Efficacy of stereotactic ablative radiotherapy in patients with oligometastatic hepatocellular carcinoma: A phase II study.

BACKGROUND & AIMS: Stereotactic ablative radiotherapy (SABR) can extend survival and offers the potential for cure in some patients with oligometastatic disease (OMD). However, limited evidence exists regarding its use in oligometastatic hepatocellular carcinoma (HCC). We aimed to prospectively investigate the efficacy and safety of SABR in patients with oligometastatic HCC. METHODS: We enrolled patients with controlled primary HCC and one to five metastatic lesions amenable to SABR. The primary endpoint was treatment efficacy defined as overall survival (OS) and progression-free survival (PFS). The secondary endpoints included time to local progression, objective response rate, disease control rate, toxicities, and quality of life (QOL), assessed using the EORTC QLQ-C30 before, and 0, 1, and 3 months after SABR. RESULTS: Overall, 40 consecutive patients received SABR on 62 lesions between 2021 and 2022. The most common locations for OMD were the lungs (48.4%), lymph nodes (22.6%), and bone (17.7%). After a median follow-up of 15.5 months, the 2-year OS was 80%. Median PFS was 5.3 months, with 1- and 2-year PFS rates of 21.2% and 0%, respectively. A shorter time to OMD from the controlled primary independently correlated with PFS (p = 0.039, hazard ratio 2.127) alongside age, Child-Pugh class, and alpha-fetoprotein (p = 0.002, 0.004, 0.019, respectively). The 2-year time to local progression, objective response rate, and disease control rate were 91.1%, 75.8%, and 98.4%, respectively. Overall, 10% of patients experienced acute toxicity, and 7.5% experienced late toxicity, with no grade 3+ toxicity. All QOL scores remained stable, whereas the patients without systemic treatments had improved insomnia and social functioning scores. CONCLUSIONS: SABR is an effective and feasible option for oligometastatic HCC that leads to excellent local tumor control and improves survival without adversely affecting QOL. IMPACT AND IMPLICATIONS: Stereotactic ablative radiotherapy (SABR) is a non-invasive treatment approach capable of efficiently ablating the target lesion; however, neither the oligometastatic disease concept nor the potential benefits of SABR have been well-defined in hepatocellular carcinoma (HCC). According to this study, SABR is an effective and safe treatment option for oligometastatic HCC, yielding excellent local tumor control and survival improvement without worsening patients' quality of life, regardless of tumor sites. We also demonstrated that patients with a later presentation of OMD from the controlled primary and lower alpha-fetoprotein levels achieved better survival outcomes. This is the first prospective study of SABR in oligometastatic HCC, providing insights for the development of novel strategies to improve oncologic outcomes. CLINICAL TRIAL NUMBER: NCT05173610.

Placenta accreta spectrum disorder at single-cell resolution: a loss of boundary limits in the decidua and endothelium.

BACKGROUND: Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology. OBJECTIVE: This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterize cellular heterogeneity at the maternal-fetal interface in placenta accreta spectrum disorders. STUDY DESIGN: To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and nonadherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression. RESULTS: In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor-like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum. CONCLUSION: Placenta accreta spectrum disorders were characterized at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and fetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from "invasive trophoblast" to "loss of boundary limits" in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries.

Orphan nuclear receptor ERR-γ regulates hepatic FGF23 production in acute kidney injury.

Fibroblast growth factor 23 (FGF23), a hormone generally derived from bone, is important in phosphate and vitamin D homeostasis. In acute kidney injury (AKI) patients, high-circulating FGF23 levels are associated with disease progression and mortality. However, the organ and cell type of FGF23 production in AKI and the molecular mechanism of its excessive production are still unidentified. For insight, we investigated folic acid (FA)-induced AKI in mice. Interestingly, simultaneous with FGF23, orphan nuclear receptor ERR-γ expression is increased in the liver of FA-treated mice, and ectopic overexpression of ERR-γ was sufficient to induce hepatic FGF23 production. In patients and in mice, AKI is accompanied by up-regulated systemic IL-6, which was previously identified as an upstream regulator of ERR-γ expression in the liver. Administration of IL-6 neutralizing antibody to FA-treated mice or of recombinant IL-6 to healthy mice confirms IL-6 as an upstream regulator of hepatic ERR-γ-mediated FGF23 production. A significant (P < 0.001) interconnection between high IL-6 and FGF23 levels as a predictor of AKI in patients that underwent cardiac surgery was also found, suggesting the clinical relevance of the finding. Finally, liver-specific depletion of ERR-γ or treatment with an inverse ERR-γ agonist decreased hepatic FGF23 expression and plasma FGF23 levels in mice with FA-induced AKI. Thus, inverse agonist of ERR-γ may represent a therapeutic strategy to reduce adverse plasma FGF23 levels in AKI.

Limitations of the Cough Sound-Based COVID-19 Diagnosis Artificial Intelligence Model and its Future Direction: Longitudinal Observation Study.

BACKGROUND: The outbreak of SARS-CoV-2 in 2019 has necessitated the rapid and accurate detection of COVID-19 to manage patients effectively and implement public health measures. Artificial intelligence (AI) models analyzing cough sounds have emerged as promising tools for large-scale screening and early identification of potential cases. OBJECTIVE: This study aimed to investigate the efficacy of using cough sounds as a diagnostic tool for COVID-19, considering the unique acoustic features that differentiate positive and negative cases. We investigated whether an AI model trained on cough sound recordings from specific periods, especially the early stages of the COVID-19 pandemic, were applicable to the ongoing situation with persistent variants. METHODS: We used cough sound recordings from 3 data sets (Cambridge, Coswara, and Virufy) representing different stages of the pandemic and variants. Our AI model was trained using the Cambridge data set with subsequent evaluation against all data sets. The performance was analyzed based on the area under the receiver operating curve (AUC) across different data measurement periods and COVID-19 variants. RESULTS: The AI model demonstrated a high AUC when tested with the Cambridge data set, indicative of its initial effectiveness. However, the performance varied significantly with other data sets, particularly in detecting later variants such as Delta and Omicron, with a marked decline in AUC observed for the latter. These results highlight the challenges in maintaining the efficacy of AI models against the backdrop of an evolving virus. CONCLUSIONS: While AI models analyzing cough sounds offer a promising noninvasive and rapid screening method for COVID-19, their effectiveness is challenged by the emergence of new virus variants. Ongoing research and adaptations in AI methodologies are crucial to address these limitations. The adaptability of AI models to evolve with the virus underscores their potential as a foundational technology for not only the current pandemic but also future outbreaks, contributing to a more agile and resilient global health infrastructure.

Safety of Drainless Donor Closure in DIEP Flap-Based Breast Reconstruction: A Prospective Analysis Using Ultrasound.

BACKGROUND: Although drainless donor closure with progressive tension suture (PTS) technique has been attempted to further reduce donor morbidity in deep inferior epigastric perforator (DIEP) flap-based breast reconstruction, its clinical safety has not yet been fully elucidated. This study prospectively investigated donor morbidity after DIEP flap elevation and drain-free donor closure. METHODS: A prospective cohort study was performed on 125 patients who underwent DIEP flap-based breast reconstruction and drainless donor closure. Postoperatively, the donor site was evaluated repetitively using ultrasonography. Development of donor complications, including any fluid accumulation and seroma (defined as detection of fluid accumulation after postoperative one month), was prospectively noted, and independent predictors for the adverse events were evaluated. RESULTS: On ultrasound examination conducted within postoperative 2 weeks, 48 patients were detected to have fluid accumulation at the donor site, which were more frequently detected in cases of delayed reconstruction and those with lesser number of PTS conducted. The majority of those events (95.8%) were resolved with one- or two-times ultrasound-guided aspirations. Five patients (4.0%) showed persistent fluid accumulation after postoperative 1 month, which were successfully treated with repetitive aspiration without requiring reoperation. No other abdominal complications developed except for three of delayed wound healing. On multivariable analyses, harvesting larger-sized flap and conducting lesser number of PTS were independent predictors for the development of fluid accumulation. CONCLUSION: The results of this prospective study suggest that drainless donor closure of the DIEP flap with meticulous placement of PTS followed by postoperative ultrasound surveillance appears to be safe and effective.

Estrogen-Related Receptor γ Maintains Pancreatic Acinar Cell Function and Identity by Regulating Cellular Metabolism.

BACKGROUND & AIMS: Mitochondrial dysfunction disrupts the synthesis and secretion of digestive enzymes in pancreatic acinar cells and plays a primary role in the etiology of exocrine pancreas disorders. However, the transcriptional mechanisms that regulate mitochondrial function to support acinar cell physiology are poorly understood. Here, we aim to elucidate the function of estrogen-related receptor γ (ERRγ) in pancreatic acinar cell mitochondrial homeostasis and energy production. METHODS: Two models of ERRγ inhibition, GSK5182-treated wild-type mice and ERRγ conditional knock-out (cKO) mice, were established to investigate ERRγ function in the exocrine pancreas. To identify the functional role of ERRγ in pancreatic acinar cells, we performed histologic and transcriptome analysis with the pancreas isolated from ERRγ cKO mice. To determine the relevance of these findings for human disease, we analyzed transcriptome data from multiple independent human cohorts and conducted genetic association studies for ESRRG variants in 2 distinct human pancreatitis cohorts. RESULTS: Blocking ERRγ function in mice by genetic deletion or inverse agonist treatment results in striking pancreatitis-like phenotypes accompanied by inflammation, fibrosis, and cell death. Mechanistically, loss of ERRγ in primary acini abrogates messenger RNA expression and protein levels of mitochondrial oxidative phosphorylation complex genes, resulting in defective acinar cell energetics. Mitochondrial dysfunction due to ERRγ deletion further triggers autophagy dysfunction, endoplasmic reticulum stress, and production of reactive oxygen species, ultimately leading to cell death. Interestingly, ERRγ-deficient acinar cells that escape cell death acquire ductal cell characteristics, indicating a role for ERRγ in acinar-to-ductal metaplasia. Consistent with our findings in ERRγ cKO mice, ERRγ expression was significantly reduced in patients with chronic pancreatitis compared with normal subjects. Furthermore, candidate locus region genetic association studies revealed multiple single nucleotide variants for ERRγ that are associated with chronic pancreatitis. CONCLUSIONS: Collectively, our findings highlight an essential role for ERRγ in maintaining the transcriptional program that supports acinar cell mitochondrial function and organellar homeostasis and provide a novel molecular link between ERRγ and exocrine pancreas disorders.

Study protocol for prospective multi-institutional phase III trial of standard of care therapy with or without stereotactic ablative radiation therapy for recurrent ovarian cancer (SABR-ROC).

BACKGROUND: Efforts have been made to investigate the role of salvage radiotherapy (RT) in treating recurrent ovarian cancer (ROC). Stereotactic ablative radiation therapy (SABR) is a state-of-the-art therapy that uses intensity modulation to increase the fractional dose, decrease the number of fractions, and target tumors with high precision. METHODS: The SABR-ROC trial is a phase 3, multicenter, randomized, prospective study to evaluate whether the addition of SABR to the standard of care significantly improves the 3-year overall survival (OS) of patients with ROC. Patients who have completed the standard treatment for primary epithelial ovarian cancer are eligible. In addition, patients with number of metastases ≤ 10 and maximum diameter of each metastatic site of gross tumor ≤ 5 cm are allowed. Randomization will be stratified by (1) No. of the following clinical factors met, platinum sensitivity, absence of ascites, normal level of CA125, and ECOG performance status of 0-1; 0-3 vs. 4; (2) site of recurrence; with vs. without lymph nodes; and (3) PARP inhibitor; use vs. non-use. The target number of patients to be enrolled in this study is 270. Participants will be randomized in a 1:2 ratio. Participants in Arm 2 will receive SABR for recurrent lesions clearly identified in imaging tests as well as the standard of care (Arm 1) based on treatment guidelines and decisions made in multidisciplinary discussions. The RT fraction number can range from 1 to 10, and the accepted dose range is 16-45 Gy. The RT Quality Assurance (QA) program consists of a three-tiered system: general credentialing, trial-specific credentialing, and individual case reviews. DISCUSSION: SABR appears to be preferable as it does not interfere with the schedule of systemic treatment by minimizing the elapsed days of RT. The synergistic effect between systemic treatment and SABR is expected to reduce the tumor burden by eradicating gross tumors identified through imaging with SABR and controlling microscopic cancer with systemic treatment. It might also be beneficial for quality-of-life preservation in older adults or heavily treated patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT05444270) on June 29th, 2022.

Loss of Dact2 alleviates cisplatin-induced nephrotoxicity through regulation of the Igfl-MAPK pathway axis.

Wnt signaling is a principal pathway regulating the essential activities of cell proliferation. Here, we investigated the effect of Wnt/ß-catenin signaling on in vivo drug-induced renal injury through the deletion of Dact2, a Wnt antagonist, and deciphered the underlying mechanism. Wild-type (WT) and Dact2 knockout (KO) mice were administered a single intraperitoneal injection of cisplatin to induce renal injury. The injury was alleviated in Dact2 KO mice, which showed lower levels of blood urea nitrogen and creatinine. RNA sequencing revealed 194 differentially expressed genes (DEGs) between WT and Dact2 KO mouse kidney before cisplatin treatment. Among them, higher levels of Igf1, one of the Wnt target genes responsible for "Positive regulation of cell proliferation" in KO mice, were confirmed along with the induction of Ki67 expression. In RNA-seq analysis comparing WT and Dact2 KO mice after cisplatin treatment, genes related to "Apoptosis" and "Activation of mitogen-activated protein kinase (MAPK) activity" were among the downregulated DEGs in KO mice. These results were corroborated in western blotting of proteins related to apoptosis and proapoptotic MAPK pathway; the expression of which was found to be lower in cisplatin-treated KO mice. Importantly, ß-catenin was found to directly bind to and regulate the transcription of Igf1, leading to the alleviation of cisplatin-induced cytotoxicity by the Wnt agonist, CHIR-99021. In addition, Igf1 knockdown accelerated cisplatin-induced cytotoxicity, accompanied by the MAPK upregulation. Our findings suggest that Dact2 knockout could protect cisplatin-induced nephrotoxicity by inhibiting apoptosis, possibly through the regulation of the Igf1-MAPK axis associated with Wnt/ß-catenin signaling.

Usefulness of indocyanine green angiography in the intraoperative evaluation of recipient vessels for microsurgical lower extremity reconstruction in ischemic vasculopathy: Report of three cases.

Choosing reliable recipient vessels is crucial for successful free flap reconstruction of lower extremity defects, especially in patients with ischemic vasculopathy. This report describes our experience with the intraoperative use of indocyanine green angiography (ICGA) for selecting recipient vessels in lower extremity free flap reconstruction cases. Three patients with lower extremity defects and ischemic vasculopathy underwent free flap reconstruction. Intraoperatively, the candidate vessels were evaluated using ICGA. In the first case, a 10 × 6 cm defect on the anterior side of the lower third of the leg caused by minor trauma and associated with peripheral arterial occlusive disease was reconstructed using a super-thin anterolateral thigh flap based on one perforator. In the second case, a 12 × 8 cm defect on the posterior side of the right lower leg caused by a dog bite and associated with severe atherosclerosis throughout all three major vessels in the lower leg was reconstructed using a muscle-sparing latissimus dorsi myocutaneous flap. In the third case, a 13.5 × 5.5 cm defect on the right lateral malleolar region, where the peroneus longus tendon was exposed due to Buerger's disease, was reconstructed using a one perforator-based super-thin anterolateral thigh flap. In all cases, ICGA was used to evaluate the functionality of the candidate recipient vessels. In two cases, the candidate vessels showed acceptable blood flow, and the operations proceeded as planned. In the third case, the planned vessels of posterior tibial vessels were not identified to have sufficient blood flow, and one of their branches showing enhancement in ICGA was selected and used as a recipient vessel. All flaps survived completely. No adverse events occurred during the follow-up period of postoperative 3 months. Our results suggest that ICGA may be a valuable diagnostic tool for evaluating the quality of candidate recipient vessels in cases where their functionality cannot be guaranteed with conventional imaging modalities.

Comparative Study on Two COVID-19 Outbreaks at a Long-Term Mental Health Facility in Korea in 2020 and 2022.

(1) Background and Objectives: There were two distinct coronavirus disease 2019 (COVID-19) outbreaks in 2020 and 2022 at a long-term mental health facility (LTMHF) in Gyeonggi Province, Korea. We aimed to compare the two outbreaks and identify differences in epidemiological and clinical outcomes due to changes in epidemic timing and management methods. (2) Materials and Methods: The structural, operational, and case-specific LTMHF data of COVID-19-confirmed patients during these outbreaks in 2020 and 2022 were retrospectively analyzed. (3) Results: Forty individuals (37 residents) in 2020 and thirty-nine (32 residents) in 2022 were confirmed to have COVID-19, and ten were infected twice. Facility isolation was implemented as an infection control measure, and one COVID-19-related death occurred in 2020. All residents and staff were vaccinated at least twice in 2022; moreover, in 2022, 38 patients (97.4%) received a third vaccination less than months before infection. The average Ct value of the cases in 2022 was significantly higher than that in 2020; however, vaccine-breakthrough (V-BT) and reinfection after vaccination rates were similar. (4) Conclusions: COVID-19 vaccination could help lower the viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was inversely correlated with Ct values, and ventilation system improvements in health facilities might reduce transmissibility.

Apigetrin Abrogates Lipopolysaccharide-Induced Inflammation in L6 Skeletal Muscle Cells through NF-κB/MAPK Signaling Pathways.

Apigetrin is a glycosidic flavonoid derived from Teucrium gnaphalodes that has a wide range of biological activities, including antioxidant, anti-inflammatory, and anticancer. Inflammation is a kind of defense mechanism in the body. Flavonoids are natural phytochemicals that exert anti-inflammatory effects in numerous cells. In the present study, we investigated the anti-inflammatory effect of apigetrin and its underlying mechanism of activity in skeletal muscle cells (L6). The determination of cytotoxicity was performed by MTT assay. We treated L6 cells with apigetrin, and nontoxic concentrations were chosen to perform further experimentation. Apigetrin inhibited the expression of iNOS and COX-2 induced by LPS in a dose-dependent manner. iNOS and COX-2 are inflammatory markers responsible for enhancing the inflammatory response. Apigetrin also inhibited the LPS-induced phosphorylation of p65 and IκB-α. NF-κB signaling regulates the inflammatory process by mediating various proinflammatory genes. Similarly, the MAPK signaling pathway consists of ERK, JNK, and p38, which plays a critical role in the production of cytokines and downstream signaling events leading to inflammation. Apigetrin significantly downregulated the phosphorylation of JNK and p38, but did not affect the phosphorylation of ERK in the LPS-stimulated cells. These findings indicate the correlation between the anti-inflammatory activity of NF-κB and the MAPK signaling pathway. Thus, our overall finding suggests that apigetrin has anti-inflammatory effects and it can be considered for further drug design on L6 skeletal muscle cells.

Characteristics and adaptability of Flavobacterium panici BSSL-CR3 in tidal flat revealed by comparative genomic and enzymatic analysis.

Tidal flat microbes play an important ecological role by removing organic pollutants and providing an energy source. However, bacteria isolated from tidal flats and their genomes have been scarcely reported, making it difficult to elucidate which genes and pathways are potentially involved in the above roles. In this study, strain BSSL-CR3, the third reported species among the tidal flat Flavobacterium was analyzed using whole-genome sequencing to investigate its adaptability and functionality in tidal flats. BSSL-CR3 is comprised of a circular chromosome of 5,972,859 bp with a GC content of 33.84%. Genome annotation and API ZYM results showed that BSSL-CR3 has a variety of secondary metabolic gene clusters and enzyme activities including α-galactosidase. BSSL-CR3 had more proteins with a low isoelectric point (pI) than terrestrial Flavobacterium strains, and several genes related to osmotic regulation were found in the genomic island (GI). Comparative genomic analysis with other tidal flat bacteria also revealed that BSSL-CR3 had the largest number of genes encoding Carbohydrate Active EnZymes (CAZymes) which are related to algae degradation. This study will provide insight into the adaptability of BSSL-CR3 to the tidal flats and contribute to facilitating future comparative analysis of bacteria in tidal flats.

Examining the role of wide excision margins in pediatric melanoma: A National Cancer Database analysis.

BACKGROUND: Although adult guidelines are often applied to children, age-specific surgical margins have not been defined for pediatric melanoma. PROCEDURE: Patients <20 years of age with invasive, cutaneous melanoma were identified using the 2004-2016 National Cancer Database and categorized as undergoing wide (>1 cm) or narrow (≤1 cm) excision. Unadjusted overall survival (OS) was compared using the Kaplan-Meier method and log-rank test. Multivariable Cox proportional hazard models were used to estimate the effect of excision margin on OS after adjustment for available covariates. RESULTS: In total, 2081 patients met study criteria: 1338 (64.3%) patients underwent wide excision whereas 743 (35.7%) underwent narrow excision. Unadjusted OS was improved in the narrow-excision group (log-rank p = .01), which was consistent among patients with thicker (>1 mm) and thinner (≤1 mm) tumors. After adjustment for patient and tumor characteristics, we found no evidence of a difference in OS for patients who underwent narrow excision compared to patients who underwent wide excision (adjusted hazard ratio 0.57, 95% confidence interval 0.32-1.01, p = .053). There was no interaction between excision margin width and Breslow depth (p = .85), indicating that the effect of excision margin width on OS does not differ based on Breslow depth. CONCLUSIONS: In this analysis, wide excision (>1 cm) does not appear to be associated with improved survival in children with melanoma regardless of tumor characteristics. Although further studies are needed to define optimal excision margins in pediatric melanoma, this study suggests that more narrow margins (≤1 cm) may be acceptable.

Anxiety During the COVID-19 Pandemic: A Web-Based Survey of Thyroid Cancer Survivors.

OBJECTIVE: Cancer patients and survivors may be disproportionately affected by COVID-19. We sought to determine the effects of the pandemic on thyroid cancer survivors' health care interactions and quality of life. METHODS: An anonymous survey including questions about COVID-19 and the Patient-Reported Outcomes Measurement Information System profile (PROMIS-29, version 2.0) was hosted on the Thyroid Cancer Survivors' Association, Inc website. PROMIS scores were compared to previously published data. Factors associated with greater anxiety were evaluated with univariable and multivariable logistic regression. RESULTS: From May 6, 2020, to October 8, 2020, 413 participants consented to take the survey; 378 (92%) met the inclusion criteria: diagnosed with thyroid cancer or noninvasive follicular neoplasm with papillary-like nuclear features, located within the United States, and completed all sections of the survey. The mean age was 53 years, 89% were women, and 74% had papillary thyroid cancer. Most respondents agreed/strongly agreed (83%) that their lives were very different during the COVID-19 pandemic, as were their interactions with doctors (79%). A minority (43%) were satisfied with the information from their doctor regarding COVID-19 changes. Compared to pre-COVID-19, PROMIS scores were higher for anxiety (57.8 vs 56.5; P < .05) and lower for the ability to participate in social activities (46.2 vs 48.1; P < .01), fatigue (55.8 vs 57.9; P < .01), and sleep disturbance (54.7 vs 56.1; P < .01). After adjusting for confounders, higher anxiety was associated with younger age (P < .01) and change in treatment plan (P = .04). CONCLUSION: During the COVID-19 pandemic, thyroid cancer survivors reported increased anxiety compared to a pre-COVID cohort. To deliver comprehensive care, providers must better understand patient concerns and improve communication about potential changes to treatment plans.

Phylogenomics-Based Reconstruction and Molecular Evolutionary Histories of Brassica Photoreceptor Gene Families.

Photosensory proteins known as photoreceptors (PHRs) are crucial for delineating light environments in synchronization with other environmental cues and regulating their physiological variables in plants. However, this has not been well studied in the Brassica genus, which includes several important agricultural and horticultural crops. Herein, we identified five major PHR gene families-phytochrome (PHY), cryptochrome (CRY), phototropin (PHOT), F-box containing flavin binding proteins (ZTL/FKF1/LKP2), and UV RESISTANCE LOCUS 8 (UVR8)-genomic scales and classified them into subfamilies based on their phylogenetic clustering with Arabidopsis homologues. The molecular evolution characteristics of Brassica PHR members indicated indirect expansion and lost one to six gene copies at subfamily levels. The segmental duplication was possibly the driving force of the evolution and amplification of Brassica PHRs. Gene replication retention and gene loss events of CRY, PHY, and PHOT members found in diploid progenitors were highly conserved in their tetraploid hybrids. However, hybridization events were attributed to quantitative changes in UVR8 and ZTL/FKF1/LKP2 members. All PHR members underwent purifying selection. In addition, the transcript expression profiles of PHR genes in different tissue and in response to exogenous ABA, and abiotic stress conditions suggested their multiple biological significance. This study is helpful in understanding the molecular evolution characteristics of Brassica PHRs and lays the foundation for their functional characterization.

An Inverse Agonist GSK5182 Increases Protein Stability of the Orphan Nuclear Receptor ERRγ via Inhibition of Ubiquitination.

The orphan nuclear receptor, estrogen-related receptor γ (ERRγ) is a constitutively active transcription factor involved in mitochondrial metabolism and energy homeostasis. GSK5182, a specific inverse agonist of ERRγ that inhibits transcriptional activity, induces a conformational change in ERRγ, resulting in a loss of coactivator binding. However, the molecular mechanism underlying the stabilization of the ERRγ protein by its inverse agonist remains largely unknown. In this study, we found that GSK5182 inhibited ubiquitination of ERRγ, thereby stabilizing the ERRγ protein, using cell-based assays and confocal image analysis. Y326 of ERRγ was essential for stabilization by GSK5182, as ligand-induced stabilization of ERRγ was not observed with the ERRγ-Y326A mutant. GSK5182 suppressed ubiquitination of ERRγ by the E3 ligase Parkin and subsequent degradation. The inhibitory activity of GSK5182 was strong even when the ERRγ protein level was elevated, as ERRγ bound to GSK5182 recruited a corepressor, small heterodimer partner-interacting leucine zipper (SMILE), through the activation function 2 (AF-2) domain, without alteration of the nuclear localization or DNA-binding ability of ERRγ. In addition, the AF-2 domain of ERRγ was critical for the regulation of protein stability. Mutants in the AF-2 domain were present at higher levels than the wild type in the absence of GSK5182. Furthermore, the ERRγ-L449A/L451A mutant was no longer susceptible to GSK5182. Thus, the AF-2 domain of ERRγ is responsible for the regulation of transcriptional activity and protein stability by GSK5182. These findings suggest that GSK5182 regulates ERRγ by a unique molecular mechanism, increasing the inactive form of ERRγ via inhibition of ubiquitination.

Factors to improve distress and fatigue in Cancer survivorship; further understanding through text analysis of interviews by machine learning.

BACKGROUND: From patient-reported surveys and individual interviews by health care providers, we attempted to identify the significant factors related to the improvement of distress and fatigue for cancer survivors by text analysis with machine learning techniques, as the secondary analysis using the single institute data from the Korean Cancer Survivorship Center Pilot Project. METHODS: Surveys and in-depth interviews from 322 cancer survivors were analyzed to identify their needs and concerns. Among the keywords in the surveys, including EQ-VAS, distress, fatigue, pain, insomnia, anxiety, and depression, distress and fatigue were focused. The interview transcripts were analyzed via Korean-based text analysis with machine learning techniques, based on the keywords used in the survey. Words were generated as vectors and similarity scores were calculated by the distance related to the text's keywords and frequency. The keywords and selected high-ranked ten words for each keyword based on the similarity were then taken to draw a network map. RESULTS: Most participants were otherwise healthy females younger than 50 years suffering breast cancer who completed treatment less than 6 months ago. As the 1-month follow-up survey's results, the improved patients were 56.5 and 58.4% in distress and fatigue scores, respectively. For the improvement of distress, dyspepsia (p = 0.006) and initial scores of distress, fatigue, anxiety, and depression (p < 0.001, < 0.001, 0.043, and 0.013, respectively) were significantly related. For the improvement of fatigue, economic state (p = 0.021), needs for rehabilitation (p = 0.035), initial score of fatigue (p < 0.001), any intervention (p = 0.017), and participation in family care program (p = 0.022) were significant. For the text analysis, Stress and Fatigue were placed at the center of the keyword network map, and words were intricately connected. From the regression anlysis combined survey scores and the quantitative variables from the text analysis, participation in family care programs and mention of family-related words were associated with the fatigue improvement (p = 0.033). CONCLUSION: Common symptoms and practical issues were related to distress and fatigue in the survey. Through text analysis, however, we realized that the specific issues and their relationship such as family problem were more complicated. Although further research needs to explore the hidden problem in cancer patients, this study was meaningful to use personalized approach such as interviews.

Magnetic resonance imaging-based validation of the 2018 FIGO staging system in patients treated with definitive radiotherapy for locally advanced cervix cancer.

OBJECTIVE: To validate the revised 2018 International Federation of Gynecologic and Obstetrics (FIGO) staging system in patients who underwent diagnostic magnetic resonance imaging (MRI) and radiotherapy (RT) for locally advanced cervix cancer. METHODS: We analyzed 677 patients who were diagnosed with pelvic MRI and treated with definitive (chemo-)RT for locally advanced cervix cancer (stage IB2/IIA2-IVA or N+) between 1992 and 2018. Patients were classified according to 2009 and 2018 FIGO staging, and survival outcomes were compared. We developed a nomogram to improve prediction of progression-free survival (PFS). RESULTS: Pelvic and paraaortic lymph nodes were positive in 331 (48.9%) and 78 (11.5%) patients, respectively. At a median follow-up of 77.9 months, the 5-year PFS was 83.5%, 65.2%, 71.0%, 60.6%, 37.6% and 38.9% for IB, IIA, IIB, IIIA, IIIB and IVA according to FIGO 2009 and 88.9%, 60.0%, 73.8%, 66.7%, 36.3%, 68.9%, 43.6%, and 38.9% for IB, IIA, IIB, IIIA, IIIB, IIIC1, IIIC2, and IVA according to FIGO 2018, respectively. Survival of stage IIIC cervix cancer depended on the local extent of the tumor: the 5-year PFS of T1, T2, and T3 stages were 80.3%, 73.9%, and 45.5% for IIIC1 and 100%, 44.9%, and 23.4% for IIIC2. Histology, tumor size, node metastasis, FIGO 2009, and treatment modality were independent prognostic factors in the Cox regression analysis, and the nomogram incorporating these factors outperformed FIGO 2009 and FIGO 2018 (AUC 0.718 vs. 0.616 vs. 0.594). CONCLUSIONS: FIGO 2018 revision was associated with heterogenous outcomes among stage III cervix cancer patients. Our nomogram can assist the FIGO system in predicting PFS after definitive RT.

Antioxidative and anti-inflammatory activity of psiguadial B and its halogenated analogues as potential neuroprotective agents.

Psiguadial B (8), and its fluoro- (8a), chloro- (8b), and bromo- (8c) derivatives were synthesized using a sodium acetate-catalyzed single step coupling of three components: ß-caryophyllene (5), diformylphloroglucinol (11), and benzaldehyde (12). These compounds efficiently and dose-dependently decreased H2O2-induced cell death, a quantitative marker of cell death, in primary cultures of mouse cortical neurons. Psiguadial B also decreased neuronal death and accumulation of ROS induced by FeCl2 in cortical cultures. The in vitro effects of these compounds in lipopolysaccharide (LPS)-induced expression of nitric oxide (NO), and TNF-α and IL-6 by suppressing the NF-κB pathway in immune cells demonstrated their antioxidative and anti-inflammatory activity. The present findings warrant further research on the development of psiguadial B-based neuroprotective agents for the treatment of neurodegenerative diseases, acute brain injuries and immunological disorders.

Role of VVZ-149, a Novel Analgesic Molecule, in the Affective Component of Pain: Results from an Exploratory Proof-of-Concept Study of Postoperative Pain following Laparoscopic and Robotic-Laparoscopic Gastrectomy.

OBJECTIVE: VVZ-149 is a small molecule that both inhibits the glycine transporter type 2 and the serotonin receptor 5 hydroxytryptamine 2 A. In a randomized, parallel-group, and double-blind trial (NCT02844725), we investigated the analgesic efficacy and safety of VVZ-149 Injections, which is under clinical development as a single-use injectable product for treating moderate to severe postoperative pain. METHODS: Sixty patients undergoing laparoscopic and robotic-laparoscopic gastrectomy were randomly assigned to receive a 10-hour intravenous infusion of VVZ-149 Injections or placebo, initiated approximately 1 hour before completion of surgical suturing. Major outcomes included pain intensity and opioid consumption via patient-controlled analgesia and rescue analgesia provided "as needed." The treatment efficacy of VVZ-149 was further examined in a subpopulation requiring early rescue medication, previously associated with the presence of high levels of preoperative negative affect in a prior Phase 2 study (NCT02489526). RESULTS: Pain intensity was lower in the VVZ-149 (n = 30) than the placebo group (n = 29), reaching statistical significance at 4 hours post-emergence (P < .05), with a 29.5% reduction in opioid consumption for 24 hours and fewer demands for patient-controlled analgesia. In the rescued subgroup, VVZ-149 further reduced pain intensity (P < .05) with 32.6% less opioid consumption for 24 hours compared to placebo patients. CONCLUSIONS: VVZ-149 demonstrated effective analgesia with reduced postoperative pain and opioid requirements. Consistent with the results from the previous Phase 2 study, patients with early rescue requirement had greater benefit from VVZ-149, supporting the hypothesis that VVZ-149 may alleviate the affective component of pain and mitigate excessive use of opioids postoperatively.