Regulation of Betaine Homocysteine Methyltransferase by Liver Receptor Homolog-1 in the Methionine Cycle.

Betaine-homocysteine S-methyltransferase (BHMT) is one of the most abundant proteins in the liver and regulates homocysteine metabolism. However, the molecular mechanisms underlying Bhmt transcription have not yet been elucidated. This study aimed to assess the molecular mechanisms underlying Bhmt transcription and the effect of BHMT deficiency on metabolic functions in the liver mediated by liver receptor homolog-1 (LRH-1). During fasting, both Bhmt and Lrh-1 expression increased in the liver of Lrh-1f/f mice; however, Bhmt expression was decreased in LRH-1 liver specific knockout mice. Promoter activity analysis confirmed that LRH-1 binds to a specific site in the Bhmt promoter region. LRH-1 deficiency was associated with elevated production of reactive oxygen species (ROS), lipid peroxidation, and mitochondrial stress in hepatocytes, contributing to hepatic triglyceride (TG) accumulation. In conclusion, this study suggests that the absence of an LRH-1-mediated decrease in Bhmt expression promotes TG accumulation by increasing ROS levels and inducing mitochondrial stress. Therefore, LRH-1 deficiency not only leads to excess ROS production and mitochondrial stress in hepatocytes, but also disrupts the methionine cycle. Understanding these regulatory pathways may pave the way for novel therapeutic interventions against metabolic disorders associated with hepatic lipid accumulation.

Exploring aryl hydrocarbon receptor expression and distribution in the tumor microenvironment, with a focus on immune cells, in various solid cancer types.

Introduction: Aryl hydrocarbon receptor (AhR) is a transcription factor that performs various functions upon ligand activation. Several studies have explored the role of AhR expression in tumor progression and immune surveillance. Nevertheless, investigations on the distribution of AhR expression, specifically in cancer or immune cells in the tumor microenvironment (TME), remain limited. Examining the AhR expression and distribution in the TME is crucial for gaining insights into the mechanism of action of AhR-targeting anticancer agents and their potential as biomarkers. Methods: Here, we used multiplexed immunohistochemistry (mIHC) and image cytometry to investigate the AhR expression and distribution in 513 patient samples, of which 292 are patients with one of five solid cancer types. Additionally, we analyzed the nuclear and cytosolic distribution of AhR expression. Results: Our findings reveal that AhR expression was primarily localized in cancer cells, followed by stromal T cells and macrophages. Furthermore, we observed a positive correlation between the nuclear and cytosolic expression of AhR, indicating that the expression of AhR as a biomarker is independent of its localization. Interestingly, the expression patterns of AhR were categorized into three clusters based on the cancer type, with high AhR expression levels being found in regulatory T cells (Tregs) in non-small cell lung cancer (NSCLC). Discussion: These findings are anticipated to serve as pivotal evidence for the design of clinical trials and the analysis of the anticancer mechanisms of AhR-targeting therapies.

CD81 and CD82 expressing tumor-infiltrating lymphocytes in the NSCLC tumor microenvironment play a crucial role in T-cell activation and cytokine production.

Introduction: To understand the immune system within the tumor microenvironment (TME) of non-small cell lung cancer (NSCLC), it is crucial to elucidate the characteristics of molecules associated with T cell activation. Methods: We conducted an in-depth analysis using single-cell RNA sequencing data obtained from tissue samples of 19 NSCLC patients. T cells were classified based on the Tumor Proportion Score (TPS) within the tumor region, and molecular markers associated with activation and exhaustion were analyzed in T cells from high TPS areas. Results: Notably, tetraspanins CD81 and CD82, belonging to the tetraspanin protein family, were found to be expressed in activated T cells, particularly in cytotoxic T cells. These tetraspanins showed strong correlations with activation and exhaustion markers. In vitro experiments confirmed increased expression of CD81 and CD82 in IL-2-stimulated T cells. T cells were categorized into CD81highCD82high and CD81lowCD82low groups based on their expression levels, with CD81highCD82high T cells exhibiting elevated activation markers such as CD25 and CD69 compared to CD81lowCD82low T cells. This trend was consistent across CD3+, CD8+, and CD4+ T cell subsets. Moreover, CD81highCD82high T cells, when stimulated with anti-CD3, demonstrated enhanced secretion of cytokines such as IFN-γ, TNF-α, and IL-2, along with an increase in the proportion of memory T cells. Bulk RNA sequencing results after sorting CD81highCD82high and CD81lowCD82low T cells consistently supported the roles of CD81 and CD82. Experiments with overexpressed CD81 and CD82 showed increased cytotoxicity against target cells. Discussion: These findings highlight the multifaceted roles of CD81 and CD82 in T cell activation, cytokine production, memory subset accumulation, and target cell cytolysis. Therefore, these findings suggest the potential of CD81 and CD82 as promising candidates for co-stimulatory molecules in immune therapeutic strategies for cancer treatment within the intricate TME.

Polo-like Kinase 4: A Multifaceted Marker Linking Tumor Aggressiveness and Unfavorable Prognosis, and Insights into Therapeutic Strategies.

(1) Background: This study investigated whether polo-like kinase 4 (PLK4) is a suitable therapeutic target or biomarker for lung adenocarcinoma (LUAD). (2) Methods: We acquired LUAD data from The Cancer Genome Atlas (TCGA) database through the UCSC Xena data portal. Gene expression, clinical, survival, and mutation data from multiple samples were analyzed. Gene enrichment analysis, unsupervised clustering of PLK4-related pathways, and differential gene expression analyses were performed. Additionally, correlations, t-tests, survival analyses, and statistical analyses were performed. (3) Results: PLK4 expression was higher in LUAD tissues than in normal tissues and was associated with poor prognosis for both overall and progression-free survival in LUAD. PLK4 was highly correlated with cell-proliferation-related pathways using Gene Ontology (GO) biological process terms. PLK4 expression and pathways that were highly correlated with PLK4 expression levels were upregulated in patients with LUAD with the TP53 mutation. (4) Conclusions: PLK4 expression affects the survival of patients with LUAD and is a potential therapeutic target for LUAD with TP53 mutations.

Fundamental frequency range and other acoustic factors that might contribute to the clear-speech benefit.

The main goal of the present study was to assess the role of the fundamental frequency (F0) range on the clear-speech benefit. Conversational- and clear-speech sentences were recorded for four male speakers: the speakers' clear-speech productions had slower speaking rates, wider F0 range, more high-frequency energy, expanded vowel space, and higher vocal intensity level relative to their conversational-speech productions. To examine if F0 range contributes to the clear-speech benefit, the F0 range of clear-speech sentences was compressed to match that of the speakers' conversational-speech sentences. Fifteen listeners were presented with conversational, clear, and F0-compressed sentences in sustained speech-shaped noise. All talkers elicited substantial intelligibility benefits (keyword percent correct) from clear and F0-compressed speech when compared with conversational speech. There was no significant difference in performance between clear and F0-compressed speech. These results leave open the possibility that a clear-speech benefit could be a result of its F0 contours rather than its wide F0 range. Intelligibility predictions based on acoustic characteristics of clear speech, specifically high-frequency emphasis and pauses, accounted for either small or negligible amounts of the clear-speech benefit.

Ambulatory Toxicity Management (AToM) Pilot: results of a pilot study of a pro-active, telephone-based intervention to improve toxicity management during chemotherapy for breast cancer.

BACKGROUND: Chemotherapy is associated with a significant risk of toxicity, which often peaks between ambulatory visits to the cancer centre. Remote symptom management support is a tool to optimize self-management and healthcare utilization, including emergency department visits and hospitalizations (ED+H) during chemotherapy. We performed a single-arm pilot study to evaluate the feasibility, acceptability, and potential impact of a telephone symptom management intervention on healthcare utilization during chemotherapy for early stage breast cancer (EBC). METHODS: Women starting adjuvant or neoadjuvant chemotherapy for EBC at two cancer centres in Ontario, Canada, received standardized, nurse-led calls to assess common toxicities at two time points following each chemotherapy administration. Feasibility outcomes included patient enrollment, retention, RN adherence to delivering calls per the study schedule, and resource use associated with calls; acceptability was evaluated based on patient and provider feedback. Impact on acute care utilization was evaluated post hoc by linking individual patient records to provincial data holdings to examine ED+H patterns among participating patients compared to contemporaneous controls. RESULTS: Between September 2013 and December 2014, 77 women were enrolled (mean age 55 years). Most commonly used regimens were AC-paclitaxel (58%) and FEC-docetaxel (16%); 78% of patients received primary granulocyte colony-stimulating factor prophylaxis. 83.8% of calls were delivered per schedule; mean call duration was 9 min. The intervention was well received by both patients and clinicians. Comparison of ED+H rates among study participants versus controls showed that there were fewer ED visits in intervention patients [incidence rate ratio (IRR) (95% CI) = 0.54 (0.36, 0.81)] but no difference in the rate of hospitalizations [IRR (95% CI) = 1.02 (0.59, 1.77)]. Main implementation challenges included identifying eligible patients, fitting the calls into existing clinical responsibilities, and effective communication to the patient's clinical team. CONCLUSIONS: Telephone-based pro-active toxicity management during chemotherapy is feasible, perceived as valuable by clinicians and patients, and may be associated with lower rates of acute care use. However, attention must be paid to workflow issues for scalability. Larger scale evaluation of this approach is in progress.

Pure-Tone-Spondee Threshold Relationships in Functional Hearing Loss: A Test of Loudness Contribution.

Purpose: The purpose of this article is to examine explanations for pure-tone average-spondee threshold differences in functional hearing loss. Method: Loudness magnitude estimation functions were obtained from 24 participants for pure tones (0.5 and 1.0 kHz), vowels, spondees, and speech-shaped noise as a function of level (20-90 dB SPL). Participants listened monaurally through earphones. Loudness predictions were obtained for the same stimuli by using a computational, dynamic loudness model. Results: When evaluated at the same SPL, speech-shaped noise was judged louder than vowels/spondees, which were judged louder than tones. Equal-loudness levels were inferred from fitted loudness functions for the group. For the clinical application, the 2.1-dB difference between spondees and tones at equal loudness became a 12.1-dB difference when the stimuli were converted from SPL to HL. Conclusions: Nearly all of the pure-tone average-spondee threshold differences in functional hearing loss are attributable to references for calibration for 0 dB HL for tones and speech, which are based on detection and recognition, respectively. The recognition threshold for spondees is roughly 9 dB higher than the speech detection threshold; persons feigning a loss, who base loss magnitude on loudness, do not consider this difference. Furthermore, the dynamic loudness model was more accurate than the static model.

Chest CT scans are frequently abnormal in asymptomatic patients with newly diagnosed acute myeloid leukemia.

Chest computed tomography (CT) findings of nodules, ground glass opacities, and consolidations are often interpreted as representing invasive fungal infection in individuals with febrile neutropenia. We assessed whether these CT findings were present in asymptomatic individuals with acute myeloid leukemia (AML) at low risk of invasive fungal disease. A retrospective study of consecutive asymptomatic adult patients with newly diagnosed AML over a 2-year period was performed at a tertiary care oncology center. Radiology reports of baseline chest CTs were reviewed. Of 145 CT scans, the majority (88%) had pulmonary abnormalities. Many (70%) had one or both of unspecified opacities (52%) and nodules (49%). Ground glass opacities (18%) and consolidations (12%) occurred less frequently. Radiologists suggested pneumonia as a possible diagnosis in 32% (n = 47) of scans. Chest CT may result in over-diagnosis of invasive fungal disease in individuals with febrile neutropenia if interpreted without correlation to the patients' clinical status.

The effect of visual cues on scoring of clinical word-recognition tests.

PURPOSE: During routine clinical speech assessment, if the person being tested were to write down what he or she heard, it would not always match what the audiologist heard while scoring the listener's vocal responses (Nelson & Chaiklin, 1970). This study demonstrated a method to assess examiner accuracy and whether speechreading cues reduce writedown-talkback errors. METHOD: Examiners were divided into 3 categories: normal hearing native speakers of English, normal hearing nonnative speakers of English, and native speakers with hearing loss. Each examiner assessed 4 normal-hearing listeners. Two NU-6 lists were presented to each listener; one was scored without visual cues and one with visual cues. Lists were presented at 50 dB HL in the presence of speech noise at 0 dB signal-to-noise ratio (SNR). RESULTS: Results analyzed by percentage of correct phonemes and words revealed fewer writedown-talkback discrepancies for all 3 examiner groups when visual cues were added, with a substantial improvement for examiners with hearing loss. CONCLUSION: The finding of errors between talkback versus writedown scoring of lists for all of the examiners, even with visual cues, suggests a need for modification of the clinical word-recognition procedure for applications that potentially affect diagnosis, rehabilitation choices, or financial compensation.

Distinguishability and chiral stability in solution: effects of decoherence and intermolecular interactions.

We examine the effect of decoherence and intermolecular interactions (chiral discrimination energies) on the chiral stability and the distinguishability of initially pure versus mixed states in an open chiral system. Under a two-level approximation for a system, intermolecular interactions are introduced by a mean-field theory, and interaction between a system and an environment is modeled by a continuous measurement of a population difference between the two chiral states. The resultant equations are explored for various parameters, with emphasis on the combined effects of the initial condition of the system, the chiral discrimination energies, and the decoherence in determining: the distinguishability as measured by a population difference between the initially pure and mixed states, and the decoherence process; the chiral stability as measured by the purity decay; and the stationary state of the system at times long relative to the time scales of the system dynamics and of the environmental effects.

Reference sound pressure level for Korean speech audiometry.

OBJECTIVE: The purpose of this study was to examine the reference sound pressure level (RSPL) for Korean speech audiometry which was defined as the reference speech recognition threshold level (RSRTL) equivalent to 0 dB HL at the audiometer. STUDY SAMPLE: Subjects consisted of 20 adults (40 ears) with normal hearing sensitivity. DESIGN: Puretone thresholds (PTs) were obtained in 2 dB steps at each octave band. The newly developed Korean bisyllabic words were used to establish the speech recognition thresholds (SRTs). The SRT was the level at 50% correct responses based on the psychometric function performed from -8 dB HL (12 dB SPL) up to the level at or above 90% correct responses in 2 dB steps. RESULTS CONCLUSIONS: The mean SRT was 23.44 dB SPL for sets comprised of 36 Korean bisyllabic words. Thus, the difference between English and Korean RSRTLs was about 3.44 dB. We recommend further study to recalculate the RSRTL for Korean speech audiometry with more subjects.

Decoherence effects in reactive scattering.

Decoherence effects on quantum and classical dynamics in reactive scattering are examined using a Caldeira-Leggett type model. Through a study of the dynamics of the collinear H + H2 reaction and the transmission over simple one-dimensional barrier potentials, we show that decoherence leads to improved agreement between quantum and classical reactions and transmission probabilities, primarily by increasing the energy dispersion in a well-defined way. Increased potential nonlinearity is seen to require larger decoherence in order to attain comparable quantum-classical agreement.