Risk of abnormal cervical cytology in HIV-infected women testing positive for both human papillomavirus and Epstein-Barr virus in genital tract specimens.

PURPOSE: Although infection with high-risk human papillomavirus (HPV) is a prerequisite for cervical cancer development, HPV infection is not sufficient to promote cancer in the majority of infected women. We tested the hypothesis that human herpesviruses might cooperate with HPV to promote the development of cervical dysplasia, an early indicator of cervical cancer development. METHODS: This study used archived specimens from a cohort of human immunodeficiency virus (HIV)-seropositive women seeking gynecological care at the Medical Center of New Orleans, Louisiana. Viral DNA was detected by PCR amplification and risk of abnormal cervical cytology was determined in relation to virus test results. RESULTS: Consensus human herpesvirus PCR with herpes speciation by restriction endonuclease digestion revealed Epstein-Barr virus (EBV) to be the most prevalent herpesvirus in cervicovaginal lavage specimens. Further analysis using an EBV-specific PCR assay and cervical swab specimens demonstrated an approximately fourfold increased risk of abnormal cervical cytology in women testing positive for cervical EBV and high-risk HPV compared to women testing positive for high-risk HPV alone. This relationship was independent of markers of advancing HIV disease. CONCLUSION: Cervical shedding of EBV appears to predict a greater risk of cervical dysplasia in HIV-infected women with a high-risk HPV infection.

Whole genome prediction of bladder cancer risk with the Bayesian LASSO.

To build a predictive model for urothelial carcinoma of the bladder (UCB) risk combining both genomic and nongenomic data, 1,127 cases and 1,090 controls from the Spanish Bladder Cancer/EPICURO study were genotyped using the HumanHap 1M SNP array. After quality control filters, genotypes from 475,290 variants were available. Nongenomic information comprised age, gender, region, and smoking status. Three Bayesian threshold models were implemented including: (1) only genomic information, (2) only nongenomic data, and (3) both sources of information. The three models were applied to the whole population, to only nonsmokers, to male smokers, and to extreme phenotypes to potentiate the UCB genetic component. The area under the ROC curve allowed evaluating the predictive ability of each model in a 10-fold cross-validation scenario. Smoking status showed the highest predictive ability of UCB risk (AUCtest = 0.62). On the other hand, the AUC of all genetic variants was poorer (0.53). When the extreme phenotype approach was applied, the predictive ability of the genomic model improved 15%. This study represents a first attempt to build a predictive model for UCB risk combining both genomic and nongenomic data and applying state-of-the-art statistical approaches. However, the lack of genetic relatedness among individuals, the complexity of UCB etiology, as well as a relatively small statistical power, may explain the low predictive ability for UCB risk. The study confirms the difficulty of predicting complex diseases using genetic data, and suggests the limited translational potential of findings from this type of data into public health interventions.

Sodium current inhibition by nanosecond pulsed electric field (nsPEF)--fact or artifact?

In two recent publications in Bioelectromagnetics it has been demonstrated that the voltage-gated sodium current (I(Na)) is inhibited in response to a nanosecond pulsed electric field (nsPEF). At the same time, there was an increase in a non-inactivating "leak" current (I(leak)), which was attributed to the formation of nanoelectropores or larger pores in the plasma membrane. We demonstrate that the increase in I(leak), in combination with a residual series resistance, leads to an error in the holding potential in the patch clamp experiments and an unanticipated inactivation of the sodium channels. We conclude that the observed inhibition of I(Na) may be largely, if not fully, artifactual.

Complex Monte Carlo Light-Driven Dynamics of Monomers in Functionalized Bond Fluctuation Model Polymer Chains.

We study Monte Carlo dynamics of the monomers and center of mass of a model polymer chain functionalized with azobenzene molecules in the presence of an inhomogeneous linearly polarized laser light. The simulations use a generalized Bond Fluctuation Model. The mean squared displacements of the monomers and the center of mass are analyzed in a period of Monte Carlo time typical for a build-up of Surface Relief Grating. Approximate scaling laws for mean squared displacements are found and interpreted in terms of sub- and superdiffusive dynamics for the monomers and center of mass. A counterintuitive effect is observed, where the monomers perform subdiffusive motion but the resulting motion of the center of mass is superdiffusive. This result disparages theoretical approaches based on an assumption that the dynamics of single monomers in a chain can be characterized in terms of independent identically distributed random variables.

Nanoscale ordering of planar octupolar molecules for nonlinear optics at higher temperatures.

We develop scenarios for orientational ordering of an in-plane system of small flat octupolar molecules at the low-concentration limit, aiming towards nonlinear-optical (NLO) applications at room temperatures. The octupoles interact with external electric poling fields and intermolecular interactions are neglected. Simple statistical-mechanics models are used to analyze the orientational order in the very weak poling limit, sufficient for retrieving the NLO signals owing to the high sensitivity of NLO detectors and measurement chains. Two scenarios are discussed. Firstly, the octupolar poling field is imparted by a system of point charges; the setup is subject to cell-related constraints imposed by mechanical strength and dielectric breakdown limit. The very weak octupolar order of benchmarking TATB molecules is shown to emerge at Helium temperatures. The second scenario addresses the dipoling of octupolar molecules with a small admixture of electric dipolar component. It requires a strong field regime to become effective at Nitrogen temperature range. An estimation of the nonlinear susceptibility coefficient matrix for both scenarios is done in the high-temperature (weak interaction) limit formalism. We argue that moderate modifications of the system like, e.g., an increase of the size of the octupole, accompanied by dipole-assisted octupoling, can increase the poling temperature above Nitrogen temperatures.

Characterization of Monte Carlo Dynamic/Kinetic Properties of Local Structure in Bond Fluctuation Model of Polymer System.

We report the results of the characterization of local Monte Carlo (MC) dynamics of an equilibrium bond fluctuation model polymer matrix (BFM), in time interval typical for MC simulations of non-linear optical phenomena in host-guest systems. The study contributes to the physical picture of the dynamical aspects of quasi-binary mosaic states characterized previously in the static regime. The polymer dynamics was studied at three temperatures (below, above and close to the glass transition), using time-dependent generalization of the static parameters which characterize local free volume and local mobility of the matrix. Those parameters play the central role in the kinetic MC model of host-guest systems. The analysis was done in terms of the probability distributions of instantaneous and time-averaged local parameters. The main result is the characterization of time scales characteristic of various local structural processes. Slowing down effects close to the glass transition are clearly marked. The approach yields an elegant geometric criterion for the glass transition temperature. A simplified quantitative physical picture of the dynamics of guest molecules dispersed in BFM matrix at low temperatures offers a starting point for stochastic modeling of host-guest systems.

Modeling of Nonlinear Optical Phenomena in Host-Guest Systems Using Bond Fluctuation Monte Carlo Model: A Review.

We review the results of Monte Carlo studies of chosen nonlinear optical effects in host-guest systems, using methods based on the bond-fluctuation model (BFM) for a polymer matrix. In particular, we simulate the inscription of various types of diffraction gratings in degenerate two wave mixing (DTWM) experiments (surface relief gratings (SRG), gratings in polymers doped with azo-dye molecules and gratings in biopolymers), poling effects (electric field poling of dipolar molecules and all-optical poling) and photomechanical effect. All these processes are characterized in terms of parameters measured in experiments, such as diffraction efficiency, nonlinear susceptibilities, density profiles or loading parameters. Local free volume in the BFM matrix, characterized by probabilistic distributions and correlation functions, displays a complex mosaic-like structure of scale-free clusters, which are thought to be responsible for heterogeneous dynamics of nonlinear optical processes. The photoinduced dynamics of single azopolymer chains, studied in two and three dimensions, displays complex sub-diffusive, diffusive and super-diffusive dynamical regimes. A directly related mathematical model of SRG inscription, based on the continuous time random walk (CTRW) formalism, is formulated and studied. Theoretical part of the review is devoted to the justification of the a priori assumptions made in the BFM modeling of photoinduced motion of the azo-polymer chains.

HCN4 current during human sinoatrial node-like action potentials.

BACKGROUND: Despite the many studies carried out over the past 40 years, the contribution of the HCN4 encoded hyperpolarization-activated 'funny' current (If) to pacemaker activity in the mammalian sinoatrial node (SAN), and the human SAN in particular, is still controversial and not fully established. OBJECTIVE: To study the contribution of If to diastolic depolarization of human SAN cells and its dependence on heart rate, cAMP levels, and atrial load. METHODS: HCN4 channels were expressed in human cardiac myocyte progenitor cells (CMPCs) and HCN4 currents assessed using perforated patch-clamp in traditional voltage clamp mode and during action potential clamp with human SAN-like action potential waveforms with 500-1500 ms cycle length, in absence or presence of forskolin to mimic ß-adrenergic stimulation and a -15 mV command potential offset to mimic atrial load. RESULTS: Forskolin significantly increased the fully-activated HCN4 current density at -140 mV by 14% and shifted the steady-state activation curve by +7.4 mV without affecting its slope. In addition, forskolin significantly accelerated current activation but slowed deactivation. The HCN4 current did not completely deactivate before the subsequent diastolic depolarization during action potential clamp. The amplitude of HCN4 current increased with increasing cycle length, was significantly larger in the presence of forskolin at all cycle lengths, and was significantly increased upon the negative offset to the command potential. CONCLUSIONS: If is active during a human SAN action potential waveform and its amplitude is modulated by heart rate, ß-adrenergic stimulation, and diastolic voltage range, such that If is under delicate control.

Photoinduced Mass Transport in Azo-Polymers in 2D: Monte Carlo Study of Polarization Effects.

We studied the impact of light polarization on photoinduced dynamics of model azo-polymer chains in two dimensions, using bond-fluctuation Monte Carlo simulations. For two limiting models-sensitive to and independent of light polarization-their dynamics driven by photoisomerization of azo-dyes as well as by thermal effects was studied, including characterization of mass transport and chain reorientations. The corresponding schemes of light-matter interaction promote qualitatively different dynamics of photoinduced motion of azo-polymer chains. In particular, they can inhibit or trigger off a directed mass transport along a gradient of light illumination. The generic dynamics of single chains is superdiffusive and is promoted by breaking a symmetry present in the polarization independent model.

Complex Dynamics of Photoinduced Mass Transport and Surface Relief Gratings Formation.

The microscopic and semi-macroscopic mechanisms responsible for photoinduced mass transport in functionalized azo-polymers are far from deeply understood. To get some insight into those mechanisms on "microscopic" scale, we studied the directed photoinduced motion of single functionalized polymer chains under various types of polarized light illumination using Monte Carlo bond fluctuation model and our kinetic Monte Carlo model for photoinduced mass transport. We found sub-diffusive, diffusive and super-diffusive regimes of the dynamics of single chains at constant illumination and mostly super-diffusive regime for directed motion in the presence of the gradient of light intensity. This regime is more enhanced for long than for short chains and it approaches the ballistic limit for very long chains. We propose a physical picture of light-driven inscription of Surface Relief Gratings (SRG) as corresponding to a dynamical coexistence of normal and anomalous diffusion in various parts of the system. A simple continuous time random walk model of SRG inscription based on this physical picture reproduced the light-driven mass transport found in experiments as well as the fine structure of SRG.

Combination treatment with infliximab and leflunomide in patients with active rheumatoid arthritis: safety and efficacy in an open-label clinical trial.

OBJECTIVE: To assess the safety and efficacy of combination therapy with infliximab and leflunomide in adults with active rheumatoid arthritis (RA) despite leflunomide therapy. METHODS: Adult patients with active RA who had received leflunomide for at least 16 weeks were eligible for this 30-week, open-label trial. All patients received ongoing oral leflunomide (20 mg/day) and 3 mg/kg infliximab administered IV at weeks 0, 2, 6, 14, and 22. The primary end point was the percentage of patients with adverse events that led to patient withdrawal and were at least possibly related to treatment. Descriptive evaluations of efficacy and other safety assessments were performed. RESULTS: Twelve out of 70 patients (17.1%; upper 90% CI 24.5%) withdrew due to treatment-related adverse events. Adverse events were reported in 69 of 72 patients (95.8%); the most common were nasopharyngitis, diarrhea, and pruritus. Serious adverse events occurred in 16 out of 72 patients (22.2%). Significant improvements were observed in efficacy assessments, including Disease Activity Score 28 (DAS28) and pain. At end point, 19.4% of the patients showed a good improvement in DAS28 score and 46.3% had a moderate improvement. American College of Rheumatology (ACR) 20, 50, and 70 responses were achieved by 47.1%, 21.4%, and 12.9% of the patients, respectively. CONCLUSION: The combination of infliximab and leflunomide neither increased the rate of toxicities nor resulted in unexpected adverse events. Treatment-related withdrawals occurred at an acceptable frequency. Patients experienced clinically significant improvements. Treatment with infliximab plus leflunomide benefits the majority of patients, but monitoring of adverse events is required.

Neurokinin-3 receptor activation selectively prolongs atrial refractoriness by inhibition of a background K+ channel.

The cardiac autonomic nervous system (ANS) controls normal atrial electrical function. The cardiac ANS produces various neuropeptides, among which the neurokinins, whose actions on atrial electrophysiology are largely unknown. We here demonstrate that the neurokinin substance-P (Sub-P) activates a neurokinin-3 receptor (NK-3R) in rabbit, prolonging action potential (AP) duration through inhibition of a background potassium current. In contrast, ventricular AP duration was unaffected by NK-3R activation. NK-3R stimulation lengthened atrial repolarization in intact rabbit hearts and consequently suppressed arrhythmia duration and occurrence in a rabbit isolated heart model of atrial fibrillation (AF). In human atrial appendages, the phenomenon of NK-3R mediated lengthening of atrial repolarization was also observed. Our findings thus uncover a pathway to selectively modulate atrial AP duration by activation of a hitherto unidentified neurokinin-3 receptor in the membrane of atrial myocytes. NK-3R stimulation may therefore represent an anti-arrhythmic concept to suppress re-entry-based atrial tachyarrhythmias, including AF.

Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel.

PURPOSE: Prognostic value of pathologic complete response (pCR) and extent of pathologic response attained with anthracycline-free platinum plus taxane neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) is unknown. We report recurrence-free survival (RFS) and overall survival (OS) according to degree of pathologic response in patients treated with carboplatin plus docetaxel NAC. PATIENTS AND METHODS: One-hundred and ninety patients with stage I-III TNBC were treated with neoadjuvant carboplatin (AUC6) plus docetaxel (75 mg/m2) every 21 days × 6 cycles. pCR (no evidence of invasive tumor in breast and axilla) and Residual cancer burden (RCB) were evaluated. Patients were followed for recurrence and survival. Extent of pathologic response was associated with RFS and OS using the Kaplan-Meier method. RESULTS: Median age was 51 years, and 52% were node-positive. pCR and RCB I rates were 55% and 13%, respectively. Five percent of pCR patients, 0% of RCB I patients, and 58% of RCB II/III patients received adjuvant anthracyclines. Three-year RFS and OS were 79% and 87%, respectively. Three-year RFS was 90% in patients with pCR and 66% in those without pCR [HR = 0.30; 95% confidence interval (CI), 0.14-0.62; P = 0.0001]. Three-year OS was 94% in patients with pCR and 79% in those without pCR (HR = 0.25; 95% CI, 0.10-0.63; P = 0.001). Patients with RCB I demonstrated 3-year RFS (93%) and OS (100%) similar to those with pCR. On multivariable analysis, higher tumor stage, node positivity, and RCB II/III were associated with worse RFS. CONCLUSIONS: Neoadjuvant carboplatin plus docetaxel yields encouraging efficacy in TNBC. Patients achieving pCR or RCB I with this regimen demonstrate excellent 3-year RFS and OS without adjuvant anthracycline.

Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD.

BACKGROUND: Patients carrying the cardiac sodium channel (SCN5A) mutation 1795insD show sudden nocturnal death and signs of multiple arrhythmia syndromes including bradycardia, conduction delay, QT prolongation, and right precordial ST-elevation. We investigated the electrophysiological characteristics of a transgenic model of the murine equivalent mutation 1798insD. METHODS AND RESULTS: On 24-hour continuous telemetry and surface ECG recordings, Scn5a(1798insD/+) heterozygous mice showed significantly lower heart rates, more bradycardic episodes (pauses > or = 500 ms), and increased PQ interval, QRS duration, and QTc interval compared with wild-type mice. The sodium channel blocker flecainide induced marked sinus bradycardia and/or sinus arrest in the majority of Scn5a(1798insD/+) mice, but not in wild-type mice. Epicardial mapping using a multielectrode grid on excised, Langendorff-perfused hearts showed preferential conduction slowing in the right ventricle of Scn5a(1798insD/+) hearts. On whole-cell patch-clamp analysis, ventricular myocytes isolated from Scn5a(1798insD/+) hearts displayed action potential prolongation, a 39% reduction in peak sodium current density and a similar reduction in action potential upstroke velocity. Scn5a(1798insD/+) myocytes displayed a slower time course of sodium current decay without significant differences in voltage-dependence of activation and steady-state inactivation, slow inactivation, or recovery from inactivation. Furthermore, Scn5a(1798insD/+) myocytes showed a larger tetrodotoxin-sensitive persistent inward current compared with wild-type myocytes. CONCLUSIONS: Mice carrying the murine equivalent of the SCN5A-1795insD mutation display bradycardia, right ventricular conduction slowing, and QT prolongation, similar to the human phenotype. These results demonstrate that the presence of a single SCN5A mutation is indeed sufficient to cause an overlap syndrome of cardiac sodium channel disease.

Dietary fish oil reduces the incidence of triggered arrhythmias in pig ventricular myocytes.

BACKGROUND: Fish oil reduces the incidence of sudden cardiac death in postmyocardial infarction patients. Triggered activity is the principal mechanism of arrhythmogenesis under these conditions. OBJECTIVE: The purpose of this study was to test whether dietary fish oil in pigs inhibits Ca2+ overload-induced triggered activity. METHODS: Pigs were fed a diet of fish oil or sunflower oil for 8 weeks. Ventricular myocytes (omega3: fish oil, n = 11; control: sunflower oil, n = 8) were isolated by enzymatic dissociation and used for patch clamp studies and intracellular Ca2+ recordings. Triggered activity was induced by rapid pacing in the presence of norepinephrine. RESULTS: Dietary fish oil reduced the incidence of triggered action potentials and delayed afterdepolarizations compared to control (9.1% in omega3 and 84.6% in control, P <.05), concomitant with a reduction in spontaneous Ca2+ release. Dietary fish oil prevented Ca2+ overload and reduced action potential prolongation in response to norepinephrine (DeltaAPD(90): 23.2 +/- 8.5 ms in omega3 and 107.4 +/- 15.9 in control, P <.05). omega3 myocytes displayed decreased sarcoplasmic reticulum Ca2+ content, reduced L-type Ca2+ current (I(Ca,L)), and less recruitment of the Na+/Ca2+ exchange current (I(NCX)) in response to norepinephrine compared to control. In the absence of norepinephrine, the slow component of the delayed rectifier current (I(Ks)) was larger in omega3 myocytes. In the presence of norepinephrine, I(Ks) increased to the same level in omega3 and control myocytes. CONCLUSION: Dietary fish oil reduces the incidence of triggered activity and prevents Ca2+ overload and AP prolongation in response to norepinephrine. Fish oil may prevent arrhythmias in patients with heart failure.

Electrophysiological properties of embryonic stem cells during differentiation into cardiomyocyte-like cell types.

The method described here to differentiate mouse embryonic stem (ES) cells into cardiomyocytes is adapted from Maltsev et al. and results in a high percentage of spontaneously beating cardiomyocyte-like cells. In order to determine to what extent the differentiating ES cells resemble true cardiomyocytes, the cells were electrophysiologically characterized during differentiation, using the whole-cell variant of the patch-clamp technique. Action potentials (APs) and membrane currents were recorded and analyzed off-line to determine electrophysiological changes during development.

Cardiac channelopathies studied with the dynamic action potential-clamp technique.

The cardiac long QT syndrome (LQTS) is characterized by a delayed repolarization of the ventricular myocytes, resulting in prolongation of the QT interval on the electrocardiogram and increased propensity to cardiac arrhythmias. Congenital LQTS has been linked to mutations in genes encoding ion channel subunits. For a better understanding of LQTS and associated arrhythmias, insight into the nature of ion channel (dys)function is indispensable. Conventionally, voltage-clamp analysis and subsequent mathematical modeling are used to study cardiac channelopathies and to link a certain genetic defect to its cellular phenotype. The recently introduced "dynamic action potential clamp" (dAPC) technique represents an alternative approach, in which a selected native ionic current of the ventricular myocyte can effectively be replaced with wild-type (WT) or mutant current recorded from a human embryonic kidney (HEK)-293 cell that is voltage clamped by the free-running action potential (AP) of the myocyte. Both a computed model of the human ventricular cell and a freshly isolated myocyte can effectively be used in dAPC experiments, resulting in rapid and unambiguous determination of the effect(s) of an ion channel mutation on the ventricular AP. The dAPC technique represents a promising new tool to study various cardiac ion channels and may also prove useful in related fields of research, for example, in neurophysiology.

Incorporated sarcolemmal fish oil fatty acids shorten pig ventricular action potentials.

BACKGROUND: Omega-3 polyunsaturated fatty acids (omega3-PUFAs) from fish oil reduce the risk of sudden death presumably by preventing life-threatening arrhythmias. Acutely administered omega3-PUFAs modulate the activity of several cardiac ion channels, but the chronic effects of a diet enriched with fish oil leading to omega3-PUFA-incorporation into the sarcolemma on membrane currents are unknown. METHODS: Pigs received a diet either rich in omega3-PUFAs or in omega9-fatty acids for 8 weeks. Ventricular myocytes (VMs) were isolated and used for patch-clamp studies. RESULTS: omega3-VMs contained higher amounts of omega3-PUFAs and had a shorter action potential (AP) with a more negative plateau than control VM. In omega3 VMs, L-type Ca(2+) current (I(Ca,L)) and Na(+)-Ca(2+) exchange current (I(NCX)) were reduced by approximately 20% and 60%, respectively, and inward rectifier K(+) current (I(K1)) and slow delayed rectifier K(+) current (I(Ks)) were increased by approximately 50% and 70%, respectively, compared to control. Densities of rapid delayed rectifier K(+) current, Ca(2+)-activated Cl(-) current, and Na(+) current (I(Na)) were unchanged, although voltage-dependence of I(Na) inactivation was more negative in omega3 VMs. CONCLUSIONS: A fish oil diet increases omega3-PUFA content in the ventricular sarcolemma, decreases I(Ca,L) and I(NCX), and increases I(K1) and I(Ks), resulting in AP shortening. Incorporation of omega3-PUFAs in the sarcolemma may have consequences for arrhythmias independent of circulating omega3-PUFAs.

Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts.

PURPOSE: Recent studies demonstrate that addition of neoadjuvant (NA) carboplatin to anthracycline/taxane chemotherapy improves pathologic complete response (pCR) in triple-negative breast cancer (TNBC). Effectiveness of anthracycline-free platinum combinations in TNBC is not well known. Here, we report efficacy of NA carboplatin + docetaxel (CbD) in TNBC. EXPERIMENTAL DESIGN: The study population includes 190 patients with stage I-III TNBC treated uniformly on two independent prospective cohorts. All patients were prescribed NA chemotherapy regimen of carboplatin (AUC 6) + docetaxel (75 mg/m2) given every 21 days × 6 cycles. pCR (no evidence of invasive tumor in the breast and axilla) and residual cancer burden (RCB) were evaluated. RESULTS: Among 190 patients, median tumor size was 35 mm, 52% were lymph node positive, and 16% had germline BRCA1/2 mutation. The overall pCR and RCB 0 + 1 rates were 55% and 68%, respectively. pCRs in patients with BRCA-associated and wild-type TNBC were 59% and 56%, respectively (P = 0.83). On multivariable analysis, stage III disease was the only factor associated with a lower likelihood of achieving a pCR. Twenty-one percent and 7% of patients, respectively, experienced at least one grade 3 or 4 adverse event. CONCLUSIONS: The CbD regimen was well tolerated and yielded high pCR rates in both BRCA-associated and wild-type TNBC. These results are comparable with pCR achieved with the addition of carboplatin to anthracycline-taxane chemotherapy. Our study adds to the existing data on the efficacy of platinum agents in TNBC and supports further exploration of the CbD regimen in randomized studies. Clin Cancer Res; 23(3); 649-57. ©2016 AACR.

Leukocyte infiltration and mRNA expression of IL-20, IL-8 and TNF-R P60 in psoriatic skin is driven by TNF-alpha.

Anti-TNF-alpha therapy with a chimeric monoclonal antibody (Infliximab, Remicade) has been shown to be highly effective in the treatment of skin lesions as well as arthritis in patients with psoriatic arthritis. In this study we investigated the molecular consequences of the in vivo TNF-alpha blockade with infliximab in psoriatic skin lesions of 6 patients with severe psoriatic arthritis. Biopsies from lesional and non-lesional skin were taken before and 10 weeks after the initiation of treatment. Immunohistochemistry and semiquantative RT-PCR were performed focusing on proinflammatory gene products. Immunohistochemistry, after three infusions, revealed a marked decrease in the expression of TNF-alpha, HLA-DR, CD3, CD15, ICAM-1 and LFA-1 positive cells. By semiquantitative RT-PCR, we analysed mRNA expression of IL-8, IL-20, TNF-R (TNF-R p60 and TNF-R p80), IL-1R I and IL-1R II, as well as ICAM-2. Before therapy, m-RNA for IL-8, IL-20, TNF-R p60, TNF-R p80, IL-1R II and ICAM-2 were detected in lesional skin. mRNA expression of IL-8 and IL-20 completely disappeared and mRNA expression of TNF-R p60 was reduced after therapy. This effect on IL-8 expression was paralleled by a decreased infiltration of leukocytes in psoriatic skin. These data suggest that the clinical response of anti-TNF-alpha therapy in patients with psoriasis or psoriatic arthritis may be, at least in part, caused by the inhibition of the production of proinflammatory cytokines and by the decreased expression of adhesion molecules with the consequence of an impaired migration of proinflammatory cells into the inflamed tissue. These data further support a critical role for TNF-alpha in the pathology of psoriasis.