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PURPOSE: The current supraomohyoid neck dissection (SOHND) is performed above the omohyoid muscle to dissect levels I, II, and III in the levels of cervical lymph nodes. However, the anatomical boundary between levels III and IV is the inferior border of the cricoid cartilage. We investigated the anatomical relationship between the omohyoid muscle and cricoid cartilage using contrast-enhanced CT (CE-CT) images to assess the validity of the current SOHND. METHODS: CE-CT images of the head and neck regions in patients were reviewed. The patients were divided into two groups: "malignant tumors" and "others". The vertebral levels corresponding to the positions of anatomical structures such as the intersection of the omohyoid muscle and internal jugular vein (OM-IJ), and the inferior border of the cricoid cartilage (CC), were recorded. RESULTS: The OM-IJ was located around the seventh cervical to the first thoracic vertebra. There was a significant difference between the malignant tumor and others groups in females (p = 0.036). The CC was located around the sixth to seventh cervical vertebrae. There was a significant sex difference in each group (malignant tumor: p < 0.0001; others: p = 0.008). Both sexes tended to have lower OM-IJ than CC, and females had significantly lower OM-IJ than males. CONCLUSION: This study provides clear anatomical evidence showing the difference between the SOHND dissection area and levels I, II, and III. It could be considered that in most cases SOHND invades level IV, not just levels I, II, and III, especially in female patients.
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Purpose Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents such as bisphosphonates (BPs) and denosumab (DMB). We investigated whether a difference exists between BP- and DMB-related osteonecrosis of the jaw (ONJ). Patients and methods Histological images of 30 patients with BP-related ONJ and 13 patients with DMB-related ONJ were observed using hematoxylin-eosin and cathepsin K staining. Moreover, bone metabolism markers in the blood and bone mineral density were measured in 18 patients with BP-related ONJ and five patients with DMB-related ONJ. Furthermore, we conducted a quantitative analysis of local bone metabolism-related genes using surgical specimens through real-time reverse transcription polymerase chain reaction. Additionally, a retrospective study of 298 patients with MRONJ examined the differences in the characteristics of BP- and DMB-related ONJ and the factors associated with treatment outcomes. Results Histological examination revealed that patients treated with DMB had more severe osteoclast suppression than those treated with BP. No significant difference was observed in blood-bone metabolism markers between the two drugs; however, the suppression of local bone metabolism-related genes was stronger in patients treated with DMB. Clinical studies indicate that DMB-related ONJ is more frequently observed without osteolysis. Conclusion BP-associated ONJ and DMB-associated ONJ were shown to differ slightly. Clinical studies indicate that osteolysis is often unclear in DMB-related ONJ, and methods of bone resection during surgery need to be established.
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An autism-associated gene Shank3 encodes multiple splicing isoforms, Shank3a-f. We have recently reported that Shank3a/b-knockout mice were more susceptible to kainic acid-induced seizures than wild-type mice at 4 weeks of age. Little is known, however, about how the N-terminal and ankyrin repeat domains (NT-Ank) of Shank3a/b regulate multiple molecular signals in the developing brain. To explore the functional roles of Shank3a/b, we performed a mass spectrometry-based proteomic search for proteins interacting with GFP-tagged NT-Ank. In this study, NT-Ank was predicted to form a variety of complexes with a total of 348 proteins, in which RNA-binding (n = 102), spliceosome (n = 22), and ribosome-associated molecules (n = 9) were significantly enriched. Among them, an X-linked intellectual disability-associated protein, Nono, was identified as a NT-Ank-binding protein. Coimmunoprecipitation assays validated the interaction of Shank3 with Nono in the mouse brain. In agreement with these data, the thalamus of Shank3a/b-knockout mice aberrantly expressed splicing isoforms of autism-associated genes, Nrxn1 and Eif4G1, before and after seizures with kainic acid treatment. These data indicate that Shank3 interacts with multiple RNA-binding proteins in the postnatal brain, thereby regulating the homeostatic expression of splicing isoforms for autism-associated genes after birth.
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BACKGROUND & AIMS: Gastric cancer is often accompanied by a loss of mucin 6 (MUC6), but its pathogenic role in gastric carcinogenesis remains unclear. METHODS: Muc6 knockout (Muc6-/-) mice and Muc6-dsRED mice were newly generated. Tff1Cre, Golph3-/-, R26-Golgi-mCherry, Hes1flox/flox, Cosmcflox/flox, and A4gnt-/- mice were also used. Histology, DNA and RNA, proteins, and sugar chains were analyzed by whole-exon DNA sequence, RNA sequence, immunohistochemistry, lectin-binding assays, and liquid chromatography-mass spectrometry analysis. Gastric organoids and cell lines were used for in vitro assays and xenograft experiments. RESULTS: Deletion of Muc6 in mice spontaneously causes pan-gastritis and invasive gastric cancers. Muc6-deficient tumor growth was dependent on mitogen-activated protein kinase activation, mediated by Golgi stress-induced up-regulation of Golgi phosphoprotein 3. Glycomic profiling revealed aberrant expression of mannose-rich N-linked glycans in gastric tumors, detected with banana lectin in association with lack of MUC6 expression. We identified a precursor of clusterin as a binding partner of mannose glycans. Mitogen-activated protein kinase activation, Golgi stress responses, and aberrant mannose expression are found in separate Cosmc- and A4gnt-deficient mouse models that lack normal O-glycosylation. Banana lectin-drug conjugates proved an effective treatment for mannose-rich murine and human gastric cancer. CONCLUSIONS: We propose that Golgi stress responses and aberrant glycans are important drivers of and promising new therapeutic targets for gastric cancer.
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Camundongos Knockout , Mucina-6 , Neoplasias Gástricas , Animais , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Glicosilação , Humanos , Mucina-6/metabolismo , Mucina-6/genética , Camundongos , Linhagem Celular Tumoral , Carcinogênese/metabolismo , Carcinogênese/genética , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Fator Trefoil-1/metabolismo , Fator Trefoil-1/genética , Organoides/metabolismo , Complexo de Golgi/metabolismo , Mucinas Gástricas/metabolismo , Modelos Animais de DoençasRESUMO
Histological observation under light microscopy has long been used in human cadaveric studies. However, it can distort the interpretations of findings if not used appropriately; there is no guide for its proper use. The aim of this article is to revisit and discuss the correct use of histology in human cadaveric studies, following discussions with experts in multiple fields of medicine, and to create the first guide for such usage. We reached a consensus with the experts, agreeing that when this principle (structure, quantification, interaction, position: SQIP) is applied to histological observations, the findings will be interpreted correctly. Appropriate use of this recommendation can make human cadaveric studies more accurate and informative. This is the first histology guide for human cadaveric studies.
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Cadáver , Microscopia , Humanos , Microscopia/métodosRESUMO
The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-Indian hedgehog feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP+ resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we specifically activated Hedgehog signaling in PTHrP+ resting chondrocytes and traced the fate of their descendants using a tamoxifen-inducible Pthrp-creER line with patched-1-floxed and tdTomato reporter alleles. Hedgehog-activated PTHrP+ chondrocytes formed large, concentric, clonally expanded cell populations within the resting zone ("patched roses") and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP+ cell descendants migrated away from the growth plate and transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a potentially novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP+ skeletal stem cells.
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Condrócitos , Proteína Relacionada ao Hormônio Paratireóideo , Proteína Vermelha Fluorescente , Camundongos , Animais , Condrócitos/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Lâmina de Crescimento , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Proteínas Hedgehog/metabolismoRESUMO
Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non-endosteal perisinusoidal niche. Single-cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor-making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast-chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell-like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation.
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Doenças Ósseas , Medula Óssea , Humanos , Medula Óssea/metabolismo , Osteogênese , Osteoblastos/metabolismo , Doenças Ósseas/metabolismo , Doenças Ósseas/patologia , Células-Tronco , Células da Medula Óssea/metabolismoRESUMO
Single-cell omics and multi-omics have revolutionized our understanding of molecular and cellular biological processes at a single-cell level. In bone biology, the combination of single-cell RNA-sequencing analyses and in vivo lineage-tracing approaches has successfully identified multi-cellular diversity and dynamics of skeletal cells. This established a new concept that bone growth and regeneration are regulated by concerted actions of multiple types of skeletal stem cells, which reside in spatiotemporally distinct niches. One important subtype is endosteal stem cells that are particularly abundant in young bone marrow. The discovery of this new skeletal stem cell type has been facilitated by single-cell multi-omics, which simultaneously measures gene expression and chromatin accessibility. Using single-cell omics, it is now possible to computationally predict the immediate future state of individual cells and their differentiation potential. In vivo validation using histological approaches is the key to interpret the computational prediction. The emerging spatial omics, such as spatial transcriptomics and epigenomics, have major advantage in retaining the location of individual cells within highly complex tissue architecture. Spatial omics can be integrated with other omics to further obtain in-depth insights. Single-cell multi-omics are now becoming an essential tool to unravel intricate multicellular dynamics and intercellular interactions of skeletal cells.
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Vertebrates form their skeletal tissues from three distinct origins (the neural crest, paraxial mesoderm, and lateral plate mesoderm) through two distinct modes of ossification (intramembranous and endochondral ossification). Since the paraxial mesoderm generates both intramembranous and endochondral bones, it is thought to give rise to both osteoprogenitors and osteo-chondroprogenitors. However, it remains unclear what directs the paraxial mesoderm-derived cells toward these different fates in distinct skeletal elements during human skeletal development. To answer this question, we need experimental systems that recapitulate paraxial mesoderm-mediated intramembranous and endochondral ossification processes. In this study, we aimed to develop a human pluripotent stem cell (hPSC)-based system that models the human intramembranous ossification process. We found that spheroid culture of the hPSC-derived paraxial mesoderm derivatives generates osteoprogenitors or osteo-chondroprogenitors depending on stimuli. The former induced intramembranous ossification, and the latter endochondral ossification, in mouse renal capsules. Transcriptional profiling supported the notion that bone signatures were enriched in the intramembranous bone-like tissues. Thus, we developed a system that recapitulates intramembranous ossification, and that enables the induction of two distinct modes of ossification by controlling the cell fate of the hPSC-derived paraxial mesoderm derivatives.
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The resting zone of the postnatal growth plate is organized by slow-cycling chondrocytes expressing parathyroid hormone-related protein (PTHrP), which include a subgroup of skeletal stem cells that contribute to the formation of columnar chondrocytes. The PTHrP-indian hedgehog (Ihh) feedback regulation is essential for sustaining growth plate activities; however, molecular mechanisms regulating cell fates of PTHrP + resting chondrocytes and their eventual transformation into osteoblasts remain largely undefined. Here, in a mouse model, we utilized a tamoxifen-inducible PTHrP-creER line with Patched-1 ( Ptch1 ) floxed and tdTomato reporter alleles to specifically activate Hedgehog signaling in PTHrP + resting chondrocytes and trace the fate of their descendants. Hedgehog-activated PTHrP + chondrocytes formed large concentric clonally expanded cell populations within the resting zone (' patched roses ') and generated significantly wider columns of chondrocytes, resulting in hyperplasia of the growth plate. Interestingly, Hedgehog-activated PTHrP + cell-descendants migrated away from the growth plate and eventually transformed into trabecular osteoblasts in the diaphyseal marrow space in the long term. Therefore, Hedgehog activation drives resting zone chondrocytes into transit-amplifying states as proliferating chondrocytes and eventually converts these cells into osteoblasts, unraveling a novel Hedgehog-mediated mechanism that facilitates osteogenic cell fates of PTHrP + skeletal stem cells.
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BACKGROUND: Lenvatinib was expected to enhance the effect of immune checkpoint inhibitors (ICIs) for unresectable HCC; however, their combination therapy failed to show the synergy in the phase III clinical trial. METHODS: To elucidate lenvatinib-induced molecular modulation, we performed bulk RNA-sequencing and digital spatial profiling of 5 surgically resected human HCC specimens after lenvatinib treatment and 10 matched controls without any preceding therapy. FINDINGS: Besides its direct antitumor effects, lenvatinib recruited cytotoxic GZMK+CD8 T cells in intratumor stroma by CXCL9 from tumor-associated macrophages, suggesting that lenvatinib-treated HCC is in the so-called excluded condition that can diminish ICI efficacy.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Inibidores de Checkpoint Imunológico , Linfócitos T CD8-PositivosRESUMO
The bone is an important organ that performs various functions, and the bone marrow inside the skeleton is composed of a complex intermix of hematopoietic, vascular, and skeletal cells. Current single-cell RNA sequencing (scRNA-seq) technology has revealed heterogeneity and sketchy differential hierarchy of skeletal cells. Skeletal stem and progenitor cells (SSPCs) are located upstream of the hierarchy and differentiate into chondrocytes, osteoblasts, osteocytes, and bone marrow adipocytes. In the bone marrow, multiple types of bone marrow stromal cells (BMSCs), which have the potential of SSPCs, are spatiotemporally located in distinct areas, and SSPCs' potential shift of BMSCs may occur with the advancement of age. These BMSCs contribute to bone regeneration and bone diseases, such as osteoporosis. In vivo lineage-tracing technologies show that various types of skeletal lineage cells concomitantly gather and contribute to bone regeneration. In contrast, these cells differentiate into adipocytes with aging, leading to senile osteoporosis. scRNA-seq analysis has revealed that alteration in the cell-type composition is a major cause of tissue aging. In this review, we discuss the cellular dynamics of skeletal cell populations in bone homeostasis, regeneration, and osteoporosis.
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Células-Tronco Mesenquimais , Osteoporose , Humanos , Adipócitos , Células-Tronco , Células da Medula Óssea , Osteoporose/genética , Osteoblastos , RNA , Diferenciação Celular/genética , Osteogênese/genéticaRESUMO
The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR)+ perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3+ endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3+ endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis.
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Medula Óssea , Osteogênese , Adulto , Humanos , Idoso , Osteogênese/genética , Medula Óssea/metabolismo , Osso e Ossos , Osteoblastos/metabolismo , Células-Tronco , Carcinogênese/genética , Carcinogênese/metabolismo , Células da Medula Óssea/metabolismo , Diferenciação CelularRESUMO
Bone development starts with condensations of undifferentiated mesenchymal cells that set a framework for future bones within the primordium. In the endochondral pathway, mesenchymal cells inside the condensation differentiate into chondrocytes and perichondrial cells in a SOX9-dependent mechanism. However, the identity of mesenchymal cells outside the condensation and how they participate in developing bones remain undefined. Here we show that mesenchymal cells surrounding the condensation contribute to both cartilage and perichondrium, robustly generating chondrocytes, osteoblasts, and marrow stromal cells in developing bones. Single-cell RNA-seq analysis of Prrx1-cre-marked limb bud mesenchymal cells at E11.5 reveals that Notch effector Hes1 is expressed in a mutually exclusive manner with Sox9 that is expressed in pre-cartilaginous condensations. Analysis of a Notch signaling reporter CBF1:H2B-Venus reveals that peri-condensation mesenchymal cells are active for Notch signaling. In vivo lineage-tracing analysis using Hes1-creER identifies that Hes1+ early mesenchymal cells surrounding the SOX9+ condensation at E10.5 contribute to both cartilage and perichondrium at E13.5, subsequently becoming growth plate chondrocytes, osteoblasts of trabecular and cortical bones, and marrow stromal cells in postnatal bones. In contrast, Hes1+ cells in the perichondrium at E12.5 or E14.5 do not generate chondrocytes within cartilage, contributing to osteoblasts and marrow stromal cells only through the perichondrial route. Therefore, Hes1+ peri-condensation mesenchymal cells give rise to cells of the skeletal lineage through cartilage-dependent and independent pathways, supporting the theory that early mesenchymal cells outside the condensation also play important roles in early bone development.
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Desenvolvimento Ósseo , Osso e Ossos , Cartilagem , Diferenciação Celular , Linhagem da Célula , Condrócitos , Células-Tronco Mesenquimais , Fatores de Transcrição HES-1 , Animais , Camundongos , Osso e Ossos/citologia , Cartilagem/citologia , Cartilagem/metabolismo , Condrócitos/citologia , Condrócitos/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Osteoblastos/citologia , Osteoblastos/metabolismo , Fatores de Transcrição HES-1/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Receptores Notch/metabolismoRESUMO
Bone contributes to the maintenance of vital biological activities. At the cellular level, multiple types of skeletal cells, including skeletal stem and progenitor cells (SSPCs), osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, orchestrate skeletal events such as development, aging, regeneration, and tumorigenesis. Osteosarcoma (OS) is a primary malignant tumor and the main form of bone cancer. Although it has been proposed that the cellular origins of OS are in osteogenesis-related skeletal lineage cells with cancer suppressor gene mutations, its origins have not yet been fully elucidated because of a poor understanding of whole skeletal cell diversity and dynamics. Over the past decade, the advent and development of single-cell RNA sequencing analyses and mouse lineage-tracing approaches have revealed the diversity of skeletal stem and its lineage cells. Skeletal stem cells (SSCs) in the bone marrow endoskeletal region have now been found to efficiently generate OS and to be robust cells of origin under p53 deletion conditions. The identification of SSCs may lead to a more limited redefinition of bone marrow mesenchymal stem/stromal cells (BM-MSCs), and this population has been thought to contain cells from which OS originates. In this mini-review, we discuss the cellular diversity and dynamics of multiple skeletal cell types and the origin of OS in the native in vivo environment in mice. We also discuss future challenges in the study of skeletal cells and OS.
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Neoplasias Ósseas , Células-Tronco Mesenquimais , Osteossarcoma , Animais , Camundongos , Osteossarcoma/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco/metabolismo , Osteoblastos/metabolismo , Neoplasias Ósseas/patologiaRESUMO
The bony notch on the inferior border of the mandible, anterior to the attachment of the masseter muscle, where the facial vessels commonly pass, has been called different names in the literature, e.g., premasseteric notch, antegonial notch, and notch for the facial vessels. Interestingly, various disciplines have leaned toward different names for this notch. Therefore, to aid in consistent communication among professionals, the present study aimed to analyze usage of these varied terms and make recommendations for the best terminology. Based on the adjacent anatomical structures used to name this notch, three groups were analyzed in this study, a group using masseter in the term, a group using gonion in the term, and a group using facial vessels in the term. A literature search found that the group using gonion in the term was found most in the literature. The orthodontics field used gonion in the term the most (29.0%: 31/107) followed by the oral and maxillofacial surgery field (14.0%: 15/107), the plastic surgery field (4.7%: 5/107), and the anatomy field (3.7%: 4/107). The dental field used gonion in this term the most (43.9%: 47/107) and the medical field used facial vessels in the term the most (33.3%: 6/18). Based on these results, the use of gonial terms for this notch seems to be preferred.
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Epileptic seizures are distinct but frequent comorbidities in children with autism spectrum disorder (ASD). The hyperexcitability of cortical and subcortical neurons appears to be involved in both phenotypes. However, little information is available concerning which genes are involved and how they regulate the excitability of the thalamocortical network. In this study, we investigate whether an ASD-associated gene, SH3 and multiple ankyrin repeat domains 3 (Shank3), plays a unique role in the postnatal development of thalamocortical neurons. We herein report that Shank3a/b, the splicing isoforms of mouse Shank3, were uniquely expressed in the thalamic nuclei, peaking from two to four weeks after birth. Shank3a/b-knockout mice showed lower parvalbumin signals in the thalamic nuclei. Consistently, Shank3a/b-knockout mice were more susceptible to generalized seizures than wild-type mice after kainic acid treatments. Together, these data indicate that NT-Ank domain of Shank3a/b regulates molecular pathways that protect thalamocortical neurons from hyperexcitability during the early postnatal period of mice.
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Transtorno do Espectro Autista , Camundongos , Animais , Convulsões , Núcleos Talâmicos , Camundongos Knockout , Isoformas de Proteínas/genética , Proteínas dos Microfilamentos/metabolismo , Proteínas do Tecido Nervoso/metabolismoRESUMO
In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5+ fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5+ fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid hormone-induced bone anabolism. Therefore, early perichondrial cells of the fetal cartilage are destined to become an adipogenic subset of stromal cells in postnatal diaphyseal bone marrow, supporting the theory that the adult bone marrow stromal compartments are developmentally prescribed within the two distinct cells-of-origins of the fetal bone anlage.
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Cartilagem , Proteínas Hedgehog , Adulto , Humanos , Osso e Ossos , Desenvolvimento Ósseo , CondrócitosRESUMO
Long QT syndromes (LQTSs) can lead to sudden cardiac death, yet these syndromes are often asymptomatic and clinically undetected, despite the prolongation of the QT interval. Currently, when a disease-causing variant is identified in an individual, presymptomatic genetic testing is available and can form part of the recommended cascade testing to identify other family members at risk. We herein report the cases of two daughters who received presymptomatic genetic testing in infancy when the proband mother had been diagnosed with LQTS type 2 (LQT2; c.1171C > T, p.Q391X in KCNH2) after suffering from cardiac arrhythmia at 30 years of age. The daughters had a normal QTc interval, but they carried the same disease-causing variant as their mother. Children with family members who have genetically confirmed LQTS have a high risk of suffering from cardiac events later in life, so genetic testing is required. This poses a complex problem, as guidelines for medical intervention and follow-up systems among asymptomatic children with LQTS have yet to be established. Genetic testing should only be performed after adequate counseling to support children later in life. Individualized long-term genetic counseling is required for both parents and children at stages throughout life.
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Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.