The xenobiotic transporter ABCC4/MRP4 promotes epithelial mesenchymal transition in pancreatic cancer.

The xenobiotic transporter ABCC4/MRP4 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and correlates with a more aggressive phenotype and metastatic propensity. Here, we show that ABCC4 promotes epithelial-mesenchymal transition (EMT) in PDAC, a hallmark process involving the acquisition of mesenchymal traits by epithelial cells, enhanced cell motility, and chemoresistance. Modulation of ABCC4 levels in PANC-1 and BxPC-3 cell lines resulted in the dysregulation of genes present in the EMT signature. Bioinformatic analysis on several cohorts including tumor samples, primary patient-derived cultured cells, patient-derived xenografts, and cell lines, revealed a positive correlation between ABCC4 expression and EMT markers. We also characterized the ABCC4 cistrome and identified four candidate clusters in the distal promoter and intron one that showed differential binding of pro-epithelial FOXA1 and pro-mesenchymal GATA2 transcription factors in low ABCC4-expressing HPAF-II and high ABCC4-expressing PANC-1 xenografts. HPAF-II xenografts showed exclusive binding of FOXA1, and PANC-1 xenografts exclusive binding of GATA2, at ABCC4 clusters, consistent with their low and high EMT phenotype respectively. Our results underscore ABCC4/MRP4 as a valuable prognostic marker and a potential therapeutic target to treat PDAC subtypes with prominent EMT features, such as the basal-like/squamous subtype, characterized by worse prognosis and no effective therapies.

Multidrug transporter MRP4/ABCC4 as a key determinant of pancreatic cancer aggressiveness.

Recent findings show that MRP4 is critical for pancreatic ductal adenocarcinoma (PDAC) cell proliferation. Nevertheless, the significance of MRP4 protein levels and function in PDAC progression is still unclear. The aim of this study was to determine the role of MRP4 in PDAC tumor aggressiveness. Bioinformatic studies revealed that PDAC samples show higher MRP4 transcript levels compared to normal adjacent pancreatic tissue and circulating tumor cells express higher levels of MRP4 than primary tumors. Also, high levels of MRP4 are typical of high-grade PDAC cell lines and associate with an epithelial-mesenchymal phenotype. Moreover, PDAC patients with high levels of MRP4 depict dysregulation of pathways associated with migration, chemotaxis and cell adhesion. Silencing MRP4 in PANC1 cells reduced tumorigenicity and tumor growth and impaired cell migration. Transcriptomic analysis revealed that MRP4 silencing alters PANC1 gene expression, mainly dysregulating pathways related to cell-to-cell interactions and focal adhesion. Contrarily, MRP4 overexpression significantly increased BxPC-3 growth rate, produced a switch in the expression of EMT markers, and enhanced experimental metastatic incidence. Altogether, our results indicate that MRP4 is associated with a more aggressive phenotype in PDAC, boosting pancreatic tumorigenesis and metastatic capacity, which could finally determine a fast tumor progression in PDAC patients.

Immune status and the efficacy of adjuvant radiotherapy for patients with localized Merkel cell carcinoma of the head and neck.

PURPOSE: Immunosuppressed (IS) patients are at increased risk for developing Merkel cell carcinoma (MCC) with worsened outcomes compared to immunocompetent (IC) patients. We sought to determine the effects of immune status on the efficacy of adjuvant RT regarding OS for patients with stage I, II or III (localized) MCC of the head and neck. METHODS/PATIENTS: The National Cancer Database was queried for patients with resected, localized MCC of the head and neck with known immune status. Kaplan-Meier methods were used to describe OS. Log-rank tests, multivariable Cox regression models and interaction effect testing were used to compare OS by subgroup categorized by patient and treatment factors including immune status and adjuvant RT receipt. RESULTS: A total of 892 (89.6%) IC and 104 (10.4%) IS patients with MCC of the head and neck were included. Adjuvant RT was associated with improved 3-year OS rate for both IS patients (49.4% vs. 35.5%, p = 0.0467) and stage I/II IC patients (72.4% vs. 62.9%, p = 0.0092). Adjuvant RT was associated with decreased hazard of death (HR 0.77, 95% CI 0.62-0.95). Interaction effect testing did not demonstrate a difference in the efficacy of adjuvant RT on OS between IC and IS status (p = 0.157). CONCLUSIONS: In this NCDB analysis, adjuvant RT was associated with decreased hazard of death for patients with localized MCC of the head and neck regardless of immune status and should be considered for both IS and IC patients.

Distribution of Rhipicephalus (Boophilus) microplus and Rhipicephalus (Boophilus) annulatus (Acari: Ixodidae) infestations detected in the United States along the Texas/Mexico border.

Species identification and global positioning system coordinates of infestations of cattle fever ticks, Rhipicephalus (Boophilus) annulatus (Say) and Rhipicephalus (Boophilus) microplus (Canestrini), were determined for 790 specimens submitted to the National Veterinary Services Laboratory between 1 October 1999 and 30 September 2010. Cattle fever tick specimens obtained by personnel of the United States Department of Agriculture-Animal and Plant Health Inspection Service-Cattle Fever Tick Eradication Program from infested cattle and wildlife along the Texas/ Mexico border were submitted for identification, as required by the program. A geographic information system database was developed that incorporates location, collection, and infestation records. Submitted ticks came from 11 Texas counties and were comprised of 19.5% R. (B.) annulatus and 80.5% R. (B.) microplus. Maps produced from this study locate and define the parapatric boundary between R. (B.) annulatus and R. (B.) microplus.

Primary prevention of cardiovascular disease: a web-based risk score for seven British black and minority ethnic groups.

OBJECTIVE: To recalibrate an existing Framingham risk score to produce a web-based tool for estimating the 10-year risk of coronary heart disease (CHD) and cardiovascular disease (CVD) in seven British black and minority ethnic groups. DESIGN: Risk prediction models were recalibrated against survey data on ethnic group risk factors and disease prevalence compared with the general population. Ethnic- and sex-specific 10-year risks of CHD and CVD, at the means of the risk factors for each ethnic group, were calculated from the product of the incidence rate in the general population and the prevalence ratios for each ethnic group. SETTING: Two community-based surveys. PARTICIPANTS: 3778 men and 4544 women, aged 35-54, from the Health Surveys for England 1998 and 1999 and the Wandsworth Heart and Stroke Study. MAIN OUTCOME MEASURES: 10-year risk of CHD and CVD. RESULTS: 10-year risk of CHD and CVD for non-smoking people aged 50 years with a systolic blood pressure of 130 mm Hg and a total cholesterol to high density lipoprotein cholesterol ratio of 4.2 was highest in men for those of Pakistani and Bangladeshi origin (CVD risk 12.6% and 12.8%, respectively). CHD risk in men with the same risk factor values was lowest in Caribbeans (2.8%) and CVD risk was lowest in Chinese (5.4%). Women of Pakistani origin were at highest risk and Chinese women at lowest risk for both outcomes with CVD risks of 6.6% and 1.2%, respectively. A web-based risk calculator (ETHRISK) allows 10-year risks to be estimated in routine primary care settings for relevant risk factor and ethnic group combinations. CONCLUSIONS: In the absence of cohort studies in the UK that include significant numbers of black and minority ethnic groups, this risk score provides a pragmatic solution to including people from diverse ethnic backgrounds in the primary prevention of CVD.

Environmental health training of promotoras in colonias along the Texas-Mexico border.

Poverty, overpopulation, and a lack of environmental controls have combined with cultural and linguistic division to produce a looming public health threat in unincorporated communities on the US-Mexico border. These rapidly multiplying colonias, from a Spanish term for neighborhoods, are settlements of varying size located along the border. Along the American side of the Texas-Mexico border alone, there are approximately 1800 colonias--the largest number of any border state--most of which lack basic water and sewer systems, paved roads, and safe and sanitary housing. Promotoras, from a Spanish term for lay community educators, are community leaders who live in the colonias and build important bridges between residents and the federal and state bureaucracies. These women have been trained to introduce their neighbors to state "systems" of government, education, and medical and social services that otherwise may lie out of reach. Promotoras are able to "translate" this training into culturally meaningful instruction that empowers community self-development. When neighbors teach neighbors, the message is received with greater trust and readiness to act.

Endoscopic sinus surgery: 4-year follow-up on the first 100 patients.

Endoscopic sinus surgery has been reported to be successful, but lack of a standardized classification system hampers comparison of results between studies, and long-term results of surgery have not been reported in a series of consecutive patients. The results of our first 100 endoscopic sinus surgery procedures, reported previously after an average 9-month follow-up, were reviewed with the application of a new classification scheme and in light of a longer (4-year) follow-up. Surgery was successful in all patients whose sinus symptoms resulted from anatomical variations or suppurative infection, but failed in some patients with hyperplastic disease or polyps. In addition, the presence of reactive airway disease or the acetylsalicylic acid (ASA) triad was a bad prognostic sign. The overall success of the procedure in relieving sinus symptoms decreased from 98% at early follow-up to 91% at 4-year follow-up. Sixty-six percent were successful after one procedure and 25% required more than one procedure to achieve success. The decline in success since our first report in 1990 was mostly attributable to late failure in patients with recurrent symptomatic polyposis. Because symptoms may not recur in these patients for up to 3 years, long-term results of surgery for this disorder are necessary. Symptoms of recurrent polyposis can be controlled medically or by revision surgery.

Characterization of particles, ammonia and endotoxin in swine confinement operations.

To define the atmospheres swine confinement operations, we measured concentrations of total and respirable dust particles, ammonia and endotoxin in the nursery and grower areas of 4 swine confinement houses. Increased ventilation in spring-summer relative to that in winter reduced concentrations of large dust particles more rapidly than it did smaller particles or ammonia. The greater decrease in large particles correlating to increased room air velocity may reflect larger particles' momentum causing impaction on surfaces. There was significant spatial variation in the concentration of airborne endotoxin within individual swine rooms and pens reflecting different mixing of large feed and smaller manure particles. Smaller particles had 4-fold higher concentrations of endotoxin than did larger particles, suggesting they had higher fecal material concentrations. Total airborne endotoxin and total suspended particulates correlated to the fraction of functional endotoxin contained in large particles, suggesting that small particles (0.5-2.0 micrometers) collide with large particles (50 micrometers). These data suggest that large non-respirable particles remove smaller respirable particles from indoor atmospheres due to kinematic coagulation.

Temporalis muscle for facial reanimation. A 13-year experience with 224 procedures.

A procedure for temporalis muscle transposition was used to reanimate the paralyzed face in 219 patients. In most cases, facial paralysis had followed an operation to remove an acoustic tumor. Analysis of the results showed this procedure to be highly successful and the method of choice, alone in cases of long-standing facial paralysis or to augment the effects of facial nerve grafting or hypoglossal-facial nerve anastomosis, in reanimating the mouth. It was successful in restoring a smile to 80% of the 219 patients and provided overall improvement in mouth function in 96%. Complications occurred in 21% of patients, with the most common being infection (12% of patients). Since one of us began to use the procedure to reanimate the eye and mouth, results of temporalis muscle transposition have been improved by the following: (1) using the procedure to reanimate the mouth only; (2) performing revision surgery, most often tightening the corner of the mouth (25% of patients), as indicated; (3) transposing only the midsection of the muscle; (4) implanting a prefabricated Silastic prosthesis to fill the muscle defect; (5) when indicated, lengthening the muscle with polytef (Gore-Tex+); and (6) placing the muscle in a tunnel lateral to the superficial musculoaponeurotic system to avoid injuring the underlying facial nerve should some spontaneous recovery of facial nerve function be possible.

Hypoglossal-facial nerve interpositional-jump graft for facial reanimation without tongue atrophy.

The hemitongue paralysis that occurs as a result of a classic hypoglossal-facial nerve crossover procedure can result in profound functional deficits in speech, mastication, and swallowing. The procedure is not an option in patients with bilateral facial paralysis or those at risk for combined cranial nerve deficits. To address some of the drawbacks and limitations of this classic procedure, we developed the hypoglossal-facial nerve interpositional jump graft (12-7 jump graft) procedure. This procedure involves interposing a nerve graft between a partially severed but functionally intact twelfth cranial nerve and the degenerated seventh cranial nerve, and is often combined with other reanimation procedures. To date, we have performed 33 12-7 jump graft procedures in 30 patients (three were treated for bilateral facial paralysis); this report describes the procedure and its indications, and details the results of 23 procedures performed in 20 patients for whom 24-month follow-up data are available. Twelfth nerve deficits occurred in only three patients in this report. Recovery of facial function began between 3 and 24 months postoperatively. Facial tone and symmetry were achieved in every patient, no patient had significant mass movement, and 13 patients (two of whom were treated for bilateral facial paralysis) had excellent and three had superb restoration of facial movement. These results show the 12-7 jump graft to be a valuable adjunct for facial reanimation in selected patients.

The location of the maxillary os and its importance to the endoscopic sinus surgeon.

As functional endoscopic sinus surgery continues to gain popularity and support, the necessity for a clear and accurate understanding of the anatomy of the ostiomeatal complex becomes essential. To clarify this anatomy, serial cadaver dissections were performed and the anatomy of the ostiomeatal complex was detailed in three dimensions, with an emphasis on precise localization of the internal os of the maxillary sinus as it relates to the orbit, natural antronasal canal, and ethmoid infundibulum. Measurements of the position of the internal os relative to the position of the anterior and posterior walls of the maxillary sinus and the position of the orbit were taken. The dimensions and configuration of the antronasal canal and its relationship to the infundibulum were also detailed. These measurements and relationships must be understood for an endoscopic sinus surgeon to locate the natural ostia without injuring the orbit.

Managing segmental facial nerve injuries by surgical repair.

This report describes our experiences and evolving philosophy with regard to managing segmental facial nerve injuries. We present the results of 13 facial nerve repairs of traumatic injury to a segment of the facial nerve. All peripheral facial nerve branches contribute essential elements to normal mimetic facial movement; therefore, we recommend early, appropriate repair of the nerve segment. This recommendation is based on principles established for managing disruptions of the main trunk of the facial nerve. It offers the patient the chance for complete recovery of facial function.

Management of the paralyzed lower eyelid by implanting auricular cartilage.

The success of a procedure to reanimate paralyzed eyelids is determined by the functional and cosmetic results. When the cornea is covered during blinking and sleeping, function has been restored, while a pleasing cosmetic result has been achieved if the eyes appear symmetrical when the lids are open. Several procedures have been developed to restore closure of the paralyzed upper eyelid (implantation of gold weights or open wire springs) or to correct lower lid lagophthalmos and ectropion (lower lid tightening with a Bick procedure or insertion of a closed eyelid spring). In some cases, even a combination of the Bick procedure and insertion of a spring may be insufficient to correct lower lid droop; therefore, we developed a technique to place cartilage into the lower eyelid to correct lid droop. The procedure, suggested by one of us (D.B.S.), has been performed on 51 patients to date. This article reviews our experience with these 51 consecutive patients.

A comparative study of virus isolation, polymerase chain reaction, and antigen detection in children of mothers infected with human immunodeficiency virus.

We report on an investigation designed to compare the polymerase chain reaction (PCR) with culture and p24 measurement for the diagnosis of human immunodeficiency virus (HIV) infection in infants and children. Forty-five children born of mothers with antibodies to HIV type 1 were studied; P24 antigen was measured in plasma, and HIV-1 proviral DNA was sought in peripheral blood mononuclear cells after amplification by PCR. In 26 cases, blood specimens were cultured for HIV; in all but two instances cultures were established at the same time that the PCR test was performed. Primer pairs in three regions of the proviral genome were used for the PCR test. There was good agreement between the results obtained from PCR tests and from cultures; of 24 children in whom both tests were done at the same time, 10 had positive results on both the culture and the PCR test, 1 had positive results on the PCR test but negative culture results, and 13 had negative results on both tests (concordance 96%). Measurement of p24 antigen in plasma was, in contrast, an insensitive marker of infection: 6 of 12 infants with positive cultures had positive p24 test results, and 8 of 18 infants had positive PCR test results. Sixteen children with subsequent seronegativity for HIV-1 had negative PCR results. This study provides further evidence that the PCR test is a valid alternative to viral culture for the diagnosis of pediatric HIV infection.

Bell's palsy: management of sequelae using EMG rehabilitation, botulinum toxin, and surgery.

Fifteen percent of patients who have had an acute episode of Bell's palsy will be left with debilitating facial dysfunction. This chapter describes our approach to managing a variety of hypo- and hyperkinetic disorders caused by injury and faulty regeneration of the facial nerve, using electromyographic rehabilitation (EMGR) (13 patients), Oculinum toxin injection (14 patients), or surgical reanimation (72 patients). Improvement was noted after EMGR in 12 of 13 patients (92%), all 14 patients treated with Oculinum experienced temporary improvement, and improvement was noted in 66 of 72 patients who underwent surgery (92%). The indications, techniques, and results of these three rehabilitative methods are discussed.

Management of facial spasm with Clostridium botulinum toxin, type A (Oculinum)

One hundred five patients received 391 graded injections of Clostridium botulinum type A toxin (Oculinum) to treat uncontrollable facial muscle spasm. Patients had essential blepharospasm (n = 61), hemifacial spasm (n = 24), or aberrant regeneration of the seventh cranial nerve (n = 20). Muscle spasms were reduced within two days of the first injection of toxin and, in most cases, the drug effect lasted three to four months. Control of facial muscle spasm was achieved in all patients. Complications related to treatment included transient blepharoptosis (n = 7), diplopia (n = 2), and altered facial expression (n = 11). Systemic side effects were not observed. Select chemodenervation of facial muscles with graded injections of botulinum toxin is a useful adjunct to control blepharospasm, hemifacial spasm, and facial spasm due to aberrant regeneration of the facial nerve.

Paralyzed eyelids reanimated with a closed-eyelid spring.

Implantation of gold weights and open wire springs to close the eyelid have provided good corneal protection in selected patients with eyelid paralysis. These techniques, however, do not overcome lower eyelid drooping. The closed-eyelid spring technique was developed to address this problem, and, to date, the author has implanted 27 closed-eyelid springs. This technique has reestablished a voluntary blink, provided corneal protection, and effectively held the lower lid in a relatively normal position in 25 of 27 patients. This report describes patient selection, surgical technique, and results of implanting closed-eyelid springs to reanimate paralyzed eyelids.