Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu

Currently, no approved monoclonal antibody (mAb) therapies exist for human multiple myeloma (MM). Here we characterized cell surface CS1 as a novel MM antigen and further investigated the potential therapeutic utility of HuLuc63, a humanized anti-CS1 mAb, for treating human MM. CS1 mRNA and protein was highly expressed in CD138-purified primary tumor cells from the majority of MM patients (more than 97%) with low levels of circulating CS1 detectable in MM patient sera, but not in healthy donors. CS1 was expressed at adhesion-promoting uropod membranes of polarized MM cells, and short interfering RNA (siRNA) targeted to CS1 inhibited MM cell adhesion to bone marrow stromal cells (BMSCs). HuLuc63 inhibited MM cell binding to BMSCs and induced antibody-dependent cellular cytotoxicity (ADCC) against MM cells in dose-dependent and CS1-specific manners. HuLuc63 triggered autologous ADCC against primary MM cells resistant to conventional or novel therapies, including bortezomib and HSP90 inhibitor; and pretreatment with conventional or novel anti-MM drugs markedly enhanced HuLuc63-induced MM cell lysis. Administration of HuLuc63 significantly induces tumor regression in multiple xenograft models of human MM. These results thus define the functional significance of CS1 in MM and provide the preclinical rationale for testing HuLuc63 in clinical trials, either alone or in combination.     

Focal nodular hyperplasia occurring after blunt abdominal trauma

Focal nodular hyperplasia of the liver is a benign neoplasm. The pathogenesis is unknown, but it was hypothesized that focal nodular hyperplasia may be a response to a vascular abnormality. We report on a case of focal nodular hyperplasia that developed in a young patient 1 year after a blunt hepatic injury.     

From the bench to the bedside: ways to improve rituximab efficacy

Rituximab (MabThera, Rituxan) is a chimeric IgG1 monoclonal antibody that specifically targets the CD20 surface antigen expressed on normal and neoplastic B-lymphoid cells. Rituximab is currently used in the treatment of both follicular and aggressive B-cell non-Hodgkin lymphomas. Despite its demonstrated clinical effectiveness, its in vivo mechanisms of action remain unknown and could differ by subtype of lymphoma. Rituximab has been shown to induce apoptosis, complement-mediated lysis, and antibody-dependent cellular cytotoxicity in vitro, and some evidence points toward an involvement of these mechanisms in vivo. Rituximab also has a delayed therapeutic effect as well as a potential "vaccinal" effect. Here, we review the current understanding of the mechanism of action of rituximab and discuss approaches that could increase its clinical activity. A better understanding of how rituximab acts in vivo should make it possible to develop new and more effective therapeutic strategies.     

PI 3-kinase, protein kinase C, and protein kinase A are involved in the trigger phase of beta1-adrenergic preconditioning

OBJECTIVE: Using an isolated non-working rat heart model, this study investigated the mechanisms of pharmacological preconditioning (PC) induced by transient beta1-adrenoreceptor (beta1-AR) stimulation with xamoterol (XA). METHODS: After 6-hydroxydopamine (6-OHDA) pretreatment and a 20-min stabilization period, hearts were perfused at constant pressure for 20 min then subjected to 40 min of global ischemia and 30 min of reperfusion (I/R, Ctrl); exposed to 0.01 microM XA for 5 min with or without 10 microM atenolol (ATE), a specific antagonist of beta1-AR, followed by a 15-min XA-free perfusion before I/R (PC, ATE-PC, respectively); treated during 20 min with either phosphoinositide (PI) 3-kinase inhibitors, LY-294002 (LY, 15 microM), or wortmaninn (WO, 0.1 microM); protein kinase C (PKC) inhibitor, GF-109203X (GF, 4 nM); or protein kinase A (PKA) inhibitor, H89 (H89, 1 microM), with an infusion starting 3 min before XA (LY-PC, WO-PC, GF-PC, and H89-PC, respectively). The main endpoints were the mean coronary flow (MCF), the left ventricular end-diastolic pressure (LVEDP), rate-pressure product (RPP), and creatine kinase (CK) release. RESULTS: XA induced an increase in the MCF after I/R (t 105 min) and a protective effect on the LVEDP, which were blocked by ATE and abolished with the different inhibitors. The transient increase in RPP following XA infusion was blocked by ATE and was not modified by the inhibitors except for H89. Recovery of RPP, measured 25 min after reperfusion, was improved by XA, blocked by ATE, and decreased with the different inhibitors. Fifteen minutes after the end of ischemia, CK release reached maximal values in all groups. XA provided significant protection whereas ATE and the four inhibitors suppressed XA-induced protection. CONCLUSION: The transient preischemic exposure to nanomolar concentrations of a beta1-AR agonist is protective against I/R. PI 3-kinase, PKC, and PKA are implicated in the trigger phase of PC. These observations were confirmed by Western blots.     

Short-Chain Fatty Acids Induce Cytoskeletal and Extracellular Protein Modifications Associated with Modulation of Proliferation on Primary Culture of Rat Intestinal Smooth Muscle Cells

Short-chain fatty acids are the main end products of bacterial fermentation of carbohydrates. Their role on the metabolism and biology of colonocytes is now well characterized. However, the functional consequences of their presence on intestinal smooth muscle cells remain poorly studied. We aimed to assess the effect of different short-chain fatty acids on ileal and colonic smooth muscle cells in primary culture and on A7R5 line. Butyrate (above 0.1 mM) inhibited A7R5 cell proliferation, while at low concentration (0.05 to 0.5 mM) butyrate significantly stimulated the proliferation of ileal and colonic myocytes in primary culture. An inhibition was observed at higher concentrations. Collagenous and noncollagenous protein synthesis was stimulated by butyrate. Moreover, butyrate stimulated actin and myosin expression. Thus, butyrate, which is produced by dietary fiber fermentation, may affect intestinal muscles by directly acting at the molecular level on myocytes.     

Doppler reference values of the fetal vertebral and middle cerebral arteries,at 19–41 weeks gestation

Objectives: Blood flow to the fetal brain is supplied by two vascular systems: the vertebral artery (VA) and the internal carotid artery with its anatomical continuation, the middle cerebral artery (ICA/MCA). In this work, our aim was to establish consistent reference values for the comparative study of both arterial systems.

Methods: The study group consisted of 2323 Doppler examinations of the VA, MCA and UA performed on 2323 single pregnancies between 19 and 41 weeks. These values were afterwards used to calculate the pulsatility index (PI), peak systolic velocity (PSV) and cerebro-placental ratio (CPR) percentiles.

Results: The VA and MCA PI reached maximum values at the end of the second trimester and decreased afterwards due to an increase in the diastolic flow. Conversely, the VA and MCA PSV increased progressively until the end of pregnancy. Regarding the VA and MCA CPR values, they were higher in the middle of the third trimester and decreased afterwards.

Conclusions: In both arterial systems, Doppler reference values have been calculated for the PI, PSV and CPR, being available for future comparative studies.     

Benign and malignant vascular tumors of the liver in adults

Vascular tumors of the liver in adult patients include cavernous hemangioma, a common benign tumor; epithelioid hemangioendothelioma, a rare, usually low-grade malignant tumor; and angiosarcoma, a rare and very aggressive tumor. All these primary mesenchymal tumors develop on a normal liver and may also affect other organs. Their pathogenesis remains largely unknown. Hepatic tumors are increasingly detected incidentally due to widespread use of modern abdominal imaging techniques. Therefore, reliable noninvasive characterization and differentiation of such liver tumors is of major importance for clinical practice. Hemangioma follows a benign course, and a nonoperative approach for the majority of these lesions is recommended. A definitive diagnosis of epithelioid hemangioendothelioma and angiosarcoma requires histopathologic examination. Liver transplantation at an early stage has greatly improved the prognosis of epithelioid hemangioendothelioma. The prognosis of angiosarcoma remains dismal. Designing a worldwide database that contains all data about patients with these rare diseases is recommended.     

Diagnostic yield and therapeutic implications of capsule endoscopy in obscure gastrointestinal bleeding

AIM: The main aim of this study was to evaluate efficacy and therapeutic impact of capsule endoscopy (CE) in obscure gastrointestinal bleeding (OGIB). In addition, we evaluated the software of automatic detection of red zones (SBI, Given Imaging). PATIENTS AND METHODS: From June 2002 to June 2003, thirty-five patients with OGIB underwent capsule endoscopy after negative upper and lower digestive endoscopy. Capsule endoscopy was performed following a 12-hour fasting period and some received 2 L of PEG the night before for bowel preparation. RESULTS: CE was performed for occult (N=18) or overt (N=17) OGIB. Potentially bleeding lesions were found in 16/35 patients (45.7%). Lesions were angiodysplasias (N=8), ulcerations (N=4), tumors (N=2) and active bleeding without visible lesion (N=2). Lesions were located in gastric antrum (N=1), duodenum (N=2) and jejuno-ileum (N=13). Endoscopic (N=10), surgical (N=2) or medical (N=1) treatments were performed in 13/35 (37%). SBI was retrospectively evaluated in 24 patients with sensitivity, specificity, positive and negative predictive value of respectively 45%, 73%, 50% and 69%. CE retention during 10 days occurred in a patient with a small bowel NSAID-induced stricture. CONCLUSION: CE is a safe and effective procedure in the management of OGIB and had a therapeutic impact in more than one third of patients.     

Palmoplantar keratosis associated with keratitis: hereditary hypertyrosinemia treated by diet

The authors report the cases of two unrelated children 16 and 5 years of age respectively, affected with hypertyrosinaemia type II. This condition is characterized by palmo-plantar hyperkeratosis associated with a herpetiform keratitis. The diagnosis is based on the finding of hypertyrosinaemia and hypertyrosyluria, and may be confirmed by their biopsy findings of a cytoplasmic tyrosine amino-transferase deficiency. It is a hereditary autosomal recessive disease. A low phenylalanine and tyrosine diet produced a spectacular improvement but the ocular complications could have been avoided by an earlier diagnosis.     

Antibiotic-resistant soil bacteria in transgenic plant fields

Understanding the prevalence and polymorphism of antibiotic resistance genes in soil bacteria and their potential to be transferred horizontally is required to evaluate the likelihood and ecological (and possibly clinical) consequences of the transfer of these genes from transgenic plants to soil bacteria. In this study, we combined culture-dependent and -independent approaches to study the prevalence and diversity of bla genes in soil bacteria and the potential impact that a 10-successive-year culture of the transgenic Bt176 corn, which has a blaTEM marker gene, could have had on the soil bacterial community. The bla gene encoding resistance to ampicillin belongs to the beta-lactam antibiotic family, which is widely used in medicine but is readily compromised by bacterial antibiotic resistance. Our results indicate that soil bacteria are naturally resistant to a broad spectrum of beta-lactam antibiotics, including the third cephalosporin generation, which has a slightly stronger discriminating effect on soil isolates than other cephalosporins. These high resistance levels for a wide range of antibiotics are partly due to the polymorphism of bla genes, which occur frequently among soil bacteria. The blaTEM116 gene of the transgenic corn Bt176 investigated here is among those frequently found, thus reducing any risk of introducing a new bacterial resistance trait from the transgenic material. In addition, no significant differences were observed in bacterial antibiotic-resistance levels between transgenic and nontransgenic corn fields, although the bacterial populations were different.