Lin? Cells Mediate Tissue Repair by Regulating MCP-1/CCL-2

Exogenous bone marrow-derived cells (BMDCs) are promising therapeutic agents for the treatment of tissue ischemia and traumatic injury. However, until we identify the molecular mechanisms that underlie their actions, there can be no rational basis for the design of therapeutic strategies using BMDCs. The pro-healing effects of BMDCs are apparent very shortly after treatment, which suggests that they may exert their effects by the modulation of acute inflammation. We investigated this hypothesis by taking advantage of the fact that BMDCs from healthy, young, but not obese, diabetic mice stimulate vascular growth. By comparing both in vitro secretion and in vivo local induction of acute phase inflammatory cytokines by these cells, we identified monocyte chemoattractant factor 1 and tumor necrosis factor α as potential mediators of BMDC-induced tissue repair. In vivo analysis of BMDC-treated ischemic limbs and cutaneous wounds revealed that the production of monocyte chemoattractant factor 1 by exogenous and endogenous BMDCs is essential for BMDC-mediated vascular growth and tissue healing, while the inability of BMDCs to produce tumor necrosis factor α appears to play a lesser but still meaningful role. Thus, measurements of the secretion of cytokines by BMDCs may allow us to identify a priori individuals who would or would not be good candidates for BMDC-based therapies.Exogenous bone marrow-derived cells (BMDCs), including peripheral blood mononuclear cells (PBMCs) promote tissue vascularization and show promise as therapeutic tools for treatment of tissue ischemia and traumatic injury. Although they may be a source of endothelial or other progenitor cells, they probably act principally through paracrine mechanisms.^1,2 BMDCs are currently being used to treat ischemic conditions in clinical trials.^3–5 However, given our rudimentary knowledge of how BMDCs act as agents of vascular growth and tissue repair, it is not surprising that results of clinical trials to date are mixed. The ability of the BMDCs to potentiate healing depends on the physiological status of both the BMDC donor and recipient, and while many subpopulations of BMDCs can potentiate vascular growth and may be of therapeutic value, their relative potency is not well characterized.^6–8 At the same time, we do not know why exogenous BMDCs promote tissue vascularization and repair in many, but not all, animal models of injury and disease (See for example,^9–13). Until we identify the molecular mechanisms underlying the action of BMDCs, there can be no rational basis for determining which cells delivered when, and at what dose might be most appropriate in a particular clinical situation. In light of this, our current study examines the molecular mechanism through which BMDCs exert their therapeutic effects.BMDC therapy can lead to remarkably rapid improvements in blood flow. As early as 48 hours after local injection of human CD34⁺ PBMCs into ischemic murine hind limbs, there is a significant increase in limb blood flow compared to untreated controls.¹⁴ However, maximal effects are not observed until many days later, well after the injected CD34⁺ cells have been essentially cleared.¹⁴ That is, the PBMCs appear to act early to initiate a pro-angiogenic cascade that persists even after the exogenous PBMCs are no longer present. Thus, BMDCs may act by modulating early inflammatory responses, responses that initiate tissue repair.In support of this hypothesis, treatment with BMDCs induces neovascularization in ischemic muscle of wild-type mice, but not in interleukin (IL)-1β knockout (Il-1β^−/−) mice.¹⁵ However, Il-1β ^−/− mononuclear cells increase expression of IL-1β and pro-angiogenic factors in ischemic muscle and can stimulate vascular growth as effectively as wild-type cells.¹⁵ This suggests that exogenous BMDCs may act by regulating the acute phase inflammatory cytokine IL-1β through an as yet unidentified molecular stimulus though they need not to secrete it themselves.Based on these findings we tested the hypothesis that BMDCs potentiate tissue repair by modulating the acute inflammatory response. We took advantage of the fact that lineage depleted (lin⁻) BMDCs from healthy young wild-type mice stimulate vascular growth while those from mice lacking the leptin receptor gene (Lepr^db) mice do not.¹¹ Differences in the secretory profiles and abilities to alter tissue levels of acute phase inflammatory cytokines between lin⁻ cells derived from these two sources were compared. We identified monocyte chemoattractant factor 1 (MCP-1) and tumor necrosis factor α (TNF-α) as potential mediators of BMDC-potentiated neovascularization and tissue repair. Studies with BMDCs from knockout mice demonstrated that production of MCP-1, but not TNF-α, by exogenous BMDCs is essential for lin⁻ BMDC-mediated vascular growth and tissue healing. We also showed that endogenous BMDCs must be able to express MCP-1 in order for exogenous BMDCs to be therapeutically beneficial.     

Study on turnaround time of biological analysis in urgent need in hospital laboratories

We have assessed turnaround time (TAT) for urgent laboratory analysis. Twelve hospital laboratories participated to this study. All laboratories have organized a classification of a management system of urgent analyses. The TAT reporting were relatively homogeneous for 12?laboratories. We have defined TAT as time of specimen receipt in the laboratory to time of results reporting. This TAT divides into 4?groups: close to 50?minutes for analyses as TP, D-dimeres, CRP (C Protein Reactive), HCG, troponin, alcoholhemia, K, lipase; 35?minutes for the cytology of cerebrospinal fluid; 25?minutes for complete blood cell count and 15?minutes for blood gases. All laboratories have accepted to TAT as a quality indicator. Quality indicator data should be collected in time to identify and correct problems to implemente effective interventions and to standardize processes among clinical laboratories.     

Differential mucosal expression of Th17-related genes between the inflamed colon and ileum of patients with inflammatory bowel disease

Background

Previous reports have shown that peptides derived from the apolipoprotein E receptor binding region and the amphipathic α-helical domains of apolipoprotein AI have broad anti-infective activity and antiviral activity respectively. Lipoproteins and viruses share a similar cell biological niche, being of overlapping size and displaying similar interactions with mammalian cells and receptors, which may have led to other antiviral sequences arising within apolipoproteins, in addition to those previously reported. We therefore designed a series of peptides based around either apolipoprotein receptor binding regions, or amphipathic α-helical domains, and tested these for antiviral and antibacterial activity.

Results

Of the nineteen new peptides tested, seven showed some anti-infective activity, with two of these being derived from two apolipoproteins not previously used to derive anti-infective sequences. Apolipoprotein J (151-170) - based on a predicted amphipathic alpha-helical domain from apolipoprotein J - had measurable anti-HSV1 activity, as did apolipoprotein B (3359-3367) dp (apoBdp), the latter being derived from the LDL receptor binding domain B of apolipoprotein B. The more active peptide - apoBdp - showed similarity to the previously reported apoE derived anti-infective peptide, and further modification of the apoBdp sequence to align the charge distribution more closely to that of apoEdp or to introduce aromatic residues resulted in increased breadth and potency of activity. The most active peptide of this type showed similar potent anti-HIV activity, comparable to that we previously reported for the apoE derived peptide apoEdpL-W.

Conclusions

These data suggest that further antimicrobial peptides may be obtained using human apolipoprotein sequences, selecting regions with either amphipathic α-helical structure, or those linked to receptor-binding regions. The finding that an amphipathic α-helical region of apolipoprotein J has antiviral activity comparable with that for the previously reported apolipoprotein AI derived peptide 18A, suggests that full-length apolipoprotein J may also have such activity, as has been reported for full-length apolipoprotein AI. Although the strength of the anti-infective activity of the sequences identified was limited, this could be increased substantially by developing related mutant peptides. Indeed the apolipoprotein B-derived peptide mutants uncovered by the present study may have utility as HIV therapeutics or microbicides.     

High-magnification ICSI overcomes paternal effect resistant to conventional ICSI

Previous studies have shown that repeated intracytoplasmic sperm injection (ICSI) failures can be caused by a paternal effect. Other studies have suggested that ICSI results are compromised if morphologically abnormal spermatozoa are injected into oocytes. This study was undertaken to evaluate the usefulness of a high-magnification optical system to select spermatozoa to be used for ICSI (high-magnification ICSI) in couples with repeated conventional ICSI failures. Couples with two or more previous conventional ICSI failures underwent an additional conventional ICSI attempt, followed by a high-magnification ICSI attempt. The outcomes of the two sequential attempts were compared. In 72 of these patients, sperm DNA integrity was assessed. In the whole group of 125 couples with repeated ICSI failures, high-magnification ICSI improved clinical outcomes (pregnancy, implantation, delivery and birth rates) without affecting biological outcomes (fertilization and cleavage rates, embryo morphology). The improvement of clinical ICSI outcomes was evident both in patients with an elevated degree of sperm DNA fragmentation and in those with normal sperm DNA status. It is concluded that high-magnification ICSI improves clinical outcomes in couples with previous repeated conventional ICSI failures.     

Postural adjustments and bearing angle use in interceptive actions

The experiment investigates the effect of ball velocity and walking direction on the adherence to the bearing angle (BA) strategy in adults. Adult participants (N=12) approached a moving ball in order to manually intercept it at a predefined target area. Results revealed that during locomotion the BA strategy was implemented, but on reaching the point of interception, this strategy broke down and the BA strategy of the wrist compensated for the movement requirements relative to the ball velocity and approach angle. Larger deviations from the BA occurred when the angle of approach was decreased and when the ball velocity increased. When the BA strategy was adhered to, postural adjustments were reduced. Increased movements occurred in a proximal–distal direction with an increasing approach angle and a faster ball velocity.An erratum to this article can be found at     

Management of crizotinib, a new individualized treatment

Crizotinib, an inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), achieves response rates of 57 % at eight weeks in patients with stage IV non-small cell lung cancer with ALK rearrangements. With such results, the crizotinib followed an accelerated procedure in the United States and obtained the Food and Drug Administration (FDA) approval based on the results of phase I studies. The results should be confirmed with one phase II study and two phase III studies in patients with ALK rearrangements. In France, the Commission of Authorization for Marketing has granted an Authorization of Temporary Use (ATU) for cohort on the 15 December 2011 to allow its administration in patients before marketing authorization.     

Vemurafenib-induced neutrophilic panniculitis

Vemurafenib is a targeted therapy, used in patients with metastatic cutaneous melanoma who carry the BRAF V600E mutation, with a relative reduction of 63% in the risk of death. Several adverse events have been described previously, such as photosensitivity or squamous-cell carcinomas. Two cases of panniculitis have been reported recently with two different selective BRAF inhibitors. We report two cases of neutrophilic panniculitis in patients treated by vemurafenib for a metastatic melanoma. Clinical and biological examinations showed no indications for an immune nor an infectious cause of neutrophilic panniculitis. Thus, we believe that vemurafenib caused this panniculitis. Treatment with vemurafenib was maintained in both patients because of the clinical and radiological tumoral responses. One patient showed spontaneous recovery, whereas the other patient presented several recurrences of panniculitis. We believe that physicians should be aware of this cutaneous side effect of vemurafenib, but it should not lead to discontinuation of this treatment.     

Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score

BACKGROUND:

Tools are lacking to assess the individual risk of severe toxicity from chemotherapy. Such tools would be especially useful for older patients, who vary considerably in terms of health status and functional reserve.

METHODS:

The authors conducted a prospective, multicentric study of patients aged ≥70 years who were starting chemotherapy. Grade 4 hematologic (H) or grade 3/4 nonhematologic (NH) toxicity according to version 3.0 of the Common Terminology Criteria for Adverse Events was defined as severe. Twenty‐four parameters were assessed. Toxicity of the regimen (Chemotox) was adjusted using an index to estimate the average per‐patient risk of chemotherapy toxicity (the MAX2 index). In total, 562 patients were accrued, and 518 patients were evaluable and were split randomly (2:1 ratio) into a derivation cohort and a validation cohort.

RESULTS:

Severe toxicity was observed in 64% of patients. The Chemotherapy Risk Assessment Scale for High‐Age Patients (CRASH) score was constructed along 2 subscores: H toxicity and NH toxicity. Predictors of H toxicity were lymphocytes, aspartate aminotransferase level, Instrumental Activities of Daily Living score, lactate dehydrogenase level, diastolic blood pressure, and Chemotox. The best model included the 4 latter predictors (risk categories: low, 7%; medium‐low, 23%; medium‐high, 54%; and high, 100%, respectively; P_trend < .001). Predictors of NH toxicity were hemoglobin, creatinine clearance, albumin, self‐rated health, Eastern Cooperative Oncology Group performance, Mini‐Mental Status score, Mini‐Nutritional Assessment score, and Chemotox. The 4 latter predictors provided the best model (risk categories: 33%, 46%, 67%, and 93%, respectively; P_trend < .001). The combined risk categories were 50%, 58%, 77%, and 79%, respectively; P_trend < .001). Bootstrap internal validation and independent sample validation demonstrated stable risk categorization and P_trend < .001.

CONCLUSIONS:

The CRASH score distinguished several risk levels of severe toxicity. The split score discriminated better than the combined score. To the authors' knowledge, this is the first score systematically integrating both chemotherapy and patient risk for older patients and has a potential for future clinical application. Cancer 2011. © 2011 American Cancer Society.