Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion

Mesenchymal stem cells (MSC) are under investigation as a therapy for a variety of disorders. Although animal models show long term regenerative and immunomodulatory effects of MSC, the fate of MSC after infusion remains to be elucidated. In the present study the localization and viability of MSC was examined by isolation and re-culture of intravenously infused MSC. C57BL/6 MSC (500,000) constitutively expressing DsRed-fluorescent protein and radioactively labeled with Cr-51 were infused via the tail vein in wild-type C57BL/6 mice. After 5 min, 1, 24, or 72 h, mice were sacrificed and blood, lungs, liver, spleen, kidneys, and bone marrow removed. One hour after MSC infusion the majority of Cr-51 was found in the lungs, whereas after 24 h Cr-51 was mainly found in the liver. Tissue cultures demonstrated that viable donor MSC were present in the lungs up to 24 h after infusion, after which they disappeared. No viable MSC were found in the other organs examined at any time. The induction of ischemia-reperfusion injury in the liver did not trigger the migration of viable MSC to the liver. These results demonstrate that MSC are short-lived after i.v. infusion and that viable MSC do not pass the lungs. Cell debris may be transported to the liver. Long term immunomodulatory and regenerative effects of infused MSC must therefore be mediated via other cell types

Collective cancer invasion forms an integrin-dependent radioresistant niche

Contains fulltext : 219833.pdf (Publisher’s version ) (Open Access)Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta1 and alphaVbeta3/beta5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta1 or alphaV integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta1/alphaV integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta1/alphaVbeta3/beta5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

HCC recurrence in HCV-infected patients after liver transplantation: SiLVER Study reveals benefits of sirolimus in combination with CNIs - a post-hoc analysis

Factors affecting outcomes in liver transplant (LTx) recipients with hepatocellular carcinoma (HCC) and hepatitis C viral (HCV) infection include the choice of immunosuppression. Here, we analyzed the HCV+ subgroup of patients from the randomized controlled, international SiLVER Study. We performed a post hoc analysis of 166 HCV+ SiLVER Study patients regarding HCC outcome after LTx. Control patients (group A: n = 88) received mTOR inhibitor (mTORi)-free, calcineurin inhibitor (CNI)-based versus sirolimus-based immunosuppression (group B: n = 78). We found no significant difference regarding HCV-RNA titers between group A and B. Since no effect in group B could be due to variable sirolimus dosing, we split group B into patients receiving sirolimus-based immunosuppression + CNIs for >50% (B1; n = 44) or <50% (B2; n = 34) of the time. While there remained no difference in HCV-RNA titer between groups, HCC recurrence-free survival in group B1 (81.8%) was markedly better versus both group A (62.7%; P = 0.0136) and group B2 (64.7%; P = 0.0326); Interestingly, further subgroup analysis revealed an increase (P = 0.0012) in liver enzyme values in group B2. Taken together, in HCV-infected patients with HCC and LTx, mTORi immunosuppression + CNIs yields excellent outcomes. Unexpectedly, higher levels of liver inflammation and poorer outcomes occur with mTORi monotherapy in the HCV+ subgroup

VEGF: A Surrogate Marker for Peripheral Vascular Disease

AbstractThis study aims to evaluate the value of VEGF as a surrogate marker for peripheral vascular disease (PVD). Prior to treatment, serum VEGF levels were evaluated by enzyme-linked immunosorbent assay (ELISA) in 293 PVD patients. Risk factors and clinical parameters of PVD were documented. Twenty-six age-matched healthy volunteers served as controls. Serum VEGF values strongly correlated with Fontaine stages (p<0.006, stage IV vs. controls). High VEGF values prior to treatment were associated with poor outcome. Serum VEGF appears to indicate the severity of PVD and might serve as a surrogate indicator of disease severity

No Acceleration of UV-Induced Skin Carcinogenesis from Evenly Spread Dietary Intake of Cyclosporine in Contrast to Oral Bolus Dosages

Dermatology-oncolog

Dose-Dependent Effects of Sirolimus on mTOR Signaling and Polycystic Kidney Disease

Genetics of disease, diagnosis and treatmen