Management of cervical intraepithelial neoplasia 2 in adolescent and young women

STUDY OBJECTIVE: To evaluate regression rates among adolescents (aged < or =21) with cervical intraepithelial neoplasia (CIN) 2 managed expectantly and to determine factors associated with disease regression. DESIGN: Cohort study using a colposcopic database of 2,996 women seen between August 1999 and November 2005. SETTING: Colposcopy clinic in urban, tertiary care medical center. PARTICIPANTS: Adolescents with CIN 2. Routine management consisted of two options: immediate treatment or repeat colposcopic evaluation in 6 months. MAIN OUTCOME MEASURES: For those managed conservatively, regression was defined either as a subsequent normal colposcopy and/or biopsy and at least 2 smears read as negative for epithelial abnormality or at least 3 consecutive negative smears if repeat colposcopy was not performed. Demographic information, including age, was assessed to determine possible associations with disease regression. RESULTS: Of the 93 adolescents, 53 (57%) elected to undergo immediate treatment with a diagnostic excisional procedure, and 40 (43%) chose management with colposcopic follow-up. Of those treated, high-grade disease (CIN 2+) was found in 40 (75%). Of the 36 young women followed conservatively (4 were lost to follow-up), regression after a median follow-up time of 378 days was documented in 14 (39%). Of the 22 adolescents not fulfilling our criteria for regression, only 3 had evidence of CIN 2 or worse during follow-up. The remaining 19 had either CIN 1 or mildly abnormal cytologic results. Kaplan-Meier survival estimates indicated younger age (< or =16 years) tended to be associated with decreased time to regression. CONCLUSION: Based on significant regression of CIN 2 among adolescent women, primary management in this population should consist of cytologic and colposcopic follow-up.     

Uterine artery Doppler in the prediction of adverse pregnancy outcome

PURPOSE OF REVIEW: To review publications, published during the past year, that have examined uterine artery Doppler findings in women with adverse pregnancy outcome. RECENT FINDINGS: Almost two-thirds of stillbirths that occur in the early preterm period (up to 32 weeks) can be predicted by uterine artery Doppler at 23 weeks. First trimester screening studies have shown that an abnormal result increases the risk of subsequent fetal growth restriction, and such women are at particularly high risk when indices remain abnormal in the second trimester. Studies combining uterine artery Doppler with maternal serum markers have demonstrated that measurement of first-trimester maternal serum pregnancy-associated plasma protein A and free beta human chorionic gonadotrophin improve sensitivities of second-trimester Doppler. As these are frequently measured in Down syndrome screening and they lend themselves in screening for pre-eclampsia. Women with abnormal first and second-trimester serum markers constitute a high-risk group. Maternal serum placental protein 13 remains a promising method for early screening, although a recent study suggests lower sensitivities than initially reported. SUMMARY: Uterine artery Doppler screening identifies women at high risk for developing adverse pregnancy outcomes. Detection rates may be increased and false positive rates reduced by combination with maternal characteristics or serum markers.     

Evidence of depot‐specific regulation of all‐trans‐retinoic acid biosynthesis in human adipose tissue

The prevalence of obesity continues to rise, underscoring the need to better understand the pathways mediating adipose tissue (AT) expansion. All‐trans‐retinoic acid (atRA), a bioactive vitamin A metabolite, regulates adipogenesis and energy metabolism, and, in rodent studies, aberrant vitamin A metabolism appears a key facet of metabolic dysregulation. The relevance of these findings to human disease is unknown, as are the specific enzymes implicated in vitamin A metabolism within human AT. We hypothesized that in human AT, family 1A aldehyde dehydrogenase (ALDH1A) enzymes contribute to atRA biosynthesis in a depot‐specific manner. To test this hypothesis, parallel samples of subcutaneous and omental AT from participants (n = 15) were collected during elective abdominal surgeries to quantify atRA biosynthesis and key atRA synthesizing enzymes. ALDH1A1 was the most abundant ALDH1A isoform in both AT depots with expression approximately twofold higher in omental than subcutaneous AT. ALDH1A2 was detected only in omental AT. Formation velocity of atRA was approximately threefold higher (p = 0.0001) in omental AT (9.8 [7.6, 11.2]) pmol/min/mg) than subcutaneous AT (3.2 [2.1, 4.0] pmol/min/mg) and correlated with ALDH1A2 expression in omental AT (β‐coefficient = 3.07, p = 0.0007) and with ALDH1A1 expression in subcutaneous AT (β‐coefficient = 0.13, p = 0.003). Despite a positive correlation between body mass index (BMI) and omental ALDH1A1 protein expression (Spearman r = 0.65, p = 0.01), BMI did not correlate with atRA formation. Our findings suggest that ALDH1A2 is the primary mediator of atRA formation in omental AT, whereas ALDH1A1 is the principal atRA‐synthesizing enzyme in subcutaneous AT. These data highlight AT depot as a critical variable for defining the roles of retinoids in human AT biology.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Rodent data suggest that dysregulated production of all‐trans‐retinoic acid (atRA), the primary bioactive metabolite of vitamin A, may contribute to body weight gain and its complications. However, the key enzymes responsible for atRA biosynthesis in human adipose tissue have not been identified, nor has the relationship between body weight and adipose tissue atRA biosynthesis been evaluated in humans.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This study sought to identify the key enzymes involved in atRA biosynthesis in human omental and subcutaneous adipose tissue. This study also quantified atRA formation velocity and explored the potential relationship between body mass index (BMI) and atRA biosynthesis in both adipose tissue depots.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study establishes that among the aldehyde dehydrogenase (ALDH) isoforms, ALDH1A1 and ALDH1A2 both contribute to atRA biosynthesis in human omental adipose tissue, whereas only ALDH1A1 contributes to atRA biosynthesis in subcutaneous adipose tissue. Both ALDH1A1 expression and atRA formation velocity are substantially higher in omental than subcutaneous adipose tissue. Omental ALDH1A1 protein expression exhibits a positive correlation with BMI, but atRA formation velocity in both omental and subcutaneous adipose tissue shows no correlation with BMI. Thus, these findings highlight discrepancies between human and rodent adipose tissue biology and, moreover, reveal depot‐specific regulation of vitamin A metabolism in human adipose tissue.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

This line of research ultimately is intended to define the roles of vitamin A metabolites in the regulation of tissue remodeling and energy partitioning in human adipose tissue. This knowledge could contribute to the delineation of mechanisms underlying progressive obesity and its complications.     

Differential Effects of Obesity,Hyperlipidaemia, Dietary Intake and Physical Inactivity on Type I versus Type IV Allergies

Background: Alongside metabolic diseases (esp. obesity), allergic disorders are becoming increasingly prevalent. Since both obesity and allergies are highly impacted by environmental determinants, with this study we assessed the potential link between metabolic implications and two distinct types of allergies. Methods: Using cross-sectional data from the German FoCus cohort, n = 385 allergy cases, either hay fever (=type I allergy, n = 183) or contact allergy (=type IV allergy, n = 202) were compared to age- and sex-matched healthy control subjects (1:1 ratio, in total n = 770) regarding their metabolic phenotype, diet, physical activity, sleep, gut microbial composition, and serum metabolite profile using suitable BMI-adjusted models. Results: Obesity and metabolic alterations were found significantly more prevalent in subjects with allergies. In fact, this relation was more pronounced in contact allergy than hay fever. Subsequent BMI-adjusted analysis reveals particular importance of co-occurring hyperlipidaemia for both allergy types. For contact allergy, we revealed a strong association to the dietary intake of poly-unsaturated fatty acids, particularly α-linolenic acid, as well as the enrichment of the corresponding metabolic pathway. For hay fever, there were no major associations to the diet but to a lower physical activity level, shorter duration of sleep, and an altered gut microbial composition. Finally, genetic predisposition for hyperlipidaemia was associated to both contact allergy and hay fever. Conclusions: Reflected by higher allergy prevalence, our findings indicate an impaired immune response in obesity and hyperlipidaemia, which is differentially regulated in type I and type IV allergies by an unfavourable lifestyle constellation and subsequent microbial and metabolic dysfunctions.     

Nucleic Acid Preservation Card Surveillance Is Effective for Monitoring Arbovirus Transmission on Crocodile Farms and Provides a One Health Benefit to Northern Australia

The Kunjin strain of West Nile virus (WNV_KUN) is a mosquito-transmitted flavivirus that can infect farmed saltwater crocodiles in Australia and cause skin lesions that devalue the hides of harvested animals. We implemented a surveillance system using honey-baited nucleic acid preservation cards to monitor WNV_KUN and another endemic flavivirus pathogen, Murray Valley encephalitis virus (MVEV), on crocodile farms in northern Australia. The traps were set between February 2018 and July 2020 on three crocodile farms in Darwin (Northern Territory) and one in Cairns (North Queensland) at fortnightly intervals with reduced trapping during the winter months. WNV_KUN RNA was detected on all three crocodile farms near Darwin, predominantly between March and May of each year. Two of the NT crocodile farms also yielded the detection of MVE viral RNA sporadically spread between April and November in 2018 and 2020. In contrast, no viral RNA was detected on crocodile farms in Cairns during the entire trapping period. The detection of WNV_KUN and MVEV transmission by FTA^TM cards on farms in the Northern Territory generally correlated with the detection of their transmission to sentinel chicken flocks in nearby localities around Darwin as part of a separate public health surveillance program. While no isolates of WNV_KUN or MVEV were obtained from mosquitoes collected on Darwin crocodile farms immediately following the FTA^TM card detections, we did isolate another flavivirus, Kokobera virus (KOKV), from Culex annulirostris mosquitoes. Our studies support the use of the FTA^TM card system as a sensitive and accurate method to monitor the transmission of WNV_KUN and other arboviruses on crocodile farms to enable the timely implementation of mosquito control measures. Our detection of MVEV transmission and isolation of KOKV from mosquitoes also warrants further investigation of their potential role in causing diseases in crocodiles and highlights a “One Health” issue concerning arbovirus transmission to crocodile farm workers. In this context, the introduction of FTA^TM cards onto crocodile farms appears to provide an additional surveillance tool to detect arbovirus transmission in the Darwin region, allowing for a more timely intervention of vector control by relevant authorities.     

Analysis of the HNF4A isoform-regulated transcriptome identifies CCL15 as a downstream target in gastric carcinogenesis

Objective:Hepatocyte nuclear factor 4α (HNF4A) has been demonstrated to be an oncogene in gastric cancer (GC). However, the roles of different HNF4A isoforms derived from the 2 different promoters (P1 and P2) and the underlying mechanisms remain obscure.Methods:The expression and prognostic values of P1- and P2-HNF4A were evaluated in The Cancer Genome Atlas (TCGA) databases and GC tissues. Then, functional assays of P1- and P2-HNF4A were conducted both in vivo and in vitro. High-throughput RNA-seq was employed to profile downstream pathways in P1- and P2-HNF4A-overexpressing GC cells. The expression and gene regulation network of the candidate target genes identified by RNA-seq were characterized based on data mining and functional assays.Results:HNF4A amplification was a key characteristic of GC in TCGA databases, especially for the intestinal type and early stage. Moreover, P1-HNF4A expression was significantly higher in tumor tissues than in adjacent non-tumor tissues (P < 0.05), but no significant differences were found in P2-HNF4A expression (P > 0.05). High P1-HNF4A expression indicated poor prognoses in GC patients (P < 0.01). Furthermore, P1-HNF4A overexpression significantly promoted SGC7901 and BGC823 cell proliferation, invasion and migration in vitro (P < 0.01). Murine xenograft experiments showed that P1-HNF4A overexpression promoted tumor growth (P < 0.05). Mechanistically, RNA-seq showed that the cytokine-cytokine receptor interactions pathway was mostly enriched in P1-HNF4A-overexpressing GC cells. Finally, chemokine (C-C motif) ligand 15 was identified as a direct target of P1-HNF4A in GC tissues.Conclusions:P1-HNF4A was the main oncogene during GC progression. The cytokine-cytokine receptor interaction pathway played a pivotal role and may be a promising therapeutic target.