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OBJECTIVES: Therapeutic interventions are crucial for perimenopausal women, given the challenging physical and psychological symptoms they face. This study focused on the development and verification of the efficacy of a cognitive behavioral therapy (CBT) protocol designed specifically for Korean perimenopausal women. STUDY DESIGN: A CBT protocol for perimenopausal women was newly developed based on theory and evidence. Forty menopausal women were randomly assigned to either the CBT group (n = 19) or treatment-as-usual (TAU) group (n = 21). Participants in the CBT group underwent 60-min weekly sessions for eight weeks. The TAU group received standard care from gynecologists. MAIN OUTCOME MEASURES: At baseline and follow-up, participants completed the Menopausal Rating Scale (MRS), World Health Organization Quality of Life Brief Version (WHOQOL-BREF), Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-15 (PHQ-15), Menopause Emotional Symptom Questionnaire (MESQ), and Subjective Memory Complaints Questionnaire. RESULTS: The CBT group showed significant changes in their MRS (F = 4.18, p = .048), WHOQOL-BREF (7.60, 0.009), GAD-7 (4.61, 0.038), PHQ-15 (5.49, 0.025), and MESQ scores (7.19, 0.011) compared to the TAU group. In the CBT group, changes in GAD-7 scores were correlated with PHQ-15 (ρ = 0.57, p < .05), MESQ (0.57, < 0.05), and WHOQOL-BREF scores (-0.53, < 0.05). CONCLUSION: CBT prevents the worsening of menopausal and emotional symptoms, anxiety, and quality of life. CBT may have had a therapeutic effect through the following mechanisms: managing anxiety by changing perceptions of menopause through education and training for coping with various menopausal symptoms and improving self-efficacy in symptom management. CLINICAL TRIAL REGISTRATION NUMBER: KCT0007517.
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OBJECTIVE: To prospectively investigate the influence of the menstrual cycle on the background parenchymal signal (BPS) and apparent diffusion coefficient (ADC) of the breast on diffusion-weighted MRI (DW-MRI) in healthy premenopausal women. MATERIALS AND METHODS: Seven healthy premenopausal women (median age, 37 years; range, 33-49 years) with regular menstrual cycles participated in this study. DW-MRI was performed during each of the four phases of the menstrual cycle (four examinations in total). Three radiologists independently assessed the BPS visual grade on images with b-values of 800 sec/mm² (b800), 1200 sec/mm² (b1200), and a synthetic 1500 sec/mm² (sb1500). Additionally, one radiologist conducted a quantitative analysis to measure the BPS volume (%) and ADC values of the BPS (ADCBPS) and fibroglandular tissue (ADCFGT). Changes in the visual grade, BPS volume (%), ADCBPS, and ADCFGT during the menstrual cycle were descriptively analyzed. RESULTS: The visual grade of BPS in seven women varied from mild to marked on b800 and from minimal to moderate on b1200 and sb1500. As the b-value increased, the visual grade of BPS decreased. On b800 and sb1500, two of the seven volunteers showed the highest visual grade in the early follicular phase (EFP). On b1200, three of the seven volunteers showed the highest visual grades in EFP. The BPS volume (%) on b800 and b1200 showed the highest value in three of the six volunteers with dense breasts in EFP. Three of the seven volunteers showed the lowest ADCBPS in the EFP. Four of the seven volunteers showed the highest ADCBPS in the early luteal phase (ELP) and the lowest ADCFGT in the late follicular phase (LFP). CONCLUSION: Most volunteers did not exhibit specific BPS patterns during their menstrual cycles. However, the highest BPS and lowest ADCBPS were more frequently observed in EFP than in the other menstrual cycle phases, whereas the highest ADCBPS was more common in ELP. The lowest ADCFGT was more frequent in LFP.
Subject(s)
Breast , Diffusion Magnetic Resonance Imaging , Menstrual Cycle , Premenopause , Humans , Female , Adult , Diffusion Magnetic Resonance Imaging/methods , Prospective Studies , Menstrual Cycle/physiology , Middle Aged , Breast/diagnostic imagingABSTRACT
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low status has recently gained attention because of the potential therapeutic benefits of antibody-drug conjugates (ADCs) in breast cancer patients. We aimed to investigate the concordance of HER2 status between core needle biopsy (CNB) and subsequent surgical resection specimens focusing on the HER2-low status. METHODS: This retrospective study was conducted in 1,387 patients with invasive breast cancer whose HER2 status was evaluated in both CNB and surgical resection specimens. The discordance rates between CNB and surgical resection specimens and the clinicopathological features associated with HER2 status discordance were analyzed. RESULTS: The overall concordance rates of HER2 status between CNB and surgical resection specimens were 99.0% (κ = 0.925) for two-group classification (negative vs. positive) and 78.5% (κ = 0.587) for three-group classification (zero vs. low vs. positive). The largest discordance occurred in CNB-HER2-zero cases with 42.8% of them reclassified as HER2-low in surgical resection. HER2 discordance was associated with lower histologic grade, tumor multiplicity, and luminal A subtype. In multivariate analysis, tumor multiplicity and estrogen receptor (ER) positivity were independent predictive factors for HER2-zero to low conversion. CONCLUSIONS: Incorporation of HER2-low category in HER2 status interpretation reduces the concordance rate between CNB and surgical resection specimens. Tumor multiplicity and ER positivity are predictive factors for conversion from HER2-zero to HER2-low status. Therefore, HER2 status should be re-evaluated in resection specimens when considering ADCs in tumors exhibiting multiplicity and ER positivity.
Subject(s)
Breast Neoplasms , Receptor, ErbB-2 , Humans , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Breast Neoplasms/metabolism , Receptor, ErbB-2/metabolism , Female , Biopsy, Large-Core Needle , Retrospective Studies , Middle Aged , Aged , Adult , Aged, 80 and over , Biomarkers, Tumor/metabolism , Biomarkers, Tumor/analysis , Receptors, Estrogen/metabolismABSTRACT
BACKGROUND: Panic disorder is a common and important disease in clinical practice that decreases individual productivity and increases health care use. Treatments comprise medication and cognitive behavioral therapy. However, adverse medication effects and poor treatment compliance mean new therapeutic models are needed. OBJECTIVE: We hypothesized that digital therapy for panic disorder may improve panic disorder symptoms and that treatment response would be associated with brain activity changes assessed with functional near-infrared spectroscopy (fNIRS). METHODS: Individuals (n=50) with a history of panic attacks were recruited. Symptoms were assessed before and after the use of an app for panic disorder, which in this study was a smartphone-based app for treating the clinical symptoms of panic disorder, panic symptoms, depressive symptoms, and anxiety. The hemodynamics in the frontal cortex during the resting state were measured via fNIRS. The app had 4 parts: diary, education, quest, and serious games. The study trial was approved by the institutional review board of Chung-Ang University Hospital (1041078-202112-HR-349-01) and written informed consent was obtained from all participants. RESULTS: The number of participants with improved panic symptoms in the app use group (20/25, 80%) was greater than that in the control group (6/21, 29%; χ21=12.3; P=.005). During treatment, the improvement in the Panic Disorder Severity Scale (PDSS) score in the app use group was greater than that in the control group (F1,44=7.03; P=.01). In the app use group, the total PDSS score declined by 42.5% (mean score 14.3, SD 6.5 at baseline and mean score 7.2, SD 3.6 after the intervention), whereas the PDSS score declined by 14.6% in the control group (mean score 12.4, SD 5.2 at baseline and mean score 9.8, SD 7.9 after the intervention). There were no significant differences in accumulated oxygenated hemoglobin (accHbO2) at baseline between the app use and control groups. During treatment, the reduction in accHbO2 in the right ventrolateral prefrontal cortex (VLPFC; F1,44=8.22; P=.006) and the right orbitofrontal cortex (OFC; F1,44=8.88; P=.005) was greater in the app use than the control group. CONCLUSIONS: Apps for panic disorder should effectively reduce symptoms and VLPFC and OFC brain activity in patients with panic disorder. The improvement of panic disorder symptoms was positively correlated with decreased VLPFC and OFC brain activity in the resting state. TRIAL REGISTRATION: Clinical Research Information Service KCT0007280; https://cris.nih.go.kr/cris/search/detailSearch.do?seq=21448.
Subject(s)
Cognitive Behavioral Therapy , Drug-Related Side Effects and Adverse Reactions , Mobile Applications , Panic Disorder , Humans , Panic Disorder/therapy , Anxiety , Anxiety DisordersABSTRACT
OBJECTIVE: The aim of this study was to increase the treatment rate of perimenopausal women by providing evidence-based nonpharmaceutical treatments through developing scientific evidence-based sports therapy and verifying its effectiveness. METHODS: In a cross-over design, a total of 33 women were assigned to two different sequences of intervention: sports therapy and telephone intervention (n = 17) or telephone intervention and sports therapy (n = 16). A self-reported clinical symptom survey was conducted before and after the experimental and control periods using the following measures: the Menopause Rating Scale, Patient Health Questionnaire 9, and Patient Health Questionnaire 15. RESULTS: There were significant differences in the changes in the scores for Menopause Rating Scale total (exercise phase, 17.8 ± 5.5 at baseline [B] and 13.5 ± 4.2 at follow-up [F]; control phase, 15.9 ± 6.0 [B] and 15.4 ± 5.3 [F]; P < 0.01), somatic symptoms (exercise phase, 9.5 ± 2.6 [B] and 6.6 ± 2.0 [F]; control phase, 8.5 ± 2.8 [B] and 8.0 ± 1.3 [F], P < 0.01), and urogenital symptoms (exercise phase, 4.9 ± 1.7 [B] and 4.1 ± 1.4 [F]; control phase, 4.3 ± 1.6 [B] and 4.4 ± 1.5 [F]; P < 0.01) between the exercise and control phases. There were also significant differences in the changes in the scores for PHQ-9 (exercise phase, 4.6 ± 4.4 [B] and 3.6 ± 3.3 [F]; control phase, 4.5 ± 3.8 [B] and 5.5 ± 4.6 [F]; P = 0.008) and PHQ-15 (exercise phase, 7.2 ± 4.4 [B] and 5.5 ± 3.5 [F]; control phase, 6.8 ± 4.4 [B] and 7.2 ± 4.9 [F]; P = 0.009) between the two phases. CONCLUSIONS: Sports therapy would improve menopause symptoms, especially somatic and urogenital symptoms. In addition, sports therapy would improve depressive moods in perimenopausal women.
Subject(s)
Hot Flashes , Sports , Female , Humans , Exercise , Menopause/psychology , Perimenopause , Cross-Over StudiesABSTRACT
OBJECTIVE: Automated breast ultrasound (ABUS) is a relevant imaging technique for early breast cancer diagnosis and is increasingly being used as a supplementary tool for mammography. This study compared the performance of ABUS and handheld ultrasound (HHUS) in detecting and characterizing the axillary lymph nodes (LNs) in patients with breast cancer. MATERIALS AND METHODS: We retrospectively reviewed the medical records of women with recently diagnosed early breast cancer (≤ T2) who underwent both ABUS and HHUS examinations for axilla (September 2017-May 2018). ABUS and HHUS findings were compared using pathological outcomes as reference standards. Diagnostic performance in predicting any axillary LN metastasis and heavy nodal-burden metastases (i.e., ≥ 3 LNs) was evaluated. The ABUS-HHUS agreement for visibility and US findings was calculated. RESULTS: The study included 377 women (53.1 ± 11.1 years). Among 385 breast cancers in 377 patients, 101 had axillary LN metastases and 30 had heavy nodal burden metastases. ABUS identified benign-looking or suspicious axillary LNs (average, 1.4 ± 0.8) in 246 axillae (63.9%, 246/385). According to the per-breast analysis, the sensitivity, specificity, positive and negative predictive values, and accuracy of ABUS in predicting axillary LN metastases were 43.6% (44/101), 95.1% (270/284), 75.9% (44/58), 82.6% (270/327), and 81.6% (314/385), respectively. The corresponding results for HHUS were 41.6% (42/101), 95.1% (270/284), 75.0% (42/56), 82.1% (270/329), and 81.0% (312/385), respectively, which were not significantly different from those of ABUS (P ≥ 0.53). The performance results for heavy nodal-burden metastases were 70.0% (21/30), 89.6% (318/355), 36.2% (21/58), 97.3% (318/327), and 88.1% (339/385), respectively, for ABUS and 66.7% (20/30), 89.9% (319/355), 35.7% (20/56), 97.0% (319/329), and 88.1% (339/385), respectively, for HHUS, also not showing significant difference (P ≥ 0.57). The ABUS-HHUS agreement was 95.9% (236/246; Cohen's kappa = 0.883). CONCLUSION: Although ABUS showed limited sensitivity in diagnosing axillary LN metastasis in early breast cancer, it was still useful as the performance was comparable to that of HHUS.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/diagnosis , Axilla/diagnostic imaging , Axilla/pathology , Retrospective Studies , Sensitivity and Specificity , Ultrasonography, Mammary/methods , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Lymphatic Metastasis/diagnostic imagingABSTRACT
OBJECTIVE: This study aimed to investigate the feasibility of ultrafast magnetic resonance imaging (MRI) and radiomic features derived from breast MRI for predicting the upstaging of ductal carcinoma in situ (DCIS) diagnosed using percutaneous needle biopsy. MATERIALS AND METHODS: Between August 2018 and June 2020, 95 patients with 98 DCIS lesions who underwent preoperative breast MRI, including an ultrafast sequence, and subsequent surgery were included. Four ultrafast MRI parameters were analyzed: time-to-enhancement, maximum slope (MS), area under the curve for 60 s after enhancement, and time-to-peak enhancement. One hundred and seven radiomic features were extracted for the whole tumor on the first post-contrast T1WI and T2WI using PyRadiomics. Clinicopathological characteristics, ultrafast MRI findings, and radiomic features were compared between the pure DCIS and DCIS with invasion groups. Prediction models, incorporating clinicopathological, ultrafast MRI, and radiomic features, were developed. Receiver operating characteristic curve analysis and area under the curve (AUC) were used to evaluate model performance in distinguishing between the two groups using leave-one-out cross-validation. RESULTS: Thirty-six of the 98 lesions (36.7%) were confirmed to have invasive components after surgery. Compared to the pure DCIS group, the DCIS with invasion group had a higher nuclear grade (P < 0.001), larger mean lesion size (P = 0.038), larger mean MS (P = 0.002), and different radiomic-related characteristics, including a more extensive tumor volume; higher maximum gray-level intensity; coarser, more complex, and heterogeneous texture; and a greater concentration of high gray-level intensity. No significant differences in AUCs were found between the model incorporating nuclear grade and lesion size (0.687) and the models integrating additional ultrafast MRI and radiomic features (0.680-0.732). CONCLUSION: High nuclear grade, larger lesion size, larger MS, and multiple radiomic features were associated with DCIS upstaging. However, the addition of MS and radiomic features to the prediction model did not significantly improve the prediction performance.
Subject(s)
Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Humans , Female , Carcinoma, Intraductal, Noninfiltrating/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/surgery , Carcinoma, Intraductal, Noninfiltrating/pathology , Magnetic Resonance Imaging/methods , Biopsy, Needle , ROC Curve , Breast Neoplasms/diagnostic imaging , Retrospective StudiesABSTRACT
Objective: : Most affective neuroscience studies use pictures from the International Affective Picture System or standard facial expressions to elicit emotional experiences. The attention system, including the prefrontal cortex, can mediate emotional regulation in response to stimulation with emotional faces. We hypothesized that emotional experience is associated with brain activity within the neocortex. In addition, modification within the neocortex may be associated with brain activity within the attention system. Methods: : Thirty-one healthy adult participants were recruited to be assessed for emotional expression using clinical scales of happiness, sadness, anxiety, and anger as and for emotional experience using brain activity in response to pictures of facial emotional expressions. The attention system was assessed using brain activity in response to the go-no-go task. Results: : We found that emotional experience was associated with brain activity within the frontotemporal cortices, while emotional expression was associated with brain activity within the temporal and insular cortices. In addition, the association of brain activity between emotional experiences and expressions of sadness and anxiety was affected by brain activity within the anterior cingulate gyrus in response to the go-no-go task. Conclusion: : Emotional expression may be associated with brain activity within the temporal cortex, whereas emotional experience may be associated with brain activity within the frontotemporal cortices. In addition, the attention system may interfere with the connection between emotional expression and experience.
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Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis around intrahepatic and extrahepatic bile ducts leading to severe hepatic cirrhosis and high mortality. Although there is an urgent clinical unmet need for PSC, no effective medical therapy has been developed to delay the disease progression until today. IL-18 binding protein (IL-18BP) is well-known to be a natural negative feedback regulator for IL-18, and we have developed a recombinant long-acting IL-18BP referred to as APB-R3 as a therapeutic agent to treat IL-18-related inflammatory diseases. Here, we aimed to study whether disrupted IL-18 signaling by APB-R3 treatment can inhibit PSC injuries in the experimental DDC diet-induced PSC rodent model. First, we found that the amounts of free IL-18 are augmented under PSC condition with increased expression of biliary IL-18 receptors. Administration of APB-R3 effectively attenuated key diagnostic parameters of PSC such as plasma ALP and GGT levels as well as bile acids levels. We also observed that blockade of IL-18 suppressed ductular reactive and proliferative phenotypes of cholangiocytes. Additionally, APB-R3 significantly ameliorated DDC diet-induced periductal fibrosis and transcriptional expressions of pro-fibrotic marker genes. Enhanced senescence associated secretory phenotype (SASP) markers in cholestatic liver disease were diminished by APB-R3 treatment. Our findings clearly demonstrate that the administration of IL-18BP biologics, APB-R3, effectively alleviates DDC diet-induced biliary injuries in rodent PSC model, implying APB-R3 can be a promising therapeutic reagent which warrants clinical human trials as new therapeutic options.
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OBJECTIVES: Menopause presents various physical and psychological disturbances for women and comes at a high financial cost. Therefore, this study aimed to identify factors influencing menopause symptoms. STUDY DESIGN: Data of Korean perimenopausal women aged 40-60 (n = 1060; mean age, 46.03 ± 4.08) were collected by a research company. Participants were classified into a "functional" group (n = 716) or a "dysfunctional" group (n = 344) according to the severity of their perimenopausal psychosomatic symptoms. To investigate the association of obstetric and psychiatric history with membership of the "dysfunctional" group, a hierarchical logistic regression analysis was conducted. RESULTS: The outcomes of all three hierarchical logistic regression models presented significant overall model fit. Among the independent variables, family history of menopausal symptoms, menarcheal age, number of pregnancies, history of postpartum depression, postpartum psychosis, and other psychiatric disorders were positively associated with being in the "dysfunctional" group, whereas age and number of deliveries were negatively associated with being in the "dysfunctional" group. CONCLUSION: A short reproductive period and short exposure to estrogen due to late menarche and early menopausal transition may be related to severe perimenopausal symptoms. The relationship between the history of postpartum mental illness and severe perimenopausal symptoms may be associated with heightened sensitivity to hormonal triggers when a woman is exposed to fluctuating ovarian sex steroid levels. The relationship between parity or gravidity and the severity of menopausal symptoms in Korean women differed from that in studies conducted in other countries, possibly due to the low birth rate in Korea.
Subject(s)
Mental Disorders , Perimenopause , Pregnancy , Female , Humans , Perimenopause/psychology , Menopause/psychology , Mental Disorders/epidemiology , Estrogens , Republic of Korea/epidemiologyABSTRACT
Amputation of the testis is very rare in clinical situations; therefore, most surgeons have no experience with an amputated testis. In this case, a 31-year-old male with schizophrenia amputated both testes due to self-mutilation. We performed replantation surgery via microscopy. On postoperative day 1, he removed his right testis by using his hand, even though his hands were restrained. The second attack disrupted the viability of the right testis. However, after proper management, we checked the normal sex hormone level by preserving the replanted left testis. We evaluated the viability of the replanted testis by performing five examinations, namely, intraoperative indocyanine green injection, testicular scan with technetium pertechnetate, contrast-enhanced computerized tomography, Doppler ultrasonography, and serum testosterone level. In this report, we aimed to describe our rare experience about management with replantation of the amputated testes and evaluation of their viability.
Subject(s)
Amputation, Traumatic , Schizophrenia , Male , Humans , Adult , Amputation, Traumatic/surgery , Testis/diagnostic imaging , Testis/surgery , Schizophrenia/surgery , Replantation/methods , HandABSTRACT
OBJECTIVE: Women experience many physical and psychological changes with the reduction of progesterone and estrogen as ovarian function gradually weakens. This study applied a music psychotherapy program as a nonpharmacological treatment method in addition to treatment using drugs such as hormone therapy for perimenopausal women. METHOD: This study's pre-post, control-experimental research compared 20 women in the music psychotherapy experimental group and 20 in the cognitive behavioral therapy (CBT) control group. The perimenopausal women aged between 40 and 60 years experienced no menstrual period for 1 year. We provided eight sessions of music psychotherapy, including CBT, each lasting 60 minutes. The study period was 4 months from the time of recruitment. RESULTS: The music therapy group showed a more significant decrease in the Menopause Rating Scale total (change over time, 9.2 points and 3.5 points, respectively; P = 0.008) and psychology subcategory (change over time, 6.5 points and 0.9 points, respectively; P = 0.004) of Menopause Rating Scale scores, compared with the CBT group. In addition, the music therapy group increased their quality of life psychological score, but the CBT group did not. CONCLUSIONS: These results suggest that music therapy can help the psychological and emotional symptoms of perimenopausal women and is effective for treatment. The study result provides a therapeutic basis for developing treatments for nonpharmacological mediation.
Subject(s)
Cognitive Behavioral Therapy , Music Therapy , Female , Humans , Adult , Middle Aged , Perimenopause , Quality of Life , Menopause , SyndromeABSTRACT
Objective: To develop an evidence-based guideline for the diagnosis and treatment of antipsychotic-induced hyperprolactinemia by adapting existing high-quality clinical guidelines with a view to improve the clinical symptoms and long-term quality of life of patients by providing appropriate management. Methods: This guideline was developed according to the ADAPTE methodology. The adaptation process included determining key health questions, systematically searching and screening guidelines, evaluating the quality and contents of these guidelines, deriving recommendations for key questions, and performing a peer review. The selection criteria for the guideline search were (1) evidence-based guidelines, (2) published within the last 5 years, and (3) written in English or Korean. Results: After evaluating the quality and content, we finally selected three guidelines for adaptation. The final output of the development process was 25 recommendations for 10 key questions. We adopted the Agency for Health Research Quality methodology and presented the level of evidence from levels I to IV. In addition, we defined the recommendation grades from grade A (strongly recommended) to D (no recommendation) based on the level of evidence and clinical significance of the recommendation. Conclusion: The development and dissemination of the adapted guideline is expected to increase the certainty of medical decision making and improve the quality of medical care. Further studies on the effectiveness and applicability of the developed guideline are necessary.
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OBJECTIVE: A detailed, well-validated scale for measuring emotional symptoms in menopausal women is lacking. We aimed to develop the Menopause Emotional Symptom Questionnaire (MESQ) and to confirm its reliability and validity among Koreans. METHODS: Eighteen primary items based on previous research results were selected using exploratory factor analysis and confirmatory factor analysis (CFA). New data, including answers to the novel MESQ, Menopause Rating Scale, Kupperman Index, Beck Depression Inventory-II, and Beck Anxiety Inventory, were collected from 200 perimenopausal women and 100 young men through a research company. Exploratory factor analysis and CFA were performed again to determine whether the MESQ accurately measures emotional symptoms in perimenopausal women. Receiver operating characteristic curve and k-means cluster analyses were used to identify the most appropriate cutoff value. RESULTS: The MESQ showed high internal consistency (Cronbach α = 0.926), and the CFA revealed that the factor structure comprised two subscales: nine items for mood/anxiety symptoms and four items for sleep symptoms. A high correlation between the total MESQ score and total scores of the existing scales was confirmed, indicating high convergence validity. Comparison of the mean MESQ scores between men and women showed significant sex difference, indicating secure known-group validity. The cutoff point of the total MESQ score between the high-risk and low-risk groups was 26. CONCLUSIONS: The novel MESQ has high validity and reliability, and this study confirmed that the MESQ is a valid tool for screening for and measuring emotional symptoms in menopausal women in Korea.
Subject(s)
Emotions , Menopause , Humans , Female , Male , Reproducibility of Results , Psychometrics , Menopause/psychology , Surveys and QuestionnairesABSTRACT
Nuclear receptor Rev-erbα (NR1D1) is a major negative regulator of the circadian clock. Numerous studies have investigated the role of circadian clock-related factors in the tumorigenesis of multiple cancer types, but little is known about the role of NR1D1 in cancer development. In this study, we identified the role of NR1D1 in lung tumorigenesis using genetically engineered mouse models of Nr1d1. Although NR1D1 overexpression or knockdown had little effect on the proliferation of NSCLC cells in vitro, NR1D1 deficiency in the tumor microenvironment increased lung cancer development compared with the control in the orthotopic model. NR1D1-deficient mice showed increased NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activation, and conditioned medium (CM) from NR1D1-deficient macrophages increased the proliferation and epithelial-mesenchymal transition (EMT) of lung cancer cells. Treatment with MCC950, a specific inhibitor of NLRP3 inflammasome, blocked tumorigenesis in NR1D1-deficient mice in an orthotopic lung cancer model. In addition, MCC950 treatment blocked the increased proliferation and EMT of cancer cells induced by CM from NR1D1-deficient macrophages in vitro. Our results showed that NR1D1 in the tumor microenvironment functions as a tumor suppressor by negatively regulating the NLRP3 inflammasome, suggesting that the NLRP3 inflammasome blockade via NR1D1 activation could be a therapeutic strategy to overcome lung cancer.
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Potentiating antitumor immunity is a promising therapeutic approach for treating a variety of cancers, including breast cancer. One potential strategy to promote antitumor immunity is targeting DNA damage response. Given that the nuclear receptor NR1D1 (also known as REV-ERBα) inhibits DNA repair in breast cancer cells, we explored the role of NR1D1 in antitumor CD8+ T-cell responses. First, deletion of Nr1d1 in MMTV-PyMT transgenic mice resulted in increased tumor growth and lung metastasis. Orthotopic allograft experiments suggested that loss of Nr1d1 in tumor cells rather than in stromal cells played a prominent role in increasing tumor progression. Comprehensive transcriptome analyses revealed that biological processes including type I IFN signaling and T cell-mediated immune responses were associated with NR1D1. Indeed, the expression of type I IFNs and infiltration of CD8+ T cells and natural killer cells in tumors were suppressed in Nr1d1-/-;MMTV-PyMT mice. Mechanistically, NR1D1 promoted DNA damage-induced accumulation of cytosolic DNA fragments and activated cGAS-STING signaling, which increased the production of type I IFNs and downstream chemokines CCL5 and CXCL10. Pharmacologic activation of NR1D1 by its ligand, SR9009, enhanced type I IFN-mediated antitumor immunity accompanied by the suppression of tumor progression and lung metastasis. Taken together, these findings reveal the critical role of NR1D1 in enhancing antitumor CD8+ T-cell responses, suggesting that NR1D1 may be a good therapeutic target for breast cancer. SIGNIFICANCE: NR1D1 suppresses breast cancer progression and lung metastasis by enhancing antitumor immunity via cGAS-STING pathway activation, which provides potential immunotherapeutic strategies for breast cancer.
Subject(s)
Interferon Type I , Lung Neoplasms , Animals , Mice , DNA Repair , Immunity , Interferon Type I/metabolism , Lung Neoplasms/pathology , Nucleotidyltransferases/genetics , Signal TransductionABSTRACT
PURPOSE: Several predictive models have been developed to predict the pathological complete response (pCR) after neoadjuvant chemotherapy (NAC); however, few are broadly applicable owing to radiologic complexity and institution-specific clinical variables, and none have been externally validated. This study aimed to develop and externally validate a machine learning model that predicts pCR after NAC in patients with breast cancer using routinely collected clinical and demographic variables. METHODS: The electronic medical records of patients with advanced breast cancer who underwent NAC before surgical resection between January 2017 and December 2020 were reviewed. Patient data from Seoul National University Bundang Hospital were divided into training and internal validation cohorts. Five machine learning techniques, including gradient boosting machine (GBM), support vector machine, random forest, decision tree, and neural network, were used to build predictive models, and the area under the receiver operating characteristic curve (AUC) was compared to select the best model. Finally, the model was validated using an independent cohort from Seoul National University Hospital. RESULTS: A total of 1,003 patients were included in the study: 287, 71, and 645 in the training, internal validation, and external validation cohorts, respectively. Overall, 36.3% of the patients achieved pCR. Among the five machine learning models, the GBM showed the highest AUC for pCR prediction (AUC, 0.903; 95% confidence interval [CI], 0.833-0.972). External validation confirmed an AUC of 0.833 (95% CI, 0.800-0.865). CONCLUSION: Commonly available clinical and demographic variables were used to develop a machine learning model for predicting pCR following NAC. External validation of the model demonstrated good discrimination power, indicating that routinely collected variables were sufficient to build a good prediction model.
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BACKGROUND: We developed and tested the psychometric properties of the Multi-dimensional assessment of suicide risk in chronic illness-20 (MASC-20), which assess suicidal behavior (SB), and its associated distress in chronic physical illness (CPI). METHODS: Items were developed by incorporating inputs from patient interviews, a review of existing instruments, and expert consultations. Pilot testing with 109 patients and field testing with 367 patients with renal, cardiovascular, and cerebrovascular diseases were conducted. We analyzed Time (T) 1 data to select items and T2 data to examine psychometric properties. RESULTS: Forty preliminary items were selected through pilot testing; 20 were finalized from field testing. Optimal internal consistency (α = 0.94) and test-retest reliability (Intra class correlation coefficient = 0.92) of the MASC-20 supported reliability. Good fit of the four-factor model (physical distress, psychological distress, social distress, and SB) from exploratory structural equation modeling demonstrated factorial validity. Its correlations with MINI suicidality (r = 0.59) and the Schedule of Attitudes Toward Hastened Death-abbreviated scores (r = 0.62) indicated convergent validity. Higher MASC-20 scores in patients with clinical levels of depression and anxiety and low health status demonstrated known-group validity. The MASC-20 distress score predicted SB beyond known SB risk factors, supporting incremental validity. A cutoff score of 16 was optimal for identifying suicide risk. The area under the curve was within a moderately accurate range. The sum of sensitivity and specificity (1.66) indicated diagnostic utility. LIMITATIONS: MASC-20's applicability to other patient populations and its sensitivity to change requires testing. CONCLUSIONS: The MASC-20 appears to be a reliable and valid tool for assessing SB in CPI.
Subject(s)
Anxiety Disorders , Anxiety , Humans , Anxiety/psychology , Anxiety Disorders/diagnosis , Chronic Disease , Psychometrics/methods , Reproducibility of Results , Suicidal Ideation , Surveys and QuestionnairesABSTRACT
Latent membrane protein 2A (LMP2A), a latent Ag commonly expressed in Epstein-Barr virus (EBV)-infected host cells, is a target for adoptive T cell therapy in EBV-associated malignancies. To define whether individual human leukocyte antigen (HLA) allotypes are used preferentially in EBV-specific T lymphocyte responses, LMP2A-specific CD8+ and CD4+ T cell responses in 50 healthy donors were analyzed by ELISPOT assay using artificial Ag-presenting cells expressing a single allotype. CD8+ T cell responses were significantly higher than CD4+ T cell responses. CD8+ T cell responses were ranked from highest to lowest in the order HLA-A, HLA-B, and HLA-C loci, and CD4+ T cell responses were ranked in the order HLA-DR, HLA-DP, and HLA-DQ loci. Among the 32 HLA class I and 56 HLA class II allotypes, 6 HLA-A, 7 HLA-B, 5 HLA-C, 10 HLA-DR, 2 HLA-DQ, and 2 HLA-DP allotypes showed T cell responses higher than 50 spot-forming cells (SFCs)/5×105 CD8+ or CD4+ T cells. Twenty-nine donors (58%) showed a high T cell response to at least one allotype of HLA class I or class II, and 4 donors (8%) had a high response to both HLA class I and class II allotypes. Interestingly, we observed an inverse correlation between the proportion of LMP2A-specific T cell responses and the frequency of HLA class I and II allotypes. These data demonstrate the allele dominance of LMP2A-specific T cell responses among HLA allotypes and their intra-individual dominance in response to only a few allotypes in an individual, which may provide useful information for genetic, pathogenic, and immunotherapeutic approaches to EBV-associated diseases.
ABSTRACT
BACKGROUND: The Patient Health Questionnaire-2 (PHQ-2) and Insomnia Severity Index-2 (ISI-2) are screening assessments that reflect the past 2-week experience of depression and insomnia, respectively. Retrospective assessment has been associated with reduced accuracy owing to recall bias. OBJECTIVE: This study aimed to increase the reliability of responses by validating the use of the PHQ-2 and ISI-2 for daily screening. METHODS: A total of 167 outpatients from the psychiatric department at the Yongin Severance Hospital participated in this study, of which 63 (37.7%) were male and 104 (62.3%) were female with a mean age of 35.1 (SD 12.1) years. Participants used a mobile app ("Mental Protector") for 4 weeks and rated their depressive and insomnia symptoms daily on the modified PHQ-2 and ISI-2 scales. The validation assessments were conducted in 2 blocks, each with a fortnight response from the participants. The modified version of the PHQ-2 was evaluated against the conventional scales of the Patient Health Questionnaire-9 and the Korean version of the Center for Epidemiologic Studies Depression Scale-Revised. RESULTS: According to the sensitivity and specificity analyses, an average score of 3.29 on the modified PHQ-2 was considered valid for screening for depressive symptoms. Similarly, the ISI-2 was evaluated against the conventional scale, Insomnia Severity Index, and a mean score of 3.50 was determined to be a valid threshold for insomnia symptoms when rated daily. CONCLUSIONS: This study is one of the first to propose a daily digital screening measure for depression and insomnia delivered through a mobile app. The modified PHQ-2 and ISI-2 were strong candidates for daily screening of depression and insomnia, respectively.