Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer

Lung cancer represents the leading cause of cancer-related deaths worldwide. Despite great advances in its management with the recent emergence of molecular targeted therapies for non-small-cell lung cancer (NSCLC), relapse of the metastatic disease always occurs within approximately one year. Epidermal growth factor receptor (EGFR) mutant tumours are the prime example of oncogene addiction and clonal evolution in oncology, regarding the emergence of resistance to first- and second-generation EGFR inhibitors. Multiple studies have revealed that the EGFR-T790M gatekeeper mutation is the main cause of tumour escape. Recently, irreversible pyrimidine-based EGFR inhibitors especially designed for this particular setting have shown robust clinical activity. However, similar to first- and second-generation inhibitors, the development of a diversified set of resistance mechanisms in response to these new compounds is an emerging issue. To date, clinical management of this growing number of patients has not been clearly established, even if anecdotal responses to subsequent molecularly guided therapies have been observed. By exhaustively reviewing and classifying all the preclinical and clinical data published on resistance to third-generation EGFR inhibitors in NSCLC, this work reveals the heterogeneity of the mechanisms that a tumour can develop to evade therapeutic pressure. Strategies currently being tested in clinical trials are discussed in light of these findings.
Dysbindin promotes progression of pancreatic ductal adenocarcinoma via direct activation of PI3K

Pancreatic ductal adenocarcinoma (PDAC) represents a biggest challenge in clinic oncology due to its invasiveness and lack of targeted therapeutics. Our recent study showed that schizophrenia susceptibility factor dysbindin exhibited significant higher level in serum of PDAC patients. However, the functional relevance of dysbindin in PDAC is still unclear. Here, we show that dysbindin promotes tumor growth both in vitro and in vivo by accelerating the G1/S phase transition in cell cycle via PI3K/AKT signaling pathway. Mechanistically, dysbindin interacts with PI3K and stimulates the kinase activity of PI3K. Moreover, overexpression of dysbindin in PDAC is correlated with clinicopathological characteristics significantly, such as histological differentiation (P = 0.011) and tumor size (P = 0.007). Kaplan-Meier survival curves show that patients with high dysbindin expression exhibit poorer overall survival, compared to those with low dysbindin expression (P < 0.001). Multivariate analysis reveals that dysbindin is an independent prognostic factor for pancreatic ductal adenocarcinoma (P = 0.001). Thus, our findings reveal that dysbindin is a novel PI3K activator and promotes PDAC progression via stimulation of PI3K/AKT. Dysbindin therefore represents a potential target for prognosis and therapy of PDAC.
Efficacy and spatial distribution of ultrasound-mediated clot lysis in the absence of thrombolytics

Summary Ultrasound and microbubble (MB) contrast agents accelerate clot lysis, yet clinical trials have been performed without defining optimal acoustic conditions. Our aim was to assess the effect of acoustic pressure and frequency on the extent and spatial location of clot lysis. Clots from porcine blood were created with a 2-mm central lumen for infusion of lipid-shelled perfluorocarbon MBs (1×107 ml-1) or saline. Therapeutic ultrasound at 0.04, 0.25, 1.05, or 2.00 MHz was delivered at a wide range of peak rarefactional acoustic pressure amplitudes (PRAPAs). Ultrasound was administered over 20 minutes grouped on-off cycles to allow replenishment of MBs. The region of lysis was quantified using contrast-enhanced ultrasound imaging. In the absence of MBs, sonothrombolysis did not occur at any frequency. Sonothrombolysis was also absent in the presence of MBs despite their destruction at 0.04 and 2.00 MHz. It occurred at 0.25 and 1.05 MHz in the presence of MBs for PRAPAs > 1.2 MPa and increased with PRAPA. At 0.25 MHz the clot lysis was located in the far wall. At 1.05 MHz, however, there was a transition from far to near wall as PRAPA was increased. The area of clot lysis measured by ultrasound imaging correlated with that by micro-CT and quantification of debris in the effluent. In conclusion, sonothrombolysis with MBs was most efficient at 0.25 MHz. The spatial location of sonothrombolysis varies with pressure and frequency indicating that the geometric relation between therapeutic probe and vascular thrombosis is an important variable for successful lysis clinically. Supported by grant (NIH R01-HL-095868).
Intensive aerobic cycling training with lower limb weights in Chinese patients with chronic stroke: discordance between improved cardiovascular fitness and walking ability

Purpose: To evaluate the effect of aerobic cycling training with lower limb weights on cardiovascular fitness (peak VO2) and walking ability in chronic stroke survivors, and to investigate the relationship between changes in these parameters. Methods: 133 Chinese patients with chronic hemiparetic stroke (mean age 58 years) were randomized to either 8-week (5×/week) aerobic cycling training with lower limb weights group (n = 68) or a low-intensity overground walking group (n = 65). Peak VO2, 6-minute walk distance (6MWD), knee muscle strength, balance and spasticity were measured before and after intervention. Results: Cycling training increased peak VO2 (24% vs. 3%, p < 0.001), 6MWD (2.7% vs. 0.5%, p < 0.001), paretic (11% vs. 1.6%, p < 0.001) and nonparetic knee strength (16% vs. 1.0%, p < 0.001). In the cycling group, percent changes in peak VO2 were positively associated with those in paretic (r = 0.491, p < 0.001) and nonparetic knee strength (r = 0.432, p < 0.001). Increased 6MWD correlated significantly with improved balance, spasticity and paretic knee strength by the stepwise regression analysis (r2 = 0.342, p = 0.004), but not fitness gains. Conclusions: The enhanced cardiovascular fitness after aerobic cycling training in Chinese patients with chronic stroke is not associated with the increased walking ability. Unparallel improvements in these parameters related different determinants may have implications for intervention strategy. Implications for Rehabiliation Patients with chronic stroke have residual physical impairments secondary to low activity levels and are often severely deconditioned. Exercise therapy is important to improve recovery in mobility and optimize cardiovascular health after stroke. The randomized control study shows that the intensive aerobic cycling training with lower limb weights improves both cardiovascular fitness and walking ability in Chinese patients with chronic stroke. However, these improvements after intervention were not parallel, indicating the determinants of improvements in these two parameters are different and may have implications for therapy prescription.
The effect of short and long term aerobic training years on systemic O2 utilization, and muscle and prefrontal cortex tissue oxygen extraction in young women.

This study aimed to determine if systemic O2 utilization (V[Combining Dot Above]O2) and tissue oxygen extraction (deoxyhemoglobin [HHb]) in the vastus lateralis (VL), gastrocnemius (GAST) and pre-frontal cortex (PFC) were different during exercise between short-term trained (STT 6 - 24 months) and long-term trained (LTT > 5 yr) young women while controlling for current training load. Thirteen STT and 13 LTT participants completed ramp incremental (RI) and square-wave constant load (SWCL) tests on a cycle ergometer. In LTT compared to STT: (i) V[Combining Dot Above]O2 was higher during the RI (p = 0.024) and SWCL (p = 0.001) tests; (ii) HHb in the VL (p = 0.044) and GAST (p = 0.027) was higher in the RI test; and (iii) there were significant group x intensity interactions for V[Combining Dot Above]O2 in the SWCL test. The additional years of aerobic training in LTT compared to STT (LTT 7.1 ± 1.9 vs STT 1.5 ± 0.4 yr) resulted in higher V[Combining Dot Above]O2, and HHb in the VL and GAST. These results indicate that in young women, independent of current training load, systemic V[Combining Dot Above]O2 and peripheral muscle O2 extraction during exercise continues to increase beyond 24 months of aerobic training.
The dental resin monomers HEMA and TEGDMA have inhibitory effects on osteoclast differentiation with low cytotoxicity

The dental resin monomers 2‐hydroxyethyl methacrylate (HEMA) and triethylene glycol dimethacrylate (TEGDMA) are released from the resin matrix due to unpolymerized monomers; once released, they influence various biological functions and the viability of cells in the oral environment. Although HEMA and TEGDMA have various effects on cells, including inflammation, inhibition of cell proliferation or differentiation, and apoptosis, the effects of these monomers on osteoclasts remain unknown. In this study, we investigated the effects of HEMA and TEGDMA on osteoclast differentiation of bone marrow‐derived macrophages or murine monocytic cell line RAW‐D. Both HEMA and TEGDMA inhibited osteoclast formation and their bone‐resorbing activity at non‐cytotoxic concentrations. Moreover, HEMA and TEGDMA decreased the expression of nuclear factor of activated T cells cytoplasmic‐1 (NFATc1), a master regulator of osteoclast differentiation, and of osteoclast markers that are transcriptionally regulated by NFATc1, including Src and cathepsin K. Regarding their effects on signaling pathways involved in osteoclast differentiation, HEMA impaired the phosphorylation of extracellular signal‐regulated kinase and Jun N‐terminal kinase, whereas TEGDMA attenuated the phosphorylation of Akt and Jun N‐terminal kinase. Thus, HEMA and TEGDMA inhibit osteoclast differentiation through different signaling pathways. This is the first report on the effects of the monomers HEMA and TEGDMA on osteoclasts. Copyright © 2017 John Wiley & Sons, Ltd.
The Evolution of Extracorporeal Life Support as a Bridge to Lung Transplantation

The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation was reported for the first time more than three decades ago; nevertheless, its use in lung transplantation was largely abandoned because of poor patient survival and frequent complications. The outcomes of patients bridged to lung transplantation using ECMO have substantially improved in the last 5 years. Recent advances in extracorporeal life support technology now allow patients with end-stage lung disease to be successfully supported for prolonged periods of time, preventing the use of mechanical ventilation and facilitating physical rehabilitation and ambulation while the patients awaits lung transplantation. This review briefly describes the evolution of ECMO use in lung transplantation and summarizes the available technology and current approaches to provide ECMO support.
New Approaches in Tumor Necrosis Factor Antagonism for the Treatment of Psoriatic Arthritis: Certolizumab Pegol

The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-α (TNF-α) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-α activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.
Positive Attitude Toward Math Supports Early Academic Success: Behavioral Evidence and Neurocognitive Mechanisms

Positive attitude is thought to impact academic achievement and learning in children, but little is known about its underlying neurocognitive mechanisms. Using a large behavioral sample of 240 children, we found that positive attitude toward math uniquely predicted math achievement, even after we accounted for multiple other cognitive-affective factors. We then investigated the neural mechanisms underlying the link between positive attitude and academic achievement in two independent cohorts of children (discovery cohort: n = 47; replication cohort: n = 28) and tested competing hypotheses regarding the differential roles of affective-motivational and learning-memory systems. In both cohorts, we found that positive attitude was associated with increased engagement of the hippocampal learning-memory system. Structural equation modeling further revealed that, in both cohorts, increased hippocampal activity and more frequent use of efficient memory-based strategies mediated the relation between positive attitude and higher math achievement. Our study is the first to elucidate the neurocognitive mechanisms by which positive attitude influences learning and academic achievement.
Volatile anaesthetics enhance the metastasis related cellular signalling including CXCR2 of ovarian cancer cells

The majority of ovarian cancer patients relapse after surgical resection. Evidence is accumulating regarding the role of surgery in disseminating cancer cells; in particular anaesthesia may have an impact on cancer re-occurrence. Here, we have investigated the metastatic potential of volatile anaesthetics isoflurane, sevoflurane and desflurane on ovarian cancer cells. Human ovarian carcinoma cells (SKOV3) were exposed to isoflurane (2%), sevoflurane (3.6%) or desflurane (10.3%) for 2 hours. Metastatic related gene expression profiles were measured using the Tumour Metastasis PCR Array and qRT-PCR. Subsequently vascular endothelial growth factor A (VEGF-A), matrix metalloproteinase 11 (MMP11), transforming growth factor beta-1 (TGF-β1) and chemokine (C-X-C motif) receptor 2 (CXCR2) proteins expression were determined using immunofluorescent staining. The migratory capacities of SK-OV3 cells were assessed with a scratch assay and the potential role of CXCR2 in mediating the effects of volatile anaesthetics on cancer cell biology were further investigated with CXCR2 knockdown by siRNA. All three volatile anaesthetics altered expression of 70 out of 81 metastasic related genes with significant increases in VEGF-A, MMP-11, CXCR2 and TGF-β genes and protein expression with a magnitude order of desflurane (greatest), sevoflurane and isoflurane. Scratch analysis revealed that exposure to these anesthetics increased migration, which was abolished by CXCR2 knockdown. Volatile anaesthetics at clinically relevant concentrations have strong effects on cancer cell biology which in turn could enhance ovarian cancer metastatic potential. This work raises the urgency for further in vivo studies and clinical trials before any conclusions can be made in term of the alteration of clinical practice.
Acute-on-Chronic Liver Failure: A Portuguese Single-Center Reference Review

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by an acute deterioration of a patient with cirrhosis, frequently associated with multi-organ failure and a high short-term mortality rate. We present a retrospective study that aims to characterize the presentation, evolution, and outcome of patients diagnosed with ACLF at our center over the last 3 years, with a comparative analysis between the group of patients that had ACLF precipitated by infectious insults of bacterial origin and the group of those with ACLF triggered by a nonbacterial infectious insult; the incidence of acute kidney injury and its impact on the prognosis of ACLF was also analyzed. Twenty-nine patients were enrolled, the majority of them being male (89.6%), and the mean age was 53 years. Fourteen patients (48.3%) developed ACLF due to a bacterial infectious event, and 9 of them died (64.2%, overall mortality rate 31%); however, no statistical significance was found (p < 0.7). Of the remaining 15 patients (51.7%) with noninfectious triggers, 11 died (73.3%, overall mortality rate 37.9%); again there was no statistical significance (p < 0.7). Twenty-four patients (83%) developed acute kidney injury (overall mortality rate 65.5%; p < 0.022) at the 28-day and 90-day follow-up. Twelve patients had acute kidney injury requiring renal replacement therapy (41.37%; overall mortality rate 37.9%; p < 0.043). Hepatic transplant was performed in 3 patients, with a 100% survival at the 28-day and 90-day follow-up (p < 0.023). Higher grades of ACLF were associated with increased mortality (p < 0.02; overall mortality 69%). Conclusions: ACLF is a heterogeneous syndrome with a variety of precipitant factors and different grades of extrahepatic involvement. Most cases will have some degree of renal dysfunction, with an increased risk of mortality. Hepatic transplant is an efficient form of therapy for this syndrome.
A new method for liposome preparation using a membrane contactor

In this article, we present a novel, scalable liposomal preparation technique suitable for the entrapment of pharmaceutical agents into liposomes. This new method is based on the ethanol-injection technique and uses a membrane contactor module, specifically designed for colloidal system preparation. In order to investigate the process, the influence of key parameters on liposome characteristics was studied. It has been established that vesicle-size distribution decreased with a decrease of the organic-phase pressure, an increase of the aqueous-phase flow rate, and a decrease of the phospholipid concentration. Additionally, special attention was paid on reproducibility and long-term stability of lipid vesicles, confirming the robustness of the membrane contactor-based technique. On the other hand, drug-loaded liposomes were prepared and filled with two hydrophobic drug models. High entrapment-efficiency values were successfully achieved for indomethacin (63%) and beclomethasone dipropionate (98%). Transmission electron microscopy images revealed nanometric quasispherical-shaped multilamellar vesicles (size ranging from 50 to 160 nm).
Zinc sparks induce physiochemical changes in the egg zona pellucida that prevent polyspermy.

During fertilization or chemically-induced egg activation, the mouse egg releases billions of zinc atoms in brief bursts known as 'zinc sparks. ' The zona pellucida (ZP), a glycoprotein matrix surrounding the egg, is the first structure zinc ions encounter as they diffuse away from the plasma membrane. Following fertilization, the ZP undergoes changes described as 'hardening', which prevent multiple sperm from fertilizing the egg and thereby establish a block to polyspermy. A major event in zona hardening is cleavage of ZP2 proteins by ovastacin; however, the overall physiochemical changes contributing to zona hardening are not well understood. Using X-ray fluorescence microscopy, transmission and scanning electron microscopy, and biological function assays, we tested the hypothesis that zinc release contributes to ZP hardening. We found that the zinc content in the ZP increases by 300% following activation and that zinc exposure modulates the architecture of the ZP matrix. Importantly, zinc-induced structural changes of the ZP have a direct biological consequence; namely, they reduce the ability of sperm to bind to the ZP. These results provide a paradigm-shifting model in which fertilization-induced zinc sparks contribute to the polyspermy block by altering conformations of the ZP matrix. This adds a previously unrecognized factor, namely zinc, to the process of ZP hardening.
Peripherally restricted viral challenge elevates extracellular glutamate and enhances synaptic transmission in the hippocampus

Peripheral infections increase the propensity and severity of seizures in susceptible populations. We have previously shown that intraperitoneal injection of a viral mimic, polyinosinic‐polycytidylic acid (PIC), elicits hypersusceptibility of mice to kainic acid (KA)‐induced seizures. This study was undertaken to determine whether this seizure hypersusceptibility entails alterations in glutamate signaling. Female C57BL/6 mice were intraperitoneally injected with PIC, and after 24 h, glutamate homeostasis in the hippocampus was monitored using the enzyme‐based microelectrode arrays. PIC challenge robustly increased the level of resting extracellular glutamate. While pre‐synaptic potassium‐evoked glutamate release was not affected, glutamate uptake was profoundly impaired and non‐vesicular glutamate release was augmented, indicating functional alterations of astrocytes. Electrophysiological examination of hippocampal slices from PIC‐challenged mice revealed a several fold increase in the basal synaptic transmission as compared to control slices. PIC challenge also increased the probability of pre‐synaptic glutamate release as seen from a reduction of paired‐pulse facilitation and synaptic plasticity as seen from an enhancement of long‐term potentiation. Altogether, our results implicate a dysregulation of astrocytic glutamate metabolism and an alteration of excitatory synaptic transmission as the underlying mechanism for the development of hippocampal hyperexcitability, and consequently seizure hypersusceptibility following peripheral PIC challenge.
The effect of direction specific thoracic spine manipulation on the cervical spine: a randomized controlled trial

Abstract Objectives: To determine the difference on neck outcomes with directional manipulation to the thoracic spine. There is evidence that thoracic spine manipulation is effective in treating patients with neck pain. However, there is no research that determines if the assessment of directional hypomobility and the selection of thrust direction offer improved outcomes. Methods: A total of 69 patients with cervical spine pain were randomly assigned to receive either a manipulation that was consistent with their thoracic spine motion loss (matched) or opposite their motion loss (unmatched). The patient was given care consistent with the orthopedic section guidelines for neck pain and the physical therapist’s clinical reasoning. Baseline outcome measures (NPRS, NDI, GROC) were taken and reassessed two days and two weeks after treatment. Results: Both groups had positive results when pain, neck disability index, and global rating of change were assessed. There was no difference between the matched and unmatched groups. Discussion: Directional manipulation of hypomobile thoracic spine segments may not be required to improved outcomes in patients with neck pain. Future studies should assess a variety of factors when determining the best available treatment, including manual therapy procedures, exercise, and patient selection. Level of Evidence: 1b.
Expanding the industrial design space through production innovation(s)

Over the decades, manufacturing firms have tried to Design for Manufacturability merely by exhorting industrial design engineers to create more producible-designs. This is most often achieved by considering the available manufacturing system capability for the product development, and it is common to run into troubles in many cases due to barriers to integrate product definition and manufacturing operations. In this paper, authors aim to explore how production innovations (as new manufacturing capabilities) can contribute to an increased industrial design space for product design engineers, enabling more design freedom while still obtaining producibility through removing and/or loosening constraints over product designs. The findings of a series of industrial case studies presented in this paper show promising outcomes on how production innovations can influence positively the expansion of the solution space of industrial design engineers. In addition, manufacturing engineers are driven to explore new materials, new manufacturing processes and new manufacturing (working) methods to support product innovation.