Inflammatory niche: Mesenchymal stromal cell priming by soluble mediators

Mesenchymal stromal/stem cells(MSCs) are adult stem cells of stromal origin that possess self-renewal capacity and the ability to differentiate into multiple mesodermal cell lineages. They play a critical role in tissue homeostasis and wound healing, as well as in regulating the inflammatory microenvironment through interactions with immune cells. Hence, MSCs have garnered great attention as promising candidates for tissue regeneration and cell therapy. Because the inflammatory niche plays a key role in triggering the reparative and immunomodulatory functions of MSCs, priming of MSCs with bioactive molecules has been proposed as a way to foster the therapeutic potential of these cells. In this paper, we review how soluble mediators of the inflammatory niche(cytokines and alarmins) influence the regenerative and immunomodulatory capacity of MSCs, highlighting the major advantages and concerns regarding the therapeutic potential of these inflammatory primed MSCs. The data summarized in this review may provide a significant starting point for future research on priming MSCs and establishing standardized methods for the application of preconditioned MSCs in cell therapy.     

Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells

Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells (MSCs) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by MSCs. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue‐derived MSCs 2 weeks earlier, or sham. STK senescence‐associated β‐galactosidase (SA‐β‐Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence‐associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue‐derived MSC delivery, and in healthy volunteers (HV). In RAS mice, STK SA‐β‐Gal activity increased, and senescence and SASP marker expression was markedly elevated. MSCs improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA‐β‐Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by MSC, whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. MSCs decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.     

Rituximab in Relapsing and Progressive Forms of Multiple Sclerosis: A Systematic Review

Background

Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.

Objectives

To evaluate the efficacy and safety of rituximab for MS treatment.

Data collection

Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.

Main results

Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MS while the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-label rituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events.

Author’s conclusion

Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.     

Beyond Breast Cancer: Mammographic Features and Mortality Risk in a Population of Healthy Women

Background

Breast fibroglandular (dense) tissue is a risk factor for breast cancer. Beyond breast cancer, little is known regarding the prognostic significance of mammographic features.

Methods

We evaluated relationships between nondense (fatty) breast area and dense area with all-cause mortality in 4,245 initially healthy women from the Breast Cancer Detection Demonstration Project; 1,361 died during a mean follow-up of 28.2 years. Dense area and total breast area were assessed using planimeter measurements from screening mammograms. Percent density reflects dense area relative to breast area and nondense area was calculated as the difference between total breast area and dense area. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression.

Results

In age-adjusted models, greater nondense and total breast area were associated with increased risk of death (HR 1.17, 95% CI 1.10-1.24 and HR 1.13, 95% CI 1.06-1.19, per SD difference) while greater dense area and percent density were associated with lower risk of death (HR 0.91, 95% CI 0.86-0.95 and HR 0.87, 95% CI 0.83-0.92, per SD difference). Associations were not attenuated with adjustment for race, education, mammogram type (x-ray or xerogram), smoking status, diabetes and heart disease. With additional adjustment for body mass index, associations were diminished for all features but remained statistically significant for dense area (HR 0.94, 95% CI 0.89-0.99, per SD difference) and percent density (HR 0.93, 95% CI 0.87-0.98, per SD difference).

Conclusions

These data indicate that dense area and percent density may relate to survival in healthy women and suggest the potential utility of mammograms beyond prediction of breast cancer risk.     

A diverse fungal community associated with Pseudorchis albida (Orchidaceae) roots

In addition to orchid mycorrhizal fungi (OrMF), the roots of orchids harbour plant fungal endophytes termed root-associated fungi (RAF). In the present study, the endangered photosynthetic orchid Pseudorchis albida was screened for OrMF and RAF using culture-dependent (isolations from root sections and pelotons) and culture-independent (cloning from root sections) techniques. The efficiency of the different approaches for detecting the fungi and the effect of the sampling season (summer or autumn) were evaluated. In total, 66 distinct OTUs of mycorrhizal and non-mycorrhizal fungi were found, which, to our knowledge, is the highest diversity of RAF that has yet been detected in a single orchid species. The OrMF community was dominated by Tulasnella species, which were mainly detected by isolation from pelotons or cloning from root sections. The roots and tubers showed higher mycorrhizal colonization in summer, corroborating the frequent reports of Tulasnella from pelotons in this season. In contrast, two helotialean fungi, Varicosporium elodeae and Leohumicola sp., the latter of which was repeatedly isolated from pelotons, were significantly more abundant in the autumn.     

Differential Effects of Selective Inhibitors Targeting the PI3K/AKT/mTOR Pathway in Acute Lymphoblastic Leukemia

Purpose

Aberrant PI3K/AKT/mTOR signaling has been linked to oncogenesis and therapy resistance in various malignancies including leukemias. In Philadelphia chromosome (Ph) positive leukemias, activation of PI3K by dysregulated BCR-ABL tyrosine kinase (TK) contributes to the pathogenesis and development of resistance to ABL-TK inhibitors (TKI). The PI3K pathway thus is an attractive therapeutic target in BCR-ABL positive leukemias, but its role in BCR-ABL negative ALL is conjectural. Moreover, the functional contribution of individual components of the PI3K pathway in ALL has not been established.

Experimental Design

We compared the activity of the ATP-competitive pan-PI3K inhibitor NVP-BKM120, the allosteric mTORC1 inhibitor RAD001, the ATP-competitive dual PI3K/mTORC1/C2 inhibitors NVP-BEZ235 and NVP-BGT226 and the combined mTORC1 and mTORC2 inhibitors Torin 1, PP242 and KU-0063794 using long-term cultures of ALL cells (ALL-LTC) from patients with B-precursor ALL that expressed the BCR-ABL or TEL-ABL oncoproteins or were BCR-ABL negative.

Results

Dual PI3K/mTOR inhibitors profoundly inhibited growth and survival of ALL cells irrespective of their genetic subtype and their responsiveness to ABL-TKI. Combined suppression of PI3K, mTORC1 and mTORC2 displayed greater antileukemic activity than selective inhibitors of PI3K, mTORC1 or mTORC1 and mTORC2.

Conclusions

Inhibition of the PI3K/mTOR pathway is a promising therapeutic approach in patients with ALL. Greater antileukemic activity of dual PI3K/mTORC1/C2 inhibitors appears to be due to the redundant function of PI3K and mTOR. Clinical trials examining dual PI3K/mTORC1/C2 inhibitors in patients with B-precursor ALL are warranted, and should not be restricted to particular genetic subtypes.     

High Urinary Tungsten Concentration Is Associated with Stroke in the National Health and Nutrition Examination Survey 1999–2010

Background

In recent years there has been an exponential increase in tungsten demand, potentially increasing human exposure to the metal. Currently, the toxicology of tungsten is poorly understood, but mounting evidence suggests that both the elemental metal and its alloys have cytotoxic effects. Here, we investigate the association between tungsten and cardiovascular disease (CVD) or stroke using six waves of the National Health and Nutrition Examination Survey (NHANES).

Methods

We investigated associations using crude and adjusted logistic regression models in a cohort of 8614 adults (18–74 years) with 193 reported stroke diagnoses and 428 reported diagnoses of CVD. We also stratified our data to characterize associations in a subset of younger individuals (18–50 years).

Results

Elevated tungsten concentrations were strongly associated with an increase in the prevalence of stroke, independent of typical risk factors (Odds Ratio (OR): 1.66, 95% Confidence Interval (95% CI): 1.17, 2.34). The association between tungsten and stroke in the young age category was still evident (OR: 2.17, 95% CI: 1.33, 3.53).

Conclusion

This study represents the most comprehensive analysis of the human health effects of tungsten to date. Individuals with higher urinary tungsten concentrations have double the odds of reported stroke. We hypothesize that the pathological pathway resulting from tungsten exposure may involve oxidative stress.