Hypertension in response to IL-6 during pregnancy: role of AT1-receptor activation

BACKGROUND: Increases in interleukin 6 (IL-6) and agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) are proposed to be important links between placental ischemia and hypertension in preeclampsia. METHODS: The purpose of this study was to determine whether IL-6 (5 ng/day), infused into normal pregnant (NP) rats, increased mean arterial pressure (MAP) and AT1-AA. MAP was analyzed in the presence and absence of an angiotensin type 1 receptor (AT1R) antagonist, losartan, L. RESULTS: MAP and AT1-AA increased from 102 ± 2 to 118 ± 4 mmHg and 0.7 ± 0.3 NP to 14.1 ± 1.4 chronotropic units with chronic IL-6 infusion. MAP responses to IL-6 were abolished in losartan pretreated rats (85 ± 4 in NP + L vs 85 ± 3 mmHg in IL-6 + L). CONCLUSION: These data indicate that IL-6 stimulates AT1-AA and that activation of the AT1R mediates IL-6 induced hypertension during pregnancy

The angiotensin II type I receptor contributes to impaired cerebral blood flow autoregulation caused by placental ischemia in pregnant rats

BACKGROUND: Placental ischemia and hypertension, characteristic features of preeclampsia, are associated with impaired cerebral blood flow (CBF) autoregulation and cerebral edema. However, the factors that contribute to these cerebral abnormalities are not clear. Several lines of evidence suggest that angiotensin II can impact cerebrovascular function; however, the role of the renin angiotensin system in cerebrovascular function during placental ischemia has not been examined. We tested whether the angiotensin type 1 (AT1) receptor contributes to impaired CBF autoregulation in pregnant rats with placental ischemia caused by surgically reducing uterine perfusion pressure. METHODS: Placental ischemic or sham operated rats were treated with vehicle or losartan from gestational day (GD) 14 to 19 in the drinking water. On GD 19, we assessed CBF autoregulation in anesthetized rats using laser Doppler flowmetry. RESULTS: Placental ischemic rats had impaired CBF autoregulation that was attenuated by treatment with losartan. In addition, we examined whether an agonistic autoantibody to the AT1 receptor (AT1-AA), reported to be present in preeclamptic women, contributes to impaired CBF autoregulation. Purified rat AT1-AA or vehicle was infused into pregnant rats from GD 12 to 19 via mini-osmotic pumps after which CBF autoregulation was assessed. AT1-AA infusion impaired CBF autoregulation but did not affect brain water content. CONCLUSIONS: These results suggest that the impaired CBF autoregulation associated with placental ischemia is due, at least in part, to activation of the AT1 receptor and that the RAS may interact with other placental factors to promote cerebrovascular changes common to preeclampsia

CD4(+) T cells play a critical role in mediating hypertension in response to placental ischemia

Similar to preeclamptic women, hypertension in the chronic Reduced Uterine Perfusion Pressure Rat Model Of Preeclampsia (RUPP) is associated with increased CD4+ T cells, cytokines, sFlt-1 and agonistic autoantibodies to the AngII receptor (AT1-AA). We examined the effect inhibition of T cell co-stimulation in RUPP rats treated with (A) (abatacept, 250 mg/kg, infused i.v. at gestation day 13), on hypertension and sFlt-1, TNF-alpha and AT1-AA. RUPP surgical procedure was performed on day 14. On day 19 MAP increased from 94+2 mmHg in Normal Pregnant (NP) to 123 +/- 3 mmHg in RUPP control rats. This response was attenuated by Abatacept, MAP was 104 +/- 2 mmHg in RUPP +/- A, and 96 +/- 2 mmHg NP +/- A. Percent circulating CD4+ T cells were 66 +/- 3% in RUPPs compared to 55 +/- 3% NP rats (p<0.04) but were normalized in RUPP +/- A rats (54 +/- 3%). The twofold increase in TNF alpha seen in RUPPs (277 +/- 47 pg/ml) was decreased to 80 +/- 18 pg/ml in RUPP+A. Placental sFlt-1 was reduced 70 % to 151 +/- 28 in RUPP +/- A compared 488 +/- 61 pg/ml in RUPP (p<0.001). AT1-AA decreased from 20 +/- 0.8 bpm in control RUPP to 6 +/- 0.7 bpm in RUPP +/- A. We next determined the effect of RUPP in causing hypertension in pregnant T cell deficient rats by examining MAP in NP (123 +/- 5 mmHg) and RUPP athymic nude rats (123 +/- 7 mmHg). In the absence of T cells, hypertension in response to placental ischemia was completely abolished. Collectively these data indicate that CD4+ Tcells in response to placental ischemia play an important role in the pathophysiology of hypertension associated with preeclampsia

Onasemnogene abeparvovec preserves bulbar function in infants with presymptomatic spinal muscular atrophy: a post-hoc analysis of the SPR1NT trial

Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function

Influence of cirrhosis on outcomes of patients with advanced intrahepatic cholangiocarcinoma receiving chemotherapy

International audienceBackground: Cirrhosis is a risk factor for intrahepatic cholangiocarcinoma (iCC). However, its exact prevalence is uncertain and its impact on the management of advanced disease is not established.Methods: Retrospective analysis of patients treated with systemic chemotherapy for advanced iCC in the 1st-line setting at 2 tertiary cancer referral centres. Cirrhosis was diagnosed based on at least one element prior to any treatment: pathological diagnosis, baseline platelets &lt;150 × 109/L, portal hypertension and/or dysmorphic liver on imaging.Results: In the cohort of patients (n = 287), 82 (28.6%) had cirrhosis (45 based on pathological diagnosis). Patients with cirrhosis experienced more grade 3/4 haematologic toxicity (44% vs 22%, respectively, P = 0.001), and more grade 3/4 non-haematologic toxicity (34% vs 14%, respectively, P = 0.001) than those without. The overall survival (OS) was significantly shorter in patients with cirrhosis: median 9.1 vs 13.1 months for those without (HR = 1.56 [95% CI: 1.19-2.05]); P = 0.002), confirmed on multivariable analysis (HR = 1.48 [95% CI: 1.04-2.60]; P = 0.028).Conclusion: Cirrhosis was relatively common in patients with advanced iCC and was associated with increased chemotherapy-induced toxicity and shorter OS. Formal assessment and consideration of cirrhosis in therapeutic management is recommended

Regulatory T cells ameliorate intrauterine growth retardation in a transgenic rat model for preeclampsia

Preeclampsia is a multisystemic syndrome during pregnancy that is often associated with intrauterine growth retardation. Immunologic dysregulation, involving T cells, is implicated in the pathogenesis. The aim of this study was to evaluate the effect of upregulating regulatory T cells in an established transgenic rat model for preeclampsia. Application of superagonistic monoclonal antibody for CD28 has been shown to effectively upregulate regulatory T cells. In the first protocol (treatment protocol), we applied 1 mg of CD28 superagonist or control antibody on days 11 and 15 of pregnancy. In the second protocol (prevention protocol), the superagonist or control antibody was applied on days 1, 5, and 9. Superagonist increased regulatory T cells in circulation and placenta from 8.49+/-2.09% of CD4-positive T cells to 23.50+/-3.05% and from 3.85+/-1.45% to 23.27+/-7.64%, respectively. Blood pressure and albuminuria (30.6+/-15.1 versus 14.6+/-5.5 mg/d) were similar in the superagonist or control antibody-treated preeclamptic group for both protocols. Rats treated with CD28 superagonist showed increased pup weights in the prevention protocol (2.66+/-0.03 versus 2.37+/-0.05 g) and in the treatment protocol (3.04+/-0.04 versus 2.54+/-0.1 g). Intrauterine growth retardation, calculated by brain:liver weight ratio, was also decreased by the superagonist in both protocols. Further analysis of brain development revealed a 20% increase in brain volume by the superagonist. Induction of regulatory T cells in the circulation and the uteroplacental unit in an established preeclamptic rat model had no influence on maternal hypertension and proteinuria. However, it substantially improved fetal outcome by ameliorating intrauterine growth retardation

Determination of parameters for the evaluation of Phosphorus/Calcium metabolism in adult normal dogs

Diseases that facilitate alterations in the metabolism of calcium (Ca) and phosphorus (Pi) are\ndiverse. Knowing and interpreting normal parameters is fundamental to making a diagnosis.\nIn this study both minerals were evaluated in the blood and urine of 52 healthy adult dogs in\nthree age ranges in years old (group A: from 1 to 5, group B: from 6 to 10, and group C: older\nthan 10).\nCalcium levels exhibited no significant difference across age groups. A significant increase (p = 0.03)\nin phosphorus was found in group C in relation to the other two groups.\nBased on the elimination of both minerals through the urine, evaluated from the fractional\nexcretion (DIP and DICa) and the relation Ca or Pi / Creatinine, a non-significant tendency\nof a lower elimination of Pi through urine was observed, according to DIP values of group C\n(p = 0.055).\nThe values of DIP and DICa were correlated with the ones in Pi or Ca/Cr in urine (r = 0.9, p < 0.0001).\nThese results allow us to infer that the mineral/Cr relation can be used when evaluating\nelimination by urine. The age range must be taken into account when interpreting results of\nphosphorus in blood and urine, since groups older than 10 years old have higher minimum\nand maximum threshold levels than the other two groups.Fil: Martiarena, B. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Castillo, V. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Endocrinología; ArgentinaFil: Regonat, M. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Patología Clínica; ArgentinaFil: Regonat, M. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Laboratorio; ArgentinaFil: Quintana, H. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Nutrición; ArgentinaFil: Quintana, H. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Nutrición; ArgentinaFil: Brandi, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Patología Clínica; ArgentinaFil: Brandi, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animales. Unidad de Laboratorio; ArgentinaFil: Lamarca, G. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Molina, E. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Hospital Escuela de Pequeños Animlaes. Unidad de Nefrología y Urología; ArgentinaFil: Ruidiaz, V. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaFil: Visintini, A. Universidad de Buenos Aires. Facultad de Ciencias Veterinarias. Cátedra de Clínica Médica de Pequeños Animales; ArgentinaLas enfermedades que alteran el metabolismo fósforo (Pi)/calcio (Ca) son variadas. Para\ndiagnosticarlas es necesario conocer e interpretar parámetros normales. Se estudiaron ambos\nminerales, en sangre y orina, en 52 perros adultos sanos, agrupados según rango etario en años:\nGA de 1 a 5; GB de 6 a 10 y GC ? de 10.\nNo se encontraron diferencias significativas para la calcemia entre los grupos. Hubo un\nincremento significativo para la fosfatemia (p 0.03) y el producto Ca x Pi (p 0.02) en el GC\nrespecto al resto.\nDe la eliminación de ambos minerales en orina, evaluada mediante la excreción fraccional (DIP\ny DICa) y por la relación Calcio o fósforo/creatinina, se observó una tendencia, no significativa,\na una menor eliminación de fósforo, según los valores de DIP en el grupo C (p 0.055). Los\nvalores de DIP y DICa se correlacionaron con los de Fósforo o Calcio/Creatinina (r 0.9, p < 0.0001),\nhaciendo que dichas relaciones pueden ser utilizadas para evaluar la excreción urinaria.\nEl rango etario debe tenerse en cuenta para interpretar resultados del fósforo en sangre y orina,\ndado que los valores de cortes mínimos y máximos son más elevados en los mayores de 10 años

Current and novel therapeutic opportunities for systemic therapy in biliary cancer

none24Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools.openMarin J.J.G.; Prete M.G.; Lamarca A.; Tavolari S.; Landa-Magdalena A.; Brandi G.; Segatto O.; Vogel A.; Macias R.I.R.; Rodrigues P.M.; Casta A.L.; Mertens J.; Rodrigues C.M.P.; Fernandez-Barrena M.G.; Da Silva Ruivo A.; Marzioni M.; Mentrasti G.; Acedo P.; Munoz-Garrido P.; Cardinale V.; Banales J.M.; Valle J.W.; Bridgewater J.; Braconi C.Marin, J. J. G.; Prete, M. G.; Lamarca, A.; Tavolari, S.; Landa-Magdalena, A.; Brandi, G.; Segatto, O.; Vogel, A.; Macias, R. I. R.; Rodrigues, P. M.; Casta, A. L.; Mertens, J.; Rodrigues, C. M. P.; Fernandez-Barrena, M. G.; Da Silva Ruivo, A.; Marzioni, M.; Mentrasti, G.; Acedo, P.; Munoz-Garrido, P.; Cardinale, V.; Banales, J. M.; Valle, J. W.; Bridgewater, J.; Braconi, C

Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage

Estrogen-mediated proliferation is fundamental to normal mammary gland development. Recent studies have demonstrated that amphiregulin is a critical paracrine regulator of estrogen action during ductal morphogenesis. These studies implicate a critical role for amphiregulin in mammary stem cell differentiation as well as breast cancer initiation and progression