218 research outputs found
In vivo confinement promotes collective migration of neural crest cells
Collective cell migration is fundamental throughout development and in many diseases. Spatial confinement using micropatterns has been shown to promote collective cell migration in vitro, but its effect in vivo remains unclear. Combining computational and experimental approaches, we show that the in vivo collective migration of neural crest cells (NCCs) depends on such confinement. We demonstrate that confinement may be imposed by the spatiotemporal distribution of a nonpermissive substrate provided by versican, an extracellular matrix molecule previously proposed to have contrasting roles: barrier or promoter of NCC migration. We resolve the controversy by demonstrating that versican works as an inhibitor of NCC migration and also acts as a guiding cue by forming exclusionary boundaries. Our model predicts an optimal number of cells in a given confinement width to allow for directional migration. This optimum coincides with the width of neural crest migratory streams analyzed across different species, proposing an explanation for the highly conserved nature of NCC streams during development
Weight cycling in treatment-seeking obese persons: data from the QUOVADIS study
OBJECTIVE: To determine parameters of weight history useful for the assessment of weight cycling and their association with
psychological distress and binge eating.
DESIGN: Cross-sectional.
SUBJECTS: A total of 1889 treatment-seeking obese subjects, enrolled by 25 Italian centers (78% female subject), aged 20–65 y
(median 45); 1691 reported previous efforts to lose weight (median age of first dieting, 30 y).
MEASUREMENTS: The number of yearly attempts to lose weight, weight gain since age 20 y, cumulative weight loss and
gain were checked by a predefined structured interview. Psychological distress was tested by means of Symptom Check-List 90
(SCL-90), Binge Eating Scale (BES) and Three Factor Eating Questionnaire (TFEQ).
RESULTS: Differences in anthropometric, clinical and psychological parameters were observed in relation to previous attempts
to lose weight. Patients in the upper quartile of parameters of weight history were considered weight cyclers. In multivariate
logistic regression analysis, after correction for age, sex and BMI, a high BES score was the only factor systematically associated
with a high frequency of dieting (OR, 1.70; 95% confidence interval, 1.22–2.36; P¼0.022), with higher cumulative weight loss
(1.42; 1.12–1.80; P¼0.003) and cumulative weight gain (1.38; 1.06–1.79; P¼0.017). However, the sensitivity, specificity and
positive predictive value of a high BES score were very low to detect cyclers. Weight cycling did not carry a higher risk of
complicating diseases.
CONCLUSIONS: Weight cycling is associated with psychological distress, and binge eating independently increases the risk, but
cannot be used to predict cycling. Also, obese patients who do not experience overeating as a loss of control discontinue
treatment or regain weight following therapy
AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications.
The mammalian target of rapamycin (mTOR) serine/threonine
kinase is the catalytic subunit of two multi-protein complexes,
referred to as mTORC1 and mTORC2. Signaling downstream
of mTORC1 has a critical role in leukemic cell biology by
controlling mRNA translation of genes involved in both cell
survival and proliferation. mTORC1 activity can be downmodulated
by upregulating the liver kinase B1/AMP-activated
protein kinase (LKB1/AMPK) pathway. Here, we have explored
the therapeutic potential of the anti-diabetic drug, metformin
(an LKB1/AMPK activator), against both T-cell acute lymphoblastic
leukemia (T-ALL) cell lines and primary samples
from T-ALL patients displaying mTORC1 activation. Metformin
affected T-ALL cell viability by inducing autophagy and
apoptosis. However, it was much less toxic against proliferating
CD4Ăľ T-lymphocytes from healthy donors. Western blot
analysis demonstrated dephosphorylation of mTORC1 downstream
targets. Unlike rapamycin, we found a marked inhibition
of mRNA translation in T-ALL cells treated with metformin.
Remarkably, metformin targeted the side population of T-ALL
cell lines as well as a putative leukemia-initiating cell subpopulation
(CD34Ăľ/CD7/CD4) in patient samples. In conclusion,
metformin displayed a remarkable anti-leukemic activity,
which emphasizes future development of LKB1/AMPK activators
as clinical candidates for therapy in T-ALL.
Leukemia (2012) 26, 91–100; doi:10.1038/leu.2011.269;
published online 4 October 201
Rapid communications Ongoing outbreak of visceral leishmaniasis in Bologna
(VL) cases has recently been reported in Bologna Province in northern Italy. Over six months from November 2012 to May 2013, 14 cases occurred, whereas the average number of cases per year was 2.6 (range: 0–8) in 2008 to 2012. VL was diagnosed in a median of 40 days (range: 15–120) from disease onset. This delay in diagnosis shows the need for heightened awareness of clinicians for autochthonous VL in Europe. From November 2012 to May 2013, public health authorities, microbiologists and clinicians in Bologna Province, northern Italy, noted an upsurge in human cases of visceral leishmaniasis. During these six months, 14 cases were notified, an over five-fold increase compared with the annual average of 2.
Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for
15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of
polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is
frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a
target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of
human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells
in the G0/G1 phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in
the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its
downstream targets, GSK-3a/b and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced
apoptosis in a T-ALL patient cell subset (CD34Ăľ/CD4/CD7), which is enriched in leukemia-initiating cells. Taken together, our
findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL
Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT
Objectives: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. Methods: One hundred and one children with WHO grade\ua0>\ua02 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0\u201310 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. Results: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade\ua0<\ua03 WHO on day +7 (P\ua0=\ua00.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0\u20133] vs. 2.5 [1\u20135], P\ua0<\ua00.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. Conclusions: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain
Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study
Medulloblastoma is the most common malignant brain tumor in children. Even if current treatment dramatically improves the prognosis, survivors often develop long-term treatment-related sequelae. The current radiotherapy standard for medulloblastoma is craniospinal irradiation with a boost to the primary tumor site and to any metastatic sites. Proton therapy (PT) has similar efficacy compared to traditional photon-based radiotherapy but might achieve lower toxicity rates. We report on our multi-centric experience with 43 children with medulloblastoma (median age at diagnosis 8.7 years, IQR 6.6, M/F 23/20; 26 high-risk, 14 standard-risk, 3 ex-infant), who received active scanning PT between 2015 and 2021, with a focus on PT-related acute-subacute toxicity, as well as some preliminary data on late toxicity. Most acute toxicities were mild and manageable with supportive therapy. Hematological toxicity was limited, even among HR patients who underwent hematopoietic stem-cell transplantation before PT. Preliminary data on late sequelae were also encouraging, although a longer follow-up is needed
Adaptive Evolution of the Myo6 Gene in Old World Fruit Bats (Family: Pteropodidae)
PMCID: PMC3631194This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
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