Abstract Introduction: The Pap test and human papillomavirus vaccine (HPVV) have the potential to eradicate cervical cancer globally, but implementation continues to prove challenging among minority populations in the United States, especially immigrants and Blacks. The goal of this study was to assess the efficacy of a regional intervention trial designed to increase Pap testing and HPVV knowledge and acceptability. Methods: The study was conducted in collaboration with community partners to enhance cultural and linguistic relevance. The intervention employed social marketing strategy using electronic (public service announcements via local TV and radio) and print media (local, ethnic newspaper and circulars) for broad, cost effective dissemination of HPVV and Pap testing information and resources. Regions were assigned to one of two intervention conditions: 1) direct mailing of printed materials with Pap test and HPVV resources and 2) direct mailing only. Women 18-70 years old were included and completed the pre- and post-intervention questionnaires. Univariate and bivariate analyses were conducted to measure changes in Pap test uptake and HPVV knowledge and acceptability from baseline to post-intervention. Results: Analyses included 322 women who had baseline and post-assessment data: African Americans (n=97), Latina English-language preferred (n= 39), Latina Spanish-language preferred (n=129), and Trinidadians (n=57). Results showed statistically significant differences in improved HPV knowledge for African Americans (p = .019), Latina Spanish (p=.009), and Trinidadians (p=.034), but not Latina English-language preferred participants. Changes in acceptability of HPV vaccine were also significant across all groups except Trinidadians. Pap testing also showed significant increases. At preintervention, 21% of women reported not having a Pap test in the past 2 years. Post-intervention results showed Pap test completion increased by 10% in the mailed intervention group and 23% in the mailed plus social marketing group. Conclusion: The results suggest utility and efficacy for the trial as both the mail-only and the mail-plus-social-marketing groups improved. However, compared to the mail condition only, mail plus social marketing seemed more likely to be effective for improving Pap testing. Our findings show multilevel contextual factors (including culture, country of origin, SES, and immigration) influenced Pap testing and HPVV acceptability. Citation Format: Kimlin Ashing, Camille Ragin, Ndifreke Etim, Francisca Rivera. Across border: Towards increasing Pap testing and HPVV knowledge and acceptability among minority populations [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B091.

El lupus eritematoso sistémico (LES) es una enfermedad compleja con formas de presentación clínica diversas en gravedad y afección orgánica. Esta peculiaridad, el no ser frecuente y la ausencia de criterios de respuesta clínicamente representativos, hacen difícil la realización de ensayos clínicos controlados en pacientes con lupus. Como consecuencia, adquieren una especial relevancia los estudios observacionales. De estos puede extraerse información inestimable sobre el pronóstico y la evolución del LES, así como de la eficacia y efectos adversos de sus tratamientos.En esta actualización realizamos una puesta al día de algunos de los principales tratamientos utilizados en el LES. Los glucocorticoides pueden tener más riesgos que beneficios si son empleados a dosis altas. Se han descrito nuevos mecanismos de acción que justifican el uso de dosis más bajas, posiblemente con igual eficacia y menos efectos adversos. La ciclofosfamida en pulsos intravenosos mantiene su papel en el tratamiento de la nefritis lúpica proliferativa y otras manifestaciones graves del LES. El micofenolato de mofetilo ha mostrado su utilidad tanto en el tratamiento de inducción de casos seleccionados de nefritis lúpica como en el tratamiento de mantenimiento. Los tratamientos biológicos han irrumpido como nuevas opciones terapéuticas. A pesar de que los ensayos clínicos no han confirmado una clara superioridad de rituximab en el tratamiento del LES, estudios observacionales muestran buenas tasas de respuesta en manifestaciones graves o en formas refractarias. Recientemente se ha incorporado belimumab al armamentario terapéutico del LES. Su lugar en la práctica habitual está aún en debate, siendo su posible escenario el de los pacientes activos que no toleren o no respondan a tratamientos estándar. La hidroxicloroquina mejora la supervivencia, disminuye el riesgo de trombosis y el riesgo de brote y es segura durante el embarazo, constituyendo en este momento el tratamiento de base de la mayoría de los pacientes con lupus.Systemic lupus erythematosus (SLE) is a complex disease with different clinical forms of presentation, including a wide range of severity and organic involvement. Such circumstance, along with the fact of the uncommon nature of the disease and the absence of clinically representative response criteria, make it difficult to design controlled clinical trials in SLE patients. As a result, observational studies have a special relevance, being a source of valuable information of SLE prognosis and outcome as well as of the efficacy and adverse effects of the different therapies. Herein we update some of the main treatments used in SLE. Steroids may have more risks than benefits if used at high doses. New mechanisms of action have been described, supporting the use of lower doses, possibly with the same efficacy and less adverse effects. Intravenous pulses of cyclophosphamide still have a role in the treatment of proliferative lupus nephritis and other serious SLE manifestations. Mycophenolate mofetil has shown its efficacy both as induction and maintenance therapy of selected cases of lupus nephritis. Biological therapies have emerged as new promising options. Although clinical trials have not confirmed a clear superiority of rituximab in SLE, observational studies have shown good response rates in severe SLE manifestations or refractory forms. Belimumab has recently been added to the therapeutic armamentarium of SLE; although its place in clinical practice is not well-defined, it may be recommended in active patients with no response or good tolerance to standard therapies. Hydroxichloroquine improves survival, decreases the risk of thrombosis and flares and is safe in pregnancy, and should be considered the baseline therapy in most SLE patients.

BACKGROUND:Diabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle.METHODOLOGY/PRINCIPAL FINDINGS:We have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TR(alpha1). This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR( alpha1) and to T(3)-responsive promoters, as shown by ChIP assays. T(3) stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related.CONCLUSIONS/SIGNIFICANCE:Our data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.

BACKGROUND/AIMS:Selective cyclooxygenase (COX)-2 inhibitors do not adversely affect renal function in experimental cirrhosis. In the current study, we investigated the molecular mechanisms underlying the effects of the selective COX-2 inhibitor, celecoxib, and assessed the influence of albumin on its actions. METHODS:Rat mesangial cells (RMC) were incubated with celecoxib in the absence or presence of albumin, and levels of selected vasoconstrictor eicosanoids, renin release and alpha-smooth muscle actin (alpha-SMA) expression were determined. The effects of celecoxib on PPARgamma were assessed in RMC co-transfected with PPARgamma and luciferase reporter constructs. RESULTS:Under resting conditions, RMC expressed COX-1, COX-2 and 12/15-lipoxygenase and mainly generated prostaglandin (PG)E2, thromboxane (TX)B2, 12-hydroxyeicosatetraenoic acid (12-HETE) and 8-epi-PGF2alpha. Celecoxib, in addition to reducing PGE2, significantly decreased 8-epi-PGF2alpha formation. In the presence of albumin, celecoxib also reduced TXB2 and 12-HETE. Albumin per se inhibited PGE2 as well as renin release. In trans-activation assays, celecoxib acted as a PPARgamma agonist whereas albumin inhibited PPARgamma as well as 15d-PGJ2-induced PPARgamma activation. Finally, celecoxib and albumin potentiated the inhibitory effect of 15d-PGJ2 on alpha-SMA expression. CONCLUSIONS:These data provide novel molecular mechanisms of celecoxib and their modulation by albumin, that may be relevant to prevent renal dysfunction in conditions of unbalanced effective blood volume.

BACKGROUND:Genetic variability could contribute to the response to pharmacological treatment in patients with nephropathy. In albuminuric diabetic patients the renoprotective effect of angiotensin I-converting enzyme (ACE) inhibition should be lower among homozygotes for the deletion allele (DD) compared to II-homozygotes.METHODS:A total of 71 non-diabetic chronic nephropathy patients were treated with losartan (n = 37) or amlodipine (n = 34). Blood pressure and proteinuria were determined before and after the treatment, and changes in the mean values were statistically compared. Patients were genotyped for the ACE-I/D, angiotensin I receptor type 1 (AGTR1)-1166 A/C, and angiotensinogen (AGT)-M235T polymorphims, and the reduction of blood pressure and proteinuria between the different genotypes were compared.RESULTS:The reduction in systolic or diastolic blood pressure was not found to be different between the ACE-I/D or AGT-M/T genotypes in patients treated with losartan or amlodipine. In patients treated with losartan, we found a significantly higher reduction of diastolic blood pressure in AGTR1-AA patients compared to AC patients (p = 0,0024). We did not find differences in proteinuria-reduction between the different genotypes in patients treated with losartan or amlodipine.CONCLUSIONS:Our data show that the effects of losartan and amlodipine on the absolute mean reduction of blood pressure and proteinuria in non-diabetic nephropathy patients are similar between the different ACE or AGT genotypes. Although based on a small number of patients, the AGTR1-AA genotype was associated with a significantly higher reduction in diastolic blood pressure among losartan-treated patients. Additional studies are necessary to refute or confirm this association.

A wealth of evidence indicates that inflammation plays a central role in the current paradigm of liver fibrosis. Kupffer cells, which represent the largest population of resident macrophages in the body [1], are uniquely positioned as the predominant primary inflammatory effector cells to initiate the inflammatory cascade leading to tissue remodeling and fibrosis. For this reason, the presence of an increased population of Kupffer cells together with the bulk release of inflammatory mediators by these macrophages are considered to be critical events during the early stages of liver inflammation and fibrosis [2,3]. Arachidonic acid metabolites derived from 5-lipoxygenase (5-LO) are essential regulators of cell growth and survival [4]. Given that we recently demonstrated that 5-LO expression and leukotriene (LT) formation are increased in livers from rats with carbon tetrachloride (CCl4)-induced cirrhosis [5], it is our hypothesis that 5-LO products play a role in Kupffer cell survival and in the pathogenesis of liver inflammation and fibrosis. Therefore, in the current study we examined the 5-LO pathway in sinusoidal liver cells and specifically analyzed the role of 5-LO in Kupffer cell growth and survival.

BACKGROUND:Selective V(2)-AVP receptor antagonists are effective in inducing aquaresis in humans and rats with cirrhosis, hyponatremia and water retention. However, it is unknown whether dual V(1a)/V(2)-AVP antagonists are also efficacious as aquaretic agents under these conditions. This is important, particularly considering that blockade of V(1a)-AVP receptors could aggravate cardiocirculatory function in decompensated cirrhosis.AIMS:To evaluate the renal, hormonal and hemodynamic effects induced by the chronic oral administration of the V(1a)/V(2)-AVP antagonist, Conivaptan, in rats with CCl(4)-induced cirrhosis, ascites and severe water retention.METHODS:We assessed the aquaretic efficacy of 10-day chronic oral administration of Conivaptan (0.5mg/kg body weight (bw)) in cirrhotic rats with hyponatremia and water retention. Urine volume (UV), osmolality (UOsm), and sodium excretion (U(Na)V) were measured daily. At the end of the study arterial pressure was also measured.RESULTS:Conivaptan produced an acute increase in UV, a reduction in UOsm and, at the end of the investigation, cirrhotic rats receiving the V(1a)/V(2)-AVP receptor antagonist did not show hyponatremia or hypoosmolality. Conivaptan also normalized U(Na)V without affecting creatinine clearance and arterial pressure.CONCLUSIONS:Dual V(1a)/V(2)-receptor antagonists may be therapeutically useful for the treatment of water retention and dilutional hyponatremia in human cirrhosis.

Background & Aims: Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension. Methods: Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either P-galactosidase (beta-gal) or constitutively active Akt (myr-Akt). Results: The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3',5'-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with beta-gal did not produce any change in these hemodynamic parameters. Conclusions: myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension.

Aim: In the present work, we studied the effects of hypoxia and triiodothyronine (T3) on phosphoglycerate mutase (PGAM) activity and expression in rabbit liver, brain, and skeletal muscle under in vivo conditions. Methods: Hypoxia was induced in a methacrylate cage with a mixture of 90% nitrogen and 10% oxygen. Hyperthyroidism was induced daily by T3 injection (250 µg/kg). Results: Hypoxia increases the PGAM activity in liver and brain, tissues which possess type PGAM-BB isozyme, but does not affect the PGAM activity in muscle which possesses type PGAM-MM isozyme. T3 administration increases the PGAM activity in muscle and liver, but does not affect the enzyme activity in the brain. In all cases, the activity changes in parallel with those of PGAM mRNA levels. Conclusion: The tissue-specific effects of hypoxia and T3 could be explained by the tissue-specific distribution of both PGAM isozyme and T3 receptors.

Renal synthesis of vasodilator prostaglandins (PGs) plays a key role in the maintenance of renal function in decompensated cirrhosis [1,2]. In fact, acute PG inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with cirrhosis and ascites is associated with a significant impairment in renal hemodynamics, sodium excretion, free water clearance and the renal response to furosemide and spironolactone [1-3]. Thus, in clinical practice, patients with decompensated cirrhosis cannot be treated with NSAIDs on a long-term basis because of the high risk of developing renal failure and refractory ascites.

Vascular remodeling is an active process that consists in important modifications in the vessel wall. Endothelium-derived nitric oxide (NO) plays a major role in this phenomenon. We assessed wall thickness (WT), total wall area (TWA), lumen diameter, and total nuclei number/cross-section (TN) in cirrhotic rats with ascites and in control rats. A second group of cirrhotic rats received the NO synthesis inhibitor, L-NAME, or vehicle daily for 11 weeks and systemic hemodynamics, arterial compliance, aortic NO synthase 3 (NOS3) protein expression, and vascular morphology were analyzed. Cirrhotic vessels showed a significant reduction in WT, TWA, and TN as compared to control vessels. Long-term inhibition of NOS activity in cirrhotic rats resulted in a significant increase in WT, TWA, and TN as compared to cirrhotic rats receiving vehicle. NOS3 protein abundance was higher in aortic vessels of nontreated cirrhotic animals than in controls. This difference was abolished by chronic treatment with L-NAME. NOS inhibition in cirrhotic rats resulted in higher arterial pressure and peripheral resistance and lower arterial compliance than cirrhotic rats receiving vehicle. Therefore, vascular remodeling in cirrhosis with ascites is a generalized process with significant functional consequences that can be negatively modulated by long-term inhibition of NOS activity.

BACKGROUND Proteinuria is a significant independent determinant of the progression of chronic renal diseases. It induces an increased synthesis of angiotensin II, endothelin and profibrogenic growth factors, such as transforming growth factor-beta (TGF-beta), by mesangial and tubular cells. The antiproteinuric effect of angiotensin-converting enzyme inhibitors (ACEIs) in diabetic and non-diabetic nephropathies predicts long-term renoprotection afforded by these drugs. Angiotensin II receptor antagonists are renoprotective in patients with type 2 diabetes, but studies about their effect in non-diabetic proteinuric nephropathies are very scarce. METHODS We randomly assigned 97 patients with non-diabetic nephropathies and proteinuria >1.5 g/24 h to treatment with losartan (50 mg daily) or amlodipine (5 mg daily) for 20 weeks. Doses of the study medications were titrated to achieve a target blood pressure <140/90 mmHg in both groups. Primary outcome was the decrease in the level of 24 h proteinuria. Secondary outcomes were changes in the plasma and urinary levels of TGF-beta. RESULTS The baseline characteristics in both groups were similar. Proteinuria decreased by 32.4% (95% confidence interval -38.4 to -21.8%) after 4 weeks of treatment and by 50.4% (-58.9 to -40.2%) after 20 weeks in the losartan group, whereas no significant proteinuria changes were observed in the amlodipine group (P < 0.001). There was no significant correlation between the level of baseline proteinuria and the proteinuria decrease induced by losartan. Both losartan and amlodipine induced a similar and significant blood pressure reduction. Target blood pressure was achieved with the initial dose of study medication (50 mg daily) in 76% of losartan group patients and in 68% of the amlodipine group patients (5 mg daily). Urinary TGF-beta significantly decreased with losartan (-22.4% of the baseline values after 20 weeks of treatment), whereas it tended to increase with amlodipine (between-group difference P < 0.05). A significant correlation between proteinuria decrease and urinary TGF-beta reduction was found in the losartan group (r = 0.41, P < 0.005). Serum creatinine and serum potassium remained stable during the study in both groups. CONCLUSIONS Losartan induced a drastic decrease in proteinuria accompanied by a reduction in urinary excretion of TGF-beta in patients with non-diabetic proteinuric renal diseases.

In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Repression of Mfn2 caused morphological and functional fragmentation of the mitochondrial network into independent clusters. Concomitantly, repression of Mfn2 reduced glucose oxidation, mitochondrial membrane potential, cell respiration, and mitochondrial proton leak. We also show that the Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity by reduced Mfn2 expression. In all, our data indicate that Mfn2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced Mfn2 expression may explain some of the metabolic alterations associated with obesity.

The existence of an increased number of Kupffer cells is recognized as critical in the initiation of the inflammatory cascade leading to liver fibrosis. Because 5-lipoxygenase (5-LO) is a key regulator of cell growth and survival, in the current investigation we assessed whether inhibition of the 5-LO pathway would reduce the excessive number of Kupffer cells and attenuate inflammation and fibrosis in experimental liver disease. Kupffer cells were the only liver cell type endowed with a metabolically active 5-LO pathway (i.e., expressed mRNAs for 5-LO, 5-LO-activating protein [FLAP], and leukotriene [LT] C4 synthase and generated LTB4 and cysteinyl-LTs). Both the selective 5-LO inhibitor AA861 and the FLAP inhibitor BAY-X-1005 markedly reduced the number of Kupffer cells in culture. The antiproliferative properties of AA861 and BAY-X-1005 were associated with the occurrence of condensed nuclei, fragmented DNA, and changes in DNA content and cell cycle frequency distribution consistent with an apoptotic process. In vivo, in carbon tetrachloride-treated rats, BAY-X-1005 had a significant antifibrotic effect and reduced liver damage and the hepatic content of hydroxyproline. Together, these findings indicate a novel mechanism by which inactivation of the 5-LO pathway could disrupt the sequence of events leading to liver inflammation and fibrosis.

The aim of the investigation was to assess whether hypoxia induces the production of endogenous vasoactive peptides in macrophages of cirrhotic patients with ascites because low tissue oxygenation is a relatively frequent event in these patients. Peritoneal macrophages were isolated from ascites, seeded on well plates, and cultured at different times under hypoxic (5% O2) or normoxic conditions (21% O2). Then, accumulation of vasoactive peptides sensitive to hypoxia including endothelin‐1 (ET‐1), vascular endothelial growth factor (VEGF), and adrenomedullin (ADM) was measured. Only VEGF and ADM were constitutively secreted, and hypoxia further stimulated the release of these vasodilator peptides. In concordance, increased messenger RNA (mRNA) levels of VEGF and ADM were found at culturing macrophages in hypoxia. This characteristic response was not observed in circulating monocytes of either cirrhotic patients or healthy subjects. Next the expression of the transcription factor, hypoxia inducible factor 1 (HIF‐1), was analyzed. Expression of HIF‐1α and HIF‐1β messengers and HIF‐1β protein subunit remained unchanged regardless of O2 tension, whereas HIF‐1α protein subunit was overexpressed under hypoxic conditions. Moreover, conditioned medium from macrophages cultured under hypoxic conditions promoted a larger nitric oxide (NO) release in endothelial cells than that of normoxic macrophages. In conclusion, these data indicate that hypoxia induces the synthesis of VEGF and ADM in macrophages of cirrhotic patients, likely through HIF‐1–enhanced transcriptional activity. These data suggest that a local reduction in O2 tension could enhance the synthesis of macrophage‐derived vasodilators, thus aggravating the circulatory disturbance of these patients.

BACKGROUND & AIMS:Recent studies have described the existence of endogenous cannabinoids with vasodilator activity because of their interaction with peripheral CB1 receptors, anandamide being the most extensively investigated. The study investigated whether endogenous cannabinoids are involved in the pathogenesis of the cardiovascular disturbances in experimental cirrhosis.METHODS:Arterial pressure, cardiac output, and total peripheral resistance were measured before and after the administration of a cannabinoid CB1 receptor antagonist to cirrhotic rats with ascites and to control rats. Blood pressure was also assessed in normotensive recipient rats after the intravenous administration of blood cells or isolated monocytes obtained from cirrhotic and control rats. Moreover, the endogenous content of anandamide was measured in circulating monocytes of cirrhotic and control rats by gas chromatography/mass spectrometry.RESULTS:CB1 receptor blockade did not modify systemic hemodynamics in control rats, but significantly increased arterial pressure and peripheral resistance in cirrhotic animals. Blood cell suspension or monocytes from cirrhotic animals, but not from controls, induced arterial hypotension in recipient rats. Finally, anandamide was solely detected in monocytes of cirrhotic animals.CONCLUSIONS:Monocytes of cirrhotic rats with ascites are activated to produce anandamide and this substance contributes to arterial hypotension in experimental cirrhosis.