Synergistic anti‐proliferative and pro‐apoptotic activity of combined therapy with bortezomib,a proteasome inhibitor,with anti‐epidermal growth factor receptor (EGFR) drugs in human cancer cells

The article to which this erratum refers was published in J Cell Physiol (2008) 216: 698–707. © 2008 Wiley‐Liss, Inc. DOI: 10.1002/jcp.21444     

Matrix fibronectin increases HIV stability and infectivity

HIV particles are detected extracellularly in lymphoid tissues, a major reservoir of the virus. We previously reported that a polymerized form of fibronectin (FN), superfibronectin (sFN), as well as a fragment of FN, III1-C, enhanced infection of primary CD4(+) T cells by HIV-1IIIB. We now show that sFN enhances infection of primary CD4(+) T cells by both R5 and X4 strains of HIV-1. Using HIV pseudotyped with different envelope glycoproteins (gp120) and HOS cells transfected with various chemokine receptors alone or in combination with the CD4 molecule, we show that sFN-mediated enhancement requires the CD4 receptor and does not alter the specificity of gp120 for different chemokine receptors. Because the III1-C fragment also resulted in enhancement, we asked whether proteolysis of FN generated fragments capable of enhancing HIV infection. We found that progressive proteolysis of FN by chymotrypsin correlates with an enhancement of HIV infection in both primary CD4(+) T cells and the IG5 reporter cell line. Furthermore, incubation of HIV with sFN significantly prolonged infectivity at 37 degrees C compared with dimeric FN or BSA. In conclusion, these results indicate that polymerized (matrix) or degraded (inflammation-associated), but not dimeric (plasma), FN are capable of enhancing infection by HIV-1, independent of the coreceptor specificity of the strains. Moreover, virions bound to matrix FN maintain infectivity for longer periods of time than do virions in suspension. This study suggests that matrix proteins and their conformational status may play a role in the pathogenesis of HIV.     

Micronucleus frequencies in exfoliated buccal cells in normal mucosa, precancerous lesions and squamous cell carcinoma

OBJECTIVE: To assess the value of micronuclei in the characterization of precancerous lesions of the oral cavity with reference to their likelihood of progressing to malignant lesions. STUDY DESIGN: The frequency of micronuclei was determined in exfoliated cells from normal oral mucosa, a preneoplastic condition (leukoplakia) and precancerous lesions with and without dysplasia, squamous cell carcinomas and sites of previous carcinomas that had been removed. RESULTS: Average micronucleus frequencies were increased in precancerous lesions as compared to normal mucosa and further increased in carcinomas, suggesting that micronuclei are a biomarker of neoplastic progression in this type of cancer. With all samples, micronucleus frequencies were systematically higher when cells were collected by vigorous than by light scraping, suggesting a decreasing gradient from basal to superficial layers of mucosa. The micronucleus frequency did not vary with the sex or age of patients, while it did vary with the anatomic site of the lesions. CONCLUSION: Although the gradual increase in micronucleus counts from normal mucosa to precancerous lesions to carcinomas suggests a link of this biomarker with neoplastic progression, the large overlapping of data prevents its use as a predictor of progression of precancerous lesions to malignancy in individual patients.     

Clinical aspects of systemic amyloid diseases

Amyloidosis is a protein misfolding disorder in which soluble proteins aggregate as insoluble amyloid fibrils. Protein aggregates and amyloid fibrils cause functional and structural organ damage respectively. To date, at least 24 different proteins have been recognized as causative agents of amyloid diseases, localized or systemic. The two most common forms of systemic amyloidosis are light-chain (AL) amyloidosis and reactive AA amyloidosis due to chronic inflammatory diseases. beta(2)-microglobulin amyloidosis is a common complication associated with long-term hemodialysis. Hereditary systemic amyloidoses are a group of autosomal dominant disorders caused by mutations in the genes of several plasma proteins. Heterogeneity in clinical presentation, pattern of amyloid-related organ toxicity and rate of disease progression is observed among systemic amyloidoses. In particular, beta(2)-microglobulin presents unique clinical features compared to the other systemic forms. The phenotypic features of hereditary systemic amyloidoses may instead overlap those of the two more common forms of acquired amyloidoses mentioned above and therefore a correct diagnosis can not rely only on clinical grounds. Unequivocal identification of the deposited protein is essential in order to avoid misdiagnosis and inappropriate treatment. Amyloid deposits can be reabsorbed and organ dysfunction reversed if the concentration of the amyloidogenic protein is reduced or zeroed. At present, the most effective approach to treatment of the systemic amyloidoses involves shutting down, or substantially reducing the synthesis of the amyloid precursor, or, as in the case of beta(2)-microglobulin, promoting its clearance.     

Histopathology, ultrastructure and immunohistochemistry of Coregonus lavaretus hearts naturally infected with Ichthyocotylurus erraticus (Trematoda)

Histopathological, ultrastructural and immunohistochemical investigations were conducted on 26 specimens of powan Coregonus lavaretus (L.) from Loch Lomond (Scotland). The hearts of all 26 powan (15 females and 11 males) investigated harboured metacercariae of the digenean trematode Ichthyocotylurus erraticus (Rudolphi, 1809). The vast majority of metacercariae were located either singly or as an aggregation of white cysts on the surface of the bulbus arteriosus. The intensity of infection ranged from 2 to 200 larvae heart(-1), although the number of metacercariae found on male powan did not exceed 13. Histochemically, the parasite cyst wall gave a strong positive reaction with periodic acid schiff (PAS) and a faint positive signal with Azan-Mallory stain. All the metacercariae cysts were embedded in a granulomatous proliferation of heart epicardium tissue, forming a reactive fibroconnective capsule around the parasite. The capsule enclosing the parasite (produced by the host's reaction to the parasite) measured 13.57 to 90.20 microm (37.43 +/- 3.56) in thickness. Within the capsule wall, eosinophilic granular cells (EGCs), granulocytes, melanocytes and, in some instances, partially degenerated or vacuolated epithelioid cells were observed in close proximity to the cyst wall. Pigment-bearing macrophages were scattered throughout the granulomatous host-tissue reaction and as macrophage aggregates (MAs) within the capsules surrounding parasites. Immunohistochemical tests were applied to infected heart sections using 12 different antisera. Nerve fibres immunoreactive to bombesin, substance P (SP), and atrial natriuretic peptide (ANP) antisera were observed in close proximity to the parasite larvae. The presence of a serotonin-like substance was also observed within host immune-cells surrounding trematode cysts. Large cells of the epicardium were found to be immunoreactive to met-enkephalin and vasoactive intestinal peptide (VIP) antisera but not immunoreactive to anti-protein gene-product 9.5 (PGP9.5) sera.     

Mcl-1 involvement in mitochondrial dynamics is associated with apoptotic cell death

The B-cell lymphoma-2 (Bcl-2) family proteins are critical regulators of apoptosis and consist of both proapoptotic and antiapoptotic factors. Within this family, the myeloid cell leukemia factor 1 (Mcl-1) protein exists in two forms as the result of alternative splicing. The long variant (Mcl-1L) acts as an antiapoptotic factor, whereas the short isoform (Mcl-1S) displays proapoptotic activity. In this study, using splice-switching antisense oligonucleotides (ASOs), we increased the synthesis of Mcl-1S, which induced a concurrent reduction of Mcl-1L, resulting in increased sensitivity of cancer cells to apoptotic stimuli. The Mcl-1 ASOs also induced mitochondrial hyperpolarization and a consequent increase in mitochondrial calcium (Ca²⁺) accumulation. The high Mcl-1S/L ratio correlated with significant hyperfusion of the entire mitochondrial network, which occurred in a dynamin-related protein (Drp1)–dependent manner. Our data indicate that the balance between the long and short variants of the Mcl-1 gene represents a key aspect of the regulation of mitochondrial physiology. We propose that the Mcl-1L/S balance is a novel regulatory factor controlling the mitochondrial fusion and fission machinery.     

Conference announcment (Windsor,Ontario) and registration form

Aquatic Ecosystem Health and Management Society

Conference announcment (Windsor, Ontario) and registration form     

Effect of (-)-cathinone, a khat leaf constituent, on dopaminergic firing and dopamine metabolism in the rat brain

The effect of (-)-cathinone (CAT), an alkaloid from khat leaves, on brain dopamine (DA) metabolism and on the firing rate of nigral DA neurons was studied in rats, in comparison with that of d-amphetamine. Like d-amphetamine, CAT (8-40 mg/kg i.p.) decreased DOPAC levels in the caudate nucleus, nucleus accumbens and frontal cortex, without modifying DA concentrations. CAT showed approximately one fifth of the potency of d-amphetamine in this effect. CAT, injected i.v. to unanesthetized, paralyzed rats, inhibited the firing rate of DA neurons in the substantia nigra, pars compacta, showing a similar potency to that of d-amphetamine in this respect. CAT-induced inhibition of dopaminergic firing was reversed by haloperidol.