The mammalian liver possesses a remarkable regenerative ability. Two modes of damage response have been described: (1) The “oval cell” response emanates from the biliary tree when all hepatocytes are ...affected by chronic liver disease. (2) A massive, proliferative response of mature hepatocytes occurs upon acute liver damage such as partial hepatectomy (PHx). While the oval cell response has been captured in vitro by growing organoids from cholangiocytes, the hepatocyte proliferative response has not been recapitulated in culture. Here, we describe the establishment of a long-term 3D organoid culture system for mouse and human primary hepatocytes. Organoids can be established from single hepatocytes and grown for multiple months, while retaining key morphological, functional and gene expression features. Transcriptional profiles of the organoids resemble those of proliferating hepatocytes after PHx. Human hepatocyte organoids proliferate extensively after engraftment into mice and thus recapitulate the proliferative damage-response of hepatocytes.
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•Human and mouse hepatocytes can be grown long-term as organoids•Hepatocyte organoids consist of progenitors and differentiated hepatocytes•Murine hepatocyte organoids reflect regeneration after partial hepatectomy•Organoids from primary human hepatocytes engraft into damaged mouse liver
Modeling the regenerative ability of the liver in response to acute damage using long-term 3D organoid cultures in mice and human cells yields proliferative hepatocytes that are able to successfully engraft in animal models.
Human papillomavirus (HPV) infection has been etiologically linked to oropharyngeal squamous cell carcinoma (OPSCC). The prevalence of HPV‐positive OPSCC varies between studies, ranging from 20 to ...90%. This may be related to the lack of a standardized HPV detection assay as well as to the time period in which HPV prevalence is investigated, as rising incidence rates are reported over the last decades. Here, we validated our previously defined test algorithm for HPV detection in formalin‐fixed paraffin‐embedded (FFPE) tumor specimen consisting of p16INK4A immunostaining followed by high‐risk HPV DNA detection by GP5+/6+ PCR on the positive cases (Smeets et al., Int J Cancer 2007;121:2465–72). In addition, we analyzed HPV prevalence rates in OPSCCs in the years 1990–2010. The test algorithm was validated on a consecutive series of 86 OPSCCs collected during 2008–2011, of which both fresh frozen and FFPE samples were available. We performed HPV‐E6 RT‐PCR on the frozen samples as gold standard and applied the algorithm to the corresponding FFPE samples. The test algorithm showed an accuracy of 98%. Using the validated algorithm, we determined the presence of an oncogenic HPV infection in 240 OPSCCs of patients diagnosed in the years 1990–2010 at our center. A significant increase in the proportion of HPV‐positive samples was observed, from 5.1% in 1990 to 29.0% in 2010 (p = 0.001). In conclusion, we confirmed the accuracy of the test algorithm for HPV detection in FFPE tumor specimen and we found a significant increase in the prevalence of HPV in OPSCC over the last two decades at our center.
What's new?
We validated our previously defined test algorithm for human papillomavirus (HPV) detection in formalin‐fixed paraffin‐embedded tumor specimen. The test algorithm showed an accuracy of 98%, and using this validated algorithm we found a significant increase in the proportion of HPV‐positive oropharyngeal squamous cell carcinomas (OPSCCs) from 5.1% in 1990 to 29.0 % in 2010. A reliable HPV detection assay is urgently awaited and the rapidly rising proportion of HPV‐induced OPSCC in the Netherlands is worrying
Sex and disgust are basic, evolutionary relevant functions that are often construed as paradoxical. In general the stimuli involved in sexual encounters are, at least out of context strongly ...perceived to hold high disgust qualities. Saliva, sweat, semen and body odours are among the strongest disgust elicitors. This results in the intriguing question of how people succeed in having pleasurable sex at all. One possible explanation could be that sexual engagement temporarily reduces the disgust eliciting properties of particular stimuli or that sexual engagement might weaken the hesitation to actually approach these stimuli.
Participants were healthy women (n = 90) randomly allocated to one of three groups: the sexual arousal, the non-sexual positive arousal, or the neutral control group. Film clips were used to elicit the relevant mood state. Participants engaged in 16 behavioural tasks, involving sex related (e.g., lubricate the vibrator) and non-sex related (e.g., take a sip of juice with a large insect in the cup) stimuli, to measure the impact of sexual arousal on feelings of disgust and actual avoidance behaviour.
The sexual arousal group rated the sex related stimuli as less disgusting compared to the other groups. A similar tendency was evident for the non-sex disgusting stimuli. For both the sex and non-sex related behavioural tasks the sexual arousal group showed less avoidance behaviour (i.e., they conducted the highest percentage of tasks compared to the other groups).
This study has investigated how sexual arousal interplays with disgust and disgust eliciting properties in women, and has demonstrated that this relationship goes beyond subjective report by affecting the actual approach to disgusting stimuli. Hence, this could explain how we still manage to engage in pleasurable sexual activity. Moreover, these findings suggest that low sexual arousal might be a key feature in the maintenance of particular sexual dysfunctions.
ABSTRACT
Psychological treatment for social anxiety disorder (SAD) has been found to be less effective than for other anxiety disorders. Targeting the vivid and distressing negative mental images ...typically experienced by individuals with social anxiety could possibly enhance treatment effectiveness. To provide both clinicians and researchers with an overview of current applications, this systematic review and meta‐analysis aimed to evaluate the possibilities and effects of imagery‐based interventions that explicitly target negative images in (sub)clinical social anxiety. Based on a prespecified literature search, we included 21 studies, of which 12 studies included individuals with a clinical diagnosis of SAD. Imagery interventions (k = 28 intervention groups; only in adults) generally lasted one or two sessions and mostly used imagery rescripting with negative memories. Others used eye movement desensitization and reprocessing and imagery exposure with diverse intrusive images. Noncontrolled effects on social anxiety, imagery distress and imagery vividness were mostly large or medium. Meta‐analyses with studies with control groups resulted in significant medium controlled effects on social anxiety (d = −0.50, k = 10) and imagery distress (d = −0.64, k = 8) and a nonsignificant effect on imagery vividness. Significant controlled effects were most evident in individuals with clinically diagnosed versus subclinical social anxiety. Overall, findings suggest promising effects of sessions targeting negative mental images. Limitations of the included studies and the analyses need to be considered. Future research should examine the addition to current SAD treatments and determine the relevance of specific imagery interventions. Studies involving children and adolescents are warranted.
There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA ...methylation biomarkers for blood-based detection of colorectal cancer.
We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection.
Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
Recent studies have reported that p16 protein overexpression qualifies as a surrogate marker identifying an oncogenic human papillomavirus (HPV) infection in oropharyngeal squamous cell carcinoma ...(OPSCC). However, there is still a percentage of OPSCCs that are positive for p16 immunohistochemistry (p16 IHC) but lack HPV DNA. The objective of this study was to characterize this group at the molecular level by performing sensitive HPV DNA‐ and RNA‐based PCR methods and genetic profiling. All patients diagnosed with an OPSCC in the period 2000–2006 in two Dutch university medical centers were included (n = 841). The presence of HPV in a tumor sample was tested by p16 IHC followed by an HPV DNA GP5+/6+ PCR. p16 IHC scored positive in 195 samples, of which 161 were HPV DNA‐positive and 34 (17%) HPV DNA‐negative. In the latter group, a SPF10‐LiPA25 assay, an HPV16 type‐specific E7 PCR and an E6 mRNA RT‐PCR were performed. Next, ten of these cases were further analyzed for loss of heterozygosity (LOH) of 15 microsatellite markers at chromosome arms 3p, 9p and 17p. Of the 34 p16‐positive but PCR‐negative OPSCCs, two samples tested positive by SPF10 assay, HPV16 E7 PCR and HPV16 E6 mRNA RT‐PCR. Three samples tested positive by SPF10 assay but negative by the HPV16‐specific assays. Nine of ten cases that were tested for LOH showed a genetic pattern comparable to that of HPV‐negative tumors. This study categorizes p16‐positive but HPV DNA‐negative OPSCCs as HPV‐negative tumors based on genetic profiling. This study highlights the importance of performing HPV testing in addition to p16 IHC for proper identification of HPV‐associated OPSCCs.
What's new?
Besides tobacco and alcohol consumption, high‐risk human papillomavirus (HPV) infection is etiologically linked to the development of oropharyngeal squamous cell carcinoma (OPSCC). Knowledge of HPV‐status provides prognostic information and may guide treatment decisions. Recent studies have reported that p16‐protein overexpression qualifies as a surrogate marker for oncogenic HPV infection in OPSCC. However, there is still a percentage of OPSCCs that are positive for p16‐immunohistochemistry (p16‐IHC) but lack HPV DNA. This study categorizes p16‐positive but HPV DNA‐negative OPSCCs as HPV‐negative tumors based on genetic profiling, highlighting the importance of HPV testing in addition to p16‐IHC for proper identification of HPV‐associated OPSCCs.
The generation or persistence of sexual arousal may be compromised when inhibitory processes such as negative emotions, outweigh sexual excitation. Disgust particularly, has been proposed as one of ...the emotions that may counteract sexual arousal. In support of this view, previous research has shown that disgust priming can reduce subsequent sexual arousal. As a crucial next step, this experimental study tested whether disgust (by means of odor) can also diminish sexual arousal in individuals who are already in a state of heightened sexual excitation.
In this study, participants were all men (N = 78). To elicit sexual arousal, participants watched a pornographic video. Following 4.30 minutes from the start of the video clip, they were exposed to either a highly aversive/disgusting odor (n = 42), or an odorless diluent/solvent (n = 36), that was delivered via an olfactometer, while the pornographic video continued. In both conditions the presentation of the odor lasted 1 second and was repeated 11 times with intervals of 26 seconds. Sexual arousal was indexed by both self-reports and penile circumference.
The disgusting odor (released when the participants were already sexually aroused) resulted in a significant decrease of both subjective and genital sexual arousal compared to the control (odorless) condition.
The finding that the inhibitory effect of disgust was not only expressed in self-report but also expressed on the penile response further strengthens the idea that disgust might hamper behavioral actions motivated by sexual arousal (e.g., poor judgment, coercive sexual behavior). Thus, the current findings indicate that exposure to an aversive odor is sufficiently potent to reduce already present (subjective and) genital sexual arousal. This finding may also have practical relevance for disgust to be used as a tool for self-defence (e.g., Invi Bracelet).
Summary Background Hypertension is the most prevalent comorbidity in individuals with chronic kidney disease. However, whether the association of the kidney disease measures, estimated glomerular ...filtration rate (eGFR) and albuminuria, with mortality or end-stage renal disease (ESRD) differs by hypertensive status is unknown. Methods We did a meta-analysis of studies selected according to Chronic Kidney Disease Prognosis Consortium criteria. Data transfer and analyses were done between March, 2011, and June, 2012. We used Cox proportional hazards models to estimate the hazard ratios (HR) of mortality and ESRD associated with eGFR and albuminuria in individuals with and without hypertension. Findings We analysed data for 45 cohorts (25 general population, seven high-risk, and 13 chronic kidney disease) with 1 127 656 participants, 364 344 of whom had hypertension. Low eGFR and high albuminuria were associated with mortality irrespective of hypertensive status in the general population and high-risk cohorts. All-cause mortality risk was 1·1–1·2 times higher in individuals with hypertension than in those without hypertension at preserved eGFR. A steeper relative risk gradient in individuals without hypertension than in those with hypertension at eGFR range 45–75 mL/min per 1·73 m2 led to much the same mortality risk at lower eGFR. With a reference eGFR of 95 mL/min per 1·73 m2 in each group to explicitly assess interaction, adjusted HR for all-cause mortality at eGFR 45 mL/min per 1·73 m2 was 1·77 (95% CI 1·57–1·99) in individuals without hypertension versus 1·24 (1·11–1·39) in those with hypertension (p for overall interaction=0·0003). Similarly, for albumin-creatinine ratio of 300 mg/g ( vs 5 mg/g), HR was 2·30 (1·98–2·68) in individuals without hypertension versus 2·08 (1·84–2·35) in those with hypertension (p for overall interaction=0·019). We recorded much the same results for cardiovascular mortality. The associations of eGFR and albuminuria with ESRD, however, did not differ by hypertensive status. Results for chronic kidney disease cohorts were similar to those for general and high-risk population cohorts. Interpretation Chronic kidney disease should be regarded as at least an equally relevant risk factor for mortality and ESRD in individuals without hypertension as it is in those with hypertension. Funding US National Kidney Foundation.
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