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Studies investigating the effects of language intervention on the re-organization of language networks in chronic aphasia have resulted in mixed findings, likely related to-among other factors-the language function targeted during treatment. The present study investigated the effects of the type of treatment provided on neural reorganization. Seventy individuals with chronic stroke-induced aphasia, recruited from three research laboratories and meeting criteria for agrammatism, anomia or dysgraphia were assigned to either treatment (N = 51) or control (N = 19) groups. Participants in the treatment group received 12-weeks of language intervention targeting sentence comprehension/production, naming, or spelling. At baseline and post-testing, all participants performed an fMRI story comprehension task, with blocks of auditorily-presented stories alternated with blocks of reversed speech. Participants in the treatment, but not control, group significantly improved in the treated language domain. FMRI region-of-interest (ROI) analyses, conducted within regions that were either active (or homologous to active) regions in a group of 22 healthy participants on the story comprehension task, revealed a significant increase in activation from pre-to post-treatment in right-hemisphere homologues of these regions for participants in the sentence and spelling, but not naming, treatment groups, not predicted by left-hemisphere lesion size. For the sentence (but not the spelling) treatment group, activation changes within right-hemisphere homologues of language regions were positively associated with changes in measures of verb and sentence comprehension. These findings support previous research pointing to recruitment of right hemisphere tissue as a viable route for language recovery and suggest that sentence-level treatment may promote greater neuroplasticity on naturalistic, language comprehension tasks, compared to word-level treatment.

Triple-negative breast cancer (TNBC) represents approximately 10-20% of Breast Cancer (BC) diagnosed worldwide and in accordance with the current guideline it is defined by the absence of expression of the of expression of the estrogen receptor (ER=60yThe majority of BC was diagnosed at an early stage. All TNBCs present ductal histotype, mostly with high proliferation rate and grading 3. Characteristics of tumors are shown in Table 1. In our cohort, PALB2 mutations were the most frequent PVs in non-BRCA genes, in line with several previous studies. Interesting, we identified RAD51C/D mutations as second PVs non-BRCA genes, in support of certain studies that suggest an association with an increased risk for TNBC and OC. In conclusion, our results support the MGP using, opening the question about the 60-year cut off for genetic testing in TNBC, regardless of family history. Table 1.Characteristics of TNBC tumors in patients carrying other than BRCA gene mutationsPALB2RAD51C/DATMMUTYHBRIPPMS2PTENNBNBARD1CHECK2TP53Number of patients165332111111Mean age at diagnosis (y)61.4 (44-94)48 (33-62)52.3 (49-54)44.3(40-50)42.5 (36-49)394958485036Ki 67 (%)=406(54.5%)4(100%)1(50%)1 (50%)1(100%)100100unknown51111000011GradingG1-23 (25%)0000001000G39 (75%)4 (100%)3 (100%)3(100%)2(100%)110101Unknown41000000010Histotypeductal14 (100%)4(100%)3(100%)3(100%)2(100%)110111others00000001000unknown21000000000Stage at diagnosisI7 (63.6%)3 (60%)01 (100%)1 (100%)010000II4 (36.4%)1 (20%)2 (100%)00001000III01 (20%)000300000unknown50121000111 Citation Format: Laura Cortesi, Marta Venturelli, Angela Toss, Claudia Piombino, Elena Barbieri, Elisabetta Razzaboni, Luca Moscetti, Federico Piacentini, Claudia Omarini, Federica Domati, Massimo Dominici. Characteristics of TNBC patients carrying other than BRCA gene mutations [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 P2-09-14.

In recent years, the improvement in health and social conditions has led to an increase in the average lifespan. Since aging is the most important risk factor for the majority of chronic human diseases, the development of therapies and intervention to stop, lessen or even reverse various age-related morbidities is an important target to ameliorate the quality of life of the elderly. The gut microbiota, that is, the complex ecosystem of microorganisms living in the gastrointestinal tract, plays an important role, not yet fully understood, in maintaining the host’s health and homeostasis, influencing metabolic, oxidative and cognitive status; for this reason, it is also named “the forgotten endocrine organ” or “the second brain”. On the other hand, the gut microbiota diversity and richness are affected by unmodifiable factors, such as aging and sex, and modifiable ones, such as diet, pharmacological therapies and lifestyle. In this review, we discuss the changes, mostly disadvantageous, for human health, induced by aging, in microbiota composition and the effects of dietary intervention, of supplementation with probiotics, prebiotics, synbiotics, psychobiotics and antioxidants and of physical exercise. The development of an integrated strategy to implement microbiota health will help in the goal of healthy aging.

The aim of this work is to evaluate the dynamics of dust deposition and characterize its elemental composition in case study at Chubut coastal Patagonia in Argentina after a shrubland fire. On 22 December 2016, a fire took place (42°20′ S–65° W) covering ~ 30 thousand hectares (300 km2) of shrublands. Immediately after the fire (2 January 2017), monthly deposition of dust was recorded using passive collectors in burned and control regions until December 2017. The dust plume of the burned region, visible from MODIS imagery, reached more than 150 km from the coast toward the marine area. In the burned region, dust deposition rates peaked in February (84.75 mg/day m−2), decreased until May (mean value = 12 mg/day m−2), and afterward remained constant (mean value = 10 mg/day m−2) above background level during the studied period. In the control region, dust deposition was constant and significantly lower (mean value = 0.19 mg/day m−2). Overall, the dust elemental composition was mainly Si and O corresponding to silicate minerals. Material from the burned region presented peaks of C. On the other hand, C signals were not present in the dust from the control region. The presence of C, suggests a direct consequence of the burned vegetation. The burned region may become a significant source of dust due to the reduced vegetation coverage, and may constitute an additional input of C into the marine ecosystem. The present study is the first report that provides insights that a burned region in Patagonia may act as a dust source.

Objective BRCA carriers are recommended to undergo prophylactic risk-reducing salpingo-oophorectomy (RRSO). Possible adverse health impacts of RRSO, particularly when done before natural menopause, can reduce the long-term satisfaction with this risk-reducing strategy. The aim of this study was to prospectively evaluate the level of satisfaction of women undergoing RRSO, also in relation to some specific characteristics at RRSO. Methods A prospective cohort study was performed in the Modena Family Cancer Clinic of the University Hospital of Modena (Italy). All BRCA1/2 confirmed mutation carriers who decided to undergo RRSO were recruited between 2016 and 2019. Results Fifty-five women (29 BRCA1 and 26 BRCA2) (mean age: 50.4 ± 7.7 years [range 35-79]) were included with a mean follow-up after RRSO of 660.9 days (1.8 years) (range 35-1,688 days) (median: 549 days). No intraepithelial (Serous Tubal Intraepithelial Carcinoma)/invasive cancers were found (0%) at RRSO. No vasomotor symptoms at 1 month after surgery were reported by 11/22 (50%) premenopausal women at RRSO. All women (100%) with new "RRSO-caused" vasomotor symptoms with no previous breast cancer initiated postmenopausal hormone therapy. At the final follow-up the satisfaction rate (0-100 visual analog scale points) of the participants was 96.4 ± 8.6 points (range 62-100). To the question "Would you undergo RRSO again if it was proposed today? (0-100 visual analog scale points)" the answer was 99.4 ± 3.2 points (range 79-100). These scores were in general very high and did not change in the different groups according to pre/postmenopausal status at RRSO, cancer survivors versus healthy women at RRSO, BRCA status, hormone therapy users/nonusers after RRSO, "RRSO-caused" symptoms versus not RRSO-caused (P > 0.05). Conclusions Findings from this prospective study suggest that satisfaction with RRSO is very high and little dependent on the participants' characteristics at surgery. Women at high risk for ovarian cancer are very satisfied with their choice of risk-reduction strategy.

Triple-negative breast cancer (TNBC) patients who do not obtain pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. Risk factors for relapse in this subset of patients are poorly characterized. This study aimed to identify predictive factors for relapse in TNBC patients without pCR after NACT. Women with TNBC treated with NACT from January 2008 to May 2020 at the Modena Cancer Center were included in the analysis. We identified 142 patients with median follow-up of 55 months. After NACT, 62 patients obtained pCR (43.9%). Young age at diagnosis (< 50 years) and high ki-67 (>20%) were significantly associated to pCR. Lack of pCR after NACT resulted in worse 5-year EFS and OS. Factors independently predicting EFS in patients without pCR were the presence of multifocal disease (HR 3.22; 95% CI, 1.28–8.11; P 0.01) and Residual Cancer Burden (RCB) III (HR 3.8; 95% CI, 1.12–12; P 0.03). These data can be used to stratify patients and potentially guide treatment decision-making, identifying appropriate candidates for treatment intensification especially in neo/adjuvant setting.

Objective: As prostate cancer (PrC) shows a BRCA mutation rate as high as 30%, it becomes crucial to find the optimal selectioncriteria for genetic testing. The primary objective of this study was to evaluate the BRCA mutation rate in families with PrC associatedwith breast and/or ovarian cancers; secondary aims were to compare the characteristics of families and BRCA-related PrC outcomeamong BRCA1 and BRCA2 carriers. Methods: Following the Modena criteria for the BRCA test, we evaluated the mutation rate in families with breast and/or ovariancancer with a Gleason score ≥7 PrCs, by testing breast or ovarian cases and inferring the mutation in the prostate cases. Thecharacteristics of families and BRCA-related PrC outcomes were measured using the chi-square (χ2) test and Kaplan–Meier methods,respectively. Results: Among 6,591 families, 580 (8.8%) with a Gleason score ≥ 7 PrCs were identified, of which 332 (57.2%) met the Modenaselection criteria for BRCA testing. Overall, 215 breast or ovarian cancer probands (64.8%) were tested, of which 41 resulted positivefor BRCA and one for CHEK2 genes (19.5%). No statistically significant differences were found in BRCA-related PrC prognosis andin the characteristics of families among BRCA1, BRCA2 and non-tested patients. Ten of 23 (44%) mutations in the BRCA2 gene fellin the prostate cancer cluster region (PCCR) at the 3′ terminal of the 7914 codon. Conclusions: It appears the Modena criteria are very useful for BRCA testing selection in families with breast and/or ovarian cancerand PrC. A trend toward a worse prognosis has been found in BRCA2 carriers.

This study reports the results of a longitudinal study examining the effects of treatment for sentence processing deficits for a 70-year-old gentleman (DK) with the agrammatic variant of Primary Progressive Aphasia (PPA). On entry into the study, he presented with a 2-year history of impaired verb and sentence processing and concomitant neural atrophy in primarily subcortical regions. Spanning an 18-month period, treatment focused on improving comprehension and production of syntactically complex, passive and object cleft, structures, consecutively. Results, derived from extensive behavioral and neurocognitive testing, showed not only improved ability to comprehend and produce both trained and untrained, less complex, linguistically related structures in offline tasks, but also improved online sentence processing strategies as revealed by partially normalized eye movements in online comprehension (i.e., emergence of thematic prediction and thematic integration) and production (i.e., use of incremental processing) tasks. Changes in neural activation from pre- to post-treatment of both structures also were found, with upregulation of tissue in both the left and right hemispheres, overlapping with regions recruited by neurotypical adults performing the same task. These findings indicate that Treatment of Underlying Forms (TUF) is effective for treatment of patients with the agrammatic variant of PPA (as it is for those with stroke-induced agrammatism), and show that unaffected neural tissue in patients with PPA is malleable and may be recruited to support language, providing evidence of experience-based plasticity in neurodegenerative disease.

A decline in muscle mass and function represents one of the most problematic changes associated with aging, and has dramatic effects on autonomy and quality of life. Several factors contribute to the inexorable process of sarcopenia, such as mitochondrial and autophagy dysfunction, and the lack of regeneration capacity of satellite cells. The physiologic decline in muscle mass and in motoneuron functionality associated with aging is exacerbated by the sedentary lifestyle that accompanies elderly people. Regular physical activity is beneficial to most people, but the elderly need well-designed and carefully administered training programs that improve muscle mass and, consequently, both functional ability and quality of life. Aging also causes alteration in the gut microbiota composition associated with sarcopenia, and some advances in research have elucidated that interventions via the gut microbiota–muscle axis have the potential to ameliorate the sarcopenic phenotype. Several mechanisms are involved in vitamin D muscle atrophy protection, as demonstrated by the decreased muscular function related to vitamin D deficiency. Malnutrition, chronic inflammation, vitamin deficiencies, and an imbalance in the muscle–gut axis are just a few of the factors that can lead to sarcopenia. Supplementing the diet with antioxidants, polyunsaturated fatty acids, vitamins, probiotics, prebiotics, proteins, kefir, and short-chain fatty acids could be potential nutritional therapies against sarcopenia. Finally, a personalized integrated strategy to counteract sarcopenia and maintain the health of skeletal muscles is suggested in this review.

Hereditary cancer syndromes are inherited disorders caused by germline pathogenic variants (PVs) that lead to an increased risk of developing certain types of cancer, frequently at an earlier age than in the rest of the population. The germline PVs promote cancer development, growth and survival, and may represent an ideal target for the personalized treatment of hereditary tumors. PARP inhibitors for the treatment of BRCA and PALB2-associated tumors, immune checkpoint inhibitors for tumors associated with the Lynch Syndrome, HIF-2α inhibitor in the VHL-related cancers and, finally, selective RET inhibitors for the treatment of MEN2-associated medullary thyroid cancer are the most successful examples of how a germline PVs can be exploited to develop effective personalized therapies and improve the outcome of these patients. The present review aims to describe and discuss the personalized systemic therapies for inherited cancer syndromes that have been developed and investigated in clinical trials in recent decades.

Background Healthy lifestyle, including caloric restriction, balanced diet and physical activity, is important in primary and secondary prevention of breast cancer (BC). It is known that Mediterranean diet reduces metabolic syndrome and insulin resistance that are associated with increased risk of BC onset and recurrence. Physical activity decreases BMI, blood concentrations of testosterone, estrogens, insulin, its resistance and strengthens anti-inflammatory pathways against tumor cells. Since January 2014, at our Institution we promoted a project named “Lifestyle Program” for high risk BC patients underwent to primary surgery. Here we presented the results of 12 months of “Lifestyle Program”. Patients and methods Since January 2014 we have prospectively enrolled all high risk patients between 18 and 70 years treated to our department for invasive early-stage breast cancer (stage I-III). High risk has been defined by one or more of the following inclusion criteria: body mass index (BMI) > 25, diagnosis of metabolic syndrome, increased level of blood testosterone and/or insulin. All high risk patients receive a periodical personalized educational intervention by a physiatrist for physical activity and by a nutritionist for a mediterranean diet low in animals fat and enriched of fibers, fruits and vegetables. All patients underwent to screening for anxiety and depression through HADS questionnaire scores. All data were analyzed by Chi-square test assuming statistical significance at p25 in 94.9% of pts at baseline vs 63.2% after 12 months of lifestyle; p=110 mg/dl in 23.5% of pts at baseline vs 10.2% at 12 months; p=27 uU/ml in 20.6% of pts at baseline vs 2.9% after 12 months; p1,2 ng/ml in 17.6% of pts at baseline vs 4.1% at 12 months; p200 mg/dl in 46.9% of pts at baseline vs 35.7% at 12 months; p170 mg/dl in 13.3% of pts at baseline vs 10.2% at 12 months; p Citation Format: Mirco Pistelli, Valentina Natalucci, Lucia Bastianelli, Laura Scortichini, Veronica Agostinelli, Filippo Merloni, Agnese Savini, Marianna Capecci, Maria Gabriella Ceravolo, Roberta Serrani, Maurizio Ricci, Marina Taus, Albano Nicolai, Elena Barbieri, Rossana Berardi. Assessing the impact of 12 months lifestyle interventions on breast cancer secondary prevention: A modeling approach [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD11-03.

The standard first-line for endocrine sensitive metastatic breast cancer (BC) is represented by endocrine therapy. Several phase III clinical trials searched for more effective endocrine strategies. Nevertheless, the use of combinations for the first-line treatment of bone-only disease (BoD) is widely discussed, due to its indolent course. Our meta-analysis aims to explore the role of new endocrine strategies in BoD. A systematic review of electronic databases was conducted to identify the phase III clinical trials comparing the standard AI to novel experimental strategies. The hazard ratios (HR) for PFS were pooled in a meta-analysis. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. 8 studies were included in the analyses. 4 trials explored the role of CDK4/6 inhibitors (Monaleesa2 and 7, Monarch3 and Paloma2), 2 trials analyzed Fulvestrant + AI (SWOG and FACT), one trial studied Fulvestrant monotherapy (FALCON), while one trial evaluated the association between Bevacizumab and Letrozole (ALLIANCE). 6 trials reported data regarding the BoD, while 2 trials included the BoD in the non-visceral disease. Overall, the meta-analyses showed a PFS advantage for the experimental arms [HR 0.70 p 0.012], with a significant moderate/high heterogeneity [I2 66.48% p 0.004]. Only the FALCON and Paloma2 showed a significant improvement in PFS, respectively for Fulvestrant and Palbociclib + Letrozole. Considering only trials reporting data for BoD, the experimental arms significantly improved the PFS [HR 0.66 p 0.005], with a low/moderate non-significant heterogeneity [I2 44.95% p 0.106]. The novel strategies showed to be able to improve the PFS of BoD. Nonetheless, only Palbociclib + Letrozole provided statistically significant data of advantage in this setting. In clinical trials, BoD is often included in the non-visceral disease subgroup. Future clinical trials should take into account the differences in natural history and better prognosis of BoD, in order to define the best approach to these patients. Citation Format: Toss A, Venturelli M, Sperduti I, Isca C, Molinaro E, Barbieri E, Piacentini F, Omarini C, Cortesi L, Cascinu S, Moscetti L. First-line treatment for endocrine sensitive bone-only metastatic breast cancer: Is more always better? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-18-06.

Given the benefits of physical activity for breast cancer survivals, this pilot study aims to assess the feasibility of the MOTIVE program at achieving and maintaining the recommended physical activity level in women diagnosed and treated breast cancer, over 16 weeks. We conduct a pilot-controlled study of 20 women diagnosed with breast cancer stage I, II or IIIa. In this study, women of Intervention Arm (n = 10) received the MOTIVE program. This group was compared to women of Control Arm (n = 10) who received only counselling. Health-related fitness measures, and quality of life were assessed at baseline (t0) and after 4 (t1), 8 (t2) and 16 (t3) weeks. Intervention Arm women reached the recommended physical activity guidelines at t1 and t2 (eff.size = 1.9 [1.0–3.1]), and 90% continued to be active, autonomously, at t3 (eff.size = 1.12 [0.21–2.12]). Intervention Arm participants’ arm strength, fitness levels and quality of life also improved over time. No significant improvements in outcome measures were observed in Control Arm participants. These results are encouraging and suggest that the MOTIVE program may be a viable, well tolerated and effective option to help breast cancer women reaching a stable physical activity level over time, which meets prevention-related goals., Physical activity; Adherence; Breast cancer; Aerobic exercise; Strength training; Secondary/tertiary prevention; Lifestyle; Public health.

Objectives The Next Generation Sequencing (NGS) based mutational study of hereditary cancer genes is crucial to design tailored prevention strategies in subjects with different hereditary cancer risk. The ease of amplicon-based NGS library construction protocols contrasts with the greater uniformity of enrichment provided by capture-based protocols and so with greater chances for detecting larger genomic rearrangements and copy-number variations. Capture-based protocols, however, are characterized by a higher level of complexity of sample handling, extremely susceptible to human bias. Robotics platforms may definitely help dealing with these limits, reducing hands-on time, limiting random errors and guaranteeing process standardization. Methods We implemented the automation of the CE-IVD SOPHiA Hereditary Cancer Solution™ (HCS) libraries preparation workflow by SOPHiA GENETICS on the Hamilton’s STARlet platform. We present the comparison of results between this automated approach, used for more than 1,000 DNA patients’ samples, and the performances of the manual protocol evaluated by SOPHiA GENETICS onto 240 samples summarized in their HCS evaluation study. Results We demonstrate that this automated workflow achieved the same expected goals of manual setup in terms of coverages and reads uniformity, with extremely lower standard deviations among samples considering the sequencing reads mapped onto the regions of interest. Conclusions This automated solution offers same reliable and affordable NGS data, but with the essential advantages of a flexible, automated and integrated framework, minimizing possible human errors and depicting a laboratory’s walk-away scenario.

Next-generation sequencing (NGS)-based cancer risk screening with multigene panels has become the most successful method for programming cancer prevention strategies. ATM germ-line heterozygosity has been described to increase tumor susceptibility. In particular, families carrying heterozygous germ-line variants of ATM gene have a 5- to 9-fold risk of developing breast cancer. Recent studies identified ATM as the second most mutated gene after CHEK2 in BRCA-negative patients. Nowadays, more than 170 missense variants and several truncating mutations have been identified in ATM gene. Here, we present the molecular characterization of a new ATM deletion, identified thanks to the CNV algorithm implemented in the NGS analysis pipeline. An automated workflow implementing the SOPHiA Genetics’ Hereditary Cancer Solution (HCS) protocol was used to generate NGS libraries that were sequenced on Illumina MiSeq Platform. NGS data analysis allowed us to identify a new inactivating deletion of exons 19–27 of ATM gene. The deletion was characterized both at the DNA and RNA level.

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. Fil: Rubilar Panasiuk, Cynthia Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina Fil: Barbieri, Elena Susana. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina Fil: Gázquez, Ayelén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús). Universidad Nacional de San Martín. Instituto de Investigaciones Biotecnológicas. Instituto de Investigaciones Biotecnológicas "Dr. Raúl Alfonsín" (sede Chascomús); Argentina Fil: Avaro, Marisa. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina Fil: Vera Piombo, Mercedes. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina Fil: Gittardi Calderón, Agustín Adolfo. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina Fil: Seiler, Erina Noé. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina Fil: Fernandez, Jimena Pía. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina Fil: Sepúlveda, Lucas Roberto. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Centro para el Estudio de Sistemas Marinos; Argentina Fil: Chaar, Florencia. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ciencias Naturales - Sede Puerto Madryn. Instituto Patagónico del Mar; Argentina

To compare the effect of high-intensity aerobic (AER), resistance (RES), and combined (COMB: RES + AER) exercise, on interstitial glucose (IG) variability and skeletal muscle signalling pathways in type 1 diabetes (T1D). T1D participants (6 M/6F) wore a flash glucose monitoring system in four randomized sessions: one control (CONT), and one AER, RES and COMB (40 min each). Mean amplitude of glycemic excursions (MAGE), standard deviation (SD) and coefficient variation (CV) of IG were used to compare the 24 h post-exercise IG variability. Blood and muscle samples were collected to compare exercise-induced systemic and muscle signalling responses related to metabolic, growth and inflammatory adaptations. Both RES and COMB decreased the 24 h MAGE compared to CONT; additionally, COMB decreased the 24 h SD and CV. In the 6–12 h post-exercise, all exercise modalities reduced the IG CV while SD decreased only after COMB. Both AER and COMB stimulated the PGC-1α mRNA expression and promoted the splicing of IGF-1Ea variant, while Akt and p38MAPK phosphorylation increased only after RES and COMB. Additionally, COMB enhanced eEF2 activation and RES increased myogenin and MRF4 mRNA expression. Blood lactate and glycerol levels and muscle IL-6, TNF-α, and MCP-1 mRNAs increased after all exercise sessions, while serum CK and LDH level did not change. COMB is more effective in reducing IG fluctuations compared to single-mode AER or RES exercise. Moreover, COMB simultaneously activates muscle signalling pathways involved in substrate metabolism and anabolic adaptations, which can help to improve glycaemic control and maintain muscle health in T1D.

Some hereditary ovarian cancer cases can be associated with a mutation of a gene involved in the DNA double-strand break repair system other than BRCA, such as BRIP1. This mutation is an emerging indication for prophylactic risk-reducing salpingo-oophorectomy (RRSO): however, anomalous tubal pathologic lesions have not yet been reported during RRSO performed for this specific indication (BRIP1), as largely reported for BRCA mutation carriers. An asymptomatic 64-year-old woman with a family history of ovarian and breast cancer agreed to undergo RRSO for a pathogenic variant of the BRIP1 gene (heterozygous NM_032043.2: c.124delT, p. Cys42Valfs) with normal BRCA genes. Histological examination showed the presence of high-grade serous carcinoma of the fimbria of the right tube of a maximum diameter of 0.4 cm (final FIGO stage IIB). The pathogenic mechanism that leads to the development of high-grade serous ovarian/fallopian tube cancer in patients with mutations of BRIP1 should be the same as for patients with mutations of BRCA1 and 2. Our case confirms to consider BRIP1 mutation to be sufficient to justify RRSO at 45-50 years old.

There is growing evidence of an association between physical activity and a reduced risk of cancer and cancer recurrence. The aim of this study was to assess the effects of exercise-conditioned human serum (HS) effects on the proliferative and tumorigenic potential of triple-negative breast cancer (TNBC) and prostate cancer (PC) cells. Moreover, modulated mechanisms and several physiological factors that can predict exercise effects were investigated. Thirty healthy sedentary subjects were recruited for the study. The subjects performed two high-intensity endurance cycling (HIEC) sessions before and after a nine-week period of high-intensity interval training (HIIT). Cell tumorigenic capacity affected by HS collected before (t0), immediately after (t1), 4 h (t2), and 24 h (t3) after the HIEC sessions was evaluated by in vitro three-dimensional colony formation. The modulation of molecular pathways was analyzed by western blotting and qPCR in TNBC and PC cells, and in TNBC xenografts in exercised mice. All of the HIEC-conditioned HS (t1, t2, and t3) markedly impacted the proliferative and the microtumor-forming capacity of both TNBC and PC cell lines, while the HS collected from the subjects at rest did not. Modulation of the Hippo and Wnt/β-catenin pathways by HIEC-conditioned HS before and after the period of HIIT was shown. Multiple linear regression analysis showed relationships between the effects of HIEC-conditioned HS in PC cells, lactate threshold and VO2max. These results highlight the potential of HIEC bouts in tumor progression control and the importance of optimizing an approach to identify physiological predictors of the effects of acute exercise in tertiary cancer prevention.

Background Elderly patients are underrepresented in clinical study where combined endocrine strategies were compared to endocrine therapy (ET) in hormone receptors positive, HER2 negative, metastatic breast cancer. The role of the new endocrine approaches in elderly women is still unclear. Methods We performed a meta-analysis of first line phase II/III randomized trials on ET versus combined strategies considering clinical benefit and safety profile. Trials with hazard ratio (HR) for PFS in elderly patients were included. Results Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. For patients on CDK 4/6 inhibitors and ET, HR was 0.57 (p

Introduction: Deficits in language comprehension and production have been repeatedly observed in Schizophrenia Spectrum Disorders (SSD). However, the characterization of the language profile of this population is far from complete, and the relationship between language deficits, impaired thinking and cognitive functions is widely debated. Objective: The aims of the present study were to assess production and comprehension of verbs with different argument structures, as well as production and comprehension of sentences with canonical and non-canonical word order in people with SSD. In addition, the study investigated the relationship between language deficits and cognitive functions. Methods: Thirty-four participants with a diagnosis of SSD and a group of healthy control participants (HC) were recruited and evaluated using the Italian version of the Northwestern Assessment of Verbs and Sentences (NAVS, Cho-Reyes & Thompson, 2012; Barbieri et al., 2019). Results: Results showed that participants with SSD were impaired – compared to HC – on both verb and sentence production, as well as on comprehension of syntactically complex (but not simple) sentences. While verb production was equally affected by verb-argument structure complexity in both SSD and HC, sentence comprehension was disproportionately more affected by syntactic complexity in SSD than in HC. In addition, in the SSD group, verb production deficits were predicted by performance on a measure of visual attention, while sentence production and comprehension deficits were explained by performance on measures of executive functions and working memory, respectively. Discussion: Our findings support the hypothesis that language deficits in SSD may be one aspect of a more generalized, multi-domain, cognitive impairment, and are consistent with previous findings pointing to reduced inter- and intra-hemispheric connectivity as a possible substrate for such deficits. The study provides a systematic characterization of lexical and syntactic deficits in SSD and demonstrates that psycholinguistically-based assessment tools may be able to capture language deficits in this population.

Prototypical items within a semantic category are processed faster than atypical items within the same category. This typicality effect reflects normal representation and processing of semantic categories and when absent may be reflective of lexical–semantic deficits. We examined typicality effects in individuals with semantic and nonsemantic variants of primary progressive aphasia (PPA; semantic—PPA-S, agrammatic—PPA-G), a neurodegenerative disorder characterized by specific decline in language function, and age-matched controls. Using a semantic category verification task, where participants were asked to decide whether visual or auditory words (category typical, atypical, or nonmembers) belonged within a specified superordinate category, we found a typicality effect (ie, faster response times for typical vs atypical items) for all participant groups. However, participants with more severe PPA-S did not show a typicality effect in either modality. Findings may reflect increased intracategory semantic blurring as the disease progresses and semantic impairment becomes more severe.

The dynamics of phytoplankton across a seasonal frontal system formed in San Jose Gulf (SJG, Patagonia Argentina) and in neighbouring shelf waters was assessed based on bio-optical satellite data (2003–2018) and spring and summer in situ samplings. Bio-optical properties of the water masses on the eastern (ED) and western (WD) domains of the seasonal frontal system of SJG showed clear differences: the year-round-vertically-mixed waters from the WD, strongly connected with the adjacent shelf waters, evidenced a brief and strong single phytoplankton bloom, while those from the ED, showing lower exchange with shelf waters and a strong vertical stratification during the warm season, displayed an earlier and long-lasting spring phytoplankton bloom, followed by a late-summer and autumn bloom, both associated with the development and erosion of the seasonal thermocline. Waters from the entire system are optically influenced by the absorption of coloured dissolved organic matter and detritus (cdom + detritus), suggesting a strong sediment load contribution from the continent and the seabed. To remark, a strong correlation between satellite chlorophyll-a (Chla-sat) and absorption by phytoplankton (aphy443) in the outer shelf waters differs from the weak correlation of those variables in the gulf's water masses, whose optical parameters are more complex. In situ Chla records may indicate wind-driven upwelling and downwelling areas in the northern and southern coasts of the ED. Dissolved nitrogen was identified as the limiting macronutrient for phytoplankton growth in the ED during summer. This work contributes relevant ecological information that may support management actions on the SJG shellfish artisanal fishery.

Simple Summary High body mass index (BMI) is correlated with an increased production of hormones (estrogens, insulin, testosterone, leptin), and pro-inflammatory cytokines, which have been associated with breast cancer (BC) risk and recurrence. Regular physical activity (PA) decreases BMI and blood concentrations of testosterone, estrogens, insulin and pro-inflammatory cytokines. Moreover, the Mediterranean diet (MD) reduces obesity, metabolic syndrome (MS) and insulin resistance, which are all associated with increased risk of BC onset and recurrence. Despite the accumulating evidence of the detrimental effect of physical inactivity and overweight on BC recurrence, weight control and PA counseling are not yet current practice. The principal aim of the lifestyle intervention is to promote weight loss through diet and physical activity in overweight and/or high-risk breast cancer survivors. Moreover, implementing a “lifestyle interventions program” in clinical practice can lead to improvements in psychophysical well-being and favor the correction of cardiovascular risk factors and compliance with endocrine therapy, potentially translating into a prognostic advantage. Abstract A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

Background Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers. Methods We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50–69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis. Results Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor–negative or HER2-positive status (odds ratio = 1.7; 95% confidence interval [CI]: 1.1–2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%–94.5%) versus 93.8% (95% CI: 86.5%–100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6–16.7). Conclusions IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.

The antimitotic agent eribulin, a synthetic analog of halichondrin B isolated from a marine sponge, resulted particularly effective in improving the overall survival of heavily pretreated metastatic breast cancer (MBC) patients in randomized Phase III clinical trials and real-life studies. However, only scant information is available on the clinical experiences of patients who underwent long-lasting eribulin treatment followed by a rechallenge. Here we presented two cases of MBC women previously treated with several lines of chemotherapy and hormonal therapies, who underwent long-lasting treatment and rechallenge with eribulin, showing a partial response in both periods. These anecdotal experiences suggest that rechallenge with eribulin could represent a treatment strategy for advanced MBC and it should be evaluated in a larger study.

Investigating the neurobiology of language impairment and treatment in chronic stroke aphasia using fMRI requires an understanding of measurement variability within and between participants. In this multicenter study, we evaluated the scan-rescan reliability of an auditory and visual (written) story comprehension paradigm in stroke participants with aphasia (N = 65) and healthy controls (N = 22). The multi-modal task was conducted twice (~1 week apart) on separate visits upon study enrolment and twice again at completion three months later. A non-language visuomotor task was studied in the aphasia group only, which was conducted once per time point (3 months apart). While participants were asked to make responses during the comprehension task, these in-scanner responses were not recorded. Reliability was assessed using intraclass correlation coefficient (ICC) at both group and individual participant levels. The visual story comprehension condition had higher reliability than the auditory condition in both groups, with participants with aphasia exhibiting lower reliability than controls in both conditions (stroke ICC = .43, healthy ICC = .81). Differences in reliability within the group of participants with aphasia were found to be partially explained by overall language impairment as well as greater head motion. In the participants with aphasia, the visuomotor paradigm was found to have greater reliability than the story comprehension task at equivalent interscan intervals (visuomotor = 0.50, comprehension = 0.34), and its reliability was not associated with language impairment. This work highlights the importance of considering the reliability of fMRI tasks in aphasia research, provides strategies to improve reliability and has potential implications for the field of clinical neuroimaging in general.

In the last decade, several clinical trials have investigated novel endocrine combinations for the first-line treatment of hormone receptor-positive metastatic breast cancer. Nevertheless, the use of combinations for the first-line treatment of bone-only disease is widely discussed as a result of its indolent natural history. We performed a comprehensive search of phase 3 randomized clinical trials published in the literature through September 2018. Our aim was to explore the role of the new endocrine approaches in bone-only metastatic breast cancer, suggesting a possible strategy for their selection. In particular, we evaluated the comparative risk of adverse event occurrence during these treatments. A total of 6 studies were deemed suitable for meta-analysis: the Monaleesa-2, Monaleesa-7, Monarch-3, Paloma-2, SWOG, and Alliance trials. Overall, the novel strategies were shown to improve progression-free survival in bone-only disease (hazard ratio = 0.65; 95% confidence interval, 0.49-0.86; P = .003). Combinations with cyclin-dependent kinase inhibitors improved progression-free survival (hazard ratio = 0.54; 95% confidence interval, 0.39-0.75; P < .001) with an acceptable toxicity profile. Abemaciclib was associated with increased anemia and gastrointestinal toxicity (especially diarrhea), whereas palbociclib was associated with increased leukopenia (but not neutropenia) compared to the other compounds. Increased aspartate aminotransferase levels were reported for both ribociclib and abemaciclib. The combination of cyclin-dependent kinase 4/6 inhibitors and endocrine therapy represents an effective and well-tolerated approach for first-line treatment in bone-only disease settings. Because no direct comparison between the 3 cyclin-dependent kinase 4/6 inhibitors is available, the selection of the most appropriate treatment should be based on toxicity profile as well as patient preference and copathologies.

Background: Sequential intra-articular injections of linear and cross-linked hyaluronic acids in the treatment of gonarthrosis Objectives: This study evaluates clinical and biochemical effects of sequential intra-articular (IA) injections of two different formulations of hyaluronic acid (HA) in gonarthrosic (GA) patients. The first formulation consists in linear HA (LHA, MW 800-1200kDa; Regenflex Starter, Regenyal Labs, Italy) and the second in an intercalated mixture of cross-linked and linear HAs (CL-LHA, MW 1-2 MDa the crosslinked form and 500kDa the linear, intercalated one; Regenflex BioPlus). Methods: 39 knee GA patients, 19 adults (50–65 years) and 20 elderly (>65 years), underwent two IA injections, i.e. LHA only at baseline and CL-LHA after 1 week. The same injections were repeated after 6 months. Clinical assessment - visual analogic scale (VAS) for pain, range of motion (ROM) and WOMAC index for knee functional limitation - was performed at baseline and after 3, 6, 9, 12 months. Blood, collected at baseline, after 1 week and 3 months, was analysed for relevant cytokines and collagen telopeptide II (CTX-II). Synovial fluid (SF) from patients with recurrent knee effusion (GA worse group) was biochemically analysed at baseline and 1 week. SF proteomic analysis was also carried out at specific time points. Results: This HA-regimen improved joint pain and function independently from the age; plasma and synovial biochemical analyses indicate the attenuation of inflammatory cytokines (IL-1β, IL-9 and IL-17) and the stabilization of CTX-II; ultrasonograph data show an improvement of cartilage conditions and thickness at 12 months. Conclusion: Sequential IA injections of LHA and CL-LHA represent a highly effective treatment especially in low degree GA patients and produce a significant and perduring improvement also in the GA worse group. The efficacy is likely dependent on the sequential administration of LHA and CL-LHA: the pharmacokinetic rationale of this combination will be discussed. References: E. Barbieri1,2*, P. Sestili1, F. Mannello1, G. Annibalini1, S. Contarelli1, L. Vallorani1, A. M. Gioacchini1, D. Ligi1, L. Croce1, Tung Tran Dang Xuan3, C. Bartolucci1 V. Stocchi1 and I. Capparucci1 1Department of Biomolecular Sciences, University Urbino Carlo Bo, via A. Saffi 2, 61029 Urbino, Italy 2Interuniversity Institute of Myology 3Stem Cells Center, Van Hanh Hospital, Hochiminh City, Viet Nam Disclosure of Interests: None declared

Background: Echinochrome A (EchA) is a pigment from sea urchins. EchA is a polyhydroxylated 1,4-naphthoquinone that contains several hydroxyl groups appropriate for free-radical scavenging and preventing redox imbalance. EchA is the most studied molecule of this family and is an active principle approved to be used in humans, usually for cardiopathies and glaucoma. EchA is used as a pharmaceutical drug. Methods: A comprehensive literature and patent search review was undertaken using PubMed, as well as Google Scholar and Espacenet search engines to review these areas. Conclusions: In the bloodstream, EchA can mediate cellular responses, act as a radical scavenger, and activate the glutathione pathway. It decreases ROS imbalance, prevents and limits lipid peroxidation, and enhances mitochondrial functions. Most importantly, EchA contributes to the modulation of the immune system. EchA can regulate the generation of regulatory T cells, inhibit pro-inflammatory IL-1β and IL-6 cytokine production, while slightly reducing IL-8, TNF-α, INF-α, and NKT, thus correcting immune imbalance. These characteristics suggest that EchA is a candidate drug to alleviate the cytokine storm syndrome (CSS).

Grammar provides the framework for understanding and producing language. In aphasia, an acquired language disorder, grammatical deficits are diversified and widespread. However, the few assessments for testing grammar in the German language do not consider current linguistic, psycholinguistic, and functional imaging data, which have been shown to be crucial for effective treatment. This study developed German language versions of the Northwestern Assessment of Verbs and Sentences (NAVS-G) and the Northwestern Anagram Test (NAT-G) to examine comprehension and production of verbs, controlling for the number and optionality of verb arguments, and sentences with increasing syntactic complexity. The NAVS-G and NAT-G were tested in 27 healthy participants, 15 right hemispheric stroke patients without aphasia, and 15 stroke patients with mild to residual aphasia. Participants without aphasia showed near-perfect performance, with the exception of (object) relative sentences, where accuracy was associated with educational level. In each patient with aphasia, deficits in more than one subtest were observed. The within and between population-groups logistic mixed regression analyses identified significant impairments in processing syntactic complexity at the verb and sentence levels. These findings indicate that the NAVS-G and NAT-G have potential for testing grammatical competence in (German) stroke patients.

Cancer is often accompanied by worsening of the patient’s iron profile, and the resulting anemia could be a factor that negatively impacts antineoplastic treatment efficacy and patient survival. The first line of therapy is usually based on oral or intravenous iron supplementation; however, many patients remain anemic and do not respond. The key might lie in the pathogenesis of the anemia itself. Cancer-related anemia (CRA) is characterized by a decreased circulating serum iron concentration and transferrin saturation despite ample iron stores, pointing to a more complex problem related to iron homeostatic regulation and additional factors such as chronic inflammatory status. This review explores our current understanding of iron homeostasis in cancer, shedding light on the modulatory role of hepcidin in intestinal iron absorption, iron recycling, mobilization from liver deposits, and inducible regulators by infections and inflammation. The underlying relationship between CRA and systemic low-grade inflammation will be discussed, and an integrated multitarget approach based on nutrition and exercise to improve iron utilization by reducing low-grade inflammation, modulating the immune response, and supporting antioxidant mechanisms will also be proposed. Indeed, a Mediterranean-based diet, nutritional supplements and exercise are suggested as potential individualized strategies and as a complementary approach to conventional CRA therapy.

The role of the right hemisphere (RH) in recovery from aphasia is incompletely understood. The present study quantified RH grey matter (GM) volume in individuals with chronic stroke-induced aphasia and cognitively healthy people using voxel-based morphometry. We compared group differences in GM volume in the entire RH and in RH regions-of-interest. Given that lesion site is a critical source of heterogeneity associated with poststroke language ability, we used voxel-based lesion symptom mapping (VLSM) to examine the relation between lesion site and language performance in the aphasic participants. Finally, using results derived from the VLSM as a covariate, we evaluated the relation between GM volume in the RH and language ability across domains, including comprehension and production processes both at the word and sentence levels and across spoken and written modalities. Between-subject comparisons showed that GM volume in the RH SMA was reduced in the aphasic group compared to the healthy controls. We also found that, for the aphasic group, increased RH volume in the MTG and the SMA was associated with better language comprehension and production scores, respectively. These data suggest that the RH may support functions previously performed by LH regions and have important implications for understanding poststroke reorganization.

Introduction: Outcomes for women with pT1aN0M0 breast cancers (BC) may vary by biologic subtype. A higher proportion of HER2-positive BCs diagnosed in the interval between scheduled screening rounds has been proposed to account for the more aggressive behaviour of interval cancers (IC) compared with screen-detected (SD) tumors. No data are available on the prognostic role of HER2-positive status in a general population of pT1aN0M0 breast tumors with known screening status. Methods: All incident pT1aN0M0 BCs (n=874), systematically collected by the Cancer Registries of Emilia Romagna Region (northern Italy) and diagnosed in women aged 50-69 from 2003 to 2009 were evaluated. Screening status was ascertained by reference to the Emilia Romagna Breast Cancer Screening Program (ERBSP) database. Patients unexposed to screening, with HER2 unknown primary tumor and/or who received adjuvant chemotherapy or trastuzumab were excluded from analysis. Results: Twenty percent of patients had HER2-positive tumors. Fifty-three percent of the entire study population were SD cancers, while 18% were ICs. Tumors with high histologic grade, high proliferative rate, negative estrogen receptor status, or HER2-positive status were more likely to be diagnosed in the interval between screening. At a median follow-up of 84 months, the 5-year invasive disease-free survival (IDFS) rates were 89% and 95% in patients with HER2-positive and HER2-negative tumors, respectively (P = 0.025). Notably, HER2-positive ICs showed poorer IDFS than HER2-positive SD tumors (84% vs. 95%, respectively; P = 0.04). No difference in IDFS rates were observed between HER2-positive SD cancers and HER2-negative SD cancers. Multivariable analysis of candidate prognostic factors for IDFS will be reported. Conclusions: In a general population of pT1aN0M0 early BCs with known screening status, IC detection may identify patients with HER2-positive pT1aN0M0 tumors in whom the rate of recurrence justifies consideration for systemic, anti-HER2, adjuvant therapy. Citation Format: Musolino A, Michiara M, Boggiani D, Sikokis A, Rimanti A, Pellegrino B, Silini EM, Campanini N, Barbieri E, Sgargi P, Falcini F, Pinto C. Prognostic impact of HER2 overexpression/amplification in women with pT1a N0 M0 breast cancer with known screening status: Results from a multicenter population-based cancer registry study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-07-23.

Purpose This study examined grammatical production impairments in primary progressive aphasia (PPA), as measured by structured tests and narrative samples. We aimed to quantify the strength of the relationship between grammatical measures across tasks, and identify factors that condition it. Three grammatical domains were investigated: overall sentence production, verb morphology, and verb-argument structure. Methods 77 participants with PPA (34 PPA-G, 16 PPA-L, 15 PPA-S and 12 other) completed a battery of grammatical tests and a narrative language sample was obtained. Accuracy scores were computed for the language tests and the narrative samples were analyzed for both accuracy of selected narrative variables as well as grammatical diversity across the three grammatical domains. Principal components analysis (PCA) and multiple regression were used to examine cross-task relationships for all measures. Results As expected on the basis of classification criteria, accuracy scores were lower for the PPA-G group as compared to the PPA-L and PPA-S participants for overall sentence production and verb morphology, but not argument structure. Grammatical accuracy in narratives strongly predicted overall language test performance in PPA-G, whereas grammatical diversity in narratives did so in PPA-L, and no significant correspondence between narrative and language test performance was found for PPA-S. For individuals with severe grammatical impairments only, error distribution for both morphology and argument structure was strongly associated in structured tasks and narratives. Conclusions Grammatical production in narrative language predicts accuracy elicited with structured language tests in PPA. However, unique narrative production patterns distinguish PPA by subtype: accuracy for PPA-G, and grammatical diversity for PPA-L. The impairment in PPA-G is likely to reflect a core impairment in grammar whereas that of PPA-L may be closely tied to the word retrieval and verbal working memory deficits that characterize this variant. This underscores the theoretical distinction between PPA-L and PPA-G, as well as the importance of including grammatical diversity measures in analyses of language production, especially for patients who do not display frank agrammatism. Further, the results suggest that measures of domain-specific language deficits (i.e., verb morphology vs. argument structure) are robust across tasks only in individuals with severe grammatical impairments.

Functional neuroimaging and lesion-symptom mapping investigations implicate a left frontal–temporal–parietal network for sentence processing. The majority of studies have focused on sentence comprehension, with fewer in the domain of sentence production, which have not fully elucidated overlapping and/or unique brain structures associated with the two domains, particularly for sentences with noncanonical word order. Using voxel-based lesion symptom mapping (VLSM) we examined the relationship between lesions within the left hemisphere language network and both sentence comprehension and production of simple and complex syntactic structures in 76 participants with chronic stroke-induced aphasia. Results revealed shared regions across domains in the anterior and posterior superior temporal gyri (aSTG, pSTG), and the temporal pole (adjusted for verb production/comprehension). Additionally, comprehension was associated with lesions in the anterior and posterior middle temporal gyri (aMTG, pMTG), the MTG temporooccipital regions, SMG/AG, central and parietal operculum, and the insula. Subsequent VLSM analyses (production versus comprehension) revealed critical regions associated with each domain: anterior temporal lesions were associated with production; posterior temporo-parietal lesions were associated with comprehension, implicating important roles for regions within the ventral and dorsal stream processing routes, respectively. Processing of syntactically complex, noncanonical (adjusted for canonical), sentences was associated with damage to the pSTG across domains, with additional damage to the pMTG and IPL associated with impaired sentence comprehension, suggesting that the pSTG is crucial for computing noncanonical sentences across domains and that the pMTG, and IPL are necessary for re-analysis of thematic roles as required for resolution of long-distance dependencies. These findings converge with previous studies and extend our knowledge of the neural mechanisms of sentence comprehension to production, highlighting critical regions associated with both domains, and further address the mechanism engaged for syntactic computation, controlled for the contribution of verb processing.

Background: Current guidelines for BC surveillance in asymptomatic pts recommend annual mammography and periodical physical examination. These recommendations arise from two trials conducted in the 1980's: since then no other randomized controlled trials (RCTs) have been conducted on BC follow-up. However our knowledge on BC biology, diagnosis of metastases and treatment has improved. The aim of this prospective RCT is to verify if the serial measurement of CEA and CA15.3 (followed by 18-FDG PET) can anticipate the diagnosis of breast cancer recurrence compared to control arm. If this intermediate end-point will be met a subsequent extension trial will investigate the impact of the earlier diagnosis of distant metastases on survival. Methods: Pts diagnosed with stage I-III BC, who underwent adequate surgery are eligible. Special histologies and low-risk cases according to St. Gallen criteria are excluded. We will include pts at the beginning of the follow-up after the conclusion of primary treatment (cohort 1), and pts that have concluded without relapse the first 5 years of follow-up (cohort 2). Eligible pts will be randomized in a 1:1 ratio to follow-up according to local practice (control arm) or to three-monthly serial dosing of CEA and CA15.3 and subsequent imaging studies (18-FDG PET) only in case of an increase of CEA and/or CA 15.3 greater than a critical difference (CEA +100% and/or CA15.3 +75%) compared to baseline (experimental arm). The following stratification factors will be used: node negative vs positive, HER2 negative vs positive, ER positive vs negative. Eight-hundred pts will be enrolled over 3 years. For such a calculation, we made the assumption of a 20% 5-year incidence of relapse. The target reduction of 3 months in restricted mean survival time (RMST) between the two arms implies a median time of diagnostic anticipation, conditional on having breast cancer recurrence, of 10 months. The follow-up will continue until 10 years from surgery. The first patient was enrolled on 23rd October 2014, up to now 434 pts have been enrolled. The present trial was approved by the Ethical Commitee of S. Orsola-Malpighi Hospital and is registered on clinicaltrials.gov (NCT02261389). Citation Format: Zamagni C, Gion M, Mariani L, Stieber P, Quercia S, Rubino D, Bernardi A, Cacciari N, Fini A, Lenzi M, Minichillo S, Pizzirani C, Pagliaro M, Tomasini S, Barbieri E. Three-monthly dynamic evaluation of CEA and CA15-3 (followed by 18-FDG PET) vs usual practice in the follow-up of early breast cancer (BC) patients (pts): A prospective randomized trial (KRONOS-patient-oriented new surveillance study, Italy) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-05-01.

Erythropoietin (EPO) is a hematopoietic growth factor that has an important role in the erythropoiesis. EPO and its receptor (EPO-R) are expressed all over in the mammalian brain. Furthermore, it has been reported that EPO may exert neuroprotective effect in animal models of brain disorders as ischemia and epilepsy. Here, we investigate whether EPO could modulate the GABA-evoked currents (I

This paper examined the effects of treatment on both offline and online sentence processing and associated neuroplasticity within sentence processing and dorsal attention networks in chronic stroke-induced agrammatic aphasia. Twenty-three neurotypical adults and 19 individuals with aphasia served as participants. Aphasic individuals were randomly assigned to receive a 12-week course of linguistically-based treatment of passive sentence production and comprehension (N = 14, treatment group) or to serve as control participants (N = 5, natural history group). Both aphasic groups performed two offline tasks at baseline and three months following (at post-testing) to assess production and comprehension of trained passive structures and untrained syntactically related and unrelated structures. The aphasic participants and a healthy age-matched group also performed an online eyetracking comprehension task and a picture-verification fMRI task, which were repeated at post-testing for the aphasic groups. Results showed that individuals in the treatment, but not in the natural history, group improved on production and comprehension of both trained structures and untrained syntactically related structures. Treatment also resulted in a shift toward more normal-like eye movements and a significant increase in neural activation from baseline to post-testing. Upregulation encompassed right hemisphere regions homologs of left hemisphere regions involved in both sentence processing and domain-general functions and was positively correlated with treatment gains, as measured by offline comprehension accuracy, and with changes in processing strategies during sentence comprehension, as measured by eyetracking. These findings provide compelling evidence in favor of the contribution of both networks within the right hemisphere to the restoration of normal-like sentence processing patterns in chronic aphasia.

Background Combined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women. Methods This meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215. Results 8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found. Conclusions The novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure L. Cortesi: Speaker Bureau / Expert testimony: Astazeneca; Speaker Bureau / Expert testimony: Pierre Fabre Pharma. F. Piacentini: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer. S. Cascinu: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly. L. Moscetti: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.

IGF1 is a key regulator of tissue growth and development and has been implicated in the initiation and progression of various cancers, including breast cancer. Through IGF1 mRNA splicing different precursor pro-peptides, i.e., the IGF1Ea, IGF1Eb and IGF1Ec pro-forms, are formed whose biological roles in the pathogenesis of breast cancer have not been established yet. The objective of this study was to assess the biological activity of the IGF1 pro-forms in human breast cancer-derived cells.The different IGF1 pro-forms were generated through transient transfection of HEK293 cells with the respective vector constructs. The resulting conditioned media were applied in vitro to MCF7, T47D and ZR751 breast cancer-derived cell cultures. The recombinant human IGF1 pro-forms were also tested for their binding affinity to an anti-IGF1 specific antibody by immunoprecipitation. To determine whether the IGF1 pro-forms induce cell proliferation, mature IGF1 was neutralised in HEK293-derived conditioned media.We found that the IGF1 pro-forms were the only forms that were produced intra-cellularly, whereas both mature IGF1 and the IGF1 pro-forms were detected extra-cellularly. We also found that E peptides can impair the IGF1 pro-form binding affinity for the anti-IGF1 antibody and, thus, hamper an accurate measurement of the IGF1 pro-forms. Additionally, we found that the IGF1 antibody can completely inhibit IGF1-induced breast cancer cell proliferation and IGF1 receptor (IGF1R) phosphorylation, wheras the same antibody was found to only partially inhibit the biological activity of the pro-forms. Moreover, we found that the IGF1 pro-form activities can completely be inhibited by neutralising the IGF1R. Finally, we compared the bioactivity of the IGF1 pro-forms to that of mature IGF1, and found that the IGF1 pro-forms were less capable of phosphorylating the IGF1R in the breast cancer-derived cells tested.Our data indicate that IGF1 pro-forms can induce breast cancer cell proliferation via the IGF1R, independent from the mature IGF1 form. These results underline the importance of an accurate assessment of the presence of IGF1 pro-forms within the breast cancer microenvironment.

Verbs are central to sentence processing, as they encode argument structure (AS) information, i.e., information about the syntax and interpretation of the phrases accompanying them. The behavioral and neural correlates of AS processing have primarily been investigated in sentence-level tasks, requiring both verb processing and verb-argument integration. In the current functional magnetic resonance imaging (fMRI) study, we investigated AS processing using a lexical decision task requiring only verb processing. We examined three aspects of AS complexity: number of thematic roles, number of thematic options, and mapping (non)canonicity (unaccusative vs. unergative and transitive verbs). Increased number of thematic roles elicited greater activation in the left posterior perisylvian regions claimed to support access to stored AS representations. However, the number of thematic options had no neural effects. Further, unaccusative verbs elicited longer response times and increased activation in the left inferior frontal gyrus, reflecting the processing cost of unaccusative verbs and, more generally, supporting the role of the IFG in noncanonical argument mapping.