[Vaccination against hepatitis B as prevention for hepatocellular carcinoma]. / Rolle der Hepatitis-B-Impfung in der Prävention des hepatozellulären Karzinoms.

BACKGROUND: Chronic infection with the hepatitis B virus (HBV) is an important risk factor for the development of hepatocellular carcinoma (HCC). Even though treatment options for HCC are constantly improving, preventive measures must not be neglected. CONCLUSION: The vaccination against hepatitis B has proven effective in preventing infection with HBV. As shown more than 20 years ago in Taiwan, vaccination programs lower not only the prevalence of HBsAg carriers but also decrease the incidence of HCC. By achieving immunity against HBV, the infection with hepatitis D virus can also be prevented. This is important in the light of HCC prevention as HBV/HDV coinfection is known to drastically increase the risk of HCC. New approaches aim for the development of therapeutic HBV vaccines ideally curing chronic infections. Beside the prevention of infections, it is pivotal to detect existing infections. This helps to minimize the HCC risk by initiating treatment in those who need it.

Glycine Lipids of Porphyromonas gingivalis Are Agonists for Toll-Like Receptor 2.

The serine-glycine dipeptide lipid classes, including lipid 430 and lipid 654, are produced by the periodontal pathogen Porphyromonas gingivalis and can be detected in lipid extracts of diseased periodontal tissues and teeth of humans. Both serine-glycine lipid classes were previously shown to engage human and mouse Toll-like receptor 2 (TLR2) and to inhibit mouse osteoblast differentiation and function through engagement of TLR2. It is not clear if other lipids related to serine-glycine lipids are also produced by P. gingivalis The goal of this investigation was to determine whether P. gingivalis produces additional lipid classes similar to the serine-glycine lipids that possess biological properties. P. gingivalis (ATCC 33277) was grown in broth culture, and lipids were extracted and fractionated by high-performance liquid chromatography (HPLC). Lipids were separated using semipreparative HPLC, and specific lipid classes were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and liquid chromatography-multiple reaction monitoring (LC-MRM) mass spectrometric approaches. Two glycine lipid classes were identified, termed lipid 567 and lipid 342, and these lipid classes are structurally related to the serine-glycine dipeptide lipids. Both glycine lipid classes were shown to promote TLR2-dependent tumor necrosis factor alpha (TNF-α) release from bone marrow macrophages, and both were shown to activate human embryonic kidney (HEK) cells through TLR2 and TLR6 but not TLR1. These results demonstrate that P. gingivalis synthesizes glycine lipids and that these lipids engage TLR2 similarly to the previously reported serine-glycine dipeptide lipids.

Treasure hunt for peptides with undefined chemical modifications: Proteomics identification of differential albumin adducts of 2-nitroimidazole-indocyanine green in hypoxic tumor.

2-Nitroimidazole is a well-known chemical probe targeting hypoxic environments of solid tumors, and its derivatives are widely used as imaging agents to investigate tissue and tumor hypoxia. However, the underlying chemistry for the hypoxia-detection capability of 2-nitroimidazole is still unclear. In this study, we deployed a biotin conjugate of 2-nitroimidazole-indocyanine green (2-nitro-ICG) for the investigation of in vivo hypoxia-probing mechanism of 2-nitro-ICG compounds. By implementing mass spectrometry-based proteomics and exhaustive data mining, we report that 2-nitro-ICG and its fragments modify mouse serum albumin as the primary protein target but at two structurally distinct sites and possibly via two different mechanisms. The identification of probe-modified peptides not only contributes to the understanding of the in vivo metabolism of 2-nitroimidazole compounds but also demonstrates a competent analytical workflow that enables the search for peptides with undefined modifications in complex proteome digests.

Phagosomal Copper-Promoted Oxidative Attack on Intracellular Mycobacterium tuberculosis.

Copper (Cu) ions are critical in controlling bacterial infections, and successful pathogens like Mycobacterium tuberculosis (Mtb) possess multiple Cu resistance mechanisms. We report, as proof of concept, that a novel Cu hypersensitivity phenotype can be generated in mycobacteria, including Mtb, through a peptide, DAB-10, that is able to form reactive oxygen species (ROS) following Cu-binding. DAB-10 induces intramycobacterial oxidative stress in a Cu-dependent manner in vitro and during infection. DAB-10 penetrates murine macrophages and encounters intracellular mycobacteria. Significant intracellular Cu-dependent protection was observed when Mtb-infected macrophages were treated with DAB-10 alongside a cell-permeable Cu chelator. Treatment with the Cu chelator reversed the intramycobacterial oxidative shift induced by DAB-10. We conclude that DAB-10 utilizes the pool of phagosomal Cu ions in the host-Mtb interface to augment the mycobactericidal activity of macrophages while simultaneously exploiting the susceptibility of Mtb to ROS. DAB-10 serves as a model with which to develop next-generation, multifunctional antimicrobials.

Applications of high-resolution magic angle spinning MRS in biomedical studies II-Human diseases.

High-resolution magic angle spinning (HRMAS) MRS is a powerful method for gaining insight into the physiological and pathological processes of cellular metabolism. Given its ability to obtain high-resolution spectra of non-liquid biological samples, while preserving tissue architecture for subsequent histopathological analysis, the technique has become invaluable for biochemical and biomedical studies. Using HRMAS MRS, alterations in measured metabolites, metabolic ratios, and metabolomic profiles present the possibility to improve identification and prognostication of various diseases and decipher the metabolomic impact of drug therapies. In this review, we evaluate HRMAS MRS results on human tissue specimens from malignancies and non-localized diseases reported in the literature since the inception of the technique in 1996. We present the diverse applications of the technique in understanding pathological processes of different anatomical origins, correlations with in vivo imaging, effectiveness of therapies, and progress in the HRMAS methodology.

Targeting tumor hypoxia: a third generation 2-nitroimidazole-indocyanine dye-conjugate with improved fluorescent yield.

Tumor hypoxia is associated with the rapid proliferation and growth of malignant tumors, and the ability to detect tumor hypoxia is important for predicting tumor response to anti-cancer treatments. We have developed a class of dye-conjugates that are related to indocyanine green (ICG, ) to target tumor hypoxia, based on in vivo infrared fluorescence imaging using nitroimidazole moieties linked to indocyanine fluorescent dyes. We previously reported that linking 2-nitroimidazole to an indocyanine dicarboxylic acid dye derivative () using an ethanolamine linker (ethanolamine-2-nitroimidazole-ICG, ), led to a dye-conjugate that gave promising results for targeting cancer hypoxia in vivo. Structural modification of the dye conjugate replaced the ethanolamine unit with a piperazineacetyl unit and led a second generation dye conjugate, piperzine-2-nitroimidazole-ICG (). This second generation dye-conjugate showed improved targeting of tumor hypoxia when compared with . Based on the hypothesis that molecules with more planar and rigid structures have a higher fluorescence yield, as they could release less absorbed energy through molecular vibration or collision, we have developed a new 2-nitroimidazole ICG conjugate, , with two carbon atoms less in the polyene linker. Dye-conjugate was prepared from our new dye (), and coupled to 2-nitroimidazole using a piperazine linker to produce this third-generation dye-conjugate. Spectral measurements showed that the absorption/emission wavelengths of 657/670 were shifted ∼100 nm from the second-generation hypoxia dye of 755/780 nm. Its fluorescence quantum yield was measured to be 0.467, which is about 5 times higher than that of (0.083). In vivo experiments were conducted with balb/c mice and showed more than twice the average in vivo fluorescence intensity in the tumor beyond two hours post retro-orbital injection as compared with . These initial results suggest that may significantly improve in vivo tumor hypoxia targeting.

Update for nurse anesthetists--anesthetic considerations for patients with amyloidosis.

Amyloidosis is a rare disease process that results in the deposition of insoluble, fibrous amyloid proteins in extracellular spaces and tissues. Amyloid fibrils can be deposited locally or may involve every organ system of the body. Advancements in the treatment for amyloidosis allow longer survival, and patients are being seen in our operating rooms for diagnostic, interventional, and curative purposes. Amyloidosis has numerous implications for anesthesia providers due to the possibility of systemic involvement. This course describes 2 cases of amyloidosis and discusses the types of amyloidosis and their anesthetic implications.

Transforming growth factor-beta is an endogenous radioresistance factor in the esophageal adenocarcinoma cell line OE-33.

Transforming growth factor (TGF)-beta has profound effects on epithelial cell differentiation and is capable of modulating the response to exposure to ionizing radiation. We recently reported that TGF-beta downregulates c-myc mRNA expression and inhibits the growth of OE-33 esophageal carcinoma cells in vitro. These studies investigate the role of TGF-beta in the in vitro radiation response of OE-33 and four other human esophageal cancer cell lines. TGF-beta enhanced radioresistance of OE-33 cells, but did not affect the radiosensitivity of either of the two other adenocarcinoma cell lines BIC1 and SEG1 or of squamous carcinomas KYSE and OE-21. The TGF-beta enhanced radioresistance phenotype was associated with induced G0/G1 cell cycle arrest and upregulation of the G1 cyclin-dependent kinase inhibitor p27kip1 as well as downregulation of c-myc protein expression. Comparison of the relative radiosensitivities of untreated cells suggested that OE-33 (SF2 = 0.71) cells were inherently more radioresistant than BIC1 or SEG1 cells (SF2 = 0.6 and 0.56, respectively). Conditioned medium obtained from unirradiated OE-33 cells enhanced radioresistance compared with fresh medium. This enhancement was abrogated by preincubation of conditioned medium with a neutralizing anti-TGF-beta antibody suggesting endogenous TGF-beta production by OE-33 cells. Enzyme-linked immunoabsorbent assays revealed that exposure to ionizing radiation increased TGF-beta production in all five cell lines. These results suggest that TGF-beta acts as an endogenous, radiation-inducible radioresistance factor in OE-33 esophageal carcinoma cells.