Colorectal cancers (CRCs) often show a dense infiltrate of cytokine-producing immune/inflammatory cells. The exact contribution of each immune cell subset and cytokine in the activation of the ...intracellular pathways sustaining CRC cell growth is not understood. Herein, we isolate tumor-infiltrating leukocytes (TILs) and lamina propria mononuclear cells (LPMCs) from the tumor area and the macroscopically unaffected, adjacent, colonic mucosa of patients who underwent resection for sporadic CRC and show that the culture supernatants of TILs, but not of LPMCs, potently enhance the growth of human CRC cell lines through the activation of the oncogenic transcription factors signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kappa B (NF-kB). Characterization of immune cell complexity of TILs and LPMCs reveals no differences in the percentages of T cells, natural killer T cells, natural killer (NK) cells, macrophages and B cells. However, T cells from TILs show a functional switch compared with those from LPMCs to produce large amounts of T helper type 17 (Th17)-related cytokines (that is, interleukin-17A (IL-17A), IL-17F, IL-21 and IL-22), tumor necrosis factor-α (TNF-α) and IL-6. Individual neutralization of IL-17A, IL-17F, IL-21, IL-22, TNF-α or IL-6 does not change TIL-derived supernatant-driven STAT3 and NF-kB activation, as well as their proproliferative effect in CRC cells. In contrast, simultaneous neutralization of both IL-17A and TNF-α, which abrogates NF-kB signaling, and IL-22 and IL-6, which abrogates STAT3 signaling, reduces the mitogenic effect of supernatants in CRC cells. IL-17A, IL-21, IL-22, TNF-α and IL-6 are also produced in excess in the early colonic lesions in a mouse model of sporadic CRC, associated with enhanced STAT3/NF-kB activation. Mice therapeutically given BP-1-102, an orally bioavailable compound targeting STAT3/NF-kB activation and cross-talk, exhibit reduced colon tumorigenesis and diminished expression of STAT3/NF-kB-activating cytokines in the neoplastic areas. These data suggest that strategies aimed at the cotargeting of STAT3/NF-kB activation and interaction between them might represent an attractive and novel approach to combat CRC.
Background and aims.
Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. At present, there are no data on sarcopenia in nursing home ...population. We evaluated the prevalence of sarcopenia and its association with functional and clinical status in a population of elderly persons aged 70 years and older living in nursing homes.
Methods.
This study was conducted selecting all the participants (n = 122) living in the teaching nursing homes of Catholic University of Rome who were aged 70 years and older from August 1, 2010, to September 30, 2010. The European Working Group on Sarcopenia in Older People (EWGSOP) criteria were adopted. Accordingly, diagnosis of sarcopenia required the documentation of low muscle mass plus the documentation of either low muscle strength or low physical performance.
Results.
Forty residents (32.8%) were identified as affected by sarcopenia. The multivariate logistic regression analysis showed a high increase in risk of sarcopenia for male residents (odds ratio OR 13.39; 95% confidence interval CI 3.51-50.63) and for residents affected by cerebrovascular disease (OR 5.16; 95% CI 1.03-25.87) or osteoarthritis (OR 7.24; 95% CI 2.02-25.95). Residents who had a body mass index higher than 21 kg/m2 had a lower risk to be sarcopenic (OR 0.76; 95% CI 0.64-0.90) relative to those with body mass index less than 21 kg/m2. Similarly, sarcopenia was less likely to be present among participants involved in leisure physical activity for 1 hour or more per day (OR 0.40; 95% CI 0.12-0.98).
Conclusions.
The present study suggests that among participants living in nursing homes, sarcopenia is highly prevalent and it is more represented among male residents (68%) than among female residents (21%). Our findings support the hypothesis that muscle mass is strongly associated with nutritional status and physical activity in nursing homes, too.
Summary
This study analyzed data of bone mineral density (BMD) from a large cohort of adults with Down syndrome (DS). BMD was found to decrease with age more rapidly in these subjects than in the ...general population, exposing adults with DS to an increased risk of osteoporosis and bone fracture.
Introduction
Down syndrome (DS) in adulthood presents with a high prevalence of osteoporosis. However, in DS, bone mineral density (BMD) can be underestimated due to short stature. Furthermore, the rate of age-related decline in BMD and its association with gender in DS has been rarely evaluated or compared with the general population. The present study is aimed at assessing the variation of BMD with age and gender in a sample of adults with DS and to compare these data with those of the general population, after adjusting for anthropometric differences.
Methods
Adults with DS, aged 18 or older, were assessed dual-energy-X-ray-absorptiometry (DXA) at the femoral neck and at the lumbar spine. They were compared with the general population enrolled in the National Health and Nutrition Examination Survey (NHANES) 2009–2010 dataset. Bone mineral apparent density (BMAD) was calculated for each individual.
Results
DXA was evaluated in 234 subjects with DS (mean age 36.93 ± 11.83 years, ranging from 20 to 69 years; 50.4% females). In the lumbar spine both mean BMD (DS 0.880 ± 0.141 vs. NHANES 1.062 ± 0.167,
p
< 0.001) and BMAD (DS 0.138 ± 0.020 vs. NHANES 0.152 ± 0.020,
p
< 0.001) were significantly lower in the DS sample than in the NAHNES cohort. The same trend was observed at the femoral neck in both BMD (DS 0.658 ± 0.128 vs. NHANES 0.835 ± 0.137,
p
< 0.001) and BMAD (DS 0.151 ± 0.030 vs. NHANES 0.159 ± 0.028,
p
<0.001). Age was associated with lower femoral neck BMAD in both samples; importantly, this association was significantly stronger in the DS sample. In the lumbar spine region, no significant association between BMAD and age could be observed in both samples.
Conclusions
Adults with DS have lower bone mineral density compared to the general population and they experience a steeper decline with age. Early screening programs are needed in DS population.
and Sex and cognitive profile may be related to the laterality of motor symptoms in idiopathic Parkinson's disease.
Parkinson's disease (PD) is well recognised as an inherently asymmetric disease ...with unilateral onset of motor symptoms. The laterality of motor symptoms may be linked to sex, clinical and demographic variables, and neuropsychological disorders. However, the available data are inconsistent. This study aimed to explore the potential association between the laterality of motor symptoms and clinical and demographic variables and deficits in specific cognitive domains.
We retrospectively recruited 97 participants with idiopathic PD without dementia; 60 presented motor symptoms on the left side and 37 on the right side. Both groups were comparable in terms of age, age at disease onset, disease duration, and severity of the neurological deficits according to the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale.
Participants with left-side motor symptoms scored lower on the Schwab and England Activities of Daily Living scale. Our sample included more men than women (67% vs. 33%). Both sexes were not equally represented in the 2 groups: there were significantly more men than women in the group of patients with left-side motor symptoms (77% vs. 23%), whereas the percentages of men and women in the group of patients with right-side motor symptoms were similar (51% vs. 49%). Both groups performed similarly in all neuropsychological tasks, but women, independently of laterality, performed better than men in the naming task.
We found a clear prevalence of men in the group of patients with left-side motor symptoms; this group also scored lower on the Schwab and England Scale. Female sex was predictive of better performance in the naming task. Sex should always be considered in disorders that cause asymmetric involvement of the brain, such as PD.
La enfermedad de Parkinson (EP) es una enfermedad asimétrica en la que los primeros síntomas se presentan solo en un lado del cuerpo. El lado de inicio de la sintomatología puede depender del sexo, de variables clínicas y demográficas y de la presencia de trastornos neuropsicológicos. Sin embargo, la evidencia disponible no es consistente. Nuestro estudio pretende determinar si el lado que presenta síntomas motores tiene alguna relación con variables clínicas y demográficas y con déficits en determinados dominios cognitivos.
Incluimos 97 individuos con EP y sin demencia; 60 de ellos tenían síntomas motores en el lado izquierdo y 37 en el lado derecho. Ambos grupos presentaban similitudes en cuanto a edad, edad de inicio de la enfermedad, duración de la enfermedad, y gravedad de los síntomas neurológicos, según la Unified Parkinson's Disease Rating Scale y la Hoehn and Yahr Scale.
Los participantes con síntomas en el lado izquierdo obtuvieron puntuaciones más bajas en la Escala de Actividades de la Vida Diaria de Schwab y England. Nuestra muestra incluía más hombres que mujeres (67 vs. 33%). Además, la distribución de hombres y mujeres no era equitativa entre los dos grupos; había un número significativamente mayor de hombres en el grupo de pacientes con síntomas en el lado izquierdo (77 vs. 23%), mientras que la distribución por sexo era similar en el grupo de pacientes con síntomas en el lado derecho (51 vs. 49%). No encontramos diferencias en las puntuaciones de ninguna de las pruebas neuropsicológicas entre los grupos. Sin embargo, las mujeres, independientemente del lado afecto, obtuvieron mejores resultados que los hombres en la prueba de denominación.
Los hombres eran mucho más numerosos en el grupo de pacientes con afectación del lado izquierdo; este grupo mostró peores puntuaciones en la escala de Schwab y England. El sexo femenino fue predictor de un mejor desempeño en la prueba de denominación. El sexo podría desempeñar un papel fundamental en la lateralidad de los síntomas en enfermedades como la EP.
Cytoplasmic mRNA movements ultimately determine the spatial distribution of protein synthesis. Although some mRNAs are compartmentalized in cytoplasmic regions, most mRNAs, such as housekeeping mRNAs ...or the poly-adenylated mRNA population, are believed to be distributed throughout the cytoplasm 1–4. The general mechanism by which all mRNAs may move, and how this may be related to localization, is unknown. Here, we report a method to visualize single mRNA molecules in living mammalian cells, and we report that, regardless of any specific cytoplasmic distribution, individual mRNA molecules exhibit rapid and directional movements on microtubules. Importantly, the β-actin mRNA zipcode increased both the frequency and length of these movements, providing a common mechanistic basis for both localized and nonlocalized mRNAs. Disruption of the cytoskeleton with drugs showed that microtubules and microfilaments are involved in the types of mRNA movements we have observed, which included complete immobility and corralled and nonrestricted diffusion. Individual mRNA molecules switched frequently among these movements, suggesting that mRNAs undergo continuous cycles of anchoring, diffusion, and active transport.
Summary
Background
Transforming growth factor (TGF)‐β1 exerts inhibitory effects on keratinocyte proliferation.
Objectives
To examine whether Smad7, a known inhibitor of TGF‐β1 signalling, is ...involved in psoriasis‐associated keratinocyte hyperproliferation.
Methods
Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara‐induced skin pathology by real‐time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell‐cycle‐associated factors, cell‐cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS.
Results
Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S‐phase of the cell cycle. Smad7‐deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S‐phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara‐treated mice reduced epidermal thickness.
Conclusions
Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation.
What's already known about this topic?
Defective transforming growth factor (TGF)‐β1/Smad signalling associates with the development of or exacerbates inflammation in many organs. Expression of TGF‐β1 and its receptors is reduced in psoriatic skin.
What does this study add?
Expression of Smad7, an inhibitor of TGF‐β1/Smad signalling, is upregulated in keratinocytes of patients with psoriasis and mice with psoriasis‐like skin inflammation.
Smad7 knockdown with a specific antisense oligonucleotide (AS) induces keratinocytes to arrest in the S‐phase of the cell cycle, thereby reducing cell proliferation in both in vitro and in vivo models of psoriasis.
What is the translational message?
Our data show that Smad7 is a critical regulator of human and mouse keratinocyte proliferation. A Smad7‐specific AS reduces cell proliferation in both in vitro and in vivo models of psoriasis.
The findings described in this work, together with our recent demonstration that Smad7 AS‐based therapy is safe and effective in patients with inflammatory bowel diseases, suggest that restoring TGF‐β signalling through Smad7 knockdown may help attenuate the pathological lesions in human psoriasis.
Linked Comment: Gallucci. Br J Dermatol 2017; 177:1480–1481.
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Most of the evidence regarding the association between particulate air pollution and emergency room visits or hospital admissions for respiratory conditions and asthma comes from the USA. European ...time-series analyses have suggested that gaseous air pollutants are important determinants of acute hospitalization for respiratory conditions, at least as important as particulate mass. The association between daily mean levels of suspended particles and gaseous pollutants (sulphur dioxide, nitrogen dioxide, carbon monoxide, ozone) was examined. The daily emergency hospital admissions for respiratory conditions in the metropolitan area of Rome during 1995-1997 were also recorded. Daily counts of hospital admissions for total respiratory conditions (43 admissions day(-1)), acute respiratory infections including pneumonia (18 day(-1)), chronic obstructive pulmonary disease (COPD) (13 day(-1)), and asthma (4.5 day(-1)) among residents of all ages and among children (0-14 yrs) were analysed. The generalized additive models included spline smooth functions of the day of study, mean temperature, mean humidity, influenza epidemics, and indicator variables for day of the week and holidays. Total respiratory admissions were significantly associated with same-day level of NO2 (2.5% increase per interquartile range (IQR) change, 22.3 microg x m(-3)) and CO (2.8% increase per IQR, 1.5 mg x m(-3)). No effect was found for particulate matter and SO2, whereas O3 was associated with admissions only among children (lag 1, 5.5% increase per IQR, 23.9 microg x m3). The effect of NO2 was stronger on acute respiratory infections (lag 0, 4.0% increase) and on asthma among children (lag 1, 10.7% increase). The admissions for all ages for asthma and COPD were associated only with same-day level of CO (5.5% and 4.3% increase, respectively). Multipollutant models confirmed the role of CO on all respiratory admissions, including asthma and COPD, and that of NO2 on acute respiratory infections. Among children, O3 remained a strong indicator of acute respiratory infections. Carbon monoxide and photochemical pollutants (nitrogen dioxide, ozone) appear to be determinants of acute respiratory conditions in Rome. Since carbon monoxide and nitrogen dioxide are good indicators of combustion products from traffic related sources, the detected effect may be due to unmeasured fine and ultrafine particles.
By means of a reduction approach to 2 x 2 quasilinear hyperbolic homogeneous systems of first-order PDEs, a full and exhaustive analysis of nonlinear wave interactions is achieved. The alteration in ...the profile as well as in the wave time distortion of the emerging pulses caused by the interaction process is illustrated in detail through exact solutions of initial value problems. Canonical forms of 2 x 2 systems which allow for special (soliton-like) hyperbolic wave interactions and of interest in applications are also determined.
BACKGROUNDand Sex and cognitive profile may be related to the laterality of motor symptoms in idiopathic Parkinson's disease. INTRODUCTIONParkinson's disease (PD) is well recognised as an inherently ...asymmetric disease with unilateral onset of motor symptoms. The laterality of motor symptoms may be linked to sex, clinical and demographic variables, and neuropsychological disorders. However, the available data are inconsistent. This study aimed to explore the potential association between the laterality of motor symptoms and clinical and demographic variables and deficits in specific cognitive domains. MATERIAL AND METHODSWe retrospectively recruited 97 participants with idiopathic PD without dementia; 60 presented motor symptoms on the left side and 37 on the right side. Both groups were comparable in terms of age, age at disease onset, disease duration, and severity of the neurological deficits according to the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr scale. RESULTSParticipants with left-side motor symptoms scored lower on the Schwab and England Activities of Daily Living scale. Our sample included more men than women (67% vs. 33%). Both sexes were not equally represented in the 2 groups: there were significantly more men than women in the group of patients with left-side motor symptoms (77% vs. 23%), whereas the percentages of men and women in the group of patients with right-side motor symptoms were similar (51% vs. 49%). Both groups performed similarly in all neuropsychological tasks, but women, independently of laterality, performed better than men in the naming task. CONCLUSIONWe found a clear prevalence of men in the group of patients with left-side motor symptoms; this group also scored lower on the Schwab and England Scale. Female sex was predictive of better performance in the naming task. Sex should always be considered in disorders that cause asymmetric involvement of the brain, such as PD.
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