltzmann equations for the bound and unbound species. However, decaying bound states attain and remain in a quasi-steady state. Here we prove in generality that this reduces the coupled system into a single Boltzmann equation of the standard form, with an effective cross-section that describes the interplay among bound-state formation, ionisation, transitions and decays. We derive a closed-form expression for the effective cross-section for an arbitrary number of bound states, and show that bound-to-bound transitions can only increase it. Excited bound levels may thus decrease the dark matter density more significantly than otherwise estimated. Our results generalise the Saha ionisation equilibrium to metastable bound states, potentially with applications beyond the dark matter thermal decoupling. [ABSTRACT FROM AUTHOR]

Background: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation.Methods: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease.Results: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms.Conclusions: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period.Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033. [ABSTRACT FROM AUTHOR]

An extensively studied mechanism to create particle-antiparticle asymmetries is the out-of-equilibrium and CP violating decay of a heavy particle. We, instead, examine how asymmetries can arise purely from 2 →2 annihilations rather than from the usual 1→2 decays and inverse decays. We review the general conditions on the reaction rates that arise from 5-matrix unitarity and CPT invariance, and show how these are implemented in the context of a simple toy model. We formulate the Boltzmann equations for this model, and present an example solution. [ABSTRACT FROM AUTHOR]

Abstract: We consider sterile neutrinos with rest masses and with vacuum flavor mixing angles for mixing with τ-neutrinos, or for mixing with muon neutrinos. Such sterile neutrinos could augment core collapse supernova shock energies by enhancing energy transport from the core to the vicinity of the shock front. The decay of these neutrinos could produce a flux of very energetic active neutrinos, detectable by future neutrino observations from galactic supernova. The relevant range of sterile neutrino masses and mixing angles can be probed in future laboratory experiments. [Copyright &y& Elsevier]

Objective . To study the immunophenotypic characteristics and clinical outcome of morphologically undifferentiated prostatic carcinoma with small-cell morphology (U-PC-SCM). Material and methods . Sixteen patients with U-PC-SCM were enrolled. The streptavidin–biotin complex immunohistochemical method was used on paraffin-embedded tissue sections to test positivity for prostate-specific antigen, prostate-specific acid phosphatase, CD57, androgen receptors, CK8-18, epithelial membrane antigen, carcinoembryonic antigen, CD56, neuron-specific enolase, chromogranin, synaptophysin, serotonin, various hormones, thyroid transcriptional factor-1 and Ki-67/MIB1. Results . Based on immunophenotypic criteria, we identified two groups of patients. The final diagnosis was U-PC (Gleason score 10) in Group 1 ( n =9) and pure or mixed neuroendocrine small-cell carcinoma in Group 2 ( n =7). Group 1 underwent total androgen blockade (TAB) with no major response and had a median survival of 9 months. In Group 2, three patients underwent TAB, two of whom died of progressive disease. The third patient showed a partial response (PR) for 18 months but eventually relapsed with liver metastatic lesions. He was then treated with cisplatin + etoposide and showed a PR for 3 months and survived for 5 months after the initiation of the second-line chemotherapy (CTH) treatment. The other four patients received six cycles of cisplatin + etoposide. There were two complete responses of >14 and >22 months, respectively and 2 PRs of 11 and 17 months, respectively, the partial responders surviving for 14 and 21 months, respectively. Conclusion . U-PC-SCM with a neuroendocrine immunophenotype is a histogenetically distinct entity with different clinical and laboratory manifestations which responds well to a cisplatin + etoposide CTH regimen. [ABSTRACT FROM AUTHOR]

Background Missed polyps during colonoscopy are considered an important factor for interval cancer appearance, especially in the ascending colon (AC). We evaluated the contribution of retroflexion to polyp and adenoma detection in the AC. Methods This prospective observational study included consecutive patients who underwent a complete colonoscopy between 06/2017 and 06/2018. The AC was examined in 2 phases: the first included 2 forward views from the hepatic flexure to the cecum; the second involved a retroflexion in the cecum, inspection up to the hepatic flexure and reinsertion to the cecum. Results The study included 655 patients, 628 (95.88%) with successful retroflexion (mean age: 62.5±10.8 years, 332 male). Indications for colonoscopy were screening in 33.28%, follow up in 36.03%, and diagnostic assessment in 30.69%. In total, 286 polyps and 220 adenomas were detected in the AC. Phase 1 identified 119 adenomas, yielding an adenoma detection rate (ADR) in the AC of 14.2% (95% confidence interval [CI] 11.52-16.84%) while phase 2 identified 86 additional adenomas, improving the ADR in the AC to 22.75% (95%CI 19.54-25.96%; P<0.01). Adenoma miss rate was 39.1% (86/225) and per-patient adenoma miss rate was 11.15% (73/655). Retroflexion proved beneficial mainly in the upper third of the AC (odds ratio [OR] 4.29, 95%CI 1.84-11.56; P<0.01) and for small (<5 mm) adenomas (OR 1.61, 95%CI 1.02-2.56; P=0.04). Multivariate analysis showed that age >60 years, detection of adenomas in forward views and the indication “follow up” influenced ADR during retroflexion. Conclusion Retroflexion is a simple and safe maneuver that increases the ADR in the AC and should complete a second forward view. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. Methods: We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. Results: The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman's rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values < 0.001). Higher sTIL density (10% increments), high density of almost each individual marker and all-high profiles conferred favorable prognosis. However, when adjusted for sTIL density, stromal and intratumoral lymphocytic subsets lost their prognostic significance, while higher sTIL density conferred up to 15% lower risk for relapse. Independently of sTIL density, higher total CD3+ and CD8+ TILs conferred 35% and 28% lower risk for relapse, respectively. Conclusions: Stromal and intratumoral CD3+, CD8+ and FOXP3+ TIL density do not seem to add prognostic information over the morphologically assessed sTIL density, which is worth introducing in routine histology reports. [ABSTRACT FROM AUTHOR]

The formation and decay of dark matter (DM) bound states deplete the thermal relic density during the chemical decoupling process, allowing for larger DM masses. While so far the bound state formation (BSF) has been described via the emission of an on-shell mediator, we point out that this particular process does not have to be the dominant one in general. If the mediator is coupled in a direct way to any relativistic species present in the early Universe, we demonstrate that BSF can much more efficiently occur through particle scattering. Consequently, DM can be heavier than previously expected. [ABSTRACT FROM AUTHOR]

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21–0.88, Wald’s p = 0.022 and HR = 0.43, 95% CI 0.21–0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19–10.50, p = 0.023 and HR = 3.37, 95% CI 1.12–10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22–0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29–12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23–0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. [ABSTRACT FROM AUTHOR]

A 51-year-old man underwent diagnostic work-up for an abnormal-appearing ampulla of Vater. Three hours after biopsy of the ampulla, the patient presented with intense symptoms suggesting acute pancreatitis, which was later confirmed with laboratory and radiographic examinations. Other causes were excluded and the acute pancreatitis was considered a procedural complication. This is a rarely reported complication that must be taken into consideration when biopsies are performed in the ampulla of Vater. [ABSTRACT FROM AUTHOR]

Background Currently only a few studies compare sequential and concomitant non-bismuth Helicobacter pylori therapies referring to high antibiotic resistance populations. Materials and methods This multicenter prospective randomized clinical trial included 353 H. pylori positive, treatment naïve, patients. All patients had positive CLO-test and/or histology and culture. They received sequential (esomeprazole 40 mg, amoxicillin 1 g/bid for 5 days, followed by 5 days of esomeprazole 40 mg, clarithromycin 500 mg and metronidazole 500 mg bid), or concomitant treatment (all drugs taken concomitantly bid for 10 days). Eradication was confirmed by 13 C-urea breath test or histology 4–6 weeks after treatment. Adverse events and adherence were evaluated. Results Allocated to concomitant were 175 (72F/103M, mean 52.3 years, 38.3% smokers, 25.7% ulcer disease) and 178 (87F/91M, mean 52 years, 31% smokers, 19.1% ulcer disease) patients to sequential treatment. There were 303/353 (85.8%) positive cultures, with the following resistances: 34% metronidazole, 27.7% clarithromycin, and 7.9% dual. Eradication rates were, respectively, 89.1% (156/175) vs. 78.7% (140/178) by intention to treat ( p = 0.01, 95% CI = 2.7–18) and 93.4%(156/167) vs. 82.8% (140/169) per protocol ( p = 0.004, 95% CI = 3.6–17.6). Overall, adherence was (98.9%, 95% CI = 97–100). Eradication rates according to resistance were the following: dual susceptible strains 67/69 (97.1%), 62/67 (92%) ( p = 0.4), metronidazole single resistant 38/39 (97.4%), 31/39 (79.5%) ( p = 0.03, 95% CI = 3.5–33), clarithromycin single resistant 25/28 (89.3%), 26/31 (83.9%) ( p = 0.8), and dual resistant 9/12 (75%), 4/11 (36.4%) ( p = 0.1) for concomitant and sequential regimens, respectively. Side effects were comparable among regimens, except from diarrhea being more frequent among patients treated with concomitant treatment. Conclusions Concomitant treatment eradication rate overcomes 90% per protocol and has a significant advantage over sequential therapy. This is probably due to its better efficacy on metronidazole resistant strains. Both regimens were well tolerated and safe. [ABSTRACT FROM AUTHOR]

Background: There is an unmet need for more efficient patient stratification for receiving trastuzumab in the metastatic breast cancer (mBC) setting, since only part of such patients benefit from the addition of this agent to chemotherapy. The aim of this study was to investigate the prognostic value of biomarkers including MYC and MET in mBC patients treated with trastuzumab-based regimens.Methods: mBC patients, locally tested as HER2-positive, treated with trastuzumab and chemotherapy between 1998 and 2010 were evaluated. Paraffin tumors (n = 229) were retrospectively centrally assessed by immunohistochemistry (IHC) for HER2, ER, PgR and Ki67; fluorescence in situ hybridization (FISH) for HER2, TOP2A and centromere (CEN) 17, MYC and CEN8, MET and CEN7; qPCR for MYC, MET copy number (CN); and, for PI3K activation (PIK3CA mutations; PTEN and phospho-mTOR protein expression). Increased CEN CN was assessed based on normal cut-offs. Time to progression (TTP) and survival were evaluated from the initiation of trastuzumab as first line treatment.Results: Among all tumors, 90 were HER2-negative upon central testing (ambiguous HER2) and the rest were true HER2-positive. Further, 156 patients presented with mBC upon relapse of pre-treated disease (R-mBC) and 65 were diagnosed at stage IV (de novo mBC). Concordance between FISH and qPCR on gene CN status was fair for MYC (Kappa = 0.458) and absent for MET. The presence of MYC CN gain with qPCR and the absence of PI3K activation were infrequent events (7 and 8 % of evaluable tumors, respectively), while 41 % of tumors had increased CEN CN in one or more chromosomes, indicative of chromosomal instability. The most consistent finding in the entire cohort and in the above patient subgroups with respect to outcome was the unfavourable effect of MYC CN gain, which was retained upon multivariable analysis (e.g., survival in the entire cohort, HR 6.02; 95 % CI 2.67-13.6; p < 0.001). Further unfavourable prognosticators were increased CEN CN in one chromosome in R-mBC but not in de novo mBC (multivariable interaction p = 0.048), PI3K activation in R-mBC (multivariable p = 0.004) and increased Ki67 for patient TTP.Conclusions: MYC gene copies, centromere status and PI3K activation may adversely impact trastuzumab treated mBC patient outcome and seem worthy validating in larger series. [ABSTRACT FROM AUTHOR]

Purpose: The urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor 1 (PAI-1) are associated with an aggressive course in breast cancer and are used to determine whether chemotherapy is needed in node-negative patients. The objective of the study was to evaluate the prognostic value of uPA and PAI-1 protein expression in advanced breast cancer patients treated with trastuzumab. Methods: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 230 patients with advanced breast cancer treated with trastuzumab and 130 patients treated with 1st line taxanes. uPA, PAI-1, ER, PgR, HER2 and Ki67 protein expression was evaluated by immunohistochemistry. Results: Central review of HER2 status revealed that only 144 (63 %) of the trastuzumab-treated patients were truly HER2-positive. Median survival was 50.7 months for the HER2-positive and 30.1 months for the HER2-negative patients ( p = 0.006) treated with trastuzumab. In multivariate Cox regression analysis of the trastuzumab cohort, a significant interaction was found, in terms of survival, between HER2 status and PAI-1 protein expression in the stroma (Wald's p = 0.002). Positive PAI-1 protein expression in the stroma of HER2-negative patients was associated with lower risk of death (HR 0.35, 95 % CI 0.19-0.65, Wald's p = 0.0008). Such an association was not observed in HER2-positive patients treated with trastuzumab or in the non-trastuzumab (validation) cohorts. Conclusions: Our results suggest that positive stromal PAI-1 protein expression may identify a subgroup of HER2-negative advanced breast cancer patients who might benefit from treatment with trastuzumab. Further studies are warranted to validate these findings in larger cohorts. [ABSTRACT FROM AUTHOR]

Although epigenetic alterations play an essential role in gliomagenesis, the relevance of aberrant histone modifications and the respective enzymes has not been clarified. Experimental data implicates histone H3 lysine (K) methyltransferases SETDB1 and SUV39H1 into glioma pathobiology, whereas linker histone variant H1.0 and H4K20me3 reportedly affect prognosis. We investigated the expression of H3K9me3 and its methyltransferases along with H4K20me3 and H1x in 101 astrocytic tumors with regard to clinicopathological characteristics and survival. The effect of SUV39H1 inhibition by chaetocin on the proliferation, colony formation and migration of T98G cells was also examined. SETDB1 and cytoplasmic SUV39H1 levels increased from normal brain through low-grade to high-grade tumors, nuclear SUV39H1 correlating inversely with grade. H3K9me3 immunoreactivity was higher in normal brain showing no association with grade, whereas H1x and H4K20me3 expression was higher in grade 2 than in normal brain or high grades. These expression patterns of H1x, H4K20me3 and H3K9me3 were verified by Western immunoblotting. Chaetocin treatment significantly reduced proliferation, clonogenic potential and migratory ability of T98G cells. H1x was an independent favorable prognosticator in glioblastomas, this effect being validated in an independent set of 66 patients. Diminished nuclear SUV39H1 expression adversely affected survival in univariate analysis. In conclusion, H4K20me3 and H3K9 methyltransferases are differentially implicated in astroglial tumor progression. Deregulation of H1x emerges as a prognostic biomarker. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 59-year-old man who was diagnosed classic Kaposi sarcoma (CKS) due to complaints of edema in the left lower extremity, skin patches, and enlargement of the inguinal lymph nodes. Topics include the presence of CKS in his family history on the mother's side, the development of palmoplantar erythrodysesthesia during the fifth cycle of chemotherapy, and the decrease in lymphedema after the chemotherapy's first dose.

Abstract: Malignant astrocytomas are highly vascular neoplasms characterized by a potent angiogenic and immunosuppressive phenotype. Th2-cytokines (IL-6/IL-8) are implicated as major regulators of glioma cell growth and invasiveness. STAT-3, a downstream transducer of cytokine signaling is positively associated with tumor angiogenesis. The present study aimed to investigate the expression of IL-8 and p-STAT-3 in 97 diffusely infiltrating astrocytomas of various grades, in relation to IL-6, VEGF, clinicopathological features, microvascular characteristics and patients’ survival. IL-8 expression was localized in neoplastic cells, being associated with p-STAT-3 (p =0.0013), IL-6 (p =0.0004) and VEGF (p <0.0001) around areas of necrosis as well as in perivascular inflammatory and endothelial cells. All the molecules under study correlated with tumor grade and degree of necrosis (p <0.05, respectively). p-STAT-3, IL-8 and VEGF expression was positively associated with microvessel density (p =0.0491, p <0.0001 and p =0.0118, respectively). Univariate analysis indicated that overexpression of IL-8 and IL-6 adversely affected survival in the entire cohort whereas increased p-STAT-3 expression was predictive of improved survival in high grade (III/IV) astrocytomas (p =0.0032). In multivariate analysis only IL-8 expression (p =0.043) retained its significance. The prognostic significance of IL-8 expression and its correlation with p-STAT-3 and VEGF implicates this novel signaling pathway in astroglial tumors progression providing new targets for effective immunotherapy. [Copyright &y& Elsevier]

Abstract: Streptococcus macedonicus ACA-DC 198, a bacteriocin producer isolated from Greek Kasseri cheese, was used in a series of in vitro and in vivo experiments in order to evaluate its pathogenic potential. The strain was examined in vitro for haemolytic activity, antibiotic resistance and presence of pathogenicity genes encountered in Streptococcus pyogenes. Subsequently, the strain was orally administered to mice (8.9 log cfu daily), continuously over a period of 12 weeks, in order to ascertain the effects of its long term consumption on animal health and gastric inflammation. S. macedonicus ACA-DC 198 was found to be non-haemolytic and sensitive to ampicillin, chloramphenicol, ciprofloxacin, erythromycin, streptomycin, tetracycline, and vancomycin, with the only resistance observed against kanamycin. PCR amplification and DNA–DNA hybridization did not reveal the presence of any of the S. pyogenes pathogenicity genes examined, namely emm, scpA, hasA, speB, smez2, speJ, sagAB, hylA, ska, speF, speG, slo, hylP2 and mga. In the mouse study, no detrimental effects were observed in the behaviour, general well being, weight gain and water consumption of the animals receiving S. macedonicus ACA-DC 198. Histologic analysis showed no evidence of inflammation in the stomach of the animals receiving S. macedonicus ACA-DC 198, while faecal microbiological analysis revealed that the strain retained its viability passing through the mouse gastrointestinal tract. Finally, no evidence of translocation to the liver, spleen and mesenteric lymph nodes was observed. In conclusion, none of the examined virulence determinants were detected in S. macedonicus ACA-DC 198 and its long term, high dosage oral administration did not appear to induce any pathogenic effect in mice. [Copyright &y& Elsevier]

Objective. The association between Helicobacter pylori (H. pylori) infection and serum lipid profile is still controversial. The aim of this study was to determine any possible relationship between H. pylori infection and the lipid profile of patients with upper gastrointestinal symptoms. Material and methods. Consecutively selected 20-70 year-old dyspeptic patients who had undergone esophagogastroduodenoscopy were evaluated for H. pylori infection using both the CLO test and Giemsa staining. Serum total cholesterol (C), HDL-C, LDL-C, apo-A1, apo-B and triglyceride levels were measured. Results. A total of 137 patients (median age 52.0 years) were studied. Total cholesterol levels were lower in H. pylori-infected patients than in H. pylori-negative patients (mean±SEM: 199.3±5.9 versus 212.6±4.6 mg/dl, p=0.08). Patients with duodenal ulcer (DU) had significantly lower levels of all measured lipidemic parameters including cholesterol, with the exception of triglycerides, in comparison with either H. pylori-positive or -negative dyspeptic patients (cholesterol: 177.6±6.5 versus 214.6±4.2 mg/dl, p<0.0001). However, there was no difference in the total cholesterol/HDL-C ratio between DU patients and the rest of the dyspeptic patients. Conclusions. Among H. pylori-positive and H. pylori-negative patients there was no difference in lipid profile apart from a trend towards total cholesterol levels being lower in H. pylori-positive patients. However, cholesterol, HDL-C, LDL-C, apo-A and apo-B were all decreased in DU patients even though this reduction did not result in a fall in the total cholesterol/HDL-C ratio. The etiologic factor differentiating the lipid profiles among dyspeptics only in H. pylori-positive patients carrying a DU could be dietetic, microbial, genetic or a combination of all three. [ABSTRACT FROM AUTHOR]

Abstract: Background: The long-term effectiveness of azathioprine, in Crohn’s disease (CD) patients remains a matter of debate. This study aims at assessing the effectiveness and safety of azathioprine in patients treated continuously for less or more than 4 years. Methods: Patients with steroid-dependent Crohn’s disease in remission on azathioprine (2–2.5 mg/kg) for between 2 and 8 years were assigned into two groups. Patients in Group A were being treated continuously for 2 to 4 years whereas patients in Group B for 4 to 8 years. Patients were followed every month for 1 year with physical examination and laboratory tests. Compliance with treatment was also assessed every month. Every 3 months the Crohn’s Disease Activity Index (CDAI) was calculated and the quality of life (QOL) Inflammatory Bowel Disease Questionnaire (IBDQ) was completed. Colonoscopy with calculation of the Crohn’s Disease Endoscopic Index of Severity (CDEIS) was performed at baseline and at the end of the study. The primary end point was relapse after 1 year. Secondary end points were safety of treatment, QOL, and endoscopic healing. Results: Fifty-eight patients were included in Group A and 42 in Group B. The relapse rates per protocol were 19.6% and 11.9%, respectively (p: not significant). There were no significant differences overall and at each time point of the study between the two treatment groups regarding compliance with and safety of treatment, CDAI, IBDQ, and CDEIS scores. Multifactorial analysis did not identify any factor influencing the remission of disease in any patient group. Conclusions: Long-term treatment with azathioprine of steroid-dependent Crohn’s disease is efficacious and safe. [Copyright &y& Elsevier]

BACKGROUND/AIM: Hepatic steatosis is considered to be mostly associated with viral factors in genotype 3 and metabolic factors in genotype 1 chronic hepatitis C, while there are rather few data for genotype 4. We determined the parameters associated with steatosis in 350 chronic hepatitis C patients, focusing on genotype 4. METHODS: Histological lesions were evaluated according to Ishak's classification and steatosis was semiquantitatively graded. Several patient characteristics on the biopsy day were also evaluated. RESULTS: Steatosis was present in 73% of patients without significant differences among genotypes. Moderate/severe steatosis was more frequent in genotype 3 than 4 (44% vs 26%, P= 0.025) and similar between genotype 4 and 1 patients. Moderate/severe steatosis was associated with body mass index (BMI) in genotype 4 ( P= 0.023) and gamma-glutamyl-transpeptidase in genotype 3 patients ( P= 0.044). In 150 nondiabetic patients with BMI ≤25 kg/m2, moderate/severe steatosis was present in 15, 40, and 11% of genotype 1, 3, and 4 patients, respectively, ( P= 0.005) and was independently associated only with genotype 3. In multivariate analysis, steatosis grade or moderate/severe steatosis was independently associated with higher BMI, genotype 3, and lower cholesterol. CONCLUSIONS: Moderate or severe steatosis is significantly less frequent in genotype 4 than 3 chronic hepatitis C patients and similar between genotype 4 and 1. In nondiabetic, nonoverweight patients, moderate or severe steatosis is present in only 10–15% of genotype 4 or 1 compared with 40% of genotype 3 patients. Thus, hepatic steatosis in genotype 4 is mostly associated with metabolic factors, similar to those in genotype 1. [ABSTRACT FROM AUTHOR]

Among the products of enteroendocrine cells are the incretins glucagon-like peptide-1 (GLP-1, secreted by L cells) and glucose-dependent insulinotropic peptide (GIP, secreted by K cells). These are key modulators of insulin secretion, glucose homeostasis, and gastric emptying. Because of the rapid early rise of GLP-1 in plasma after oral glucose, we wished to definitively establish the absence or presence of L cells, as well as the relative distribution of the incretin cell types in human duodenum. We confirmed the presence of proglucagon and pro-GIP genes, their products, and glucosensory molecules by tissue immunohistochemistry and RT-PCR of laser-captured, single duodenal cells. We also assayed plasma glucose, incretin, and insulin levels in subjects with normal glucose tolerance and type 2 diabetes for 120 min after they ingested 75 g of glucose. Subjects with normal glucose tolerance (n = 14) had as many L cells (15 ± 1), expressed per 1,000 gut epithelial cells, as K cells (13 ± 1), with some containing both hormones (L/K cells, 5 ± 1). In type 2 diabetes, the number of L and L/K cells was increased (26 ± 2; P < 0.001 and 9 ± 1; P < 0.001, respectively). Both L and K cells contained glucokinase and glucose transporter-1, -2, and -3. Newly diagnosed type 2 diabetic subjects had increased plasma GLP-1 levels between 20 and 80 min, concurrently with rising plasma insulin levels. Significant coexpression of the main incretin peptides occurs in human duodenum. L and K cells are present in equal numbers. New onset type 2 diabetes is associated with a shift to the L phenotype. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this prospective study was to assess whether the coadministration of azathioprine (AZA) and olsalazine is superior to AZA monotherapy in maintaining remission of steroid-dependent ulcerative colitis (UC).METHODS: Patients with steroid-dependent UC in remission were randomized to receive AZA alone (2.2 mg/kg) or in combination with olsalazine (0.5 g tid). Remission was defined as steroid withdrawal, an Ulcerative Colitis Clinical Activity Index (UCCAI) score of<2, an Ulcerative Colitis Disease Activity Index (UCDAI) score of 0, and a negative colonoscopy and histology. Patients were followed in the outpatient clinic every month for 2 yr. The study protocol included 1) monthly clinical examination, assessment of UCCAI, hematological and biochemical tests, and compliance with treatment; 2) a sigmoidoscopy and completion of inflammatory bowel disease quality-of-life questionnaire (IBD-Q) and UCDAI every 3 months; and 3) total colonoscopy with biopsies at the end of the first and second year of the trial.RESULTS: Seventy patients were randomized to receive AZA alone (n= 34) or with olsalazine (n= 36). Three patients in each group developed side effects or could not comply with treatment and were withdrawn from the study. Three patients receiving AZA relapsed after the first year of the study and three after the second year of the study (19%). In the combination therapy group four patients relapsed after the first year of study and two after the second year of the study (18%). Relapse rates were not significant whether analyzed by intention-to-treat or per protocol. There were no significant differences between groups in time to relapse or discontinuation of treatment, UCCAI, UCDAI, or IBD-Q scores. However, the number of adverse events and the cost of treatment were significantly higher, whereas compliance with treatment was poorer in the combination therapy.CONCLUSION: Patients with steroid-dependent UC successfully maintained in remission on AZA are not in need of 5-aminosalicylic acid compounds. [ABSTRACT FROM AUTHOR]

Describes the carcinoma of the of the uterine cervix metastasizing to a renal cell carcinoma and a urothelial carcinoma of the urinary bladder metastasizing to a solitary fibrous tumor of the pleura. Reports of two cases and review of literature; Reported cases of tumor-to-tumor metastases; Prognostic markers and mechanisms of metastasis; Biological and clinical aspects of cancer metastasis.