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IntroductionBipolar disorder (BD) is a complex mental disorder. Cognitive dysfunction represents a core feature, strongly related with patients’ functional outcome. Functional Remediation (FR), is an integrated neuropsychological and psychosocial rehabilitation treatment aimed at enhancing cognitive functions in order to achieve full functional recovery(Torrent et al., 2013). Evidence highlighted an association of neurotrophins and cognitive dysfunctions. Particularly, BDNF has been investigated a potential biomarker. Preliminary studies explored the effects induced through FR interventions on serum BDNF levels(Bonnin et al., 2019). Evidences suggest that high BDNF serum levels are related to good cognitive functioning(Mora et al., 2019). Results require further explorations. The present pilot study targets to identify the neurobiological correlates of response, investigating the potential neuroprotective role of the FR.ObjectivesAssess the effectiveness of FR in ameliorate cognitive deficits measured with BAC-A and psychosocial functioning with FAST, in modifying BDNF levels in a sample of euthymic patients with BD, compared to standard treatment.MethodsTwo arms(1:1)randomized, rater-blinded, controlled study of 30out-patients with BD-I and BD-II, according to DSM-5 criteria. Patients between 18 and 55 years in euthymic phase. Neurocognitive and clinical assessments, at the same times, serum assessment of BDNF levels will be performed.All patients will be assessed at baseline(T0), at the end of treatment(T1) and at the 3-month follow-up(T2).ResultsAfter treatment, patients receiving FR show better cognitive and psychosocial performance than those receiving TAU.ConclusionsGiven the important role of neutrophins in the pathogenesis of BD, identifying BD-specific biomarkers would contribute to understand the underlying neuro-pathophysiological processes and to personalize treatments.DisclosureNo significant relationships.

BackgroundJuvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. TNF inhibitors (TNFi) have dramatically changed the prognosis of this disease, but once achieved disease remission, it is not clear how and when stop therapy.ObjectivesOur purpose is to describe a multicentric cohort of JIA patients treated with the first course of Adalimumab and Etanercept in whom therapy was discontinued to persistent remission and identify predictors of relapse.MethodsIn a multicentric Italian retrospective study (Florence, Brescia, Trieste and Bari), patients with oligoarticular and polyarticular JIA were enrolled if they stopped therapy for persistent remission after the first course of Adalimumab and Etanercept. We collected demographic, clinical and laboratory data at onset and during biologic treatment.Results136 patients were enrolled (102 female, median age at onset 3 years (R1-15)), of whom 76 (55.9%) had oligoarticular JIA and 55 (40.4%) had uveitis. ANA positivity was found in 99(72.8%) (Table 1). TNFis were started at median age of 6 years (R1-16), with a median time intercourse between TNFi initiation and diagnosis of 12 months (0-127m). Seventy-nine (59.3%) were treated with ADA, and 57 (40.7%) with ETA. Remission was achieved after a median time of 4 months (R 1-32) and TNFi was discontinued after a median time of 30 months (R 6-90). TNFi were stopped in the 76.5% increasing the interval of administration, 18.4% reducing the dose, and 16.9% abrupt discontinuation. 106 patients (79.4%) relapsed after a median time of 6 months (R 0.5-96) for arthritis in 71 (66.9%), uveitis in 19 (17.9%), both in 18 (16.9%). Patients who relapsed were more frequently female (χ² 5.9 p<0.014), had history of uveitis (χ² 7.4 p<0.006), younger at onset (median 3 vs 7, p<0.001) and when TNFi was started (6 vs 9.5, p 0.002). Moreover, the time intercourse between diagnosis and TNFi initiation was longer (13 vs 8.5 months, p 0.02) and the weaned of therapy happened in shorter time (6 vs 9 m, p 0.005) (Table 1). Patients who not-relapse suspended TNFi more frequently lengthening intervals of administration (χ² 5.2 p0.015). Relapse free survival curve after withdrawal evaluated with Kaplan-Meier showed that patients with uveitis had a significantly earlier relapse (Log Rank χ² = 12.8 p <0.0001)ConclusionAlthough this is a retrospective study, we highlighted that early age at onset and at TNFi initiation, presence of uveitis and a long time to start biologics seem to be significantly more frequent in subjects who relapse, while stop therapy lengthening the interval of drug administration might be protective.Table 1.Characteristics of JIA patients after drug withdrawal (relapse Vs no-relapse)Entire cohort(136) n (%)Not relapse(28)Relapse(108)Test and p valueFemale n, %102 (75%)16 (57.1%)86 (79.1%)χ² 5.9 p 0.014Age at diagnosis, years, m (R)3 (1-15)7 (1-15)3 (1-11)p<0.001Uveitis history, n (%)55 (40.4%)550χ² 7.4 p<0.006Type of JIApOligo n (%)eOligo n (%)Poli n (%)55 (40.4%)21 (15.4%)60 (44.1%)12313431847nsANA positivity99 (72.8%)1683χ² 4.3 p 0.03Comorbdity n291019χ²4.35 p 0.037HLA B271467χ²3.9 p 0.048Type of BiologicsADA 79ETA 57ADA 13ETA 15ADA 66ETA 42nsCharacteristics at biologic starting and withdrawalAge at B initiation years, m, R6 (1-16)9.5 (1-15)6 (1-16)p0.002Concomitant therapy111 MTX (81.6%)20(71.4%)91(84.2%)χ² 6.58 p 0.03Time between diagnosis and B (months)12 (0-127)8.5 (0-117)13 (1-127)p0.021Time free from relapse out of therapy months6 (0.5-96)16 (4-96)5 (0.5-66)p<0.001Type of flareArthritisUveitisBoth71 (66.9%)19 (17.9%)18 (16.9%)-711918nsContinuation of concomitant therapy after stop B63339χ² 0.68 p 0.43N of months to stop B6 (0-22)9 (0-22)6 (0-22)p 0.005Modality to stop BLengthening intervalsReduction of doseAbrupt104 (76.5%)25 (18.4)16 (11.8%)26(92.8%)4178 (72.2%)2115χ² 5.2 p0.02Abbreviations: n number, m median, R range, pOligo persistent oligoarthritis, eOligo: extended oligoarthritis, Poli polyarticular, B biologic, ns: non significantREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Background: Neurocognitive impairment is a prominent characteristic of bipolar disorder (BD), linked with poor psychosocial functioning. This study’s purpose is to evaluate the effectiveness of functional remediation (FR) in enhancing neurocognitive dysfunctions in a sample of remitted patients with diagnosis of BD in comparison to treatment as usual—TAU. To quantify the neurocognitive damage, the Brief Assessment of Cognition in Affective Disorders (BAC-A) will be used, and the overall psychosocial functioning will be measured with the Functioning Assessment Short Test—FAST. Methods: The randomized, rater-blinded, controlled study will include two arms (1:1) encompassing 54 outpatients with diagnosis of BD-I and BD-II, as defined by the DSM-5 criteria. In the experimental phase, remitted patients aged 18–55 years will be involved. At the baseline, at the end of intervention and at the 6-month follow-up, patients will be evaluated using clinical scales (Young Mania Rating Scale (Y-MRS) and Hamilton Depression Rating Scale (HAM-D)). Neurocognitive measurements and psychosocial functioning will be valued, respectively, with BAC-A and FAST. Discussion: The primary expected outcome is that following FR intervention, patients will exhibit improved cognitive abilities and psychosocial outcomes compared to the participants in the TAU group. It is now recognized that neurocognitive deficits are potential predictors of functional outcome in patients with BD. In recent years, there has been a growing interest in the implementation of interventions that, in addition to symptomatic remission, are also aimed at neurocognitive dysfunctions in order to achieve a recovery of psychosocial functioning.

In this study the efficacy and safety of long term losartan administration on renal haemodynamics were evaluated in mild to moderate hypertensives (Ht). After run in period with placebo 18 Ht without renal or cardiovascular disease were allocated to losartan (50 mg/die for one year) treatment. Renal haemodynamics measurements included renal plasma flow (ERPF) and glomerular filtration rate (GFR) by standardized radionuclide study. Effective renal blood flow (ERBF), filtration fraction (FF) and renal vascular resistance (RVR) were also calculated. Blood pressure was evaluated monthly whereas renal haemodynamics and function were detected at baseline, after 6 and 12 months of losartan administration. Losartan induced a significant (p < 0.001) decrease in SBP, DBP and MBP vs baseline values both at 6 months and at 12 months. In addition a significant decrease in RVR (p < 0.009) and in FF (p < 0.001) without relevant change in ERPF, ERBF and GFR was found only at 6 months but after one year of treatment RVR returned at basal conditions. In conclusion our data indicated that long term control in blood pressure induced by losartan administration was associated to a reduction of RVR after 6 months of treatment but these improvements in renal haemodynamics disappears after one year.

Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD) characterized by damage of large bowel mucosa and frequent extra-intestinal autoimmune comorbidities. The role played in IBD pathogenesis by molecular chaperones known to interact with components of the immune system involved in inflammation is unclear. We previously demonstrated that mucosal Hsp60 decreases in UC patients treated with conventional therapies (mesalazine, probiotics), suggesting that this chaperonin could be a reliable biomarker useful for monitoring response to treatment, and that it might play a role in pathogenesis. In the present work we investigated three other heat shock protein/molecular chaperones: Hsp10, Hsp70, and Hsp90. We found that the levels of these proteins are increased in UC patients at the time of diagnosis and decrease after therapy, supporting the notion that these proteins deserve attention in the study of the mechanisms that promote the development and maintenance of IBD, and as biomarkers of this disease (e.g., to monitor response to treatment at the histological level).

Extracellular vesicles (EVs) shuttle proteins, RNA, DNA, and lipids crucial for cell-to-cell communication. Recent findings have highlighted that EVs, by virtue of their cargo, may also contribute to breast cancer (BC) growth and metastatic dissemination. Indeed, EVs are gaining great interest as non-invasive cancer biomarkers. However, little is known about the biological and physical properties of EVs from malignant BC lesions, and even less is understood about EVs from non-malignant lesions, such as breast fibroadenoma (FAD), which are clinically managed using conservative approaches. Thus, for this pilot study, we attempted to purify and explore the proteomic profiles of EVs from benign breast lesions, HER2+ BCs, triple–negative BCs (TNBCs), and continuous BC cell lines (i.e., BT-549, MCF–10A, and MDA-MB-231), combining experimental and semi-quantitative approaches. Of note, proteome-wide analyses showed 49 common proteins across EVs harvested from FAD, HER2+ BCs, TNBCs, and model BC lines. This is the first feasibility study evaluating the physicochemical composition and proteome of EVs from benign breast cells and primary and immortalized BC cells. Our preliminary results hold promise for possible implications in precision medicine for BC.

The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.

The CRyogenic InfraRed Echelle Spectrograph (CRIRES) Upgrade project CRIRES\\(^{+}\\) extended the capabilities of CRIRES. It transformed this VLT instrument into a cross-dispersed spectrograph to increase the wavelength range that is covered simultaneously by up to a factor of ten. In addition, a new detector focal plane array of three Hawaii 2RG detectors with a 5.3 \\(\\mu\\)m cutoff wavelength replaced the existing detectors. Amongst many other improvements, a new spectropolarimetric unit was added and the calibration system has been enhanced. The instrument was installed at the VLT on Unit Telescope 3 at the beginning of 2020 and successfully commissioned and verified for science operations during 2021, partly remotely from Europe due to the COVID-19 pandemic. The instrument was subsequently offered to the community from October 2021 onwards. This article describes the performance and capabilities of the upgraded instrument and presents on sky results.