Testing the PEST hypothesis using relevant Rett mutations in MeCP2 E1 and E2 isoforms.

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms.

The sperm nuclear basic proteins of the sword fern (Polystichum munitum).

Sperm nuclear basic proteins (SNBPs) were isolated from extracted antheridia-rich male gametophytes raised from spores of the swordfern, Polystichum munitum. Electrophoretic (acetic acid-urea PAGE and SDS-PAGE) and chromatographic (rp-HPLC) characterization of the nuclear proteins exhibited the characteristics of the histone (H-type). In both types of gel electrophoresis, histones H1, H2A, and H2B showed an altered electrophoretic mobility corresponding to that which is routinely observed for the histones in other plants. Histones present during spermatogenesis of the fern P. munitum were compared with the few current SNBPs known to be present in higher and lower evolutionary plant clades. A transition from an early protamine (P-type) SNBPs in charophytes and bryophytes to the (H-type) SNBP observed here is reminiscent of similar reversions observed in the animal kingdom.

Protamines and the sperm nuclear basic proteins Pandora's Box of insects.

Insects are the largest group of animals when it comes to the number and diversity of species. Yet, with the exception of Drosophila, no information is currently available on the primary structure of their sperm nuclear basic proteins (SNBPs). This paper represents the first attempt in this regard and provides information about six species of Neoptera: Poecillimon thessalicus, Graptosaltria nigrofuscata, Apis mellifera, Nasonia vitripennis, Parachauliodes continentalis, and Tribolium castaneum. The SNBPs of these species were characterized by acetic acid urea gel electrophoresis (AU-PAGE) and high-performance liquid chromatography fractionated. Protein sequencing was obtained using a combination of mass spectrometry sequencing, Edman N-terminal degradation sequencing and genome mining. While the SNBPs of several of these species exhibit a canonical arginine-rich protamine nature, a few of them exhibit a protamine-like composition. They appear to be the products of extensive cleavage processing from a precursor protein which are sometimes further processed by other post-translational modifications that are likely involved in the chromatin transitions observed during spermiogenesis in these organisms.

RECIST 1.1, mRECIST, and Choi criteria for evaluating treatment response and survival outcomes in hepatocellular carcinoma patients treated with atezolizumab plus bevacizumab.

OBJECTIVES: We aimed to compare the early responder rates, defined as complete or partial responders, using response evaluation criteria in solid tumors (RECIST) 1.1, modified RECIST (mRECIST), and Choi criteria in advanced HCC patients treated with atezolizumab-bevacizumab (atezo-bev), and to correlate them with progression-free survival (PFS) and overall survival (OS). METHODS: This retrospective study included advanced HCC patients treated with ≥ 3 cycles of atezo-bev. Two reviewers assessed responses using RECIST 1.1, mRECIST, and Choi criteria at 1st follow-up imaging. Kaplan-Meier curves with log-rank tests evaluated and compared PFS and OS. Cox proportional hazard models identified survival outcome predictors. Kappa statistics assessed inter-reader agreement. RESULTS: We evaluated 77 patients (65 men; mean age, 62.8 ± 12.3 years). Choi's criteria revealed the highest early responders rate (53.2%), exceeding mRECIST (32.5-33.8%) and RECIST 1.1 (24.7-26.0%), with an excellent agreement in all criteria (κ, 0.85-0.95). Across criteria, a consistent number of patients progressed (23-26) and was associated with significantly poor OS (ps ≤ 0.049). Responders by any criteria showed longer PFS (ps ≤ 0.009), and 1-year OS (ps ≤ 0.01). Choi criteria linked to significantly better OS without landmark (p = 0.003), with 1-year OS rates at 76.9% for responders vs 38.1% for non-responders. Cox analysis identified responders by Choi criteria as a significant OS predictor. CONCLUSION: Choi criteria identified more early responders than RECIST 1.1 and mRECIST, significantly correlating with improved OS. Choi criteria could be considered as a formal response assessment criterion for the emerging atezo-bev systemic treatment. CLINICAL RELEVANCE STATEMENT: For atezo-bev treatment of advanced HCC, more comprehensive response criteria, such as Choi criteria, could be effective in identifying early responders and predicting survival outcomes along with RECIST 1.1 and mRECIST. KEY POINTS: Choi criteria identified a higher rate of early responders compared to mRECIST and RECIST1.1 following atezo-bev treatment. Responders by all criteria had longer PFS and 1-year OS, and only those by Choi criteria experienced longer OS without landmark time. Choi criteria, with RECIST 1.1 and mRECIST, is an effective response assessment tool for atezo-bev treatment.

Artificial intelligence model for enhancing the accuracy of transvaginal ultrasound in detecting endometrial cancer and endometrial atypical hyperplasia.

OBJECTIVES: Transvaginal ultrasound is typically the initial diagnostic approach in patients with postmenopausal bleeding for detecting endometrial atypical hyperplasia/cancer. Although transvaginal ultrasound demonstrates notable sensitivity, its specificity remains limited. The objective of this study was to enhance the diagnostic accuracy of transvaginal ultrasound through the integration of artificial intelligence. By using transvaginal ultrasound images, we aimed to develop an artificial intelligence based automated segmentation model and an artificial intelligence based classifier model. METHODS: Patients with postmenopausal bleeding undergoing transvaginal ultrasound and endometrial sampling at Mayo Clinic between 2016 and 2021 were retrospectively included. Manual segmentation of images was performed by four physicians (readers). Patients were classified into cohort A (atypical hyperplasia/cancer) and cohort B (benign) based on the pathologic report of endometrial sampling. A fully automated segmentation model was developed, and the performance of the model in correctly identifying the endometrium was compared with physician made segmentation using similarity metrics. To develop the classifier model, radiomic features were calculated from the manually segmented regions-of-interest. These features were used to train a wide range of machine learning based classifiers. The top performing machine learning classifier was evaluated using a threefold approach, and diagnostic accuracy was assessed through the F1 score and area under the receiver operating characteristic curve (AUC-ROC). RESULTS: 302 patients were included. Automated segmentation-reader agreement was 0.79±0.21 using the Dice coefficient. For the classification task, 92 radiomic features related to pixel texture/shape/intensity were found to be significantly different between cohort A and B. The threefold evaluation of the top performing classifier model showed an AUC-ROC of 0.90 (range 0.88-0.92) on the validation set and 0.88 (range 0.86-0.91) on the hold-out test set. Sensitivity and specificity were 0.87 (range 0.77-0.94) and 0.86 (range 0.81-0.94), respectively. CONCLUSIONS: We trained an artificial intelligence based algorithm to differentiate endometrial atypical hyperplasia/cancer from benign conditions on transvaginal ultrasound images in a population of patients with postmenopausal bleeding.

The Effectiveness of Cognitive-Focused Interventions for Adults With Diabetes: A Systematic Review.

BACKGROUND: Adults with diabetes and impaired memory and executive functions are more likely to experience difficulties in diabetes self-management and achieving glycemic targets. The purpose of this systematic review was to evaluate the evidence of the effects of cognitive-focused interventions on cognitive ability, diabetes self-management, and management of glycemic levels for middle-aged adults and older adults with diabetes. METHODS: A systematic review of randomized controlled/clinical trials published in English between 2012 and 2022 was conducted. A search was performed using 5 databases (PubMed, CINAHL, Embase, Web of Science, and Scopus) in addition to hand-searching. The search terms included diabetes, adults, cognitive-focused intervention, cognition, self-management, and hemoglobin A1C (HbA1C). RESULTS: Eleven studies met the inclusion criteria. Cognitive ability and diabetes self-management were assessed using different measurements, and glycemic levels were measured with HbA1C. Nine studies applied cognitive training, one provided working memory training, and one used occupational therapy. Eight studies combined cognitive training with a co-intervention, including self-efficacy, lifestyle management, physical training, chronic disease self-management program, square-stepping exercise, psychoeducational intervention, and empowerment. Eight studies showed statistically significant improvements in at least one cognitive domain. CONCLUSIONS: Cognitive-focused interventions have a positive effect on improving memory and executive function. However, the evidence of cognitive-focused interventions on diabetes self-management and glycemic levels has not been established. Future studies to improve cognition using effective strategies to improve cognitive function enhancing diabetes self-management behaviors and managing glycemic levels are warranted.

Prognostic Factors of Pulmonary Metastasectomy for Oligometastatic Hepatocellular Carcinoma Spread to the Lungs.

Background/Objectives: Pulmonary metastasis is the most prevalent type of extrahepatic hepatocellular carcinoma (HCC) metastasis. International guidelines recommend systemic treatment for patients with HCC having pulmonary metastases. However, the role of pulmonary metastasectomy (PM) remains relatively unexplored. Therefore, we assessed the survival outcomes and the factors influencing them in patients who underwent PM for metastatic HCC. Methods: Clinical data were collected from patients with HCC who underwent PM for metastasis at a single tertiary center between January 2004 and December 2022. Recurrence-free survival and overall survival were assessed using Kaplan-Meier curves. The Cox proportional hazards model was used to identify factors associated with survival outcomes. Results: Overall, 63 patients underwent PM with a median follow-up time of 84.0 months. The cumulative survival rates after the initial PM at 1, 2, and 5 years were 79.1%, 63.9%, and 35.6%, respectively. In multivariate analysis, early intrathoracic recurrence <6 months, number and size of metastases, resection margin status, and PM bilaterality were significantly associated with overall survival. A larger size of the primary HCC, increased number of repeated PM, and frequent lobectomy were more common in patients with early (<6 months) recurrence after PM than in those without early recurrence. Conclusions: PM in patients with metastatic HCC may provide acceptable survival outcomes for those with smaller, unilateral lung metastases that can be resected with generous surgical margins. However, early recurrence with reduced overall survival is likely in patients with a larger-size initial HCC after prior PM and lobectomy.

Machine learning approach to classifying declines of physical function and muscle strength associated with cognitive function in older women: gait characteristics based on three speeds.

Background: The aging process is associated with a cognitive and physical declines that affects neuromotor control, memory, executive functions, and motor abilities. Previous studies have made efforts to find biomarkers, utilizing complex factors such as gait as indicators of cognitive and physical health in older adults. However, while gait involves various complex factors, such as attention and the integration of sensory input, cognitive-related motor planning and execution, and the musculoskeletal system, research on biomarkers that simultaneously considers multiple factors is scarce. This study aimed to extract gait features through stepwise regression, based on three speeds, and evaluate the accuracy of machine-learning (ML) models based on the selected features to solve classification problems caused by declines in cognitive function (Cog) and physical function (PF), and in Cog and muscle strength (MS). Methods: Cognitive assessments, five times sit-to-stand, and handgrip strength were performed to evaluate the Cog, PF, and MS of 198 women aged 65 years or older. For gait assessment, all participants walked along a 19-meter straight path at three speeds [preferred walking speed (PWS), slower walking speed (SWS), and faster walking speed (FWS)]. The extracted gait features based on the three speeds were selected using stepwise regression. Results: The ML model accuracies were revealed as follows: 91.2% for the random forest model when using all gait features and 91.9% when using the three features (walking speed and coefficient of variation of the left double support phase at FWS and the right double support phase at SWS) selected for the Cog+PF+ and Cog-PF- classification. In addition, support vector machine showed a Cog+MS+ and Cog-MS- classification problem with 93.6% accuracy when using all gait features and two selected features (left step time at PWS and gait asymmetry at SWS). Conclusion: Our study provides insights into the gait characteristics of older women with decreased Cog, PF, and MS, based on the three walking speeds and ML analysis using selected gait features, and may help improve objective classification and evaluation according to declines in Cog, PF, and MS among older women.

Reliability of the DI-60 Digital Image Analyzer for Detecting Platelet Clumping and Obtaining Accurate Platelet Counts.

Pseudothrombocytopenia caused by platelet clumping (PC) can lead to unnecessary platelet transfusions or underdiagnosis of hematologic neoplasms. To overcome these limitations, we assessed the capacity of the Sysmex DI-60 digital morphology analyzer (Sysmex, Kobe, Japan) for detecting PC and determining an accurate platelet count in the presence of PC. For this purpose, 135 samples with or without PC (groups Y and N, respectively) were processed by an examiner (a hematologic specialist) using both the Sysmex XN-9000 and DI-60 analyzers. Although the platelet aggregate (PA) and giant platelet (GP) counts reported by the DI-60 and the examiner exhibited strong correlations, they proved inadequate as effective indicators for screening samples containing PC. Between the PA and GP counts and four platelet indices (the platelet distribution width [PDW], mean platelet volume [MPV], platelet large cell ratio [P_LCR], and plateletcrit [PCT]) reported by the XN-9000, we observed statistically significant correlations (both overall and with group Y), but they were relatively weak. The platelet counts determined using the DI-60 and light microscopy in group Y showed substantial variations. Although the performance of the DI-60 was reliable for detecting PA and GP in smear images, such fixed areas are not representative of whole samples. Further, in the presence of PC, the resulting platelet counts determined using the DI-60 were not sufficiently accurate to be accepted as the final count.

A preoperative scoring system for predicting the extraprostatic extension of prostate cancer following radical prostatectomy using magnetic resonance imaging and clinical factors.

PURPOSE: We aimed to develop a preoperative prediction model for extraprostatic extension (EPE) in prostate cancer (PCa) patients following radical prostatectomy (RP) using MRI and clinical factors. METHODS: This retrospective study enrolled 266 consecutive patients who underwent RP for PCa in 2022. These patients were divided into a training set (n = 187) and a test set (n = 79) through random assignment. The evaluated variables included age, prostate-specific antigen (PSA) level, prostate volume, PSA density (PSAD), index tumor length on MRI, Prostate Imaging-Reporting and Data System (PI-RADS) category, and EPE-related MRI features as defined by PI-RADS v2.1. A predictive model was constructed through multivariable logistic regression and subsequently translated into a scoring system. The performance of this scoring system in terms of prediction and calibration was assessed using C statistics and the Hosmer‒Lemeshow test. RESULTS: Among patients in the training and test cohorts, 74 (39.6%) and 25 (31.6%), respectively, exhibited EPE after RP. The formulated scoring system incorporated the following factors: PSAD, index tumor length, bulging prostatic contour, and tumor-capsule interface > 10 mm as identified on MRI. This scoring system demonstrated strong prediction performance for EPE in both the training (C statistic, 0.87 [95% confidence interval, 0.86-0.87]) and test cohorts (C statistic, 0.85 [0.83-0.89]). Furthermore, the scoring system exhibited good calibration in both cohorts (P = 0.988 and 0.402, respectively). CONCLUSION: Our scoring system, built upon MRI features defined by the PI-RADS, offers valuable assistance in assessing the likelihood of EPE after RP.

Interpretation of Complete Tumor Response on MRI Following Chemoradiotherapy of Rectal Cancer: Inter-Reader Agreement and Associated Factors in Multi-Center Clinical Practice.

OBJECTIVE: To measure inter-reader agreement and identify associated factors in interpreting complete response (CR) on magnetic resonance imaging (MRI) following chemoradiotherapy (CRT) for rectal cancer. MATERIALS AND METHODS: This retrospective study involved 10 readers from seven hospitals with experience of 80-10210 cases, and 149 patients who underwent surgery after CRT for rectal cancer. Using MRI-based tumor regression grading (mrTRG) and methods employed in daily practice, the readers independently assessed mrTRG, CR on T2-weighted images (T2WI) denoted as mrCRT2W, and CR on all images including diffusion-weighted images (DWI) denoted as mrCRoverall. The readers described their interpretation patterns and how they utilized DWI. Inter-reader agreement was measured using multi-rater kappa, and associated factors were analyzed using multivariable regression. Correlation between sensitivity and specificity of each reader was analyzed using Spearman coefficient. RESULTS: The mrCRT2W and mrCRoverall rates varied widely among the readers, ranging 18.8%-40.3% and 18.1%-34.9%, respectively. Nine readers used DWI as a supplement sequence, which modified interpretations on T2WI in 2.7% of cases (36/1341 [149 patients × 9 readers]) and mostly (33/36) changed mrCRT2W to non-mrCRoverall. The kappa values for mrTRG, mrCRT2W, and mrCRoverall were 0.56 (95% confidence interval: 0.49, 0.62), 0.55 (0.52, 0.57), and 0.54 (0.51, 0.57), respectively. No use of rectal gel, larger initial tumor size, and higher initial cT stage exhibited significant association with a higher inter-reader agreement for assessing mrCRoverall (P ≤ 0.042). Strong negative correlations were observed between the sensitivity and specificity of individual readers (coefficient, -0.718 to -0.963; P ≤ 0.019). CONCLUSION: Inter-reader agreement was moderate for assessing CR on post-CRT MRI. Readers' varying standards on MRI interpretation (i.e., threshold effect), along with the use of rectal gel, initial tumor size, and initial cT stage, were significant factors associated with inter-reader agreement.

Practice guidelines for managing extrahepatic biliary tract cancers.

Backgrounds/Aims: Reported incidence of extrahepatic bile duct cancer is higher in Asians than in Western populations. Korea, in particular, is one of the countries with the highest incidence rates of extrahepatic bile duct cancer in the world. Although research and innovative therapeutic modalities for extrahepatic bile duct cancer are emerging, clinical guidelines are currently unavailable in Korea. The Korean Society of Hepato-Biliary-Pancreatic Surgery in collaboration with related societies (Korean Pancreatic and Biliary Surgery Society, Korean Society of Abdominal Radiology, Korean Society of Medical Oncology, Korean Society of Radiation Oncology, Korean Society of Pathologists, and Korean Society of Nuclear Medicine) decided to establish clinical guideline for extrahepatic bile duct cancer in June 2021. Methods: Contents of the guidelines were developed through subgroup meetings for each key question and a preliminary draft was finalized through a Clinical Guidelines Committee workshop. Results: In November 2021, the finalized draft was presented for public scrutiny during a formal hearing. Conclusions: The extrahepatic guideline committee believed that this guideline could be helpful in the treatment of patients.