081, r=−1.742, respectively). PBMCs of patients with chronic TB stimulated in vitro with PPD (median ± SE = 0.674 ± 0.120 ng/mL, range 0.475–1.345 ng/mL) R428 mw and H37Ra (median ± SE = 0.435 ± 0.173 ng/mL, range 0.408–1.521 ng/mL) produced greater amounts of granulysin than did healthy controls, the difference not being significant (P= 0.089, r=−1.698 and P= 0.497, r=−0.679, respectively). Similar median amounts of granulysin were produced by PBMCs of newly diagnosed and relapsed TB stimulated in vitro with PPD and H37Ra but higher amounts by PBMCs of chronic TB, the difference not being

significant (newly diagnosed and chronic TB: P= 0.330, r=−0.974 for PPD and P= 0.242, r=−1.169 for H37Ra; relapsed and chronic TB: P= 0.232, r=−1.196 for PPD and P= 0.380, r=−0.878 for H37Ra) (Fig. 2). In contrast to granulysin, the circulating IFN-γ concentrations Selleckchem Rapamycin in patients with newly diagnosed TB (median

± SE = 6.15 ± 4.58 pg/mL, range < 4.7–300 pg/mL) and relapsed TB (median ± SE = 7.93 ± 8.86 pg/mL, range <4.7–310.73 pg/mL) were significantly higher than those of healthy controls (median ± SE = <4.7 ± 0.20 pg/mL, range <4.7–10.13 pg/mL) (P < 0.001, r=−3.923 and P < 0.001, r=−4.325, respectively). Circulating IFN-γ concentrations in most chronic TB patients were similar to those of healthy individuals (median ± SE = <4.7 ± 3.76 pg/mL, range <4.7–123.69 pg/mL) (P= 0.051, r=−3.486). The median concentrations of IFN-γ were similar in patients with newly Myosin diagnosed and relapsed TB, but both were higher than in chronic TB, the difference not being significant (P= 0.395, r=−0.851 and P= 0.333, r=−0.968, respectively) (Fig. 3). The median IFN-γ production by PBMCs of newly diagnosed TB patients stimulated in vitro with PPD (median ± SE = 535 ± 94 pg/mL, range <4.7–2400 pg/mL) was higher than that of healthy controls (median ± SE = 434 ± 57 pg/mL,

range 326–562 pg/mL) (P= 0.591, r=−0.537). However, most newly diagnosed TB-PBMCs stimulated in vitro with H37Ra produced higher IFN-γ concentrations (range <4.7–8025 pg/mL), but the median was similar (median ± SE = 270 ± 260 pg/mL) to that of healthy controls (median ± SE = 351 ± 120 pg/mL, range 76–556 pg/mL) (P= 0.914, r=−0.107). Supernatant from PBMCs without stimulation was used as a cell control (median ± SE = 14.29 ± 8.88 pg/mL, range 9.85–48.06 pg/mL), while supernatant from newly diagnosed TB-PBMCs without stimulation was used as a control for IFN-γ production (median ± SE = <4.7 ± 5.08 pg/mL, range <4.7–231 pg/mL). IFN-γ production by PBMCs from half the patients with relapsed TB stimulated either with PPD (range <4.7–4225 pg/mL) or H37Ra (range <4.7–2575 pg/mL) was higher than that of normal controls. However, their medians (median ± SE = 260 ± 258 pg/mL for PPD, and median ± SE = 138 ± 136 pg/mL for H37Ra) were lower than those of healthy controls; these differences were not significant (P= 0.823, r=−0.223 and P= 0.412, r=−0.821, respectively).

© 2014 CDK inhibitor Wiley Periodicals, Inc. Microsurgery, 2014. “
“We present a case of successful operative management of an iatrogenic rectourethral fistula with a pedicled vastus lateralis musculofascial flap. The fistula was created during radical prostatectomy operation. During the operation, it was deemed possible to spare this patient from a diverting colostomy and primarily repair a rectal injury. Postoperatively, however, a rectourethral fistula occurred, which was confirmed on retrograde urethrogram. A first attempt failed to close the fistula utilizing the transanal rectal flap advancement technique.

A novel technique was attempted using a pedicled vastus lateralis musculofascial flap. This is the first report to our knowledge of repairing a rectourethral fistula with a pedicled vastus lateralis musculofascial flap. © 2011 Wiley-Liss, Inc. Microsurgery, 2011 “
“Hand pain is a major complaint in 80% of the patients LEE011 mw with complete brachial plexus palsy; and, in 80% of these patients, the C5 root is ruptured and the C6-T1 roots avulsed from the spinal cord. It has been suggested that pain in brachial plexus injuries may not arise from avulsed roots, but rather from ruptured roots.

Traditionally the C5 root dermatome does not extend to the hand. We have hypothesized that in total lesions of the brachial plexus the C5 root dermatome expands, reaching the hand. In 20 patients with confirmed C5 root rupture and C6-T1 root avulsion, we investigated the distribution of C5 root paresthesia six to eight weeks after grafting. After cervical percussion in search of Tinel’s sign, maps related to reported paresthesia were drawn on the affected limb. We observed that paresthesia following C5 root percussion reached the hands and fingers, dermatomes linked to the C6 and C8 roots. Immediately after percussion, for Ponatinib in vitro a few seconds, 14 patients who complained of pain during examination reported the augmentation of numbness and pain resolution. After brachial plexus injury, the C5 root dermatome expands and modulates hand pain. © 2013 Wiley Periodicals,

Inc. Microsurgery 34:292–295, 2014. “
“Suitable recipient vessels for free-flap transfer are hard to find in the posterior thigh. To investigate the versatility of accompanying artery of sciatic nerve as a recipient vessel in this region, we performed computed tomographic angiographic study of 20 consecutive healthy thighs in 10 patients. The presence and internal diameter of the accompanying artery were studied. The accompanying artery of the sciatic nerve was present in 11 thighs (55%) and the internal diameter of the artery at the mid-thigh level ranged from 2.1 to 3.2 mm. We used this artery as a recipient vessel for free flaps transferred to reconstruct extensive thigh defects in three patients with sarcomas. In all patients the flaps survived without vascular compromise.

Overall, these findings sustain a prominent role for TNF-α in the pathogenesis of PBC, suggesting that anti-TNF-α treatment, currently used for most inflammatory rheumatic conditions, such as RA, ankylosing

spondylitis (AS), and CD, may also represent a promising agent in PBC. Pathway analysis selleck chemicals llc of both the Italian and Canadian GWAS PBC cohorts have highlighted the phosphatidylinositol signaling system pathway, which is an integral component of the adaptive immune response and is essential for the maintenance of self-tolerance [41]. Possible involvement of the phosphatidylinositol pathway in PBC appears to fit well with the TNF hypothesis as this signaling system has been shown to mediate the effects of TNF-α on NF-κB activation [72, 73]. The same pathway analysis also identified the hedgehog (Hh) signaling system, suggesting

its involvement in PBC genetic susceptibility. Hh proteins comprise a group of secreted proteins that are involved in organogenesis and have been shown to promote adult stem cell proliferation [74-76]. Hh signaling has been widely described in PBC. It is involved in the ductular response to cholestatic damage in PBC, characterized by periportal accumulation of proliferating bile ductular cells and associated stromal elements, including myofibroblastic cells and fibrous matrix [77]. Hh signaling was found to be increased in a murine model of bile check details duct ligation in periportal epithelial cells expressing pan-cytokeratin, representing potential liver progenitor cell populations [63]. Hh signaling has also been shown to be able to promote the survival of biliary epithelial cells, possibly mediated through the inhibition of caspase activity [16]. Lastly, Hh signaling pathway activation has

been associated with upregulation of ductular cell expression of genes that promote inflammatory response, such as the gene producing Cxcl16; Hh dependent induction of Cxcl16, demonstrated find more in both bile duct ligated rats and humans with PBC, resulted in Natural Killer T (NKT) cell chemotaxis toward cholangiocytes in vitro [17]. Hh signaling may represent an important protective factor within the damaged liver, promoting the survival of small periportal epithelial cells representing potential hepatic progenitor cells. Despite the preliminary nature of these studies, the Hh signaling pathway may represent a new therapeutic target to protect or promote cell proliferation and tissue repair within the chronically damaged liver in PBC and other chronic liver diseases. Some scientists believe that, as humans did not evolve in an environment of drug therapies, there is no evolutionary pressure on responses to recently developed pharmacologic agents.

OHASHI YASUSHI1, TAI REIBIN1, AOKI TOSHIYUKI1, MIZUIRI SONOO2, OGURA TOYOKO3, TANAKA YOSHIHIDE1, OKADA TAKAYUKI1, AIKAWA ATSUSHI1, SAKAI KEN1 1Department of Nephrology, School of Medicine, Faculty of Medicine, Toho University, Tokyo; 2Division of Nephrology, Ichiyokai Harada Hospital, Hiroshima; 3Department of Nutrition, Toho University Omori Medical Center, Tokyo Introduction: Fluid imbalance due to sodium

retention and malnutrition click here can be characterized by the ratio of extracellular water (ECW) to intracellular water (ICW). Our objectives are to investigate whether fluid imbalance between ICW and ECW is a risk factor for adverse outcomes. Methods: Body fluid composition was measured in 149 patients with chronic kidney disease from 2005 to 2009, who were followed until death, loss to follow-up, or August 2013. Patients were categorized according to the ECW/ICW ratio tertile. The ratio of ECW to total body water, calculated by the Watson formula, was used as an indicator of ECW excess. Main outcomes were adverse see more renal outcomes, as defined by a decline of 50% or more

from baseline glomerular filtration rate or initiation of renal replacement therapy, cardiovascular events, and all-cause mortality. Results: Patients with higher tertile tended to be older and have diabetes mellitus, treatment-resistant hypertension, ECW excess, decreased protein intake per calorie, lower renal function, hypoalbuminemia, and higher proteinuria and furosemide usage (P < 0.01). Compared with patients in the lowest tertile during a median 4.9-year follow-up, those in the highest tertile had the worst adverse renal outcomes (15.9 vs. 5.1 per 100 patient-years, P < 0.001), cardiovascular events (4.1 vs. 0.3 per 100 patient-years, P = 0.002), and mortality (11.2 vs. 1.3 per 100 patient-years, P < 0.001)

by Kaplan–Meier survival analysis. The adjusted hazard ratio (95% confidence intervals) for adverse renal outcomes, cardiovascular events, and all-cause mortality were 1.15 (1.03–1.26, P = 0.011), 1.12 (0.93–1.31, P = 0.217), and 1.29 (1.11–1.50, P < 0.001), respectively. Conclusion: Fluid diglyceride imbalance between ICW and ECW, driven by cell volume decrease and ECW excess, was associated with adverse renal outcomes and mortality. These findings emphasize the importance of cell volume retention as well as appropriate extracellular volume. CHEN SZU-CHIA1, HUANG JIUN-CHI1,2, CHANG JER-MING1,2, HWANG SHANG-JYH1, CHEN HUNG-CHUN1 1Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital; 2Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University Introduction: The P wave parameters measured by 12-lead electrocardiogram (ECG) are commonly used as noninvasive tool to assess for left atrial enlargement.

2). The early responding C12Id+ HA-specific B cells were also not significantly different with regard to expression of CD24, one of the markers identified by Linton et al. 41 to correspond with extrafollicular foci development, although we measured CD24 expression with an anti-CD24 mAb different from that used by that earlier study (data not shown). Thus, LN seem to lack a specific resident B-cell subpopulation comparable to the MZ B-cell population in the spleen that can facilitate rapid responses to early blood-borne infection. Instead,

follicular (C12Id+ HA-specific) B cells provide this rapid, BGJ398 molecular weight strong (Fig. 1) and protective 2 extrafollicular B-cell response (Fig. 3). Various models have been proposed to explain the regulation of extra- versus intra-follicular B-cell responses 22, 26, 39–41, 46. The influenza virus model system described here and available tools to study the C12Id-specific responses provide an excellent opportunity to further analyze this important differentiation process in vivo in

the context of an infection. Our study identifies C12Id-expressing HA-specific B cells as predominant contributors to a strong extrafollicular B-cell response in regional MedLN, the site of much of the early Ab response to this virus. Predominant HCS assay participation of the C12Id-expressing HA-specific cells in extrafollicular responses is consistent with earlier findings that failed to find any mutated C12Id-sequences among HA-specific B cells 27, i.e. these cells showed no signs of affinity maturation. However, we show here that while C12Id+ cells vigorously participate in extrafollicular foci responses (Fig. 3), they can also initiate

germinal centers (Fig. 4). While we cannot completely rule out that C12Id+ B cells that mutated their BCR might have lost the idiotope that allowed us to stain these cells for FACS analysis, Alectinib datasheet the earlier extensive sequence studies on B cells from mice at various times after immunization (26), make this trivial explanation somewhat unlikely. Given the recent studies by Paus et al. 22 that implicated BCR-affinity for antigen in the selection process, our studies might suggest that high-affinity interactions with antigen are a necessary, but likely not sufficient, signal for extrafollicular foci development as C12Id+ HA-specific cells are able to also initiate germinal centers (Figs. 3 and 4). Failure to expand this germinal center response during early infection, rather than an inability to initiate it, might result in the irregular kinetics and small frequencies of C12Id+ germinal center B cells observed here (Fig. 4). This interpretation is not only consistent with the presented data, but also with earlier studies using the (4-hydroxy-3-nitrophenyl) acetyl system, which demonstrated that extrafollicular foci and germinal center B cells can have a common precursor 25, 26, 39. The vigorous infection-induced extrafollicular foci response is likely supported and modulated by external signals.

[3, 4] IPA accounts for 90–98% of invasive Aspergillus infections; however, extrapulmonary aspergillosis may be present in 25–60% of cases and is almost always caused by haematogenous spread of pulmonary foci. IA has a wide spectrum of clinical presentations, making diagnosis challenging. In 2006, it has been reported that only a quarter of IA cases confirmed

by autopsy had been diagnosed premortem, which demonstrates that there is a lot to be done in terms of early diagnosis.[5, 6] Lewis and colleagues published an autopsy-based study in 2013 which showed that rates of premortem diagnosis of Aspergillus infections might have improved over the last decade. They analysed autopsy data from over 20 years and found that in the first 5 years of the study 84% of the invasive

fungal ALK targets infections were diagnosed postmortem, while in the last 4 years this number decreased to 49%.[7] Most likely reasons for an ongoing increase of IA diagnosed premortem are the introduction of new diagnostic tools, such as Galactomannan or Lateral flow Device testing as well as improved culture methods.[3, 8-10] IA is still associated with mortality rates of about 40%. Early initiation of systemic antimould therapy remains the most important measure CYC202 ic50 to reduce mortality.[11] Surgical debridement is an important therapeutic option mainly in cases of extrapulmonary IA. Evidence for surgical interventions exists primarily in localised infections of children and adults. In disseminated infections, the evidence for the benefit of surgical interventions other than for diagnostic purposes is poor. The main intentions for surgical interventions are: (i) to obtain material for diagnosis, (ii) to decrease the burden of infected tissue and (iii) to facilitate antifungal penetration. Surgical/invasive interventions are nearly always indicated only in combination with systemic

antifungal therapy. Naturally, there are no randomised or controlled clinical studies available on surgical interventions in IA, limiting the evidence MycoClean Mycoplasma Removal Kit to mostly uncontrolled single-centre case series (Table 1).[12] Here, we will review the role of surgical interventions in the treatment of different clinical manifestations of IA. Cerebral (intradural) aspergillosis is associated with the highest mortality of all different manifestations of IA. The infection spreads to the CNS either by haematological dissemination from pulmonary foci or expands directly from paranasal sinus infection. Aspergillus spp. may also enter the CNS due to traumatic inoculation or during surgical procedures.[13] CNS aspergillosis often presents with neurological symptoms, such as altered mental status, a focal neurological deficit, seizure, persistent headache or rarely meningeal signs.

[1] APS may occur in isolation, or in association with systemic

lupus erythematosus (SLE) or other autoimmune conditions, where it is sometimes referred to as ‘secondary’. Amongst the clinical and laboratory criteria for the diagnosis of APS[2, 3] is the presence of antiphospholipid (aPL) antibodies, demonstrated through prolongation of phospholipid-dependent clotting time in vitro (‘lupus anticoagulant’, LA) or by specific enzyme-linked immunosorbent assay (ELISA) for high-titre anti–β2-glycoprotein MG-132 in vivo 1 (anti-β2-GP1) or anticardiolipin (aCL) antibodies. APS-related thrombotic events may be venous, arterial or both.[4] Venous thrombosis most commonly results in lower limb deep venous thrombosis (DVT) and/or pulmonary embolism (PE), whereas arterial thrombosis typically beta-catenin inhibitor involves the

cerebral circulation. APS may also cause thrombotic microangiopathy (TMA), with biopsy of affected organs revealing microvascular endothelial injury, intimal expansion and fibrin deposition culminating in microvascular thrombosis.[5] Occasionally TMA is the only manifestation of APS, and it remains unclear which factors in patients with APS predispose to TMA rather than macrovascular thrombosis.[6] In ‘catastrophic’ antiphospholipid syndrome (CAPS), TMA involving the kidneys, lungs, brain and other organs leads to acute multiorgan failure.[7] CAPS occurs in less than 1% of patients with APS, but in nearly half these cases it is the first manifestation of APS.[8] Fenbendazole Hence awareness of CAPS is important, with one series reporting acute CAPS-associated mortality of 44%.[8] Thrombocytopenia and microangiopathic haemolytic anaemia (MAHA) are often absent.[8] APS may cause renal disease through TMA or large vessel thrombosis (Table 1).[9] APS-related renal TMA affects the glomerular tuft and intrarenal vessels and may present with hypertension, haematuria, proteinuria and renal failure. It was originally described in patients with lupus nephritis,[10] later as a

complication of pregnancy in a cohort of women, some of whom had SLE.[11] It may also form a part of systemic TMA as seen in CAPS.[12, 13] Establishing APS as the cause of renal TMA requires confirmation of persistent aPL antibody positivity and exclusion of alternative or additional causes of TMA (discussed below). APS-associated nephropathy (APSN) now includes the acute lesion of TMA and/or chronic vascular changes: fibrous intimal hyperplasia, arterial or arteriolar occlusion, and focal cortical atrophy.[14, 15] Progression of APS-related renal TMA to end-stage kidney disease (ESKD) has been reported in a limited number of cases,[14, 16, 17] whilst the renal prognosis of other components of APSN remains unclear.

69 As such, this is the most promising vaccine adjuvant to date. It was licensed for use in CKD patients in Europe in 2005. Finally, studies have investigated whether intradermal (ID) vaccination may afford improved seroconversion. HBV vaccination in healthcare workers was evaluated in a Cochrane review in 2005.70 Low-dose ID injection was shown to provide lower anti-HBs levels than high-dose intramuscular (IM)

vaccination in this immunocompetent group of recipients. The following year a meta-analysis of IM versus ID vaccination in HD patients concluded that the ID route generated a superior anti-HBs response at the end of the vaccination protocol, but no significant differences in antibody levels were seen over longer follow-up.71 A similar conclusion was reached from a single, high throughput screening compounds small study of 60 chronic ambulatory peritoneal dialysis patients who were randomized

to ID or IM vaccination.72 The peak anti-HBs titres were reached earlier in the ID group, and a higher seroconversion rate attained, but there was no difference between the two groups in maintenance of seroprotective anti-HBs levels over 2 years of follow-up. The ID route is more technically challenging and causes an increased incidence of local reactions. Given that the majority of dialysis patients will respond to primary IM vaccination, the deltoid IM route seems preferable for primary learn more vaccination, with the ID route reserved for the more troublesome group of non-responders. The antibody response to hepatitis B vaccination declines with time. It is current practice to administer booster doses to those with an adequate initial response whose anti-HBs levels fall below 10 IU/L. For those who do not respond adequately to the initial vaccination course, a revaccination schedule may be employed. Bock et al. assessed the effect of a shorter revaccination course of injections in a small group of Sitaxentan HD patients.73 In this randomized controlled trial, no improved efficacy for a shorter revaccination schedule was demonstrated. By contrast Barraclough

et al. used eight weekly ID injections of low-dose HBV vaccine in patients initially unresponsive to a standard vaccination schedule.74 In a randomized comparison with a 2-dose, 8-week IM vaccination schedule, the patients receiving ID vaccination had a significantly greater seroconversion rate, with a trend towards longer seroprotection in responders. The ID injections were well-tolerated. The findings were consistent with a prospective, randomized study from Italy in 1997.75 Alternatively, a small observational study from Israel found that the use of the third-generation vaccine Bio-Hep-B in a revaccination protocol yielded seroprotective anti-HBs levels in 25 of 29 initial non-responders (86%) to a standard vaccination schedule.76 Patients should therefore be vaccinated according to guidelines, with the recommended ‘double dose’ of 40 µg.

As shown in Fig. 5D

and E, CTLA4 reduction in Treg cells did not compromise its efficacy in protecting the tumor cells from destruction by self-antigen-specific Teff cells. Our studies with three different tumor cell lines for two types of cancers, insulinoma and lymphoma, illustrated a quantitative impact by CTLA4 on autoimmune Teff cells. These implanted tumor models enabled the studies in an antigen-specific manner. It would be desirable to validate the key finding in naturally developed tumors. We used a spontaneous breast cancer model, BALB-neuT mice [36], to test the impact of subtle CTLA4 reduction on self-tolerance of tumors. In this model, it was shown that overexpression of a self-antigen in tumors promoted a dominant self-tolerance in the tumor microenvironment that facilitated Napabucasin solubility dmso breast cancer development [37]. In humans, genetic studies have associated breast cancer with polymorphisms of the CTLA4 locus [19, 20]. The CTLA4KD7 or PL4 transgenic lines

were crossed with BALB-neuT transgenic mice. The CTLA4KD7+neuT+ mice, compared with CTLA4KD7−neuT+ littermate or PL4+neuT+ controls, had a delayed incidence of breast cancer (Fig. 6A). Among the animals that had breast tumors, the age of tumor onset was significantly delayed in CTLA4KD7+neuT+ mice than in controls (Fig. 6B), and the tumor grew at a slower pace (Fig. 6C) and with a significantly smaller mass (Fig. 6D). A histopathological analysis of the breast tumors revealed that whereas control neuT+ mice exhibited minimal sign of immune destruction of the tumors, AZD4547 concentration substantial lymphocytic infiltration and inflammatory damage were evident in the tumors from CTLA4KD7+neuT+ mice (Fig. 6E). This difference in the tumor pathology was consistent with increased activation of both CD4+ and CD8+ Teff cells in the CTLA4KD7+neuT+ mice versus controls (Supporting Information PAK6 Fig. 3). Taken together with the critical role of dominant peripheral self-tolerance in breast cancer development demonstrated by a

previous study [37], the results suggest that genetically relevant, physiological levels of CTLA4 quantitative variations can play a critical role in unmasking self-antigen-specific antitumor immunity, perhaps by diminishing local tolerance at the tumor site. Furthermore, the CTLA4KD model enabled us to provide the first experimental evidence for a role of CTLA4 in spontaneous tumor onset and progression. Further studies are needed to understand the exact mechanisms by which CTLA4 reduction impacts spontaneous breast cancer development. Clinical trials with anti-CTLA4 antibody blockade has produced remarkable antitumor benefit but also suggested that autoimmunity, at least in part, actually mediated the tumor destruction. We sought to characterize how autoimmune Teff and Treg cells were implicated and impacted by CTLA4 blockade in tumor-bearing animals. NOD.

As an example, C-C motif chemokine ligand 2 (CCL2) has been taken into account, because its over-expression was correlated with increased macrophage infiltration and poor prognosis in human cancers,[27-29] and macrophage infiltration

and the growth of tumours were reduced when CCL2 was inhibited.[22, 30-33] The tie between CCL2 and M2 macrophages is particularly clear in CCL2+ melanoma. For instance, pharmacological inhibition of CCL2 with bindarit reduced tumour growth, macrophage recruitment and necrotic tumour masses in human melanoma xenograft.[30] One of the CCL2-targeting agents, trabectedin, has been efficiently used in clinic to treat human ovarian cancer[34] and myxoid liposarcoma.[35] According to those reports, trabectedin could suppress the recruitment 3-deazaneplanocin A manufacturer of monocytes selleck to tumour sites and inhibit their differentiation to mature TAMs, which may contribute to trabectedin-induced tumour rejection. The association of CCL2 with TAM recruitment was further supported by a phase II clinical study, in which anti-interleukin-6 (IL-6) antibody siltuximab reduced macrophage infiltration in tumour tissue via declining the plasma level of some chemoattractants such as CCL2, vascular endothelial growth factor (VEGF) and C-X-C motif chemokine ligand-12 (CXCL-12).[36] As an alternative way to suppress the chemoattractive

activity of CCL2, neutralizing its receptor, C-C motif chemokine receptor 2 (CCR2), is also challenged. One pharmacological inhibitor of CCR2 (RS102895) has exhibited negative effects on macrophage migration.[37] In addition, the efficacy of two humanized monoclonal antibodies ioxilan (mAbs; CNTO888 and MLN1202) specific for CCL2/CCR2 are under clinical investigation (see ClinicalTrials.gov; study identifier: NCT00537368, NCT00992186, NCT01204996, MLN1202 and NCT01015 560). Another important chemoattractant for macrophages is macrophage colony-stimulating factor (M-CSF). In human hepatocellular carcinoma, there is a significant association

between high M-CSF expression and high macrophage density, each relates to poor overall survival of patients.[17] In an M-CSF-deficient mouse model of pancreatic neuroendocrine tumour, macrophage infiltration was decreased by ~ 50% during all stages of tumour progression.[38] In another experiment, treatment with M-CSF antibody suppressed tumour growth by 40% in human MCF-7 breast cancer xenografts.[39] More recently, two M-CSF receptor inhibitors (JNJ-28312141 and GW2580) were found to decrease TAM count and suppress tumour growth, angiogenesis and metastasis.[40, 41] In contrast to standard VEGF inhibition, the continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside tumour sites.[41] This implies that M-CSF might be a good candidate in the therapies aiming to inhibit macrophage recruitment or angiogenesis.