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Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia
No full textData related to manuscript "Exploiting B-cell Receptor Stereotypy to Design Tailored Immunotherapy in Chronic Lymphocytic Leukemia" by Rovida A*, Maccalli C*, Scarfò L, Dellabona P, Stamatopoulos K, Ghia P. Clin Cancer Res. 2021 Feb 1;27(3):729-739. doi: 10.1158/1078-0432.CCR-20-1632. *Contributed equall
Profound architectural and functional readjustments of the secretory pathway in decidualization of endometrial stromal cells
No full textCertain cell types must expand their exocytic pathway to guarantee efficiency and fidelity of protein secretion. A spectacular case is offered by decidualizing human endometrial stromal cells (EnSCs). In the midluteal phase of the menstrual cycle, progesterone stimulation induces proliferating EnSCs to differentiate into professional secretors releasing proteins essential for efficient blastocyst implantation. Here, we describe the architectural rearrangements of the secretory pathway of a human EnSC line (TERT-immortalized human endometrial stromal cells (T-HESC)). As in primary cells, decidualization entails proliferation arrest and the coordinated expansion of the entire secretory pathway without detectable activation of unfolded protein response (UPR) pathways. Decidualization proceeds also in the absence of ascorbic acid, an essential cofactor for collagen biogenesis, despite also the secretion of some proteins whose folding does not depend on vitamin C is impaired. However, even in these conditions, no overt UPR induction can be detected. Morphometric analyses reveal that the exocytic pathway does not increase relatively to the volume of the cell. Thus, differently from other cell types, abundant production is guaranteed by a coordinated increase of the cell size following arrest of proliferation.
DOI: 10.1111/tra.1282
Correlation of Computed Tomography Parameters with Histology, Stage and Prognosis in Surgically Treated Thymomas
No full textThe histological classification and staging of thymic tumors remains a matter of debate. The correlation of computed tomography (CT) parameters with tumor histology and stage also still has to be completely assessed. The aim of this study was therefore to analyze the correlation of radiological parameters with histological and staging classifications of thymomas evaluating their prognostic role.
Methods: Data of 50 patients with thymoma submitted to a complete surgical treatment between 2005 and 2015 were retrospectively analyzed. Tumors were classified according to the WHO and Suster and Moran (S&M) histological classifications and to the Masaoka–Koga and tumor, node and metastases (TNM) staging systems. The correlation of CT features with histology and stage and the prognostic role of histopathological and radiological features were assessed.
Results: Five-year overall (OS) and disease-free survival (DFS) were 90.3% and 81.1%, respectively. A significant correlation of DFS with the Masaoka–Koga (p = 0.001) and TNM staging systems (p = 0.002) and with the S&M (p = 0.02) and WHO histological classifications (p = 0.04) was observed. CT scan features correlated with tumor stage, histology and prognosis. Moderately differentiated tumors (WHO B3) had a significantly higher incidence of irregular shape and contours (p = 0.002 and p = 0.001, respectively) and pericardial contact (p = 0.036). A larger tumor volume (p = 0.03) and a greater length of pleural contact (p = 0.04) adversely influenced DFS. The presence of pleural (p < 0.001) or lung invasion (p = 0.02) and of pleural effusion (p = 0.004) was associated with a significantly worse OS.
Conclusions: Pre-operative CT scan parameters correlate with stage and histology, and have a prognostic role in surgically treated thymomas.
doi.org/10.3390/medicina5701001
Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes DOI: 10.1073/pnas.2025804118
No full textData related to manuscript "Dysregulated copper transport in multiple sclerosis may cause demyelination via astrocytes" by Colombo et al, PNAS July 6, 2021 118 (27) e2025804118
DOI: 10.1073/pnas.202580411
Selective association of cytokine levels and kynurenine/tryptophan ratio with alterations in white matter microstructure in bipolar but not in unipolar depression
No full textBipolar (BD) and major depression (MDD) disorders are severe mental illnesses characterised by altered levels of immune/inflammatory markers and disrupted white matter (WM) microstructure. A pro-inflammatory state was suggested to activate indoleamine 2,3-dioxygenase which, in turn, increases the amount of tryptophan (Trp) converted into kynurenine (Kyn). We investigated whether plasma levels of Trp, Kyn and Kyn/Trp ratio are associated with peripheral levels of immune/inflammatory markers and whether they are related to WM integrity in 100 MDD and 66 BD patients. Patients also underwent MRI, and fractional anisotropy (FA) was estimated as a measure of WM microstructure. BD patients showed higher Kyn levels and Kyn/Trp ratio than MDD patients, and lower FA in several WM tracts, including the corpus callosum and the inferior fronto-occipital fasciculus (IFO). Lower Trp levels associated with a more severe depressive symptomatology irrespective of diagnosis and with lower FA in the corpus callosum (CC) and external capsule (EC). We found an association of immune/inflammatory markers with Kyn/Trp ratio selectively in BD patients: IL-1β and TNF-α showed a positive relationship and IL-2 and IL-9 a negative relationship; in addition, higher IL-4 correlated with lower Kyn levels; higher Kyn/Trp ratio and IL-1β correlated with lower FA in the CC and IFO. Notably, the detrimental effect of IL-1β on the IFO was moderated by the Kyn/Trp ratio. These data suggest that in BD, cytokines and the conversion of Trp into Kyn may affect WM microstructure and support the idea that distinct mechanisms underlie the pathophysiology of BD and MDD.
DOI: 10.1016/j.euroneuro.2021.11.00
The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes
No full textDOI: 10.15252/emmm.202012433.
MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed-forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT-typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity
High sensitivity of ROSE-supported ERCP-guided brushing on biliary strictures
No full textEndoscopic Retrograde CholangioPancreatography (ERCP) plays a major role in biliary strictures, with brushing being a cheap and fast method to acquire cytological specimen, despite a sensitivity around 45%. Rapid On-Site Evaluation (ROSE) is widely used for Endoscopic Ultrasound-acquired cytological specimen adequacy, improving its sensitivity and specificity, nevertheless, no study evaluated its role for ERCP-guided brushing. Our aim was to assess the diagnostic yield of ERCP-guided brushing of biliary strictures when supported by ROSE. This is the database from a retrospective single-center study, including patients undergoing ERCP-guided brush cytology supported by ROSE for biliary strictures. Recorded data included patient’s clinical-radiological and ERCP features. Final diagnosis was determined after surgery, intraductal biopsy or adequate follow-up. The diagnostic yield was calculated and a subgroup analysis for factors associated with false negative or true positive result was performed.
This is the first study evaluating the use of ROSE as support for ERCP-guided brushing of biliary strictures, with a sensitivity far higher than those reported for brushing alone, and at least comparable to those of more expensive and invasive techniques
Prevalence and risk factors of ellipsoid zone damage after pars plana vitrectomy for idiopathic epiretinal membrane
No full textPrevalence and risk factors of ellipsoid zone damage after pars plana vitrectomy for idiopathic epiretinal membrane
DOI: 10.1097/IAE.000000000000332
Investigating predictive factors of dialectical behavior therapy skills training efficacy for alcohol and concurrent substance use disorders: A machine learning study
No full textDialectical Behavior Therapy Skills Training (DBT-ST) as stand-alone treatment has demonstrated
promising outcomes for the treatment of alcohol use disorder (AUD) and concurrent substance use disorders
(SUDs). However, no studies have so far empirically investigated factors that might predict efficacy of this
therapeutic model.275 treatment-seeking individuals with AUD and other SUDs were consecutively admitted to a 3-month DBT-ST program (in- + outpatient; outpatient settings). The machine learning routine applied (i.e. penalized regression combined with a nested cross-validation procedure) was conducted in order to estimate predictive values of a wide panel of clinical variables in a single statistical framework on drop-out and substance-use behaviors, dealing with related multicollinearity, and eliminating redundant variables.
DOI: 10.1016/j.drugalcdep.2021.10872
Data for "Identification of a retinoic acid-dependent hemogenic endothelial progenitor from human pluripotent stem cells"
No full textThe generation of hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from hemogenic endothelium (HE) in a NOTCH and retinoic acid (RA)-dependent manner. While a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, prior to HE specification, is actually comprised of two distinct KDR+CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, while CXCR4+ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Further, both RA-independent (RAi) and -dependent (RAd) HE harbor transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human hematopoietic development provides essential resolution to the regulation and origins of the multiple waves of hematopoiesis. These insights provide the basis for the generation of specific hematopoietic populations, including the de novo specification of HSCs