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Treatment of colorectal metastatic cancer is still challenging, despite recent improvements in chemotherapy. A genetic cancer profile, such as the KRAS (Kirsten rat sarcoma) gene status, plays a key role in individualized tailored therapy. Molecular targeted therapy added to neo-adjuvant chemotherapy can achieve a better pathological response and prolong survival. Pathological complete response of colorectal cancer stage IV is rare. A 47-year-old female patient presented with rectal adenocarcinoma and three liver metastases (cT3d/4, N2, Ml). After seven cycles of Bevacizumab and CAPOX in neoadjuvant setting, we noted more than 70.0% regression of metastases and complete regression of the primary tumor. We performed low anterior resection of rectum and synchronous subsegmental resection of S3, because the other two lesions were not detectable. Pathology revealed complete response of the primary and also secondary tumors. After 8 months, diagnostic tests did not show any sign of recurrence and the remaining liver lesions disappeared. Colorectal cancer is a heterogeneous disease and it is necessary to identify patients who are at-risk of recurrence and suitable for neoadjuvant therapy. Genetic biomarkers play an important role in metastatic colorectal cancer treatment. Because of the mutated KRAS gene, Bevacizumab was added to cytotoxic therapy achieving a complete pathological response of primary tumor and metastasis. This case is unique because all reported cases with similar results, described staged surgery and one of reverse staged surgery, but with similar results. This neoadjuvant therapy has extraordinary results for colorectal cancer stage IV and can help disease-free and long-term survival.

The aim of the present paper is to discuss some recent results concerning the behavior of low-dimensional materials under strain. This concerns the electrical conductivity calculations of 1D structures under strain, within the Hubbard model, as well as ab initio investigations of phonon, electron-phonon, and superconducting properties of doped graphene and MgB2 monolayer. Two different experimental approaches to strain engineering in graphene have been considered regarding local strain engineering on monolayer flakes of graphene using atomic force microscopy and dynamic plowing lithography technique as well as the effects of mechanical straining on liquid phase exfoliated graphene and change of sheet resistance of graphene films. [ABSTRACT FROM AUTHOR]

Pulmonary diseases are known to be largely inhomogeneous. To evaluate such inhomogeneities, we are testing an image-based method to measure gas flow in the lung regionally. Dynamic, spin-density-weighted hyperpolarized ^3He MR images performed during slow inhalation of this gas were analyzed to quantify regional inflation rate. This parameter was measured in regions of interest (ROIs) that were defined by a rectangular grid that covered the entire rat lung and grew dynamically with it during its inflation. We used regional inflation rate to quantify elastase-induced emphysema and to differentiate healthy ( n = 8) from elastase-treated ( n = 9) rat lungs as well as healthy from elastase-treated areas of one rat unilaterally treated with elastase in the left lung. Emphysema was also assessed by gold standard morphological and well-established hyperpolarized ^3He MRI diffusion measurements. Mean values of regional inflation rates were significantly different for healthy and elastase-treated animals and correlated well with the apparent diffusion coefficient of ^3He and morphological measurements. The image-based biomarker inflation rate may be useful for the assessment of regional lung ventilation. [ABSTRACT FROM PUBLISHER]

The choice of the anti-HER2 agent depends on country-specific availability, the specific, previously administered anti-HER2 therapy and the relapse-free interval, although there is not much published data on the use of lapatinib after progression on pertuzumab and/or T-DM1. The aim of this research is to determine efficacy of lapatinib in this setting. This research included 111 patients with metastatic HER2 positive breast cancer who received lapatinib with capecitabine at The Oncology Institute of Vojvodina. Lapatinib was given to 83 patients after trastuzumab without prior exposure to pertuzumab or T-DM1 while 28 patients received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1. In order to determine efficacy of lapatinib in both groups, we measured progression free survival (PFS) and overall survival (OS), as well as by subsets: hormonal status (ER-positive and/or PR-positive tumours versus ER-negative and PR-negative tumours), the number of positive axillary lymph nodes (four or more positive axillary lymph nodes versus less than four positive axillary lymph nodes), marker of proliferation (Ki-67 ≥ 30 versus Ki-67 < 30), disease free interval (metastatic recurrence ≤ 1 year after initial diagnosis versus metastatic recurrence > 1 year after initial diagnosis or de novo metastatic disease. Median PFS was 5.6 months (95% CI 4.6-6.6) in the group of patients who received lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM 1 and 7.4 months (95% CI 6.1-10.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.79; 95% CI 0.61-0.98; P = 0.09). The patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes, marker of proliferation Ki 67 ≥ 30 and metastatic recurrence ≤ 1 year after initial diagnosis, had a similar PFS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Median OS was 10.1 months (95% CI 8.6-NR) in the group that received lapatinib after exposure to trastuzumab, pertuzumab and/or T-DM1 and 16.3 months (95% CI 14.4-20.2) in the group of patients who received lapatinib after trastuzumab (HR, 0.76; 95% CI, 0.59-0.94; P = 0.04). Patients with negative prognostic factors such as hormone receptor negativity, more than four positive axillary lymph nodes and marker of proliferation Ki 67 ≥ 30, had no distinctly worse OS, regardless of receiving lapatinib after prior exposure to trastuzumab, pertuzumab and/or T-DM1 or without prior exposure. Lapatinib with capecitabine is an effective therapeutic option, especially in patients with negative prognostic factors, who have received prior chemotherapy, trastuzumab, pertuzumab, T-DM1 and remains an acceptable option for HER2 positive metastatic breast cancer until the novel drugs are approved in developing countries.

Type 2 Innate lymphoid cells (ILC2s) are implicated in helminth infections and asthma where they play a role in the production of Th2-type cytokines. ILC2s express the IL-33 receptor and are a major cell type thought to mediate the effects of this cytokine in vivo. To study the signalling pathways that mediate IL-33 induced cytokine production, a culture system was set up to obtain pure populations of ILC2s from mice. Inhibitors of the p38α/β and ERK1/2 MAPK pathways reduced the production of IL-5, IL-6, IL-9, IL-13 and GM-CSF by ILC2 in response to IL-33, with inhibition of p38 having the greatest effect. MK2 and 3 are kinases activated by p38α; MK2/3 inhibitors or knockout of MK2/3 in mice reduced the production of IL-6 and IL-13 (two cytokines implicated in asthma) but not IL-5, IL-9 or GM-CSF in response to IL-33. MK2/3 inhibition also suppressed IL-6 and IL-13 production by human ILC2s. MK2/3 were required for maximal S6 phosphorylation, suggesting an input from the p38α-MK2/3 pathway to mTOR1 activation in ILC2s. The mTORC1 inhibitor rapamycin also reduced IL-6 and IL-13 production, which would be consistent with a model in which MK2/3 regulate IL-6 and IL-13 via mTORC1 activation in ILC2s.

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis and chronic bronchitis (CB). Rehydration by hypertonic saline is efficacious but suffers from a short duration of action. We tested whether epithelial sodium channel (ENaC) inhibition would rehydrate normal and dehydrated airways to increase mucociliary clearance (MCC) over a significant time frame. For this, we used a tool compound (Compound A), which displays nanomolar ENaC affinity and retention in the airway surface liquid (ASL). Using normal human bronchial epithelial cultures (HBECs) grown at an air-liquid interface, we evaluated in vitro potency and efficacy using short-circuit current (I(sc)) and ASL height measurements where it inhibited I(sc) and increased ASL height by ∼ 50% (0.052 μM at 6 h), respectively. The in vivo efficacy was investigated in a modified guinea pig tracheal potential difference model, where we observed an effective dose (ED50) of 5 μg/kg (i.t.), and by MCC measures in rats and sheep, where we demonstrated max clearance rates at 100 μg/kg (i.t.) and 75 μg/kg (i.t.), respectively. Acute cigarette smoke-induced ASL height depletion in HBECs was used to mimic the situation in patients with CB, and pretreatment prevented both cigarette smoke-induced ASL dehydration and lessened the decrease in ciliary beat frequency. Furthermore, when added after cigarette smoke exposure, Compound A increased the rate of ASL rehydration. In conclusion, Compound A demonstrated significant effects and a link between increased airway hydration, ciliary function, and MCC. These data support the hypothesis that ENaC inhibition may be efficacious in the restoration of mucus hydration and transport in patients with CB., (Copyright © 2015 the American Physiological Society.)

We investigate the response of a dense monodisperse quasi-two-dimensional colloid suspension when a particle is dragged by a constant velocity optical trap. Consistent with microrheological studies of other geometries, the perturbation induces a leading density wave and trailing wake. We also use a hybrid version of Stokesian dynamics simulations to parse direct colloid-colloid and hydrodynamic interactions. We go on to analyze the underlying individual particle-particle collisions in the experimental images. The displacements of particles occur in chains reminiscent of stress propagation in sheared granular materials. From these data, we can reconstruct steady-state dipolar-like flow patterns that were predicted for dilute suspensions and previously observed in granular analogs to our system. The decay of this field differs, however, from point Stokeslet calculations, indicating that the nonzero size of the colloids is important. Moreover, there is a pronounced angular dependence that corresponds to the surrounding colloid structure, which develops in response to the perturbation. Put together, our results show that the response of the complex fluid is highly anisotropic owing to the fact that the effects of the perturbation propagate through the structured medium via chains of colloid-colloid collisions.

Pulmonary diseases are known to be largely inhomogeneous. To evaluate such inhomogeneities, we are testing an image-based method to measure gas flow in the lung regionally. Dynamic, spin-density-weighted hyperpolarized (3)He MR images performed during slow inhalation of this gas were analyzed to quantify regional inflation rate. This parameter was measured in regions of interest (ROIs) that were defined by a rectangular grid that covered the entire rat lung and grew dynamically with it during its inflation. We used regional inflation rate to quantify elastase-induced emphysema and to differentiate healthy (n = 8) from elastase-treated (n = 9) rat lungs as well as healthy from elastase-treated areas of one rat unilaterally treated with elastase in the left lung. Emphysema was also assessed by gold standard morphological and well-established hyperpolarized (3)He MRI diffusion measurements. Mean values of regional inflation rates were significantly different for healthy and elastase-treated animals and correlated well with the apparent diffusion coefficient of (3)He and morphological measurements. The image-based biomarker inflation rate may be useful for the assessment of regional lung ventilation.

In preclinical research, allergic asthma is investigated in rats sensitised with the antigen ovalbumin (OVA), followed by a challenge with aerosolised OVA to induce an inflammatory reaction of the lower airways. This causes diffuse, nonfocal ventilation defects that lead to heterogeneously distributed signal intensities in hyperpolarised (HP) (3)He MR images, which are difficult to assess directly by diagnostic grading or volumetry. Texture analysis can characterise these changes and does not require segmentation of the lung structures prior to the analysis. The aim of this work was to evaluate a texture analysis approach to quantify changes in lung ventilation in HP (3)He MRI of OVA-challenged rats. OVA-challenged animals were treated with two different compound doses to evaluate the sensitivity of the texture analysis. Four groups were investigated using HP (3)He MRI at 4.7 T: controls, vehicle-treated, and low- and high-dose budesonide-treated rats. In addition, broncho-alveolar lavage was performed and the eosinophil cell count was used as a biological reference marker. First-order texture, geometrical features and features based on second-order statistics using run-length and grey-level co-occurrence matrices were calculated. In addition, wavelet transforms were applied to compute first-order statistics on multiple scales. The texture analysis was able to show significant differences between the control and untreated vehicle groups as well as between the vehicle and treatment groups. This is in agreement with the findings of the eosinophil cell counts, which were used as a marker for the severity of inflammation. However, not all features used in the different texture analysis methods could differentiate between the treatment groups. In conclusion, texture analysis can be used to quantify changes in lung ventilation as measured with HP (3)He MRI after therapeutic intervention with budesonide., (Copyright © 2011 John Wiley & Sons, Ltd.)

Experimental stroke and excitotoxic brain lesion to the striatum increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN+ neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.

The process of large RNA folding is believed to proceed from many collapsed structures to a unique functional structure requiring precise organization of nucleotides. The diversity of possible structures and stabilities of large RNAs could result in non-exponential folding kinetics (e.g. stretched exponential) under conditions where the molecules have not achieved their native state. We describe a single-molecule fluorescence resonance energy transfer (FRET) study of the collapsed-state region of the free energy landscape of the catalytic domain of RNase P RNA from Bacillus stearothermophilus (C(thermo)). Ensemble measurements have shown that this 260 residue RNA folds cooperatively to its native state at >or=1 mM Mg(2+), but little is known about the conformational dynamics at lower ionic strength. Our measurements of equilibrium conformational fluctuations reveal simple exponential kinetics that reflect a small number of discrete states instead of the expected inhomogeneous dynamics. The distribution of discrete dwell times, collected from an "ensemble" of 300 single molecules at each of a series of Mg(2+) concentrations, fit well to a double exponential, which indicates that the RNA conformational changes can be described as a four-state system. This finding is somewhat unexpected under [Mg(2+)] conditions in which this RNA does not achieve its native state. Observation of discrete well-defined conformations in this large RNA that are stable on the seconds timescale at low [Mg(2+)] (<0.1 mM) suggests that even at low ionic strength, with a tremendous number of possible (weak) interactions, a few critical interactions may produce deep energy wells that allow for rapid averaging of motions within each well, and yield kinetics that are relatively simple.