Implementation of First-trimester Screening and Prevention of Preeclampsia: a Stepped Wedge Cluster-randomized Trial in Asia.

BACKGROUND: This trial aimed to assess the efficacy, acceptability and safety of a first-trimester screen-and-prevent strategy for preterm preeclampsia (PE) in Asia. METHODS: Between 1st August 2019 and 28th February 2022, this multicenter stepped wedge cluster randomized trial included maternity/diagnostic units from ten regions in Asia. The trial started with a period where all recruiting centers provided routine antenatal care without study-related intervention. At regular six-week intervals, one cluster was randomized to transit from non-intervention phase to intervention phase. In the intervention phase, women underwent first-trimester screening for preterm PE using a Bayes theorem-based triple-test. High-risk women, with adjusted risk for preterm PE ≥ 1 in 100, received low-dose aspirin from <16 weeks until 36 weeks. RESULTS: Overall, 88.04% (42,897/48,725) of women agreed to undergo first-trimester screening for preterm PE. Among those identified as high-risk in the intervention phase, 82.39% (2,919/3,543) received aspirin prophylaxis. There was no significant difference in the incidence of preterm PE between the intervention and non-intervention phases (adjusted odds ratio [aOR] 1.59; 95% confidence interval [CI] 0.91 to 2.77). However, among high-risk women in the intervention phase, aspirin prophylaxis was significantly associated with a 41% reduction in the incidence of preterm PE (aOR 0.59; 95%CI 0.37 to 0.92). Additionally, it correlated with 54%, 55% and 64% reduction in the incidence of PE with delivery at <34 weeks (aOR 0.46; 95%CI 0.23 to 0.93), spontaneous preterm birth <34 weeks (aOR 0.45; 95%CI 0.22 to 0.92) and perinatal death (aOR 0.34; 95%CI 0.12 to 0.91), respectively. There was no significant between-group difference in the incidence of aspirin-related severe adverse events. CONCLUSIONS: The implementation of the screen-and-prevent strategy for preterm PE is not associated with a significant reduction in the incidence of preterm PE. However, low-dose aspirin effectively reduces the incidence of preterm PE by 41% among high-risk women. The screen-and-prevent strategy for preterm PE is highly accepted by a diverse group of women from various ethnic backgrounds beyond the original population where the strategy was developed. These findings underpin the importance of the widespread implementation of the screen-and-prevent strategy for preterm PE on a global scale.

A critical evaluation of the external and internal maneuvers for resolution of shoulder dystocia.

In the management of shoulder dystocia, it is often recommended to start with external maneuvers, such as the McRoberts maneuver and suprapubic pressure, followed by internal maneuvers including rotation and posterior arm delivery. However, this sequence is not based on scientific evidence of its success rates, the technical simplicity, or the related complication rates. Hence, this review critically evaluates the success rate, technique, and safety of different maneuvers. Retrospective reviews showed that posterior arm delivery has consistently higher success rates (86.1%) than rotational methods (62.4%) and external maneuvers (56.0%). McRoberts maneuver was thought to be a simple method, however, its mechanism is not clear. Furthermore, McRoberts position still requires subsequent traction on the fetal neck, which presents a risk for brachial plexus injury. The 2 internal maneuvers have anatomic rationales with the aim of rotating the shoulders to the wider oblique pelvic dimension or reducing the shoulder width. The techniques are not more sophisticated and requires the accoucher to insert the correct hand (according to fetal face direction) through the more spacious sacro-posterior region and deep enough to reach the fetal chest or posterior forearm. The performance of rotation and posterior arm delivery can also be integrated and performed using the same hand. Retrospective studies may give a biased view that the internal maneuvers are riskier. First, a less severely impacted shoulder dystocia is more likely to have been managed by external maneuvers, subjecting more difficult cases to internal maneuvers. Second, neonatal injuries were not necessarily caused by the internal maneuvers that led to delivery but could have been caused by the preceding unsuccessful external maneuvers. The procedural safety is not primarily related to the nature of the maneuvers, but to how properly these maneuvers are performed. When all these maneuvers have failed, it is important to consider the reasons for failure otherwise repetition of the maneuver cycle is just a random trial and error. If the posterior axilla is just above the pelvic outlet and reachable, posterior axilla traction using either the accoucher fingers or a sling is a feasible alternative. Its mechanism is not just outward traction but also rotation of the shoulders to the wider oblique pelvic dimension. If the posterior axilla is at a higher sacral level, a sling may be formed with the assistance of a long right-angle forceps, otherwise, more invasive methods such as Zavanelli maneuver, abdominal rescue, or symphysiotomy are the last resorts.

Social network position, trust behavior, and neural activity in young adolescents.

Our social interactions take place within numerous social networks, in which our relationships with others define our position within these networks. In this study, we examined how the centrality of positions within social networks was associated with trust behavior and neural activity in 49 adolescents (Mage = 12.8 years, SDage = 0.4 years). The participants played a trust game with a cartoon animation as a partner, which showed adaptive behavior in response to the participant and was generally untrustworthy. Social network positions were obtained in secondary school classrooms where the participants and their classmates reported on who their friends were. Using social network analysis, a score was calculated that indicated the centrality of everyone's position within the friendship network. The results showed that more central social network positions were associated with higher levels of initial trust behavior, although no evidence was found for a relationship between network position and the adaptation of trust behavior. The results of the functional MRI analyses showed that the centrality of the network positions was positively associated with caudate activity when making trust decisions. Furthermore, the adolescents with more central network positions also showed stronger increases of caudate activity when the partner's return was processed compared to the adolescents with less central network positions. The current study provides initial evidence that social network positions in friendship networks relate to socio-cognitive behavior and neural activity in adolescents.

Increased interference from conflicting perspectives and gender differences: A longitudinal study during adolescence.

Adolescents need to develop adequate perspective-taking skills to successfully navigate their increasingly complex social environments. This study investigated adolescents' development of the cognitive processes of egocentric and altercentric interference that influence perspective-taking abilities. Using the Dot Perspective Task, participants' (N = 803; 50.9% female) egocentric and altercentric interference was measured during 3 consecutive years from 12 to 14 years of age. Linear mixed model analyses showed that whereas overall task performance improved over time, egocentric and altercentric interference increased over time. These results suggest that perspective taking develops at slower rates when there are conflicting perspectives than in situations with no conflict. Moreover, we found that girls showed less egocentric interference than boys. This result provides task-based evidence that supports previous findings of higher self-reported perspective taking in adolescent girls than in adolescent boys.

A Few Close Friends? Adolescent Friendships' Effect on Internalizing Symptoms Is Serially Mediated by Desire for More Friends and Social Goal Orientation.

Interpersonal connection is a fundamental human motivation, and the extent to which it is fulfilled is a strong predictor of symptoms of internalizing disorders such as social anxiety and depression, perhaps especially during the "social reorienting" period of adolescence. However, little is known about the contribution to this effect of the individual's social motivations, which are intensified during adolescence. Furthermore, social goal orientation - an individual's priorities and intentions in social interactions - is an important predictor of vulnerability to internalizing symptoms. Adolescents spend most of their waking lives in classrooms, bounded social networks with a limited pool of candidates for befriending. This study investigated whether friendships within one's class protects against internalizing symptoms in part by reducing the desire for more classmate friendships, which may tend to promote maladaptive social goals. Participants were 423 young adolescents (M age = 13.2, sd = 0.52 years; 49.4% girls). As predicted, adolescents' number of reciprocated classroom friendships had a protective effect on internalizing symptoms which was serially mediated by desire for more such friendships, and social goal orientation. However, only demonstration-avoidance goals significantly predicted internalizing symptoms. Unreciprocated friendship nominations were unexpectedly associated with stronger desire and more social anxiety symptoms. The results suggest that the effect of number of friends is mediated by the individual's thoughts and feelings about their number of friendships, such that a strong desire for more friendships promotes maladaptive goals, oriented toward social status and consequently less oriented toward the cultivation of interpersonal intimacy with the friends they already have.

The Effect of Relative Pubertal Maturation and Perceived Popularity on Symptoms of Depression and Social Anxiety in Adolescent Boys and Girls.

Research has shown that adolescents - particularly girls - who mature relatively early often experience more internalizing problems. This effect is thought to be partially driven by psychosocial mechanisms, but previous research based relative pubertal maturation on complete samples or population standards, instead of considering the adolescents' direct peer environment. In the current study the level of adolescents' pubertal development was assessed relative to their classmates in order to examine relative pubertal maturation. The effects of adolescents' relative pubertal status, and their perceived popularity, on symptoms of social anxiety and depression in adolescents were studied. All analyses were also performed for absolute pubertal maturation. Participants were 397 young adolescents (Mage = 13.06, SD = 0.36, 49.9% girls) at timepoint 1, and 307 (Mage = 14.08, SD = 0.36, 50.5% girls) at timepoint 2. A significant positive relationship was found between relative pubertal timing and symptoms of depression for girls but not boys. Social anxiety symptoms were not significantly related to relative pubertal timing in either sex. Relative pubertal maturation had no effect on change in or persistence of depressive and social anxiety symptoms one year later. The effects of the comparison with the immediate peer environment, did not seem to explain more variance in internalizing symptoms than the effects of early maturation.

Development of the neural correlates of self- and other-referential processing across adolescence.

During adolescence, major changes in brain mechanisms take place and differentiated representations of both the self and of others are developed. Although studies have investigated the neural mechanisms of self- and other-referential processing in adolescents, the development of these mechanisms remain largely unaddressed. Here, we report a three-year longitudinal study with annual measurements, and investigate the developmental trajectories of activity and connectivity underlying self- and other-referential processes in 34 participants from early to mid-adolescence (mean age timepoints 1, 2, 3 = 12.9, 13.9, 15.0 years). Moreover, we probe whether these correlates continue to develop from mid-adolescence to young adulthood by comparing neural correlates of the adolescents at the last measurement to an independent group of 42 young adults (mean age 22 years). Participants underwent functional MRI while performing a trait judgement task in which they indicated whether an adjective described themselves, a similar or a dissimilar peer. Brain activity within the dorsal medial prefrontal cortex (dMPFC) and right temporal parietal junction (TPJ) showed a quadratic change from early to mid-adolescence, with a peak in activity at the second measurement when evaluating the self, the similar and dissimilar peer. No differential activity was observed when comparing the adolescents to young adults. Functional connectivity did not change from early to mid-adolescence, however, connectivity of the dMPFC with a posterior midline region during self- and other-referential processing relative to the control condition reduced from mid-adolescence to young adulthood. Together, these findings provide insight in the developmental trajectories of brain activity and connectivity underlying the development of the self-concept and representations of peers in adolescence.

Clonal relationship and alcohol consumption-associated mutational signature in synchronous hypopharyngeal tumours and oesophageal squamous cell carcinoma.

BACKGROUND: The patients with dual oesophageal squamous cell carcinoma (ESCC) and hypopharyngeal cancer (HPC) have poor prognosis; their underlying genetic pathogenesis is unclear. We hypothesise that development of synchronous ESCC/HPC depends on multicentricity or independent origin, rather than multifocality due to local or lateral spreading. METHOD: Multiple region whole-exome sequencing (M-WES) and clonality analysis were used to assess clonal relationship and spatial inter- or intra-tumour heterogeneity (ITH) in 62 tumour regions from eight dual ESCC/HPC and ten ESCC patients. RESULTS: All synchronous ESCC/HPC patients had COSMIC 16 mutation signatures, compared to only 40% ESCC in the current study (p = 0.013) and public data set (n = 165, p = 0.003). This alcohol consumption-related mutation signature 16, commonly involved in multiple alcohol-related cancers, was significantly associated with drinking and alcohol metabolism-related ADH1B rs1229984. The mutational landscape and copy number profiles were completely distinct between the two primary tumours; clonality analysis further suggested the two primary tumours shared no or only one clone accompanying independent subclone evolution. M-WES strategy demonstrated higher sensitivity and accuracy for detection of mutational prevalence and the late branch mutations among different regions in the ESCC tumours, compared to traditional sequencing analysis based on single biopsy strategy. Patients with high ITH assessed by cancer cell fraction analysis after M-WES were significantly associated with both relapse and survival. CONCLUSIONS: Our hypothesis-generating M-WES ITH assessment data have implications for prognostication. Collectively, our findings support multicentric independent clonal evolution, the field cancerisation theory, and suggest novel insights implicating an aetiologic role of alcohol metabolism in dual ESCC/HPC carcinogenesis.

Dynamic changes in maternal immune biomarkers during labor in nulliparous vs multiparous women.

BACKGROUND: Immunomodulation is observed in human parturition. However, data from longitudinal studies for the prelabor phase and the active phase of labor are lacking, and no study had compared the immune responses during labor between nulliparous and multiparous women. OBJECTIVE: This study aimed to investigate the temporal changes of immune biomarkers in maternal blood from the prelabor phase to the latent and active phases of labor and to compare the dynamic changes between nulliparous and multiparous women. STUDY DESIGN: A prospective case-control study was conducted on women who had induction of labor at term followed by vaginal delivery. Maternal blood was serially collected at 3 consecutive time points: (1) before the onset of labor, (2) during the latent phase of labor, and (3) during the active phase of labor. Peripheral immune cells were measured by 4-color flow cytometry, and the plasma concentrations of cytokines and chemokines were measured by cytometric bead arrays. A longitudinal comparison was made to assess the dynamic changes in inflammatory parameters over 3 time points in nulliparous and multiparous women, respectively, and a cross-sectional comparison was made between nulliparous and multiparous women. RESULTS: A total of 40 women, including 20 nulliparous and 20 multiparous, were included in the study. Prelabor circulating levels of macrophage inflammatory protein-1ß, monokine induced by gamma interferon, and interferon gamma-induced protein-10 were higher in multiparous women than in nulliparous women. In the latent phase of labor, the innate immune system in both groups responded with increases in neutrophils and interleukin 6, and the nulliparous women showed a more pronounced response. During the active phase of labor, such innate immune response continued with both groups, with additional increases in natural killer cells, monocyte chemoattractant protein-1, interleukin 8, and interleukin 10. Conversely, the adaptive immune system in nulliparous women showed a reduction in both cytotoxic and helper T cells, whereas the adaptive immune system in multiparous women only had a reduction in helper T cells, showing a smaller reduction. CONCLUSION: Innate and adaptive immune responses partake in immunomodulation during human parturition. Nulliparous and multiparous women showed different responses in their blood levels of immune cells and biomarkers during the different phases of labor.

Dual inhibition of cMET and EGFR by microRNA-338-5p suppresses metastasis of esophageal squamous cell carcinoma.

MicroRNAs, as a group of post-transcriptional regulators, regulate multiple pathological processes including metastasis during tumor development. Here, we demonstrated the metastasis-suppressive function of microRNA (miR)-338-5p in esophageal squamous cell carcinoma (ESCC). Overexpression of miR-338-5p had inhibitory effect on invasive ability of ESCC cells and extracellular matrix degradation, whereas silencing miR-338-5p had opposite effects. Mechanistically, miR-338-5p directly targeted the 3' untranslated regions of hepatocellular growth factor receptor cMet (cMET) and epidermal growth factor receptor (EGFR). As a result, miR-338-5p inhibited the downstream signaling cascades of cMET and EGFR and repressed cMET- and EGFR-mediated ESCC cell invasion. Re-expression of cMET or EGFR in miR-338-5p overexpressing ESCC cells was sufficient to derepress ESCC cell invasion both in vitro and in vivo. We further showed that such manipulation downregulated the expression and secretion of matrix metalloproteinases 2 and 9, which resulted in impaired extracellular matrix degradation and cell invasion. Most importantly, systemic delivery of miR-338-5p mimic significantly inhibited metastasis of ESCC cells in nude mice. Taken together, our results uncovered a previously unknown mechanism through which miR-338-5p suppresses ESCC invasion and metastasis by regulating cMET/EGFR-matrix metalloproteinase 2/9 axis and highlighted the potential significance of miR-338-5p-based therapy in treating patients with metastatic ESCC.

Neural correlates of self- and other-referential processing in young adolescents and the effects of testosterone and peer similarity.

During adolescence, self-concept develops profoundly, accompanied by major changes in hormone levels. Self-evaluations become more complex, and peers and their opinions increasingly salient. Neuroimaging studies have investigated self- and other-related processing in adolescents, however, the influence of similarity of peers on these processes is still unclear, as well as functional connectivity underlying such processes. We investigated the effect of peer similarity on neural activity and connectivity underlying self- and other-referential processing, by distinguishing between a similar and dissimilar peer when making other-evaluations. Moreover, we explored the association between testosterone and brain activity during self-evaluations. Sixty-six young adolescents underwent functional MRI while performing a trait judgement task in which they indicated whether an adjective described themselves, a similar or a dissimilar classmate. The ventral medial prefrontal cortex (MPFC) showed increased engagement in self-referential processing, and the posterior cingulate cortex and right temporal parietal junction during other-evaluations. However, activity did not differ between the similar and dissimilar other conditions. Functional connectivity of the ventral MPFC included the striatum when evaluating the similar peer and frontoparietal regions when evaluating the dissimilar peer. Furthermore, inter-individual differences in testosterone levels were positively associated with dorsal MPFC activity in males. This study provides insight into the influence of peer similarity on activity and connectivity underlying other-referential processing in young adolescents, and suggests that testosterone affects neural correlates of self-referential processing.

BRCA2 loss-of-function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese.

Esophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole-exome sequencing (WES) included 186 familial ESCC patients from high-risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate-risk Hong Kong Chinese. A WES approach identified BRCA2 loss-of-function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10-10 ). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild-type somatic allelic loss via loss of heterozygosity. Gene-based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10-5 ), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.

Machine learning and treatment outcome prediction for oral cancer.

BACKGROUND: The natural history of oral squamous cell carcinoma (OSCC) is complicated by progressive disease including loco-regional tumour recurrence and development of distant metastases. Accurate prediction of tumour behaviour is crucial in delivering individualized treatment plans and developing optimal patient follow-up and surveillance strategies. Machine learning algorithms may be employed in oncology research to improve clinical outcome prediction. METHODS: Retrospective review of 467 OSCC patients treated over a 19-year period facilitated construction of a detailed clinicopathological database. 34 prognostic features from the database were used to populate 4 machine learning algorithms, linear regression (LR), decision tree (DT), support vector machine (SVM) and k-nearest neighbours (KNN) models, to attempt progressive disease outcome prediction. Principal component analysis (PCA) and bivariate analysis were used to reduce data dimensionality and highlight correlated variables. Models were validated for accuracy, sensitivity and specificity, with predictive ability assessed by receiver operating characteristic (ROC) and area under the curve (AUC) calculation. RESULTS: Out of 408 fully characterized OSCC patients, 151 (37%) had died and 131 (32%) exhibited progressive disease at the time of data retrieval. The DT model with 34 prognostic features was most successful in identifying "true positive" progressive disease, achieving 70.59% accuracy (AUC 0.67), 41.98% sensitivity and a high specificity of 84.12%. CONCLUSION: Machine learning models assist clinicians in accessing digitized health information and appear promising in predicting progressive disease outcomes. The future will see increasing emphasis on the use of artificial intelligence to enhance understanding of aggressive tumour behaviour, recurrence and disease progression.

The effect of social feedback from peers on adolescent cognitive control.

INTRODUCTION: Social feedback can influence cognitive control during adolescence, particularly if provided by peers. The main aim of this study was to investigate if feedback given by liked or disliked peers differentially influenced adolescents' cognitive control. The second aim was to investigate if these effects could be linked to the participants' social embeddedness in their classroom. METHODS: A personalized incentive go/no-go task was administered to 45 early adolescents (M = 11.6 years, 25 male) and 68 late adolescents (M = 16.7, 38 male) in the Netherlands. Feedback was given after no-go trials in two social feedback conditions (displaying a picture of a real liked or disliked classmate) and in a non-social control condition. RESULTS: Performance on the task significantly improved with age. We found no differences between conditions in cognitive control, as measured by d-prime. However, analysis of task speed revealed slower reaction times during the liked peer condition as compared to the disliked peer and the control condition, potentially suggesting that participants responded more cautiously, or alternatively that participants were more distracted. These effects did not differ between age groups. Participants' differences in task performance were not reflected in their social embeddedness in the classroom. CONCLUSIONS: This study shows that the same kind of social feedback can have different effects on adolescent behaviour depending on the peer delivering the feedback. It demonstrates the importance of studying the effects of real life social environments to better understand and utilize their impact on adolescent development.

The Teenage Brain: Public Perceptions of Neurocognitive Development during Adolescence.

Over the past decade, important insights have been obtained into the neurocognitive development during adolescence. To better understand how these neuroscientific insights impact the real world, we investigated how neuroscience has shaped public perceptions of the "teenage brain" and if these perceptions influence adolescent behavior. When asking to generate free associations with the word "teenage brain," adolescents ( n = 363, Mage = 14.47 years) and parents ( n = 164, Mage = 47.16 years) more often mention undesirable behaviors (e.g., "irresponsible") than desirable behaviors (e.g., "creative"). Despite these dominantly negative associations, priming adolescents with positively versus negatively framed statements about adolescent brain development did not influence their subsequent risk-taking, impulsivity, and performance on response-to-failure tasks. However, we did find a more nuanced effect, related to how much adolescents agreed with the negative versus positive priming statements: Adolescents' negative beliefs about adolescent brain development reinforced negative behaviors by increased risk-taking behaviors, and adolescents' positive beliefs reinforced positive behaviors by using positive strategies to cope with academic setbacks. The current findings underline the impact of views that build up over time and that these are not easily influenced by a one-time instance of information but rather reinforce the impact of new information. To prevent negative perceptions of the teenage brain from becoming self-fulfilling prophecies, it is important that communication about adolescent neurocognitive development is framed in a more balanced way. Neuroscientists need to be more aware of how their research impacts the real world, before we are fully ready for "real-world neuroscience."

MicroRNA-338-5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells by targeting Id-1.

5-Fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that microRNA (miR)-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by reexpression of Id-1. In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.

Probiotics modulated gut microbiota suppresses hepatocellular carcinoma growth in mice.

The beneficial roles of probiotics in lowering the gastrointestinal inflammation and preventing colorectal cancer have been frequently demonstrated, but their immunomodulatory effects and mechanism in suppressing the growth of extraintestinal tumors remain unexplored. Here, we adopted a mouse model and metagenome sequencing to investigate the efficacy of probiotic feeding in controlling s.c. hepatocellular carcinoma (HCC) and the underlying mechanism suppressing the tumor progression. Our result demonstrated that Prohep, a novel probiotic mixture, slows down the tumor growth significantly and reduces the tumor size and weight by 40% compared with the control. From a mechanistic point of view the down-regulated IL-17 cytokine and its major producer Th17 cells, whose levels decreased drastically, played critical roles in tumor reduction upon probiotics feeding. Cell staining illustrated that the reduced Th17 cells in the tumor of the probiotic-treated group is mainly caused by the reduced frequency of migratory Th17 cells from the intestine and peripheral blood. In addition, shotgun-metagenome sequencing revealed the crosstalk between gut microbial metabolites and the HCC development. Probiotics shifted the gut microbial community toward certain beneficial bacteria, including Prevotella and Oscillibacter, that are known producers of antiinflammatory metabolites, which subsequently reduced the Th17 polarization and promoted the differentiation of antiinflammatory Treg/Tr1 cells in the gut. Overall, our study offers novel insights into the mechanism by which probiotic treatment modulates the microbiota and influences the regulation of the T-cell differentiation in the gut, which in turn alters the level of the proinflammatory cytokines in the extraintestinal tumor microenvironment.

Tumor xenograft animal models for esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer worldwide and highly prevalent in less developed regions. Management of ESCC is challenging and involves multimodal treatments. Patient prognosis is generally poor especially for those diagnosed in advanced disease stage. One factor contributing to this clinical dismal is the incomplete understanding of disease mechanism, for which this situation is further compounded by the presence of other limiting factors for disease diagnosis, patient prognosis and treatments. Tumor xenograft animal models including subcutaneous tumor xenograft model, orthotopic tumor xenograft model and patient-derived tumor xenograft model are vital tools for ESCC research. Establishment of tumor xenograft models involves the implantation of human ESCC cells/xenografts/tissues into immunodeficient animals, in which mice are most commonly used. Different tumor xenograft models have their own advantages and limitations, and these features serve as key factors to determine the use of these models at different stages of research. Apart from their routine use on basic research to understand disease mechanism of ESCC, tumor xenograft models are actively employed for undertaking preclinical drug screening project and biomedical imaging research.

Whole-exome sequencing reveals critical genes underlying metastasis in oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers, owing to a high frequency of metastasis. However, little is known about the genomic landscape of metastatic ESCC. To identify the genetic alterations that underlie ESCC metastasis, whole-exome sequencing was performed for 41 primary tumours and 15 lymph nodes (LNs) with metastatic ESCCs. Eleven cases included matched primary tumours, synchronous LN metastases, and non-neoplastic mucosa. Approximately 50-76% of the mutations identified in primary tumours appeared in the synchronous LN metastases. Metastatic ESCCs harbour frequent mutations of TP53, KMT2D, ZNF750, and IRF5. Importantly, ZNF750 was recurrently mutated in metastatic ESCC. Combined analysis from current and previous genomic ESCC studies indicated more frequent ZNF750 mutation in diagnosed cases with LN metastasis than in those without metastasis (14% versus 3.4%, n = 629, P = 1.78 × 10-5 ). The Cancer Genome Atlas data further showed that ZNF750 genetic alterations were associated with early disease relapse. Previous ESCC studies have demonstrated that ZNF750 knockdown strongly promotes proliferation, migration, and invasion. Collectively, these results suggest a role for ZNF750 as a metastasis suppressor. TP53 is highly mutated in ESCC, and missense mutations are associated with poor overall survival, independently of pathological stage, suggesting that these missense mutations have important functional impacts on tumour progression, and are thus likely to be gain-of-function (GOF) mutations. Additionally, mutations of epigenetic regulators, including KMT2D, TET2, and KAT2A, and chromosomal 6p22 and 11q23 deletions of histone variants, which are important for nucleosome assembly, were detected in 80% of LN metastases. Our study highlights the important role of critical genetic events including ZNF750 mutations, TP53 putative GOF mutations and nucleosome disorganization caused by genetic lesions seen with ESCC metastasis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.