Visualization of left bronchial-to-coronary artery communication after distal bronchial artery embolization for bronchiectasis

We present a 44-year-old woman in whom a bronchialto-coronary artery communication via the conus branch was discovered after distal bronchial artery embolization with gelatin sponge for hemoptysis. If this bronchial-to-coronary artery anastomosis, not visible prior to embolization, had been inadvertently embolized, the patient could have developed a myocardial infarction. To reduce the likelihood of a serious complication, the possibility of this anastomosis should be kept in mind and angiography should be repeated before attempting proximal bronchial artery embolization.     

A comparative immunohistochemical study of Kuru and senile plaques with a special reference to glial reactions at various stages of amyloid plaque formation.

The authors examined 10 patients with Gerstmann-Sträussler syndrome or Creutzfeldt-Jakob disease and 10 with Alzheimer''s disease (AD). Immunohistochemistry using anti-prion protein (PrP) and anti-beta/A4 protein (beta/A4) coupled with formic acid pretreatment could detect Congophilic and non-Congophilic deposits. Prion protein deposits were classified into five types and compared with types of beta/A4 deposits. Kuru plaques with multicentric cores and fine granular deposits were a characteristic feature of PrP deposits. Some types of PrP or beta/A4 deposits depend on the anatomic sites. To clarify the relationship of microglia and astrocytes to PrP or beta/A4 deposits, double-immunostaining method was performed. In both kuru and senile plaques, microglia were closely linked to the Congophilic plaques. Astrocytes, however, extended their processes toward the plaques even in the non-Congophilic plaques. These observations strongly suggest that similar glial association with plaque formation may be involved in both kuru and senile plaques, although the amyloid core proteins differ.     

Structural analysis of the receptors for granulocyte colony-stimulating factor on neutrophils.

We investigated granulocyte colony-stimulating factor (G-CSF) receptors on neutrophils from three patients with chronic myelogenous leukemia (CML) in the chronic phase, in comparison with four normal volunteers. Because we experienced some difficulties in radioiodinating intact recombinant human G-CSF, we developed a new derivative of human G-CSF termed YPY-G-CSF. It was easy to iodinate this protein using the lactoperoxidase method because of two additional tyrosine residues, and its radioactivity was higher than that previously reported. The biological activity of YPY-G-CSF as G-CSF was fully retained. Scatchard analysis demonstrated that CML neutrophils had a single class of binding sites (1400 +/- 685/cell) with a dissociation constant (Kd) of 245 +/- 66 pM. The number of sites and Kd value of CML neutrophils were not significantly different from those of normal neutrophils (p greater than 0.9). Cross-linking studies revealed two specifically labeled bands of [125I]YPY-G-CSF-receptor complexes with apparent molecular masses of 160 and 110 kd on both normal and CML neutrophils. This is the first report describing two receptor proteins on neutrophils. According to the analyses of the proteolytic process of these cross-linked complexes and proteolytic mapping, we assume that alternative splicing or processing from a single gene may generate two distinct receptor proteins that bind specifically to G-CSF but have different fates in intracellular metabolism.     

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.A long-term goal in contemporary cancer nanomedicine has been to design and generate drug delivery systems that improve the narrow therapeutic window associated with conventional chemotherapeutics (1, 2). Conceptually, several nanotechnology-based entity candidates, including protocells (3), biosynthetic nanoparticles (NPs), viruses, and liposome-based nanoparticles, could be targeted for active delivery through a defined cell surface ligand receptor system and/or physically triggered for finely tuned cargo release (2, 4, 5).Numerous efforts have been made to functionalize NPs by combining them with antibodies, aptamers, peptides, vitamins, or carbohydrates (6–8), but the majority of studies involve untargeted nanoplatforms (4, 9). In practice, targeting NPs is far from trivial, and ongoing challenges include synthesis and purification, selection of an appropriate ligand receptor, and specific composition for NP conjugation. Even the conjugation reaction itself may alter the binding of the tumor-targeting moiety to its receptor through conformational changes, steric freedom restriction, or orientation distortion (10, 11). Unfortunately, the cost-to-benefit ratio of these modifications often elevate the complexity of the NP synthesis, complicating regulatory hurdles because of formulations that are heterogeneous or difficult to reproduce (10, 12, 13).To minimize such drawbacks, NPs can be functionalized via virus-based nanoplatforms as an alternative for targeted cargo delivery (14–16). In particular, filamentous bacteriophage (phage)—a prokaryotic virus—is an attractive candidate to develop a bionanomedicine for cancer therapeutics because phage particles are cost-effectively produced with biological uniformity, as well as being physically robust and stable under harsh conditions (17). Notably, phage-based nanoplatforms are biocompatible and nonpathogenic with eukaryotic organisms and are able to preserve the desired cell targeting and internalization (18). Moreover, phage particles are ideal for incorporating other NPs, which can be released after reaching the tumor site. An admixture of colloidal gold NP (AuNP) with phage particles spontaneously organizes into hydrogel network-like fractal structures (19, 20). These hydrogel networks offer convenient multifunctional integration within a single entity for tumor targeting, enhanced fluorescence and dark-field microscopy, near-infrared (NIR) photon-to-heat conversion, and surface-enhanced Raman scattering (SERS)-based detection (20, 21).In the present work, we developed a tumor targeting theranostic (meaning a combination of therapeutics and diagnostics) hydrogel-based nanoplatform that enables ligand-directed tumor targeting, multimodal imaging capability, and triggered therapeutic cargo release. Our data suggest that targeted hydrogel photothermal therapy represents a functional theranostic approach (fostering “see and treat, treat and see”) in the diagnosis and management of tumors.     

Infiltration of antitumor immunocytes into the sentinel node in gastric cancer

The sentinel node (SN) is regarded as the first drainage lymph node, and tumor cells are considered likely to directly affect the SN. However, few reports have identified differences between SNs and non-SNs in cancer patients. Subjects in this study included 27 patients with gastric cancer who underwent curative operation and intraoperative detection of SNs by radioisotope methods. The mean number of SNs was 3.2 (range 1 to 5). Degree of infiltration of natural killer cells, dendritic cells, MIB-1 labeling index, and CD3-ξ expression of lymphocytes in SNs and non-SNs were examined by means of immunohistochemical methods. Degree of infiltration was compared according to depth of invasion and between SNs and non-SNs. Patients with early-stage cancer displayed a greater degree of infiltration of MIB-1 labeling index and CD3-ξ expression than patients with pT2 or pT3 lesions (P<0.05). The MIB-1 labeling index in SNs was significantly lower than that in non-SNs (P<0.05). However, no significant difference was observed in infiltration of natural killer cells, dendritic cells, or CD3-ξ. Morphologic changes of dendritic cells in SNs were not definite. Our results suggest that SNs in gastric cancer might not be suppressed, unlike in breast cancer and melanoma. SN paralysis may depend on tumor- and organ-specific characteristics or exogenous stimulation from the gastric mucosa. Studies in progress will help to identify immunologic paralysis of the SN in various types of cancer. Attention must therefore be paid to organ specificity.     

Combined therapy with estrogen and testosterone eliminates the aggravating effect of estrogen replacement therapy on glomerular injury in hypercholesterolemic female Imai rats

Hypercholesterolemic Imai rats spontaneously develop proteinuria and glomerulosclerosis, especially male animals. Ovariectomy aggravates glomerular injury in female Imai rats. However, estrogen replacement therapy did not abolish this aggravating effect of ovariectomy and rather aggravated glomerular injury with an increase in serum levels of lipids and growth hormone (GH). Whereas we have already reported that treatment with testosterone in addition to estrogen reduces GH levels and attenuates glomerular injury as compared with estrogen alone in male Imai rats, in the present study, to investigate whether increased GH levels may contribute to an enhancing effect of estrogen on glomerular injury, we treated ovariectomized female Imai rats with estrogen pulse testosterone. Group 1 was sham operated and group 2 was ovariectomized at 6 weeks of age. Groups 3, 4, and 5 were ovariectomized and received estrogen, testosterone, or estrogen plus testosterone, respectively. Body weight, urinary protein, and serum constituents were investigated every 4 weeks from 12 to 24 weeks of age. At 24 weeks of age, the rats were studied morphologically. Each treatment with estrogen or testosterone equally aggravated glomerular injury with an increase in both proteinuria and serum lipids with increased serum GH levels in estrogen-treated rats but without influencing GH levels in testosterone-treated rats; combined treatment with estrogen plus testosterone resulted in a reduction of both proteinuria and serum lipids to levels of the controls and attenuated glomerular injury to levels close to those of controls with a reduction of the elevated serum GH levels. These results suggest that increased GH levels may contribute to an enhancing effect of estrogen replacement therapy on glomerular injury and that testosterone, when administered to the estrogen-treated rats, seems to exert an attenuating effect on glomerular injury by suppressing GH levels.