Dead cells in melanoma tumors provide abundant antigen for targeted delivery of ionizing radiation by a mAb to melanin

Melanoma is a cancer with a rising incidence, and metastatic disease is almost always lethal. We investigated the feasibility of targeting melanin, an intracellular melanocyte pigment, to deliver cytotoxic radiation to human melanoma cells in vivo by using a melanin-binding mAb (6D2). Nude mice bearing MNT1 pigmented human melanoma tumors were treated with mAb 6D2 labeled with 1.5 mCi (1 Ci = 37 GBq) of the beta-emitter 188-Rhenium (188Re) and manifested inhibition of tumor growth and prolonged survival. mAb 6D2 bound tumor melanin and demonstrated no crossreactivity with normal melanized tissues in black mice. The mechanism of melanin targeting involved Ab binding to extracellular melanin released during tumor cell turnover or to dying cells with permeable membranes. In this approach, the cytotoxic radiation emanating from labeled Ab bound to melanin is presumably delivered by "crossfire" effect to the adjacent viable tumor cells. Our results establish the feasibility of targeting melanin released from dead melanoma cells in tumors with radiolabeled Abs to achieve a therapeutic effect. In contrast to conventional tumor antigens, melanin is insoluble, resistant to degradation, and can be expected to accumulate in targeted tissues, suggesting that the efficacy of therapy could increase with each subsequent treatment cycle.     

Hospital-acquired conditions after bariatric surgery: we can predict,but can we prevent?

Background

Centers for Medicare and Medicaid Services initiated a non-payment policy for certain hospital-acquired conditions (HACs) in 2008. This study aimed to determine the rate of the three most common HACs (surgical site infection (SSI), urinary tract infection (UTI), and venous thromboembolism (VTE)) among bariatric surgery patients. Additionally, the association of HACs with patient factors and the effect of HACs on post-operative outcomes were investigated.

Methods

Patients over 18 years with a body mass index (BMI) ≥35 who underwent bariatric surgery were identified using the American College of Surgeons’ National Surgical Quality Improvement Program (ACS-NSQIP) database (2005–2012). Patients were grouped into two categories: HAC versus no HAC patients and baseline characteristics and outcomes, including 30-day mortality, reoperation, and mean length of stay (LOS) were compared. Multivariable logistic regression analysis was performed to identify the risk factors for developing a HAC.

Results

98,553 patients were identified, 2,809 (2.9 %) developed at least one HACs. SSI was the most common HAC (1.8 %), followed by UTI (0.7 %) and VTE (0.4 %). The rate of these HACs significantly decreased from 4.6 % in 2005–2006 to 2.5 % in 2012 (p < 0.001). Laparoscopic gastric banding was associated with the lowest rates of HAC (1.3 %) and open gastric bypass with the highest (8.0 %). HAC patients had significantly higher rates of in-hospital mortality (0.8 vs. 0.1 %, p < 0.001) and LOS (3.9 vs. 2.1 days, p < 0.001). On adjusted analysis, open GBP patients had 5.36-fold higher odds of developing a HAC. Interestingly, the presence of a resident surgeon 7–11 years post graduation was associated with significantly increased odds of HACs (1.86, 1.50–2.31, p < 0.001).

Conclusion

Our data demonstrate a strong correlation between these three HACs following bariatric surgery and factors intrinsic to the bariatric patient population. This calls into question the non-payment policy for inherent patient factors on which they cannot have impact. These findings are important to help inform health care policy decisions regarding access to care for bariatric surgery patients.     

Structure and function of gustatory neurons in the nucleus of the solitary tract: II. Relationships between neuronal morphology and physiology

This study employed intracellular recording and labeling techniques to examine potential relationships between the physiology and morphology of brainstem gustatory neurons. When we considered the neuronal response to the four “prototypic” tastants, we were able to demonstrate a positive correlation between breadth of responsiveness and the number of dendritic branch points. An analysis of the response to eight tastants also revealed an association between dendritic spine density and the breadth of responsiveness, with more narrowly tuned neurons exhibiting more spines. Interestingly, a neuron's “best response” was a relatively poor predictor of neuronal morphology. When we focused on those neurons that responded to only one tastant, however, a number of potentially important relationships became apparent. We found that the cells that only responded to quinine were smaller than the neurons that only responded to NaCl, HCl, or sucrose. The HCl-only neurons, however, were more widespread in the rostrocaudal dimension than the neurons that only responded to NaCl. A number of additional structure-function relationships were identified when we examined the neuronal response to selected tastants. We found that neurons that responded to sucrose but not quinine, as well as neurons that responded to quinine but not sucrose, were more widespread in the mediolateral dimension than neurons that responded to both sucrose and quinine. We also discovered that the neurons that responded to NaCl, but not to NH₄Cl or KCl, were larger than neurons that responded to all three salts. We believe that these results support the hypothesis that there are relationships between the structure and function of gustatory neurons in the nucleus of the solitary tract, with the data highlighting the importance of three themes: 1) the relationship between dendritic specializations and tuning, 2) the relationship between dendritic arbor orientation and response properties, and 3) the potential importance of stimulus-specific neurons. © 1996 Wiley-Liss, Inc.     

Selective localization and regulated release of calcitonin gene-related peptide from dense-core vesicles in engineered PC12 cells

Introduction of the gene for calcitonin into the neuroendocrine PC12 cell line resulted in the expression of the neuronal-specific splice product, calcitonin gene-related peptide (CGRP). Expression of this neuropeptide did not require treatment of the PC12 cells with NGF. By all available criteria, including biochemical, immunological, and morphological analysis, we have determined that the CGRP in stably transfected PC12 cells is sorted selectively into the large, dense-core catecholamine-containing secretory vesicles. Conversely, the CGRP is excluded from the small, synaptophysin-rich vesicles present in the same cells. Stimulation conditions that trigger the release of catecholamines cause a parallel burst in the release of CGRP. In all these respects, the engineered PC12 cells process the foreign CGRP in a manner similar to that seen in spinal motor neurons in vivo. These results indicate that this small (37 amino acids) peptide contains sorting information sufficient for targeting to large, dense-core vesicles in heterologous cells, placing very narrow constraints on the possible location of sorting signals. In addition, this CGRP-expressing cell line opens the possibility of studying the physiological role of CGRP in the establishment and maintenance of neuromuscular contacts. © 1996 Wiley-Liss, Inc.     

静息状态脑功能网络的研究及应用

目的:对静息状态网络的研究方法、初步的研究成果等作以介绍,并结合静息状态网络在阿尔茨海默病早期预警中的应用,介绍静息状态脑网络的应用。资料来源:应用计算机检索PubMed1980-01/2006-12与静息状态网络相关的文献,检索词“restingstate,functional connectivity”,并限定文献语言种类为“English”;同时计算机检索万方数据库1995-01/2006-12有关方面的文献,检索词为“静息,功能连接,阿尔茨海默病”,并限定语言种类为中文。资料选择:对资料进行初审,选取包括静息状态的相关文献,开始查找原文。纳入标准:①有关静息状态脑网络和功能连接的研究。②有关阿尔茨海默病的研究。排除标准:重复研究。资料提炼:共收集到53篇有关静息状态网络方面的研究,排除23篇重复性研究,30篇符合要求。资料综合:近年来,研究者发现大脑处于无任务的静息状态时,仍然存在着某种功能活动。这些现象表明大脑在静息状态时可能存在有组织的网络。这有助于对人脑高级意识和某些认知疾病的研究,因此,有关这方面的工作越来越受到人们的重视。结论:对静息状态网络的本质和规律的研究还很有限,对这个网络所支持的精确的功能还有待于进一步研究。     

Multiple sclerosis: serial study of gadolinium-enhanced MR imaging

Thirteen patients with definite multiple sclerosis (MS), studied 16-24 months previously with magnetic resonance (MR) imaging with and without enhancement by intravenously administered gadolinium diethylenetriaminepentaacetic acid (DTPA) dimeglumine, were reexamined with a similar protocol. Assessment of enhancement and clinical activity in both studies revealed that enhancement was observed in 13 of 14 cases in which clinical activity had changed within 4 weeks of the study and thus appeared more sensitive than clinical examination in determining active disease. The 3-minute postinjection, short repetition time image (TR) was the most efficient for depicting enhancement. Enhancing lesions (active plaques) arose from previously hyper- or isointense regions on long TR images. Previously active lesions reverted to areas of iso- or hyperintensity on long TR images. Serial comparison of long TR images in this population reveals a decrease in high-intensity lesions on long TR images in some cases and an increase in others. The findings of high-intensity regions on long TR images and previously enhancing lesions both becoming isointense suggests that transient inflammatory changes with concomitant edema without demyelination and/or with significant remyelination may occur in some MS lesions. MS lesions are dynamic; both active and inactive lesions may show dramatic change on longitudinal MR imaging studies.     

Contrasting effects of recombinant human granulocyte-macrophage colony- stimulating factor (CSF) and granulocyte CSF treatment on the cycling of blood elements in childhood-onset cyclic neutropenia

Recombinant human granulocyte colony-stimulating factor (G-CSF) treatment has been shown to increase average neutrophil counts substantially in patients with childhood-onset cyclic neutropenia (or "cyclic hematopoiesis"), but not to eliminate the cyclic oscillations of neutrophil counts or those of other blood elements (monocytes, platelets, eosinophils, and reticulocytes) that are characteristic of this hematopoietic disorder. Indeed, oscillations of neutrophil counts are amplified during G-CSF treatment. We have compared the effects of recombinant granulocyte-macrophage-CSF (GM-CSF) with those of G-CSF in three patients with this disease (2 men and 1 woman, 17, 30, and 32 years of age). These patients were treated with GM-CSF (2.1 micrograms/kg/day, subcutaneously) for 6 weeks, preceded and followed by 6 to 13 weeks of detailed observation to document changes in the cyclic oscillations of blood neutrophils and other blood elements; two of the patients were subsequently treated with G-CSF (5.0 micrograms/kg/d, subcutaneously) and observed for comparable periods of time. Unlike G-CSF treatment, which increased average neutrophil counts more than 20-fold, GM-CSF increased neutrophil counts only modestly, from 1.6- to 3.9-fold, although eosinophilia of varying prominence was induced in each patient. However, at the same time, GM-CSF treatment dampened or eliminated the multilineage oscillations of circulating blood elements (neutrophils, monocytes, platelets, and/or reticulocytes) in each of the patients. In contrast, G-CSF treatment of the same patients markedly amplified the oscillations of neutrophil counts and caused the cycling of other blood elements (monocytes in particular) to become more distinct. These findings support the conclusion that the distinctive cycling of blood cell production in childhood-onset cyclic neutropenia results from abnormalities in the coordinate regulation of both GM-CSF-responsive, multipotential progenitor cells and G-CSF-responsive, lineage-restricted, neutrophil progenitors.     

Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase

Obstructive sleep apnea leads to chronic intermittent hypoxia (CIH) and is associated with atherosclerosis. We have previously shown that C57BL/6J mice exposed to CIH and a high-cholesterol diet develop dyslipidemia, atherosclerosis of the aorta, and upregulation of a hepatic enzyme of lipoprotein secretion, stearoyl coenzyme A desaturase 1 (SCD-1). We hypothesized that (1) SCD-1 deficiency will prevent dyslipidemia and atherosclerosis during CIH; and (2) human OSA is associated with dyslipidemia and upregulation of hepatic SCD. C57BL/6J mice were exposed to CIH or normoxia for 10 weeks while being treated with either SCD-1 or control antisense oligonucleotides. Obese human subjects underwent sleep study and bariatric surgery with intraoperative liver biopsy. In mice, hypoxia increased hepatic SCD-1 and plasma very-low-density lipoprotein cholesterol levels and induced atherosclerosis lesions in the ascending aorta (the cross-section area of 156514+/-57408 microm(2)), and descending aorta (7.0+/-1.2% of the total aortic surface). In mice exposed to CIH and treated with SCD-1 antisense oligonucleotides, dyslipidemia and atherosclerosis in the ascending aorta were abolished, whereas lesions in the descending aorta showed 56% reduction. None of the mice exposed to normoxia developed atherosclerosis. In human subjects, hepatic SCD mRNA levels correlated with the degree of nocturnal hypoxemia (r=0.68, P=0.001). Patients exhibiting oxyhemoglobin desaturations at night showed higher plasma triglyceride and low-density lipoprotein cholesterol levels, compared to subjects without hypoxemia. In conclusion, CIH is associated with dyslipidemia and overexpression of hepatic SCD in both humans and mice alike; SCD-1 deficiency attenuates CIH-induced dyslipidemia and atherosclerosis in mice.