Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1ß production.

Double-stranded DNA (dsDNA) in the cytoplasm triggers the production of interleukin 1ß (IL-1ß) as an antiviral host response, and deregulation of the pathways involved can promote inflammatory disease. Here we report a direct cytosolic interaction between the DNA-damage sensor Rad50 and the innate immune system adaptor CARD9. Transfection of dendritic cells with dsDNA or infection of dendritic cells with a DNA virus induced the formation of dsDNA-Rad50-CARD9 signaling complexes for activation of the transcription factor NF-κB and the generation of pro-IL-1ß. Primary cells conditionally deficient in Rad50 or lacking CARD9 consequently exhibited defective DNA-induced production of IL-1ß, and Card9(-/-) mice had impaired inflammatory responses after infection with a DNA virus in vivo. Our results define a cytosolic DNA-recognition pathway for inflammation and a physical and functional connection between a conserved DNA-damage sensor and the innate immune response to pathogens.

Distal Pancreatectomy: Extent of Resection Determines Surgical Risk Categories.

BACKGROUND: Recently, subclassification of pancreatoduodenectomy in 4 differing types has been reported, because additional major vascular and multivisceral resections have been shown to be associated with an increased risk of postoperative morbidity and mortality. OBJECTIVE: To classify distal pancreatectomy (DP) based on the extent of resection and technical difficulty and to evaluate postoperative outcomes with regards to this classification system. METHODS: All consecutive patients who had undergone DP between 2001 and 2020 in a high-volume pancreatic surgery center were included in this study. DPs were subclassified into 4 distinct categories reflecting the extent of resection and technical difficulty, including standard DP (type 1), DP with venous (type 2), multivisceral (type 3), or arterial resection (type 4). Patient characteristics, perioperative data, and postoperative outcomes were analyzed and compared among the 4 groups. RESULTS: A total of 2135 patients underwent DP. Standard DP was the most frequently performed procedure (64.8%). The overall 90-day mortality rate was 1.6%. Morbidity rates were higher in patients with additional vascular or multivisceral resections, and 90-day mortality gradually increased with the extent of resection from standard DP to DP with arterial resection (type 1: 0.7%; type 2: 1.3%; type 3: 3%; type 4: 8.7%; P <0.0001). Multivariable analysis confirmed the type of DP as an independent risk factor for 90-day mortality. CONCLUSIONS: Postoperative outcomes after DP depend on the extent of resection and correlate with the type of DP. The implementation of the 4-type classification system allows standardized reporting of surgical outcomes after DP improving comparability of future studies.

Who Do We Fail to Rescue after Pancreatoduodenectomy? Outcomes Among >4000 Procedures Expose Windows of Opportunity.

OBJECTIVE: Our investigation on in-hospital mortality after 4474 pancreatoduodenectomies aimed to identify time-dependent risks as well as windows of opportunity to rescue patients from complications. BACKGROUND: Pancreatoduodenectomy is generally considered a safe procedure with a 1-10% perioperative mortality based on complexity and surgical volume. Yet, patients are susceptible for life-threatening complications particularly with extended resections. Recognition of distinct vulnerabilities over time while patients recover is required to permit focused monitoring, sophisticated resource allocation, and greatest surgical safety. METHODS: Patients who deceased in-hospital after pancreatoduodenectomy between 2003-2021 were retrieved from the institutional pancreatectomy registry and analyzed in detail with respect to their postoperative course. RESULTS: Among 4474 pancreatoduodenectomies, 156 patients deceased in-hospital (3.5%). When assessing root causes of mortality, we observed 3 different clusters of complications which were postpancreatectomy-specific (47.4%), visceral vasculature-associated (25.6%), or cardiopulmonary in origin (23.7%). The median times of root cause onset in the 3 categories were postoperative day (POD) 9, POD 4.5 (P=0.008) and POD 3 (P<0.001), and medians of in-hospital mortality were POD 31, POD 18 (P=0.009) and POD 8 (P<0.001), respectively. Intervals between root cause onset and mortality varied with medians of 23 days, 11 days (P=0.017), and 1 days (P<0.001). The 3 categories were similarly distributed between different types of surgical complexity. CONCLUSION: Postpancreatectomy-specific complications prompt almost half of in-hospital mortalities after pancreatoduodenectomy, with rather long intervals for interventions to prevent failure to rescue. In contrast, visceral vasculature-related events and cardiopulmonary complications dominate early in-hospital mortalities with short intervals until mortality, demanding rigorous management of such events or preoperative conditioning. These data externally validate a previous high-volume initiative and highlight distinct windows of opportunity to optimize perioperative safety.

Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer.

BACKGROUND & AIMS: As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. METHODS: We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. RESULTS: We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. CONCLUSIONS: Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Human placental mesenchymal stromal cells are ciliated and their ciliation is compromised in preeclampsia.

BACKGROUND: The development of the human placenta is tightly coordinated by a multitude of placental cell types, including human chorionic villi mesenchymal stromal cells (hCV-MSCs). Defective hCV-MSCs have been reported in preeclampsia (PE), a gestational hypertensive disease characterized by maternal endothelial dysfunction and systemic inflammation. Our goal was to determine whether hCV-MSCs are ciliated and whether altered ciliation is responsible for defective hCV-MSCs in preeclamptic placentas, as the primary cilium is a hub for signal transduction, which is important for various cellular activities. METHODS: In the present work, we collected placental tissues from different gestational stages and we isolated hCV-MSCs from 1st trimester, term control, and preeclamptic placentas. We studied their ciliation, functionality, and impact on trophoblastic cell lines and organoids formed from human trophoblast stem cells (hTSCs) and from the trophoblastic cell line JEG-3 with various cellular and molecular methods, including immunofluorescence staining, gene analysis, spheroid/organoid formation, motility, and cellular network formation assay. The statistical evaluation was performed using a Student's t test (two-tailed and paired or homoscedastic) or an unpaired Mann-Whitney U test (two-tailed). RESULTS: The results show that primary cilia appeared abundantly in normal hCV-MSCs, especially in the early development of the placenta. Compared to control hCV-MSCs, the primary cilia were truncated, and there were fewer ciliated hCV-MSCs derived from preeclamptic placentas with impaired hedgehog signaling. Primary cilia are necessary for hCV-MSCs' proper signal transduction, motility, homing, and differentiation, which are impaired in preeclamptic hCV-MSCs. Moreover, hCV-MSCs derived from preeclamptic placentas are significantly less capable of promoting growth and differentiation of placental organoids, as well as cellular network formation. CONCLUSIONS: These data suggest that the primary cilium is required for the functionality of hCV-MSCs and primary cilia are impaired in hCV-MSCs from preeclamptic placentas.

Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production.

Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.

Sca-1 is a marker for cell plasticity in murine pancreatic epithelial cells and induced by IFN-ß in vitro.

BACKGROUND & AIMS: Sca-1 is a surface marker for murine hematopoietic stem cells (HSCs) and type-I interferon is a key regulator for Lin-Sca-1+ HSCs expansion through Ifnar/Stat-1/Sca-1-signaling. In this study we aimed to characterize the role and regulation of Sca-1+ cells in pancreatic regeneration. METHODS: To characterize Sca-1 in vivo, immunohistochemistry and immunofluorescence staining of Sca-1 was conducted in normal pancreas, in cerulein-mediated acute pancreatitis, and in Kras-triggered cancerous lesions. Ifnar/Stat-1/Sca-1-signaling was studied in type-I IFN-treated epithelial explants of adult wildtype, Ifnar-/-, and Stat-1-/- mice. Sca-1 induction was analyzed by gene expression and FACS analysis. After isolation of pancreatic epithelial Lin-Sca-1+cells, pancreatosphere-formation and immunofluorescence-assays were carried out to investigate self-renewal and differentiation capabilities. RESULTS: Sca-1+ cells were located in periacinar and periductal spaces and showed an enrichment during cerulein-induced acute pancreatitis (23.2/100 µm2 ± 4.9 SEM) and in early inflammation-mediated carcinogenic lesions of the pancreas of KrasG12D mice (35.8/100 µm2 ± SEM 1.9) compared to controls (3.6/100 µm2 ± 1.3 SEM). Pancreatic Lin-Sca-1+ cells displayed a small population of 1.46% ± 0.12 SEM in FACS. In IFN-ß treated pancreatic epithelial explants, Sca-1 expression was increased, and Lin-Sca-1+ cells were enriched in vitro (from 1.49% ± 0.36 SEM to 3.85% ± 0.78 SEM). Lin-Sca-1+ cells showed a 12 to 51-fold higher capacity for clonal self-renewal compared to Lin-Sca-1- cells and generated cells express markers of the acinar and ductal compartment. CONCLUSIONS: Pancreatic Sca-1+ cells enriched during parenchymal damage showed a significant capacity for cell renewal and in vitro plasticity, suggesting that corresponding to the type I interferon-dependent regulation of Lin-Sca-1+ hematopoietic stem cells, pancreatic Sca-1+ cells also employ type-I-interferon for regulating progenitor-cell-homeostasis.

Interferon-ß production via Dectin-1-Syk-IRF5 signaling in dendritic cells is crucial for immunity to C. albicans.

Type I interferon (IFN) is crucial during infection through its antiviral properties and by coordinating the immunocompetent cells involved in antiviral or antibacterial immunity. Type I IFN (IFN-α and IFN-ß) is produced after virus or bacteria recognition by cytosolic receptors or membrane-bound TLR receptors following the activation of the transcription factors IRF3 or IRF7. IFN-ß production after fungal infection was recently reported, although the underlying mechanism remains controversial. Here we describe that IFN-ß production by dendritic cells (DCs) induced by Candida albicans is largely dependent on Dectin-1- and Dectin-2-mediated signaling. Dectin-1-induced IFN-ß production required the tyrosine kinase Syk and the transcription factor IRF5. Type I IFN receptor-deficient mice had a lower survival after C. albicans infection, paralleled by defective renal neutrophil infiltration. IFN-ß production by renal infiltrating leukocytes was severely reduced in C. albicans-infected mice with Syk-deficient DCs. These data indicate that Dectin-induced IFN-ß production by renal DCs is crucial for defense against C. albicans infection.

Genetically Determined Telomere Length Is Associated with Pancreatic Neuroendocrine Neoplasms Onset.

INTRODUCTION: Telomere length (TL) is a potential indicator of cancer predisposition; however, the multitude of techniques used to measure it causes the results to be heterogeneous and, in some cases, controversial. In the last years, several studies adopted a strategy based on TL-associated genetic variants to generate a polygenic score, often referred as teloscore, used in lieu of direct TL measurement. For pancreatic neuroendocrine neoplasms (PanNEN), this strategy has not been attempted yet. METHODS: A teloscore was generated using 11 SNPs (NAF1-rs7675998, ZNF676-rs409627, TERC-rs10936599, CTC1-rs3027234, PXK-rs6772228, DHX35-rs6028466, OBFC1-rs9420907, ZNF208-rs8105767, ACYP2-rs11125529, TERT-rs2736100, and ZBTB46-rs755017), and 291 PanNEN cases and 1,686 controls collected by the PANcreatic Disease ReseArch (PANDoRA) consortium were genotyped to analyse the association of the teloscore and its individual SNPs with the risk of developing PanNEN. RESULTS: An association between genetically determined long telomeres and the risk of developing PanNEN (OR = 1.99, CI: 1.33-2.98, p = 0.0008) for highest versus median (third) quintile was observed. In addition, two novel SNPs associated with PanNEN risk were identified: ZNF676-rs409627 (ORC/C_vs_G/G = 2.27, CI: 1.58-3.27, p = 8.80 × 10-6) and TERT-rs2736100 (ORC/A_vs_C/C = 2.03, CI: 1.42-2.91, p = 1.06 × 10-4). CONCLUSION: In conclusion, this study provides for the first time a clear indication of the association between long genetically determined telomeres and increased risk of developing PanNEN.

Do preterm-born children and adolescents have greater need for dental care as compared to full term-born controls?

BACKGROUND: Preterm birth has been shown to cause various long-term health issues. Children who were born preterm have also been observed to have more dental behaviour management problems (DBMP) during dental examinations and treatment than children born full term. It is known that dental radiographic examinations can be uncomfortable and cause anxiety in paediatric patients. Thus, our aims were to retrospectively compare dental care related examinations and treatments carried out in three different age intervals (3-6 years, 7-12 years, and 13-19 years) among preterm- and full-term born children and adolescents. METHODS: The present study included 311 patient files: 122 very preterm-born and 33 extremely preterm-born children and adolescents (< 32 gestational weeks). A matched control group of 156 full term-born children and adolescents (≥ 37 gestational weeks) was analysed for comparison. Various factors, including DBMP, missed appointments, dental caries, and radiographic examinations, were retrieved from the dental records for three age intervals: 3-6 years, 7-12 years, and 13-19 years. RESULTS: Extremely preterm-born children missed significantly more dental appointments and presented with more DBMP during dental examinations and treatment than full term-born children in the 3-6-year age group; the same was observed for the very preterm-born in the 7-12-year age group. No significant differences in DBMP during bitewing and periapical examinations or in number of bitewing, periapical and panoramic radiographs occurred between the groups in any age interval. CONCLUSION: Preterm-born children and adolescents may need more flexibility in booking and receive reminders for scheduled visits with the general dental team. Due to the non-significant differences in dental care related oral examinations and treatments, the same dental care service may be applied to the preterm- and full-term born children and adolescents.

Noninvasive Discrimination of Low and High-risk Pancreatic Intraductal Papillary Mucinous Neoplasms.

OBJECTIVE: To propose a noninvasive diagnostic approach, which allows reliable distinction between low- and high-risk pancreatic intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: IPMNs are identifiable precursor lesions of pancreatic cancer, of which surgical resection is warranted prior to the development of invasive carcinoma, but low-grade IPMNs should not be unnecessarily resected. However, diagnostic tools that preoperatively enable accurate risk stratification of IPMNs are missing. METHODS: This single-center, retrospective cohort study included 56 patients who underwent surgical resection for IPMN including 18 low-risk (low-grade) and 38 high-risk (high-grade/invasive carcinoma) IPMNs, from whom clinical features and serum samples were prospectively obtained. An antibody microarray platform was used to analyze the serum proteome. Based on serum markers and selected clinical characteristics support vector machine models were constructed to predict the risk of IPMN malignancy. RESULTS: A serum protein signature discriminating low- and high-risk IPMN patients was identified. Combinations of established clinical features and the newly identified serum biomarkers correctly distinguished low- and high-risk IPMNs in 93% on 1000-fold cross-validation. CONCLUSIONS: This study highlights the synergistic predictive value of combining a novel serum protein signature with conventional clinical characteristics to risk-stratify IPMN patients. If these findings are supported by larger validation studies, they might enable more rational decision-making in clinical management of IPMN patients in conjunction with clinical guidelines.

Do preterm-born adolescents have a poorer oral health-related quality of life?

BACKGROUND: To evaluate oral health-related quality of life (OHRQoL) over a period of five years using the Oral Health Impact Profile (OHIP-14) questionnaire in a population of Swedish adolescents born preterm and full term. METHODS: In a longitudinal study of adolescents aged 12-14 and 17-19, changes over time in OHRQoL were measured by using OHIP-14. The OHIP-14 score, self-reported chronic illness, temporomandibular disorder (TMD pain) and subjective orthodontic treatment need were compared between 98 extremely and very preterm born (< 32 gestational week) and 93 full-term controls (≥ 37 gestational week) at two ages. The chi-square test was used for comparisons within the extremely-, very-, and full-term control groups, and to contrast the differences of mean scores of OHIP-14, the ANOVA test was used for comparisons within the study groups of extremely preterm, very preterm and full term-born adolescents. RESULTS: All adolescents reported a good self-perceived OHRQoL. No significant differences in the comparisons of the total mean scores were revealed between the groups, between gender or in domain-specific scores over the 5-year period. Very preterm adolescents with reported chronic illness at 12-14 years of age showed significantly higher mean scores of OHIP-14 compared with those without chronic illness (p = 0.015). At age 17-19, significantly higher mean scores of OHIP-14 were reported by very preterm adolescents with TMD pain compared to those without TMD pain (p = 0.024). Significantly higher mean scores of OHIP-14 were found among the extremely preterm (p = 0.011) and very preterm born adolescents (p = 0.031) with a subjective need of orthodontic treatment compared with those without orthodontic treatment need. CONCLUSIONS: Poor OHRQoL measured with OHIP-14 in very preterm adolescents aged 12-14 was related to chronic illness and aged 17-19 to TMD pain. In addition, extremely and very preterm-born adolescents with subjective orthodontic treatment need at 17-19 years of age also reported poor OHRQoL. To improve the dentist-patient relationship and achieve more successful treatment results, it is important for dental clinicians to understand the impact that chronic illness, TMD pain and orthodontic treatment need has on OHRQoL in preterm-born adolescents.

Caspase-8: clipping off RIG-I signaling.

Activation of the RIG-I signaling molecule is essential for antiviral immunity but mechanisms downmodulating the response are ill defined. In this issue of Immunity, Rajput et al. (2011) describe caspase-8-mediated RIP1 cleavage as a key step for restricting RIG-I signaling.

CBCT of Swedish children and adolescents at an oral and maxillofacial radiology department. A survey of requests and indications.

Objectives: This retrospective study investigated requests and indications for cone-beam computed tomography (CBCT) in children and adolescents over a 3-year period at one oral and maxillofacial radiology department. Specific aims were to determine what technical settings were used, which caregivers write the referrals, and how often and for what reasons re-exposure was necessary.Materials and methods: Patients <19 years of age who had been referred to the department and undergone a CBCT scan during 2015-2017 were included in the study.Results: CBCT were made in 617 of the 3847 eligible referrals. The most common referral was from general practice dentists (GPD) (43%). Mean age of the patients was 12.5 years (range: 6-18). Nineteen different types of requests were identified. The most common request was assessment of an ectopic canine with a question about potential resorption of adjacent teeth (38.6%). Forty (6.5%) of the CBCT needed to be re-taken due to patient motion artefacts.Conclusions: The most common request and indication for CBCT examination of children and young adults were to assess an ectopic canine and determine the presence of resorption of adjacent teeth. Referrals from GPDs were the most frequent and the largest age group was the 11- to 15-year olds. The reason for re-exposures was motion artefacts. High scanning speed to reduce motion artefacts and a half rotation (180°) to reduce the radiation dose to the patient should be preferred. The need for continuous work with quality and systematic monitoring of radiographic procedures at any radiology department should be given high priority.

The Function of Oncogene B-Cell Lymphoma 6 in the Regulation of the Migration and Invasion of Trophoblastic Cells.

Human placentation is a highly invasive process. Deficiency in the invasiveness of trophoblasts is associated with a spectrum of gestational diseases, such as preeclampsia (PE). The oncogene B-cell lymphoma 6 (BCL6) is involved in the migration and invasion of various malignant cells. Intriguingly, its expression is deregulated in preeclamptic placentas. We have reported that BCL6 is required for the proliferation, survival, fusion, and syncytialization of trophoblasts. In the present work, we show that the inhibition of BCL6, either by its gene silencing or by using specific small molecule inhibitors, impairs the migration and invasion of trophoblastic cells, by reducing cell adhesion and compromising the dynamics of the actin cytoskeleton. Moreover, the suppression of BCL6 weakens the signals of the phosphorylated focal adhesion kinase, Akt/protein kinase B, and extracellular regulated kinase 1/2, accompanied by more stationary, but less migratory, cells. Interestingly, transcriptomic analyses reveal that a small interfering RNA-induced reduction of BCL6 decreases the levels of numerous genes, such as p21 activated kinase 1, myosin light chain kinase, and gamma actin related to cell adhesion, actin dynamics, and cell migration. These data suggest BCL6 as a crucial player in the migration and invasion of trophoblasts in the early stages of placental development through the regulation of various genes associated with the migratory machinery.

Temporomandibular pain in adolescents with a history of preterm birth.

AIM: To evaluate the frequency of temporomandibular disorder (TMD) pain among adolescents with a history of preterm birth compared to a matched control group. METHODS: A group of 192 preterm-born adolescents was followed up at the age of 17-19 years and compared to matched controls. Self-report questionnaires included screening questions about TMD pain, chronic diseases, general health, depression, anxiety, anger, antisocial behaviour and self-concept. TMD pain was defined as answering "yes" to one or both of the following questions: "Do you have pain in the temple, face, temporomandibular joint or jaws once a week or more?" and "Do you have pain when you open your mouth wide or chew once a week or more often?" Data analysis was performed using chi-square test and logistic regression model with likelihood ratio test. RESULTS: A TMD pain frequency of 23% of preterm-born adolescents and 26% among the controls was found, with no significant differences between the groups. Neither were there differences regarding anxiety, depression, anger or self-confidence. Within the preterm group, adolescents with TMD pain registered tension and pain in the body, trouble sleeping, stomach pain and feelings of hopelessness about the future. The controls with TMD pain, more reported having a bad life, feeling like a failure and having bodily pain. Among tested background variables, only TMJ locking or intermittent locking once a week or more was found to explain TMD pain in adolescents. CONCLUSION: A high frequency of TMD pain was found in both groups, one possible explanation could be TMJ dysfunction.

Transforming Growth Factor Beta 3-Loaded Decellularized Equine Tendon Matrix for Orthopedic Tissue Engineering.

Transforming growth factor beta 3 (TGFß3) promotes tenogenic differentiation and may enhance tendon regeneration in vivo. This study aimed to apply TGFß3 absorbed in decellularized equine superficial digital flexor tendon scaffolds, and to investigate the bioactivity of scaffold-associated TGFß3 in an in vitro model. TGFß3 could effectively be loaded onto tendon scaffolds so that at least 88% of the applied TGFß3 were not detected in the rinsing fluid of the TGFß3-loaded scaffolds. Equine adipose tissue-derived multipotent mesenchymal stromal cells (MSC) were then seeded on scaffolds loaded with 300 ng TGFß3 to assess its bioactivity. Both scaffold-associated TGFß3 and TGFß3 dissolved in the cell culture medium, the latter serving as control group, promoted elongation of cell shapes and scaffold contraction (p < 0.05). Furthermore, scaffold-associated and dissolved TGFß3 affected MSC musculoskeletal gene expression in a similar manner, with an upregulation of tenascin c and downregulation of other matrix molecules, most markedly decorin (p < 0.05). These results demonstrate that the bioactivity of scaffold-associated TGFß3 is preserved, thus TGFß3 application via absorption in decellularized tendon scaffolds is a feasible approach.