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Value-based care (VBC) organizations – and especially Accountable Care Organizations – rely on strategies that shift care from hospitals to skilled nursing facilities to manage costs and still ensure high [...]

Insulin, which is secreted from pancreatic β-cells, decreases blood glucose by stimulating glucose uptake into skeletal muscle and adipose tissue as well as by suppressing hepatic glucose production. Plasma insulin [...], IGF-1 and insulin promote β-cell expansion by inhibiting β-cell death and stimulating β-cell proliferation, and the phosphatidylinositol (PI) 3-kinase/Akt pathway mediates insulin and IGF-1 action. Impaired β-cell expansion is a risk factor for type 2 diabetes. Here, we identified SH2B1, which is highly expressed in β-cells, as a novel regulator of β-cell expansion. Silencing of SH2B1 in INS-1 832/13 β-cells attenuated insulin- and IGF-1-stimulated activation of the PI 3-kinase/Akt pathway and increased streptozotocin (STZ)-induced apoptosis; conversely, overexpression of SH2B1 had the opposite effects. Activation of the PI 3-kinase/Akt pathway in β-cells was impaired in pancreas-specific SH2B1 knockout (PKO) mice fed a high-fat diet (HFD). HFD-fed PKO mice also had increased β-cell apoptosis, decreased β-cell proliferation, decreased β-cell mass, decreased pancreatic insulin content, impaired insulin secretion, and exacerbated glucose intolerance, Furthermore, PKO mice were more susceptible to STZ-induced β-cell destruction, insulin deficiency, and hyperglycemia. These data indicate that SH2B1 in β-cells is an important prosurvival and proproliferative protein and promotes compensatory β-cell expansion in the insulin-resistant state and in response to β-cell stress. Diabetes 2014;63:585-595 | DOI: 10.2337/db13-0666

Obesity-induced inflammation contributes to the development of type 2 diabetes, metabolic syndrome, and cardiovascular disease (1-3). Accumulation of activated leukocytes in metabolic tissues is a driving force for obesity-associated metabolic [...], The proinflammatory activation of leukocytes in adipose tissue contributes to metabolic disease. How crosstalk between immune cells initiates and sustains adipose tissue inflammation remains an unresolved question. We have examined the hypothesis that adipose tissue macrophages (ATMs) interact with and regulate the function of T cells. Dietary obesity was shown to activate the proliferation of effector memory [CD4.sup.+] T cells in adipose tissue. Our studies further demonstrate that ATMs are functional antigen-presenting cells that promote the proliferation of interferon-γ-producing [CD4.sup.+] T cells in adipose tissue. ATMs from lean and obese visceral fat process and present major histocompatibility complex (MHC) class II-restricted antigens. ATMs were sufficient to promote proliferation and interferon-γ production from antigen-specific [CD4.sup.+] T cells in vitro and in vivo. Diet-induced obesity increased the expression of MHC II and T-cell costimulatory molecules on ATMs in visceral fat, which correlated with an induction of T-cell proliferation in that depot. Collectively, these data indicate that ATMs provide a functional link between the innate and adaptive immune systems within visceral fat in mice.

Insulin decreases blood glucose both by promoting glucose uptake into skeletal muscle and adipose tissue and by suppressing hepatic glucose production. In type 2 diabetes, the ability of insulin to [...], OBJECTIVE--SH2B1 is a SH2 domain-containing adaptor protein expressed in both the central nervous system and peripheral tissues. Neuronal SH2B1 controls body weight; however, the functions of peripheral SH2B1 remain unknown. Here, we studied peripheral SH2B1 regulation of insulin sensitivity and glucose metabolism. RESEARCH DESIGN AND METHODS--We generated TgKO mice expressing SH2B1 in the brain but not peripheral tissues. Various metabolic parameters and insulin signaling were examined in TgKO mice fed a high-fat diet (HFD). The effect of SH2B1 on the insulin receptor catalytic activity and insulin receptor substrate (IRS)-1/IRS-2 dephosphorylation was examined using in vitro kinase assays and in vitro dephosphorylation assays, respectively. SH2B1 was coexpressed with PTP1B, and insulin receptor-mediated phosphorylation of IRS-1 was examined. RESULTS--Deletion of peripheral SH2B1 markedly exacerbated HFD-induced hyperglycemia, hyperinsulinemia, and glucose intolerance in TgKO mice. Insulin signaling was dramatically impaired in muscle, liver, and adipose tissue in TgKO mice. Deletion of SH2B1 impaired insulin signaling in primary hepatocytes, whereas SH2B1 overexpression stimulated insulin receptor autophosphorylation and tyrosine phosphorylation of IRSs. Purified SH2B1 stimulated insulin receptor catalytic activity in vitro. The SH2 domain of SH2B1 was both required and sufficient to promote insulin receptor activation. Insulin stimulated the binding of SH2B1 to IRS-1 or IRS-2. This physical interaction inhibited tyrosine dephosphorylation of IRS-1 or IRS-2 and increased the ability of IRS proteins to activate the phosphatidylinositol 3-kinase pathway. CONCLUSIONS--SH2B1 is an endogenous insulin sensitizer. It directly binds to insulin receptors, IRS-1 and IRS-2, and enhances insulin sensitivity by promoting insulin receptor catalytic activity and by inhibiting tyrosine dephosphorylation of IRS proteins.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjsurg.2005.05.055 Byline: Tristan D. Yan, Ratnasari Padang, Hong Xia, Jing Zhao, Jie Li, David L. Morris Keywords: Colorectal liver metastasis; Edge cryotherapy; Hepatic cryotherapy; Liver resection Abstract: The liver resection margin is prognostically significant for patients with colorectal liver metastases. Management plans for patients with suboptimal resection margins have not been adequately addressed. This article reports the long-term results of edge cryotherapy in 120 patients with suboptimal resection margins. Author Affiliation: University of New South Wales, Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia Article History: Received 21 February 2005; Revised 27 May 2005

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjsurg.2005.04.011 Byline: Koroush S. Haghighi, Frank Wang, Julie King, Steven Daniel, David L. Morris Keywords: Radiofrequency ablation; Liver resection; Hemorrhage; Disclosure Abstract: Intraoperative blood loss has been shown to be an important factor correlating with morbidity and mortality in liver surgery. A 5-cm long instrument with variably deployable metal electrodes using in-line radiofrequency ablation (ILRFA) energy was used for hepatic transection in an attempt to reduce bleeding. Author Affiliation: The University of New South Wales, Department of Surgery, St George Hospital, Kogarah, NSW 2217, Australia Article Note: (footnote) The InLine probe is now owned by Resect Medical. D.L.M. and S.D. declare a financial interest in this company.

Background. Somatostatin has been shown to inhibit in vitro and xenograft growth of human colon cancer. The kinetic index, proliferating cell nuclear antigen (PCNA), has previously been used to measure the effects of manipulation of growth of normal rectal epithelium. Methods. Twenty-five patients with distal colorectal cancer were considered for entry in a presurgical study of Sandostatin (Sandoz, East Hanover, NJ) 1 mg every 8 hours. Biopsies were performed pretreatment, during treatment (14 days), and day of surgical resection (2 days off treatment). A control series of 16 patients underwent endoscopic and subsequent surgical biopsy. A kinetic index was created called PCNA-maximum proliferative index (PCNA-MPI), which was reproducible within one biopsy and between two separate biopsies. Multiple biopsies were taken from the growing edge of tumors, the most cellular and best-stained fields selected, and the highest 6 of 10 separate counted fields were used to produce PCNA-MPI. Results. A significant decline in PCNA-MPI was observed in 6 of the 10 treated patients for whom all three biopsies were available, followed by a significant elevation on withdrawal of treatment. Changes in PCNA-MPI in the control group were less frequent and smaller. Conclusions. Sandostatin causes a reduction in PCNA-MPI in patients with human colorectal cancer. Cancer 1995; 76:572-8. Key words: colorectal cancer, proliferating cell nuclear antigen, somatostatin, clinical trial.

Background. Liver metastases from neuroendocrine tumors often present with disabling symptoms due to syndromes of hormonal excess. A locally destructive technique such as hepatic cryotherapy not only alleviates symptoms but may improve survival in this group of patients. Methods. Six patients with metastatic neuroendocrine tumors were treated with hepatic cryotherapy. Four patients were symptomatic and three of these had elevated tumor markers from ectopic hormone production. Results. All patients are alive and asymptomatic, with a median follow-up of 24 months (range, 6 months to 6 years). All have had a complete radiologic response. All with elevated preoperative markers have had a greater than 89%, decrease in tumor markers. Coagulopathy occurred in two patients necessitating additional surgery, but there was no other morbidity attributable to the cryotherapy. Conclusion. To the authors' knowledge, this study demonstrates for the first time that hepatic cryotherapy offers supportive treatment for patients with neuroendocrine tumors metastatic to the liver. Cryotherapy alleviates symptoms and may improve survival. Cancer 1995; 76:501-9.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4Aand C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4Aprotecting more strongly than C4Bin both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4Aand C4Bgenerated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

In an effort to cut costs, newspaper chains nationwide have consolidated design operations at a few sites. These design hubs have changed the newspaper production process and removed designers from newsrooms; yet, top designers are able to work with their peers in a major city to produce all titles for a chain. This study uses a quantitative analysis of front pages collected from 435 newspapers throughout the United States to examine the quality of newspaper designs at hub and nonhub-designed newspapers. It concludes that hub designed newspapers are generally better designed than nonhub newspapers.

The digital revolution has ushered in a new era of front page design, with newspapers of all sizes embracing navigation tools and promotions. This study updates the work of Pasternack and Utt examining newspaper design trends in 1984 and 1995. This study examines the state of current front page design. Furthermore, it explores the use of design hubs and their effect on page design in newspaper chains.

AimsTo investigate the expression pattern of microRNA-451 (miR-451) in patients with colorectal carcinoma and correlate with the expression of its target gene MIF(macrophage migration inhibitory factor).MethodsMatched cancer and non-cancer fresh frozen tissues were prospectively collected from 70 patients (35 men and 35 women) who underwent resection of colorectal adenocarcinoma. These tissues collected were extracted for miR and complementary DNA conversion. Then, miR-451 expressions in these tissues were measured by quantitative real-time PCR. The expression was correlated with clinical and pathological parameters of these patients. In addition, paraffin blocks of 10 colorectal carcinomas with lowest expression of miR-451 were used for the study of MIF protein expression by immunohistochemistry.ResultsmiR-451 was downregulated in majority of the colorectal cancer tissues when compared with their matched normal tissues (84.3%, n=59/70). Downregulation of miR-451 correlates significantly with presence of coexisting adenoma (91.4%, p=0.025). In addition, persistence of cancer or cancer recurrence after surgery showed significant correlation with downregulation of miR-451 (80% vs 0%; p=0.028). There is no significant correlation between miR-451 expression and age, gender of the patients as well as size, grades, pathological stages, presence of lymphovascular permeation, perineural invasion and microsatellite instability status of the colorectal carcinoma (p>0.05). Majority of the cases (80%) with low expression of miR-451 showed high levels of MIF protein expression confirming the inverse relationship between miR-451 and MIF expressions.ConclusionsThe results showed that miR-451 could play a role in development and progression of colorectal cancer and likely by targeting MIF.

BackgroundA major systemic lupus erythematosus (SLE) susceptibility locus lies within a common inversion polymorphism region (encompassing 3.8 – 4.5  Mb) located at 8p23. Initially implicated genes included FAM167A-BLKand XKR6, of which BLKreceived major attention due to its known role in B-cell biology. Recently, additional SLE risk carried in non-inverted background was also reported.Objective and methodsIn this case –control study, we further investigated the ‘extended’ 8p23 locus (~ 4  Mb) where we observed multiple SLE signals and assessed these signals for their relation to the inversion affecting this region. The study involved a North American discovery data set (~1200  subjects) and a replication data set (> 10 000  subjects) comprising European-descent individuals.ResultsMeta-analysis of 8p23 SNPs, with p < 0.05 in both data sets, identified 51 genome-wide significant SNPs (p < 5.0 × 10−8). While most of these SNPs were related to previously implicated signals (XKR6-FAM167A-BLKsubregion), our results also revealed two ‘new’ SLE signals, including SGK223-CLDN23-MFHAS1(6.06 × 10−9≤ meta p ≤ 4.88 × 10−8) and CTSB(meta p = 4.87 × 10−8) subregions that are located > 2 Mb upstream and ~ 0.3  Mb downstream from previously reported signals. Functional assessment of relevant SNPs indicated putative cis-effects on the expression of various genes at 8p23. Additional analyses in discovery sample, where the inversion genotypes were inferred, replicated the association of non-inverted status with SLE risk and suggested that a number of SLE risk alleles are predominantly carried in non-inverted background.ConclusionsOur results implicate multiple (known+novel) SLE signals/genes at the extended 8p23 locus, beyond previously reported signals/genes, and suggest that this broad locus contributes to SLE risk through the effects of multiple genes/pathways.

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.

CD40‐deficient mice fail to induce conventional CD4+cells in adipose tissue associated with decreased markers of antigen presentation in ATMs. Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen‐presenting cells and CD4+T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity‐induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen‐presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40‐deficient mice had reduced accumulation of conventional CD4+T cells (Tconv: CD3+CD4+Foxp3−) in visceral fat compared with wild‐type mice. By contrast, the number of regulatory CD4+T cells (Treg: CD3+CD4+Foxp3+) in lean and obese fat was similar between wild‐type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild‐type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40‐deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity‐induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4+T cells; however, this is largely dispensable for the development of obesity‐induced inflammation and insulin resistance in mice.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Chronic systemic inflammation is a hallmark feature of obesity and type 2 diabetes. Both resident and recruited islet macrophages contribute to the proinflammatory milieu of the diabetic islet. However, macrophages also appear to be critical for β-cell formation during development and support β-cell replication in experimental models of pancreas regeneration. In light of these findings, perhaps macrophages in the islet need to be viewed more as a fulcrum where deleterious inflammatory activation is balanced with beneficial tissue repair processes. Undoubtedly, defining the factors that contribute to the ontogeny, heterogeneity, and functionality of macrophages in normal, diseased, and regenerating islets will be necessary to determine whether that fulcrum can be moved to preserve functional β-cell mass in persons with diabetes. The intent of this review is to introduce the reader to emerging concepts of islet macrophage biology that may challenge the perception that macrophage accumulation in islets is merely a pathological feature of type 2 diabetes.

As professional soldiers and warriors, it is our duty to keep track of ongoing operations and assess how the contemporary operational environment (COE) impacts training. In the past year, we [...]

As the 1st Armor Training Brigade (ATB) transforms to meet the needs of the force, so do the units within it. None exemplify this spirit of change more than 3d [...]

At the 1st Armor Training Brigade, we are training tomorrow's combat veteran today. He has been in the Army for less than 2 months, but within 6 months, he will [...]

Infusing warrior ethos into each and every soldier, regardless of military occupational specially, is one of the key lessons learned from the current operational environment (COE) in Iraq. The Chief [...]

In recent months, there has been much talk throughout the Army about changing the entry-level training of our Soldiers. Proposed modifications to make training more realistic and more battle focused [...]

MUC1 is a glycoprotein that is overexpressed in tumor cells. In normal cells it forms a protective layer against microbes and toxic chemicals, besides providing lubrication on ductal surfaces. Oversecretion of MUC1 provide cancer cells with invasiveness, metastasis, and resistance to death induced by reactive oxygen species. MUC1 is made up of 2 heterodimers, MUC1-N and MUC1-C. MUC1-N is heavily glycosylated at 5 regions of the variable N-tandem repeats. MUC1-C is divisible into extracellular, intracellular, and cytoplasmic domain (MUC1-C/CD). The extracellular domain serves as a docking site for epidermal growth factor receptors and other receptor kinases; the transmembrane domain serves to relay messages from extracellular to MUC1-C/CD. The MUC1-C/CD has 5 phosphorylating sites that on interacting with the SH2 domain of specific proteins can stimulate tumor growth. Therapies targeting MUC1 consists of monoclonal antibodies (MAb), vaccines, or small molecules (aptamers). MAb therapies are mainly aimed at MUC1-N with little success, however, new generation of MAb are being developed for MUC1-C. Vaccines (peptide, carbohydrate, glycopeptide, DNA, and dendritic cell) have been developed that recognizes the aberrant glycosylated region of the variable N-tandem repeats in MUC1-N, whereas new generation vaccines are aimed at the cytoplasmic region of MUC1-C. Aptamers (peptides that resemble DNA, RNA) have been used for blocking the dimerization of CQC region and the 5 phosphorylating region of MUC1-C. In addition, aptamers have been used as cytotoxic drug carriers. However, none of the therapies for MUC1 are currently in clinical application, as they need further refinement and evaluation.

SUMMARYIn this article, we review two liver-directed therapies that are currently used for the palliative treatment of primary and secondary hepatic malignancies, transcatheter arterial chemoembolization (TACE), including a new type of TACE with drug-eluting beads, and radioembolization. Important developments and administration techniques for all therapies are discussed, as well as their integration into the current routine clinical care for management of metastatic colorectal cancer. According to published data from clinical trials, as presented in this review, both radioembolization and TACE/TACE with drug-eluting beads have been proven to be safe and effective in selected patients with chemorefractory liver metastases from colorectal cancer. For patients with unresectable liver-only or liver-dominant disease who have failed standard chemotherapy options or for whom chemotherapy is contraindicated, new modalities, such as those discussed, are particularly valid and promising if clinical guidelines for patient selection and treatment administration are followed.

Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3–5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

Background Overexpression of MUC1 predicts poor survival in most cancers. Routine immunohistochemical detection of MUC1 is performed for differential diagnosis in malignant peritoneal mesothelioma (MPM). However, the prognostic significance of MUC1 in MPM has not been determined.Method We investigated MUC1 expression and other prognostic factors in relation to survival in 42 patients (20 males and 22 females) for whom archival samples were available, using immunohistochemistry. MUC1 was expressed in 38/42 (90%) patients. Its prognostic significance was statistically analyzed using the Kaplan-Meier method.Results High expression of MUC1 (immunohistochemical score of 5-8), was correlated with poor survival in several categories: all subtypes of tumors (p=0.001), male gender (p=0.017), female gender (p=0.001), epitheloid tumors (p=0.001), epitheloid tumors in males (p=0.005), epitheloid tumors in females (p=0.003), and age at diagnosis (AAD) <60 years (p=0.001). Amongst the other clinicopathological variables, univariate analysis also showed that male gender (p=0.007), sarcomatoid histology (p=0.001), peritoneal cancer index (PCI) ≥20 (p=0.013) and AAD ≥60 (p=0.001), correlated with poor survival. Multivariate analysis showed that only AAD ≥60 (p=0.049) was an independent prognostic factor, and that high MUC1 expression significantly correlated with the following categories: all subtypes of tumors (p=0.001), male gender (p=0.002), female gender (p=0.031), epitheloid tumors (p=0.031), and AAD <60y (p=0.012).Conclusion AAD and high MUC1 expression in the tumor are indicators of poor prognosis. MUC1 evaluation by immunohistochemistry may serve as a useful prognostic tool in MPM, but may need further confirmation in a larger patients' cohort.

Pelvic exenteration is a potentially curative treatment for locally advanced primary or recurrent rectal cancer.

Uptake of drug-loaded micelles by tumour cell lines can be the crucial step in the creation of an efficient drug delivery system. Crosslinking of micelles has increasingly been proposed as a pathway to create stable nanoparticles. So far, little is known how crosslinking can affect the interaction of these nanocarriers with cells. The aim of this study is therefore to investigate the effect of crosslinking on exo- and endocytosis. RAFT (reversible addition fragmentation chain transfer) polymerization has been used to synthesize the block copolymer poly(methyl methacrylate)-block-poly(polyethylene glycol methyl ether methacrylate) PMMA-b-P(PEGMEMA), which was subsequently self-assembled into micelles of 20 nm. For comparison, the micelles were shell-crosslinked by incorporating methacrylic acid into the shell, which was used as a reactive group for crosslinking with 1,8-diaminooctane. The hydrodynamic diameter of the shell-crosslinked micelle was with 25 nm similar to that of the non-crosslinked one. Endocytosis of both micelles was significantly reduced by the presence of NaN3or at 4 °C suggesting an energy dependent process. The internalization pathways of the block copolymer micelles in OVCAR-3 cells were elucidated using endocytosis inhibitors. Both nanoparticles, micelles and shell-crosslinked micelles, were internalized by caveolae mediated endocytosis while clathrin mediated endocytosis did not play a noticeable role. Shell-crosslinking therefore did not have an effect on endocytosis. However, a considerable difference was found in the exocytosis of both particles. While the micelle was lodged inside the cell for an extended period of time with less than 3% released in two hours, the shell-crosslinked micelle quickly exited the OVCAR-3 cells (25% in two hours). For comparison, a small molecule (Lucifer yellow) was found to be only marginally faster than the crosslinked micelles (40% in 2 h). These results could have implications on the use polymer–drug conjugates or drug carriers where the drug needs to be released before the polymer undergoes exocytosis.

Surgical extirpation of neuroendocrine neoplasms hepatic metastases (NENHM) provides the best opportunity of long-term survival but is not feasible in the majority of patients given the widespread presentation of liver disease. Combining resection with local ablation can potentially expand the resection criteria and thereby improve survival. The present study critically evaluates the progression-free survival (PFS) and overall survival (OS) of patients with NENHM who underwent concomitant hepatic resection and cryoablation.

The purpose of this review is to summarise the current understanding of genetic associations with systemic lupus erythematosus (SLE) sub-phenotypes, and to discuss how improvement in statistical methodology and data quality will increase our understanding of SLE generally.

Liver transplantation is believed to be the best treatment option for selected patients with hepatocellular carcinoma (HCC). However, the shortage of organs and the risk of tumor progression while on the waiting list has hampered this effective treatment modality from being routinely offered. Hence, the second option of hepatic resection must be considered. The aim of this study is to report the results of hepatic resection in transplantable patients.

Improved survival of colorectal cancer has been made over the last 3 decades; reasons may be attributed to early detection through screening, and better treatment options. Advancements in modern systemic chemotherapy for colorectal cancer include oxaliplatin-based and irinotecan-based combination and the introduction of biological agents such as bevacizumab and cetuximab. Systemic therapies need to be used in patients with high risk stage II and stage III colorectal cancer and in patients with metastatic disease. Evidence for liver resection and ablation, pulmonary metastasectomy andor radiofrequency ablation, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for metastasis to sites of the liver, lung, and peritoneum respectively are well established. The biggest challenge is to select the right patients for metastasectomy and to pursue metastatic disease as a chronic disease to ensure appropriate personalized therapy, pursue second-line therapies or repeat surgeries, and minimize toxicities of therapies.

Proinflammatory adipose tissue macrophages (ATMs) contribute to obesity-associated disease morbidity. We will provide an update of the current state of knowledge regarding the phenotypic and functional diversity of ATMs in lean and obese mice and humans.

Background Patients with liver metastases from pancreatic adenocarcinomas have a dismal prognosis. Surgical resection remains the only curative option but is appropriate for only a minority of patients as a treatment option. This is the first study to examine the safety and efficacy of radioembolization with yttirum-90 microspheres for these patients.Patients and methods All patients with histologically proven pancreatic carcinoma liver metastases referred to a single institution from 2006–2009 were included in the study. After radioembolization, follow-up abdominal computed tomography scans were performed to assess response according to the Response Criteria in Solid Tumors guidelines.Results Seven patients were identified from our prospectively collected data base. Of the five patients with available computed tomography follow-up, 2 patients achieved a partial response and 1 patient had stable disease. One patient with partial response survived for nearly 15 months after radioembolization therapy. No patient experienced major post-radioembolization complications.Conclusions Radioembolization with yttrium-90 microspheres may have a useful role in treating patients with pancreatic carcinoma liver metastases in a multimodality setting. Results of the current study warrant further investigation of this novel treatment. Free full text available at www.tumorionline.it