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Introduction: This study aimed to evaluate the chemomechanical properties and biocompatibility of recently introduced premixed putty-type bioactive ceramic cements (PPBCs)., Methods: Including ProRoot MTA (PMTA) as a control, BC RRM fast-set putty (BCPT), Well-Root PT (WRPT), One-Fil PT (OFPT), and Endocem MTA premixed (ECPM) were compared to evaluate setting time, radiopacity, pH change, and microhardness. Biocompatibility on human dental pulp cells was compared using CCK-8 assay. Mineralization potential was evaluated using alkaline phosphatase activity, Alizarin Red S (ARS) staining, and quantitative real-time polymerase chain reaction with odontogenic gene marker. For data analysis, 1-way analysis of variance and Tukey's post hoc test were used at the significance level of 95%., Results: Among the PPBCs, BCPT presented the longest (552 ± 27) setting time (minutes) and others showed significantly shorter time than PMTA (334 ± 22) (P < .05). WRPT (6.20 ± 0.54) and OFPT (5.82 ± 0.50) showed significantly higher radiopacity values (mmAl) and others showed similar value compared with PMTA (P > .05). All PPBCs showed high alkaline pH from fresh materials and tended to increase according to time periods from 30 minutes to 12 hours. ECPM showed the highest value of microhardness (81.62 ± 5.90), WRPT showed similar, and others showed lower than PMTA (P < .05). All PPBCs showed biocompatibility in CCK-8 assay. All PPBCs showed similar or better value compared with PMTA in ALP and ARS staining, and ALP and DSPP marker expression (P < .05)., Conclusions: The PPBCs showed clinically acceptable chemomechanical properties and favorable mineralization potential., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

The maternal microbiome is an important regulator of gestational health, but how it affects the placenta as the interface between mother and fetus remains unexplored. Here, we show that the maternal gut microbiota supports placental development in mice. Depletion of the maternal gut microbiota restricts placental growth and impairs feto-placental vascularization. The maternal gut microbiota modulates metabolites in the maternal and fetal circulation. Short-chain fatty acids (SCFAs) stimulate cultured endothelial cell tube formation and prevent abnormalities in placental vascularization in microbiota-deficient mice. Furthermore, in a model of maternal malnutrition, gestational supplementation with SCFAs prevents placental growth restriction and vascular insufficiency. These findings highlight the importance of host-microbial symbioses during pregnancy and reveal that the maternal gut microbiome promotes placental growth and vascularization in mice.

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals., Competing Interests: Declaration of interests William D. Foulkes has research funding from AstraZeneca. Sophie Sun has a consulting and advisory relationship with Novartis, Bristol-Myers Squibb, Pfizer, Purdue, Takeda, and AstraZeneca. Kasmintan A. Schrader has a consulting and advisory relationship with and has received honoraria from AstraZeneca Canada and Pfizer and research funding from AstraZeneca Canada. Dean Regier has a consulting/advisory relationship with Roche Canada and AstraZeneca. Trevor J. Pugh has a consulting and advisory relationship with Chrysalis Biomedical Advisors and the Canadian Pension Plan Investment Board, is on the scientific advisory board for Illumina, has received honoraria from AstraZeneca, Merck, PACT Pharma, and SAGA Diagnostics, and has research funding from Roche (Genentech), the National Institutes of Health, and the US Department of Defense. Yvonne Bombard has ownership interests and intellectual property rights as an inventor and patent holder with Genetics Adviser. The other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Black cumin seeds (black seed; BS) contain various bioactive compounds, such as thymoquinone (TQ). Roasting and ultrasound-assisted enzymatic treatment (UAET) as pre-treatments can increase the phytochemical content in the BS oil. This study aimed to investigate the effects of pre-treatments on the TQ content and the yield of the BS oil and to profile the composition of defatted BS meal (DBSM), followed by evaluating antioxidant properties of the DBSM., Results: The extraction yield of crude oil from BS was not affected by the roasting time. The highest extraction yield (47.8 ± 0.4%) was obtained with UAET cellulase-pH 5 (enzyme concentration of 100%). Roasting decreased the TQ content of the oil, while the UAET cellulase-pH 5 treatment with an enzyme concentration of 100% yielded the highest TQ (125.1 ± 2.7 μg mL -1 ). Additionally, the UAET cellulase-pH 5 treatment increased total phenolics and flavonoids of DBSM by approximately two-fold, compared to roasting or ultrasound treatment (UT) alone. Principal component analysis revealed that the UAET method might be more suitable for extracting BS oil with higher TQ content than roasting and UT., Conclusion: Compared to roasting or UT, using ultrasound along with cellulase could improve the oil yield and TQ in the oil from BS and obtain the DBSM with higher phenolics, flavonoids, and antioxidant activity. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: To obtain updated estimates of the incidence and prevalence of neurofibromatosis type 1 (NF1) and type 2 (NF2)., Study Design: We conducted a systematic search of NF1 and NF2 incidence or prevalence studies, in OVID Medline, OVID Embase, Web of Science, and Cinahl. Studies were appraised with the Joanna Briggs Institute Prevalence Critical Appraisal tool. Pooled incidence and prevalence rates were estimated through random-effects meta-analysis., Results: From 1,939 abstracts, 20 studies were fully appraised and 12 were included in the final review. Pooled NF1 prevalence was 1 in 3,164 (95%CI: 1 in 2,132-1 in 4,712). This was higher in studies that screened for NF1, compared to identification of NF1 through medical records (1 in 2,020 and 1 in 4,329, respectively). NF1 pooled birth incidence was 1 in 2,662 (95%CI: 1 in 1,968-1 in 3,601). There were only 2 studies on NF2 prevalence, so data were not pooled. Pooled NF2 birth incidence was 1.08 per 50,000 births (95%CI: 1 in 32,829-1 in 65,019)., Conclusion: We present updated estimates of the incidence and prevalence of NF1 and NF2, to help plan for healthcare access and allocation. The prevalence of NF1 from screening studies is higher than from medical record studies, suggesting that the disease may be under recognized. More studies are needed regarding the prevalence of NF2., (© 2023. Institut National de la Santé et de la Recherche Médicale (INSERM).)

Emerging evidence indicates that intracellular calcium (Ca 2+ ) levels and their regulatory proteins play essential roles in normal stem cell proliferation and differentiation. Cancer stem-like cells (CSCs) are subpopulations of cancer cells that retain characteristics similar to stem cells and play an essential role in cancer progression. Recent studies have reported that the Orai3 calcium channel plays an oncogenic role in human cancer. However, its role in CSCs remains underexplored. In this study, we explored the effects of Orai3 in the progression and stemness of oral/oropharyngeal squamous cell carcinoma (OSCC). During the course of OSCC progression, the expression of Orai3 exhibited a stepwise augmentation. Notably, Orai3 was highly enriched in CSC populations of OSCC. Ectopic Orai3 expression in non-tumorigenic immortalized oral epithelial cells increased the intracellular Ca 2+ levels, acquiring malignant growth and CSC properties. Conversely, silencing of the endogenous Orai3 in OSCC cells suppressed the CSC phenotype, indicating a pivotal role of Orai3 in CSC regulation. Moreover, Orai3 markedly increased the expression of inhibitor of DNA binding 1 (ID1), a stemness transcription factor. Orai3 and ID1 exhibited elevated expression within CSCs compared to their non-CSC counterparts, implying the functional importance of the Orai3/ID1 axis in CSC regulation. Furthermore, suppression of ID1 abrogated the CSC phenotype in the cell with ectopic Orai3 overexpression and OSCC. Our study reveals that Orai3 is a novel functional CSC regulator in OSCC and further suggests that Orai3 plays an oncogenic role in OSCC by promoting cancer stemness via ID1 upregulation.

Aim: The genetic etiologies of cardiomyopathies and arrhythmias have not been fully elucidated. Materials & methods: Research findings from genome analyses in a cardiomyopathy and arrhythmia cohort were gathered. Gene-disease relationships from two databases were compared with patient phenotypes. A literature review was conducted for genes with limited evidence. Results: Of 43 genes with candidate findings from 18 cases, 23.3% of genes had never been curated, 15.0% were curated for cardiomyopathies, 16.7% for arrhythmias and 31.3% for other conditions. 25.5% of candidate findings were curated for the patient's specific phenotype with 11.8% having definitive evidence. MYH6 and TPCN1 were flagged for recuration. Conclusion: Findings from genome sequencing in disease cohorts may be useful to guide gene-curation efforts.

Understanding the behavior of organic carbon in municipal solid waste landfills is a major challenge for estimating methane (CH 4 ) emissions using the Intergovernmental Panel on Climate Change (IPCC) first-order decay (FOD) model. According to the IPCC guidelines, the default values of CH 4 correction factor (MCF) and fraction of CH 4 (F) for active aeration landfills are set as 0.4 and 0.5, respectively. However, whether it is reasonable to apply the default values of MCF and F to active aeration landfills is questionable. This study aims to estimate the MCF and develop a method to determine the F value for active aeration landfills. In this investigation, three landfill sites were operated as active aeration landfills to estimate the MCF and the F. The study results indicate that MCF values were lower than the default value of 0.4 provided in the IPCC guidelines under aerobic conditions with a CH 4 concentration of less than 5%. According to the carbon balance analyses, there was a mismatch between the theoretical CH 4 /CO 2 ratio based on the F default value of 0.5 and the measured CH 4 /CO 2 ratio. Using the F calculation method proposed in this study, the theoretical CH 4 /CO 2 ratio and the measured CH 4 /CO 2 ratio was calculated equally. The F values during air injection ranged from 0.25 to 0.93 at three landfill sites, suggesting that adapting the F default value of 0.5 for active aeration landfills may lead to significant errors in the estimation of CH 4 emissions using the IPCC FOD model., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Two-photon microscopy (TPM) is an attractive biomedical imaging method due to its large penetration depth and optical sectioning capability. In particular, label-free autofluorescence imaging offers various advantages for imaging biological samples. However, relatively low intensity of autofluorescence leads to low signal-to-noise ratio (SNR), causing practical challenges for imaging biological samples. In this study, we present TPM using a pulse picker to utilize low pulse repetition rate of femtosecond pulsed laser to increase the pulse peak power of the excitation source leading to higher emission of two-photon fluorescence with the same average illumination power. Stronger autofluorescence emission allowed us to obtain higher SNR images of arterial and liver tissues. In addition, by applying the time gating detection method to the pulse signals obtained by TPM, we were able to significantly reduce the background noise of two-photon images. As a result, our TPM system using the pulsed light source with a 19 times lower repetition rate allowed us to obtain the same SNR image more than 19 times faster with the same average power. Although high pulse energy can increase the photobleaching, we also observed that high-speed imaging with low total illumination energy can mitigate the photobleaching effect to a level similar to that of conventional illumination with a high repetition rate. We anticipate that this simple approach will provide guidance for SNR enhancement with high-speed imaging in TPM as well as other nonlinear microscopy., (© 2023. Springer Nature Limited.)

GV1001, a 16 amino acid peptide derived from the catalytic segment of human telomerase reverse transcriptase, was developed as an anti-cancer vaccine. Subsequently, it was found to exhibit anti-inflammatory and anti-Alzheimer's disease properties. Periodontitis is a risk factor for a variety of systemic diseases, including atherosclerosis, a process in which chronic systemic and vascular inflammation results in the formation of plaques containing lipids, macrophages, foam cells, and tissue debris on the vascular intima. Thus, we investigated the effect of GV1001 on the severity of ligature-induced periodontitis, vascular inflammation, and arterial lipid deposition in mice. GV1001 notably reduced the severity of ligature-induced periodontitis by inhibiting gingival and systemic inflammation, alveolar bone loss, and vascular inflammation in wild-type mice. It also significantly lowered the amount of lipid deposition in the arterial wall in ApoE -deficient mice receiving ligature placement without changing the serum lipid profile. In vitro, we found that GV1001 inhibited the Receptor Activator of NF-κB ligand (RANKL)-induced osteoclast formation and tumor necrosis factor-α (TNF-α)-induced phenotypic changes in endothelial cells. In conclusion, our study suggests that GV1001 prevents the exacerbation of periodontitis and atherosclerosis associated with periodontitis partly by inhibiting local, systemic, and vascular inflammation and phenotypic changes of vascular endothelial cells.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS. As part of a randomised controlled trial evaluating the outcomes and costs of disclosing all clinically significant SFs from GS, we consulted genetics and primary care experts to determine a feasible workflow to manage SFs. Consensus was sought to determine appropriate clinical recommendations for each category of SF and which clinician specialist would provide follow-up care. We developed a communication and referral plan for each category of SFs. This involved referrals to specialised clinics, such as an Adult Genetics clinic, for highly penetrant medically actionable findings. Common and non-urgent SFs, such as pharmacogenomics and carrier status results for non-family planning participants, were directed back to the family physician (FP). SF results and recommendations were communicated directly to participants to respect autonomy and to their FPs to support follow-up of SFs. We describe a model for the return and referral of all clinically significant SFs to facilitate the utility of GS and promote the health benefits of SFs. This may serve as a model for others returning GS results transitioning participants from research to clinical settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Adrenal cortical carcinoma is an aggressive and rare malignancy of steroidogenic cells of the adrenal gland. Most adult adrenal cortical carcinomas are sporadic, but a small fraction may be associated with inherited tumor syndromes, such as Li-Fraumeni, multiple endocrine neoplasia 1, Lynch syndrome, and Beckwith-Wiedemann syndrome, as well as isolated case reports of non-syndromic manifestations occurring in the context of other pathogenic germline variants. Birt-Hogg-Dubé (BHD) is a rare autosomal dominant syndrome caused by germline pathogenic variants in the FLCN gene. BHD syndrome causes a constellation of symptoms, including cutaneous manifestations, pulmonary cysts and pneumothorax, and risk of renal tumors. With the exception of a single case of adrenal cortical carcinoma, very few reports on the occurrence of adrenal cortical neoplasia in patients with BHD syndrome have been described. However, information on variant allele fraction in the tumor was not available in the index case, which precludes any mechanism supporting loss of heterozygosity. Here we present a case of an adult-onset adrenal cortical carcinoma in a 50-year-old female, found to harbor a germline likely pathogenic variant in the FLCN gene, denoted as c.694C > T (p.Gln232Ter). Genetic testing on the tumor revealed the same FLCN variant at an allele fraction of 83%, suggesting a contributory role to the pathogenesis of the adrenal cortical carcinoma. This case further supports the expansion of the clinical presentation and tumor spectrum of BHD syndrome and the need to consider germline FLCN testing in the clinical genetic workup of patients with adrenal cortical carcinomas., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To report the genotype and phenotype of a cohort of unselected uveal melanoma (UM) patients who had germline multi-gene panel genetic testing, including the BAP1 gene, from a large multi-ethnic cancer centre. We describe the central role of the medical genetics clinic in collaboration with oncologists in a mainstreaming model to facilitate genetic testing, counselling and streamlining of patients with hereditary cancer predisposition., Methods: A retrospective chart review of clinical and genetic findings of unselected UM patients who had germline genetic testing between December 2019 and October 2021 was conducted. Extracted DNA from peripheral blood samples were analyzed with a multi-gene panel that included at least six genes associated with hereditary melanoma. The correlation between the genotype and the phenotype of the cohort was evaluated. Statistical analysis comprised descriptive and comparative statistics with significance assigned at p  < .05. The genetics clinic streamlined patients among the relevant oncology clinics for cancer screening in germline BAP1 positive individuals., Results: In unselected UM patients, 3.5% (4/114) tested positive for a BAP1 pathogenic variant. Germline BAP1 status was associated with a family history of mesothelioma ( p  = .0015) and metastatic disease ( p  = .017). There were no other significant associations between the patient- or tumour-related characteristics and germline BAP1 results., Conclusion: A germline BAP1 mutation was detected in 3.5% of unselected UM patients. The oncologist-initiated and genetics-led mainstreaming model is a straightforward process and can be utilized for offering genetic testing to all UM patients.

This study aimed to investigate the anti-inflammatory effects of ellagitannins from black raspberry seeds (BS) in vivo and the structural effects of ellagitannins on glucagon-like peptide-1 (GLP-1) secretion and intestinal bitter taste receptor (TAS2R) stimulation. For animal study, BS ellagitannin fraction (BSEF) was orally administered to mice with colitis induced by dextran sulfate sodium (DSS). The BSEF supplementation alleviated colonic inflammation, regulated inflammation-related cytokine levels in the mice with colitis, and increased the total GLP-1 secretion and GLP-1 receptor mRNA level in the inflamed gut. It also augmented the colonic gene expressions of mouse TAS2R (mTAS2R) 108, 119, 126, 131, 138, and 140; meanwhile, only mTAS2R108 expression was downregulated by DSS treatment. Six BS ellagitannins (sanguiin H-6, casuarictin, pedunculagin, acutissimin A, castalagin, and vescalagin) induced GLP-1 secretion in STC-1 cells and upregulated mTAS2R108, 119, 126, and 138 gene expressions. The major ellagitannins in BS (sanguiin H-6, casuarictin, pedunculagin, and acutissimin A) upregulated the gene expressions of mTAS2R131 and/or 140 known to be specifically distributed in mouse colon. Through molecular docking with mTAS2R108, the hexahydroxydiphenoyl, flavan-3-ol, glucose, and nonahydroxytriphenoyl moieties of the six BS ellagitannins were predicted to be involved in interacting with the receptor. BS ellagitannins could be promising candidates for preventing colon inflammation, likely via GLP-1 secretion induced by intestine-specific TAS2Rs.

Purpose: Genomic sequencing can generate complex results, including variants of uncertain significance (VUS). In general, VUS should not inform clinical decision-making. This study aimed to assess the public's expected management of VUS., Methods: An online, hypothetical survey was conducted among members of the Canadian public preceded by an educational video. Participants were randomized to 1 of 2 arms, VUS or pathogenic variant in a colorectal cancer gene, and asked which types of health services they expected to use for this result. Expected health service use was compared between randomization arms, and associations between participants' sociodemographic characteristics, attitudes, and medical history were explored., Results: Among 1003 respondents (completion rate 60%), more participants expected to use each type of health service for a pathogenic variant than for a VUS. However, a considerable proportion of participants expected to request monitoring (73.4%) and consult health care providers (60.9%) for a VUS. There was evidence to support associations between expectation to use health services for a VUS with family history of genetic disease, family history of cancer, education, and attitudes toward health care and technology., Conclusion: Many participants expected to use health services for a VUS in a colorectal cancer predisposition gene, suggesting a potential disconnect between patients' expectations for VUS management and guideline-recommended care., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Coconut haustorium (CH) is formed inside coconut shell during coconut germination. This study aimed to investigate the compositions and contents of CH phytochemicals. Phytochemical compositions and contents in CH were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and spectrophotometrical method. Five phenolic acids and four flavonoids were identified in CH. Ferulic acid and myricetin were the most abundant among phenolic acids and flavonoids identified in CH, respectively. Nepetariaside and 1-methylene-5α-androstan-3α-ol-17-one glucuronide were the most abundant terpenoids and steroid derivatives identified in CH, respectively. To our knowledge, this study screened several classes of phytochemicals in CH for the first. Terpenoids and steroid derivatives were likely to be more major phytochemicals than phenolic acids and flavonoids in CH. The functionality of CH itself and the compounds found in CH might be utilized in functional foods or cosmetics., Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01300-6., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© The Korean Society of Food Science and Technology 2023.)

Reflex genetic testing of tumor tissue is being completed to direct cancer treatment; however, the patient impact of this genetic testing model is unknown. This survey study evaluates psychological outcomes following tumor and germline genetic testing in individuals with a new diagnosis of high-grade serous ovarian cancer (HGSOC). Individuals were recruited from two hospitals in Toronto, Canada. Participants completed surveys 1 week after receiving tumor results and 1 week after receiving germline results (which included genetic counseling). Outcomes included cancer-related distress (Impact of Events Scale: IES), genetic testing-related distress (Multidimensional Impact of Cancer Risk Assessment: MICRA), and patient satisfaction. Paired t-tests were used to evaluate differences in outcomes following each genetic test result; Cohen's d was used to evaluate effect size. Subgroup analyses were undertaken according to age at diagnosis (<60 years vs. ≥60 years) and test results (any positive vs. both negative). McNemar's test assessed differences in satisfaction. Fifty-two individuals were included in the analyses. Mean IES scores were similar following disclosure of tumor and germline results (27.39 vs. 26.14; p = 0.481; d = 0.101). Compared to following tumor result disclosure, MICRA scores were significantly lower following receipt of germline results with genetic counseling (27.23 vs. 22.69; p = 0.007; d = 0.435). Decreases in MICRA scores from tumor to germline result disclosure were greater for those diagnosed <60 years or those who received only negative test results. Most individuals were satisfied/highly satisfied following tumor (85.7%) and germline (89.8%) results disclosure (p = 0.774). Reflex tumor, and subsequent germline, genetic testing is a new model of care for cancer patients. In our cohort, genetic testing-related distress decreased significantly following receipt of germline results with genetic counseling, especially for individuals diagnosed under 60 years and those receiving only negative results. Most individuals were satisfied with this model of care., (© 2022 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

We aimed to describe patient preferences for a broad range of secondary findings (SF) from genomic sequencing (GS) and factors driving preferences. We assessed preference data within a trial of the Genomics ADvISER, (SF decision aid) among adult cancer patients. Participants could choose from five categories of SF: (1) medically actionable; (2) polygenic risks; (3) rare diseases; (4) early-onset neurological diseases; and (5) carrier status. We analyzed preferences using descriptive statistics and drivers of preferences using multivariable logistic regression models. The 133 participants were predominantly European (74%) or East Asian or mixed ancestry (13%), female (90%), and aged > 50 years old (60%). The majority chose to receive SF. 97% (129/133) chose actionable findings with 36% (48/133) choosing all 5 categories. Despite the lack of medical actionability, participants were interested in receiving SF of polygenic risks (74%), carrier status (75%), rare diseases (59%), and early-onset neurologic diseases (53%). Older participants were more likely to be interested in receiving results for early-onset neurological diseases, while those exhibiting lower decisional conflict were more likely to select all categories. Our results highlight a disconnect between cancer patient preferences and professional guidelines on SF, such as ACMG's recommendations to only return medically actionable secondary findings. In addition to clinical evidence, future guidelines should incorporate patient preferences., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We developed a photocatalyzed Giese reaction of various weakly activated Michael acceptors with a neutral silicon-based radical precursor and applied it at large-scale using a continuous flow reactor. The developed method successfully overcomes the substrate scope limitations of previous studies, shows good functional groups tolerance, and affords good to excellent yields. On the basis of mechanistic studies, we propose a reaction mechanism that involves an in situ generated alkoxymethyl radical via single-electron oxidation of α-trimethylsilyl-substituted ethers.

Spinach has been suggested as a potential rotation crop for increasing crop yield by enhancing beneficial fungal microbes in continuous monocropping. However, no research on the use of spinach as a green manure has been reported. Thus, we tested the effects of spinach and Korean mustard cultivars (green and red mustards) (10 g pot -1 ) as green manure on soil chemical properties, pepper productivity, and soil microbiome of long-year pepper-monocropped soil. Spinach improved the soil nutrition (e.g., pH, SOM, TN, NH 4 + , and K), weed suppression, and pepper growth. Spinach had by far the highest fruit yield, over 100% pepper fruit yield increment over the mustard green manures and control. Our study showed that the major influencing factors to cause a shift in both bacterial and fungal community assemblies were soil pH, TC TN, and K. Following green manure amendment Bacillota, especially Clostridium, Bacillus and Sedimentibacter, were enriched, whereas Chloroflexi and Acidobacteriota were reduced. In addition, spinach highly reduced the abundance of Leotiomycetes and Fusarium but enriched Papiliotrema. FAPROTAX and FUNGuild analysis revealed that predicted functional profiles of bacterial and fungal communities in spinach-amended soil were changed. Spinach-treated soil was differentially abundant in function related to hydrocarbon degradation and functional guilds of symbiotrophs and ectomycorrhizal. This study contributes significantly to our understanding of how the soil fertility and soil microbiome alteration via spinach green manure application as a pre-plant soil treatment might help alleviate continuous cropping obstacles., (© 2023. The Author(s).)

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis., Significance: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517., (©2023 The Authors; Published by the American Association for Cancer Research.)

In our previous study, black raspberry (BR) reduced the serum levels of trimethylamine- N -oxide and cholesterol in rats fed excessive choline with a high-fat diet (HFC). We hypothesized that gut microbiota could play a crucial role in the production of trimethylamine and microbial metabolites, and BR could influence gut microbial composition. This study aimed to elucidate the role of BR on changes in gut microbiota and microbial metabolites in the rats. The phylogenetic diversity of gut microbiota was reduced in the rats fed HFC, while that in the BR-fed group was restored. The BR supplementation enriched Bifidobacterium and reduced Clostridium cluster XIVa. In the BR-fed group, most cecal bile acids and hippuric acid increased, while serum lithocholic acid was reduced. The BR supplementation upregulated Cyp7a1 and downregulated Srebf2 . These results suggest that BR extract may change gut bacterial community, modulate bile acids, and regulate gene expression toward reducing cholesterol., Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01267-4., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© The Korean Society of Food Science and Technology 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Globally, cardiac arrest (CA) is a leading cause of death and disability. Asphyxial CA (ACA)-induced kidney damage is a crucial factor in reducing the survival rate. The purpose of this study was to investigate the role of antioxidant enzymes in histopathological renal damage in an ACA rat model at different time points. A total of 88 rats were divided into five groups and exposed to ACA except for the sham group. To evaluate glomerular function and oxidative stress, serum levels of blood urea nitrogen (BUN) and creatinine (Crtn) and malondialdehyde (MDA) levels in renal tissues were measured. To determine histopathological damage, hematoxylin and eosin staining, periodic acid-Schiff staining, and Masson's trichrome staining were performed. Expression levels of antioxidant enzymes including superoxide dismutase-1 (SOD-1), superoxide dismutase-2 (SOD-2), catalase (CAT), and glutathione peroxidase (GPx) were measured by immunohistochemistry (IHC). Survival rate of the experimental rats was reduced to 80% at 6 h, 55% at 12 h, 42.9% at 1 day, and 33% at 2 days after return of spontaneous circulation. Levels of BUN, Crtn, and MDA started to increase significantly in the early period of CA induction. Renal histopathological damage increased markedly from 6 h until two days post-CA. Additionally, expression levels of antioxidant enzymes were significantly decreased at 6 h, 12 h, 1 day, and 2 days after CA. CA-induced oxidative stress and decreased levels of antioxidant enzymes (SOD-1, SOD-2, CAT, GPx) from 6 h to two days could be possible mediators of severe renal tissue damage and increased mortality rate.

Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page-supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient in filtration and prioritization: a median of just two CNVs per case were selected for review, yet it captured all P/LP findings (92.5% of which ranked 1st). SCIP was also able to identify one pathogenic CNV previously missed. SCIP was benchmarked against AnnotSV and a spreadsheet-based manual workflow and performed superiorly than both. In conclusion, SCIP is a novel software package for efficient clinical CNV interpretation, substantially faster and more accurate than previous tools (available at https://github.com/qd29/SCIP , a video tutorial series is available at https://bit.ly/SCIPVideos )., (© 2022. The Author(s).)

Ginseng is a profitable crop worldwide; however, the ginseng replanting problem (GRP) is a major threat to its production. Soil amendment is a non-chemical method that is gaining popularity for alleviating continuous cropping obstacles, such as GRP. However, the impact of soil amendment with either cow dung or canola on GRP reduction and the associated soil microbiota remains unclear. In the present study, we evaluated the effect of soil amendment with cow dung, canola seed powder, and without amendment (control), on the survival of ginseng seedling transplants, the soil bacterial and fungal communities, and their associated metabolic functions. The results showed that cow dung increased ginseng seedling survival rate by 100 percent and had a remarkable positive effect on ginseng plant growth compared to control, whereas canola did not. Cow dung improved soil nutritional status in terms of pH, electrical conductivity, NO 3 - , total carbon, total phosphorus, and available phosphorus. The amplicon sequencing results using Illumina MiSeq showed that canola had the strongest negative effect in reducing soil bacterial and fungal diversity. On the other hand, cow dung stimulated beneficial soil microbes, including Bacillus , Rhodanobacter , Streptomyces , and Chaetomium , while suppressing Acidobacteriota. Community-level physiological profiling analysis using Biolog Ecoplates containing 31 different carbon sources showed that cow dung soil had a different metabolic activity with higher utilization rates of carbohydrates and polymer carbon sources, mainly Tween 40 and beta-methyl-d-glucoside. These carbon sources were most highly associated with Bacillota. Furthermore, predicted ecological function analyses of bacterial and fungal communities showed that cow dung had a higher predicted function of fermentation and fewer functions related to plant pathogens and fungal parasites, signifying its potential to enhance soil suppressiveness. Co-occurrence network analysis based on random matrix theory (RMT) revealed that cow dung transformed the soil microbial network into a highly connected and complex network. This study is the first to report the alleviation of GRP using cow dung as a soil amendment, and the study contributes significantly to our understanding of how the soil microbiota and metabolic alterations via cow dung can aid in GRP alleviation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tagele, Kim, Jeong, Lim, Jung, Lee, Kim and Shin.)

Von Hippel-Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individuals to developing tumors in many organs. There is significant phenotypic variability and genetic variants encountered within this syndrome, posing a considerable challenge to patient care. The lack of VHL variant data sharing paired with the absence of aggregated genotype-phenotype information results in an arduous process, when characterizing genetic variants and predicting patient prognosis. To address these gaps in knowledge, the Clinical Genome Resource (ClinGen) VHL Variant Curation Expert Panel (VCEP) has been resolving a list of variants of uncertain significance within the VHL gene. Through community curation, we crowdsourced the laborious task of variant annotation by modifying the ClinGen Community Curation (C3)-developed Baseline Annotation protocol and annotating all published VHL cases with the reported genotype-phenotype information in Hypothes.is, an open-access web annotation tool. This process, incorporated into the ClinGen VCEP's workflow, will aid in their curation efforts. To facilitate the curation at all levels of genetics expertise, our team developed a 4-day biocuration training protocol and resource guide. To date, 91.3% of annotations have been completed by undergraduate and high-school students without formal academic genetics specialization. Here, we present our VHL-specific annotation protocol utilizing Hypothes.is, which offers a standardized method to present case-resolution data, and our biocuration training protocol, which can be adapted for other rare disease platforms. By facilitating training for community curation of VHL disease, we increased student engagement with clinical genetics while enhancing knowledge translation in the field of hereditary cancer. Database URL: https://hypothes.is/groups/dKymJJpZ/vhl-hypothesis-annotation., (© The Author(s) 2023. Published by Oxford University Press.)

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Background: Patients with alopecia areata (AA) may access a wide range of sources for information about AA, including the recently developed ChatGPT. Assessing the quality of health information provided by these sources is crucial, as patients are utilizing them in increasing numbers., Objectives: The aim of the study was to evaluate appropriateness and accuracy of responses to common patient questions about AA generated by ChatGPT., Methods: Responses generated by ChatGPT 3.5 and ChatGPT 4.0 to 25 questions addressing common patient concerns were assessed by multiple attending dermatologists in an academic center for appropriateness and accuracy. Appropriateness of responses by both models for use in two hypothetical contexts as follows: (1) for patient-facing general information websites, and (2) for electronic health record (EHR) message drafts., Results: The accuracy across all responses was 4.41 out of 5. Accuracy scores of responses ChatGPT 3.5 responses had a mean of 4.29, whereas those generated by ChatGPT 4.0 had mean accuracy score of 4.53. Assessments ranged from 100% of responses rated as appropriate for the general question category to 79% questions about management for an EHR message draft. Raters largely preferred responses generated by ChatGPT 4.0 versus ChatGPT 3.5. Reviewer agreement was found to be moderate across all questions, with a 53.7% agreement and Fleiss' κ co-efficient of 0.522 (p value &lt;0.001)., Conclusions: The large language model ChatGPT outputted mostly appropriate information for common patient concerns. While not all responses were accurate, the trend toward improvement with newer iterations suggests potential future utility for patients and dermatologists., (© 2023 S. Karger AG, Basel.)

Pyoderma gangrenosum (PG) is a rare, and often challenging to diagnose, inflammatory disorder with relatively high rates of morbidity and mortality. Central to the diagnosis of PG is histologic evaluation and exclusion of other entities. Large-scale studies investigating the proportion of patients receiving a thorough diagnostic work-up, as well as prevalence studies regarding comorbidities and systemic treatment in PG using claims-based data, are sparse. Our objective was to identify patients diagnosed with PG and describe the diagnostic work-up and prevalence of common comorbidities and therapies in this population using claims-based data in a retrospective cohort study. In order to better understand practices of diagnostic work-up, we captured rates of skin biopsy, tissue culture, and/or surgical debridement prior to initial diagnosis. We also identified the prevalence of PG-associated comorbidities and initial immunosuppressive therapy given for PG. Of the 565 patients diagnosed with PG, 9.4% underwent skin biopsy, 8% tissue culture, and 1.4% both skin biopsy AND tissue culture prior to diagnosis. Inflammatory bowel disease was the most prevalent comorbidity (16.3%). The most common treatment administered was systemic corticosteroids (17%). Although practice guidelines explicitly delineate histology and exclusion of infection as important diagnostic criteria, only a minority of patients in this study underwent skin biopsy and/or tissue culture prior to receiving a diagnosis of PG, suggesting that patients may receive a diagnosis of PG without having tissue evaluation. Such discordance between practice guidelines and "real-world" practice inevitably increases the risk for misdiagnosis of PG and misdirected treatment with immunosuppressants for presumptive PG in cases of PG mimickers. Moreover, comorbidities associated with PG may occur, or be identified in, a lower proportion of patients as compared with what is reported in the existing literature. Study limitations include a population restricted to < 65 years with commercial insurance and the reliance upon ICD diagnostic coding to capture the population., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Genomic sequencing (GS) can reveal secondary findings (SFs), findings unrelated to the reason for testing, that can be overwhelming to both patients and providers. An effective approach for communicating all clinically significant primary and secondary GS results is needed to effectively manage this large volume of results. The aim of this study was to develop a comprehensive approach to communicate all clinically significant primary and SF results. A genomic test report with accompanying patient and provider letters were developed in three phases: review of current clinical reporting practices, consulting with genetic and non-genetics experts, and iterative refinement through circulation to key stakeholders. The genomic test report and consultation letters present a myriad of clinically relevant GS results in distinct, tabulated sections, including primary (cancer) and secondary findings, with in-depth details of each finding generated from exome sequencing. They provide detailed variant and disease information, personal and familial risk assessments, clinical management details, and additional resources to help support providers and patients with implementing healthcare recommendations related to their GS results. The report and consultation letters represent a comprehensive approach to communicate all clinically significant SFs to patients and providers, facilitating clinical management of GS results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This study aimed to identify ellagitannins in black raspberry seeds (BRS) and to optimize accelerated solvent extraction of ellagitannins using an artificial neural network (ANN) coupled with genetic algorithm. Fifteen monomeric and dimeric ellagitannins were identified in BRS. For ANN modeling, extraction time, extraction temperature, and solvent concentration were set as input variables, and total ellagitannin content was set as output variable. The trained ANN had a mean squared error value of 0.0102 and a regression correlation coefficient of 0.9988. The predicted optimal extraction conditions for maximum total ellagitannin content were 63.7% acetone, 4.21 min, and 43.9 °C. The actual total ellagitannin content under the optimal extraction conditions was 13.4 ± 0.0 mg/g dry weight, and the prediction error was 0.75 ± 0.27%. This study is the first attempt to analyze the composition of ellagitannins in BRS and to determine optimal extraction conditions for maximum total ellagitannin content from BRS., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: As research on hereditary hematologic malignancy syndromes (HHMS) are accumulating, cancer genetics clinics are identifying more adult hematology patients with an inherited component to their disease. However, investigations for HHMS are complex, and there is no formal consensus on genetic testing criteria., Methods: We developed genetic testing criteria for adult hematology patients through a comprehensive literature review and our experience at the Princess Margaret Cancer Centre. We validated our criteria by applying them retrospectively to patients referred to our clinic for HHMS assessment., Results: Our genetic testing criteria are comprehensive of myeloid malignancies, lymphoid malignancies, and bone marrow failure, including age at diagnosis, family history, and genetic test results in blood and bone marrow. Of the 104 patients who met the criteria, 26% had at least 1 actionable variant in any gene associated with an increased risk of cancer and 13% had an actionable variant resulting in an HHMS diagnosis. A total of 15 patients had incidental findings, including 11 patients with a pathogenic variant associated with carrier status for an autosomal recessive disorder and 4 patients with a mosaic result., Conclusion: Our high gene positivity rate shows the utility of a broad approach to germline testing in an adult hematology population., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

Competing Interests: The authors declare no conflicts of interest.

Introduction: During regenerative endodontic procedures, the microenvironment of the canal is formed by the degree of disinfection and release of ions from the applied materials onto the top surface. This study aimed to characterize the effects of amnion-chorion membrane and collagen membrane on pulp-dentin regeneration compared to calcium silicate cements (CSCs), focusing on cell migration, mineralization potential, anti-inflammation, and angiogenesis., Methods: Two CSCs and 2 membranes were used: ProRoot MTA (Dentsply, Tulsa, OK, USA), RetroMTA (BioMTA, Seoul, Korea), Collagen Membrane (Genoss, Suwon, Korea), and BioXclude (amnion-chorion membrane; Snoasis Medical, Colorado, USA). Transwell and scratch assays were used to evaluate cell migration and wound healing. Mineralization potential was evaluated using alkaline phosphatase activity, Alizarin red S staining, and quantitative real-time polymerase chain reaction for the expression of marker genes. Quantitative real-time polymerase chain reaction was used to measure the levels of angiogenic genes and inflammatory mediators. An endothelial tube formation assay was used to assess angiogenesis., Results: The membranes showed superior migration and wound healing compared with CSCs. Except for RetroMTA, ProRoot MTA and the 2 membranes showed high alkaline phosphatase activity and mineralization nodule formation and upregulated mRNA expression of markers for mineralization. Membranes upregulated the mRNA of angiogenesis genes and increased the capillary tube formation of endothelial cells compared to CSCs. Furthermore, the membrane matrix decreased the expression of inflammatory genes., Conclusions: Collagen membrane and Amnion-chorion membrane showed prominent cell migration, angiogenesis, and healing effects against inflammation, as well as comparable mineralization potential compared to CSCs, recommending the use of membrane as a matrix., (Copyright © 2022 American Association of Endodontists. All rights reserved.)

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome where individuals are predisposed to tumor development in the brain, adrenal gland, kidney, and other organs. It is caused by pathogenic variants in the VHL tumor suppressor gene. Standardized disease information has been difficult to collect due to the rarity and diversity of VHL patients. Over 4100 unique articles published until October 2019 were screened for germline genotype-phenotype data. Patient data were translated into standardized descriptions using Human Genome Variation Society gene variant nomenclature and Human Phenotype Ontology terms and has been manually curated into an open-access knowledgebase called Clinical Interpretation of Variants in Cancer. In total, 634 unique VHL variants, 2882 patients, and 1991 families from 427 papers were captured. We identified relationship trends between phenotype and genotype data using classic statistical methods and spectral clustering unsupervised learning. Our analyses reveal earlier onset of pheochromocytoma/paraganglioma and retinal angiomas, phenotype co-occurrences and genotype-phenotype correlations including hotspots. It confirms existing VHL associations and can be used to identify new patterns and associations in VHL disease. Our database serves as an aggregate knowledge translation tool to facilitate sharing information about the pathogenicity of VHL variants., (© 2022 The Authors. Human Mutation published by Wiley Periodicals LLC.)

Alcohol consumption is associated with an increased risk of several cancers, including oral/oropharyngeal squamous cell carcinoma (OSCC). Alcohol also enhances the progression and aggressiveness of existing cancers; however, its underlying molecular mechanism remains elusive. Especially, the local carcinogenic effects of alcohol on OSCC in closest contact with ingestion of alcohol are poorly understood. We demonstrated that chronic ethanol exposure to OSCC increased cancer stem cell (CSC) populations and their stemness features, including self-renewal capacity, expression of stem cell markers, ALDH activity, and migration ability. The ethanol exposure also led to a significant increase in aerobic glycolysis. Moreover, increased aerobic glycolytic activity was required to support the stemness phenotype of ethanol-exposed OSCC, suggesting a molecular coupling between cancer stemness and metabolic reprogramming. We further demonstrated that chronic ethanol exposure activated NFAT (nuclear factor of activated T cells) signaling in OSCC. Functional studies revealed that pharmacological and genetic inhibition of NFAT suppressed CSC phenotype and aerobic glycolysis in ethanol-exposed OSCC. Collectively, chronic ethanol exposure promotes cancer stemness and aerobic glycolysis via activation of NFAT signaling. Our study provides a novel insight into the roles of cancer stemness and metabolic reprogramming in the molecular mechanism of alcohol-mediated carcinogenesis.

Competing Interests: None disclosed.

Hyperlipidemia is a major risk of atherosclerosis; however, systemic inflammatory diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus and systemic sclerosis are also known risks for the development of atherosclerosis. Periodontitis, a local and systemic inflammatory condition, has also been reported as a risk for atherosclerosis, but the specific link between periodontitis and atherosclerosis remains somewhat controversial. We previously reported that ligature‑induced periodontitis exacerbates atherosclerosis in hyperlipidemic Apolipoprotein E‑deficient ( ApoE ‑/‑ ) mice. To understand whether hyperlipidemia is necessary for the development and exacerbation of atherosclerosis associated with periodontitis, the present study created ligature‑induced periodontitis in both wild‑type (WT) and ApoE ‑/‑ mice. Subsequently, the status of local, systemic and vascular inflammation, serum lipid contents and arterial lipid deposition were examined with histological analysis, µ CT, en face analysis, serum lipid and cytokine measurements, reverse transcription‑quantitative PCR and immunohistochemical analysis. Ligature placement induced severe periodontitis in both WT and ApoE ‑/‑ mice at the local level as demonstrated by gingival inflammation, alveolar bone loss, increased osteoclastic activities and inflammation in alveolar bone. Systemic inflammation was also induced by ligature placement in both WT and ApoE ‑/‑ mice, albeit more so in ApoE ‑/‑ mice. The serum cholesterol levels were not altered by the ligature in both WT and ApoE ‑/‑ mice. However, the vascular inflammation and arterial lipid deposition were induced by ligature‑induced periodontitis only in ApoE ‑/‑ mice, but not in WT mice. The present study indicated that the coupling of systemic inflammation and hyperlipidemia was necessary for the development and exacerbation of atherosclerosis induced by ligature‑induced periodontitis in mice.

The purpose of this randomized controlled clinical trial was to assess the short-term clinical effectiveness of sealer-based root canal obturation using calcium-silicate-based sealer (CSBS) and epoxy-resin-based sealer (ERBS). A total of eighty patients (eighty teeth) were enrolled and seventy-two patients (seventy-two teeth) were randomly assigned into four different sealer groups: AH Plus (AH, Dentsply Sirona), ADseal (AD, Meta Biomed), CeraSeal (CS, Meta Biomed), or EndoSeal TCS (ES, Maruchi). At the first visit, root canal treatment was performed using ProTaper. Next, the NiTi file system and passive ultrasonic irritation was applied with 2.5% NaOCl. At the second visit, the teeth were obturated with a sealer-based obturation technique using the assigned sealer. The quality of filling obturation was evaluated with postoperative radiographs in terms of the presence of voids and sealer extrusion. The patients were recalled at 1-week, 1-month, and 3-month intervals, and pain levels were measured using visual analog scales (VAS), and clinical examination performed with percussion and palpation. Radiographs were also taken. The results were statistically compared by using the χ2 test or Fisher exact test. Among the 80 teeth included, 72 teeth received allocated intervention and 71 teeth were included in the analysis (98.6% recall). There was no significant difference among the sealers in void and sealer extrusion (p > 0.05). Postoperative pain was not indicated prominently regardless of the type of sealer. For a 3-month follow-up period, all cases were maintained successfully except for one case from AD. According to the findings, there was no significant difference between CSBS and ERBS in terms of postoperative pain or the healing process, and the variation in filling quality appears to be linked to the properties of each product.

Background: Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1., Case Presentation: A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics., Conclusions: We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1., (© 2022. The Author(s).)