Phenotypic and functional effects of heat shock protein 90 inhibition on dendritic cell

The 90-kDa heat shock protein (Hsp90) plays an important role in conformational regulation of cellular proteins and thereby cellular signaling and function. As Hsp90 is considered a key component of immune function and its inhibition has become an important target for cancer therapy, we here evaluated the role of Hsp90 in human dendritic cell (DC) phenotype and function. Hsp90 inhibition significantly decreased cell surface expression of costimulatory (CD40, CD80, CD86), maturation (CD83), and MHC (HLA-A, B, C and HLA-DP, DQ, DR) markers in immature DC and mature DC and was associated with down-regulation of both RNA and intracellular protein expression. Importantly, Hsp90 inhibition significantly inhibited DC function. It decreased Ag uptake, processing, and presentation by immature DC, leading to reduced T cell proliferation in response to tetanus toxoid as a recall Ag. It also decreased the ability of mature DC to present Ag to T cells and secrete IL-12 as well as induce IFN-gamma secretion by allogeneic T cells. These data therefore demonstrate that Hsp90-mediated protein folding is required for DC function and, conversely, Hsp90 inhibition disrupts the DC function of significant relevance in the setting of clinical trials evaluating novel Hsp90 inhibitor therapy in cancer.     

Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression

PDAC (pancreatic ductal adenocarcinoma) is among the most deadly of human malignances. A hallmark of the disease is a pronounced collagen-rich fibrotic extracellular matrix known as the desmoplastic reaction. Intriguingly, it is precisely these areas of fibrosis in which human PDAC tumours demonstrate increased expression of a key collagenase, MT1-MMP [membrane-type 1 MMP (matrix metalloproteinase); also known as MMP-14]. Furthermore, a cytokine known to mediate fibrosis in vivo, TGF-β1 (transforming growth factor-β1), is up-regulated in human PDAC tumours and can promote MT1-MMP expression. In the present review, we examine the regulation of PDAC progression through the interplay between type I collagen (the most common extracellular matrix present in human PDAC tumours), MT1-MMP and TGF-β1. Specifically, we examine the way in which signalling events through these pathways mediates invasion, regulates microRNAs and contributes to chemoresistance.     

Shiga toxin-producing Escherichia coli and enteropathogenic Escherichia coli in healthy goats in India: occurrence and virulence properties

AIMS: To describe the occurrence and virulence gene pattern of shiga toxin-producing Escherichia coli (STEC) and enteropathogenic E. coli (EPEC) in healthy goats of Jammu and Kashmir, India. METHODS AND RESULTS: A total of 220 E. coli strains belonging to 60 different 'O' serogroups was isolated from 206 local (nonmigratory) and 69 migratory goats. All the 220 strains were screened for the presence of stx(1), stx(2), eaeA and hlyA genes. Twenty-eight E. coli (75.6%) strains from local and nine (24.3%) strains from migratory goats belonging to 18 different serogroups showed at least presence of one virulence gene studied. Twenty-eight strains (16.47%) (belonging to 13 different serogroups) from local goats carried stx(1) gene alone or in combination with stx(2) gene, while as only one strain (2%) from migratory goats possessed stx(2) gene alone. Interestingly in the present study none of the STEC strains carried eaeA gene. Similarly, none of the strains from local goats possessed eaeA and none of the migratory goats possessed stx(1) gene. Eight strains (16%) (belonging to four different serogroups) from migratory goats carried eaeA gene. Twenty-five (14.7%) and seven (14%) strains from local and migratory goats harboured hlyA gene respectively. CONCLUSIONS: Healthy goats of Jammu and Kashmir state serve as a reservoir of STEC and EPEC. Further studies in this direction are needed to work out whether or not they are transmitted to humans in this part of world. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first report of isolation of STEC and EPEC strains from healthy goats in Jammu and Kashmir State of India, which could be a source of infection to humans.     

Radioiodination of p-hydroxyphenylisopropyladenosine: development of a new ligand for adenosine receptors

dl-p-Hydroxyphenylisopropyladenosine has been iodinated with 125I and tested as a ligand of adenosine receptors in membranes from rat brain using a filtration assay. Binding studies using l-[3H]phenylisopropyladenosine as a ligand were carried out in parallel, and the binding of both ligands could be displaced by dl-p-hydroxyphenylisopropyladenosine and l-phenylisopropyladenosine in a similar fashion. These data establish the feasibility of using radioiodinated derivatives of adenosine as ligands of suitable types of adenosine receptors.     

Microanatomy and cytochemistry of the gastro-respiratory tract of an air-breathing cobitidid fish,Lepidocephalichthys guntea

Gastro-respiratory tract of the loach,Lepidocephalichthys guntea has been studied with special reference to the nature of its mucus secreting epithelia. The mucous cells are strongly PAS-positive and their number per unit area (mm²) in the mucosal layers of oesophagus, intestinal bulb, intestine and rectum are 733, 531, 223 and 540, respectively. The air-breathing segment of the gut is completely devoid of neutral mucosubstances, and there is a predominance of acidic mucosubstances over the neutral ones throughout the digestive tube. The air-blood pathway of the accessory respiratory organ is about 2.6 μm which is higher than the values of air-breathing organs of other fishes.     

Vascular organization of the head and respiratory organs of the air-breathing catfish,Heteropneustes fossilis

Light and scanning electron microscopy of vascular replicas from the facultative air-breathing fish Heteropneustes fossilis show modifications in the macrocirculation of the respiratory organs and systemic circulation, whereas, gill microcirculation is similar to that found in typical water-breathing fish. Three and sometimes four ventral aortae arise directly from the bulbus. The most ventral vessel supplies the first pair of arches. Dorsal to this another aorta supplies the second gill arches, and a third, dorsal to, and larger than the other two, supplies the third and fourth arches and the air sacs. Occasionally a small vessel that may be the remnant of a primitive aortic arch arises from the first ventral aorta and proceeds directly to the mandibular region without perfusing gill tissue. The air sac is perfused by a large-diameter extension of the afferent branchial artery of the fourth gill arch and its circulation is in parallel with the gill arches. Blood drains from the air sac into the fourth arch epibranchial artery. A number of arteries also provide direct communication between the efferent air sac artery and the dorsal aorta. All four gill arches are well developed and contain respiratory (lamellar) and nonrespiratory (interlamellar and nutrient) networks common to gills of water-breathing fish. Air sac lamellae are reduced in size. The outer 30% of the air sac lamellar sinusoids are organized into thoroughfare channels; the remaining vasculature, normally embedded in the air sac parenchyma, is discontinuous. A gill-type interlamellar vasculature is lacking in the air sac circulation. Despite the elaborate development of the ventral aortae, there is little other anatomical evidence to suggest that gill and air sac outflow are separated and that dorsal aortic oxygen tensions are maintained when the gills are in a hypoxic environment. Physiological adjustments to hypoxic water conditions probably include temporal regulation of gill and air sac perfusion to be effective, if indeed they are so.     

Evaluating scoring functions for docking and designing beta-secretase inhibitors

Several simple scoring methods were examined for 2 series of beta-secretase (BACE-1) inhibitors to identify a docking/scoring protocol which could be used to design BACE-1 inhibitors in a drug discovery program. Both the PLP1 score and MMFFs interaction energy (E(inter)) performed as well or better than more computationally intensive methods for a set of substrate-based inhibitors, while the latter performed well for both sets of inhibitors.