Noninvasive optical measures of CBV,StO2, CBF index,and rCMRO2 in human premature neonates' brains in the first six weeks of life

The article to which this erratum refers was published in Hum Brain Mapp 2010 (Vol. 31), DOI: 10.1002/hbm.20868.     

Toward a new and noninvasive diagnostic method of papillary thyroid cancer by using peptide vectorized contrast agents targeted to galectin-1

The incidence of papillary thyroid cancer has increased these last decades due to a better detection. High prevalence of nodules combined with the low incidence of thyroid cancers constitutes an important diagnostic challenge. We propose to develop an alternative diagnostic method to reduce the number of useless and painful thyroidectomies using a vectorized contrast agent for magnetic resonance imaging. Galectin-1 (gal-1), a protein overexpressed in well-differentiated thyroid cancer, has been targeted with a randomized linear 12-mer peptide library using the phage display technique. Selected peptides have been conjugated to ultrasmall superparamagnetic particles of iron oxide (USPIO). Peptides and their corresponding contrast agents have been tested in vitro for their specific binding and toxicity. Two peptides (P1 and P7) were selected according to their affinity toward gal-1. Their binding has been revealed by immunohistochemistry on human thyroid cancer biopsies, and they were co-localized with gal-1 by immunofluorescence on TPC-1 cell line. Both peptides induce a decrease in TPC-1 cells’ adhesion to gal-1 immobilized on culture plates. After coupling to USPIO, the peptides preserved their affinity toward gal-1. Their specific binding has been corroborated by co-localization with gal-1 expressed by TPC-1 cells and by their ability to compete with anti-gal-1 antibody. The peptides and their USPIO derivatives produce no toxicity in HepaRG cells as determined by MTT assay. The vectorized contrast agents are potential imaging probes for thyroid cancer diagnosis. Moreover, the two gal-1-targeted peptides prevent cancer cell adhesion by interacting with the carbohydrate-recognition domain of gal-1.     

Modalities of Invasive Arterial Pressure Monitoring in Critically Ill Patients: A Prospective Observational Study

Few studies assessed modalities of invasive arterial pressure monitoring (IAPM). We evaluated effects on measured values of various combinations of transducer level, catheter access site, and patient position.Prospective observational study in consecutive adults admitted to a French intensive care unit in 2009 to 2011 and fulfilling our inclusion criteria. Four combinations (B–E) of transducer level, catheter access site, and patient position were compared with a reference combination (A) (A: patient supine with all catheters in the same plane and a single transducer level (M) for zero point reference (Z) aligned on the phlebostatic axis; B: 45° head-of-bed elevation with M and Z aligned on the phlebostatic axis; C: 45° head-of-bed elevation with M aligned on the catheter access site and Z on the phlebostatic axis; D: 45° head-of-bed elevation with M and Z aligned on the catheter access site; and E: 45° head-of-bed elevation with M aligned on the phlebostatic axis and Z on the catheter access site).We included 103 patients, 68 men and 35 women, with a median age of 69 years (interquartile range [IQR], 56–78); at inclusion, 91 (88.3%) received mechanical ventilation, 45 (43.7%) catecholamines, and 66 (64.1%) sedation. The IAPM access site was femoral in 49 (47.6%) and radial in 54 (52.4%) patients, with 62 of 103 (60.2%) catheters on the right side. Measured absolute mean arterial pressure values were significantly higher with 3 study combinations (C–E) than with the reference combination (A). After adjustment, the differences versus A (median, 83 [IQR, 74–92] mm Hg) remained significant for D (median, 91 [IQR, 85–100] mm Hg, P < 0.001) and E (median, 88 [IQR, 77–99] mm Hg, P < 0.001). The difference versus A was not significant for B (median, 85 [IQR, 76–94] mm Hg, P = 0.21) or C (median, 90 [IQR, 84–100] mm Hg, P = 0.006).Several modalities used for zeroing and/or transducer leveling during IAPM may result in statistically and clinically significant overestimation of measured mean arterial pressure values. For patients in the 45° head-of-bed elevation position, aligning the Z on the phlebostatic axis provides values that are not significantly different from those obtained using the reference supine modality.     

Phase II study of 131I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP

Purpose

We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of ¹³¹I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL).

Methods

Patients received ¹³¹I-mIBG on day 1, with intravenous topotecan daily on days 1–5. A second activity of ¹³¹I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21–25. Peripheral blood stem cells were infused on day 31.

Results

Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2–20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1–26). Median number of prior lines of treatment was 3 (1–7). Objective response rate was 13% (95% confidence interval [CI]: 4–31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6–32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years).

Conclusion

MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.     

Sleep Abnormalities in Wilson’s Disease

Purpose of review

The aim of this article was to review the different sleep disorders associated with Wilson’s disease (WD), their mechanisms and their treatments.

Recent findings

Some of these disorders such as REM sleep behavior disorder or sleepiness can appear as a prodromal phase phenomenon in WD allowing an early treatment of the disease and sometimes a resolution of the sleep disorder.

Summary

Sleep disorders in WD are frequent combining insomnia, daytime sleepiness, restless legs syndrome (RLS), cataplexy-like episodes, and REM sleep behavior disorder (RBD). Sleep recordings confirm these disorders. Mechanisms involved in these disorders are complex associating (a) lesions of the pathways regulating sleep and wake or mood but also controlling movement, (b) iatrogenic effects of the treatments, and (3) consequences of the motor or dysautonomic or metabolic disorders.

     

Examination of HER3 targeting in cancer using monoclonal antibodies

The human EGF receptor (HER/EGFR) family of receptor tyrosine kinases serves as a key target for cancer therapy. Specifically, EGFR and HER2 have been repeatedly targeted because of their genetic aberrations in tumors. The therapeutic potential of targeting HER3 has long been underestimated, due to relatively low expression in tumors and impaired kinase activity. Nevertheless, in addition to serving as a dimerization partner of EGFR and HER2, HER3 acts as a key player in tumor cells’ ability to acquire resistance to cancer drugs. In this study, we generated several monoclonal antibodies to HER3. Comparisons of their ability to degrade HER3, decrease downstream signaling, and inhibit growth of cultured cells, as well as recruit immune effector cells, selected an antibody that later emerged as the most potent inhibitor of pancreatic cancer cells grown as tumors in animals. Our data predict that anti-HER3 antibodies able to intercept autocrine and stroma–tumor interactions might strongly inhibit tumor growth, in analogy to the mechanism of action of anti-EGFR antibodies routinely used now to treat colorectal cancer patients.Growth factors and their plasma-membrane–embedded receptors regulate cellular proliferation and migration during both embryogenesis and oncogenesis (1). One example entails the epidermal growth factor (EGF) family and the corresponding human EGF receptor (HER)/ERBB family of four receptor tyrosine kinases: the EGF receptor (EGFR or ERBB1), HER2 (c-Neu or ERBB2), HER3 (ERBB3), and HER4 (ERBB4) (2). The intracellular parts of ERBB/HER receptors harbor a catalytic tyrosine kinase domain (3). After ligand binding to an ectodomain, these receptors form active homodimers or heterodimers (4–7). Unlike EGFR, HER3/ERBB3 presents very low tyrosine kinase activity (8). Nevertheless, it binds neuregulins (NRGs) and exerts profound influence on signaling pathways, primarily through dimerization with EGFR and HER2. In line with roles in cancer progression, and similarly to EGFR and HER2, mutant forms of HER3 have recently been reported in colon and gastric cancer (9).Cancer therapies that use monoclonal antibodies (mAbs) to target ERBB/HER family members are becoming a mainstay in oncology. For example, trastuzumab, which targets HER2, is currently used to treat gastric and breast cancer (10, 11). However, the majority of patients with metastatic HER2-positive breast cancer will become trastuzumab-resistant after prolonged treatment, a development significantly less common in an adjuvant or neo-adjuvant setting. It has been reported that trastuzumab-resistant tumors show elevated expression of HER3 (12), and, similarly, inhibition of HER2 using a kinase inhibitor also up-regulates HER3 (13). Likewise, HER3 has been implicated in the development of resistance to treatment with other ERBB/HER-targeted therapies (14, 15), agents blocking insulin-like growth factor receptors (16), and chemotherapeutic agents (17). For these reasons, anti-HER3 antibodies (Abs) are being developed by several laboratories, and some have reached initial clinical trials.Importantly, anticancer mechanisms of therapeutic Abs are multifactorial and incompletely understood. The involvement of Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity, as well as various cellular processes such as triggering of apoptosis, blocking angiogenesis, inhibiting tumor cell proliferation, interfering with signaling cascades, and accelerating receptor internalization, have been described (18). Our own studies proposed critical involvement of the endocytic system. In particular, combinations of two mutually noncompetitive Abs (Abs against different epitopes that do not cause steric hindrance) to EGFR (19) or to HER2 (20, 21) have been shown to accelerate receptor endocytosis and inhibit tumor growth, better than either Ab alone. Furthermore, a recently completed clinical trial that combined with chemotherapy two mutually noncompetitive anti-HER2 mAbs, for the treatment of HER2-positive breast cancer (22), confirmed the clinical benefit of combining noncompetitive mAbs.Anti-HER3 agents that are being developed or are in clinical trials show promising results, yet their efficacy might be viewed, in general, as variable and rather modest (23). Hence, it is imperative to develop new agents and resolve their molecular mechanisms of action. In this study, we generated in mice a relatively broad series of anti-HER3 mAbs and examined them for the ability to both degrade HER3 and decrease downstream signaling. The new mAbs displayed a variety of biochemical and biological attributes, such as binding affinity to HER3, ability to displace NRG and block downstream signals, sort HER3 for degradation, and recruit natural killer cells. Ultimately, the Abs were tested in vitro and in tumor-bearing animals for their ability to inhibit growth of cancer cells. We focus on an especially potent tumor-inhibitory Ab that can displace NRG, robustly sort HER3 for intracellular degradation, and also recruit immune effector cells.