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BACKGROUND The guidelines published by the Papanicolaou Society of Cytopathology (PSC) intend to unify the reporting language in pancreaticobiliary specimens and improve communication between cytopathologists and clinicians. The six categories in the system will determine the best management for patients. However, there is limited evidence regarding the risk of malignancy (ROM) associated with each category. METHODS A retrospective search was performed for pancreaticobiliary fine-needle aspiration (FNA) reports with corresponding surgical follow-up. Cases were reclassified according to the PSC. The ROM, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each category. RESULTS A total of 297 cases were identified and reclassified as: 30 nondiagnostic (category I), 45 negative for malignancy (II), 20 atypical (III), 42 neoplastic: other (IVB), 19 suspicious for malignancy (V), and 141 malignant (VI). The absolute ROM was 10% for category I, 8.9% for category II, 60% for category III, 4.8% for category IV when the neoplasms were not characterized as malignant, and 100% when categorized as malignant; 100% for category V, and 95.7% for category VI. Sensitivity, specificity, positive predictive value, and negative predictive value for neoplasia and malignancy, including categories IV to VI, were 96.6%, 88.4%, 97.5%, and 84.4%, respectively. CONCLUSIONS The categories developed by the PSC stratify the ROM. Aspirates designated as categories V and VI had the highest ROM. Our rate of atypical category complies with the recommended rate of

Introduction D-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends lifespan in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. Methods The conventional human GlcN dose is 1,500 mg x day-1 but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly due to its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, on physical performance and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1,000 mg x Kg-1) for six weeks. We measured exercise performance (grip strength, motor coordination and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (MDA, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, Catalase and PRDX6) and MAPKs (p38 and ERK ½) were also determined in skeletal muscle. Results and conclusions Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination and may have a synergistic effect with exercise training on running distance.

Salivary gland neoplasms are uncommon, and most exhibit epithelial differentiation. Mesenchymal neoplasms of the salivary gland are rare, and the incidence ranges from 1.9% to 5%. The aim of this study is to identify the types and clinical-pathological features of mesenchymal salivary neoplasm and review their differential diagnosis. A retrospective search for mesenchymal neoplasms of salivary glands from our institution's pathology archives from the 2004–2021 period and consultation files of one of the authors (AER) was performed. The clinical data were obtained from available medical records, and the histological slides and ancillary studies were retrieved and reviewed. We identified a total of 68 cases that form the study cohort. Thirty-five patients were male, and thirty-three patients were female, with a mean age of 48 years (range, 7 months–79 years), and the male to female ratio was 1:.94. Sixty-three (92.6%) of sixty-eight tumors were benign and included: 38 (56%) lipomas, 9 (13%) hemangiomas, 7 (10.3%) schwannomas, 3 (4.4%) neurofibromas, 3 (4.4%) lymphangioma, 2 (3%) solitary fibrous tumors, 1 (1.5%) myofibroma. Five of sixty-eight (7.4%) were malignant and included: 3 (4.4%) Adamantinoma-like Ewing sarcomas, 1 (1.5%) malignant peripheral nerve sheath tumor (MPNST), and 1 (1.5%) malignant solitary fibrous tumor. The involved sites included: parotid (55), submandibular gland (5), parapharyngeal space (5), buccal mucosa minor salivary gland (2), and sublingual gland (1). Sixty-seven patients underwent surgical resection. One patient with lymphangioma manifested a recurrence/persistence a week post-surgery. One patient with a parotid hemangioma developed post-operative numbness, and another patient developed chronic postauricular pain after surgery. Two patients with MPNST and one patient with adamantinoma-like Ewing sarcoma underwent neoadjuvant chemoradiation and were disease-free after treatment. The remaining 37 patients with available follow-up ranging from 7 days to 96 months (mean, 18 months) had a favorable outcome and were disease-free after treatment. Mesenchymal neoplasms of salivary gland are rare; most are benign and demonstrate adipocytic, endothelial, and schwannian differentiation; awareness of their development is important for adequate diagnosis. The mainstay of treatment is surgical excision, with the extent determined by tumor type. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

Demographic aging is one of the most serious challenges facing our society. Although we live longer, we do not live better because it is considered that approximately 16–20% of our life is spent in late-life morbidity. Older people have the greatest risk of developing frailty increasing the risk of presenting various adverse health events such as low quality of life, disability, hospitalization and even death. Frail men and women over 65 years old have lower muscle quality and muscle mass and higher percentage of body fat than non-frail people of the same age. In this review we will address the main physiological changes in the muscular and nervous system associated to aging. More specifically we will review the changes in muscle mass, quality, and strength relating them with the decrease in capillarization and muscular oxidative capacity as well as with the alterations in protein synthesis in the muscle with aging. The last section of the manuscript will be devoted to the animal models of frailty and the indexes developed to measure frailty in these models. We will finally address the importance of exercise training as an intervention to delay or even reverse frailty. Keywords: Sarcopenia, Multicomponent exercise, Disability, Skeletal muscle, Healthy aging

Primary sarcomas of the larynx are rare and are associated with diagnostic and treatment challenges. Studies of these tumors are limited, and most examples have been reported as small series. To further increase our understanding of laryngeal sarcomas, we reviewed our experience of an adult cohort. A retrospective search for laryngeal sarcomas from our pathology archives and consultation files of one of the authors was performed. We studied 27 primary laryngeal sarcomas that included 25 males, and 2 females, with a mean age of 60 years (range 33–85). The cases included conventional chondrosarcoma (16), well-differentiated liposarcoma (2), clear cell chondrosarcoma (1), leiomyosarcoma (2), high grade myxofibrosarcoma (2), high grade myofibroblastic sarcoma (1), low-grade myofibroblastic sarcoma (1), malignant granular cell tumor (1), and Kaposi sarcoma (1). Data on treatment and follow-up was available in 17 and 16 cases, respectively. 12 patients underwent partial laryngeal resection; five had total laryngectomy, and the patient with Kaposi sarcoma received combined highly active antiretroviral therapy and chemotherapy. Three patients developed local recurrence, and two patients developed metastases. The remaining patients with follow up had a favorable outcome and were disease-free after treatment. The important differential diagnosis of spindle cell sarcoma is sarcomatoid squamous cell carcinoma, and their distinction often requires extensive sampling of the mucosal surface and immunohistochemical analysis. The mainstay of treatment for laryngeal sarcomas is surgical removal, with the extent dictated by tumor type and grade. Adjuvant therapy is reserved for high-grade sarcomas and may be given in a neoadjuvant or adjuvant setting.

The Paris System (TPS) for reporting urine cytology was developed for standardization of diagnosis focusing on the detection of high-grade urothelial carcinoma (HGUC). Probably the most challenging task for TPS is to provide criteria for the atypical urothelial cell (AUC) category. The TPS criteria for AUC include increased nuclear/cytoplasmic (N/C) ratio (0.5) and 1 of the 3 minor criteria including nuclear hyperchromasia (NH), coarse chromatin (CC) and irregular nuclear membrane (INM). We evaluated TPS-AUC diagnostic value and investigated whether other morphologic parameters can improve its criteria.Urine samples with diagnoses of AUC collected during a 6-month period were re-reviewed. Data captured included N/C ratio0.5, NH, CC, INM, and 2 additional criteria including enlarged nuclear size (ENS) and the presence of nucleolus (N). ENS was considered when the nucleus was 2 times larger than the urothelial cell or 3 times larger than lymphocyte.By applying the TPS-AUC criteria, the rate of atypia diagnosis reduced in comparison to Pre-TPS (9% versus 13%, P = 0.02). Among the AUC minor criteria, NH was the best criterion with the highest interobserver agreement (IOA) and correlation with HGUC (k = 0.342, r = 0.61, P0.001) and strong PPV (93.6%). ENS had the highest PPV (95.8%) and, after NH, had the highest IOA and correlation with HGUC (k = 0.29, r = 0.52, P0.001).TPS improves the diagnostic value of urine cytology, particularly in cases with atypia. ENS is a strong criterion for increasing the diagnostic value of AUC and potentially can improve TPS performance as a minor criterion.

Background and purpose Abdominal aortic aneurysm (AAA) is a multifactorial disease characterized by chronic inflammation, oxidative stress, and proteolytic activity in the aortic wall. Targeting Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is a promising strategy for chronic inflammatory diseases. We investigated the vasculoprotective role of suppressor of cytokine signalling-1 (SOCS1), the negative JAK/STAT regulator, in experimental AAA. Experimental approach A synthetic, cell permeable peptide (S1) mimic of SOCS1 kinase inhibitory domain to suppress STAT activation was evaluated in the well-established mouse model of elastase-induced AAA by monitoring changes in aortic diameter, cellular composition, and gene expression in abdominal aorta. S1 function was further evaluated in cultured vascular smooth muscle cells (VSMC) and macrophages exposed to elastase or elastin-derived peptides. Key results S1 peptide prevented AAA development, evidenced by reduced incidence of AAA, aortic dilation and elastin degradation, partial restoration of medial VSMC, and decreased inflammatory cells and oxidative stress in AAA tissue. Mechanistically, S1 suppressed STAT1/3 activation in aorta, downregulated cytokines and metalloproteinases, and altered the expression of cell differentiation markers by favouring anti-inflammatory M2 macrophage and contractile VSMC phenotypes. In vitro, S1 suppressed the expression of inflammatory and oxidative genes, reduced cell migration, and reversed the phenotypic switch of macrophages and VSMC. By contrast, SOCS1 silencing promoted inflammatory response. Conclusion and implications This preclinical study demonstrates the therapeutic potential of SOCS1-derived peptide to halt AAA progression by suppressing JAK/STAT-mediated inflammation and aortic dilation. S1 peptide may therefore be a valuable option for the treatment of AAA.

Breast cancers are heterogeneous with variable morphologic features, biologic behavior and response to therapy. Traditional histopathologic features such as size, grade, and lymph node status may be used to provide a general estimate of outcome, stratifying patients into broad prognostic groups with prescribed guidelines for therapy. With this approach however, up to 85% of breast cancer patients are overtreated, and at the other end of the spectrum, 20% of patients succumb to their disease despite receiving maximum therapy. The current routine testing for the Estrogen receptor (ER) and HER2 growth factor receptor (HER2) represents the earliest attempts to provide a targeted approach to breast cancer therapy, based on molecular drivers of the disease. The pioneering works by Perou and Sorlie et al using global gene expression profiling introduced a molecular taxonomy of breast cancer with associated prognostic implications. The Luminal, HER2-enriched, and Basal-like intrinsic subtypes are generally characterized by the presence or absence of ER and HER2. They have been further analyzed and refined using integration of genomic and transcriptomic data made possible by advancements in high throughput molecular techniques and bioinformatics. Indeed, an increased understanding of the genomic landscape of these subtypes, and the molecular basis of breast cancer growth regulation, holds the promise of a more personalized patient selection for specific targeted therapies and improved outcomes.

Background Pseudocarcinomatous squamous hyperplasia (PSH) within the bone is uncommon and closely mimics well-differentiated squamous cell carcinoma (SCC). It arises from cutaneous or mucosal surfaces and grows directly into the bone. This study analyzes a large series of PSH and discusses the clinicopathologic features that facilitate its distinction from SCC. Design Cases were identified from the surgical pathology files between 1985 and 2020. Results The 31 cases included 21 males, 9 females, 1 unknown sex; who were 20 to 87 years old (average: 59 y). Sites included mandible-17, maxilla-5, toes-4, and 1 case from finger, femur, tibia, ischium, and unknown. Fourteen patients had a history of SCC, 13 treated with resection and chemoradiation and developed infected osteoradionecrosis, 4-medication-related osteonecrosis, 3-peripheral vascular disease, and diabetes mellitus, 3-trauma, 3-osteomyelitis, 3-unknown, and 1-hematologic malignancy. All cases exhibited severe osteomyelitis and nests of reactive keratinizing squamous epithelium that matured towards the bone surface, lacked significant atypia, or mitotic activity but permeated the medullary cavity. Patients with previous SCC developed PSH after 2 months to 8 years (average: 4 y). Nineteen of 30 patients had follow-up (2 to 48 mo, average: 17 mo); 6 patients experienced repeated debridements over 2 months to 1 year; no patient developed SCC. Conclusions PSH involving bone is infrequent, complicates severe osteomyelitis, and is often therapy related. The clinical findings are usually not concerning for malignancy, however, the histologic findings are an important diagnostic pitfall because they mimic SCC.

To analyze the effect of disease-modifying antirheumatic drugs (DMARDs) on the outcome of interstitial lung disease secondary to rheumatoid arthritis (RA-ILD).We performed a multicenter, prospective, observational study of patients with RA-ILD receiving DMARDs between 2015 and 2017. The patients were assessed using high-resolution computed tomography and pulmonary function tests at baseline and at 24 months. The radiological assessment was centralized. The main outcome measure at 24 months was changed in lung function (improvement, stabilization, worsening, or death). We recorded the 28-joint Disease Activity Score 28 (DAS28) and adverse events. A logistic regression analysis was performed to identify factors associated with worsening of ILD.After 24 months, lung disease was stabilized in 40 patients (57.1%), improved in 8 (11.4%), and worse in 21 (30.0%). One patient (1.4%) died. The factors associated with worsening of ILD in the multivariate analysis were treatment with abatacept, tocilizumab, or rituximab (OR, 0.102 [95%CI, 0.015-0.686]), DAS28 (OR, 1.969 [95%CI, 1.005-3.857]), and smoking (OR, 6.937 [95%CI, 1.378-4.900]). During follow-up, 30 patients (42.9%) experienced an adverse event, which was severe in 12 cases (17.1%).Lung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. Non-anti-TNF DMARDs reduce the risk of worsening of lung disease in 90% of patients. The inflammatory activity of RA and smoking, on the other hand, are associated with worsening. Key Points • We have performed prospectively evaluated lung and joint function in patients with RA-ILD receiving treatment with various DMARDs. • In our study, the lung function is stable and inflammatory activity well controlled in most patients with RA-ILD receiving treatment with DMARDs. • Neither csDMARDs nor anti-TNF agents were associated with a significant risk of worsening of lung disease, whereas non-anti-TNF bDMARDs could reduce the risk of worsening of lung disease. • Smoking and poor control of joint involvement were the main factors associated with worsening of lung disease.

The SARS-CoV-2-caused COVID-19 pandemic has resulted in a devastating threat to human society in terms of health, economy, and lifestyle. Although the virus usually first invades and infects the lung and respiratory track tissue, in extreme cases, almost all major organs in the body are now known to be negatively impacted often leading to severe systemic failure in some people. Unfortunately, there is currently no effective treatment for this disease. Pre-existing pathological conditions or comorbidities such as age are a major reason for premature death and increased morbidity and mortality. The immobilization due to hospitalization and bed rest and the physical inactivity due to sustained quarantine and social distancing can downregulate the ability of organs systems to resist to viral infection and increase the risk of damage to the immune, respiratory, cardiovascular, musculoskeletal systems and the brain. The cellular mechanisms and danger of this “second wave” effect of COVID-19 to the human body, along with the effects of aging, proper nutrition, and regular physical activity, are reviewed in this editorial article.

High power Semiconductor Optical Amplifiers (SOA) are often integrated in optical systems such as mode locked lasers, hybrid, or monolithically integrated Master Oscillator Power Amplifiers (MOPA) for applications such as LIDAR systems or free space optical communications. Both these applications require high power and signal modulation, either for data transmission or specific LIDAR adapted signals, which can be provided by either modulating the amplitude of the seed laser or using an external modulator. It is also possible to directly modulate the gain of the SOA by modulating the input current. However, as the input power of the SOA is often high in these configurations (around 1 mW), it operates under the saturation regime. In this article, we present an experimental study of the dynamic characteristics of a two-section high power SOA. DC characteristics for different pump current pairs are measured. The S21 parameter is measured, and a model is proposed to understand and predict the dynamic response of the SOA. The impact of the gain saturation with regards to input power on the behavior of the SOA is investigated by pumping the two sections with different current values. Extinction ratio and eye diagrams are measured in three different configurations with the modulation applied on a seed DFB laser, on the input section, then on the output section of the SOA at 1 Gbps, 2.5 Gbps, and 5 Gbps.

Background: A number of guidelines have been developed to improve standardization of the terminology and criteria for cytologic specimens obtained from the thyroid, pancreas, lung, and salivary glands. A major goal of these guidelines is to improve reproducibility and understanding of the reporting of diagnostic results among cytopathologists and between cytopathologists and clinicians. The International Academy of Cytology Yokohama System for Reporting Breast Fine-Needle Aspiration Biopsy Cytopathology (IAC YSRB) is the most recent of these guidelines. The value of this system is, in part, dependent upon interobserver reproducibility. Design: Ninety consecutive fine-needle aspiration biopsies (FNAB) of the breast, performed over a 6-year period, were independently evaluated by 4 board-certified pathologists blinded to the original diagnoses. The 5 diagnostic categories used were those of the IAC YSRB according to published criteria for these categories. Observed agreement and chance corrected agreement (Fliess κ) were calculated. Differences in κ values were evaluated using the T statistic of Gwent. Statistical calculations were performed using STATA v16.0 (STATA Corp., College Station, TX, USA). Results: Overall agreement between observers was good. Observed unweighted agreement was 69% and weighted agreement was 91%. The majority of diagnoses were concordant (68.6%). Conclusions: Interobserver agreement of 4 cytopathologists was good using the 5 categories of the IAC YRSB (69%). Agreement was greater among pathologists with more years of experience. The IAC YSRB system appears to provide greater agreement among viewers than guidelines for cytologic specimens obtained from some other body sites (salivary gland and lung). Most discrepancies were only by a single category, with only 22/113 (19%) differing by more than one category.

Diabetes mellitus (DM) is a high‐impact disease commonly characterized by hyperglycemia, inflammation, and oxidative stress. Diabetic nephropathy (DN) is a common diabetic microvascular complication and the leading cause of chronic kidney disease worldwide. This study investigates the protective effects of the synthetic flavonoid hidrosmin (5‐O‐(beta-hydroxyethyl) diosmin) in experimental DN induced by streptozotocin injection in apolipoprotein E deficient mice. Oral administration of hidrosmin (300 mg/kg/day, n = 11) to diabetic mice for 7 weeks markedly reduced albuminuria (albumin‐to‐creatinine ratio: 47 ± 11% vs. control) and ameliorated renal pathological damage and expression of kidney injury markers. Kidneys of hidrosmin‐treated mice exhibited lower content of macrophages and T cells, reduced expression of cytokines and chemokines, and attenuated inflammatory signaling pathways. Hidrosmin treatment improved the redox balance by reducing prooxidant enzymes and enhancing antioxidant genes, and also decreased senescence markers in diabetic kidneys. In vitro, hidrosmin dose‐dependently reduced the expression of inflammatory and oxidative genes in tubuloepithelial cells exposed to either high‐glucose or cytokines, with no evidence of cytotoxicity at effective concentrations. In conclusion, the synthetic flavonoid hidrosmin exerts a beneficial effect against DN by reducing inflammation, oxidative stress, and senescence pathways. Hidrosmin could have a potential role as a coadjutant therapy for the chronic complications of DM., This work was supported by grants from the Spanish Ministry of Science and Innovation- FEDER funds (Retos Colaboración RTC2017-6089-1 and Retos Investigación RTI2018-098788-B-I00) and Instituto de Salud Carlos III (PI20/00487 and DTS 19/00093)

Aging has increased the prevalence of frailty, and type 2 diabetes (T2D) has also increased in prevalence. Diabetes and oxidative stress (OS) have been shown to be related to frailty. However, the exact mechanism by which it occurs is not fully known. Our aim was to analyze body composition in community-dwelling older diabetic people treated in our center and to evaluate the possible relation between OS, frailty, and body composition. We included 100 adults older than 65 years with T2D. We found that 15% were frail and 57% were prefrail. The patients included in the nonrobust group showed increased levels of OS. Our study shows that the presence of T2D in the geriatric population is associated with a high prevalence of frailty and high OS levels, conditions that cause greater morbidity and mortality and that highlight the importance of the diagnosis of frailty in this population.

The present study aimed to analyze the impact of a multicomponent training (MCT) program in a group of non-active older adults, comparing two different dose distributions. Twenty-four individuals, assigned to two groups, completed 15 weeks of MCT (2 days/week). The continuous group (CMCT, n = 14, 9 females, 71.07 ± 5.09 years) trained for 60 min/session in the morning. The accumulated group (AMCT, n = 10, 5 females, 72.70 ± 3.59 years) performed the same exercises, volume, and intensity, but the training was distributed twice per day (30 min in the morning, 30 more in the afternoon). Bonferroni post hoc comparisons revealed significant (p &lt, 0.001) and similar large improvements in both groups in lower limb strength (five times sit-to-stand test: CMCT, 12.55 ± 2.83 vs. 9.44 ± 1.72 s, AMCT, 10.37 ± 2.35 vs. 7.46 ± 1.75 s). In addition, there were large gains in preferred walking speed and instrumental daily life activities, which were higher for CMCT and AMCT, respectively (in this order: 1.00 ± 0.18 vs. 1.44 ± 0.26 m/s and 1.09 ± 0.80 vs. 1.58 ± 0.18 m/s, 33.07 ± 2.88 vs. 36.57 ± 1.65 points and 32.80 ± 1.93 vs. 36.80 ± 0.92 points), improvements in cardiorespiratory fitness, now moderate for CMCT (474.14 ± 93.60 vs. 529.64 ± 82.76 m) and large for AMCT (515.10 ± 20.24 vs. 589.60 ± 40.38 m), and medium and similar enhancements in agility in both groups (TUG test: CMCT: 7.49 ± 1.11 vs. 6.77 ± 1.16 s, AMCT: 6.84 ± 1.01 vs. 6.18 ± 0.62 s). None of the protocols had an impact on the executive function, whereas health-related quality of life showed a trend to significance in the whole sample only (EQindex overall sample, p = 0.062, d = 0.48 CMCT, d = 0.34 AMCT). Regardless of the type of dose distribution, starting multicomponent training improves physical function in non-active older adults, but does not improve cognitive function at mid-term. Because both forms of MCT showed similar compliance, slightly positive differences in accumulated strategies may indicate some benefits related to breaking afternoon sedentary behaviors, which deserves further research in longer and larger interventions. The mixed nature of MCT suggests accumulative group interventions may be a promising approach to address sedentary aging.

International audience; We present a complete characterization of reflective electroabsorption modulators (EAMs) monolithically integrated with semiconductor optical amplifiers (SOAs), components that are capable of operating beyond 50 Gb/s in the C-band. The devices are based on GaInAsP multiple quantum wells on InP substrate, leveraging semi-insulating buried heterostructure waveguide definition and butt-joint integration technologies. Different device configurations, based on 80-μm and 150-μm long EAMs, are fabricated and characterized in both static and dynamic modes. The frequency response of the 80-μm long EAM is still flat at 26.5 GHz (setup upper limit) whereas the 150-μm long EAM exhibits a 3-dB cutoff bandwidth of 23 GHz. A zero-chirp is achieved for EAM reverse bias voltages between −1.2 V and −1.5 V depending on the wavelength. Under large-signal modulation, the frequency chirp induced by the shorter EAM is almost half that of the longer EAM, with their respective peak values being +1.5/−2 GHz and +3.2/−3.7 GHz (rising/falling edges) at 1545 nm (−1.3 V bias, 2.6 V voltage swing). We obtained high dynamic extinction ratios of ~14.5 dB and ~8 dB from the longer and the shorter EAMs, respectively, when they are operated at 25 Gb/s using non-return-to-zero coding. Finally, we achieved 12 km and 16 km colorless transmissions in the C-band (between 1530 nm and 1545 nm) over a standard single-mode fiber without equalization using the 150-μm and the 80-μm EAMs, respectively, with 4.5 dB and 2.5 dB dispersion penalties at a bit error rate of 10E−3.

Abdominal aortic aneurysm (AAA) is characterised by the presence of B cells and immunoglobulins in the aortic wall, mainly in the adventitia. Kappa (κ) and lambda (λ) free light chains (FLCs) are produced from B cells during immunoglobulin synthesis. This study investigated the presence and prognostic value of combined FLCs (cFLCs or summed κ and λ) in patients with AAA. cFLCs were analysed by a turbidimetric specific assay in tissue conditioned media from AAA samples (n = 34) compared with healthy aortas (n = 34) from France and in plasma samples from patients with AAA (n = 434) and age matched controls (n = 104) selected from the Viborg Vascular (VIVA) AAA screening trial in Denmark. t test, logistic regression, and Cox regression were used to test whether plasma cFLCs serve as a marker for AAA presence and whether cFLCs were predictive of death, major adverse cardiovascular events (MACE), or major adverse lower limb events (MALE). Increased cFLC levels were detected in the AAA adventitial layer compared with the AAA medial layer and healthy media layer (13.65 ± 3.17 vs. 6.57 ± 1.01 vs. 0.49 ± 0.09 mg/L, respectively, p < .050). The upper tertile of plasma cFLCs was independently associated with AAA presence after correcting for confounders (odds ratio [OR] 7.596, 95% confidence intervals [CI] 3.117 - 18.513; p < .001). Of 434 patients with AAA, 89 (20.5%) died, 104 (24.0%) suffered MACE, and 63 (14.5%) suffered MALE, during a five year follow up. In univariable analysis, the cFLC upper tertile was associated with a higher risk of death, MACE, and MALE (p < .001 for all). After adjustment for confounders, cFLCs remained an independent predictor of all cause mortality (hazard ratio [HR] 4.310, 95% CI 2.157 - 8.609; p < .001), MACE (HR 2.153, 95% CI 1.218 - 3.804; p = .008), or MALE (HR 3.442, 95% CI 1.548 - 7.652; p = .002) for those in the upper tertile. Increased cFLCs are observed in adventitial tissue of patients with AAA, indicating local activation of B cells. Plasma cFLC levels are an independent predictor of death, MACE, and MALE in patients with AAA. This study was funded by the Spanish MINECO (PID2019- 106814RB-I00 and PGC2018-097019-B-I00), la Caixa Foundation (HR17-00247), CAM (S2017/BMD-3673), and Fondo de Investigaciones Sanitarias ISCiii-FEDER (PI19/ 00128). Sí

Background: Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods: Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results: The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). Conclusions: Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty. This work was supported by Instituto de Salud Carlos III CB16/10/00435 (CIBERFES) (PID2019-110906RB-I00/AEI/10.13039/501100011033) from the Spanish Ministry of Innovation and Science; 109_RESIFIT from Fundación General CSIC; PROMETEO/2019/097 de ‘Consellería, de Sanitat de la Generalitat Valenciana’ and EU Funded H2020-DIABFRAIL-LATAM (Ref: 825546); European Joint Programming Initiative ‘A Healthy Diet for a Healthy Life’ (JPI HDHL); and the ERA-NET Cofund ERA-HDHL (GA No. 696295 of the EU Horizon 2020 Research and Innovation Programme). Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). Work in the laboratory of P.J.F.-M. was funded by the FBBVA and the Ramón Areces Foundations. Work in the laboratory of P.M.-C. and A.L.S was funded by by MWRF and Fundació La Marató/TV3-80/19-202021 to P.M.C. and Fundació La Marató de TV3 (Project 202033 to A.L.S.), MINECO-Spain (RTI2018-096068), ERC-2016-AdG-741966, LaCaixa-HEALTH-HR17-00040, MDA, UPGRADE-H2020-825825, AFM, and DPP-Spain; María-de-Maeztu-Program for Units of Excellence to UPF (MDM-2014-0370); and Severo-Ochoa-Program for Centers of Excellence to CNIC (SEV-2015-0505). A.S.-P. was supported by a fellowship from the Spanish ‘Ministerio de Educación, Cultura y Deporte’, award FPU 14/00098.

Background Abdominal aortic aneurysm (AAA), a degenerative vascular pathology characterized by permanent dilation of the aorta, is considered a chronic inflammatory disease involving innate/adaptive immunity. However, the functional role of antibody‐dependent immune response against antigens present in the damaged vessel remains unresolved. We hypothesized that engagement of immunoglobulin G (IgG) Fc receptors (FcγR) by immune complexes (IC) in the aortic wall contributes to AAA development. We therefore evaluated FcγR expression in AAA lesions and analysed whether inhibition of FcγR signaling molecules (γ‐chain and Syk kinase) influences AAA formation in mice. Methods FcγR gene/protein expression was assessed in human and mouse AAA tissues. Experimental AAA was induced by aortic elastase perfusion in wild‐type (WT) mice and γ‐chain knockout (γKO) mice (devoid of activating FcγR) in combination with macrophage adoptive transfer or Syk inhibitor treatment. To verify the mechanisms of FcγR in vitro, vascular smooth muscle cells (VSMC) and macrophages were stimulated with IgG IC. Results FcγR overexpression was detected in adventitia and media layers of human and mouse AAA. Elastase‐perfused γKO mice exhibited a decrease in AAA incidence, aortic dilation, elastin degradation, and VSMC loss. This was associated with (1) reduced infiltrating leukocytes and immune deposits in AAA lesions, (2) inflammatory genes and metalloproteinases downregulation, (3) redox balance restoration, and (4) converse phenotype of anti‐inflammatory macrophage M2 and contractile VSMC. Adoptive transfer of FcγR‐expressing macrophages aggravated aneurysm in γKO mice. In vitro, FcγR deficiency attenuated inflammatory gene expression, oxidative stress, and phenotypic switch triggered by IC. Additionally, Syk inhibition prevented IC‐mediated cell responses, reduced inflammation, and mitigated AAA formation. Conclusion Our findings provide insight into the role and mechanisms mediating IgG‐FcγR‐associated inflammation and aortic wall injury in AAA, which might represent therapeutic targets against AAA disease., Our work suggests a pathogenic role of IgG IC interaction with activating FcγR present in infiltrating and VSMC during AAA formation. These results support the investigation of novel immunotherapeutic strategies targeting FcγRs and/or downstream molecules to inhibit humoral immune damage in AAA

ObjectivesWe aimed to determine the interobserver reproducibility in diagnosing low-grade ductal carcinoma in situ (DCIS). We also aimed to compare the interobserver variability using a proposed two-tiered grading system as opposed to the current three-tiered system.MethodsThree expert breast pathologists and one junior pathologist identified low-grade DCIS from a set of 300 DCIS slides. Months later, participants were asked to grade the 300 cases using the standard three-tiered system.ResultsUsing the two-tiered system, interobserver agreement among breast pathologists was considered moderate (κ = 0.575). The agreement was similar (κ = 0.532) with the junior pathologist included. Using the three-tiered system, pathologists’ agreement was poor (κ = 0.235).ConclusionsPathologists’ reproducibility on diagnosing low-grade DCIS showed moderate agreement. Experience does not seem to influence reproducibility. Our proposed two-tiered system of low vs nonlow grade, where the intermediate grade is grouped in the nonlow category has shown improved concordance.

Paget’s disease (PD) of the breast is an uncommon disease of the nipple usually accompanied by an underlying carcinoma, often HER2 + , and accounting for 0.5–5% of all breast cancer. To date, histogenesis of PD of the breast remains controversial, as two theories—transformation and epidermotropic—have been proposed to explain this disease. Currently, animal models recapitulating PD of the nipple have not been described. HER2-enriched DT13 breast cancer cells were injected into the mammary fat pad of NOD scid gamma null (NSG) female mice. Immunohistochemical staining and pathological studies were performed on tumor samples, and diagnosis of PD of the nipple was confirmed by expression of proteins characteristic of Paget cells (epidermal growth factor 2 (HER2), androgen receptor (AR), cytokeratin 7 (CK7), cytokeratin 8/18 (CK8/18), and mucin 1 (MUC1)). In addition, DT13 cells grown in 2D culture and in soft agar assays were sensitive to in vitro treatment with pharmacological inhibitors targeting Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. Mice developed tumors and nipple lesions that were detected exclusively on the tumor-bearing mammary fat pad. Tumor cells were positive for proteins characteristic of Paget cells. In vitro, DT13 cells were sensitive to inhibition of Her2, adenylyl cyclase, mTOR, and PI3K signaling pathways. Our results suggest that injection of HER2 + DT13 cells into the mammary fat pad of NSG mice recapitulates critical aspects of the pathophysiology of PD of the nipple, supporting the epidermotropic theory as the more likely to explain the histogenesis of this disease.

Background Fine-needle aspiration (FNA) of a neck mass is frequently the initial diagnostic procedure for patients with human papillomavirus-positive head and neck squamous cell carcinoma. By performing a p16 immunocytochemistry (ICC) stain on FNA material, the pathologist can help to direct the treating physician's search for the primary site and to select the proper management for the patient. There is currently no established threshold for the evaluation of p16 ICC in cytology samples. This study was aimed at establishing an optimal threshold for p16 ICC interpretation in cytology samples. Methods The pathology databases were searched for all neck-mass FNAs diagnosed as squamous cell carcinoma from January 2010 to March 2019. p16 ICC was performed on cytology smears, and the percentage and intensity of p16-positive cells were assessed. Receiver operating characteristic (ROC) curves were plotted to determine the best cutoff threshold for p16 positivity on cytology smears. Results p16 ICC was performed on 50 cytology smears. An analysis of 8 different thresholds (combinations of the percentage and intensity of the p16 stain) using ROC curves demonstrated the best threshold to be 50% p16 staining with a sensitivity of 74% and a specificity of 100%. Applying the threshold used for surgical specimens (70%) to cytology samples resulted in a low sensitivity (45%). Conclusions p16 ICC on cytology smears shows diminished staining in comparison with surgical samples. Using 50% staining as the cutoff to consider positivity for p16 in cytology smears is proposed to decrease false-negative results while maintaining specificity.

The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2DM‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP‐TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP‐TAZ complex as a potential driver.

It has been suggested that exercise training and probiotic supplementation could decelerate the progress of functional and biochemical deterioration in APP/PS1 transgenic mice (APP/PS1TG). APP/PS1TG mice were subjected to exercise training and probiotic treatments and functional, biochemical and microbiome markers were analyzed. Under these conditions the mice significantly outperformed controls on The Morris Maze Test, and the number of beta-amyloid plaques decreased in the hippocampus. B. thetaiotaomicron levels correlated highly with the results of the Morris Maze Test (p

International audience; Background Exercise is increasingly recognized as an effective strategy to improve cancer prevention and prognosis. Several biological mechanisms mediating these benefits have been proposed, but the role of epigenetics remains largely unknown. Since epigenetics is highly susceptible to lifestyle factors, we hypothesized that exercise could affect the epigenome landscape in cancer tissues. Methods Rats implanted with AT1 prostate tumors were randomized to either control or exercise training. microRNA expression, DNA methylation and histone acetylation were analyzed in the tumor tissue. Results MiR-27a-5p appeared to be differently expressed between sedentary and trained rats. Furthermore, exercise increased global DNA methylation and decreased DNA methyltransferases mRNA expression in the tumor tissue. Histone acetylation however remained unaltered. Conclusion Overall, exercise might reverse some of the cancer-related epigenetic alterations in the prostate tumor tissue.

Background and Aims Diabetic nephropathy is the leading cause of chronic kidney disease worldwide. Hyperglycemia in concert with cytokines activate Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and induce gene expression of many inflammatory and oxidative stress mediators, which are critical events at all stages of diabetic kidney disease. Suppressor of cytokine signaling 1 (SOCS1) is a STAT-inducible protein and a negative feedback regulator of JAK/STAT pathway. The microRNA-155 is an epigenetic modulator of SOCS1 gene by repressing its translation and, at the same time, is a transcriptional target of STAT, thus completing another regulatory loop of JAK/STAT pathway. Therefore, our aim was to explore the interplay between miR-155 and JAK/STAT/SOCS1 axis in experimental diabetic nephropathy. Method In streptozotocin-induced type 1 diabetic aged mice (wild-type and apolipoprotein E (apoE) knockout) we analyzed the kidney levels of miR-155 and markers of renal damage, inflammation and oxidative stress. In vitro, the expression of miR-155, SOCS1 and STAT1 in mesangial, tubuloepithelial and macrophage cell lines were modulated by silencing/inhibition or overexpression/mimicking experiments to further determine the JAK/STAT pathway activation and expression of downstream target genes. Results In vivo, type 1 diabetes significantly upregulated miR-155 expression in kidneys from both wild-type and apoE knockout mice (1.8- and 4.5-fold vs respective non-diabetic controls). The miR-155 levels directly correlated with parameters of renal damage (serum creatinine, albuminuria, kidney-to-body weight ratio and renal score) and the mRNA expression of chemokines (Ccl2 and Ccl5) and pro-oxidant enzymes (Nox2 and Nox4), but inversely with antioxidant genes (Sod1 and Cat). In vitro, the expression of miR-155 was increased in renal cells and macrophages exposed to hyperglycemia and/or inflammatory conditions. Overexpression of miR-155 reduced SOCS1 expression, enhanced STAT1 and STAT3 activation and pro-inflammatory cytokines and chemokines (Il6, Tnfa, Ccl2 and Cxcl10) expression. By contrast, miR-155 antagonist upregulated SOCS1 and had a protective effect on renal cells by decreasing STAT1/3 phosphorylation and pro-inflammatory gene expression. Additionally, loss- or gain-of function experiments indicate a direct implication of SOCS1 in the regulation of miR-155 expression by STAT transcription factors. Conclusion Our study indicates a pro-inflammatory role of miR-155 in diabetic kidney disease by downregulating renal expression of SOCS1. Therefore, antagonism of miR-155 may have a renoprotective effect in diabetic nephropathy through SOCS1-mediated feedback inhibition of JAK/STAT overactivation. Ongoing in vivo studies with miR-155 inhibitor in experimental diabetes will clarify its role in the development and progression of diabetic nephropathy.

Figure 1(b) in [V. F. Gili et al, Opt. Express 24, 15965 (2016)10.1364/OE.24.015965] is corrupted and is corrected in this erratum.

The main epigenetic features in aging are: reduced bulk levels of core histones, altered pattern of histone post-translational modifications, changes in the pattern of DNA methylation, replacement of canonical histones with histone variants, and altered expression of non-coding RNA. The identification of epigenetic mechanisms may contribute to the early detection of age-associated subclinical changes or deficits at the molecular and/or cellular level, to predict the development of frailty, or even more interestingly, to improve health trajectories in older adults. Frailty reflects a state of increased vulnerability to stressors as a result of decreased physiologic reserves, and even dysregulation of multiple physiologic systems leading to adverse health outcomes for individuals of the same chronological age. A key approach to overcome the challenges of frailty is the development of biomarkers to improve early diagnostic accuracy and to predict trajectories in older individuals. The identification of epigenetic biomarkers of frailty could provide important support for the clinical diagnosis of frailty, or more specifically, to the evaluation of its associated risks. Interventional studies aimed at delaying the onset of frailty and the functional alterations associated with it, would also undoubtedly benefit from the identification of frailty biomarkers. Specific to the article yet reasonably common within the subject discipline.

Deficiencies in fruit and vegetable intake have been associated with oral cancer (oral cavity and oropharyngeal). Salivary rinses contain measurable biomarkers including soluble CD44 (solCD44) and total protein, which are known markers of oral cancer risk. This study investigates the effect of nutritional factors on solCD44 and protein levels to evaluate oral cancer risk and survival. We evaluated solCD44 and protein levels from 150 patients with oral and oropharyngeal squamous cell carcinoma and 150 frequency-matched controls. We subsequently characterized the effect of food group consumption and these biomarkers on progression-free survival (PFS) and overall survival (OS). Patients reported eating fewer servings of salad (p = 0.015), while controls reported eating fewer servings of potatoes (p &lt, 0.001). Oral cancer patients who consumed at least one serving per week of green salad were found to have significantly lower CD44 levels than those who ate salad less frequently (mean of log2[solCD44]1.73 versus 2.25, p = 0.014). Patients who consumed at least one serving per week of &ldquo, salad or other vegetables&rdquo, had significantly longer PFS (median 43.5 versus 9.1 months, p = 0.003, adjusted hazard ratio (HR) = 0.39 p = 0.014) and OS (median 83.6 versus 10 months, p = 0.008, adjusted HR = 0.04 p = 0.029). These findings suggest that dietary factors, namely greater green salad and vegetable intake, may be associated with lower CD44 levels and better prognosis in oral cancer patients.

International audience; We experimentally present a 10-Gb/s Fiber Wireless IFoF/V-band uplink of four625Mbaud 16QAM signals with a linear, high-power monolithically integrated reflective electroabsorptionmodulator with semiconductor optical amplifier for 5G mmWave fronthaul networks.

Oxidative stress contributes not only to the pathogenesis of type 2 diabetes (T2D) but also to diabetic vascular complications. It follows that antioxidants might contribute to limiting the diabetes burden. In this review we focus on ellagic acid (EA), a compound that can be obtained upon intestinal hydrolysis of dietary ellagitannins, a family of polyphenols naturally found in several fruits and seeds. There is increasing research on cardiometabolic effects of ellagitannins, EA, and urolithins (EA metabolites). We updated research conducted on these compounds and (I) glucose metabolism; (II) inflammation, oxidation, and glycation; and (III) diabetic complications. We included studies testing EA in isolation, extracts or preparations enriched in EA, or EA-rich foods (mostly pomegranate juice). Animal research on the topic, entirely conducted in murine models, mostly reported glucose-lowering, antioxidant, anti-inflammatory, and anti-glycation effects, along with prevention of micro-and macrovascular diabetic complications. Clinical research is incipient and mostly involved non-randomized and low-powered studies, which confirmed the antioxidant and anti-inflammatory properties of EA-rich foods, but without conclusive results on glucose control. Overall, EA-related compounds might be potential agents to limit the diabetes burden, but well-designed human randomized controlled trials are needed to fill the existing gap between experimental and clinical research., A.S.-V. is recipient of the Instituto de Salud Carlos III Miguel Servet fellowship (grant CP II17/00029).

In this paper we present the development of a photonic integrated circuit on InP with an array of antenna-integrated uni-travelling carrier photodiodes to increase the output power levels. Fabricated device consists of a single optical input and monolithically integrated optical power splitter. Due to fabrication issues the contact resistance was considerably above the expected values of 50 ohm and consequently recorded output power is much lower than expected. Nevertheless, the free-space emission of a 50 GHz signal has been successfully demonstrated as a proof of concept.

We present a colorless transmitter based on a reflective electroabsorption modulator (EAM) monolithically integrated with a semiconductor optical amplifier (SOA). A semi-insulating buried heterostructure (SI-BH) technology is used to define the device waveguide structures. The integration of the SOA allows to fully compensate for insertion losses. We observe up to +2 dB net gain in the fiber-coupled output power, for 90 mA SOA bias current. We demonstrate 25 Gb/s operation with non-return-to-zero (NRZ) modulation format, with a dynamic extinction ratio (DER) up to 14 dB for 2.6 V peak-to-peak EAM driving voltage. Colorless operation is demonstrated over 15 nm spectral range in the C-band. We achieved 10 km dispersion limited transmission distance at 25 Gb/s NRZ with a penalty of 3 dB at 10−3 bit error rate (BER).

Highlights • Low levels of physical activity are a risk factor associated with Alzheimer's disease. • Older adults who exercise are more likely to maintain cognition. • Exercise modulates amyloid β turnover, inflammation, synthesis, and release of neurotrophins, and cerebral blood flow., Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written over the ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid β turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations.

Context.— An abundance of clinical reports focused on specific laboratory parameters have been reported on coronavirus disease 19 (COVID-19), but a systematic analysis synthesizing these findings has not been performed. Objective.— To review and summarize the current available literature on the predictive role of various biomarkers in COVID-19 patients. Data Sources.— A literature search was performed using databases including PubMed, medRxiv, and bioRxiv. A total of 72 papers were reviewed, including 54 peer-reviewed papers and 18 non–peer-reviewed preprints. Conclusions.— Although the markers are considered nonspecific, acute-phase reactants, including C-reactive protein (CRP), ferritin, serum amyloid A (SAA), and procalcitonin, were reported as sensitive markers of acute COVID-19 disease. Significantly elevated white blood cell count; marked lymphopenia; decreased CD3, CD4, or CD8 T-lymphocyte counts; high neutrophil count; thrombocytopenia; and markedly elevated inflammatory biomarkers were associated with severe disease and the risk of developing sepsis with rapid progression. Trends observed by serial laboratory measurements during hospitalization, including progressive decrease of lymphocyte count, thrombocytopenia, elevated CRP, procalcitonin, increased liver enzymes, decreased renal function, and coagulation derangements, were more common in critically ill patient groups and associated with a high incidence of clinical complications. Elevated interleukin 6 level and markedly increased SAA were most often reported in severely and critically ill patients. Indicators of systemic inflammation, such as neutrophil to lymphocyte ratio, systemic immune-inflammation index, or COVID-19 Severity Score, may be used to predict disease severity, outcome, and mortality. Interpretation of the data reported in the studies reviewed here is limited because of the study design (mostly retrospective), limited sample size, and a lack of defined clinical criteria.

Objectives To examine and summarize the current literature on serologic methods for the detection of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods A literature review was performed using searches in databases including PubMed, medRxiv, and bioRxiv. Thirty-two peer-reviewed papers and 23 preprints were examined. Results The studies included lateral flow immunoassay, enzyme-linked immunosorbent assay, chemiluminescence immunoassay, and neutralizing antibody assays. The use of all major SARS-CoV-2 antigens was demonstrated to have diagnostic value. Assays measuring total antibody reactivity had the highest sensitivity. In addition, all the methods provided opportunities to characterize the humoral immune response by isotype. The combined use of IgM and IgG detection resulted in a higher sensitivity than that observed when detecting either isotype alone. Although IgA was rarely studied, it was also demonstrated to be a sensitive marker of infection, and levels correlated with disease severity and neutralizing activity. Conclusions The use of serologic testing, in conjunction with reverse transcription polymerase chain reaction testing, was demonstrated to significantly increase the sensitivity of detection of patients infected with SARS-CoV-2. There was conflicting evidence regarding whether antibody titers correlated with clinical severity. However, preliminary investigations indicated some immunoassays may be a surrogate for the prediction of neutralizing antibody titers and the selection of recovered patients for convalescent serum donation.

Diabetic nephropathy (DN) is associated with an increased morbidity and mortality, resulting in elevated cost for public health systems. DN is the main cause of chronic kidney disease (CKD) and its incidence increases the number of patients that develop the end-stage renal disease (ESRD). There are growing epidemiological and preclinical evidence about the close relationship between inflammatory response and the occurrence and progression of DN. Several antiinflammatory strategies targeting specific inflammatory mediators (cell adhesion molecules, chemokines and cytokines) and intracellular signaling pathways have shown beneficial effects in experimental models of DN, decreasing proteinuria and renal lesions. A number of inflammatory molecules have been shown useful to identify diabetic patients at high risk of developing renal complications. In this review, we focus on the key role of inflammation in the genesis and progression of DN, with a special interest in effector molecules and activated intracellular pathways leading to renal damage, as well as a comprehensive update of new therapeutic strategies targeting inflammation to prevent and/or retard renal injury., The authors work has been supported by grants from Instituto de Salud Carlos III (ISCIII, FIS-FEDER PI17/00130, PI17/01495, PI19/00588, ERA-PerMed-JTC2018-PERSTIGAN AC18/00071), Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM) and Cardiovascular (CIBERCV), Fondecyt Project (No. 1160465), Spanish Ministry of Science and Innovation (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369), and Spanish Societies of Cardiology (SEC), Nephrology (SEN) and Atherosclerosis (SEA). The “PFIS” and “Sara Borrell” training program of the ISCIII supported the salary of MGH (FI18/00310), SR-M (CD19/00021) and CH-B (CP16/00017). Córdoba University supported the salary of C.G.C.

INTRODUCTION AND OBJECTIVE:Identifying biomarkers to predict BCG response before beginning the treatment is an unsolved need in the clinical practice for patients with high risk non-muscle invasive...

INTRODUCTION AND OBJECTIVE:There is an increasing interest in finding a valid alternative for patients with non-muscle invasive bladder cancer (NMIBC). HIVEC-HR is a pilot trial that aims to compar...

we present a 50 Gb/s O-band reflective electroabsorption modulator operating in both non-return-to-zero (NRZ) and PAM-4 modulation formats without equalization. We obtained >9 dB NRZ dynamic extinction ratio for a peak-to-peak voltage of 2.4 V.

IntroductionDiabetic nephropathy (DN) is the leading cause of chronic kidney disease worldwide. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway participates in the development and progression of DN. Among the different mechanisms involved in JAK/STAT negative regulation, the family of suppressor of cytokine signaling (SOCS) proteins has been proposed as a new target for DN. Our aim was to evaluate the effect of SOCS1 mimetic peptide in a mouse model of obesity and type 2 diabetes (T2D) with progressive DN.Research design and methodsSix-week-old BTBR (black and tan brachyuric) mice with the ob/ob (obese/obese) leptin-deficiency mutation were treated for 7 weeks with two different doses of active SOCS1 peptide (MiS1 2 and 4 µg/g body weight), using inactive mutant peptide (Mut 4 µg) and vehicle as control groups. At the end of the study, the animals were sacrificed to obtain blood, urine and kidney tissue for further analysis.ResultsTreatment of diabetic mice with active peptide significantly decreased urine albumin to creatinine ratio by up to 50%, reduced renal weight, glomerular and tubulointerstitial damage, and restored podocyte numbers. Kidneys from treated mice exhibited lower inflammatory infiltrate, proinflammatory gene expression and STAT activation. Concomitantly, active peptide administration modulated redox balance markers and reduced lipid peroxidation and cholesterol transporter gene expression in diabetic kidneys.ConclusionTargeting SOCS proteins by mimetic peptides to control JAK/STAT signaling pathway ameliorates albuminuria, morphological renal lesions, inflammation, oxidative stress and lipotoxicity, and could be a therapeutic approach to T2D kidney disease.

Muscle mass and strength are very important for exercise performance. Training-induced musculoskeletal injuries usually require periods of complete immobilization to prevent any muscle contraction of the affected muscle groups. Disuse muscle wasting will likely affect every sport practitioner in his or her lifetime. Even short periods of disuse results in significant declines in muscle size, fiber cross sectional area, and strength. To understand the molecular signaling pathways involved in disuse muscle atrophy is of the utmost importance to develop more effective countermeasures in sport science research. We have divided our review in four different sections. In the first one we discuss the molecular mechanisms involved in muscle atrophy including the main protein synthesis and protein breakdown signaling pathways. In the second section of the review we deal with the main cellular, animal, and human atrophy models. The sources of reactive oxygen species in disuse muscle atrophy and the mechanism through which they regulate protein synthesis and proteolysis are reviewed in the third section of this review. The last section is devoted to the potential interventions to prevent muscle disuse atrophy with especial consideration to studies on which the levels of endogenous antioxidants enzymes or dietary antioxidants have been tested. Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Diabetes mellitus (DM), and its micro and macrovascular complications, is one of the biggest challenges for world public health. Despite overall improvement in prevention, diagnosis and treatment, its incidence is expected to continue increasing over the next years. Nowadays, finding therapies to prevent or retard the progression of diabetic complications remains an unmet need due to the complexity of mechanisms involved, which include inflammation, oxidative stress and angiogenesis, among others. Flavonoids are natural antioxidant compounds that have been shown to possess anti-diabetic properties. Moreover, increasing scientific evidence has demonstrated their potential anti-inflammatory and anti-oxidant effects. Consequently, the use of these compounds as anti-diabetic drugs has generated growing interest, as is reflected in the numerous in vitro and in vivo studies related to this field. Therefore, the aim of this review is to assess the recent pre-clinical and clinical research about the potential effect of flavonoids in the amelioration of diabetic complications. In brief, we provide updated information concerning the discrepancy between the numerous experimental studies supporting the eficacy of flavonoids on diabetic complications and the lack of appropriate and well-designed clinical trials. Due to the well-described beneficial effects on different mechanisms involved in diabetic complications, the excellent tolerability and low cost, future randomized controlled studies with compounds that have adequate bioavailability should be evaluated as add-on therapy on well-established anti-diabetic drugs, This paper was not funded. The authors work has been supported by FEDER-ISCIII Funds (PI17/00130, PI17/01495), Spanish Ministry of Economy and Competitiveness (RTI2018-098788-B-100, DTS17/00203, DTS19/00093, RYC-2017-22369), Spanish Society of Cardiology (SEC), Spanish Society of Nephrology (SEN) and Spanish Society of Atherosclerosis (SEA). TCO is an employee of FAES Pharma. The authors (except JAM) have an ongoing research project in common with FAES Pharma on Flavonoids in diabetic complications under the auspices of the joint-RETOS Collaborations Project 2017 (RTC-2017-6089-1), program supported by Spanish Ministry of Economy and Competitiveness.

Introduction In Spain, the guidelines for cervical cancer screening include a recommendation to enroll in external quality control programs. The Spanish Society of Cytology (SEC) has initiated its own quality control program of gynecological cytology (QCPGC). Aim To describe and discuss the results of the second round of SECs QCPGC. Material and method The cases are selected by a group of expert cytologists. The cases with an agreement of 75% of four cytopathologists were used. The cases were scanned with Aperio. The scanned cases not available were excluded. We included a total of 23 cases, 1 negative, 15 low grade lesions (4 ASCUS and 11 LSIL) and 7 high grade lesions (1 ASCH and 6 HSIL). Sixteen cases were studied with ThinPrep™ platform and in 7 cases the SurePath™ platform was used. Results Sixteen hospitals participated. The global mean concordance was 70.6%. The mean concordance in the type of lesion was 63.1%. The concordance was 71.9% in negative diagnoses, 56.2% in ASCUS, 69.5% in LSIL and 82.8% in HSIL The discordant cases were diagnosed more frequently as negative and ASCUS. 4.4% of cases had major discordances (HSIL or ASCH versus negatives). Conclusions Our results are similar to those reported in the literature, with very few severe discordances.

Objectives We analyze the relationship between CD44, epidermal growth factor receptor (EGFR), and p16 expression in oral cavity and oropharyngeal cancers in a diverse population. We also describe whether particular patterns of staining are associated with progression-free survival and overall survival. Study Design Prospective study, single-blind to pathologist and laboratory technologist. Setting Hospital based. Subjects and Methods Immunohistochemistry, comprising gross staining and cellular expression, was performed and interpreted in a blinded fashion on 24 lip/oral cavity and 40 oropharyngeal cancer specimens collected between 2007 and 2012 from participants of a larger study. Information on overall survival and progression-free survival was obtained from medical records. Results Nineteen cases were clinically p16 positive, 16 of which were oropharyngeal. Oral cavity lesions were more likely to exhibit strong CD44 membrane staining ( P = .0002). Strong CD44 membrane and strong EGFR membrane and/or cytoplasmic staining were more common in p16-negative cancers ( P = .006). Peripheral/mixed gross p16 staining pattern was associated with worse survival than the universal staining on univariate and multivariate analyses ( P = .006, P = .030). This held true when combining gross and cellular localization for p16. For CD44, universal gross staining demonstrated poorer overall survival compared with the peripheral/mixed group ( P = .039). CD44 peripheral/mixed group alone and when combined with universal p16 demonstrated the best survival on multivariate analysis ( P = .010). Conclusion In a diverse population, systematic analysis applying p16, CD44, and EGFR gross staining and cellular localization on immunohistochemistry demonstrates distinct patterns that may have prognostic potential exceeding current methods. Larger studies are warranted to investigate these findings further.

Physical exercise performed regularly is known to improve health and to reduce the risk of age-related diseases. Furthermore, there is some evidence of cognitive improvement in physically active middle-aged and older adults. We hypothesized that long-term physically active middle-aged men may have developed brain resilience that can be detected with the analysis of peripheral blood markers. We aimed to analyze the activation of pathways potentially modulated by physical activity in a cohort of healthy amateur rugby players (n = 24) and control subjects with low physical activity (n = 25) aged 45¿65 years. We had previously reported neuropsychological improvement in immediate memory responses in the player group compared to the controls. Here, we tested the expression of selected genes of longevity, inflammation, redox homeostasis, and trophic signaling in whole blood mRNA. Analyses were also performed on blood samples of young (aged 15¿25 years) control subjects with low physical activity (n = 21). Physical activity and other lifestyle factors were thoroughly recorded with standardized questionnaires. Interestingly, middle-aged control subjects showed lower levels of expression of SIRT1, SIRT3, CAT, and SOD1 than the young controls, although rugby players maintained the expression levels of these genes at a young-like level. Middle-aged players showed lower levels of IL1B than the non-physically active groups. However, there was a tendency towards a decrease in trophic and transduction factors in middle-aged groups as compared to the young controls. A statistical study of Spearman¿s correlations supported a positive effect of sporting activity on memory and executive functions, and on peripheral gene expression of SIRT1, SIRT3 and downstream genes, in the middle-aged rugby players. Our results indicate that the SIRT1-SIRT3 axis, and associated neuroprotective signaling, may contribute to the anti-aging resilience of the brain mediated by physical exercise., This work was supported by the following grants: Ajut Mario Sàlvia i Ferret 2014 de l’Institut d’Estudis Catalans (IEC), Barcelona, ‘‘Per Incentivar la Recerca en Biomedicina i Estil de Vida’’ (Grant to Incentivize the Research in Biomedicine and Lifestyles); SAF2016-77703 from the Spanish MINECO (Ministerio de Economía y Competitividad) and FEDER.

International audience; The paper presents a fabrication platform based on silicon nitride embedded in silica on silicon wafers. Long Bragg gratings have been fabricated for narrow linewidth lasers. A narrow stop-band (0.2 nm) Bragg gratings with etched facet chips is achieved in this platform. Heaters have been integrated on the chips allowing tuning of the Bragg wavelength over 1.5 nm. Lasers have been obtained and tested by butt-coupling of one of these Bragg gratings to a reflective semiconductor optical amplifier (R-SOA). On these laser cavities we obtained a continuous tuning range of 0.16 nm and a discontinuous tuning range of 1.5 nm.