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Despite significant advancements in ichthyoplankton collection and data processing, challenges persist in the taxonomic identification of these organisms, particularly their eggs. To overcome these challenges, a novel technique has been developed to facilitate the identification of live eggs collected directly in wild. This user-friendly technique includes the collection, processing of the material, and field incubation. Sampling must be conducted using a pelagic net towed at low speed, preferably during early evening. The material processing involves pre-sorting and sorting to remove eggs and larvae. The separated eggs, kept in an aerated bowl, can be identified based on their morphological and meristic characteristics. Unidentified eggs can be placed in plastic bags with oxygen and incubated directly in the aquatic environment for 48–72 h. After this incubation period, the hatched larvae at the yolk-sac or preflexion stage, are identified to the lowest possible taxonomic level. Depending on the study's purpose, hatched larvae and field-collected larvae can be transported to research centers for further development, released back into the natural environment, or fixed to complete the collection. The application of this technique supports management and monitoring programs by identifying spawning areas through egg identification, forming broodstock, and replenishing threatened species, thereby enhancing scientific collections of ichthyoplankton. Additionally, it reduces mortality in ichthyoplankton techniques, including endangered species. Therefore, we believe that this novel taxonomic technique for identifying live ichthyoplankton represents a paradigm shift in the monitoring, management, and conservation of fish, as well as in ecological stewardship and advances in this area of research. [ABSTRACT FROM AUTHOR]

Background: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. Methods: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC. Results: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size. Conclusions: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies. [ABSTRACT FROM AUTHOR]

Background: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. Patients and methods: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). Results: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine – cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). Discussion: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas. [ABSTRACT FROM AUTHOR]

Sudden changes in pacing cycle length are frequently associated with repolarization abnormalities initiating cardiac arrhythmias, and physiologists have long been interested in measuring the likelihood of these events before their manifestation. A marker of repolarization stability has been found in the electrical restitution (ER), the response of the ventricular action potential duration to a pre- or post-mature stimulation, graphically represented by the so-called ER curve. According to the restitution hypothesis (ERH), the slope of this curve provides a quantitative discrimination between stable repolarization and proneness to arrhythmias. ER has been studied at the body surface, whole organ, and tissue level, and ERH has soon become a key reference point in theoretical, clinical, and pharmacological studies concerning arrhythmia development, and, despite criticisms, it is still widely adopted. The ionic mechanism of ER and cellular applications of ERH are covered in the present review. The main criticism on ERH concerns its dependence from the way ER is measured. Over the years, in fact, several different experimental protocols have been established to measure ER, which are also described in this article. In reviewing the state-of-the art on cardiac cellular ER, I have introduced a notation specifying protocols and graphical representations, with the aim of unifying a sometime confusing nomenclature, and providing a physiological tool, better defined in its scope and limitations, to meet the growing expectations of clinical and pharmacological research. [ABSTRACT FROM AUTHOR]

Brewer's spent yeast (BSY) is a prevalent by-product of the brewing industry currently used in animal feed as a cheap source of protein. In this study, chemical composition of BSY from two different beer production (American IPA, BSY1, and Imperial Stout, BSY2) was characterized, aiming for potential use as nutraceutical sources. Cytotoxicity of BSY extracts was also tested in freshly isolated peripheral blood mononuclear cells (PBMCs) and in tumoral (pancreatic cancer tumor cells, PANC-1, and colorectal adenocarcinoma tumor cells, CACO-2) and non-tumoral (umbilical vein endothelial cells, HUVEC) cell lineages. BSY samples showed similar lipid and ash content, but slight differences in the content of reducing sugars, total proteins, moisture and total proteins. BSY2 sample presented higher glucans and phenolic compound concentrations than BSY1. Main phenolic compounds identified were xanthohumol, ferulic acid, p-coumaric acid (BSY1 and BSY2), and gallic acid (BSY2). BSY1 and BSY2 extracts showed similar antioxidant capacity. Neither BSY1 nor BSY2 were cytotoxic to PBMCs, HUVEC and CACO-2, but were cytotoxic to PANC-1 cells, in a concentration-dependent manner. Our findings revealed that the residue of brewery can be a value-added functional food product with an adjuvant role against PANC-1 cell lines. [ABSTRACT FROM AUTHOR]

Background: Trop-2 and Nectin-4 are transmembrane proteins overexpressed in many tumours and targets of antibody–drug conjugates (ADC). In metastatic colorectal cancer (mCRC), the role of Trop-2 and Nectin-4 has been poorly investigated. Methods: Tumour samples of patients randomised in the phase III TRIBE2 were assessed for Trop-2 and Nectin-4 expression. Results: Three hundred eighty-six tumours were assessed for Trop-2 expression. 90 (23%), 115 (30%) and 181 (47%) were Trop-2 high, medium and low, respectively. Patients with low Trop-2 tumours achieved longer PFS (12 versus 9.9 months, p = 0.047) and OS (27.3 versus 21.3 months, p = 0.015) than those with high/medium Trop-2 tumours. These findings were confirmed in multivariate analysis (p = 0.022 and p = 0.023, respectively). A greater OS benefit from treatment intensification with FOLFOXIRI/bevacizumab was observed in patients with high/medium Trop-2 tumours (p-for-interaction = 0.041). Two hundred fifty-one tumours were assessed for Nectin-4 expression. Fourteen (5%), 67 (27%) and 170 (68%) were high, medium and low, respectively. No prognostic impact was observed based on Nectin-4 expression and no interaction effect was reported between Nectin-4 expression groups and treatment arm. Conclusions: In mCRC, expression levels of Trop-2 and Nectin-4 are heterogeneous, suggesting a target-driven development of anti-Trop2 and anti-Nectin-4 ADCs. Medium/high Trop-2 expression is associated with worse prognosis and higher benefit from chemotherapy intensification. [ABSTRACT FROM AUTHOR]

Based on morphobathymetric and seismic reflection data, we studied a large landslide body from the eastern Sea of Marmara (NW Turkey), along the main strand of the North Anatolian Fault, one of the most seismically active geological structures on Earth. Due to its location and dimensions, the sliding body may cause tsunamis in case of failure possibly induced by an earthquake. This could affect heavily the coasts of the Sea of Marmara and the densely populated Istanbul Metropolitan area, with its exposed cultural heritage assets. After a geological and geometrical description of the landslide, thanks to high-resolution marine geophysical data, we simulated numerically possible effects of its massive mobilization along a basal displacement surface. Results, within significant uncertainties linked to dimensions and kinematics of the sliding mass, suggest generation of tsunamis exceeding 15–20 m along a broad coastal sector of the eastern Sea of Marmara. Although creeping processes or partial collapse of the landslide body could lower the associated tsunami risk, its detection stresses the need for collecting more marine geological/geophysical data in the region to better constrain hazards and feasibility of specific emergency plans. [ABSTRACT FROM AUTHOR]

Autoimmune encephalitis (AE) associated to antibodies against GABA A R is a rare form of encephalitis. On the other hand, thymoma has been linked to antibodies against both muscular and neuronal epitopes, even if concurrent positivity for more than one antibody is exceptional, and their contribution to the clinical course and treatment decision is unclear. We report a case of a 73-year-old male with AE associated with thymoma secreting both anti-GABAaR and anti-titin antibodies. Clinical presentation included status epilepticus, behavioural changes and cognitive decline. While the status was stopped with lacosamide, AE treatment included first- and second-line immunomodulation, in addition to thymoma's removal. Nonetheless, the patient experienced a worsening in cognitive and behavioural status. [ABSTRACT FROM AUTHOR]

Watershed infarcts can involve the brainstem, with lesions distributed across the terminal supply from the vertebral and cerebellar arteries. Brain imaging can highlight a comma-shaped lesion at the edge of vertebral and posteroinferior cerebellar artery vascularization territory. Such peculiar MRI lesion shape might suggest a watershed hypoperfusion etiology and direct workup towards causes of hemodynamic impairment, including postural hypotension, cardiac failure, or vertebral artery origin occlusion. [ABSTRACT FROM AUTHOR]

Allogenic red blood cell transfusions exert a potential detrimental effect on the survival when delivered to cancer patients undergoing surgery with curative intent. We performed a systematic review and meta-analysis to assess the association between perioperative allogenic red blood cell transfusions and risk of death as well as relapse after surgery for localized solid tumors. PubMed, the Cochrane Library, and EMBASE were searched from inception to March 2019 for studies reporting the outcome of patients receiving transfusions during radical surgery for non-metastatic cancer. Risk of death and relapse were pooled to provide an adjusted hazard ratio with a 95% confidence interval [hazard ratio (HR) (95% confidence interval {CI})]. Mortality and relapse associated with perioperative transfusion due to cancer surgery were evaluated among participants (n = 123 studies). Overall, RBC transfusions were associated with an increased risk of death [HR = 1.50 (95% CI 1.42–1.57), p < 0.01] and relapse [HR = 1.36 (95% CI 1.26–1.46), p < 0.01]. The survival was reduced even in cancer at early stages [HR = 1.45 (1.36–1.55), p < 0.01]. In cancer patients undergoing surgery, red blood cell transfusions reduced the survival and increased the risk of relapse. Transfusions based on patients' blood management policy should be performed by applying a more restrictive policy, and the planned preoperative administration of iron, if necessary, should be pursued. [ABSTRACT FROM AUTHOR]

Background: In mCRC, CEA is used to monitor response to systemic therapy together with imaging. After the end of induction, no major improvement in tumour shrinkage is expected, and the availability of a marker able to predict progressive disease (PD) versus no-PD might allow avoiding CT scans.Methods: We pooled data from patients with baseline CEA ≥ 10 ng/mL included in TRIBE and TRIBE2 studies with the aim of identifying a threshold for percent increase of CEA from nadir able to predict PD after the end of the induction therapy.Results: In total, 1178 paired CEA and radiological assessments from 434 patients were included. According to the optimal cut-off determined by ROC, a CEA increase of at least 120% from nadir differentiated between PD and no-PD with a sensitivity of 74% and a specificity of 78%, excluding PD in the 92% of radiological assessments and allowing to avoid the 67% of CT scans. However, CEA cut-off of 120% was not able to detect radiological PD in 26% of cases. In order to mitigate this issue, a different clinically relevant threshold was evaluated based on the best sensitivity cut-off. Therefore, using any CEA increase from nadir as a threshold, the sensitivity grew to 93% and only in the 7% of cases the radiological PD was not detected.Conclusions: In mCRC with baseline CEA ≥ 10 ng/mL, CEA values can accurately predict PD versus no-PD after the end of the first-line induction therapy. [ABSTRACT FROM AUTHOR]

Salicylic acid (SA) is a plant hormone that stimulates the growth and metabolism of plants, also acting as an abiotic elicitor. This study aimed to evaluate the effect of SA on leaf production, leaf area and synthesis of secondary compounds in yarrow plants. The experiments were conducted under field conditions in two consecutive years and f-received SA foliar applications (T1-control; T2-1.0 mmol L−1 applications at 20, 60 and 100 days after planting (DAP) and T3-1.0 mmol L−1 applications at 100 DAP during 3 days). The exogenous application of SA resulted in increases in leaf area (total and specific), number of leaves and leaf mass ratio of yarrow plants, polyphenolic compounds, phenylalanine ammonia-lyase and chalcone synthase enzymes and the antioxidant activity of the plant extract. The HPLC–DAD–MS/MS analysis of phenolic compounds revealed increases in the amounts of quinic acid and rutin. The results of this research lead us to affirm that SA exerted both the hormonal effect on number of leaves and leaf area, and also acted as eliciting substance. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here. Methods: Pa tients with mGC/mGEJC treated with ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC). Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50–1.11) and 0.67 (95% CI 0.52–0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI. Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile. [ABSTRACT FROM AUTHOR]

Introduction: The combination of anti-EGFRs and doublet chemotherapy is considered the optimal upfront option for patients with RAS/BRAF wild-type left-sided metastatic colorectal cancer (mCRC). The prophylactic or reactive treatment with tetracyclines for EGFR inhibitor-induced skin toxicity is currently clinical practice, though non-conclusive results are available. Methods: We performed a post hoc analysis of the Valentino study that randomized RAS wild-type mCRC patients to two panitumumab-based maintenance regimens after the first-line induction, aimed at assessing the safety and efficacy of the administration of a pre-emptive doxycycline prophylaxis for anti-EGFR-related skin toxicity. We assessed the rate of treatment-related and panitumumab-related adverse events (AEs), treatment intensity, progression-free survival (PFS), and overall survival (OS). Results: A total of 226 patients, out of the 229 enrolled in the Valentino study, were eligible for the analysis. Overall, 143 (63%) and 83 (37%) patients received or not the antibiotic prophylaxis for skin toxicity. Any grade and G3/4 panitumumab-related AEs were reported in 89% versus 92% (p = 0.650) and 27% versus 27% (p = 1.000) patients who received or not the pre-emptive prophylaxis, respectively. Any grade and G3/4 skin rash occurred in 81% versus 90% (p = 0.085) and 27% versus 25% (p = 0.876) patients receiving or not the prophylaxis, respectively. No significant differences in terms of treatment duration, treatment delays or dose reductions, PFS, and OS were observed in the two sub-populations. Conclusion: The adequate management of anti-EGFR-related skin toxicity is fundamental to optimize the outcome of mCRC patients, balancing the survival benefit with patients' quality of life, especially in the first-line setting. [ABSTRACT FROM AUTHOR]

Background: Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. Objective: In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. Patients and Methods: p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan–Meier method, while the log-rank test was used for survival comparison. Results: Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. Conclusions: In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients. [ABSTRACT FROM AUTHOR]

The advent of immunotherapy in onco-haematology has represented a kind of revolution that has been able to modify the prognosis of numerous tumours that until recently would have been rapidly lethal. While much is known about the mechanism of action of these drugs, relatively little is known about the factors that represent potential predictors of response and toxicity. Among these factors, the simultaneous administration of antibiotics and/or steroids seems to have a negative impact. Furthermore, several retrospective studies have highlighted the strong link between cancer and gut microbiota, regardless of the tumour site, and how microbiota, playing a key role in the prevention of systemic inflammation at various levels and in the intestinal homeostasis, can be negatively influenced by the dysbiosis caused by antibiotic therapy administered during or in the weeks immediately preceding the start of immunotherapy. Moreover, we assume that the concurrent administration of steroids, which is often necessary in cancer patients, likely results in a deleterious effect on the therapeutic outcomes of immunotherapy. In this review, we will try to clarify the evidence on the possible detrimental effects of antibiotics and steroids, which are currently considered the double enemies of anticancer immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Steroids are commonly used for managing brain edema in patients with glioblastoma multiforme (GBM), treated with surgery and concomitant temozolomide-based chemoradiotherapy (CTRT). The adverse effects of glucocorticoids include lymphopenia, hyperglycemia, and risk of infection. We report the results of a meta-analysis evaluating the effects of steroids on outcome when associated with the treatment of GBM. Methods: PubMed, the Cochrane Library, and Embase were searched from inception until September 2019 for observational or prospective studies reporting prognosis of adult patients with GBM and treated or not treated with steroids. Overall survival (OS) was the primary endpoint, and progression-free survival (PFS) was the secondary endpoint. The effect size was reported as hazard ratios (HRs) with a 95% confidence interval (CI), and an HR > 1 associated with the worst outcome in steroid users compared to non-users. Results: Twenty-two publications were retrieved from studies selected for a total of 8,752 patients. In the primary analysis (n = 22 studies reporting data), OS was reduced in GBM patients taking steroids during treatment (HR = 1.54, 95% CI 1.37–1.75; p < 0.01). Similarly, PFS was inferior in steroid users in n = 9 studies with data available (HR = 1.28, 95% CI 1.1–1.49; p < 0.01). Conclusions: In patients with GBM and treated with RT and/or CT, association with steroids significantly reduces survival and PFS. Use of the lowest dose of glucocorticoids for the shortest period needed to achieve the treatment goals and prevention of steroid-associated complications are essential aims of treatment of this disease. [ABSTRACT FROM AUTHOR]

The Marsili Seamount (Tyrrhenian Sea, Italy) is the largest submarine volcano in the Mediterranean Sea, located in the middle of the Marsili Basin, facing the Calabrian and Sicilian coasts on its eastern side, and the coasts of Sardinia on the opposite side. It has erupted in historical times, and its summit crest is affected by widespread hydrothermal activity. This study looks at mass failures taking place at different depths on the flanks of the volcano and estimates their associated tsunamigenic potential. Mass failure, tsunami generation, and propagation have been simulated by means of numerical models developed by the Tsunami Research Team of the University of Bologna. In all, we consider five cases. Of these, three scenarios, one regarding a very small detachment and two medium-sized ones (between 2 and 3 km3 failure volume), have been suggested as possible failure occurrences in the published literature on a morphological basis and involve the north-eastern and north-western sectors of the volcano. The two additional cases, one medium-sized and one extreme, intended as a possible worst-case scenario (volume 17.6 km3), affecting the eastern flank. Results indicate that small-volume failures are not able to produce significant tsunamis; medium-size failures can produce tsunamis which dangerously affect the coasts if their detachment occurs in shallow water, i.e., involves the volcano crest; and extreme volume failures have the potential to create disastrous tsunamis. In all the simulations, tsunami waves appear to reach the Aeolian Islands in around 10 min and the coasts of Calabria and Sicily in 20 min. This study highlights that there is a potential for dangerous tsunamis generation from collapses of the Marsili volcano and as a consequence a need to intensify research on its status and stability conditions. More broadly, this investigation should also be extended to the other volcanic seamounts of the Tyrrhenian Sea, since their eruptive style, evolution, and tsunamigenic potential are still poorly known. [ABSTRACT FROM AUTHOR]

Spontaneous intracranial hypotension results from a spinal CSF leak and usually presents with orthostatic headache, although acephalgic presentations have anecdotally been reported. The underlying low CSF volume, rarely, leads to serious complications such as cerebral venous thrombosis and coma. We report a patient presenting with cerebral venous thrombosis secondary to acephalgic spontaneous intracranial hypotension. An epidural blood patch was performed; nonetheless, the patient intracracal condition deteriorated to coma and neuroimages showed a deep brain swelling with midbrain distortion, subsequently complicated by intracranial pontine hemorrhage. [ABSTRACT FROM AUTHOR]

Notwithstanding its complexity in terms of numerical implementation and limitations in coping with problems involving extreme deformation, the finite element method (FEM) offers the advantage of solving complicated mathematical problems with diverse boundary conditions. Recently, a version of the particle finite element method (PFEM) was proposed for analyzing large-deformation problems. In this version of the PFEM, the finite element formulation, which was recast as a standard optimization problem and resolved efficiently using advanced optimization engines, was adopted for incremental analysis whilst the idea of particle approaches was employed to tackle mesh issues resulting from the large deformations. In this paper, the numerical implementation of this version of PFEM is detailed, revealing some key numerical aspects that are distinct from the conventional FEM, such as the solution strategy, imposition of displacement boundary conditions, and treatment of contacts. Additionally, the correctness and robustness of this version of PFEM in conducting failure and post-failure analyses of landslides are demonstrated via a stability analysis of a typical slope and a case study on the 2008 Tangjiashan landslide, China. Comparative studies between the results of the PFEM simulations and available data are performed qualitatively as well as quantitatively. [ABSTRACT FROM AUTHOR]

Background: FOLFOXIRI/bevacizumab (bev) is a first-line regimen of proven activity and efficacy in metastatic colorectal cancer. The upfront exposure to three cytotoxics raises concerns about the efficacy of treatments after progression.Methods: We performed a pooled analysis of treatments after progression to upfront FOLFOXIRI/bev in patients enrolled in two randomised Phase 3 studies (TRIBE and TRIBE2) that compared FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev. Response rate, progression-free survival (2nd PFS) and overall survival (2nd OS) during treatments after progression were assessed. The RECIST response in first line and the oxaliplatin and irinotecan-free interval (OIFI) were investigated as potential predictors of benefit from FOLFOXIRI ± bev reintroduction.Results: Longer 2nd PFS was reported in patients receiving FOLFOXIRI ± bev reintroduction compared to doublets ± bev or other treatments (6.1 versus 4.4 and 3.9 months, respectively, P = 0.013), and seems limited to patients achieving a response during first line (6.9 versus 4.2 and 4.7 months, respectively, P = 0.005) and an OIFI ≥ 4 months (7.2 versus 6.5 and 4.6 months, respectively, P = 0.045).Conclusions: First-line FOLFOXIRI/bev does not impair the administration of effective second-line therapies. First-line response and longer OIFI seem associated with improved response and 2nd PFS from FOLFOXIRI ± bev reintroduction, without impacting 2nd OS. [ABSTRACT FROM AUTHOR]

Background: Immune-inflammatory biomarkers (IIBs) showed a prognostic relevance in patients with metastatic CRC (mCRC). We aimed at evaluating the prognostic power of a new comprehensive biomarker, the Pan-Immune-Inflammation Value (PIV), in patients with mCRC receiving first-line therapy.Methods: In the present pooled-analysis, we included patients enrolled in the Valentino and TRIBE trials. PIV was calculated as: (neutrophil count × platelet count × monocyte count)/lymphocyte count. A cut-off was determined using the maximally selected rank statistics method. Generalised boosted regression (GBR), the Kaplan-Meier method and Cox hazards regression models were used for survival analyses.Results: A total of 438 patients were included. Overall, 208 patients (47%) had a low-baseline PIV and 230 (53%) had a high-baseline PIV. Patients with high PIV experienced a worse PFS (HR, 1.66; 95% CI, 1.36-2.03, P < 0.001) and worse OS (HR, 2.01; 95% CI, 1.57-2.57; P < 0.001) compared to patients with low PIV. PIV outperformed the other IIBs in the GBR model and in the multivariable models.Conclusion: PIV is a strong predictor of survival outcomes with better performance than other well-known IIBs in patients with mCRC treated with first-line therapy. PIV should be prospectively validated to better stratify mCRC patients undergoing first-line therapy. [ABSTRACT FROM AUTHOR]

Purpose: Established that the only approved agents in previously treated metastatic colorectal cancer (CRC) are trifluoridine/tipiracil and regorafenib, we conducted a systematic review of all the published phase 2–3 trials, with the scope to evaluate the benefit of any later-line regimens in refractory metastatic CRC. Methods: Phase 2–3 studies that enrolled patients with stage IV disease receiving salvage therapies for refractory CRC were identified using electronic databases (Pubmed, EMBASE, and Cochrane Library). Clinical outcomes were pooled using a point estimates for the weighted values of median overall survival (OS), progression-free survival (PFS), response rate (ORR), stable disease rate (SD), and 6-month and 1-year OS. Results: Overall, 7556 patients were included from 67 studies (n = 70 arms). Overall, the pooled ORR and SD were 15.4% (95% CI 13–18%) and 36.9% (95% CI 33.5–40.6%). Median PFS, 6-month and 1-year OS, and median OS were 3.2 (95% CI 2.9–3.3) months, 65.4% (95% CI 61.9–68.8%), 36% (95% CI 32.3–39.9%) and 8.8 (95% CI 8.3–9.2) months. Overall survival was different in the monochemotherapy, polychemotherapy, chemotherapy + targeted therapy, and targeted therapy alone arms (7.6, 9.5, 10.3, and 7.9 months, respectively, P for difference = 0.01). Median PFS were respectively 2.3, 3.9, 3.8, and 2.6, respectively (P for difference < 0.01). Conclusions: Overall, combination therapy (polychemotherapy with or without targeted agents) is associated with a higher control of disease and better outcome than approved agents. Treatment, if possible, should be personalized according to the patients' conditions, physician preference and molecular profile of disease. [ABSTRACT FROM AUTHOR]

Mt. Athos, Northern Greece, is a monastic community with life since ~ 1000 AD, a UNESCO worldwide cultural heritage site that was repeatedly hit by earthquakes. On 8 November 1905, a large earthquake, with estimated magnitude ranging from 6.8 to 8.3, caused destruction in Mt. Athos, but the event remains little known since only few documentary sources have been utilized so far. We collected a set of sources including contemporary press reports, letters, manuscripts and books. We reconstructed the earthquake impact field and organized a database containing (1) assignment of macroseismic intensity in 44 observation points at epicentral distances up to ~ 660 km, and (2) identification of sites where important co-seismic ground failures were reported, e.g., landslides and rock falls. From magnitude-intensity relationships, a macroseismic magnitude of ~ 7 equivalent to Ms was estimated, which is close to recent instrumental estimates of ~ Mw 7.2. The examined sources revealed for the first time that a local but powerful tsunami with an ~ 3-m run-up was generated by earthquake-triggered landslides in southern Mt. Athos. Eleven persons were reportedly killed. Both the landslide and the tsunami were numerically simulated by a scenario of massive landslide entering the sea. The synthetic marigrams obtained from the simulation are consistent with the historical tsunami descriptions. Another little-known tsunami was reported in Mt. Athos in association to the large 1585 earthquake. We concluded that a comprehensive hazard assessment in Mt. Athos should take into account not only strong earthquakes but also associated phenomena like landslides and tsunamis. [ABSTRACT FROM AUTHOR]

It is well-established that SPECT-CT lung scintigraphy has higher diagnostic accuracy for detecting pulmonary embolism than traditional planar images. Noncontrast perfusion single-photon emission CT/CT scanning: a new test for the expedited, high-accuracy diagnosis of acute pulmonary embolism. Therefore, in this clinical setting, SPECT-CT imaging must be recommended to unmask small perfusion defects. [Extracted from the article]

Objectives: Evaluate the bone remodeling during orthodontic movement with corticotomy when submitted to low-intensity electrical stimulation application (microcurrent—MC) and low-level laser therapy (LLLT). Material and methods: One hundred and fifty Wistar rats were divided into the following 5 groups: (C) submitted to tooth movement; (Cort) tooth movement/corticotomy; (Cort-L) tooth movement/corticotomy/laser AsGaAl 808 nm (4.96J/50s); (Cort-Mc) tooth movement/corticotomy/microcurrent (10 μA/5 min); (Cort-L-Mc) tooth movement/corticotomy and laser/microcurrent alternated. Inflammation, angiogenesis, and osteogenesis were evaluated in the periodontal ligament (PDL) and alveolar bone on the 7th, 14th, and 21st days of orthodontic movement. Results: The quantification of inflammatory infiltrate, angiogenesis and expression of TGF-β1, VEGF, and collagen type I were favorably modulated by the application of therapies such as low-level laser therapy (LLLT), MC, or both combined. However, electrical stimulation increased fibroblasts, osteoclasts and RANK numbers, birefringent collagen fiber organization, and BMP-7 and IL-6 expression. Conclusions: Low-level laser therapy (LLLT) and MC application both improved the process of bone remodeling during orthodontic treatment with corticotomy. Still, electrical current therapy promoted a more effective tooth displacement but presented expected root resorption similar to all experimental treatments. Clinical relevance: It is important to know the effects of minimally invasive therapies on cellular and molecular elements involved in the bone remodeling of orthodontic treatment associated with corticotomy surgery, in order to reduce the adverse effects in the use of this technique and to establish a safer clinical routine. [ABSTRACT FROM AUTHOR]

This paper presents a mass flow model that includes gravity force, material stresses, drag force and topography effects solving a set of hyperbolic partial differential equations by using a so-called depth-averaged technique. The model is non-linear and general enough to tackle various problems of interest for geophysics and environmental engineering, such as the dynamic evolution of flow-like avalanches, the dam break problem (involving only water flow) and the generation of tsunami waves by landslides. The model is based on a Eulerian fluid solver, using a second-order central scheme with a minmod-like limiter; is tested against a number of typical benchmark cases, including analytical solutions and experimental laboratory data; and also compared with other numerical codes. Through this model, we study a historical tsunamigenic event occurred in 1783 in Scilla, Italy, that resulted to be catastrophic with a toll exceeding 1500 fatalities. The landslide is reconstructed by a mixture debris flow, and results are compared with the observational data and other numerical simulations. [ABSTRACT FROM AUTHOR]

Because of work's contribution to recovery, governments have moved to improve employment rates of people with severe mental disorders (SMDs). Social enterprises (SEs) have been identified as a means to achieve employment. In Ontario, Canada, the Ministry of Health and Long-Term Care (MOHLTC) have provided SEs government subsidies. Public funding arrangements create a potential trade-off for governments that must decide how to distribute constrained budgets to meet a variety of public needs. In Ontario, the government is potentially faced with choosing between supporting employment versus healthcare services. This study addresses the question, are there significant differences in service use and costs from the MOHLTC's perspective for people with SMDs working in SEs versus those who are not working and looking for work? Our results indicate there is a significant difference in healthcare use between the two groups suggesting there could be less healthcare use associated with SE employment. [ABSTRACT FROM AUTHOR]

Introduction: One year is the standard duration of adjuvant trastuzumab for human epidermal receptor-2 (HER2) positive (HER2+) breast cancer (BC). Indeed, a shorter duration of trastuzumab can reduce cardiotoxicity and the costs involved and could provide the same benefit as a one-year treatment. We evaluated the available evidence from randomised controlled trials (RCTs) by comparing 1 year versus a shorter duration of adjuvant trastuzumab for HER2+ BC.Patients and methods: A systematic search of PubMed, EMBASE, The Cochrane Library and conference proceedings was carried out in order to identify the RCTs that investigated a standard versus a shorter duration of adjuvant trastuzumab in HER2+ BC patients. Using the fixed and random effects models, the pooled hazard ratios (HRs) and risk ratio (RR) with 95% confidence intervals (CI) were calculated for overall survival (OS), disease-free survival (DFS) and cardiac events.Results: Five RCTs with a total of 11,381 patients were included. Overall, one year of adjuvant trastuzumab improved OS (HR 1.22, 95% CI 1.07-1.39; P = 0.003) and DFS (HR 1.19, 95% CI 1.08-1.3; P < 0.001) compared with a shorter duration (6 months and 9 weeks). In the subgroup analysis, there was a trend towards better DFS with the 1-year duration for patients with high-risk features, and also for concomitant administration of chemotherapy and trastuzumab. Cardiac events were significantly lower with a shorter duration (RR 0.4, 95% CI 0.32-0.49; P < 0.001).Conclusions: One-year adjuvant trastuzumab is associated with better DFS and OS compared with shorter durations and should still be considered the standard duration. However, selected patients with low-risk HER2+ BC can most likely be spared from an excess of cardiac toxicity with a shorter course. [ABSTRACT FROM AUTHOR]

The 1963 Vajont landslide is a key case in landslide literature, because it was catastrophic and because a lot of accurate data were collected before and after its occurrence. In this paper, the main focus is on the possible heterogeneity of the sliding surface involved by the landslide motion, which is reflected by a heterogeneous distribution of the dynamic basal friction coefficient μ. Assuming a given zonation of the sliding surface, our strategy was to apply a 2D Lagrangian model to compute the landslide motion and to find the values of μ for each zone, leading to the best agreement between the computed and the observed final deposit. Following some hints from the literature, we have explored heterogeneous configurations composed of up to four different zones, including also the homogeneous case, by means of a 2D numerical model (UBO-BLOCK2) that handles the landslide as a mesh of blocks and runs quickly enough to allow the computation of tens of thousands of simulations in a reasonable computing time. It is found that the four-zone zonation produces the best fit (or the least misfit), which is a strong hint that the gliding surface involved different geotechnical units. [ABSTRACT FROM AUTHOR]

Lichen planus (LP) is a chronic, mucocutaneous inflammatory disease of an unknown aetiology. The disease has been associated with certain viruses, and the factors such as DAMPs (damage-associated molecular patterns) and PAMPs (pathogen-associated molecular patterns) may also contribute to the inflammatory response in LP. HMGB1 (high mobility group box 1 protein) is one of the major DAMPs that induces inflammation and could trigger LP disease. The present study was aimed to examine TLR4, RAGE and HMGB1 production in epidermis or dermis by immunohistochemistry and the respective expression of these targets in the skin lesions of patients with LP. Moreover, we measured HMGB1 serum levels by ELISA. The results showed similar profile of expression by HMGB1 and TLR4, which are decreased at epidermis and up-regulated at dermis of skin lesions of LP patients that was sustained by intense cellular infiltration. RAGE expression was also increased in dermis of LP. Although there is increased RAGE protein levels, a decreased RAGE transcript levels was detected. Similar HMGB1 serum levels were detected in the LP and control groups. This study demonstrates that HMGB1 and TLR4 could contribute to the inflammatory LP process in skin. [ABSTRACT FROM AUTHOR]

Recent studies have identified patterns of genetic organization during schooling in the reproductive period of several Neotropical freshwater migratory fish. However, population segregation during non-reproductive periods is still unknown for most species. In this study, we investigated the genetic structure of populations of Salminus brasiliensis, a high-value large migratory freshwater fish, sampled during the non-reproductive season. We analysed 89 adults from Uruguay River Basin (Brazil) collected during the two consecutive non-reproductive periods, and assessed the genetic diversity levels using eleven microsatellite loci. Our results showed that populations are genetically structured, suggesting these fish can remain grouped likely due to a cooperative behaviour, not related to reproduction, in a typical shoaling behaviour. Besides, we found high genetic diversity for S. brasiliensis from the Turvo State Park area, highlighting the importance of this conservation unit as a relevant area for maintaining the genetic variability of S. brasiliensis in the Uruguay River. [ABSTRACT FROM AUTHOR]

Background: Ramucirumab-alone or combined with paclitaxel-represents one of the main options for patients failing first-line treatment for advanced gastric cancer.Objective: The RAMoss study aimed to evaluate the safety and efficacy profile of ramucirumab in the "real-life setting".Patients and Methods: Patients from 25 Italian hospitals started therapy consisting of ramucirumab 8 mg/kg i.v. d1,15q28 with or without paclitaxel 80 mg/m2 i.v. d1,8,15q28. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results: One hundred sixty-seven patients with disease progression on first-line therapy received ramucirumab as monotherapy (10%) or combined with paclitaxel (90%). Median treatment duration was 4 months (1-17 months). Global incidence of grade (G) 3-4 toxicity was 9.6%, and for neutropenia 5.4%; treatment was discontinued due to toxicity in 3% of patients. The most frequent adverse events (AE) were G1-2 fatigue (27.5%), G1-2 neuropathy (26.3%), and G1-2 neutropenia (14.9%). ORR was 20.2%. Stable disease was observed in 39.2% of patients, with a disease control rate of 59.4%. With a median follow-up of 11 months, median PFS was 4.3 months (95% confidence interval [CI] 4.1-4.7), whereas median OS was 8.0 months (95% CI: 7.09-8.9). In a multivariate analysis, ECOG performance status <1 or ≥1 (HR 1.13, 95% CI 1.0-1.27, p = 0.04) and the presence versus absence of peritoneal metastases (HR 1.57, 95% CI 1.63-2.39, p = 0.03) were independent poor prognostic factors.Conclusions: These "real-life" efficacy data on ramucirumab treatment are in line with previous randomized trials. Ramucirumab is well tolerated in daily clinical practice. [ABSTRACT FROM AUTHOR]

Background: Previous findings suggested that bevacizumab might be able to improve response rate (RR) in colorectal cancer patients with high lactic dehydrogenase (LDH) basal levels.Methods: We conducted a phase II trial to prospectively ascertain whether bevacizumab in combination with FOLFIRI could have an improved clinical activity in patients with high LDH serum levels. Primary end point of the study was RR; secondary end points were median overall survival and median progression-free survival (mPFS).Results: A total of 81 patients were enrolled. No difference in terms of ORR (39% vs 31% for low vs high LDH level stratum, P=0.78) and mPFS (14.16 vs 10.29 months, HR: 1.07, 95% CI: 0.51-2.24, P=0.83) between the strata was observed, whereas overall survival (OS) was significantly longer for patients with low LDH (24.85 vs 15.14 months, HR: 4.08, 95% CI: 1.14-14.61, P=0.0004). In a not-pre-planned exploratory analysis using different cut-off ranges for LDH, we observed RR up to 70%, with no improvement in progression-free survival or OS.Conclusions: The CENTRAL trial failed to demonstrate that high LDH levels were related to a significantly improved RR in patients receiving first-line FOLFIRI and bevacizumab. The LDH serum levels should then no further be investigated as a predictive factor in this setting. [ABSTRACT FROM AUTHOR]

It is widely accepted that mature sperm contains RNA. The first hypothesis was that sperm RNAs have no functions of their own but are simply residues of spermatogenesis reflecting the events that occurred during their formation in the testes. More recently new discoveries have essentially expanded these views, showing that sperm mRNAs constitute a population of stable full-length transcripts, many of which are selectively retained during spermatogenesis and delivered to oocytes contributing to early embryo development. It is well known that semen quality can be influenced by occasional physical stress, infection, and variation in temperature and the definition of new markers for evaluation of semen could offer knowledge about the fertility potential of a semen sample. The aim of the present study was to evaluate the presence and the relative quantity of transcripts and protein of heat shock protein 70 (HSP70), 90 (HSP90) and clusterin (CLU) in Percoll-selected spermatozoa collected from seven adult boars of proven fertility routinely employed for artificial insemination. Our results showed the presence of HSP70, HSP90 and CLU transcripts with different level of expression: high for HSPs and low for CLU transcripts. The transcript level of both HSPs are similar among selected spermatozoa derived from high quality sperm with the exception of one boar that showed a reduced content of HSP70 and HSP90 mRNA together with a lower semen quality. At protein level, both HSPs were detected with similar amount among all seven boars whilst no band was evidenced for CLU protein. [ABSTRACT FROM AUTHOR]

Background: The data from randomised trials suggested that primary tumour sidedness could represent a prognostic and predictive factor in colorectal cancer (CRC) patients, particularly during treatment with anti-epidermal growth factor receptor (EGFR) therapy. However, an in-deep molecular selection might overcome the predictive role of primary tumour location in this setting.Methods: We conducted a retrospective analysis in which tumour samples from RAS/BRAF wild-type (WT) metastatic CRC patients treated with second-third-line irinotecan/cetuximab were analysed for EGFR gene copy number (GCN) and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Median follow-up duration was 14.3 months.Results: Eighty-eight patients were included in the study, 27.3% had right-sided CRC, 72.7% had left-sided CRC; 36.4% had EGFR GCN<2.12 tumour, 63.6% had EGFR GCN⩾2.12 tumour; 50% had EGFR promoter-methylated tumour. Right-sided colorectal cancer (RSCRC) were associated with reduced overall response rate (ORR) (4.2% for RSCRC vs 35.9% for left sided colorectal cancer (LSCRC), P=0.0030), shorter progression-free survival (PFS) (3.0 vs 6.75 months, P<0.0001) and shorter overall survival (OS) (8 vs 13.6 months, P<0.0001). EGFR GCN<2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN<2.12 vs 39.3% for EGFR GCN⩾2.12 tumours, P=0.0009), shorter PFS (3.5 vs 6.5 months, P=0.0006) and shorter OS (8.5 vs 14.0 months, P<0.0001). Epidermal growth factor receptor-methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, P=0.0001), shorter PFS (3 vs 7.67 months, P<0.0001) and shorter OS (8 vs 17 months, P<0.0001). At multivariate analysis, EGFR GCN and EGFR promoter methylation maintained their independent role for ORR (respectively P=0.0082 and 0.0025), PFS (respectively P=0.0048 and<0.0001) and OS (respectively P=0.0001 and<0.0001).Conclusions: In our study, an accurate molecular selection based on an all RAS and BRAF analysis along with EGFR GCN and EGFR promoter methylation status seems to be more relevant than primary tumour sidedness in the prediction of clinical outcome during cetuximab/irinotecan therapy. However, these data need to be validated with future prospective and translational studies. [ABSTRACT FROM AUTHOR]

Purpose: Non-small cell lung cancer (NSCLC) is a condition with significant clinical burden for patients and relevant economic impact. Limited evidence exists on the management costs of NSCLC patients, especially in the late phases of the disease. The main objective of this analysis was to evaluate the economic impact of clinical management of NSCLC patients in the Italian population. Methods: This evaluation was an economic analysis of the observational and multicentre study LIFE, which described the therapeutic approach in routine clinical practice for NSCLC patients, progressing after first-line treatment. This study evaluated resource consumption in different Italian hospitals, including specialist visits, hospitalizations, accesses to first aid, pharmacological treatment, laboratory tests and palliative care. The National Healthcare Service perspective was adopted. Results: In this study, N = 191 patients enrolled in the LIFE study were included. Patients were aged 64.2 years and were predominantly males (66%). In the different line of treatments, monthly costs of patients ranged between €1471 (first line) and €1788 (third line). The overall healthcare cost over the average period of observation (16.4 months) was €25,859 per patient. Overall, oncology therapy was the cost driver, although the composition of medical costs changed across the different lines of treatment, with costs for concomitant medication and palliative care being predominant in late phase of the disease. Conclusions: The economic burden of NSCLC is extremely high during the overall period of treatment, and a significant level of care is required in each stage of the disease. [ABSTRACT FROM AUTHOR]

Objective: The use of pulse pressure variation (PPV) and systolic pressure variation (SPV) is possible during controlled ventilation (MV). Even in acute respiratory failure, controlled MV tends to be replaced by assisted ventilatory support. We tested if PPV and SPV during flow triggered synchronized intermittent mechanical ventilation (SIMV) could be as accurate as in controlled MV.Methods: Prospective case-controlled study. Thirty patients who met criteria of weaning from controlled MV. Twenty minutes pressure support ventilation with 3 min(-1) flow triggered SIMV breathes (10 ml kg(-1)) T1, then three consecutive breaths in controlled MV (respiratory rate 12 min(-1),10 ml kg(-1)) T2. PPV and SPV were measured in T1 and T2. Correlation and Bland-Altman analysis were used to compare respective values of PPV and SPV in the two modes of ventilation.Results: Significant correlations were found between dynamic indices in SIMV during pressure support ventilation and those in controlled MV mode. The mean differences between two measurements were: PPV 0.6+/-2.8% (limit of agreement: -5.0 and 6.2), SPV 0.5+/-2.3 mmHg (limit of agreement: -4.0 and 5.1).Conclusions: PPV and SPV measured during SIMV fitted with the findings in controlled MV. Dynamic indexes could be accurately monitored in patients breathing with assisted respiratory assistance adding an imposed large enough SIMV breath. [ABSTRACT FROM AUTHOR]

Background: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer.Methods: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA.Results: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively).Conclusion: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation. [ABSTRACT FROM AUTHOR]

Isolation-by-distance is recognized as a useful model for describing the spatial distribution of gene frequencies depending on dispersal characteristics of the species under study. However, some species may have populations that occupy the same geographic distribution during the breeding season yet reproduce at different time periods resulting in isolation-by-time (IBT). IBT may complicate investigations of spatial population structure if samples are obtained from multiple discrete time periods or may remain undiscovered if surveys are conducted with limited temporal scope. IBT has been observed in several studies of anadromous fishes (primarily salmon) as well as a few examples in taxa such as frogs, plants, birds and insects, but has not been rigorously tested in freshwater fishes. In this study, we assessed spatial and temporal genetic variation and tested for IBT in Dourado ( Salminus brasiliensis), a large and commercially-important potamodromous fish species found in multiple river basins of South America. Using 11 polymorphic microsatellite loci, we estimated genetic differentiation of 317 adult Dourado collected monthly during the breeding season at three locations along the Uruguay River in southern Brazil. Analyses identified three populations that were clustered in time (i.e. early, middle and late), suggesting an IBT pattern of population structure with no significant spatial structure. Our results contribute to the mounting evidence across a wide range of taxa that suggests IBT may be more common that currently considered, even for species with very high dispersal capabilities such as potamodromous fishes. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the effects of a low-intensity electric current on tissue reorganization during experimental orthodontic tooth movement. Materials and methods: Thirty-two animals were divided into two groups evaluated on days 3 and 7: OTM-orthodontic tooth movement and OTM + MC-orthodontic tooth movement and microcurrent application (10 μA/5 min). The samples were processed for histological, morphometric, and Western blotting analysis. Results: Analysis of the periodontal ligament (PL) showed a significantly smaller number of granulocytes in the OTM + MC group on day 7.The number of fibroblasts was significantly higher in the OTM + MC group on days 3 and 7. The area of birefringent collagen fibers was more organized in the OTM + MC group on days 3 and 7. The number of blood vessels was significantly higher in the OTM + MC group on day 7. Microcurrent application significantly increased the number of osteoclasts in the compression region of the PL. In the OTM + MC group on day 7 of tooth movement, the expression of TGF-β1 and VEGF was significantly reduced whereas the expression of bFGF was increased in PL. Conclusions: Electrical stimulation enhances tissue responses, reducing the number of granulocytes and increasing the number of fibroblasts, blood vessels, and osteoclasts and modulates the expression of TGF-β1, VEFG, and bFGF. Clinical relevance: This technique is used in many areas of medicine, but poorly explored in dentistry and orthodontics. This treatment is cheap and non-invasive and can be applied by own orthodontist, and it can improve the treatment with a faster and safe tooth movement, without pain. [ABSTRACT FROM AUTHOR]

The seismic crisis that hit Calabria (South Italy) since the beginning of 1783, lasted 3 years with strong earthquakes concentrated in the first 2 months, causing many fatalities and great destruction, as reported by several detailed historical reports. Following an earthquake that occurred on February 6, 1783, a mass with volume of about 6 Mm detached from the flank of Mount Pacì and collapsed into the sea. In 1 min, huge waves attacked the nearby village of Scilla and killed most of the people that had gathered in the wide shore named Marina Grande to escape from seismic danger. More than 1500 people died due to the tsunami, many buildings were destroyed. In the paper, such catastrophic event is studied by means of numerical models. First we reconstruct the initial sliding mass and compute its motion through a Lagrangian model; then, we simulate the tsunami generation, propagation and flooding on the coast of Scilla by means of a nonlinear shallow-water equations model. The results of the simulation are compared against the detailed description of the tsunami effects available from several historical accounts and are found to be in a very satisfactory agreement with the 6-8 m inundation height reported in the Marina Grande beach. [ABSTRACT FROM AUTHOR]

Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma.Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml(-l) intradermally)+GEM (1000 mg m(-2) intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected.Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44-1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33-0.87, P=0.01).Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study. [ABSTRACT FROM AUTHOR]

Background: Since 2013, informative trials exploring the optimal use of available biologic agents in the first-line setting of metastatic colorectal cancer (mCRC) have been presented. These trials have opened a stimulating debate on the biological effect that first-line therapies may have on subsequent lines of treatment even long after the first-line progression.Materials and Methods: We reviewed available preclinical and clinical data on the effect of different sequences of the biological drugs approved for use in mCRC patients. The importance of molecular selection of patients based on RAS mutational status and toxicity and quality-of-life issues were also analyzed.Results: Convincing evidence exists on the optimal therapeutic effect obtained by using anti-EGFR agents in first-line treatment before anti-VEGF agents. On the contrary, up-front anti-VEGF agents' use seems to determine biological changes that increase the risk of acquired resistance to subsequent EGFR inhibitors. This hypothesis is confirmed by the scarce evidence of EGFR inhibitor activity in second-line treatment. Such a therapeutic optimum is subject to a fine molecular selection based on RAS mutational status.Conclusion: There is accumulating evidence suggesting that, after precise and well-established molecular selection, anti-EGFR agents deliver their maximum efficacy in mCRC patients when given early in the treatment strategy. Their toxicity profile seems manageable under the supervision of experienced physicians. Large randomized trials prospectively confirming the impact of different sequencing strategies are eagerly awaited. [ABSTRACT FROM AUTHOR]

Background: Several randomized clinical trials (RCTs) have demonstrated the efficacy of trastuzumab-based adjuvant therapy in HER2-positive breast cancer (BC). However, RCT patients may not invariably be representative of patients routinely seen in clinical practice (CP). To address this issue, we compared the clinical and tumor features of RCT and CP patients with HER2-positive BC. Patients and methods: From January to December 2012, 650 consecutive patients with HER2-positive early BC, treated in 36 different types of Italian healthcare facilities, were enrolled in this study. Age, treatment, tumor size (T), nodes (N), grade (G), estrogen receptor (ER) and progesterone receptor (PgR) status were prospectively collected in these CP patients. The same data were extracted from the main adjuvant trastuzumab RCTs and pooled using the random-effects model of DerSimonian and Laird. RCT and CP patients were compared by using the Cochran Q statistics. Results: Versus RCT patients, CP patients were more likely to be older than 50 years (65 vs. 49 %; p < 0.0001) and to have HR (ER and/or PgR)-positive (72 vs. 54 %; p < 0.0001) BC and less likely to have tumor >2 cm ( T ≥ 2 cm 39 vs. 59 %; p < 0.0001), positive N (47 vs. 89 %; p < 0.0001) and a high G (61 vs. 67 %; p = 0.0241). CP patients more frequently received adjuvant endocrine therapy (70 vs. 57 %; p < 0.0003) and less frequently adjuvant chemotherapy (97 vs. 99.7 %; p < 0.0001). Conclusions: Most tumor and clinical features differed significantly between CP and RCT patients. These data raise concerns about the applicability of RCT results to CP patients. [ABSTRACT FROM AUTHOR]

Many relevant aspects of the breeding ecology of South American migratory fishes remain obscure. We conducted kinship analyses and parental reconstruction based on microsatellite genotypes of 41 Salminus brasiliensis larvae sampled from a single natural spawning event. Polygynandry involving 25 (12:13) potential parents was suggested, supporting ecological observations of aggregation during spawning. Some parents contributed up to five half-sibling larvae genotypes, implying a skewed contribution of genes to the progeny. This study contributed to preliminary insights into the S. brasiliensis genetic mating system. [ABSTRACT FROM AUTHOR]