Human T-cell lymphotropic virus type 1 infection of CD34+ hematopoietic progenitor cells induces cell cycle arrest by modulation of p21(cip1/waf1) and survivin

Human T-cell lymphotropic virus type 1 (HTLV-1) is an oncogenic retrovirus and the etiologic agent of adult T-cell leukemia (ATL), an aggressive CD4(+) malignancy. HTLV-2 is highly homologous to HTLV-1; however, infection with HTLV-2 has not been associated with lymphoproliferative diseases. Although HTLV-1 infection of CD4(+) lymphocytes induces cellular replication and transformation, infection of CD34(+) human hematopoietic progenitor cells (HPCs) strikingly results in G(0)/G(1) cell cycle arrest and suppression of in vitro clonogenic colony formation by induction of expression of the cdk inhibitor p21(cip1/waf1) (p21) and concurrent repression of survivin. Immature CD34(+)/CD38(-) hematopoietic stem cells (HSCs) were more susceptible to alterations of p21 and survivin expression as a result of HTLV-1 infection, in contrast to more mature CD34(+)/CD38(+) HPCs. Knockdown of p21 expression in HTLV-1-infected CD34(+) HPCs partially abrogated cell cycle arrest. Notably, HTLV-2, an HTLV strain that is not associated with leukemogenesis, does not significantly modulate p21 and survivin expression and does not suppress hematopoiesis from CD34(+) HPCs in vitro. We speculate that the remarkable differences in the activities displayed by CD34(+) HPCs following infection with HTLV-1 or HTLV-2 suggest that HTLV-1 uniquely exploits cell cycle arrest mechanisms to establish a latent infection in hematopoietic progenitor/hematopoietic stem cells and initiates preleukemic events in these cells, which eventually results in the manifestation of ATL.     

CD30-positive T-cell lymphoproliferative disorder of the oral mucosa--an indolent lesion: report of 4 cases

Four cases of CD30-positive T-cell lymphoproliferative disorder (CD30+ LPD) of the oral mucosa are described. This article aims to draw attention to this entity and to emphasize its usual benign clinical behavior despite its resemblance to T-cell lymphoma. All the patients were adults. Three of the lesions were on the dorsal surface of the tongue and 1 affected the buccal mucosa. All biopsies showed a dense lymphoid infiltrate composed of CD30+ atypical T cells with a polymorphous infiltrate in the background, which included eosinophils. In 1 case, monoclonal T-cell expansion was detected by molecular techniques. Three cases tested for Epstein-Barr virus were all negative. It is concluded that primary CD30+ T-cell LPD of the oral mucosa can be regarded as the oral counterpart of cutaneous CD30+ LPD such as lymphomatoid papulosis or anaplastic large cell lymphoma. Recognition of the condition is important to avoid overtreatment.     

Differential role of organic anion-transporting polypeptides in estrone-3-sulphate uptake by breast epithelial cells and breast cancer cells

The purpose of this study was to investigate the differential expression and function of organic anion-transporting polypeptides (OATPs) in breast epithelial and breast cancer cells. Estrone-3-sulfate (E3S), a substrate for 7 of 11 OATPs, is a predominant source of tumor estrogen in postmenopausal, hormone-dependent patients with breast cancer. Overexpression of certain OATPs (e.g., OATP1A2) reported in breast tumor tissues compared with surrounding normal tissues could contribute toward two to three times higher tumoral E3S concentration. Little is known about expression and function of other OATP family members among breast epithelial and breast cancer cells. We therefore compared gene and protein expression of seven OATPs (OATP1A2, OATP1B1, OATP1B3, OATP1C1, OATP2B1, OATP3A1, and OATP4A1) in immortalized breast epithelial cells (MCF10A), hormone-dependent breast cancer cells (MCF7), and hormone-independent breast cancer cells (MDA/LCC6-435, MDA-MB-231, and MDA-MB-468) by quantitative polymerase chain reaction and immunoblotting, respectively. Expression of solute carrier superfamily encoding for OATPs (SLCO) 1A2, 1B1, 1B3, 2B1, and 3A1 is exclusive, similar, or significantly higher in cancer cells compared with MCF10A cells. Protein expression of OATPs is found to be either exclusive or higher in cancer cells compared with MCF10A cells. Specificity of OATP-mediated E3S uptake is observed only in cancer cells, with the highest total uptake in MCF7 cells. Transport kinetics of E3S uptake demonstrates transport efficiency that is 10 times greater in the MCF7 cells than in the hormone-independent cells. These data suggest that OATPs could be a novel therapeutic target for hormone-dependent breast cancers, particularly in postmenopausal patients, where the major source of tumor estrogen is E3S.     

Discovery of safe and orally effective 4-aminoquinaldine analogues as apoptotic inducers with activity against experimental visceral leishmaniasis

Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.     

Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models

Histone deacetylase (HDAC) inhibitors may offer novel approaches in the treatment of asthma. We postulate that trichostatin A (TSA), a Class 1 and 2 inhibitor of HDAC, inhibits airway hyperresponsiveness in antigen-challenged mice. Mice were sensitized and challenged with Aspergillus fumigatus antigen (AF) and treated with TSA, dexamethasone, or vehicle. Lung resistance (R(L)) and dynamic compliance were measured, and bronchial alveolar lavage fluid (BALF) was analyzed for numbers of leukocytes and concentrations of cytokines. Human precision-cut lung slices (PCLS) were treated with TSA and their agonist-induced bronchoconstriction was measured, and TSA-treated human airway smooth muscle (ASM) cells were evaluated for the agonist-induced activation of Rho and intracellular release of Ca(2+). The activity of HDAC in murine lungs was enhanced by antigen and abrogated by TSA. TSA also inhibited methacholine (Mch)-induced increases in R(L) and decreases in dynamic compliance in naive control mice and in AF-sensitized and -challenged mice. Total cell counts, concentrations of IL-4, and numbers of eosinophils in BALF were unchanged in mice treated with TSA or vehicle, whereas dexamethasone inhibited the numbers of eosinophils in BALF and concentrations of IL-4. TSA inhibited the carbachol-induced contraction of PCLS. Treatment with TSA inhibited the intracellular release of Ca(2+) in ASM cells in response to histamine, without affecting the activation of Rho. The inhibition of HDAC abrogates airway hyperresponsiveness to Mch in both naive and antigen-challenged mice. TSA inhibits the agonist-induced contraction of PCLS and mobilization of Ca(2+) in ASM cells. Thus, HDAC inhibitors demonstrate a mechanism of action distinct from that of anti-inflammatory agents such as steroids, and represent a promising therapeutic agent for airway disease.     

Wound pH-responsive sustained release of therapeutics from a poly(NIPAAm-co-AAc) hydrogel

Wound pH strongly influences residence time and activity of various growth factors during wound healing. Hence, a pH-responsive sustained release growth factor delivery system could be beneficial for effective treatment of wound. In this context, an effort was made to evaluate the potential of a poly(N-isopropylacrylamide-co-acrylic acid) hydrogel as pH-sensitive sustained release system for wound-pH-dependent therapeutics delivery. The polymer was synthesized via radical copolymerization and influence of pH on lower critical solution temperature (LCST), microarchitechture and swelling of the hydrogel was evaluated. Results showed a pH-dependent variation in the physical properties of the hydrogel within the wound pH range. Fluorescence recovery after photobleaching (FRAP) analysis endorsed a pH dependent restricted diffusion of the BSA in the hydrogel. Later, release of bovine serum albumin (BSA), vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) (each 5%, w/v) from the hydrogel within the range of wound pH (pH 6.7-7.9) were examined. Analysis showed non-Fickian release of therapeutics from the hydrogel with a significant variation in release rate and cumulative release with the increase in pH. Retention of the bioactivity of the released EGF was confirmed by studying murine dermal fibroblast cell proliferation in vitro. Finally, a growth factor (EGF or VEGF)-loaded hydrogel was applied on a murine excisional wound model and showed augmentation of wound healing in comparison to conventional sustained release growth factor therapy.     

Surface Modification of Nanocrystalline LiMn2O4 Using Graphene Oxide Flakes

In this work, a facile, wet chemical synthesis was utilized to achieve a series of lithium manganese oxide (LiMn₂O₄, (LMO) with 1–5%wt. graphene oxide (GO) composites. The average crystallite sizes estimated by the Rietveld method of LMO/GO nanocomposites were in the range of 18–27 nm. The electrochemical performance was studied using CR2013 coin-type cell batteries prepared from pristine LMO material and LMO modified with 5%wt. GO. Synthesized materials were tested as positive electrodes for Li-ion batteries in the voltage range between 3.0 and 4.3 V at room temperature. The specific discharge capacity after 100 cycles for LMO and LMO/5%wt. GO were 84 and 83 mAh g⁻¹, respectively. The LMO material modified with 5%wt. of graphene oxide flakes retained more than 91% of its initial specific capacity, as compared with the 86% of pristine LMO material.