Prognostic/predictive factors in breast cancer

This can be an exciting time for pathologists and cytopathologists as we refine or knowledge of prognostic/predictive factors in breast cancer. We can become more visible in our role as consultants to the other physicians, and more engaged in our role as re-searchers. Recent advances in computer science, coupled with the availability of new biological markers, now provide unique opportunities for us to expand our diagnostic abilities and also predict the biologic behavior of a given tumor. Thus, we must become more familiar with emerging concepts and technologies in different disciplines.     

A 10‐Year Study of Dermatophytoses in Isfahan,Iran

Dermatophyte infections are very common worldwide and their epidemiological characteristics vary according to the geographical region and have altered in the last decades. The aim of the present investigation was to determine the diversity of causative agents of dermatophytoses and describe the epidemiological condition of infection in Isfahan, Iran, between 2003 and 2012. Specimens were collected from hair, nail, and skin and were examined by conventional methods such as direct microscopy, culture on sabouraud dextrose agar with chloramphenicol and cycloheximide (Mycosel agar) and sabouraud glucose agar, Trichophyton agars, growth on rice grains, urease test, and hair perforation test. Of 13,469 clinically suspected cases, 11.5% were affected with dermatophytoses. Tinea capitis was the most frequent form of infection (52.7%), followed by tinea corporis (24%), tinea pedis (8.9%). Trichophyton verrucosum was the most prevalent causative agent (40.6%), followed by T. mentagrophytes var. interdigitale (17.6%), Epidermophyton floccosum (13%), T. violaceum (12%), T. rubrum (4.1%). Age range of patients was between 1 and 80 years. Housewives were the most patients in our study. The study emphasizes importance of epidemiological surveys of dermatophyte species for the better management of infection.     

Echocardiographic findings in patients with sickle cell disease

Pulmonary hypertension is a complication of sickle cell disease that is associated with increased mortality. Whether this complication is associated with hemolysis has been questioned. Systolic pulmonary artery blood pressure can be estimated from echocardiography-determined tricuspid regurgitation velocity (TRV). A velocity of 2.5 m/s or higher suggests possible pulmonary hypertension. A retrospective review of hospital records from adult patients with sickle cell disease undergoing echocardiography in 2006 and 2007 was performed at a tertiary level hospital. Echocardiographic, demographic, and clinical laboratory data were collected. Echocardiographic results were available for 105 adult sickle cell patients. Of these, 62 (59%) had a TRV ≥2.5 m/s and 24 (22.8%) had a TRV ≥3.0 m/s. Mitral valve regurgitation was observed in 44% and left ventricular abnormalities (defined by either hypertrophy or dilation) in 28% of cases. Elevated TRV had independent and significant associations with greater age, higher serum lactate dehydrogenase (LDH) concentration, and lower hemoglobin concentration. We confirmed that elevated TRV is common among hospital-based adults with sickle cell disease. Significant, independent associations were found with both elevated LDH concentration and degree of anemia, suggesting that hemolytic and other mechanisms contribute to pulmonary hypertension in patients with sickle cell disease.     

Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration

Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.     

Receptor Recognition of and Immune Intracellular Pathways for Veillonella parvula Lipopolysaccharide

Veillonella parvula is an anaerobic gram-negative coccus that is part of the normal flora of the animal and human mouth and gastrointestinal and genitourinary tracts. Oral V. parvula is involved in the development of early periodontal disease as well as different types of serious infections. Present data on molecular mechanisms responsible for innate immune response against Veillonella are very scanty. The aim of this study was to investigate the Toll-like receptor (TLR) pathways responsible for V. parvula lipopolysaccharide (LPS) and to identify the intracellular pathways induced by this recognition. V. parvula LPS stimulated tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) release in human peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Pretreatment of cells with a TLR4 antagonist significantly reduced TNF-α and IL-6 production in PBMC stimulated with either Veillonella or Escherichia coli LPS. However, V. parvula LPS was 10- to 100-fold less active than E. coli LPS for cytokine induction. TNF-α, IL-1β, IL-6, and IL-10 were released in wild-type and TLR2^−/−, but not TLR4^−/−, mouse macrophage cultures. V. parvula LPS was able to activate the human PBMC p38 mitogen-activated protein kinase (MAPK). A specific p38 MAPK inhibitor strongly inhibited V. parvula LPS-induced TNF-α, IL-1β, IL-6, and IL-10. In conclusion, V. parvula LPS is able to induce cytokine production in both human and murine in vitro models, although it is less effective than Enterobacteriaceae LPS. V. parvula LPS-stimulated cytokine induction, as well as p38 MAPK activation, are TLR4-dependent features.Veillonella organisms are small, nonfermentative, strictly anaerobic, gram-negative cocci which form part of the normal flora of the oral, genitourinary, respiratory, and intestinal tracts of humans and animals (10). The genus Veillonella was first isolated by Veillon and Zuber in 1898 and currently consists of eight species (28).Veillonella species have been reported as causes of serious infections, including meningitis (6), osteomyelitis and discitis (7, 28), prosthetic joint infection (26), and acute and chronic pleuropulmonary infection (33).Risk factors for Veillonella infection include periodontal disease, immunodeficiency, intravenous drug use, and premature birth (28). V. parvula is an important pathogen implicated in periodontitis and other dental infections (3, 18), and it is one of the most common anaerobic pathogens in chronic maxillary sinusitis and deep neck infections (9, 37). V. parvula has also been reported as a pathogen for osteomyelitis (34) and abscessed orchiepididymitis with sepsis (4). Endovascular infections reportedly may range from bacteremia to severe endocarditis and fatal cases of sepsis (8, 14, 25).Lipopolysaccharides (LPS) are major pathogenic factors of gram-negative bacteria. LPS from aerobic and facultative bacteria have been extensively studied (5). On the contrary, very little is known regarding the biological activity of LPS from anaerobic microorganisms such as Veillonella (10, 24, 29, 32). In addition, little is known about cellular and molecular mechanisms responsible for innate immune response against V. parvula, as well as for inflammatory reactions leading to severe periodontitis or sinusitis. Toll-like receptors (TLRs) recognize microbial compounds (36) and trigger the inflammatory and immune responses against pathogens. Immunohistochemical localization of TLR2 and TLR4 in gingival tissue of periodontitis patients has been reported (30). In mammals, engagement of TLRs by LPS results in the recruitment of cytoplasmic signaling molecules (12, 36), which eventually activates mitogen-activated protein kinases (MAPKs), including p38, JNK, and extracellular signal-regulated kinase (ERK). MAPK activation leads to cytokine release (2).However, the interaction between oral V. parvula LPS and TLRs has not been directly studied yet. The aim of this study was to investigate the potential role of TLR2 and TLR4 for the recognition of Veillonella parvula LPS in both human peripheral blood mononuclear cells (PBMC) and in TLR2 and TLR4 knockout (KO) mouse macrophages, as well as the intracellular kinase signaling pathways induced after challenge of monocytes with Veillonella parvula LPS.