Cancer mucosa antigens as a novel immunotherapeutic class of tumor-associated antigen

Colorectal cancer is a leading cause of cancer-related mortality worldwide. Surgery and chemoradiation exhibit incomplete efficacy and, ultimately, 50% of patients die of metastatic disease. In the context of that unmet clinical need, immunotherapeutic approaches have enjoyed limited success, partly because of a paucity of suitable antigen targets. However, exploitation of immune compartmentalization, employing antigens with expression restricted to normal intestinal mucosa and derivative colorectal tumors--cancer mucosa antigens (CMAs)--may represent a previously unrecognized class of immune targets supporting efficacious antitumor immunotherapy. Guanylyl cyclase C (GCC) is an intestine/colorectal cancer-restricted protein ideally suited as the first CMA for clinical evaluation.     

In the Eye of the Storm: Bioethics in the Time of COVID-19

HSS Journal ® -     

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [¹¹C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [¹¹C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [¹¹C]PHNO binding between the groups at baseline. However, baseline [¹¹C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V_T: 16.5±4 vs 13.7±2.9, p=0.040), a region in which the [¹¹C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V_T) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V_T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [¹¹C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.     

Balloon dilatation of porcine bioprosthetic valves in the pulmonary position

Balloon dilatation (BD) of bioprosthetic valves was investigated in vivo and in vitro. Four children with stenotic bioprosthetic porcine valves in the pulmonary position underwent BD of the valve 10 to 24 months after its insertion. Average valve gradient was reduced from 47.5 to 27 mm Hg. Obstruction at the conduit-branch pulmonary artery connection became apparent after dilatation of the valve. These distal stenoses were also dilated. BD technique was tested in vitro with the use of nonstenotic valves in fresh conduits. No damage to the valve or to the conduit was found when oversized balloons were used in a standard fashion or intentionally inflated until rupture. It is concluded that conduit replacement may be deferred by balloon dilatation of obstructed biological valves and/or a stenotic conduit-pulmonary artery anastomosis.     

Clinical brain proton magnetic resonance spectroscopy for management of Alzheimer's and sub-cortical ischemic vascular dementia in older people

This study examined the clinical usefulness of magnetic resonance spectroscopy (MRS) performed using an automated single voxel technique at 1.0 T field strength in a district general hospital magnetic resonance (MR) scanner in the assessment of older people referred to a memory clinic with suspected dementia. Of 50 elderly subjects (M:F 20:30) examined and followed-up clinically over more than 2 years, 20 had clinical Alzheimer's disease (AD), 18 had clinical vascular dementia, six had mixed features and three were normal. Three normal volunteers were also studied. MRS was performed at the same time as structural magnetic resonance imaging (MRI), added <15 min to the examination and was well-tolerated in all patients studied. Patients with AD had significantly higher myoinositol/creatine (MI/Cr) ratios (mean +/- S.D.: 0.82 +/- 0.04) compared to those with vascular dementia (mean +/-S. D.: 0.71 +/- 0.07, P<0.00001) and normal subjects (mean +/- S.D.: 0.72 +/- 0.036, P<0.0002); there was little overlap between the AD and vascular groups. The mixed dementia group also had significantly higher MI/Cr ratios (mean +/- S.D.: 0.80 +/- 0.05) than vascular dementia (P<0.01) and normal (P<0.03) groups, but with considerable overlap. No significant differences were shown for N-acetyl aspartate or choline/creatine ratios between the different clinical groups. These data suggest that MI/Cr ratios can distinguish patients with AD from normal subjects and those with sub-cortical ischemic vascular dementia and that MRS will be useful to clinicians managing persons with AD in a district general hospital setting.     

Stimulation of secretory antibody following oral administration of antigen

IgA antibodies produced by plasma cells in secretory tissues associated with mucosal surfaces represent a major host defense against infectious agents. Precursors of these IgA-producing cells originate in gut-associated lymphoid tissue and, to a lesser extent, in bronchial-associated lymphoid tissue and migrate via the blood not only to gut but also to other mucosal tissues, forming a common mucosal immune system. Oral administration of antigen leads to priming of precursor cells in the gut and subsequent occurrence of specific secretory IgA (S-IgA) antibody in saliva, milk, tears, and the respiratory and genital tracts. On the basis of a review of the world literature, it has been concluded that oral live vaccines elicit higher antibody titers in remote-site secretions and in serum than do oral killed vaccines, which usually stimulate only relatively low levels of local secretory antibody. Oral immunization induces S-IgA in children and adults (including the elderly) without detectable adverse effects. Despite a number of remaining questions, oral immunization against extraintestinal infections is a promising area for future clinical studies.     

胰腺癌组织VEGF和MVD表达与CT灌注成像的关系

血管内皮生长因子作为肿瘤血管生成的一种主要调控因子,与微血管密度密切相关．胰腺癌组织的血管内皮生长因子和微血管密度的测定对于判断患者的预后,指导临床治疗和判断疗效等具有重要作用．CT灌注成像可以通过无创伤检查反映胰腺癌的肿瘤血管构成, 在治疗前后提供有价值依据,对胰腺癌的诊治有重要意义．     

Psychotic experiences and suicidal behavior: testing the influence of psycho-socioenvironmental factors

Purpose

Research has produced inconsistent results with respect to whether the association between psychotic experiences and suicidal behavior is independent of co-occurring clinical and socioenvironmental factors, despite substantial evidence linking the two phenomena. This study tests whether a comprehensive set of demographic, socioenvironmental, and clinical variables account for the statistical association between psychotic experiences and suicidal behaviors.

Methods

We utilized blocked multivariable logistic regression models to analyze the association between 12-month psychotic experiences and 12-month suicide behaviors (ideation, plan, and attempt) on a subsample (N = 2307) of the National Comorbidity Survey Replication. The models adjusted for socio-demographic characteristics, environmental factors in the form of childhood adversity, mental health service utilization, and psychiatric and substance abuse disorders.

Results

Psychotic experiences were significantly associated with suicidal ideation, even after adjusting for socio-demographics, childhood adversity. However, the significant association between psychotic experiences and suicidal ideation was not robust to the inclusion of mental health service utilization and psychiatric disorders. There was no significant association between psychotic experiences and suicide plan. Psychotic experiences were associated with a significantly increased risk of reporting suicide attempts (OR 6.52; 95% CI 1.36–31.11), even after adjusting for the full set of variables.

Conclusions

Although psychotic experiences were not associated with suicidal ideation after statistical adjustments, psychotic experiences were associated with a significantly increased risk of suicide attempts after the inclusion of common risk factors and co-morbidities. Thus, psychotic experiences should be included in routine psychiatric assessments to identify the individuals most at risk for attempting suicide.