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关键词： Pristimerin   Sorafenib resistance   Conditionally reprogrammed hepatocellular carcinoma cells   Endoplasmic reticulum stress   Akt/FoxO1/p27(kip1) signaling  

摘要： Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Sorafenib (SORA), as a first-line therapeutic drug, has been used to treat HCC, but resistance poses a major limitation on the efficacy of SORA chemotherapy. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells in vitro. Purpose: The aim of this study was to investigate whether PRIS can exert synergistic anti-tumor effects with the combination of SORA, and if so, through what mechanism. Methods: Conditionally reprogrammed patient derived-primary hepatocellular carcinoma cells (CRHCs) were isolated from human liver cancer tissues and treated with SORA and PRIS. Cell proliferation, apoptosis, migration and tube formation ability were detected by DNA content quantification, flow cytometry, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively. Results: Initially, we observed that the combination of the two drugs had a much stronger inhibitory effect on CRHCs growth than either drug alone. Moreover, the combination of 2 mu M SORA and 1 mu M PRIS exhibited a significant anti-migrative and anti-invaded effect on CRHCs, and remarkably inhibited capillary structure formation of Human Umbilical Vein Endothelial Cells (HUVECs). Furthermore, the combined treatment with SORA and PRIS synergistically induced intrinsic apoptosis in CRHCs, involving a caspase-4-dependent mechanism paralleled by an increased Bax/Bcl-xL ratio. These activities were mediated through ROS generation and the induction of endoplasmic reticulum (ER) stress and mitochondrial dysfunction. GRP78 silencing or ER stress inhibitor 4-phenylbutyric acid administration was revealed to abolish the anticancer effects of PRIS, indicating the critical role of

关键词： Dermatophytosis   Trichophyton indotineae   Outbreak   India   Multiresistance  

摘要： A severe outbreak of highly virulent and multi-resistant dermatophytosis by species in the Trichophyton mentagrophytes/T. interdigitale complex is ongoing in India. The correct identity of the etiologic agent is a much-debated issue. In order to define species limits, a taxonomic study was undertaken combining molecular, morphological, and physiological characteristics as evidence of classification. Molecular characteristics show that T. mentagrophytes s. str. and T. interdigitale s. str. can be distinguished with difficulty from each other, but are unambiguously different from the Indian genotype, T. indotineae by sequences of the HMG gene. The entities were confirmed by multilocus analysis using tanglegrams. Phenotypic characters of morphology and physiology are not diagnostic, but statistically significant differences are observed between the molecular siblings. These properties may be drivers of separate evolutionary trends. Trichophyton mentagrophytes represents the ancestral, homothallic cloud of genotypes with a probable geophilic lifestyle, while T. indotineae and T. interdigitale behave as anthropophilic, clonal offshoots. The origin of T. indotineae, which currently causes a significant public health problem, is zoonotic, and its emergence is likely due to widespread misuse of antifungals.

关键词： Thoracic aorta   Hypertension   Stress fiber   Mechanotransduction   Principal direction   Photobleaching  

摘要： Stress fibers (SFs) in cells transmit external forces to cell nuclei, altering the DNA structure, gene expression, and cell activity. To determine whether SFs are involved in mechanosignal transduction upon intraluminal pressure, this study investigated the SF direction in smooth muscle cells (SMCs) in aortic tissue and strain in the SF direction. Aortic tissues were fixed under physiological pressure of 120 mmHg. First, we observed fluorescently labeled SFs using two-photon microscopy. It was revealed that SFs in the same smooth muscle layers were aligned in almost the same direction, and the absolute value of the alignment angle from the circumferential direction was 16.8 degrees +/- 5.2 degrees (n = 96, mean +/- SD). Second, we quantified the strain field in the aortic tissue in reference to photo-bleached markers. It was found in the radial-circumferential plane that the largest strain direction was - 21.3 degrees +/- 11.1 degrees, and the zero normal strain direction was 28.1 degrees +/- 10.2 degrees. Thus, the SFs in aortic SMCs were not in line with neither the largest strain direction nor the zero strain direction, although their orientation was relatively close to the zero strain direction. These results suggest that SFs in aortic SMCs undergo stretch, but not maximal and transmit the force to nuclei under intraluminal pressure.

关键词： Immune evasion   Tumour immunology  

摘要： Human primary and metastatic tumors harbor CD4(+) T-reg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 T-reg-like CD4(+) T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy. Regulatory T (T-reg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4(+) T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3(+) T-reg and eomesodermin homolog (EOMES)(+) type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not T-reg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1-targeted immunotherapy. Collectively, these findings highlight the heterogeneity of T-reg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

关键词： Programmed cell death 1   Programmed death ligand 1   Breast cancer   Clinical and pathologic features   Pathologic complete response   Recurrence-free survival  

摘要： Purpose The interaction of the programmed cell death 1 (PD-1) receptor on tumor-infiltrating lymphocytes with programmed death ligand 1 (PD-L1) on tumor cells downregulates anti-tumor immunity. This study evaluated associations between PD-1 and PD-L1 expression in primary breast cancer, clinical characteristics, and patient outcomes. Methods Microarray data from the Investigation of Serial Studies to predict your therapeutic response with imaging and molecular analysis (I-SPY 1) study (n = 149) was used to evaluate PD-1 and PD-L1 expression. Associations with clinical features and chemotherapy response were determined using Kruskal-Wallis and Wilcoxon rank sum tests, respectively. Recurrence-free survival (RFS) associations were determined with the Cox proportional hazard model. Associations of PD-1 and PD-L1 and selected genes associated with breast cancer, as well as a predictor of olaparib response (PARPi-7), were determined in I-SPY 1 and 2 other datasets: METABRIC (n = 1992) and TCGA (n = 817), using Pearson correlations. Results In I-SPY 1, PD-1 expression was higher in triple-negative breast cancer (TNBC) and HER2 + breast cancer (p = 0.003), and grade 2/3 tumors (p = 0.043), and was associated with pathologic complete response (p = 0.006). PD-L1 expression in the lowest quintile was associated with worse RFS, even after subtype adjustment (HR 2.33, p = 0.01). PD-1 and PD-L1 gene expression correlated with the expression of immune-related genes and PARPi-7. Conclusions PD-1 expression is higher in breast cancers with aggressive features such as TNBC. Low PD-L1 expression may be an adverse prognostic factor. PD-1 and PD-L1 gene expression correlates with the expression of immune-related and DNA damage repair genes.

摘要： Purpose : To explore novel role and molecular mechanism of a natural osmoprotectant ectoine in protecting corneal barrier function through promoting anti-inflammatory cytokine IL-37 in human corneal epithelial cells (HCECs) under hyperosmolarity stress, an in vitro dry eye model. Methods : Primary HCECs were established from donor limbal tissue. The confluent cultures in iso-osmolar medium were switched to hyperosmotic media (400-500 mOsM), without or with prior incubation of ectoine at different concentrations (1-40 mM) for 2-48 hours. Cell viability and proliferation were evaluated by WST assay. The integrity of apical barrier junction proteins and the expression of cytokines and cathepsin S were evaluated by RT-qPCR, ELISA, immunostaining and confocal microscopy. Results : HCECs were survived well in 450mOsM but partially damaged in 500mOsM media. Ectoine well protected HCEC survival and proliferation in 450 and 500mOsM media. The integrity of corneal epithelial barrier was largely disrupted in HCECs exposed to 450 mOsM, as shown by 3D confocal images of immunofluorescent staining of tight junction proteins ZO-1 and occludin. Ectoine at 10-20mM well protected the barrier proteins under hyperosmotic stress. The expression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) were dramatically stimulated by hyperosmolarity but significantly suppressed by Ectoine at 5-40 mM as quantified by RT-qPCR and ELISA. The protease cathepsin S, which was stimulated by hyperosmolarity and TNF-α, directly disrupted epithelial barrier while its inhibitor LY3000328 restored the barrier integrity. Interestingly, IL-37 decreased significantly in HCECs by hyperosmolarity, but prior-incubation of ectoine increased IL-37 at mRNA and protein levels, suppressed TNF-α and cathepsin S activity, and protected cells from barrier disruption under hyperosmolarity. Furthermore, rhIL-37 was observed to suppress pro-inflammatory cytokines and TNF-α-induced cathepsin S in HCECs exposed to hyperos

关键词： Primary cutaneous lymphoma   Primary cutaneous CD4+small   medium-sized pleomorphic T-cell lymphoproliferative disorder   Cutaneous T-cell lymphoma  

摘要： Background: Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder (SMPLPD) is a provisional entity within the 2016 World Health Organization classification of primary cutaneous lymphomas. The condition is currently classified as a lymphoproliferative disorder to emphasize its benign course and discourage aggressive, systemic treatment modalities. Objective: To provide a relevant synthesis for the dermatological practitioner on the prevalence, presentation, and treatment of SMPLPD. Methods: We conducted an updated systematic literature review and a retrospective chart review of diagnosed cases of SMPLPD from 2 Canadian academic cutaneous lymphoma centers. Results: A total of 23 studies with 136 cases were extracted from the systematic review and 24 patients from our retrospective chart review. SMPLPD proved relatively common accounting for 12.5% of all cutaneous T-cell lymphomas encountered in our cutaneous lymphoma clinics, second in frequency only to mycosis fungoides. The typical clinical presentation was that of an older individual (median age 59 years) with an asymptomatic solitary lesion on their upper extremity. The most common clinical differentials were cutaneous lymphoid hyperplasia, basal cell carcinoma, and lymphoma unspecified. T follicular helper markers were reliably detected. The main treatment modalities were surgical excision, local radiation therapy, and topical or intralesional steroids. Cure was achieved in the vast majority of cases. Conclusions: SMPLPD is an underdiagnosed T-cell lymphoma with an overtly benign clinical course. The condition has an excellent prognosis and responds well to skin-directed therapies. Practitioners should be aware of this condition to avoid aggressive systemic treatments.

关键词： triple negative breast cancer   basal like 2   targeted therapy   immunotherapy   daphnane type diterpenoids   protein kinase C   natural products   pharmacology   traditional Chinese herbal medicine  

摘要： Simple Summary Most breast cancers express the estrogen, progesterone, and/or HER2 receptors and patients are treated with inhibitors targeting these receptors. Triple negative breast cancers (TNBCs) lack these receptors and thus patients with TNBC do not benefit from existing targeted therapies. There is a continued search for effective targets for the treatment of these heterogeneous tumors. We identified a class of plant-derived natural products, including yuanhuacine, that selectively kill cells that represent a molecularly defined subtype of TNBC. These compounds also promote expression of an immunological profile that is beneficial for engaging the immune system, which could provide an added benefit in TNBC. The mechanism of action of both the TNBC selectivity and immunological phenotypes is associated with activation of protein kinase C. Yuanhuacine has potent antitumor efficacy in a mouse model of TNBC, identifying a new therapeutic target for the treatment of this deadly disease. The heterogeneity of triple negative breast cancer (TNBC) has led to efforts to further subtype this disease with the hope of identifying new molecular liabilities and drug targets. Furthermore, the finding that TNBC is the most inherently immunogenic type of breast cancer provides the potential for effective treatment with immune checkpoint inhibitors and immune adjuvants. Thus, we devised a dual screen to identify compounds from natural product extracts with TNBC subtype selectivity that also promote the expression of cytokines associated with antitumor immunity. These efforts led to the identification of yuanhuacine (1) as a potent and highly selective inhibitor of the basal-like 2 (BL2) subtype of TNBC that also promoted an antitumor associated cytokine signature in immune cells. The mechanism of action of yuanhuacine for both phenotypes depends on activation of protein kinase C (PKC), defining a novel target for the treatment of this clinical TNBC subtype. Yuanhuacine showed p

关键词： randomized controlled trial   non-small cell lung cancer   pathological N2   adjuvant radiotherapy  

摘要： The standard treatment for pathological N2 Stage Ill non-small cell lung cancer with negative surgical margins in Japan is cisplatin-based adjuvant chemotherapy. However, recent studies suggest that the addition of thoracic radiotherapy after adjuvant chemotherapy prolongs survival. While thoracic radiotherapy is considered to prolong survival by improving locoregional control, it is known to increase radiation-induced adverse events. We began a randomized controlled trial in January 2021 in Japan to confirm the superiority of radiotherapy over observation after adjuvant chemotherapy in pathological N2 Stage Ill non-small cell lung cancer patients with negative surgical margins. We aim to accrue 330 patients from 47 institutions over 5 years. The primary endpoint is relapse-free survival;the secondary endpoints are overall survival, proportion of patients completing radiotherapy in the radiotherapy arm, early adverse events, late adverse events in the radiotherapy arm, serious adverse events and local recurrence.