Anaplastic large cell lymphomas (ALCLs) frequently carry oncogenic fusions involving the anaplastic lymphoma kinase (ALK) gene. Targeting ALK using tyrosine kinase inhibitors (TKIs) is a therapeutic ...option in cases relapsed after chemotherapy, but TKI resistance may develop. By applying genomic loss-of-function screens, we identified PTPN1 and PTPN2 phosphatases as consistent top hits driving resistance to ALK TKIs in ALK+ ALCL. Loss of either PTPN1 or PTPN2 induced resistance to ALK TKIs in vitro and in vivo. Mechanistically, we demonstrated that PTPN1 and PTPN2 are phosphatases that bind to and regulate ALK phosphorylation and activity. In turn, oncogenic ALK and STAT3 repress PTPN1 transcription. We found that PTPN1 is also a phosphatase for SHP2, a key mediator of oncogenic ALK signaling. Downstream signaling analysis showed that deletion of PTPN1 or PTPN2 induces resistance to crizotinib by hyperactivating SHP2, the MAPK, and JAK/STAT pathways. RNA sequencing of patient samples that developed resistance to ALK TKIs showed downregulation of PTPN1 and PTPN2 associated with upregulation of SHP2 expression. Combination of crizotinib with a SHP2 inhibitor synergistically inhibited the growth of wild-type or PTPN1/PTPN2 knock-out ALCL, where it reverted TKI resistance. Thus, we identified PTPN1 and PTPN2 as ALK phosphatases that control sensitivity to ALK TKIs in ALCL and demonstrated that a combined blockade of SHP2 potentiates the efficacy of ALK inhibition in TKI-sensitive and -resistant ALK+ ALCL.
•Genome-wide screening identifies PTPN1 and PTPN2 as phosphatases involved in ALK inhibitor resistance in lymphoma.•PTPN1 and PTPN2 regulate ALK and SHP2 phosphorylation, and combined inhibition of ALK and SHP2 is an effective approach to treat ALCL.
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Purpose
To determine the potential role of intraoperative dexamethasone intravitreal implant (DEX-I) in reducing diabetic macular edema (DME) worsening after phacoemulsification.
Methods
This was a ...prospective study on 19 eyes of 19 patients with type 2 diabetes mellitus with DME and cataract. Mean preoperative Early Treatment Diabetic Retinopathy Study visual acuity (VA) was 16.7 letters. Mean foveal thickness (FT) was 451 μm. The DME was naive in 11 eyes and refractory in 8 eyes. All eyes underwent a standard phacoemulsification and intraocular lens implantation; DEX-I was injected at the end of surgery. Follow-up was performed at 1 week and then monthly until DME recurrence (up to 8 months).
Results
At 1 week, mean VA improved by 15 letters (range 0-29 letters) and mean FT decreased by 147 μm (range 69-236 μm). Improvement consolidated at month 1, with a mean VA improvement of 18 letters (range 3-32 letters) and a mean improvement in FT of 193 μm (range 76-304 μm), remaining stable at month 2 after surgery in all eyes. The DME recurred in 1 eye at month 3, in 14 eyes (73.8%) between months 4 and 5, and after month 6 in 4 eyes (21%). Refractory DMEs demonstrated the same benefit but recurred earlier than naive ones (4 months versus 5.8 months, p<0.01).
Conclusions
Intraoperative DEX-I prevents DME worsening after phacoemulsification. Its positive effects last for at least 3 months.
To define the mean time of first recurrence of diabetic macular edema (DME) after a single injection of dexamethasone intravitreal implant (DEX-I), reducing the burden of monthly visits during a PRN ...regimen of treatment.
Twenty phakic eyes with DME (12 eyes naïve and 8 eyes with edema persistent after previous treatments) were followed monthly after DEX-I injection until evidence of first recurrence of edema, defined as a change in visual acuity (VA) ≥5 letters and/or in foveal thickness (FT) ≥50 µm. Reaching this point, the eyes were re-treated. Monitored parameters were changes in VA, FT, intraocular pressure (IOP), and lens opacity.
Maximal efficacy was registered at month 1, when mean VA improved by 14 letters (19%), FT decreased by 325 µm (43.7%), and in 15 eyes (75%) edema was completely reabsorbed. The mean time of first recurrence was 5.1 months. No statistical difference was found between eyes with naïve or persistent DME. Five eyes needed topical medication for modest temporary IOP increase (21-24 mm Hg) between months 2 and 4. No increase in lens opacities was registered during follow-up.
According to the results of this study, the first signs of DME recurrence after DEX-I injection appear at a mean time of 5 months, suggesting that an appropriate and prudent time schedule for a PRN regimen could be limited to monthly tonometry and a first complete examination not before 4 months.
BackgroundThe prospective DIabetes and CATaract Study II (DICAT II) was performed to characterise the risks of cataract surgery to the retinae of patients with early diabetic macular oedema ...(E-DMO).MethodsDICAT II was a prospective, comparative, multicentre, observational study involving six Italian clinics. Patients were aged ≥55 years, had type 1 or 2 diabetes with spectral-domain optical coherence tomography evidence of ESASO classification Early DMO. Group 1 eyes (78 eyes, 78 patients) underwent phacoemulsification-based cataract surgery. Group 2 eyes (65 eyes, 65 patients) had E-DMO and either clear media or had undergone uncomplicated cataract surgery ≥1 year previously. Central subfield thickness (CST) and best-corrected visual acuity (BCVA) were assessed in both groups.ResultsThe negative impact of surgery on CST was evident after the first postoperative week; CST peaked during the first month, then rapidly decreased. CST worsening ≥10 µm was observed in 63/78 eyes (80.7%) and 29/65 eyes (44.6%) in Groups 1 and 2, respectively (p < 0.0001). CST worsening of ≥50 µm was observed in 51 eyes (65.4%) and 10 eyes (15.4%) in Groups 1 and 2, respectively (p < 0.0001). Mean CST worsening was lower in Group 2 than in Group 1 (38.6 ± 30.4 µm vs 85.5 ± 55.3 µm, p < 0.0001) with a lower BCVA loss (−2.6 ± 3.5 letters vs −8.2 ± 6.2 letters, p < 0.0001). Higher glycaemic levels and HBA1c levels were significantly associated with the risk of >50 μm CST worsening in eyes from both groups.ConclusionEarly DMO is associated with poorer outcomes after cataract surgery and requires close pre- and postoperative monitoring.
Purpose
To report on the prevalence of diabetes, diabetic macula oedema (DME) and retinopathy and their respective grading in a large cohort of patients undergoing cataract surgery.
Methods
Data on ...previous diagnosis of diabetes, fasting glucose, glycated haemoglobin, presence and type of retinopathy and other maculopathy of 3657 patients over 55 years of age undergoing cataract surgery in 13 centres scattered throughout Italy were analysed.
Results
A total of 20.4% of patients were known diabetics and 27.9% of diabetics showed signs of retinopathy. Haemoglobin A1C was higher than 48 mmol/L (6.5%) in 32% of diabetics and 2.4% non-diabetics. Fasting blood glucose level was higher than 120 mg/dL in 4.3% non-diabetics and 50% diabetics. Duration of diabetes did not significantly correlate with either fasting glucose or glycated haemoglobin, while higher grades of diabetic retinopathy were significantly more prevalent as duration of disease increased. DME was present in almost 40% of diabetics and 22% of patients showed non-diabetic maculopathy.
Discussion
Diabetic retinopathy and DME worsen after cataract extraction thus complicating long-term prognosis and requiring expensive injective therapy. Since unknown diabetics represent 2–4% of the many million cataract candidates and even known diabetics show poor metabolic control and high rates of DME, preoperative medical testing and accurate retinopathy screening may prove both ethically necessary and cost-effective.
Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL ...belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance
to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK
STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL.
El ciberacoso es un fenómeno relacionado con internet, reconocido y en crecimiento. Aunque el enfoque de la investigación en este campo está expandiéndose rápidamente, la mayoría de las ...investigaciones se centraron en las experiencias de adolescentes en países industrializados, como los de Europa occidental o países anglosajones. Pero, los jóvenes de los países en desarrollo ¿están expuestos a los mismos riesgos? Para responder a esta pregunta, este trabajo presenta una parte de los resultados de un proyecto más amplio, y centra su atención en la incidencia de episodios de ciberacoso entre los estudiantes de secundaria en Colombia. Los datos se recogieron sobre una muestra de 359 estudiantes, 64.1% varones y 35.9% mujeres, entre los 13 y los 19 años de edad, utilizando un cuestionario entregado en horario escolar. El análisis demuestra que los episodios de ciberacoso están bastante extendidos en el grupo de la muestra; teniendo en cuenta que más del 60% de los jóvenes entrevistados estuvo involucrado (ya sea como víctima o como acosador) en al menos 2 episodios en los 6 meses anteriores a la investigación. Las diferencias entre los sexos han sido analizadas, pero no han dado resultados significativos. En conclusión este estudio pone en evidencia la necesidad de una investigación más profunda y amplia del ciberacoso, tanto entre la población masculina como entre la femenina, de los así llamados "países en desarrollo", porque parece que la difusión de éste fenómeno está afectando también a la juventud de éstos países.
Many medium-sized Italian cities share the problem of having incorporated or having to integrate within the urban area relevant industrial components that influence both the overall quality of life ...and the environment in a strict sense. Sustainability perspectives are a relevant starting point for guiding companies’ development and growth strategies. At the same time, this aspect constitutes a strategic opportunity for urban development, that is still conditioned by the direct presence of companies that, in the best scenario, simply comply with current regulations in term of sustainability. The classic stakeholder theory, which is widely diffused in organizational culture, must be revised to solidify the understanding of the role of local stakeholders, who are passively involved in the environmental impact of companies’ activities. Studying the awareness, among the different corporate components, of environmental issues, is a very relevant step to trigger processes of effective improvement. In this article, we would like to argue that a greater understanding of sustainability issues on the part of decision-makers and employees of companies is a key that can have concrete effects on an aggregate level in the urban dimension. To verify this hypothesis, we propose a case study comparing three organisations, composed of ten plants spread across the Italian territory and all located in the proximity of medium-sized cities. Adopting a mixed qualitative-quantitative methodology, the work crosses primary qualitative data (semi-structured interviews with key players), quantitative data and secondary data relating to the territorial context. The results allow to highlight limits and potential of the industrial-urban coexistence, with a specific focus on the relation between private and public actors.
This review aims to provide a comprehensive overview of various aspects related to cosmetic product packaging, highlighting both advancements and challenges in the field. Initially, it offers a ...general description of the main materials used in cosmetic containers, including plastic, glass, paper, and aluminum. This is followed by an analysis of the existing EU legislative frameworks that govern cosmetic packaging, encompassing chemical, food, and waste regulations. The paper also discusses recent EU regulatory proposals and guidelines from trade associations aimed at enhancing the sustainability of cosmetic packaging materials. Additionally, the role of recycled and bio-based packaging materials in promoting environmental sustainability is analyzed. Overall, this review aims to provide insights for experts in the field on how to balance safety, functionality, and environmental responsibility in cosmetic packaging.
Purpose To analyse the long anatomical and functional outcome of a subgroup of the DICAT II study cohort, consisting of 26 patients undergoing cataract surgery and withdrawn from the study for a ...clinically significant worsening of early diabetic macular edema (DME). Materials Patients who underwent cataract surgery and withdrawn from the DICAT II study for a clinically significant worsening of early DME with at least 12 months follow–up after the dropout. The study population was divided into two groups according to the clinical evaluation at one-year follow-up: ongoing treatment patients for DME (Treatment group, TG) and patients no longer treated (Non Treatment group, NTG). Results Central foveal thickness (CFT) at baseline and dropout time were higher in TG than in the NTG, with a statistically significant difference ( p < 0.05). In addition, TG patients reported a higher levels of glycated hemoglobin at time baseline compared to NTG patients (7.81 ± 1.15 vs 7.02 ± 0.56; p = 0.048). The linear regression analysis demonstrated a statistically significant relationship between the visual acuity and the ongoing treatment group at one-year follow-up (p = 0.042). Conclusion The study provides parameters to be considered when assessing the risk of developing persistent DME after cataract surgery in diabetic patients. In particular, CFT at baseline and dropout time have been reported to be an effective and predictable OCT biomarkers when evaluating DME progression. During the evaluation of the systemic disease, similar results were found for the glycated hemoglobin at baseline.
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