Up-regulation of METCAM/MUC18 promotes motility, invasion, and tumorigenesis of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Conflicting research has identified METCAM/MUC18, an integral membrane cell adhesion molecule (CAM) in the Ig-like gene super-family, as both a tumor promoter and a tumor suppressor in the development of breast cancer. To resolve this, we have re-investigated the role of this CAM in the progression of human breast cancer cells.</p> <p>Methods</p> <p>Three breast cancer cell lines were used for the tests: one luminal-like breast cancer cell line, MCF7, which did not express any METCAM/MUC18, and two basal-like breast cancer cell lines, MDA-MB-231 and MDA-MB-468, which expressed moderate levels of the protein.</p> <p>MCF7 cells were transfected with the human METCAM/MUC18 cDNA to obtain G418-resistant clones which expressed the protein and were used for testing effects of human METCAM/MUC18 expression on <it>in vitro </it>motility and invasiveness, and <it>in vitro </it>and <it>in vivo </it>tumorigenesis. Both MDA-MB-231 and MDA-MB-468 cells already expressed METCAM/MUC18. They were directly used for <it>in vitro </it>tests in the presence and absence of an anti-METCAM/MUC18 antibody.</p> <p>Results</p> <p>In MCF7 cells, enforced METCAM/MUC18 expression increased <it>in vitro </it>motility, invasiveness, anchorage-independent colony formation (<it>in vitro </it>tumorigenesis), and <it>in vivo </it>tumorigenesis. In both MDA-MB-231 and MDA-MB-468 cells, the anti-METCAM/MUC18 antibody inhibited both motility and invasiveness. Though both MDA-MB-231 and MDA-MB-468 cells established a disorganized growth in 3D basement membrane culture assay, the introduction of the anti-METCAM/MUC18 antibody completely destroyed their growth in the 3D culture.</p> <p>Conclusion</p> <p>These findings support the notion that human METCAM/MUC18 expression promotes the progression of human breast cancer cells by increasing their motility, invasiveness and tumorigenesis.</p

Delayed reperfusion deficits after experimental stroke account for increased pathophysiology.

Cerebral blood flow and oxygenation in the first few hours after reperfusion following ischemic stroke are critical for therapeutic interventions but are not well understood. We investigate changes in oxyhemoglobin (HbO(2)) concentration in the cortex during and after ischemic stroke, using multispectral optical imaging in anesthetized mice, a remote filament to induce either 30 minute middle cerebral artery occlusion (MCAo), sham surgery or anesthesia alone. Immunohistochemistry establishes cortical injury and correlates the severity of damage with the change of oxygen perfusion. All groups were imaged for 6 hours after MCAo or sham surgery. Oxygenation maps were calculated using a pathlength scaling algorithm. The MCAo group shows a significant drop in HbO(2) during occlusion and an initial increase after reperfusion. Over the subsequent 6 hours HbO(2) concentrations decline to levels below those observed during stroke. Platelets, activated microglia, interleukin-1α, evidence of BBB breakdown and neuronal stress increase within the stroked hemisphere and correlate with the severity of the delayed reperfusion deficit but not with the ΔHbO(2) during stroke. Despite initial restoration of HbO(2) after 30 min MCAo there is a delayed compromise that coincides with inflammation and could be a target for improved stroke outcome after thrombolysis

Step down tests are the tasks that most differentiate the kinematics of women with patellofemoral pain compared to asymptomatic controls.

BACKGROUND: Studies evaluating kinematics lead to different conclusions, not all changes appear in all assessed tasks and in all subgroups of patients with patellofemoral pain (PFP). The inconsistencies between studies could be reduced if we knew which task separates patients best from healthy controls. RESEARCH QUESTION: Identify which functional task, between gait, forward step down (FSD), lateral step down (LSD), stair ascent and descent and propulsion and landing phase of the single leg hop test (SLHT), differentiates the three-dimensional kinematics of women with patellofemoral pain from asymptomatic women. METHODS: This cross-sectional study evaluated thirty-five PFP and thirty-five asymptomatic women during the execution of the following tasks: gait, FSD, LSD, stair ascent and descent and the propulsion and landing phase of single leg hop test. Frontal, sagittal and transverse plane angles of the trunk, pelvis and hip, frontal and sagittal plane angles of the knee, ankle dorsiflexion, foot progression angle and hindfoot eversion were analyzed through the Movement Deviation Profile (MDP). To compare the groups, the multivariate analysis with Bonferroni post hoc test were used, with a significance level of p < 0.01. To identify which task presented the most difference between the groups, the Z-score of the mean MDP was calculated. RESULTS: For all tasks, the groups presented significant differences. According to the Z-score, the groups got farther apart considering the MDP for each task in the following order: LSD (7.97), FSD (7.62), landing phase of SLHT (3.43), gait (2.85), propulsion phase of SLHT (1.64), descending stairs (1.63) and ascending stairs (1.00). SIGNIFICANCE: We suggest that step down tests should be included in the assessment of PFP patients, since these tests most differentiate the kinematics of women with and without PFP. Identifying the tasks with the highest sensitivity to detect the kinematic differences is expected to improve clinical decision-making

Genome wide association mapping of grain arsenic, copper, molybdenum and zinc in rice (Oryza sativa L.) grown at four international field sites

Peer reviewedPublisher PD

Induction of fibroblast senescence generates a non-fibrogenic myofibroblast phenotype that differentially impacts on cancer prognosis

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two

Mobocertinib (TAK-788) in EGFR Exon 20 Insertion+ Metastatic NSCLC: Patient-Reported Outcomes from EXCLAIM Extension Cohort.

Mobocertinib, an oral, first-in-class epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for EGFR exon 20 insertions (ex20ins), achieved durable responses in adults with previously treated EGFR ex20ins+ metastatic non-small cell lung cancer (mNSCLC) in the EXCLAIM extension cohort of a phase 1/2 study (N = 96; NCT02716116). We assessed patient-reported outcomes (PROs) with mobocertinib 160 mg once daily (28-day cycles) in EXCLAIM (N = 90) with the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ-C30) v3.0, lung cancer module (QLQ-LC13), EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire, and selected PRO Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire. Median treatment duration was 6.8 (range, 0.0-18.8) months (median follow-up: 13.0 [0.7-18.8] months; data cutoff: 1 November 2020). Clinically meaningful improvements in lung cancer symptoms measured by EORTC QLQ-LC13 were observed for dyspnea (54.4% of patients), cough (46.7%), and chest pain (38.9%), evident at cycle 2 and throughout treatment (least-squares mean [LSM] changes from baseline: dyspnea, -3.2 [p = 0.019]; cough, -9.3 [p < 0.001]; chest pain, -8.2 [p < 0.001]). EORTC QLQ-C30 results indicated no statistically significant changes in global health status/quality of life (LSM change from baseline: -1.8 [p = 0.235]). On symptom scores, significant worsening from baseline was observed for diarrhea (LSM change from baseline: +34.1; p < 0.001) and appetite loss (+6.6; p = 0.004), while improvements were observed for dyspnea (LSM change from baseline: -5.1 [p = 0.002]), insomnia (-6.5 [p = 0.001]), and constipation (-5.7 [p < 0.001]). EQ-5D-5L health status was maintained. Common PRO-CTCAE symptoms were diarrhea, dry skin, rash, and decreased appetite (mostly low grade); in the first 24 weeks of treatment, 64.4% of patients had worsening diarrhea frequency and 67.8% had worsening dry skin severity. Overall, PROs with mobocertinib showed clinically meaningful improvement in lung cancer-related symptoms, with health-related quality of life maintained despite changes in some adverse event symptom scales

Vibrationally induced inversion of photoelectron forward-backward asymmetry in chiral molecule photoionization by circularly polarized light

Electron–nuclei coupling accompanying excitation and relaxation processes is a fascinating phenomenon in molecular dynamics. A striking and unexpected example of such coupling is presented here in the context of photoelectron circular dichroism measurements on randomly oriented, chiral methyloxirane molecules, unaffected by any continuum resonance. Here, we report that the forward-backward asymmetry in the electron angular distribution, with respect to the photon axis, which is associated with photoelectron circular dichroism can surprisingly reverse direction according to the ion vibrational mode excited. This vibrational dependence represents a clear breakdown of the usual Franck–Condon assumption, ascribed to the enhanced sensitivity of photoelectron circular dichroism (compared with other observables like cross-sections or the conventional anisotropy parameter-β) to the scattering phase off the chiral molecular potential, inducing a dependence on the nuclear geometry sampled in the photoionization process. Important consequences for the interpretation of such dichroism measurements within analytical contexts are discussed

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/non-neurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration