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Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-γ (IFN-γ) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-γ, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-γ-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A are involved in anti-tumor immunity by inhibiting the IFN-γ signaling pathway, which can be considered as potential targets to improve the responsive rate of PD-1/PD-L1 blockade.

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CKLF (chemokine-like factor)-MARVEL transmembrane domain containing protein 6 (CMTM6) is a novel regulator to maintain the stability of PD-L1. CMTM6 can colocalize and interact with PD-L1 on the recycling endosomes and cell membrane, preventing PD-L1 from lysosome-mediated degradation and proteasome-mediated degradation thus increasing the half-life of PD-L1 on the cell membrane. The difficulties in obtaining stable full-length PD-L1 and CMTM6 proteins hinder the research on their structures, function as well as related drug development. Using lauryl maltose neopentyl glycol (LMNG) as the optimized detergent and a cell membrane mimetic strategy, we assembled a stable membrane-bound full-length CMTM6-PD-L1 complex with amphipol A8-35. When the PD-1/PD-L1-CMTM6 interactions were analyzed, we found that CMTM6 greatly enhanced the binding and delayed the dissociation of PD-1/PD-L1, thus affecting immunosuppressive signaling and anti-apoptotic signaling. We then used the CMTM6-PD-L1 complex as immunogens to generate immune repertoires in camels, and identified a functional anti-CMTM6 nanobody, called 1A5. We demonstrated that the anti-CMTM6 nanobody greatly decreased T-cell immunosuppression and promoted apoptotic susceptibility of tumor cells in vitro, and mainly relied on the cytotoxic effect of CD8+ T-cells to exert tumor growth inhibitory effects in CT26 tumor-bearing mice. In conclusion, the stable membrane-bound full-length CMTM6-PD-L1 complex has been successfully used in studying PD-1/PD-L1-CMTM6 interactions and CMTM6-targeting drug development, suggesting CMTM6 as a novel tumor immunotherapy target.

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BACKGROUND: Development of Traditional Chinese Medicine (TCM) syndrome-specific outcome measures is needed for the evaluation of TCM syndrome-specific therapies. We constructed a Kidney Deficiency Syndrome Questionnaire (KDSQ) for the evaluation of the common TCM syndromes Kidney-Yin Deficiency Syndrome (KDS-Yin) and Kidney-Yang Deficiency Syndrome (KDS-Yang) in middle-aged women with menopausal symptoms. METHODS: KDS-Yin and KDS-Yang were traditionally defined by expert opinion were validated by exploratory factor analysis (EFA) and structural equation modeling (SEM). Content validity was tested by EFA on a sample of 236 women from a seminar and SEM on another sample of 321 women from a postal survey. Other psychometric properties were tested on 292 women from the seminar at baseline and two systematically selected sub-samples: 54 who reported no changes in discomforts 11-12 days after the baseline and 31 who reported changes in discomforts 67-74 days after the baseline. All participants completed the KDSQ, the Greene Climacteric Scale and the standard 12-item Short Form Health Survey. RESULTS: The EFA and SEM established the measurement models of KDS-Yin and KDS-Yang supporting content validity of the KDSQ. Internal consistency was good (Cronbach's Alpha >0.70). Construct validity was supported by theoretically-derived levels of correlation with the established external measures. Test-retest reliability was strong (ICC(agreement): KDS-Yin, 0.94; KDS-Yang, 0.93). The KDSQ was responsive to changes over time as tested by effect size and longitudinal validity. CONCLUSIONS: The KDSQ was a valid and reliable measure for KDS-Yin and KDS-Yang in Hong Kong Chinese middle-aged women with menopausal symptoms.

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OBJECTIVES: A standard description regarding the diagnosis of traditional Chinese medicine (TCM) syndromes based on validated evidence is needed for education, practice and evaluation of TCM syndrome-specific treatments. We studied whether an evidence-based four-step approach proposed for the validation of TCM syndromes could validate Kidney-Yin deficiency syndrome (KDS-Yin) and Kidney-Yang deficiency syndrome (KDS-Yang) in middle-aged women with menopausal symptoms. METHODS: TCM classic and contemporary literature were reviewed for the symptoms and the domain changes of KDS-Yin and KDS-Yang. Factor analysis was used to explore whether these symptoms could be grouped according to their mutual relationships in a sample of women. Latent tree models were constructed based on the factor loadings and justifiability by the theory, and were tested by structural equation modelling on another sample of women. RESULTS: The symptoms and domain changes were reviewed from the TCM literature. Exploratory factor analysis (EFA) identified symptom patterns on a sample of 236 women. Based on the findings and the TCM literature, latent tree models of KDS-Yin and KDS-Yang, showing their domain changes and domain symptoms, were constructed and could be confirmed by structural equation modelling on a sample of 323 women. CONCLUSION: KDS-Yin and KDS-Yang in middle-aged women with menopausal symptoms were validated and the four-step approach may be used to validate TCM syndromes.

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OBJECTIVES: The aim of this study was to translate the standard Greene Climacteric Scale (GCS) and a urogenital symptom scale into colloquial Chinese (Hong Kong) and test their validity and reliability in Hong Kong Chinese women. METHODS: The scales were translated with standard techniques, and cross-cultural construct validity, internal consistency, test-retest reliability, and responsiveness were tested on samples of women aged 40 to 60 years recruited from the community. RESULTS: A total of 611 women, with mean (SD) age of 48.9 (5.3) years, provided completed scales for the study. Confirmatory factor analysis demonstrated construct validity of the translated standard GCS. The items were found to have good homogeneity in measuring the scale concepts (Cronbach alpha > 0.7). But the three-item urogenital scale had poor internal consistency (Cronbach alpha = 0.43), and a combination of this scale with the standard GCS resulted in a reduced model fit to the data. Test-retest reliability for the GCS was good on women recruited for a retest (n = 52). The translated GCS was found to be responsive to change over time (effect size, 0.59; n = 19). CONCLUSIONS: The Chinese (Hong Kong) version of the standard GCS is a valid and cultural-equivalent instrument. Our data do not support inclusion of the urogenital scale to the standard GCS. Measurement of urogenital symptoms is subject to further study.

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