The loss of skeletal muscle strength is a consequence of aging. In women, there is an even greater loss of muscle strength due to reduced ovarian hormones that occurs during menopause. Estradiol (E
2
...) has been shown to mitigate the detrimental effects on muscle strength in females. However, the underlying molecular mechanisms of estradiol's beneficial effects are not completely understood. Here we have focused on signaling by microRNAs (miRs) which are known to be potential biomarkers for disease (1). miRs are small RNA molecules that work as post‐transcriptional regulators by blocking translation. Previously we have shown in women that there are several E
2
responsive miRs in skeletal muscle (2). MiR‐21 is a specific miRNA that is frequently up‐regulated in cancer and has a key role in apoptosis. Apoptosis signaling has a potential role in muscle atrophy contributing to loss of muscle strength with aging.
METHODS
Adult C57BL/6 mice were either sham operated (ovary‐intact) or ovariectomized (OVX) under isoflurane anesthesia. Four weeks later, extensor digitorum longus (EDL) muscles from the OVX mice were isolated and underwent a series of repetitive maximal isometric tetanic contractions in the presence or absence of E
2
in the bathing medium, after which muscles were snap frozen and analyzed for miR‐21. Gastrocnemius muscles and blood serum were also collected for miR‐21 analysis.
RESULTS
OVX mice had 11‐fold higher miR‐21 levels in gastrocnemius muscles (p < 0.01) compared to sham mice, but serum levels did not differ (p = 0.18). Electrically stimulated muscle contractions in vitro increased the expression of miR‐21 in EDL muscles, whereas acute E
2
exposure diminished the contraction‐induced upregulation of miR‐21 in OVX mice.
CONCLUSION
Our preliminary results show that E
2
deficiency via OVX leads to high miR‐21 levels in skeletal muscle and that a short term exposure of muscle to E
2
can blunt muscle contraction‐induced upregulation of miR‐21. More studies are needed to find out mechanisms through which E
2
affects miR‐21 levels.
Support or Funding Information
This study is supported by NIH grant R01‐AG031743.
Aim
We tested the hypothesis of a more aggressive disease process at diagnosis of type 1 diabetes during fall and winter, the colder seasons with consistently observed higher incidence of type 1 ...diabetes.
Methods
Seasonality in the manifestation of type 1 diabetes was examined in 4993 Finnish children and adolescents. Metabolic characteristics, beta‐cell autoantibodies and HLA class II genetics were analysed at clinical diagnosis.
Results
Significant seasonality was observed with higher number of new cases during fall and winter (n = 1353/27.1% and n = 1286/25.8%) compared with spring and summer (n = 1135/22.7% and n = 219/24.4%) (p < 0.001). The youngest children (aged 0.5–4 years) differed from the older ones (aged 5–14 years) as a minority of them were diagnosed in winter (p = 0.019) while the older children followed the same pattern as that seen in the total series. Poorer metabolic decompensation was observed during seasons with lower number of new diagnoses.
Conclusion
The heterogeneity in the seasonality of diabetes manifestation between younger and older children suggests that different environmental factors may trigger the disease at different ages. Poorer clinical condition associated with seasons with a lower number of new cases may be more likely to be due to a delay in seeking medical help than to a more aggressive autoimmunity.
We studied the short- and long-term effects of imatinib in hospitalized COVID-19 patients.
Participants were randomized to receive standard of care (SoC) or SoC with imatinib. Imatinib dosage was ...400 mg daily until discharge (max 14 days). Primary outcomes were mortality at 30 days and 1 year. Secondary outcomes included recovery, quality of life and long COVID symptoms at 1 year. We also performed a systematic review and meta-analysis of randomized trials studying imatinib for 30-day mortality in hospitalized COVID-19 patients.
We randomized 156 patients (73 in SoC and 83 in imatinib). Among patients on imatinib, 7.2% had died at 30 days and 13.3% at 1 year, and in SoC, 4.1% and 8.2% (adjusted HR 1.35, 95% CI 0.47–3.90). At 1 year, self-reported recovery occurred in 79.0% in imatinib and in 88.5% in SoC (RR 0.91, 0.78–1.06). We found no convincing difference in quality of life or symptoms. Fatigue (24%) and sleep issues (20%) frequently bothered patients at one year. In the meta-analysis, imatinib was associated with a mortality risk ratio of 0.73 (0.32–1.63; low certainty evidence).
The evidence raises doubts regarding benefit of imatinib in reducing mortality, improving recovery and preventing long COVID symptoms in hospitalized COVID-19 patients.
•We found no short or long-term benefit from imatinib in hospitalized COVID-19.•Pooled evidence raises doubts regarding benefit of imatinib in reducing mortality.•Fatigue and sleeping problems common at 1 year after hospitalized COVID-19.
Objective: To assess the documentation of a do-not-attempt-resuscitation (DNAR) or do-not-hospitalize (DNH) orders in the medical record and to determine factors related to these orders.
Materials ...and methods: Five thousand six hundred and fifty four subjects from three different levels of institutional long-term care (LTC), chronic care hospitals (
n=1989), nursing homes (
n=3310), and assisted living (
n=355) in 67 LTC facilities in 19 municipalities were assessed.
Results: Out of these patients, 751 (13%) had a DNAR order and only 36 (0.6%) had a DNH order. The variation in DNAR orders between individual LTC institutions was enormous, ranging from 0 to 92%. In logistic regression analysis, individual institutions and their local caring cultures had the strongest explanatory value (
R
2=0.49) for advance orders to limit therapy. Impaired activity in daily living (ADL) function (
R
2=0.11), impaired cognition (
R
2=0.07), level of LTC (
R
2=0.05), and diagnoses (
R
2=0.04) did not provide adequate explanations. Terminal prognosis was not significantly associated with advance orders.
Conclusions: We found marked differences in the use of DNAR and DNH orders between caring units. Diseases and ADL status were only weakly significant as background factors. Open discussions, general guidelines, and research about the adequacy of DNAR decisions are needed to improve equality and self-empowerment among the elderly residing in institutions.
Objectivo: Avaliar a documentação da decisão de não reanimar (DNAR) ou de não hospitalizar (DNH) nos registos médicos e determinar factores relacionados com estas ordens.
Materiais e métodos: Foram avaliados 5654 doentes de instituições de cuidados continuados (LTC) de 3 nı́veis diferentes, hospitais de cuidados crónicos (
n = 1989), lares de enfermagem (
n = 3310) e de apoio a doentes (
n = 355) em 67 instituições LTC de 19 municı́pios.
Resultados: Destes doentes, 751 (13%) tinham ordem DNAR e apenas 36 (0,6%) tinham ordem DNH. A variação na DNAR entre instituições NTC individuais foi enorme, variando de 0 a 92%. Na análise de regressão logı́stica as instituições individuais e as suas culturas locais de cuidados tiveram o maior valor explicativo (
R
2 = 0,49) para as directivas avançadas de limite de intervenção terapêutica. Alterações na capacidade para actividades de vida diária (ADL) (
R
2 = 0,11), alterações cognitivas (
R
2 = 0,07), nı́vel de LTC (
R
2 = 0,05) e diagnósticos (
R
2 = 0,04) não proporcionaram explicações adequadas. O prognóstico terminal não estava significativamente associado com as directivas avançadas.
Conclusões: Encontramos diferenças profundas no uso das ordens DNAR e DNH entre unidades de cuidados. As doenças e estado de ADL tinham pouco significado como factores explicativos. São necessárias discussões abertas, recomendações gerais e investigação acerca das decisões adequadas de DNAR para melhorar a equidade e autodeterminação entre os idosos a residirem em instituições.
Objetivos: Evaluar la documentación de las órdenes de no intentar reanimación (DNAR) o de no hospitalizar (DNH) en el registro médico, y determinar los factores relacionados con estas órdenes.
Materiales y métodos: Se evaluaron 5654 sujetos de instituciones de cuidados de largo plazo(LTC), hospitales de cuidados de enfermos crónicos (
n = 1989), casas de reposo (
n = 3310), e instituciones de vida asistida (
n = 355) en 67 instituciones de LTC en 19 municipalidades.
Resultados: De estos pacientes, 751 (13%) tenı́a órdenes de DNAR y solo 36 (0.6%) tenı́a órdenes de DNH. La variación entre las DNAR de las distintas instituciones fue enorme, variando en un rango entre el 0 al 92%. En análisis de regresión logı́stica, las instituciones individuales y sus culturas locales de cuidados tuvieron el valor explicatorio mas fuerte (
R
2 = 0.49) para órdenes que limiten terapias. Las limitaciones en actividades en las funciones de vida diaria (ADL) (
R
2 = 0.11), limitaciones cognitivas (
R
2 = 0.07), nivel de LTC (
R
2 = 0.05) y diagnóstico (
R
2 = 0.04) no proporcionaron explicaciones adecuadas. El pronóstico terminal no estuvo significativamente asociado con órdenes adelantadas.
Conclusiones: Encontramos diferencias marcadas en el uso de la órdenes DNAR y DNH entre las distintas unidades de cuidados. El diagnóstico y el estado de ADL fueron débilmente significativos como factores de antecedentes. Se necesitan discusiones abiertas, guı́as generales, e investigación acerca de lo adecuado de las decisiones de DNAR para mejorar la equidad y poder sobre su tratamiento en los ancianos residentes en instituciones.
Primary effusion lymphomas (PELs) are aggressive Kaposi's sarcoma herpesvirus (KSHV)-induced malignancies with median survival time <6 months post-diagnosis. Mutations in the TP53 gene seldom occur ...in PELs, suggesting that genetic alterations in the TP53 are not selected during PEL progression. We have reported that p53 reactivation by an inhibitor of the p53-MDM2 interaction, Nutlin-3, induces selective and massive apoptosis in PEL cells leading to efficient anti-tumor activity in a subcutaneous xenograft model for PEL. Here, we show compelling anti-tumor activity of Nutlin-3 in the majority of intraperitoneal PEL xenografts in vivo. Interestingly, our results demonstrate that spontaneous induction of viral lytic replication in tumors could drastically attenuate the p53-dependent apoptotic response to Nutlin-3. Moreover, viral reactivation compromised p53-dependent apoptosis in PEL cells treated with genotoxic anti-cancer agents doxorubicin and etoposide. We have recently demonstrated that the Ser/Thr kinases Pim 1 and 3 are required to trigger induction of the lytic replication cascade of KSHV. We have now assessed the ability of a novel Pim kinase inhibitor to restore the Nutlin-3-induced cytotoxicity in lytic PEL cells. PEL cells induced to lytic replication by phorbol esters showed 50% inhibition of active viral replication following treatment with the Pim kinase inhibitor. Importantly, co-treatment of these cells with the kinase inhibitor and Nutlin-3 resulted in a robust restoration of the Nutlin-3-induced cell death. These results highlight the potential impact of activation of viral lytic replication on disease progression and response to treatment in KSHV-induced lymphomas.
Hantaviruses are among the main emerging infectious agents in Europe. Their mode of transmission in natura is still not well known. In particular, social features and behaviours could be crucial for ...understanding the persistence and the spread of hantaviruses in rodent populations. Here, we investigated the importance of kinclustering and dispersal in hantavirus transmission by combining a fine-scale spatiotemporal survey (4 km²) and a population genetics approach. Two specific host-hantavirus systems were identified and monitored: the bank vole Myodes, earlier Clethrionomys glareolus--Puumala virus and the common vole Microtus arvalis--Tula virus. Sex, age and landscape characteristics significantly influenced the spatial distribution of infections in voles. The absence of temporal stability in the spatial distributions of viruses suggested that dispersal is likely to play a role in virus propagation. Analysing vole kinship from microsatellite markers, we found that infected voles were more closely related to each other than non-infected ones. Winter kin-clustering, shared colonies within matrilineages or delayed dispersal could explain this pattern. These two last results hold, whatever the host-hantavirus system considered. This supports the roles of relatedness and dispersal as general features for hantavirus transmission.
Much recent attention in the study of adaptation of organismal form has centered on developmental regulation. As such, the highly conserved respiratory machinery of eukaryotic cells might seem an ...unlikely target for selection supporting novel morphologies. We demonstrate that a dramatic molecular evolutionary rate increase in subunit I of cytochrome c oxidase (COX) from an active-trapping lineage of carnivorous plants is caused by positive Darwinian selection. Bladderworts (Utricularia) trap plankton when water-immersed, negatively pressured suction bladders are triggered. The resetting of traps involves active ion transport, requiring considerable energy expenditure. As judged from the quaternary structure of bovine COX, the most profound adaptive substitutions are two contiguous cysteines absent in ≈99.9% of databased COX I sequences from Eukaryota, Archaea, and Bacteria. This motif lies directly at the docking point of COX I helix 3 and cytochrome c, and modeling of bovine COX I suggests the possibility of an unprecedented helix-terminating disulfide bridge that could alter COX/cytochrome c dissociation kinetics. Thus, the key adaptation in Utricularia likely lies in molecular energetic changes that buttressed the mechanisms responsible for the bladderworts' radical morphological evolution. Along with evidence for COX evolution underlying expansion of the anthropoid neocortex, our findings underscore that important morphological and physiological innovations must often be accompanied by specific adaptations in proteins with basic cellular functions.
Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting ...target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7- Delta 24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7- Delta 24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7- Delta 24 and the orthotopic model for further translational studies.
We investigated the factors mediating selection acting on two MHC class II genes (DQA and DRB) in water vole (Arvicola scherman) natural populations in the French Jura Mountains. Population genetics ...showed significant homogeneity in allelic frequencies at the DQA1 locus as opposed to neutral markers (nine microsatellites), indicating balancing selection acting on this gene. Moreover, almost exhaustive screening for parasites, including gastrointestinal helminths, brain coccidia and antibodies against viruses responsible for zoonoses, was carried out. We applied a co-inertia approach to the genetic and parasitological data sets to avoid statistical problems related to multiple testing. Two alleles, Arte-DRB-11 and Arte-DRB-15, displayed antagonistic associations with the nematode Trichuris arvicolae, revealing the potential parasite-mediated selection acting on DRB locus. Selection mechanisms acting on the two MHC class II genes thus appeared different. Moreover, overdominance as balancing selection mechanism was showed highly unlikely in this system.
Conditionally replicating adenoviruses (CRAds) that replicate in tumor but less in normal cells are promising anticancer agents. A major determinant of their potency is their capacity for infecting ...target cells. The primary receptor for serotype 5 adenovirus (Ad5), the most widely used serotype in gene therapy, is the coxsackie-adenovirus receptor (CAR). CAR is expressed variably and often at low levels in various tumor types including advanced breast cancer. We generated a novel p16/retinoblastoma pathway-dependent CRAd, Ad5.pK7-Δ24, with a polylysine motif in the fiber C-terminus, enabling CAR-independent binding to heparan sulfate proteoglycans (HSPG). Ad5.pK7-Δ24 mediated effective oncolysis of all breast cancer cell lines tested. Further, we utilized noninvasive, fluorescent imaging for analysis of antitumor efficacy in an orthotopic model of advanced hormone refractory breast cancer. A therapeutic benefit was seen following both intratumoral and intravenous delivery. Murine biodistribution similar to Ad5, proven safe in trials, suggests feasibility of clinical safety testing. Interestingly, upregulation of CAR was seen in low-CAR M4A4-LM3 breast cancer cells in vivo, which resulted in better than expected efficacy also with an isogenic CRAd with an unmodified capsid. These results suggest utility of Ad5.pK7-Δ24 and the orthotopic model for further translational studies.
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