Glioblastoma multiforme (GBM) is a lethal disease characterized by an overall survival of about 1 year, making it one of the most aggressive tumours, with very limited therapeutic possibilities. ...Specific biomarkers for early diagnosis as well as innovative therapeutic strategies are urgently needed to improve the management of this deadly disease. In this work, we demonstrated that vesicular galectin‐3‐binding protein (LGALS3BP), a glycosylated protein overexpressed in a variety of human malignancies, is a potential GBM disease marker and can be efficiently targeted by a specific antibody–drug conjugate (ADC). Immunohistochemical analysis on patient tissues showed that LGALS3BP is highly expressed in GBM and, compared with healthy donors, the amount of vesicular but not total circulating protein is increased. Moreover, analysis of plasma‐derived extracellular vesicles from mice harbouring human GBM revealed that LGALS3BP can be used for liquid biopsy as a marker of disease. Finally, an ADC targeting LGALS3BP, named 1959‐sss/DM4, specifically accumulates in tumour tissue, producing a potent and dose‐dependent antitumor activity. In conclusion, our work provides evidence that vesicular LGALS3BP is a potential novel GBM diagnostic biomarker and therapeutic target deserving further preclinical and clinical validation.
LGALS3BP is overexpressed in glioblastoma multiforme (GBM) and is highly enriched in GBM‐derived extracellular vesicles. We established a panel of patient‐derived GBM cell lines and developed a cell‐derived xenograft preclinical model. Our data reported that extracellular LGALS3BP can be used as a potential liquid biopsy GBM marker and can be efficiently targeted by a specific antibody–drug conjugate.
The invasive and lethal nature of Glioblastoma multiforme (GBM) necessitates the continuous identification of molecular targets and search of efficacious therapies to inhibit GBM growth. The GBM ...resistance to chemotherapy and radiation it is attributed to the existence of a rare fraction of cancer stem cells (CSC) that we have identified within the tumor core and in peritumor tissue of GBM. Since Notch1 pathway is a potential therapeutic target in brain cancer, earlier we highlighted that pharmacological inhibition of Notch1 signalling by γ-secretase inhibitor-X (GSI-X), reduced cell growth of some c-CSC than to their respective p-CSC, but produced negligible effects on cell cycle distribution, apoptosis and cell invasion. In the current study, we assessed the effects of Hes1-targeted shRNA, a Notch1 gene target, specifically on GBM CSC refractory to GSI-X. Depletion of Hes1 protein induces major changes in cell morphology, cell growth rate and in the invasive ability of shHes1-CSC in response to growth factor EGF. shHes1-CSC show a decrease of the stemness marker Nestin concurrently to a marked increase of neuronal marker MAP2 compared to pLKO.1-CSC. Those effects correlated with repression of EGFR protein and modulation of Stat3 phosphorylation at Y705 and S727 residues. In the last decade Stat3 has gained attention as therapeutic target in cancer but there is not yet any approved Stat3-based glioma therapy. Herein, we report that exposure to a Stat3/5 inhibitor, induced apoptosis either in shHes1-CSC or control cells. Taken together, Hes1 seems to be a favorable target but not sufficient itself to target GBM efficaciously, therefore a possible pharmacological intervention should provide for the use of anti-Stat3/5 drugs either alone or in combination regimen.
Abstract
Background
We designed this study with the aim of comparing POEM and laparoscopic Heller myotomy+Dor fundoplication (LHD) by matching 2 groups of consecutive patients, treated in 2 ...high-volume Centers, with the propensity score (PS).
Methods
Patients undergoing treatment for achalasia from 2014 to 2017 were selected: by applying the PS, 140 patients in both centers were matched. LHD and POEM were performed following established techniques. Patients were followed with clinical, endoscopic and pH-manometry evaluations.
Results
POEM required a shorter operation time (47 min 35-57) and postoperative stay (2 days 2-2) compared to LHD (95 min 85-105 and 3 days 3-3, respectively, p<0.001). No mortality was recorded in either group. Seven complications were recorded in the POEM group (5 mucosal perforations) and 3 in the LHD group (3 mucosal perforations)(p=0.33). At a median follow up of 24 mos. 15-30 for POEM and 31 mos. 15-41 for LHD (p<0.05), the median Eckardt score did not differ: moreover, 99.3% of the POEM patients and 97.7% of the LHD patients showed an Eckardt score ≤ 3 (p <0.12). Four years after the treatment, the probability to be symptom free was > 90% for both groups (98.2% for POEM and 93.9% for LHD, p=0.2, Log-rank test). HR-Manometry showed a similar reduction in the LES pressure and 4sIRP; however, 24-h pH-monitoring showed an abnormal exposure to acid in 38.4% of POEM patients, as compared to 17.1% of LHD patients (p<0.01) and esophagitis was found in 37.4% of the POEM and 15.2% of LHD patients (p<0.05). Finally, the need for PPI therapy was higher in the POEM group (38.8%) compared to the LHD group (15.1%), p<0.001.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
55.
A New Method of Estimating Intracranial Elastance Anile, Carmelo, MD; De Bonis, Pasquale, PhD; Mangiola, Annunziato, MD ...
Interdisciplinary neurosurgery,
06/2014, Letnik:
1, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract Objective Current methods of calculating Intracranial Elastance Index (IEI) depend from CSF pulse-wave, whose shape may deeply change during ICP rising. The main aim of this study was to ...evaluate the reliability and specificity of a novel method to calculate IEI (method C), based on the integral of the CSF pulse-wave area. Method Twenty ventricular infusion-tests of patients with idiopathic NPH were re-evaluated. We have compared method C with the most widely used methods to calculate IEI: a modified Szewczykowski method (diastolic ICP against CSF pulse-wave amplitude-method A) and a modified Czosnyka method (diastolic ICP against the fundamental harmonic-method B). R-squared (R2 ) was calculated for each test. Means were compared through ANOVA and t-test. Results Mean R2 values for methods A, B and C were 0.91 ± 0.06, 0.9 ± 0.06 and 0.96 ± 0.03, respectively. Mean R2 values obtained through method A vs C and through method B vs C were significantly different (p = .006 and p = .001, respectively), while values obtained through method A vs B were not (p = 1). Analysis of ICP tracks demonstrated that 9 patients showed no different shape of the ICP wave during the infusion test, while the remaining 11 did. The mean R2 values obtained through method A vs C and through method B vs C were significantly different (p < .001 for both) for patients showing a different shape of the ICP wave during the infusion test. Conclusions Method C seems to be the most reliable method to calculate IEI, as it is independent from CSF pulse wave modifications.
A defective, normal or enhanced hemostasis has been reported in Duchenne muscular dystrophy (DMD). A retrospective analysis of intra-and postoperative (up to 36
h) estimated blood losses was ...performed in 156 patients undergoing spinal surgery for: DMD (
n=31), idiopathic scoliosis (IS) (
n=70), poliomyelitis (
n=10), cerebral palsy (CP) (
n=28), spinal muscular atrophy (SMA) (
n=17). Platelet aggregation and bleeding times were also investigated in DMD patients. Immunohistochemistry for dystrophin was performed in platelets, megakaryocytes and blood vessels of normal tissues. DMD patients showed significantly higher intraoperative estimated blood losses (DMD: 3495±890
ml; IS: 2269±804
ml; poliomyelitis: 2582±1252
ml; CP: 2071±683
ml; SMA: 2464±806
ml;
P<0.05), while postoperative blood losses were similar among different groups. Higher estimated blood losses in DMD were independent of the duration of surgery, body weight, gender, age, vertebral levels or preoperative Cobb angle. DMD children had significantly prolonged bleeding times, but retained normal platelet function. From control samples dystrophin was expressed in vascular smooth muscle cells, but not in platelets. DMD appears to be characterized by immediate bleeding during highly-invasive surgery and increased bleeding time without platelet abnormalities. Considering dystrophin expression in normal vascular smooth muscle cells, these results altogether suggest a selective defect of primary hemostasis in DMD, likely to be due to impaired vessel reactivity.
Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies ...and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.
In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.
We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.
Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.
SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831.
Malignant gliomas, with an incidence of 5 cases per 100,000 population per year, represent the most common primary brain tumour. They have an overall survival length of less than 2 years. Many ...different adjuvant therapies have been developed. Among them, Photodynamic Therapy (PDT), that is based on photochemical reactions between light and tumoral tissue selectively labelled with exogenous photosensitizing agents. Among photosensitizers, m-THPC (Temoporfin), seems to be the most promising one for the treatment of brain tumors, but, unfortunately, it causes problems of high skin photosensitivity. To by-pass this problem, we devised an intratumoral route of administration of this photosensitizer. The aim of this study is to investigate and compare the uptake of m-THPC in brain tumor and normal tissue after systemic and intratumoral administration of the drug. 30 female Wistar rats received m-THPC 12 days after C6 tumor implantation. Temoporfin was administered intratumorally in 24 rats at two different concentrations. 6 rats constituted the control group and received m-THPC by means of an intraperitoneal injection. The brains were extracted at 4 h, 24 h and 96 h after Temoporfin injection. The samples were examined with a confocal laser scanning microscope. All samples showed high fluorescence emission exclusively in the tumour area, without appreciable differences between the samples taken at the different times of sacrifice and the two routes of administration. No fluorescence whatsoever was detected among normal brain tissue surrounding the tumour. The intratumoral route appears to give comparable results to the systemic one, regarding intracellular uptake efficiency and tumour - normal tissue ratio, with the advantage of a much shorter time needed to reach optimal intratumoural concentration - that is just four hours from m-THPC injection.
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