Inhibition of HIV-1 multiplication by a modified U7 snRNA inducing Tat and Rev exon skipping

The HIV-1 regulatory proteins Tat and Rev are encoded by multiply spliced mRNAs that differ by the use of alternative 3' splice sites at the beginning of the internal exon. If these internal exons are skipped, the expression of these genes, and hence HIV-1 multiplication, should be inhibited. We have previously developed a strategy, based on antisense derivatives of U7 small nuclear RNA, that allows us to induce the skipping of an internal exon in virtually any gene. Here, we have successfully applied this approach to induce a partial skipping of the Tat, Rev (and Nef) internal exons. Three functional U7 constructs were subcloned into a lentiviral vector. Two of them strongly reduced the efficiency of lentiviral particle production compared to vectors carrying either no U7 insert or unrelated U7 cassettes. This defect could be partly or fully compensated by coexpressing Rev from an unspliced mRNA in the producing cell line. Upon stable transduction into CEM-SS or CEM T-lymphocytes, the most efficient of these constructs inhibits HIV-1 multiplication. Although the inhibition is not complete, it is more efficient in combination with another mechanism inhibiting HIV multiplication. Therefore, this new approach targeting HIV-1 regulatory genes at the level of pre-mRNA splicing, in combination with other antiviral strategies, may be a useful new tool in the fight against HIV/AIDS. Copyright (c) 2007 John Wiley & Sons, Ltd

Natural antibodies target virus-antibody complexes to organized lymphoid tissue

Natural antibodies (NA) specific for infectious pathogens are found at low titer (usually <1:40) in the serum of healthy, non-immunized, individuals. Therefore, NA are part of the first line of defence against blood borne microorganisms. They directly neutralize viral infections or lyse pathogens by activating the complement cascade. In addition, recent studies highlighted their role in the pooling of infectious pathogens and other antigens to the spleen. This prevents infection of vital target organs and enhances the induction of adaptive immune responses. Specific T and B-cell responses are exclusively induced in highly organized secondary lymphoid organs including lymph nodes and the spleen. As a consequence, mice with disrupted microorganisation of lymphoid organs have defective adaptive immunity. In addition, some pathogens including lymphocytic choriomeningitis virus (LCMV), Leishmania and HIV developed strategies to destroy the splenic architecture in order to induce an acquired immunosuppression and to establish persistent infection. NA antibodies enhance early neutralizing antibodies in the absence of T help mainly by targeting antigen to the splenic marginal zone. In addition, by activating the complement cascade, NA enhance T cell and T-cell dependent B-cell responses. Therefore, natural antibodies are an important link between innate and adaptive immunity.

Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells

Sphingosine kinases (SK) catalyze the production of sphingosine-1-phosphate which in turn regulates cell responses such as proliferation and migration. Here, we show that exposure of the human endothelial cell line EA.hy 926 to hypoxia stimulates a increased SK-1, but not SK-2, mRNA, protein expression, and activity. This effect was due to stimulated SK-1 promoter activity which contains two putative hypoxia-inducible factor-responsive-elements (HRE). By deletion of one of the two HREs, hypoxia-induced promoter activation was abrogated. Furthermore, hypoxia upregulated the expression of HIF-1alpha and HIF-2alpha, and both contributed to SK-1 gene transcription as shown by selective depletion of HIF-1alpha or HIF-2alpha by siRNA. The hypoxia-stimulated SK-1 upregulation was functionally coupled to increased migration since the selective depletion of SK-1, but not of SK-2, by siRNAs abolished the migratory response. In summary, these data show that hypoxia upregulates SK-1 activity and results in an accelerated migratory capacity of endothelial cells. SK-1 may thus serve as an attractive therapeutic target to treat diseases associated with increased endothelial migration and angiogenesis such as cancer growth and progression.

Decreased hypoxia-induced neovascularization in angiopoietin-2 heterozygous knockout mouse through reduced MMP activity

BACKGROUND/AIMS: Proliferative diabetic retinopathy is characterized by the formation of retinal neovascularization. Angiopoietin-2 (Ang-2) and matrix metalloproteinase (MMP) play a critical role in angiogenesis. However, the precise location and function of Ang-2 during formation of retinal neovascularizations driven by hypoxia in relation to MMP activity have not been elucidated. In this study, we investigated the response of Ang-2 heterozygous knockout retinas (Ang2(+/-) mouse) to hypoxia and its link to MMP activity in an oxygen-induced retinopathy (OIR) model. METHODS: Pre-retinal neovascularizations were quantitated in vertical sections. Intra-retinal angiogenesis was assessed by whole mount immunofluorescence staining of retinas. MMP activity was examined in retinal protein lysate and whole mount retinal in situ zymography. RESULTS: Ang2(+/-) retinas subjected to the OIR model showed 33% reduced neovascularization and 271% increased avascular zones at postnatal day 17. In the OIR model, Ang-2 was modestly expressed in pre-retinal neovascularizations and venules, but strongly in arterioles and capillary sprouts. MMPs were activated in close association to where Ang-2 is expressed. MMP activity was substantially decreased in Ang2(+/-) retinas. CONCLUSIONS: Our present data suggest the spatially concomitant expression of Ang2 and MMPs, and that Ang2 modulates hypoxia-induced neovascularization by regulating MMP activity.

When do combinations of diuretics make sense?

Diuretics are commonly prescribed by physicians to contract the ECF volume. In two clinical situations combining different classes of diuretics make sense: First, if a loop diuretic at maximal dose alone does not lead to sufficient diuresis or second, if the side effect of a diuretic needs to be corrected by adding a diuretic of another class. The latter is clinically often used to counteract loop or thiazide diuretic-induced hypokalemia by the addition of a potassium sparing diuretic. Key to a reasonable combination of diuretics is understanding of the pharmaco-kinetics and knowledge of the molecular targets of the diuretics involved.

Prolonged platelet activation in individuals with elevated blood pressure in response to a moderate exercise challenge

We examined the magnitude of 20-min moderate exercise-induced platelet activation in 50 volunteers with normal (n=31) or elevated blood pressure (EBP; n=19). Blood was drawn before, immediately after, and 25 min after exercise. Antibody-staining for platelet activation markers, P-selectin, and fibrinogen receptors was done with and without adenosine diphosphate (ADP) stimulation in whole blood for flow cytometric analyses. Exercise led to increases in percent aggregated platelets and percent platelets expressing P-selectin or PAC-1 binding (ps< or =.001). This increase in percent platelets expressing P-selectin continued even after a 25-min rest only in the EBP group (p< or =.01) accompanied by an increase in percent of aggregated platelets (p< or =.05). Although ADP stimulation led to increased platelet activation at rest, it was attenuated following exercise, even among EBP individuals. A moderate exercise challenge induced prolonged platelet activation in individuals with EBP but attenuation in activation to further stimulation by an agonist. Findings suggest that a recovery period after physical stress appears critical in individuals with high BP regarding platelet activation and aggregation, which can lead to an acute coronary syndrome in vulnerable individuals.

In vitro induction of functional allergen-specific CD4+ CD25high Treg cells in horses affected with insect bite hypersensitivity

BACKGROUND Insect bite hypersensitivity (IBH) is a recurrent allergic dermatitis of horses with similarities to human atopic eczema, caused by bites of insects of the genus Culicoides. Previous studies suggested a dysregulated T cell tolerance to Culicoides allergen in IBH-affected horses. OBJECTIVE We have investigated whether the suppressive function of CD4(+) CD25(high) cells is impaired in IBH-affected horses and possible ways to restore it. METHODS CD4(+) CD25(-) cells sorted from peripheral blood mononuclear cells (PBMC) were stimulated with irradiated autologous PBMC pulsed with Culicoides or tetanus toxoid as control antigen, in the presence of CD4(+) CD25(high) cells. Furthermore, Culicoides-specific CD4(+) CD25(high) regulatory cells were expanded or induced from CD4(+) CD25(-) cells in vitro in the presence of a combination of rIL-2 and rTGF-β1 (rIL-2/rTGF-β1) or of retinoic acid and rapamycin (RetA/Rapa). Proliferation was determined by [(3) H] thymidine incorporation and cytokine production measured by flow cytometry. RESULTS The ability of Culicoides- but not tetanus-stimulated CD4(+) CD25(high) cells to suppress proliferation of CD4(+) CD25(-) cells was significantly lower in IBH-affected horses (28%) than in healthy controls (86%). The decreased suppression in IBH-affected horses was associated with a significantly higher proportion of IL-4(+) cells and a lower percentage of FoxP3(+) IL-10(+) compared to controls. Addition of rIL-2/rTGF-β1 or of RetA/Rapa to Culicoides-stimulated CD4(+) CD25(high) cells from IBH-affected horses significantly increased the proportion of FoxP3(+) IL-10(+) cells. We also found that RetA/Rapa induced a more significant decrease in the frequency of IL-4(+) cells than rIL-2/rTGF-β1. Moreover, the suppressive activity of Culicoides-stimulated CD4(+) CD25(high) cells was significantly restored by both rIL-2/rTGF-β1and RetA/Rapa, albeit in an antigen-unspecific manner. In contrast, in vitro induced Culicoides-specific CD4(+) CD25(high) cells suppressed proliferation of CD4(+) CD25(-) cells in an antigen-specific manner. CONCLUSION AND CLINICAL RELEVANCE The in vitro induction of functional allergen-specific Treg cells in IBH-affected horses suggests a potential therapeutic use of these cells in allergy.

Liver fat content and lipid metabolism in dairy cows during early lactation and during a mid-lactation feed restriction.

During the transition period, the lipid metabolism of dairy cows is markedly affected by energy status. Fatty liver is one of the main health disorders after parturition. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages in lactation [NEB at the onset of lactation postpartum (p.p.) and a deliberately induced NEB by feed restriction near 100 d in milk] on liver triglyceride content and parameters of lipid metabolism in plasma and liver based on mRNA abundance of associated genes. Fifty multiparous dairy cows were studied from wk 3 antepartum to approximately wk 17 p.p. in 2 periods. According to their energy balance in period 1 (parturition to wk 12 p.p.), cows were allocated to a control (CON; n=25) or a restriction group (RES; 70% of energy requirements; n=25) for 3 wk in mid lactation starting at around 100 d in milk (period 2). Liver triglyceride (TG) content, plasma nonesterified fatty acids (NEFA), and β-hydroxybutyrate were highest in wk 1 p.p. and decreased thereafter. During period 2, feed restriction did not affect liver TG and β-hydroxybutyrate concentration, whereas NEFA concentration was increased in RES cows as compared with CON cows. Hepatic mRNA abundances of tumor necrosis factor α, ATP citrate lyase, mitochondrial glycerol-3-phosphate acyltransferase, and glycerol-3-phosphate dehydrogenase 2 were not altered by lactational and energy status during both experimental periods. The expression of fatty acid synthase was higher in period 2 compared with period 1, but did not differ between RES and CON groups. The mRNA abundance of acetyl-coenzyme A-carboxylase showed a tendency toward higher expression during period 2 compared with period 1. The solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1) was upregulated in wk 1 p.p. and also during feed restriction in RES cows. In conclusion, the present study shows that a NEB has different effects on hepatic lipid metabolism and TG concentration in the liver of dairy cows at early and later lactation. Therefore, the homeorhetic adaptations during the periparturient period trigger excessive responses in metabolism, whereas during the homeostatic control of endocrine and metabolic systems after established lactation, as during the period of feed restriction in the present study, organs are well adapted to metabolic and environmental changes.

Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis

Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli-induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin-antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

Ecosystem service trade-offs and stakeholder claims - a meso-scale study from a Madagascar biodiversity hotspot

The north-eastern escarpment of Madagascar has been labelled a global biodiversity hotspot due to its extremely high rates of endemic species which are heavily threatened by accelerated deforestation rates and landscape change. The traditional practice of shifting cultivation or "tavy" used by the majority of land users in this area to produce subsistence rice is commonly blamed for these threats. A wide range of stakeholders ranging from conservation to development agencies, and from the private to the public sector has therefore been involved in trying to find solutions to protect the remaining forest fragments and to increase agricultural production. Consequently, provisioning, regulating and socio-cultural services of this forest-mosaic landscape are fundamentally altered leading to trade-offs between them and consequently new winners and losers amongst the stakeholders at different scales. However, despite a growing amount of evidence from case studies analysing local changes, the regional dynamics of the landscape and their contribution to such trade-offs remain poorely understood. This study therefore aims at using generalised landscape units as a base for the assessment of multi-level stakeholder claims on ecosystem services to inform negotiation, planning and decision making at a meso-scale. The presented study applies a mixed-method approach combining remote sensing, GIS and socio-economic methods to reveal current landscape dynamics, their change over time and the corresponding ecosystem service trade-offs induced by diverse stakeholder claims on the regional level. In a first step a new regional land cover classification for three points in time (1995, 2005 and 2011) was conducted including agricultural classes characteristic for shifting cultivation systems. Secondly, a novel GIS approach, termed “landscape mosaics approach” originally developed to assess dynamics of shifting cultivation landscapes in Laos was applied. Through this approach generalised landscape mosaics were generated allowing for a better understanding of changes in land use intensities instead of land cover. As a next step we will try to use these landscape units as proxies to map provisioning and regulating ecosystem services throughout the region. Through the overlay with other regional background data such as accessibility and population density and information from a region-wide stakeholder analysis, multiscale trade-offs between different services will be highlighted. The trade-offs observed on the regional scale will then be validated through a socio-economic ground-truthing within selected sites at the local scale. We propose that such meso-scale knowledge is required by all stakeholders involved in decision making towards sustainable development of north-eastern Madagascar.

Risk of incident stroke in patients with Alzheimer disease or vascular dementia

OBJECTIVE To explore the risk of ischemic stroke, hemorrhagic stroke, or TIA in patients with Alzheimer disease (AD) or vascular dementia (VD). METHODS We conducted a follow-up study with a nested case-control analysis using the UK-based General Practice Research Database. We included patients aged 65 years and older with an incident diagnosis of AD or VD between 1998 and 2008 and a comparison group of dementia-free patients. We estimated incidence rates of ischemic stroke, hemorrhagic stroke, or TIA in patients with AD, VD, or without dementia, and we calculated odds ratios with 95% confidence intervals (CIs) of developing such an outcome in patients with AD or VD, stratified by use of antipsychotic drugs. RESULTS We followed 6,443 cases with AD, 2,302 with VD, and 9,984 dementia-free patients over time and identified 281 cases with incident ischemic stroke, 139 with hemorrhagic stroke, and 379 with TIA. The incidence rates of ischemic stroke for patients with AD, VD, or no dementia were 4.7/1,000 person-years (PYs) (95% CI 3.8-5.9), 12.8/1,000 PYs (95% CI 9.8-16.8), and 5.1/1,000 PYs (95% CI 4.3-5.9), respectively. Compared with dementia-free patients, the odds ratio of developing a TIA for patients with AD treated with atypical antipsychotic drugs was 4.5 (95% CI 2.1-9.2). CONCLUSIONS Patients with VD, but not AD, have a markedly higher risk of developing an ischemic stroke than those without dementia. In patients with AD, but not VD, use of atypical antipsychotic drugs was associated with an increased risk of TIA.

Seizures in patients with Alzheimer's disease or vascular dementia: a population-based nested case-control analysis

PURPOSE Patients with Alzheimer's disease (AD) have an increased risk of developing seizures or epilepsy. Little is known about the role of risk factors and about the risk of developing seizures/epilepsy in patients with vascular dementia (VD). The aim of this study was to assess incidence rates (IRs) of seizures/epilepsy in patients with AD, VD, or without dementia, and to identify potential risk factors of seizures or epilepsy. METHODS We conducted a follow-up study with a nested case-control analysis using the United Kingdom-based General Practice Research Database (GPRD). We identified patients aged ≥65 years with an incident diagnosis of AD or VD between 1998 and 2008 and a matched comparison group of dementia-free patients. Conditional logistic regression was used to estimate the odds ratio (OR) with a 95% confidence interval (CI) of developing seizures/epilepsy in patients with AD or VD, stratified by age at onset and duration of dementia as well as by use of antidementia drugs. KEY FINDINGS Among 7,086 cases with AD, 4,438 with VD, and 11,524 matched dementia-free patients, we identified 180 cases with an incident diagnosis of seizures/epilepsy. The IRs of epilepsy/seizures for patients with AD or VD were 5.6/1,000 person-years (py) (95% CI 4.6-6.9) and 7.5/1,000 py (95% CI 5.7-9.7), respectively, and 0.8/1,000 py (95% CI 0.6-1.1) in the dementia-free group. In the nested case-control analysis, patients with longer standing (≥3 years) AD had a slightly higher risk of developing seizures or epilepsy than those with a shorter disease duration, whereas in patients with VD the contrary was observed. SIGNIFICANCE Seizures or epilepsy were substantially more common in patients with AD and VD than in dementia-free patients. The role of disease duration as a risk factor for seizures/epilepsy seems to differ between AD and VD.

Influences of porcine circo-, arteriviruses and cathelicidins in plasmacytoid dendritic cell-derived interferon-alpha responses

Type I interferons (IFNs), mainly IFN-α/β play a crucial role in innate defense against viruses. In addition to their direct antiviral activity, type I IFNs have antitumoral and immunomodulatory effects. Although all cells are virtually able to induce IFN-α, the plasmacytoid dendritic cell (pDC) subset represents the ultimate producers of IFN-α as well as other proinflammatory cytokines. Due to the specific expression of TLR7 and TLR9 recognizing single-stranded (ss) RNA and unmethylated CpG motifs respectively, pDCs can secrete up to 1000 times more IFN-α than any cellular types. Additionally, it is well known that several cytokines including type I and II IFNs, Flt3-L, IL-4 and GM-CSF favor pDC-derived IFN-α responses to unmethylated CpG motifs. In a first step, we aimed to characterize and clarify the interactions of two porcine viruses with pDCs. The double-stranded DNA replicative forms of porcine circovirus type 2 (PCV2) were demonstrated to inhibit CpG-induced IFN- α by pDCs. Our study showed that none of the cytokines known to enhance pDC responsiveness can counter-regulate the PCV2-mediated inhibition of IFN-α induced by CpG, albeit IFN-γ significantly reduced the level of inhibition. Interestingly, the presence of IFN-γ enabled pDCs to induce IFN-α to low doses of PCV2. We also noted that after DNase treatment, PCV2 preparations were still able to stimulate pDCs. These data suggest that encapsulated viral ssDNA promotes the induction of IFN-α in pDCs treated with IFN-γ whereas free DNA, presumably as double-stranded forms, was responsible for inhibiting pDC responses. Regarding PRRSV, it has been reported that North American isolates did not induce and even inhibited IFN-α response in pDCs. However, PRRSV infection was also shown to lead to an induction of IFN-α in the serum and in the lungs suggesting that certain cells are responsive to the virus. Contrasting to previous reports we found that numerous PRRSV isolates directly induced IFN-α in pDCs. This response was still observed after UV-inactivation of viruses and required TLR7 signaling. The inhibition of CpG-induced IFN-α was weak and strain dependent, again contrasting with a previous report. We also observed that IFN-γ and IL-4 enhanced IFN-α response to two prototype strains, VR-2332 and LVP23. In summary, we demonstrated that both PCV2 and PRRSV promote IFN-α secretion in pDCs in vitro suggesting that IFN-α detected in PCV2- or PRRSV-infected animal might originate from pDCs. On the other hand, PRRSV replication is restricted to the macrophage (MΦ) lineage. These innate immune cells represent a heterogeneous population which can be induce to “classical” (M1) and “alternative” (M2) activated MΦ acquiring inflammatory or “wound-healing” functional properties, respectively. Nonetheless, little is known about the effect of polarization into M1 or M2 and the susceptibility of these cells to PRRSV. Thus, we examined the impact of cytokine on MΦ polarization into M1 or M2. Infections of these cells by several PRRSV isolates enabled the discrimination of PRRSV isolate in a genotype- and irulencedependent manner in M1 and IFN-β-activated MΦ. In contrast, the expression of PRRSV nucleocapsid in M2 or inactivated MΦ was indistinguishable among the PRRSV isolates tested. In the last part of my Thesis, we investigated the influence of three synthetic porcine cathelicidin peptides for their ability to deliver nucleic acid to pDCs. We reported that all cathelicidins tested can complex and quickly deliver nucleic acids resulting in IFN-α induction. Moreover, we show that the typical α- helical amphipathic conformation is required to mediate killing of bacteria but not for inducing IFN-α secretion by pDCs. Furthermore, we found that E.coli treated with one of these cathelicidins is able to induce significantly higher levels of IFN-α compared to a non-sense version of the peptide. These data suggest that cathelicidins could influence the immune response in a two-step process. First, these peptides target bacteria leading to cell lysis. In turn, cathelicidins form complexes and deliver extracellular microbial nucleic acids released into pDCs. These pDC-derived IFN-α responses could be of particular relevance in driving the adaptive immune responses against microbial infections.

Short communication: Circulating and milk adiponectin change differently during energy deficiency at different stages of lactation in dairy cows

Adiponectin, one of the most abundant adipokines in circulation, is known for its role in regulation of body metabolism. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages of lactation (lactational NEB at the onset of lactation and an induced NEB by feed restriction near 100 d of lactation) on circulating adiponectin concentrations. We also investigated the effect of feed restriction on adiponectin concentrations in milk and the relationships of blood and milk adiponectin with selected plasma or milk variables and with measures of body condition. Plasma adiponectin was measured in 50 multiparous Holstein dairy cows throughout 3 experimental periods [i.e., period 1=3 wk antepartum up to 12 wk postpartum, period 2=3 wk of feed restriction starting at around 100 d in milk with a control (n=25) and feed-restricted group (50% of energy requirements; n=25), and period 3=subsequent realimentation period for 8 wk]. Milk adiponectin was investigated among 21 multiparous cows at wk 2 and wk 12 of period 1 and wk 2 of period 2. Adiponectin concentrations in plasma and skim milk were measured using an in-house ELISA specific for bovine adiponectin. Major changes in circulating adiponectin concentrations were observed during the periparturient period, whereas energy deficiency during established lactation at around 100 d in milk and subsequent refeeding did not affect plasma adiponectin. Together with lower adiponectin concentrations in milk (µg/mL), the reduction in milk yield led to decreased adiponectin secretion via milk (mg/d) at the second week of feed restriction. Irrespective of time and treatment, milk adiponectin represented about 0.002% of total milk protein. Mean adiponectin concentrations in milk (0.61 ± 0.03 µg/mL) were about 92% lower than the mean plasma adiponectin concentrations (32.1 ± 1.0 µg/mL). The proportion of the steady-state plasma adiponectin pool secreted daily via milk was 2.7%. In view of the similar extent of NEB in both periods of energy deficiency, decreasing adiponectin concentrations seems important for accomplishing the adaptation to the rapidly increasing metabolic rates in early lactation, whereas the lipolytic reaction toward feed restriction-induced NEB during established lactation seems to occur largely independent of changes in circulating adiponectin.

Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity

Prosenescence therapy has recently emerged as a novel therapeutic approach for treating cancer. However, this concept is challenged by conflicting evidence showing that the senescence-associated secretory phenotype (SASP) of senescent tumor cells can have pro- as well as antitumorigenic effects. Herein, we report that, in Pten-null senescent tumors, activation of the Jak2/Stat3 pathway establishes an immunosuppressive tumor microenvironment that contributes to tumor growth and chemoresistance. Activation of the Jak2/Stat3 pathway in Pten-null tumors is sustained by the downregulation of the protein tyrosine phosphatase PTPN11/SHP2, providing evidence for the existence of a novel PTEN/SHP2 axis. Importantly, treatment with docetaxel in combination with a JAK2 inhibitor reprograms the SASP and improves the efficacy of docetaxel-induced senescence by triggering a strong antitumor immune response in Pten-null tumors. Altogether, these data demonstrate that immune surveillance of senescent tumor cells can be suppressed in specific genetic backgrounds but also evoked by pharmacological treatments.