Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype

Multiple myeloma (MM) cells specifically attract peripheral-blood monocytes, while interaction of MM with bone marrow stromal cells (BMSCs) significantly increased monocyte recruitment (p<0.01). The CXCL12 chemokine, produced by both the MM and BMSCs, was found to be a critical regulator of monocyte migration. CXCL12 production was up-regulated under MM-BMSCs co-culture conditions, whereas blockage with anti-CXCR4 antibodies significantly abrogated monocyte recruitment toward a MM-derived conditioned medium (p<0.01). Furthermore, elevated levels of CXCL12 were detected in MM, but not in normal BM samples, whereas malignant MM cells often represented the source of increased CXCL12 in the BM. Blood-derived macrophages effectively supported MM cells proliferation and protected them from chemotherapy-induced apoptosis. Importantly, MM cells affected macrophage polarization, elevating the expression of M2-related scavenger receptor CD206 in macrophages and blocking LPS-induced TNFα secretion (a hallmark of M1 response). Of note, MM-educated macrophages suppressed T-cell proliferation and IFNγ production in response to activation. Finally, increased numbers of CXCR4-expressing CD163+CD206+ macrophages were detected in the BM of MM patients (n=25) in comparison to MGUS (n=11) and normal specimens (n=8).Taken together, these results identify macrophages as important players in MM tumorogenicity, and recognize the CXCR4/CXCL12 axis as a critical regulator of MM-stroma interactions and microenvironment formation.     

Prevalence of Paroxysmal Nocturnal Hemoglobinuria Clones in Myeloproliferative Neoplasm Patients: A Cross-Sectional Study

IntroductionThe myeloproliferative neoplasms (MPN) are clonal diseases that confer an increased risk of thrombohemorrhagic complications. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease associated with an increased thrombotic risk. Small PNH clones are prevalent in aplastic anemia and myelodysplastic syndrome patients, but their prevalence in MPN patients is unknown.Patients and MethodsConsecutive patients with MPN followed up at a single center were recruited. PNH clones were analyzed in erythrocytes and white blood cells by flow cytometry.ResultsPNH clones were detected in 2% of patients and were more common in JAK2 V617F positive patients. We could not detect any differences in clinical manifestations or complications in patients either with or without PNH clones because of the small patient numbers.ConclusionThe prevalence of PNH clones in MPN is similar to that described in myelodysplastic syndromes. Whether PNH clones influence MPN phenotype and complications should be studied prospectively in larger patient cohorts and over long-term follow-up.     

Postoperative radiotherapy of astrocytomas

Astrocytomas account for the majority of primary brain tumors. Low-grade tumors are slowly growing tumors with relatively long overall survival. However, a high percentage of these tumors transform to more malignant, high-grade tumors. High-grade gliomas (anaplastic astrocytomas and glioblastoma multiforme) have a poor prognosis. Treatment options are capable of prolonging the natural history of the disease, but the long-term survival is poor. This review discusses the different postoperative treatment options and the prognostic factors in low- and high-grade astrocytomas.     

L1-CAM in a membrane-bound or soluble form augments protection from apoptosis in ovarian carcinoma cells

OBJECTIVE: Apoptosis resistance is a hallmark of cancer progression, a phenomenon frequently observed in ovarian carcinoma. We reported previously, that L1 adhesion molecule (CD171) is overexpressed in ovarian and endometrial carcinomas and that L1 expression is a predictor of poor outcome. We investigated a possible role of L1 in apoptosis resistance. METHODS: We used L1 transfectants and ovarian carcinoma cell lines and induced apoptosis by different stimuli such as C2-ceramide, staurosporine, cisplatin or hypoxia. RESULTS: We found that cells expressing L1 are more resistant against apoptosis. In HEK293 cells, L1-expresssion leads to a sustained ERK, FAK and PAK phosphorylation. Soluble L1 only partially rescued HEK293 cells from apoptosis. Treatment with apoptotic stimuli upregulated the anti-apoptotic molecule Bcl-2 to a greater extend in HEK293 cells expressing L1. In the ovarian carcinoma cell line OVMz, the depletion of L1 by RNA interference sensitized cells for apoptosis induction. No changes in activation of ERK or FAK were observed after L1 knockdown. The selection of m130 ovarian carcinoma or SW707 colon carcinoma cells with cisplatin leads to upregulated expression of L1. CONCLUSIONS: Our results suggest a link between L1 expression and chemoresistance of ovarian carcinomas. Upregulation of L1 after cisplatin treatment might indicate a more malignant tumor phenotype given the established role of L1 in cell motility and invasion.     

Utilization of minimally invasive breast biopsy for the evaluation of suspicious breast lesions

Background

Percutaneous needle biopsy, also known as minimally invasive breast biopsy (MIBB), has become the gold standard for the initial assessment of suspicious breast lesions. The purpose of this study is to determine modern rates of MIBB and open breast biopsy.

Methods

The Florida Agency for Health Care Administration outpatient surgery and procedure database was queried for patients undergoing open surgical biopsy and MIBB between 2003 and 2008.

Results

Although there was an increase in the use of MIBB, the overall rate of open surgical biopsy remained high (∼30%). A reduction in the open biopsy rate from 30% to 10% could be associated with a charge reduction of >$37.2 million per year.

Conclusions

The current rate of open surgical breast biopsy remains high. Interventions and quality initiatives are warranted, which could lead to a reduction in unnecessary operations for women, improved patient care, and a reduction in breast health care costs.     

An evaluation of strategies to improve the quality and content of hospital‐based postnatal care in a metropolitan Australian hospital

Aim and objective. This study aimed to design, implement and evaluate strategies to improve the quality and content of hospital‐based postnatal care. Background. Following birth, women report physical health problems, difficulties with breastfeeding, a lack of parenting self‐efficacy and there is high occurrence of postnatal distress and depression. Despite these significant needs, women are frequently dissatisfied with the advice and support they receive from hospital‐based postnatal care. Design. A pre/post test design compared the effect of multifaceted strategies on perceptions of quality and content of postnatal care, knowledge and experience of postnatal problems, parenting self‐efficacy and breastfeeding outcomes. The key strategy, ‘one‐to‐one time’, focused on providing women an uninterrupted period of time each day when a midwife would be available to discuss women’s concerns about their health and that of their baby. Method. A convenience sample of 146 women at baseline and 148 women postintervention completed a postal self‐report questionnaire between 2–4 weeks postpartum. Results. There were no significant differences between baseline and postintervention groups in perceived quality of care, breastfeeding outcomes and maternal self‐efficacy. Women experiencing health issues, including insufficient milk supply, backache, abnormal bleeding and urinary incontinence, were more likely to report that they received good or excellent care and advice in the postintervention group. Strategies to increase rest appeared effective with women less likely to report excessive tiredness postintervention. The key strategy, ‘one‐to‐one time’ was not consistently implemented, 57% of women reported they received 10 minutes or less of uninterrupted time with a midwife and only 11% reported that they were provided with 20 minutes or more. Conclusion. There is the potential for individualised care to impact on outcomes for women but established routines and institutional priorities are difficult to change. Relevance to clinical practice. Midwives require both skill development and time to be able to sensitively listen to women’s needs in the hospital postnatal setting.     

Reversal of cycloheximide-induced amnesia by adrenergic receptor stimulation

Amnesia for a multiple trial appetitive spatial dicrimination habit induced by the protein synthesis inhibitor cycloheximide (CXM) was reversed by peripheral injections of both alpha (clonidine) and beta (isoproterenol) norepinephrine receptor stimulators. Stimulation of dopamine receptors with piribedil and acetylcholine receptors with pilocarpine was ineffective in reversing amnesia. The clonidine-induced recovery was blocked by phentolamine and the isoproterenol recovery by propranolol. Examination of the temporal parameters of clonidine-induced recovery indicated that the amnesia was prevented if the agonist was injected either before training and CXM treatment, up to 1 hr after training and up to 3 hr prior to testing. Clonidine also alleviated amnesia induced by another protein synthesis inhibitor anisomycin, for a shock motivated brightness discrimination habit. These data suggest that the transient amnesia induced by CXM may be a consequence of disruption of adrenergic mechanisms and more specifically that norepinephrine may play an important role in memory retrieval.