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Individuals on the autism spectrum often exhibit atypicality in their sensory perception, but the neural underpinnings of these perceptual differences remain incompletely understood. One proposed mechanism is an imbalance in higher-order feedback re-entrant inputs to early sensory cortices during sensory perception, leading to increased propensity to focus on local object features over global context. We explored this theory by measuring visual evoked potentials during contour integration as considerable work has revealed that these processes are largely driven by feedback inputs from higher-order ventral visual stream regions. We tested the hypothesis that autistic individuals would have attenuated evoked responses to illusory contours compared with neurotypical controls. Electrophysiology was acquired while 29 autistic and 31 neurotypical children (7-17 years old, inclusive of both males and females) passively viewed a random series of Kanizsa figure stimuli, each consisting of four inducers that were aligned either at random rotational angles or such that contour integration would form an illusory square. Autistic children demonstrated attenuated automatic contour integration over lateral occipital regions relative to neurotypical controls. The data are discussed in terms of the role of predictive feedback processes on perception of global stimulus features and the notion that weakened “priors” may play a role in the visual processing anomalies seen in autism.SIGNIFICANCE STATEMENTChildren on the autism spectrum differ from typically developing children in many aspects of their processing of sensory stimuli. One proposed mechanism for these differences is an imbalance in higher-order feedback to primary sensory regions, leading to an increased focus on local object features rather than global context. However, systematic investigation of these feedback mechanisms remains limited. Using EEG and a visual illusion paradigm that is highly dependent on intact feedback processing, we demonstrated significant disruptions to visual feedback processing in children with autism. This provides much needed experimental evidence that advances our understanding of the contribution of feedback processing to visual perception in autism spectrum disorder.

As part of New York State's Ending the Epidemic (EtE) initiative, sexual health clinics (SHCs) in New York City invested in clinic enhancements and expanded their HIV-related services to increase access to HIV prevention interventions and treatment. The objective of this study was to estimate and describe the change in SHC operating costs related to clinic enhancements and expanded patient services implemented as part of the EtE initiative.A comprehensive microcosting approach was used to collect retrospective cost information from SHCs, broken down by category and programmatic activity. Cost information was collected from 8 clinics across New York City during two 6-month time periods before (2015) and during (2018-2019) EtE.Eight SHCs reported comprehensive cost data. Costs increased by $800,000 on average per clinic during the 6-month EtE period. The cost per visit at an SHC increased by $120 on average to $381 (ranging from $302 to $464) during the EtE period. Personnel costs accounted for 69.9% of EtE costs, and HIV-related medications accounted for 8.9% of costs. Employment of social workers and patient navigators increased costs by approximately $150,000 on average per clinic. Postexposure prophylaxis was the costliest medication with average expenditures of $103,800 per clinic.This study demonstrates the key drivers of cost increases when offering enhanced HIV services in SHCs. Documenting the changes in resources necessary to implement these services and their costs can inform other health departments on the viability of offering enhanced HIV services within their own clinics.

Syngas produced by biomass and waste gasification processes must be ade-quately clean of tar compounds before being utilized in value-added applica-tions. Syngas cleaning by tar cracking at high temperatures is a promisingtechnique that can utilize different kinds of catalysts. However, their use islimited by the deposition of coke layers, which induces a masking phenome-non on the active surface, and, consequently, the rapid deactivation of the cat-alyst. This study addresses how the temperature (750 and 800 C) and thesteam concentration (0% and 7.5%) can affect the extent of water–gas andreforming reactions between steam and coke deposits. Two catalysts wereused: a market-available activated carbon and an iron-based alumina catalyst.The tests showed better performance of the Fe/γ-Al2O3catalyst. A massincrease of the bed was measured in tests with both the catalysts, which con-firms the deposition of the coke layer produced by tar dehydrogenation andcarbonization. Scanning electronic microscopy-energy-dispersive X-ray analy-sis (SEM-EDX) and Raman spectroscopy were utilized to investigate the natureof coke layers over the catalyst surface, with the aim of acquiring informationabout their reactivity towards the water gas reaction. SEM-EDX observationsindicate that the thickness of these carbon layers is less than 2μm. Ramanspectra suggest a negligible effect of the reaction temperature in the testedrange and, in particular, that the amorphous nature of coke layers deposited inthe presence of steam is relatively more graphitic than that obtained withoutsteam.

Background Comprehensive evaluation of the quality-adjusted life-years (QALYs) lost attributable to chlamydia, gonorrhea, andtrichomoniasis in the United States is lacking. Methods We adapted a previous probability-tree model to estimate the average number of lifetime QALYs lost due to genital chlamydia, gonorrhea, and trichomoniasis, per incident infection and at the population level, by sex and age group. We conducted multivariate sensitivity analyses to address uncertainty around key parameter values. Results The estimated total discounted lifetime QALYs lost for men and women, respectively, due to infections acquired in 2018, were 1541 (95% uncertainty interval [UI], 186–6358) and 111 872 (95% UI, 29 777–267 404) for chlamydia, 989 (95% UI, 127–3720) and 12 112 (95% UI, 2 410–33 895) for gonorrhea, and 386 (95% UI, 30–1851) and 4576 (95% UI, 13–30 355) for trichomoniasis. Total QALYs lost were highest among women aged 15–24 years with chlamydia. QALYs lost estimates were highly sensitive to disutilities (health losses) of infections and sequelae, and to duration of infections and chronic sequelae for chlamydia and gonorrhea in women. Conclusions The 3 sexually transmitted infections cause substantial health losses in the United States, particularly gonorrhea and chlamydia among women. The estimates of lifetime QALYs lost per infection help to prioritize prevention policies and inform cost-effectiveness analyses of sexually transmitted infection interventions.

Background/Aim: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. Patients and Methods: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy – General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. Results: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. Conclusion: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.

Whether adjuvant therapy with aromatase inhibitors (AIs) causes sleep disturbances or not in postmenopausal women with early breast cancer (EBC) is still a controversial issue.Between March 2014 and November 2017, validated questionnaires for assessing insomnia, anxiety, depression, quality of life (QoL) and restless legs syndrome (RLS) were administered to 160 EBC patients at baseline and after 3, 6, 12, and 24 months of AI therapy.AI therapy significantly decreased the patients' QoL, but did not influence insomnia, anxiety or depression. However, it significantly increased the frequency and severity of RLS. Patients with RLS at baseline (19%) or who developed RLS during AI therapy (26.3%) reported statistically lower quality of sleep, higher anxiety and depression, and worse QoL compared to patients who never reported RLS (54.7%).Although AI therapy does not affect sleep quality, it may increase RLS frequency. The presence of RLS could identify a group of EBC patients who may benefit from psychological support.

Treatment of human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) is rapidly evolving. Despite either surgery or radiotherapy (RT), with or without chemotherapy (CT), being acceptable in intermediate and locally advanced diseases, there is uncertainty regarding the best treatment option for these patients. Therefore, we performed a network meta-analysis (NMA) to compare the relative efficacy of different treatments for HPV+ oropharyngeal carcinoma.Randomized clinical trials that enrolled adults with non-metastatic HPV+ oropharynx cancer and provided data about overall survival (OS) and/or progression-free survival (PFS) and/or locoregional control and distant metastases (LRC and DM) were included. Fixed- or random-effects models were fit using a Bayesian approach to NMA. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (CrIs). The primary outcome was OS.A total of 844 citations were screened; 11 randomized clinical trials were included (HPV+ stage III-IV cancer, mainly oropharynx carcinomas). Nine treatment arms were compared. Radiotherapy (altered or standard fractionation) + triweekly cisplatin (HR 3.8; 95% CrIs 0.29-65 and 0.3; 95% CrIs 0.03-2.51) was superior to RT in term of OS (P score = 0.42 and 0.16). Radiotherapy with low and high cisplatin doses appeared similar (HR 1.57; 95% CrIs 0.19-12.72). Altered fractionation or standard RT + 3-weekly cisplatin are the 2 highest-ranked options in terms of PFS (P score = 0.35 and 0.34).This meta-analysis confirms the role of cisplatin added to RT as the best option for HPV+ oropharyngeal carcinoma. RT+ 3-weekly cisplatin is likely to be the best radical treatment in terms of OS and PFS.

Background The presence of parametric excitation in dynamic structures, caused by friction, crack, varying compliance, electromagnetic field, etc. may generate unbounded responses. In the literature there exist several numerical analyses of systems affected by parametric excitation, while experimental studies are less frequent. Objective The goal of the paper is to create a demonstrator of a parametrically excited system, whose stability can be modified through a controlled physical parameter. This work also investigates the applicability of the recently developed stability analysis method named Jacobian Based Approach (JBA). Methods This paper studies a simple experimental set-up comprising of a cantilever beam mounted on a spring with time – varying stiffness, achieved through the use of an electromagnet. The test rig allows measuring directly the magnetic force without any preknowledge of the values of electrical parameters. Results obtained from the test rig are compared with numerical results obtained from the Finite Element model. In this study, Hill’s method and JBA are employed to obtain the stability plot highlighting the regions of parametric instabilities. Results Good agreement is found between experimental and numerical data and the presence of unstable behavior is verified through the use of the well – known Hill’s method and the JBA. Furthermore, this study demonstrates that the stability plot, highlighting the unstable regions, computed by JBA is in complete agreement with the one obtained by Hill’s method. Conclusions It is shown how the parametric instability can be triggered through the regulation of a simple physical parameter, i.e. the gap between the electromagnet and the beam. The numerical model analyzed by the ad – hoc technique proposed by the authors i.e. JBA has been proven to have predictive capabilities in studying a system under parametric excitation and could be a potential substitution for state-of-the-art stability analysis techniques such Hill’s method.

Introduction: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs), but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. Methods: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally advanced/metastatic, well-/moderately differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints are disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers, and safety. Results: The number of patients was 40; 60% were male. Primary tumor site was lung (90%) and thymus (10%). Carcinoid type was typical (20.0%) and atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval (CI) 20.63–51.68; nonacceptability threshold ≤10%, p < 0.0001; not significantly above clinically relevant threshold ≥30%, p = 0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95% CI: 29.26–61.51) and clinically relevant (p = 0.0320 at ≥30% threshold). Median PFS was 37.1 (95% CI: 24.1–52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. Conclusions: This study showed that the LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs.

Purpose Whether or not androgen receptor (AR) axis could still be targetable in castration resistant prostate cancer (CRPC) patients with disease progression to next generation hormonal agents (NGHAs) is a controversial issue. Results Serum testosterone in CRPC patients has a positive prognostic role and increasing testosterone levels after androgen deprivation therapy (ADT) withdrawal or testosterone supplementation, as part of a bipolar androgen therapy (BAT) strategy, has been shown to potentially restore sensitivity to previous lines of NGHAs. Conclusion These data suggest that maintenance of ADT in CRPC patients receiving further lines of treatment, as recommended by current international guidelines, could be questionable. Conversely, testosterone supplementation aimed to re-sensitize CRPC to further hormonal manipulation is a strategy worth to be explored in future clinical trials.

Context As patients are now living with prostate cancer for longer, the long-term impact of hormonal treatment on bone health is an increasingly debated subject. Objective To characterize the changes in bone mineral density (BMD) and bone turnover markers after degarelix administration in prostate cancer patients without bone metastases. To explore the predictive role of body composition on treatment induced bone loss. Methods BMD and body composition (lean body mass, fat body mass, and appendicular mass index [ALMI]) were assessed by dual X-ray absorptiometry on study entry and after 12 months of degarelix therapy. Alkaline phosphate (ALP) and C-terminal telopeptide of type I collagen (CTX) were assessed at baseline, and 6 and 12 months. Results Twenty-nine patients entered the study. Degarelix administration was associated with a significant decrease in BMD after 12 months (2.4% reduction from baseline at lumbar spine). Serum CTX and ALP increased significantly (median increase from baseline 99% and 19.3%, respectively). An inverse correlation was observed between ALMI and CTX, but not ALP, at both baseline (Pearson r = –0.62, P Conclusion Degarelix administration is associated with a significant decrease in BMD and increase in bone turnover markers. ALMI is a promising predictor of bone loss in prostate cancer patients receiving androgen deprivation therapy, and ALMI changes during therapy are associated with bone turnover derangement favoring bone quality alterations.

This paper focuses on the issue of housing in inner areas, presenting a project of the candidacy of the Campania region for the PINQuA national funding programme, which was launched by the Italian Ministry of Infrastructure and Transport in 2020. The project is based on the hypothesis that it is possible to reverse the demographic trend in marginalised areas – characterised by a declining population, a high old-age index, a lack of basic services and, at the same time, a high potential for innovation – with building renovation and differentiated housing offers with high standards of quality and services. Through a systemic and place-based approach, the research uses pilot cases to experiment on themes linked to new housing demands, digital and green innovation, proximity welfare and social cohesion through a multi-actor and multi-level process.

Network approaches can be used to study sociosexual partnerships and identify individuals at high risk of infection. Little is known about the cost structure of these services and their association with STD diagnoses.We collected costs associated with using a peer network strategy to recruit men who have sex with men and transwomen of color in 4 counties in North Carolina: Guilford, Forsyth, Durham, and Wake from February through October 2019. We used a comprehensive costing approach to gather detailed retrospective information on the intervention cost, broken down by category and programmatic activity.The sociosexual networks collected consisted of 31 initial seeds (index cases) and 49 peers of those seeds. In peers, 5 cases of human immunodeficiency virus (HIV) and 10 cases of syphilis were identified. The cost per case (HIV or syphilis) identified was $7325. Personnel costs accounted for 80% of total expenditures, followed by laboratory expenses (12%). Personnel cost was distributed between disease intervention specialist patient navigators (51%), nonclinical (37%), and management (12%) staff. General administration was the costliest programmatic activity (37%), followed by case management and field services (37%), and study activities (11%). The estimated average cost per patient tested was $2242.Finding positive peer cases in nonclinical settings is costly but may be crucial for limiting the spread of sexually transmitted diseases. The cost of staff was the major driver. This study demonstrates that using a network strategy can be a cost-effective way to identify, test, and refer patients at high risk of syphilis and HIV infections to care.

Adrenocortical carcinoma (ACC) is a rare cancer of the adrenal gland with generally very unfavourable outcome. Two molecular subgroups, C1A and C1B, have been previously identified with a significant association with patient survival. In this work, we study chromatin state organization characterized by histone modifications using ChIP-sequencing in adult ACC. We describe the super-enhancer landscape of ACC, characterized by H3K27ac, and identify super-enhancer regulated genes that play a significant role in tumorigenesis. We show that the super-enhancer landscape reflects differences between the molecular sub-groups C1A and C1B and identify networks of master transcription factors mirroring these differences. Additionally, we study the effects of molecules THZ1 and JQ1 previously reported to affect super-enhancer-driven gene expression in ACC cell lines. Our results reveal that the landscape of histone modifications in ACC is linked to its molecular subgroups and thus provide the groundwork for future analysis of epigenetic reprogramming in ACC.

Cystinosis, a rare lysosomal storage disease, is characterized by cystine crystallization and accumulation within tissues and organs, including the kidneys and brain. Its impact on neural function appears mild relative to its effects on other organs, but therapeutic advances have led to substantially increased life expectancy, necessitating deeper understanding of its impact on neurocognitive function. Behaviorally, some deficits in executive function have been noted in this population, but the underlying neural processes are not understood. Using standardized cognitive assessments and a Go/No-Go response inhibition task in conjunction with high-density electrophysiological recordings (EEG), we sought to investigate the behavioral and neural dynamics of inhibition of a prepotent response and of error monitoring (critical components of executive function) in individuals with cystinosis, when compared to age-matched controls. Thirty-seven individuals diagnosed with cystinosis (7-36 years old, 24 women) and 45 age-matched controls (27 women) participated in this study. Analyses focused on N2 and P3 No-Go responses and error-related positivity (Pe). Atypical inhibitory processing was shown behaviorally. Electrophysiological differences were additionally found between the groups, with individuals with cystinosis showing larger No-Go P3s. Error-monitoring was likewise different between the groups, with those with cystinosis showing reduced Pe amplitudes.

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Supplementary Data from Immunomodulation of FOXP3+ Regulatory T Cells by the Aromatase Inhibitor Letrozole in Breast Cancer Patients

Purpose: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-α signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival.Experimental Design: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral “metronomic” cyclophosphamide (50 mg/d).Results: Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (P < 0.0001 and P < 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (P < 0.03 and P = 0.50, respectively) and a greater Treg reduction was observed in responding patients (P < 0.03).Conclusion: This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-α-negative tumors in combination with immunotherapy approaches.

Purpose: Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane.Experimental Design: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests.Results:ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane.Conclusion: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC. Clin Cancer Res; 18(12); 3452–61. ©2012 AACR.

The Trino hill is an isolated relief located in north-western Italy, close to Trino municipality. The hill was subject of multidisciplinary studies during the 70s, when, because of quarry activities and agricultural arrangements, five concentrations of lithic artefacts were recognized and referred to a Palaeolithic frequentation of the area. During the 80s and the 90s, surface collections continued, but the lithic finds have never been subject of specific studies. Even if most of the lithic assemblages count a few lithic implements, four collection areas (3, 13 E, 13 W and 14) have significative lithic assemblages, representing the most important evidence of a Palaeolithic frequentation of the Po plain in north-western Italy. The present work, in the limits imposed by a surface and not systematic collection, propose a technological study of the lithic artefacts from the Trino hill, with the aim to define the main features of the technological behaviour of the human groups that inhabited the area. The results obtained allow to clearly identify a Middle Palaeolithic frequentation of the Trino hill, characterized by the exploitation of vein quartz and other local raw materials; allochthonous varieties of chert were used in the next frequentation phases to produce blades and bladelets. Even if part of the laminar production can be referred to Neolithic, most of that remains of indeterminate chronology and could be the result of both an Upper Palaeolithic and Neolithic human presence.

The paper proposes to carry out a preliminary analysis of the Italian food value chain based on the analysis of social agriculture, in particular social farms associated with “antimafia activities”. The analysis is based on the assumption that social agriculture is multifactorial. The text is based on three case studies from different Italian regions: Sicily, Campania and Lazio. The Sicilian farm is the most developed in terms of production sophistication; the small Campania farm gives great importance to non-commodity results, including well-being and landscape restoration; and the farm in Lazio offers a tangential response to the mafia's activities, although its managers carry out a form of direct resistance to the mafia in Rome. Le texte se propose de mener une analyse préliminaire de la chaîne de valeur de l’alimentation italienne à partir de l’analyse de l’agriculture sociale, en particulier les fermes sociales associées aux « activités antimafia ». L’analyse part du principe selon lequel l’agriculture sociale est multifactorielle. Le texte repose sur trois études de cas issues de régions italiennes différentes : la Sicile, la Campanie et le Latium. La ferme sicilienne est la plus développée en termes de sophistication de la production ; la ferme de Campanie, de petite taille, accorde une grande importance résultats non liés aux produits de base, notamment le bien-être et la restauration des paysages ; la ferme située dans le Latium, enfin, offre une réponse tangentielle aux activités de la mafia, bien que ses gestionnaires les définissent comme une forme de résistance directe à la mafia à Rome.

FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.

Purpose The management of patients with advanced/metastatic adrenocortical carcinoma (ACC) is challenging, EDP-M (etoposide, doxorubicin, cisplatin combined with mitotane) is the standard regimen. However, it is quite toxic, so an adequate supportive therapy is crucial to reduce as much as possible the side effects and maintain the dose intensity of cytotoxic agents. Methods We describe the main side effects of the EDP-M scheme and the best way to manage them based on the experience of the Medical Oncology Unit of the Spedali Civili of Brescia. We also deal with the administration of EDP-M in specific frail patients, such as those with huge disease extent and poor performance status (PS) and those with mild renal insufficiency. Results In patients with hormone secreting ACC the rapid control of Cushing syndrome using adrenal steroidogenesis inhibitors such as metyrapone or osilodrostat is mandatory before starting EDP-M. Primary prophylaxis of neutropenia with Granulocyte-Colony Stimulating Factors is crucial and should be introduced at the first chemotherapy cycle. Possible mitotane induced hypoadrenalism should be always considered in case of persistent nausea and vomiting and asthenia in the interval between one cycle to another. In case of poor PS. A 24 h continuous infusion schedule of cisplatin could be an initial option in patients with poor PS as well as to reduce the risk of nefrotoxocity in patients with mild renal impairment. Conclusion A careful and accurate supportive care is essential to mitigate EDP-M side effects as much as possible and avoid that, due to toxicity, patients have to reduce doses and or postpone cytotoxic treatment with a negative impact on efficacy of this chemotherapy regimen.

SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus-Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs' regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24-2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.

Introduction. Antibody-drug conjugates (ADCs) represent a new class of molecular-targeted drugs, which are being developed to selectively target tumor cells and minimize toxicities. Three ADCs, namely trastuzumab emtansine (TDM-1), sacituzumab govitecan, and trastuzumab deruxtecan, are currently approved for the treatment of metastatic breast cancer (MBC). Acute gastrointestinal toxicities are relatively frequent with these agents. We performed a pooled analysis evaluating gastrointestinal adverse events (AEs) in patients with MBC treated with ADCs. Methods. PubMed, Embase, and the Cochrane Library were searched from inception until December 2020 for phase 2 and 3 trials reporting frequency and severity of gastrointestinal AEs in patients treated with ADCs. Data were collected for nausea, vomiting, diarrhea, constipation, and abdominal pain: overall and grade 3-4 toxicity rates according to NCI-CTCAE were described and expressed as proportions. A pre-specified subgroup analysis according to type of agent was also performed. Results. Ten studies, involving a total of 4020 patients, were included in the analysis. Gastrointestinal AEs were very frequent with sacituzumab govitecan and trastuzumab deruxtecan but were mostly low-grade. These novel ADCs were characterized by a significantly higher incidence of nausea (65.6% with sacituzumab govitecan, 77.2% with trastuzumab deruxtecan), vomiting (43.7% and 46.6%), and diarrhea (59.7% and 30.2%) compared to TDM-1. Diarrhea was the main AEs associated with sacituzumab govitecan (grade 3 in 7.5% of patients). Abdominal pain and constipation were reported less frequently. Conclusions. Gastrointestinal AEs, especially nausea and diarrhea, are common in patients with MBC treated with novel ADCs. Prevention and treatment of these side effects are essential to maintain the dose intensity of ADCs and optimize the treatment compliance of patients. Table. Gastrointestinal toxicities of the different ADCs in MBC patients in the current pooled analysis.Gastrointestinal toxicities Toxicity pooled % (CI 95%)Sacituzumab govitecanTDM-1Trastuzumab deruxtecanp*p**p#NauseaAll gradesG3-G457.8 (46.9-68)2.2 (1-4.9)65.6 (61-70)4.3 (2.2-8.3)38.1 (32-44.5)0.8 (0.5-1.2)77.2 (72-81.6)2.6 (0.2-30.6)< 0.01< 0.01< 0.01< 0.01< 0.010.71DiarrheaAll grades G3-G434 (21.8-48.8)2.4 (1.7-3.3)59.7 (52.4-66.6)7.5 (4.3-12.7)17.5 (11.-25.4)0.9 (0.6-1.6)30.2 (25.3-35.7)2.4 (1.1-4.9)< 0.01< 0.01< 0.010.03< 0.010.015VomitingAll grades G3-G432.5 (23.6-42.8)2.7 (1.4-5)43.7 (33.5-54.5)4.4 (1.7-10.8)18.2 (15.3-21.4)1.3 (0.9-1.8)46.6 (41-52.3)4.4 (2.5-7.4)< 0.01< 0.01< 0.01< 0.01NSNSAbdominal painAll grades G3-G414.8 (9.4-22.5)1.2 (0.7-2.1)20.1 (11.9-31.8)1.3 (0.4-3.9)6.2 (4.2-9)1.2 (0.5-2.9)14.5 (9.8-21)0.9 (0.3-3.1)< 0.01NS< 0.01NSNSNSConstipationAll grades G3-G428.7 (20.4-38.9)0.6 (0.4-0.9)32.2 (18.6-49.6)0.8 (0.3-2.6)18 (12-26.1)0.5 (0.3-0.9)35.9 (30.7-41.5)0.7 (0.2-2.7)< 0.01NS< 0.01°NSNSNS* Statistically significant difference (p < 0.05) among the three ADCs.** Statistically significant difference (p < 0.05) for TDM-1 versus the other two ADCs.# Statistically significant difference (p < 0.05) for sacituzumab govitecan versus trastuzumab deruxtecan.° This value was not significant for T-DM1 versus sacituzumab govitecan comparison.CI, confidence interval; NS, not significant. Citation Format: Pierluigi di Mauro, Rebecca Pedersini, Fausto Petrelli, Antonio Ghidini, Vito Amoroso, Lara Laini, Maria Chiara Parati, Paolo Bossi, Alfredo Berruti. Gastrointestinal toxicity of antibody-drug conjugates (ADCs) in metastatic breast cancer: A pooled analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-15.

The use of in-fiber core-to-cladding coupling components for thermal heating purposes has been well assessed in the last decades within the development of fiber optic devices for flow measurements and water thermal conductivity calculation. In these devices, light travelling in the fiber core is transferred into the cladding and absorbed by a metallic layer surrounding the fiber, with the consequent resistive heating generation. Here we demonstrate for the first time the use of a Turn-Around-Point (TAP) Long Period Grating (LPG) as resonant core-to-cladding light coupling mechanism for the fabrication of a highly efficient heating device based on metallic coated Fiber Bragg Grating (FBG). A properly designed TAP LPG was fabricated by means of point-to-point UV laser and spliced to a 150 nm thick Au-coated FBG. The heating efficiency characterizations of the final device were analyzed, in both air and water, by evaluating the temperature increase in the gold layer surrounding the FBG at incremental values of the injected power. Collected results confirm that the use of LPGs involving the excitation of higher order cladding modes provides an excellent transferring mechanism of the fiber core light into the cladding, which in turn guarantees very high thermal heating efficiency to the final device. Moreover, by comparing such results with the performance of other in-fiber core-to-cladding coupling components already presented in literature, it was found that the TAP LPG-based device exhibits an actuation efficiency 2.5 times greater, thus resulting the most effective and highly performing solution for energy transfer to the metallic overcoat.

BackgroundTriple-negative breast cancer (TNBC) is an aggressive cancer subtype, owing to its high metastatic potential: Patients who develop brain metastases (BMs) have a poor prognosis due to the lack of effective systemic treatments. Surgery and radiation therapy are valid options, while pharmacotherapy still relies on systemic chemotherapy, which has limited efficacy. Among the new treatment strategies available, the antibody-drug conjugate (ADC) sacituzumab govitecan has shown an encouraging activity in metastatic TNBC, even in the presence of BMs.Case presentationA 59-year-old woman was diagnosed with early TNBC and underwent surgery and subsequent adjuvant chemotherapy. A germline pathogenic variant in BReast CAncer gene 2 (BRCA2) was revealed after genetic testing. After 11 months from the completion of adjuvant treatment, she had pulmonary and hilar nodal relapse and began first-line chemotherapy with carboplatin and paclitaxel. However, after only 3 months from starting the treatment, she experienced relevant disease progression, due to the appearance of numerous and symptomatic BMs. Sacituzumab govitecan (10 mg/kg) was started as second-line treatment as part of the Expanded Access Program (EAP). She reported symptomatic relief after the first cycle and received whole-brain radiotherapy (WBRT) concomitantly to sacituzumab govitecan treatment. The subsequent CT scan showed an extracranial partial response and a near-to-complete intracranial response; no grade 3 adverse events were reported, even if sacituzumab govitecan was reduced to 7.5 mg/kg due to persistent G2 asthenia. After 10 months from starting sacituzumab govitecan, a systemic disease progression was documented, while intracranial response was maintained.ConclusionsThis case report supports the potential efficacy and safety of sacituzumab govitecan in the treatment of early recurrent and BRCA-mutant TNBC. Despite the presence of active BMs, our patient had a progression-free survival (PFS) of 10 months in the second-line setting and sacituzumab govitecan was safe when administered together with radiation therapy. Further real-world data are warranted to confirm sacituzumab govitecan efficacy in this patient population.

Blade mistuning in blisks arises primarily from the scatters of blade geometry profiles caused by manufacturing tolerance, in-service wear, blade repairs, etc. There is a recent trend to capture the blade-to-blade geometry variances through precise geometry measurements by a 3D optical scanning system in order to obtain an improved blade geometric mistuning evaluation capability. However, this usually leads to prohibitive computational costs due to the large-scale, high-fidelity industrial blisk finite element models. This paper develops an original model reduction approach, Sector Mode Assembling Reduction Technique (SMART), specifically for the high-fidelity blisk model fully mistuned by blade geometric variances, with either topologically compatible or incompatible blade meshes. The basic idea ofSMART is to construct the sector-level reduction mode basis by strategically assembling the truncated cyclic modes independently computed for each “isolated” sector with assumed cyclic symmetry at the sector interfaces. Benefiting from the block structure of the SMART mode basis, the reduced-order models are derived by a series of sector-level projections with a relatively low memory requirement and computational cost. Another hidden benefit is that the SMART approach enables efficient structural modification predictions of the global blisk modes because only the modes of the sectors undergoing blade modification need to be re-evaluated and replaced in theSMARTmodebasis. TheSMARTapproach is applied into a high-fidelity “as-measuredmodel” ofa blended blisk, constructed upon the geometry measurement by the state-of-the-art 3D optical scanning technology. It is fully demonstrated that the reduced-order model derived by SMART, featured by a minimal size, is able to reproduce the dynamics of the full-order as-measured blisk model with high accuracy.

Appendix 1

Rhododendron ripense Makino is a Japanese endemic species of evergreen azaleas, belonging to Ericaceae family. The species has been widely utilised for breeding for 400 years due to its high ornamental value and ability to adapt to different environmental conditions, leading to the creation of several varieties for ornamental purposes. The Rhododendron genus is also known to establish root association with soil fungi. Among the root-associated fungi, the mycorrhizal ones represent a very important group. Ericoid mycorrhizae indeed can act as biostimulants for plants, favouring the nutrient uptake in exchange of carbon, and are able to alleviate certain environmental stresses, facilitating the establishment, survival and persistence of hosting plants in variable habitats. In this work the diversity of root-associated cultivable fungi was thus investigated in R. ripense in the native range of the species. Two sites have been chosen for the sampling, one above and one below the Obara dam constructed on the Hiikawa River, Shimane Prefecture (Japan). The sampling has included bulk soil and hairy roots. The culturable fungi were isolated and molecularly identified through the sequencing of the ITS and 28S DNA regions. In this work, it is reported a snapshot of the biodiversity of the culturable fungi isolated in two years (2012 and 2015) from R. ripense roots in the two natural sites.

In order to complete this set of three companion papers, in this last, we focus our attention on environmental monitoring by taking advantage of photonic technologies. After reporting on some configurations useful for high precision agriculture, we explore the problems connected with soil water content measurement and landslide early warning. Then, we concentrate on a new generation of seismic sensors useful in both terrestrial and under water contests. Finally, we discuss a number of optical fiber sensors for use in radiation environments.

BACKGROUND Non-clear cell (ncc) metastatic renal-cell carcinoma (RCC) has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart. New systemic combination therapies have emerged for metastatic RCC (mRCC), but the pivotal phase III trials excluded patients with nccRCC, which constitute about 30% of metastatic RCC cases. AIM To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup. METHODS The present study is a multicenter retrospective observational analysis aiming to assess the activity, efficacy, and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting. RESULTS Overall, 48 patients were included. At the median follow-up of 40.6 mo, the objective response rate was 27.1%, the disease control rate was 83.3%, and the median progression-free survival and overall survival were 12.3 (95% confidence interval [CI]: 3.6-20.9) and 27.7 (95%CI: 18.2-37.1) mo, respectively. Grade 3 adverse events occurred in 20% of patients, and no grade 4 or 5 toxicities were found. CONCLUSION Pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.