Radiation therapy (RT) is a critical part of definitive therapy for pediatric high-grade glioma (pHGG). RT is designed to treat residual tumor defined on conventional MRI (cMRI), though pHGG lesions ...may be ill-characterized on standard imaging. Spectroscopic MRI (sMRI) measures endogenous metabolite concentrations in the brain, and Choline (Cho)/N-acetylaspartate (NAA) ratio is a highly sensitive biomarker for metabolically active tumor. We provide a preliminary report of our study introducing a novel treatment approach of whole brain sMRI-guided proton therapy for pHGG. An observational cohort (c1 = 10 patients) receives standard of care RT; a therapeutic cohort (c2 = 15 patients) receives sMRI-guided proton RT. All patients undergo cMRI and sMRI, a high-resolution 3D whole-brain echo-planar spectroscopic imaging (EPSI) sequence (interpolated resolution of 12 µL) prior to RT and at several follow-up timepoints integrated into diagnostic scans. Treatment volumes are defined by cMRI for c1 and by cMRI and Cho/NAA ≥ 2x for c2. A longitudinal imaging database is used to quantify changes in lesion and metabolite volumes. Four subjects have been enrolled (c1 = 1/c2 = 3) with sMRI imaging follow-up of 4-18 months. Preliminary data suggest sMRI improves identification of pHGG infiltration based on abnormal metabolic activity, and using proton therapy to target sMRI-defined high-risk regions is safe and feasible.
Oxidative stress has been implicated in mechanisms leading to neuronal cell injury in various pathological states of the brain. Alzheimer’s disease (AD) is a progressive disorder with cognitive and ...memory decline, speech loss, personality changes and synapse loss. Many approaches have been undertaken to understand AD, but the heterogeneity of the etiologic factors makes it difficult to define the clinically most important factor determining the onset and progression of the disease. However, increasing evidence indicates that factors such as oxidative stress and disturbed protein metabolism and their interaction in a vicious cycle are central to AD pathogenesis.Brains of AD patients undergo many changes, such as disruption of protein synthesis and degradation, classically associated with the heat shock response, which is one form of stress response. Heat shock proteins are proteins serving as molecular chaperones involved in the protection of cells from various forms of stress.Recently, the involvement of the heme oxygenase (HO) pathway in anti-degenerative mechanisms operating in AD has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein (APP). HO induction occurs together with the induction of other HSPs during various physiopathological conditions. The vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, products of HO-catalyzed reaction, represent a protective system potentially active against brain oxidative injury. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response.Increasing interest has been focused on identifying dietary compounds that can inhibit, retard or reverse the multi-stage pathophysiological events underlying AD pathology. Alzheimer’s disease, in fact, involves a chronic inflammatory response associated with both brain injury and β-amyloid associated pathology. All of the above evidence suggests that stimulation of various repair pathways by mild stress has significant effects on delaying the onset of various age-associated alterations in cells, tissues and organisms. Spice and herbs contain phenolic substances with potent antioxidative and chemopreventive properties, and it is generally assumed that the phenol moiety is responsible for the antioxidant activity. In particular, curcumin, a powerful antioxidant derived from the curry spice turmeric, has emerged as a strong inducer of the heat shock response. In light of this finding, curcumin supplementation has been recently considered as an alternative, nutritional approach to reduce oxidative damage and amyloid pathology associated with AD. Here we review the importance of the heme oxygenase pathway in brain stress tolerance and its significance as an antidegenerative mechanism potentially important in AD pathogenesis. These findings have offered new perspectives in medicine and pharmacology, as molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. In particular, manipulation of endogenous cellular defense mechanisms such as the heat shock response, through nutritional antioxidants or pharmacological compounds, represents an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. Consistent with this notion, maintenance or recovery of the activity of vitagenes, such as the HO gene, conceivably may delay the aging process and decrease the occurrence of age-related neurodegenerative diseases.
Accurate radiation therapy (RT) targeting is crucial for glioblastoma treatment but may be challenging using clinical imaging alone due to the infiltrative nature of glioblastomas. Precise targeting ...by whole-brain spectroscopic MRI, which maps tumor metabolites including choline (Cho) and N-acetylaspartate (NAA), can quantify early treatment-induced molecular changes that other traditional modalities cannot measure. We developed a pipeline to determine how spectroscopic MRI changes during early RT are associated with patient outcomes to provide insight into the utility of adaptive RT planning. Data were obtained from a study (NCT03137888) where glioblastoma patients received high-dose RT guided by the pre-RT Cho/NAA twice normal (Cho/NAA ≥ 2x) volume, and received spectroscopic MRI scans pre- and mid-RT. Overlap statistics between pre- and mid-RT scans were used to quantify metabolic activity changes after two weeks of RT. Log-rank tests were used to quantify the relationship between imaging metrics and patient overall and progression-free survival (OS/PFS). Patients with lower Jaccard/Dice coefficients had longer PFS (
= 0.045 for both), and patients with lower Jaccard/Dice coefficients had higher OS trending towards significance (
= 0.060 for both). Cho/NAA ≥ 2x volumes changed significantly during early RT, putting healthy tissue at risk of irradiation, and warranting further study into using adaptive RT planning.
To analyze the presence of bovine beta-LG in breast milk.
Human milk samples from 14 healthy non-atopic women on diets with different cow's milk contents were examined. The total concentration of ...beta-LG immuno-like proteins (beta-LGIP) was determined by enzyme linked immunosorbent assay (ELISA). Identification of antigens was done by N-terminal sequencing.
beta-LGIP reactivity of the milk from subjects on different diets was not significantly different. Human lactoferrin, beta-casein and alpha-lactalbumin, were identified as cross-reacting antigens.
False-positive results in ELISA determinations of bovine beta-LG in human milk might be due to cross-reactions between polyclonal antibodies and different protein antigens.
Background:
The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural ...history.
Aim:
To investigate epidemiology, clinical presentation, and natural history of NET.
Design and setting:
A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-entero-pancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study.
Results:
93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0±16.4 yr, significantly anticipated in MEN1 patients (47.7±16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hyper-secretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1 -associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET.
Conclusions:
The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.
Abstract
OBJECTIVE
To describe the procedure of prostatic artery embolization (PAE) in dogs with prostatic carcinoma and to evaluate the short-term outcome for treated dogs.
ANIMALS
20 client-owned ...dogs with prostatic carcinomas between May 2014 and July 2017.
PROCEDURES
In this prospective cohort study, dogs with carcinoma of the prostate underwent PAE with fluoroscopic guidance. Before and after PAE, dogs underwent CT and ultrasonographic examinations of the prostate, and each owner completed a questionnaire about the dog's clinical signs. Results for before versus after PAE were compared.
RESULTS
Prostatic artery embolization was successfully performed in all 20 dogs. Tenesmus, stranguria, and lethargy were significantly less common 30 days after PAE (n = 2, 1, and 0 dogs, respectively), compared with before PAE (9, 10, and 6 dogs, respectively). Median prostatic volume was significantly less 30 days after PAE (14.8 cm
3
; range, 0.4 to 48.1 cm
3
; interquartile 25th to 75th percentile range, 6.7 to 19.5 cm
3
), compared with before PAE (21.7 cm
3
; range, 2.9 to 77.7 cm
3
; interquartile range, 11.0 to 35.1 cm
3
). All dogs had a reduction in prostatic volume after PAE, with a median prostatic volume loss of 39.4% (95% CI, 20.3% to 59.3%).
CONCLUSIONS AND CLINICAL RELEVANCE
Prostatic artery embolization was associated with decreased prostate volume and improved clinical signs in this cohort. The short-term response to PAE appears promising, and evaluation of the long-term impact on survival time is needed.
Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and ...alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients' intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients.
Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNF-neutralizing activity was assessed with a reporter cell line.
We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin.
Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.
Abstract Background: Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of ...diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. Purpose: The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.
We review recent studies on the role played by non-liquid, water-containing matrices on the dynamics and structure of embedded proteins. Two proteins were studied, in water–trehalose matrices: a ...water-soluble protein (carboxy derivative of horse heart myoglobin) and a membrane protein (reaction centre from
Rhodobacter sphaeroides). Several experimental techniques were used: Mössbauer spectroscopy, elastic neutron scattering, FTIR spectroscopy, CO recombination after flash photolysis in carboxy-myoglobin, kinetic optical absorption spectroscopy following pulsed and continuous photoexcitation in Q
B containing or Q
B deprived reaction centre from
R. sphaeroides. Experimental results, together with the outcome of molecular dynamics simulations, concurred to give a picture of how water-containing matrices control the internal dynamics of the embedded proteins. This occurs, in particular, via the formation of hydrogen bond networks that anchor the protein surface to the surrounding matrix, whose stiffness increases by lowering the sample water content. In the conclusion section, we also briefly speculate on how the protein–matrix interactions observed in our samples may shed light on the protein–solvent coupling also in liquid aqueous solutions.
Objective
To describe and compare onset and intensity of thoracic duct (TD) coloration in healthy dogs after intrahepatic injection of either indocyanine green (ICG) visualized by intraoperative ...near‐infrared fluorescence lymphography (NIRFL) or direct thoracoscopic visualization of methylene blue dye (MB).
Study Design
Prospective study.
Animals
Healthy adult Beagle dogs (n = 5).
Methods
All dogs had biochemical panels and complete blood counts preoperatively. Computed tomography lymphography (CTL) was performed prior to a standard 3‐port thoracoscopic approach. A mixture of MB and ICG was injected by ultrasound‐guided percutaneous injection into right or left‐sided hepatic lobes. Data collected included dose of contrast agent (MB vs. ICG), injection site, timing, and quality of operative TD identification. Potential hepatic injury was assessed by repeat laboratory evaluation and abdominal ultrasound 14 days postoperatively.
Results
Preoperative CTL provided a diagnostic study in 5/5 dogs. After intrahepatic injection of combined dyes, NIRFL allowed visualization of TDs in 5/5 dogs, but MB did not result in visible TD coloration in any dog. Intrahepatic injection of ICG achieved successful NIRFL in a median time of 6 minutes and persisted for the 20 minute observation period in all five dogs. All dogs recovered without complication and were subsequently adopted.
Conclusion
NIRFL of the TD can be achieved with intraoperative hepatic injection of ICG. Intrahepatic injection of MB did not result in visible TD coloration.
Clinical Significance
Hepatic intra‐parenchymal injection is a reliable alternative portal into the TD system for intraoperative visualization of TD anatomy using ICG in dogs.
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