Mechanisms of acquired resistance to trastuzumab‐based treatment in gastric cancer are largely unknown. In this study, we analyzed 22 pairs of tumor samples taken at baseline and post‐progression in ...patients receiving chemotherapy and trastuzumab for advanced HER2‐positive immunohistochemistry (IHC) 3+ or 2+ with in‐situ hybridization (ISH) amplification gastric or gastroesophageal cancers. Strict clinical criteria for defining acquired trastuzumab resistance were adopted. Loss of HER2 positivity and loss of HER2 over‐expression were defined as post‐trastuzumab IHC score <3+ and absence of ISH amplification, and IHC “downscoring” from 2+/3+ to 0/1+, respectively. HER2 IHC was always performed, while ISH was missing in 3 post‐progression samples. Patients with initial HER2 IHC score 3+ and 2+ were 14 (64%) and 8 (36%), respectively. Loss of HER2 positivity and HER2 over‐expression was observed in 32 and 32% samples, respectively. The chance of HER2 loss was not associated with any of the baseline clinicopathological variables. The only exception was in patients with initial IHC score 2+ versus 3+, for both endpoints of HER2 positivity (80 vs. 14%; p = 0.008) and HER2 over‐expression (63 vs. 14%; p = 0.025). As already shown in breast cancer, loss of HER2 may be observed also in gastric cancers patients treated with trastuzumab‐based chemotherapy in the clinical practice. This phenomenon may be one of the biological reasons explaining the failure of anti‐HER2 second‐line strategies in initially HER2‐positive disease.
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Patients with cancers positive for human epidermal growth factor receptor 2 (HER2) generally fail to respond to second‐line treatments, particularly when first‐line therapy included use of the HER2‐targeted agent trastuzumab. Post‐progression changes in HER2 expression, however, have not been studied extensively, and as a consequence, their therapeutic relevance is unclear. In this study, HER2 loss was associated with acquired resistance to trastuzumab in almost one‐third of patients with gastric or gastroesophageal cancers that initially were HER2‐positive. The findings suggest that after failure of trastuzumab, HER2 status should be reassessed prior to inclusion in clinical trials with targeted agents.
Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression ...remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions.
We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO
) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSC
) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPO
induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells.
We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.
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•Dramatic self-heating until self-combustion tannery sludge.•Pyrophoric iron sulfides formation in tannery sludge drying under suboxic atmosphere.•In the sludge, the chemistry of iron ...sulfides in marine systems is reproduced.•Lab-scale preparation of reactive dried sludge.•Sludge characterization by physical and chemical analytical techniques.
Similarly to many powders of solids, dried sludge originated from tannery wastewater may result in a self-heating process, under given circumstances. In most cases, it causes a moderate heating (reaching 70–90°C), but larger, off-design residence times in the drier, in a suboxic atmosphere, extremely reactive solids can be produced. Tannery waste contains several chemicals that mostly end up in the wastewater treatment sludge. Unexpected and uncontrolled self heating could lead to a combustion and even to environmental problems. Elaborating on previous studies, with the addition of several analytical determinations, before and after the self-heating, we attempted to formulate a mechanism for the onset of heating. We demonstrated that the system Fe/S/O has been involved in the process. We proved that the formation of small quantities of pyrophoric iron sulfides is the key. They are converted to sulfated by reaction with water and oxygen with exothermic processes. The pyrite/pyrrhotite production depends on the sludge drying process. The oxidation of sulfides to oxides and sulfates through exothermic steps, reasonably catalyzed by metals in the sludge, occurs preferentially in a moist environment. The mechanism has been proved by reproducing in the laboratory prolonged heating under anoxic/suboxic atmosphere.
The paper reports the results of a project aiming to obtain multifunctional binary and ternary polymer nanocomposites with enhanced mechanical and anti-microbial properties. To this end a DGEBA-based ...epoxy resin is loaded using montmorillonite clays and later used as matrix for glass fibre reinforced laminates. Both binary and ternary nanomodified specimens are manufactured and subjected to mechanical testing. An accurate analysis of the effect of nanomodification on the biological activity is carried out as well.
•Results from nanocomposites with enhanced mechanical and anti-microbial properties are presented.•Epoxy is loaded with nanoclays and used as matrix for glass fibre reinforced laminates.•Binary and ternary nanomodified specimens are manufactured and tested.•The effect of nanomodification on the biological activity is studied.
Our aim was to compare contrast-enhanced MR angiography (CE-MRA) and 3D time-of-flight (TOF) MRA at 3T for follow-up of coiled cerebral aneurysms.
Fifty-two patients treated with Guglielmi detachable ...coils for 54 cerebral aneurysms were evaluated at 3T MRA. 3D TOF MRA (TR/TE = 23/3.5; SENSE factor = 2.5) and CE-MRA by using a 3D ultrafast gradient-echo sequence (TR/TE = 5.9/1.8; SENSE factor = 3) enhanced with 0.1-mmol/kg gadobenate dimeglumine were performed in the same session. Source images, 3D maximum intensity projection, 3D shaded surface display, and/or 3D volume-rendered reconstructions were evaluated in terms of aneurysm occlusion/patency and artifact presence.
In terms of clinical classification, the 2 MRA sequences were equivalent for 53 of the 54 treated aneurysms: 21 were considered fully occluded, whereas 16 were considered to have a residual neck and 16 were considered residually patent at follow-up MRA. The remaining aneurysm appeared fully occluded at TOF MRA but had a residual patent neck at CE-MRA. Visualization of residual aneurysm patency was significantly (P = .001) better with CE-MRA compared with TOF MRA for 10 (31.3%) of the 32 treated aneurysms considered residually patent with both sequences. Coil artifacts were present in 5 cases at TOF MRA but in none at CE-MRA. No relationship was apparent between the visualization of patency and either the size of the aneurysm or the interval between embolization and follow-up.
At follow-up MRA at 3T, unenhanced TOF and CE-MRA sequences are similarly effective at classifying coiled aneurysms as occluded or residually patent. However, CE-MRA is superior to TOF MRA for visualization of residual patency and is associated with fewer artifacts.
Dental caries in pits and fissures of molars is still very common in young people, despite a gradual reduction in their incidence and prevalence. Prevention with the aid of dental fissure sealants ...can help to reduce the onset of decay. In vitro tests were conducted to compare the bond strength to enamel of self-etching sealants versus those applied using the conventional procedure.
The lingual surface of 40 extracted, caries-free, mandibular third molars was milled to make them flat. The prepared teeth were randomly divided into two groups of 20 teeth each: those in Group A were treated with Clinpro (3M ESPE, St. Paul, MN, USA); those in Group B with Quick Seal (BJM Laboratories Ltd, Or-Yehuda, Israel). Cylinders of sealant were attached to the enamel of the flat surfaces of the samples using a polymerisation process treating the surfaces involved according to the type of material. All samples underwent load testing by means of a universal test machine.
The results of the load testing, measured in MPa, were analysed using the Student's t-test for independent samples and the differences proved significant, indicating that the traditionally- applied sealant (mean strength 21.06 MPa) assured a significantly stronger bond (p <.05) than the self-etching sealant (mean strength 10.43 MPa) under our experimental conditions. CONCLUSION Conventional sealants generally provide a considerably higher bond strength than self-etching sealants.
Primary biliary cholangitis (PBC) can be associated with impaired health-related quality of life (HRQoL) caused by symptoms, mainly pruritus and fatigue, and eventually depression.Treatment ...confidence strongly affects HRQoL in PBC, and UDCA has been reported to be a positive factor in enhancing trust therapy. No real-life data on this and HRQoL exist regarding obeticholic acid (OCA) second-line therapy.
To assess the impact of OCA on biochemistry, patients’ illness perception and HRQoL of PBC patients
We designed a phase 4 observational open label study (Protocol AOP1515) and collected at baseline and every 6 months from starting OCA biochemistry, adverse events, reported symptoms and the results of following questionnaires: PBC-40, Fatigue Impact Scale(FIS), 5-D Itch scale, EuroQoL-5D-5L. Changes in symptoms after OCA introduction were assessed by Wilcoxon paired rank test.
Nineteen (60%) over 32 patients who started OCA treatment between March 2018 and April 2022 for insufficient response to UDCA agreed to participate. Median duration of OCA treatment was 32(15-53) months with no drug discontinuation due to adverse events. A decrease of alkaline phosphatase compared to baseline below 1.5xULN and 1xULN was observed in 47%,67%,64%,67% and 16%,21%,35%,17% patients at 6,12,18,24 months, respectively. At the time of starting OCA, significant pruritus, fatigue, cognitive and social dysfunction, emotional impairment, and general symptoms were present in 5%,32%,11%,53%,37%, 21% patients, respectively. No significant aggravation of itch or other symptoms was observed after OCA introduction, except for a transient aggravation in emotional domain at 12 months (85-10vs.149-19, p=0.005). A trend over a significant reduction of fatigue evaluated by FIS at 36 months was observed (450-82vs.10.50-42,p=0.06). All patients reported a significant and persistent general improvement after OCA introduction.
People with PBC and insufficient response to UDCA experienced a biochemical and subjective improvement after OCA introduction and no aggravation of objectively assessed HRQoL.
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