Development and validation of [18 F]-PSMA-1007 PET-based radiomics model to predict biochemical recurrence-free survival following radical prostatectomy.

PURPOSE: Biochemical recurrence (BCR) following radical prostatectomy (RP) is a significant concern for patients with prostate cancer. Reliable prediction models are needed to identify patients at risk for BCR and facilitate appropriate management. This study aimed to develop and validate a clinical-radiomics model based on preoperative [18 F]PSMA-1007 PET for predicting BCR-free survival (BRFS) in patients who underwent RP for prostate cancer. MATERIALS AND METHODS: A total of 236 patients with histologically confirmed prostate cancer who underwent RP were retrospectively analyzed. All patients had a preoperative [18 F]PSMA-1007 PET/CT scan. Radiomics features were extracted from the primary tumor region on PET images. A radiomics signature was developed using the least absolute shrinkage and selection operator (LASSO) Cox regression model. The performance of the radiomics signature in predicting BRFS was assessed using Harrell's concordance index (C-index). The clinical-radiomics nomogram was constructed using the radiomics signature and clinical features. The model was externally validated in an independent cohort of 98 patients. RESULTS: The radiomics signature comprised three features and demonstrated a C-index of 0.76 (95% CI: 0.60-0.91) in the training cohort and 0.71 (95% CI: 0.63-0.79) in the validation cohort. The radiomics signature remained an independent predictor of BRFS in multivariable analysis (HR: 2.48, 95% CI: 1.47-4.17, p < 0.001). The clinical-radiomics nomogram significantly improved the prediction performance (C-index: 0.81, 95% CI: 0.66-0.95, p = 0.007) in the training cohort and (C-index: 0.78 95% CI: 0.63-0.89, p < 0.001) in the validation cohort. CONCLUSION: We developed and validated a novel [18 F]PSMA-1007 PET-based clinical-radiomics model that can predict BRFS following RP in prostate cancer patients. This model may be useful in identifying patients with a higher risk of BCR, thus enabling personalized risk stratification and tailored management strategies.

Frizzled receptors (FZDs) in Wnt signaling: potential therapeutic targets for human cancers.

Frizzled receptors (FZDs) are key contributors intrinsic to the Wnt signaling pathway, activation of FZDs triggering the Wnt signaling cascade is frequently observed in human tumors and intimately associated with an aggressive carcinoma phenotype. It has been shown that the abnormal expression of FZD receptors contributes to the manifestation of malignant characteristics in human tumors such as enhanced cell proliferation, metastasis, chemotherapy resistance as well as the acquisition of cancer stemness. Given the essential roles of FZD receptors in the Wnt signaling in human tumors, this review aims to consolidate the prevailing knowledge on the specific status of FZD receptors (FZD1-10) and elucidate their respective functions in tumor progression. Furthermore, we delineate the structural basis for binding of FZD and its co-receptors to Wnt, and provide a better theoretical foundation for subsequent studies on related mechanisms. Finally, we describe the existing biological classes of small molecule-based FZD inhibitors in detail in the hope that they can provide useful assistance for design and development of novel drug candidates targeted FZDs.

Robotic-assisted burring in total hip replacement: A new surgical technique to optimise acetabular preparation.

BACKGROUND: In Total Hip replacement (THR) surgery, a critical step is to cut an accurate hemisphere into the acetabulum so that the component can be fitted accurately and obtain early stability. This study aims to determine whether burring rather than reaming the acetabulum can achieve greater accuracy in the creation of this hemisphere. METHODS: A preliminary robotic system was developed to demonstrate the feasibility of burring the acetabulum using the Universal Robot (UR10). The study will describe mechanical design, robot trajectory optimisation, control algorithm development, and results from phantom experiments compared with both robotic reaming and conventional reaming. The system was also tested in a cadaver experiment. RESULTS: The proposed robotic burring system can produce a surface in 2 min with an average error of 0.1 and 0.18 mm, when cutting polyurethane bone block #15 and #30, respectively. The performance was better than robotic reaming and conventional hand reaming. CONCLUSION: The proposed robotic burring system outperformed robotic and conventional reaming methods to produce an accurate acetabular cavity. The findings show the potential usage of a robotic-assisted burring in THR for acetabular preparation.

Exploring hydrogen-bond structures in cellulose during regeneration with anti-solvent through two-dimensional correlation infrared spectroscopy.

Cellulose, renowned for its excellent biocompatibility, finds extensive applications in both industrial and laboratory settings. However, few studies have specifically addressed the mechanistic evolution of hydrogen bond networks in cellulose during the dissolution and regeneration processes. In this research, the regeneration mechanism of cellulose in water and ethanol is investigated through molecular dynamics simulations. The results indicate that the ability of water molecules to disrupt hydrogen bonds between cellulose and ionic liquids is stronger than that of ethanol, which is more conducive to promoting the regeneration of cellulose. Besides, the Fourier transform infrared spectroscopy coupled with two-dimensional correlation infrared spectroscopy techniques are employed to unveil the evolution sequence of hydrogen bonds during dissolution and regeneration: ν(OH) (absorbed water) â†’ ν(O3-H3···O5) (intrachain) â†’ ν(O6-H6···O3') (interchain) â†’ ν(O2-H2···O6) (intrachain) â†’ ν(OH) (free). This study not only enhances our understanding of the intricate hydrogen bond dynamics in cellulose dissolution and regeneration but also provides a foundation for the expanded application of cellulose in diverse fields.

Detection and isolation of genotype 3 subtype b hepatitis E viruses from wild boars in Japan.

To conduct an epidemiological study of hepatitis E virus (HEV) in Japanese wild boars, we collected 179 serum and 162 fecal specimens from wild boars in eight Japanese prefectures; 39 of the serum samples (21.8%) were positive for anti-HEV IgG antibodies. RT-qPCR revealed HEV RNA in 11 serum samples (6.1%) and 5 fecal samples (3.1%). We obtained 412 bp of the viral genome sequences of ORF2 from five pairs of serum and fecal samples. All strains were subtype b in genotype 3 (HEV-3b) but separated into different clusters. We determined the entire genome sequence of HEV-3b strain WB0567 using a fecal specimen and isolated this strain by cell culture using PLC/PRF/5 cells. Eleven nucleotide mutations had occurred during virus replication. These results suggest that HEV-3b circulated uniformly among wild boars in Japan. Direct sequencing using a suspected animal's samples is indispensable for predicting original HEV nucleotide sequences.

Long non-coding RNA LncTUG1 regulates favourable compression force-induced cementocytes mineralization via PU.1/TLR4/SphK1 signalling.

Orthodontic tooth movement (OTM) is a highly coordinated biomechanical response to orthodontic forces with active remodelling of alveolar bone but minor root resorption. Such antiresorptive properties of root relate to cementocyte mineralization, the mechanisms of which remain largely unknown. This study used the microarray analysis to explore long non-coding ribonucleic acids involved in stress-induced cementocyte mineralization. Gain- and loss-of-function experiments, including Alkaline phosphatase (ALP) activity and Alizarin Red S staining, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunofluorescence analyses of mineralization-associated factors, were conducted to verify long non-coding ribonucleic acids taurine-upregulated gene 1 (LncTUG1) regulation in stress-induced cementocyte mineralization, via targeting the Toll-like receptor 4 (TLR4)/SphK1 axis. The luciferase reporter assays, chromatin immunoprecipitation assays, RNA pull-down, RNA immunoprecipitation, and co-localization assays were performed to elucidate the interactions between LncTUG1, PU.1, and TLR4. Our findings indicated that LncTUG1 overexpression attenuated stress-induced cementocyte mineralization, while blocking the TLR4/SphK1 axis reversed the inhibitory effect of LncTUG1 on stress-induced cementocyte mineralization. The in vivo findings also confirmed the involvement of TLR4/SphK1 signalling in cementocyte mineralization during OTM. Mechanistically, LncTUG1 bound with PU.1 subsequently enhanced TLR4 promotor activity and thus transcriptionally elevated the expression of TLR4. In conclusion, our data revealed a critical role of LncTUG1 in regulating stress-induced cementocyte mineralization via PU.1/TLR4/SphK1 signalling, which might provide further insights for developing novel therapeutic strategies that could protect roots from resorption during OTM.

Generation of JC Polyoma Pseudovirus for High-Throughput Measurement of Neutralizing Antibodies.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses.

Piezo1 contributes to alveolar bone remodeling by activating ß-catenin under compressive stress.

INTRODUCTION: The mechanosensitive ion channel, Piezo1, is responsible for transducing mechanical stimuli into intracellular biochemical signals and has been identified within periodontal ligament cells (PDLCs). Nonetheless, the precise biologic function of Piezo1 in the regulation of alveolar bone remodeling by PDLCs during compressive forces remains unclear. Therefore, this study focused on elucidating the role of the Piezo1 channel in alveolar bone remodeling and uncovering its underlying mechanisms. METHODS: PDLCs were subjected to compressive force and Piezo1 inhibitors. Piezo1 and ß-catenin expressions were quantified by quantitative reverse transcription polymerase chain reaction and Western blot. The intracellular calcium concentration was measured using Fluo-8 AM staining. The osteogenic and osteoclastic activities were assessed using alkaline phosphatase staining, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blot. In vivo, orthodontic tooth movement was used to determine the effects of Piezo1 on alveolar bone remodeling. RESULTS: Piezo1 and activated ß-catenin expressions were upregulated under compressive force. Piezo1 inhibition reduced ß-catenin activation, osteogenic differentiation, and osteoclastic activities. ß-catenin knockdown reversed the increased osteogenic differentiation but had little impact on osteoclastic activities. In vivo, Piezo1 inhibition led to decreased tooth movement distance, accompanied by reduced ß-catenin activation and expression of osteogenic and osteoclastic markers on the compression side. CONCLUSIONS: The Piezo1 channel is a key mechanotransduction component of PDLCs that senses compressive force and activates ß-catenin to regulate alveolar bone remodeling.

Recent advances in hepatitis A virus research and clinical practice guidelines for hepatitis A virus infection in Japan.

In 2018, there was a hepatitis A outbreak in Japan, and hepatitis A virus (HAV) infection is considered a sexually transmitted disease. In general, patients with hepatitis A should be given attention, and this disease should be prevented more than ever. The Japan Agency for Medical Research and Development (AMED) Hepatitis A and E viruses (HAV and HEV) Study Group has worked on the project to create "Recent Advances in Hepatitis A Virus (HAV) Research and Clinical Practice Guidelines for HAV Infection in Japan". The group consists of expert hepatologists and virologists who gathered at virtual meeting on August 5, 2023. Data about the pathogenesis, infection routes, diagnosis, complications, several factors for the severities, vaccination, and current and future treatments for hepatitis A were discussed and debated for a draft version. The participants assessed the quality of cited studies. The finalized recommendations are presented in this review. The recent advances in HAV research and clinical practice for HAV infection in Japan, have been reviewed by the AMED HAV and HEV Study Group.

A practical online prediction platform to predict the survival status of laryngeal squamous cell carcinoma after 5 years.

OBJECTIVE: Currently, there are few practical tools for predicting the prognosis of laryngeal squamous cell carcinoma (LSCC). This study aims to establish a model and a convenient online prediction platform to predict whether LSCC patients will survive 5 years after diagnosis, providing a reference for further evaluation of patient prognosis. METHODS: This is a retrospective study based on data collected from two centers. Center 1 included 117 LSCC patients with survival prognosis data, and center 2 included 33 patients, totaling 150 patients. All data were divided into independent training sets (60 %) and testing sets (40 %). Eight machine learning (ML) algorithms were used to establish models with 11 clinical parameters as input features. The accuracy, sensitivity, specificity, and receiver operating characteristic curve (ROC) of the testing set were used to evaluate the models, and the best model was selected. The model was then developed into a website-based 5-year survival status prediction platform for LSCC. In addition, we also used the SHapley Additive exPlanations (SHAP) tool to conduct interpretability analysis on the parameters of the model. RESULTS: The LSCC 5-year survival status prediction model using the support vector machine (SVM) algorithm achieved the best results, with accuracy, sensitivity, specificity, and area under the ROC curve (AUC) of 85.0 %, 87.5 %, 75.0 %, and 81.2 % respectively. The online platform for predicting the 5-year survival status of LSCC based on this model was successfully established. The SHAP analysis shows that the clinical stage is the most important feature of the model. CONCLUSION: This study successfully established a ML model and a practical online prediction platform to predict the survival status of laryngeal cancer patients after 5 years, which may help clinicians to better evaluate the prognosis of LSCC.

A New Transoral Vestibulum Single Incision Endoscopic-Assisted Thyroidectomy with Gasless.

OBJECTIVE: We developed a novel method for thyroidectomy using a single-incision oral vestibular approach. To assess its advantages and disadvantages, we compared the perioperative parameters of this approach with those of transoral three-incision thyroidectomy and trans-areolar thyroidectomy. METHODS: In a study of 136 papillary thyroid carcinoma patients (2016-2018), precise thyroidectomy and neck dissection were conducted. Among them, 52 chose single-incision oral vestibular approach, 33 chose three-incision variant, and 51 underwent trans-areolar thyroidectomy. Perioperative aspects of the transoral single-incision group were compared with those of transoral three-incision group, and transthoracic group. RESULTS: In the cohort, meticulous tumor level VI lymph node dissection was performed, achieving intended resection extent with one case requiring a switch from transoral to transthoracic approach. No nerve palsy occurred in the transoral group. Thyroidectomy duration varied significantly across groups. Transoral single-incision had a shorter duration than transoral three-incision and longer than transthoracic. Minor differences were observed in blood loss and drainage. Perioperative factors like hematoma, infection, hypocalcemia, et al., remained consistent. Notably, no tumor recurrence was observed in this study. CONCLUSIONS: This new transoral video-assisted neck surgery (TOVANS) method for thyroidectomy without gas insufflation approach did not increase the surgical complexity compared with the transoral vestibular three-incision thyroidectomy and the trans-areolar thyroidectomy. LEVEL OF EVIDENCE: 3 Laryngoscope, 2023.

Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment.

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.

Deep learning technique to detect craniofacial anatomical abnormalities concentrated on middle and anterior of face in patients with sleep apnea.

OBJECTIVES: The aim of this study is to propose a deep learning-based model using craniofacial photographs for automatic obstructive sleep apnea (OSA) detection and to perform design explainability tests to investigate important craniofacial regions as well as the reliability of the method. METHODS: Five hundred and thirty participants with suspected OSA are subjected to polysomnography. Front and profile craniofacial photographs are captured and randomly segregated into training, validation, and test sets for model development and evaluation. Photographic occlusion tests and visual observations are performed to determine regions at risk of OSA. The number of positive regions in each participant is identified and their associations with OSA is assessed. RESULTS: The model using craniofacial photographs alone yields an accuracy of 0.884 and an area under the receiver operating characteristic curve of 0.881 (95% confidence interval, 0.839-0.922). Using the cutoff point with the maximum sum of sensitivity and specificity, the model exhibits a sensitivity of 0.905 and a specificity of 0.941. The bilateral eyes, nose, mouth and chin, pre-auricular area, and ears contribute the most to disease detection. When photographs that increase the weights of these regions are used, the performance of the model improved. Additionally, different severities of OSA become more prevalent as the number of positive craniofacial regions increases. CONCLUSIONS: The results suggest that the deep learning-based model can extract meaningful features that are primarily concentrated in the middle and anterior regions of the face.

LITTIP/Lgr6/HnRNPK complex regulates cementogenesis via Wnt signaling.

Orthodontically induced tooth root resorption (OIRR) is a serious complication during orthodontic treatment. Stimulating cementum repair is the fundamental approach for the treatment of OIRR. Parathyroid hormone (PTH) might be a potential therapeutic agent for OIRR, but its effects still lack direct evidence, and the underlying mechanisms remain unclear. This study aims to explore the potential involvement of long noncoding RNAs (lncRNAs) in mediating the anabolic effects of intermittent PTH and contributing to cementum repair, as identifying lncRNA-disease associations can provide valuable insights for disease diagnosis and treatment. Here, we showed that intermittent PTH regulates cell proliferation and mineralization in immortalized murine cementoblast OCCM-30 via the regulation of the Wnt pathway. In vivo, daily administration of PTH is sufficient to accelerate root regeneration by locally inhibiting Wnt/ß-catenin signaling. Through RNA microarray analysis, lncRNA LITTIP (LGR6 intergenic transcript under intermittent PTH) is identified as a key regulator of cementogenesis under intermittent PTH. Chromatin isolation by RNA purification (ChIRP) and RNA immunoprecipitation (RIP) assays revealed that LITTIP binds to mRNA of leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) and heterogeneous nuclear ribonucleoprotein K (HnRNPK) protein. Further co-transfection experiments confirmed that LITTIP plays a structural role in the formation of the LITTIP/Lgr6/HnRNPK complex. Moreover, LITTIP is able to promote the expression of LGR6 via the RNA-binding protein HnRNPK. Collectively, our results indicate that the intermittent PTH administration accelerates root regeneration via inhibiting Wnt pathway. The lncRNA LITTIP is identified to negatively regulate cementogenesis, which activates Wnt/ß-catenin signaling via high expression of LGR6 promoted by HnRNPK.

Low Replication Efficiency of a Japanese Rabbit Hepatitis E Virus Strain in the Human Hepatocarcinoma Cell Line PLC/PRF/5.

A Japanese rabbit hepatitis E virus (HEV) strain, JP-59, has been identified in a feral rabbit. When this virus was transmitted to a Japanese white rabbit, it caused persistent HEV infection. The JP-59 strain shares an <87.5% nucleotide sequence identity with other rabbit HEV strains. Herein, to isolate JP-59 by cell culture, we used a 10% stool suspension recovered from a JP-59-infected Japanese white rabbit and contained 1.1 × 107 copies/mL of the viral RNA and using it to infect a human hepatocarcinoma cell line, PLC/PRF/5. No sign of virus replication was observed. Although long-term virus replication was observed in PLC/PRF/5 cells inoculated with the concentrated and purified JP-59 containing a high titer of viral RNA (5.1 × 108 copies/mL), the viral RNA of JP-59c that was recovered from the cell culture supernatants was <7.1 × 104 copies/mL during the experiment. The JP-59c strain did not infect PLC/PRF/5 cells, but its intravenous inoculation caused persistent infection in rabbits. The nucleotide sequence analyses of the virus genomes demonstrated that a total of 18 nucleotide changes accompanying three amino acid mutations occurred in the strain JP-59c compared to the original strain JP-59. These results indicate that a high viral RNA titer was required for JP-59 to infect PLC/PRF/5 cells, but its replication capability was extremely low. In addition, the ability of rabbit HEVs to multiply in PLC/PRF/5 cells varied depending on the rabbit HEV strains. The investigations of cell lines that are broadly susceptible to rabbit HEV and that allow the efficient propagation of the virus are thus needed.

Nationwide epidemiologic and genetic surveillance of hepatitis E in Japan, 2014-2021.

Hepatitis E virus (HEV) is an emerging causative agent of acute hepatitis. To clarify the epidemiology of HEV and characterize the genetic diversity of the virus in Japan, nationwide enhanced surveillance and molecular characterization studies of HEV in Japan were undertaken from 2014 to 2021. In total, 2770 hepatitis E cases were reported, of which 88% were domestic cases, while only 4.1% represented cases following infection abroad. In addition, 57% of domestic infections occurred in males aged in their 40s-70s. For domestic cases, infection via pork meat consumption continued to be the most reported route. Analysis of the 324 sequences detected between 2016 and 2021 showed that the majority of domestic HEV strains belong to Genotype 3a (G3a) and G3b. In contrast, six of eight cases of G1 HEV reflected infection abroad. Our results suggest that HEV is circulating widely in Japan, with genotypes G3a and G3b being most prevalent. Continued surveillance is necessary to monitor future trends and changes in the epidemiology of HEV in Japan.

Recent advances in horizontal alveolar bone regeneration.

Alveolar bone loss is widespread in all age groups and remains a severe hazard to periodontal health. Horizontal alveolar bone loss is the pattern of bone loss more commonly seen in periodontitis. Until now, limited regenerative procedures have been applied to treating horizontal alveolar bone loss in periodontal clinics, making it the least predictable periodontal defect type. This article reviews the literature on recent advances in horizontal alveolar bone regeneration. The biomaterials and clinical and preclinical approaches tested for the regeneration of the horizontal type of alveolar bone are first discussed. Furthermore, current obstacles for horizontal alveolar bone regeneration and future directions in regenerative therapy are presented to provide new ideas for developing an effective multidisciplinary strategy to address the challenge of horizontal alveolar bone loss.

Discovery of a miniaturized PROTAC with potent activity and high selectivity.

The approved small-molecule inhibitors of anaplastic lymphoma kinase (ALK) have shown remarkable efficacy in some subset of cancer patients. However, the numerous ALK mutants or fusion partners are resistant to such drugs, greatly limiting their application in clinic. Despite the drug design strategy of proteolysis-targeting chimera (PROTAC) holds great potential to overcome drug resistance in theory, there are obvious disadvantages for the reported PROTACs that include high molecular weight, long linkers, difficult synthesis routes as well as insufficient evidence in activity for diverse ALK mutants. In this study, we designed and synthesized a miniaturized PROTAC of ALK named AP-1 following the principle of minimalist design. Two simple chemical units of ligands and a minimized linker with only two atoms were selected for synthesis of AP-1. At cellular level, AP-1 successfully degraded three types of ALK mutants including NPM-ALK, EML4-ALK and F1174L mutation ALK form with potent activity, high selectivity in ALK-positive cells. In xenograft mouse model, AP-1 showed the stronger antitumor efficacy than ceritinib as well as ALK degraders reported in literatures. AP-1 with an extremely simple PROTAC structure can be served as an effective candidate drug for therapy of various types of ALK-positive cancers. And the design principle of AP-1 has a good guiding significance for overcoming the disadvantages such as excessive molecular weight and poor solubility of PROTAC.