Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis

AbstractBackgroundDecoy receptor 3 (DcR3), a decoy receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily, is overexpressed in some forms of cancer. It was recently reported that DcR3 could protect endothelial cells from apoptosis, implying a potential role in the development of vessels, whereas its role in the lymphangiogenesis remains unclear. In the present study, we studied the DcR3 expression and its relationship with the lymphatic microvessel density (LMVD) to investigate if it played a role in the lymph metastasis of human breast cancer.Materials and methodsReal-time polymerase chain reaction and immunohistochemistry were performed to measure the messenger RNA and protein expression of DcR3 in the breast cancer tissues, noncancerous counterparts, and axillary lymph node from 63 patients. LMVD in these specimens was assessed by counting the D2-40 labeled–microvessels. Furthermore, the correlations between DcR3 expression and LMVD and other clinicopathologic parameters were analyzed.ResultsDcR3 was overexpressed in the breast cancer tissue of 58 patients (92.1%) and was also expressed in vascular endothelial cells and tumor cells in the lymph nodes. LMVD in cancer tissue and lymph nodes were both positively correlated to the aberrant expression of DcR3.ConclusionsThe relevance between DcR3 overexpression and LMVD revealed the existence of possible links between DcR3 and lymphangiogenesis. Based on these findings, it is important to further explore the regulation of lymphangiogenesis operated by the reverse tumor necrosis factor signaling of DcR3

An exaggerated epinephrine-adrenergic receptor signaling impairs uterine decidualization in mice.

Our understanding of the relationship between stress-derived epinephrine and early pregnancy failure remains incomplete. Here, we explored the effect of epinephrine exposure on early pregnancy and pseudopregnancy in mice. Increased expression of adrenergic receptors Adra1b, Adra2b and Adrb2 was observed during decidualization and post-implantation embryogenesis was delayed or survival impaired. Epinephrine treatment also impaired decidualization in both the gravid and pseudopregnant uterus, suggesting the effect on decidualization was independent of the conceptus. This included a suppression of endometrial stroma cell proliferation and of key decidualization regulators, including COX2, BMP2 and WNT4. Collectively, these data demonstrate that maternal epinephrine exposure during early pregnancy impairs uterine decidualization and embryo development, underlying early pregnancy failure

An exaggerated epinephrine-adrenergic receptor signaling impairs uterine decidualization in mice

Abstract(#br)Our understanding of the relationship between stress-derived epinephrine and early pregnancy failure remains incomplete. Here, we explored the effect of epinephrine exposure on early pregnancy and pseudopregnancy in mice. Increased expression of adrenergic receptors Adra1b, Adra2b and Adrb2 was observed during decidualization and post-implantation embryogenesis was delayed or survival impaired. Epinephrine treatment also impaired decidualization in both the gravid and pseudopregnant uterus, suggesting the effect on decidualization was independent of the conceptus. This included a suppression of endometrial stroma cell proliferation and of key decidualization regulators, including COX2, BMP2 and WNT4. Collectively, these data demonstrate that maternal epinephrine exposure during early pregnancy impairs uterine decidualization and embryo development, underlying early pregnancy failure

Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes

ObjectiveAbnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM.MethodsA total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity.ResultsCompared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity.ConclusionElevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM

An Integrative Pharmacology Model for Decoding the Underlying Therapeutic Mechanisms of Ermiao Powder for Rheumatoid Arthritis

As a systemic inflammatory arthritis disease, rheumatoid arthritis (RA) is complex and hereditary. Traditional Chinese medicine (TCM) has evident advantages in treating complex diseases, and a variety of TCM formulas have been reported that have effective treatment on RA. Clinical and pharmacological studies showed that Ermiao Powder, which consists of Phellodendron amurense Rupr. (PAR) and Atractylodes lancea (Thunb.) DC. (ALD), can be used in the treatment of RA. Currently, most studies focus on the anti-inflammatory mechanism of PAR and ALD and are less focused on their coordinated molecular mechanism. In this research, we established an integrative pharmacological strategy to explore the coordinated molecular mechanism of the two herbs of Ermiao Powder in treating RA. To explore the potential coordinated mechanism of PAR and ALD, we firstly developed a novel mathematical model to calculate the contribution score of 126 active components and 85 active components, which contributed 90% of the total contribution scores that were retained to construct the coordinated functional space. Then, the knapsack algorithm was applied to identify the core coordinated functional components from the 85 active components. Finally, we obtained the potential coordinated functional components group (CFCG) with 37 components, including wogonin, paeonol, ethyl caffeate, and magnoflorine. Also, functional enrichment analysis was performed on the targets of CFCG to explore the potential coordinated molecular mechanisms of PAR and ALD. The results indicated that the CFCG could treat RA by coordinated targeting to the genes involved in immunity and inflammation-related signal pathways, such as phosphatidylinositol 3‑kinase/protein kinase B signaling pathway, mitogen-activated protein kinase signaling pathway, tumor necrosis factor signaling pathway, and nuclear factor-kappa B signaling pathway. The docking and in vitro experiments were used to predict the affinity and validate the effect of CFCG and further confirm the reliability of our method. Our integrative pharmacological strategy, including CFCG identification and verification, can provide the methodological references for exploring the coordinated mechanism of TCM in treating complex diseases and contribute to improving our understanding of the coordinated mechanism

Tunable Charge Transport and Spin Dynamics in Two-Dimensional Conjugated Metal-Organic Frameworks

Two-dimensional conjugated metal-organic frameworks (2D c-MOFs) have attracted increasing interest in electronics due to their (semi)conducting properties. Charge-neutral 2D c-MOFs also possess persistent organic radicals that can be viewed as spin-concentrated arrays, affording new opportunities for spintronics. However, the strong π-interaction between neighboring layers of layer-stacked 2D c-MOFs annihilates active spin centers and significantly accelerates spin relaxation, severely limiting their potential as spin qubits. Herein, we report the precise tuning of the charge transport and spin dynamics in 2D c-MOFs via the control of interlayer stacking. The introduction of bulky side groups on the conjugated ligands enables a significant dislocation of the 2D c-MOFs layers from serrated stacking to staggered stacking, thereby spatially weakening the interlayer interactions. As a consequence, the electrical conductivity of 2D c-MOFs decreases by 6 orders of magnitude, while the spin density achieves more than a 30-fold increase and the spin-lattice relaxation time (T1) is increased up to ∼60 μs, hence being superior to the reference 2D c-MOFs with compact stackings whose spin relaxation is too fast to be detected. Spin dynamics results also reveal that spinless polaron pairs or bipolarons play critical roles in the charge transport of these 2D c-MOFs. Our strategy provides a bottom-up approach for enlarging spin dynamics in 2D c-MOFs, opening up pathways for developing MOF-based spintronics

AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells

Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.publishedVersio

Control of the Hydroquinone/Benzoquinone Redox State in High-Mobility Semiconducting Conjugated Coordination Polymers

Conjugated coordination polymers (c-CPs) are unique organic–inorganic hybrid semiconductors with intrinsically high electrical conductivity and excellent charge carrier mobility. However, it remains a challenge in tailoring electronic structures, due to the lack of clear guidelines. Here, we develop a strategy wherein controlling the redox state of hydroquinone/benzoquinone (HQ/BQ) ligands allows for the modulation of the electronic structure of c-CPs while maintaining the structural topology. The redox-state control is achieved by reacting the ligand TTHQ (TTHQ=1,2,4,5-tetrathiolhydroquinone) with silver acetate and silver nitrate, yielding Ag4TTHQ and Ag4TTBQ (TTBQ=1,2,4,5-tetrathiolbenzoquinone), respectively. In spite of sharing the same topology consisting of a two-dimensional Ag−S network and HQ/BQ layer, they exhibit different band gaps (1.5 eV for Ag4TTHQ and 0.5 eV for Ag4TTBQ) and conductivities (0.4 S/cm for Ag4TTHQ and 10 S/cm for Ag4TTBQ). DFT calculations reveal that these differences arise from the ligand oxidation state inhibiting energy band formation near the Fermi level in Ag4TTHQ. Consequently, Ag4TTHQ displays a high Seebeck coefficient of 330 μV/K and a power factor of 10 μW/m ⋅ K2, surpassing Ag4TTBQ and the other reported silver-based c-CPs. Furthermore, terahertz spectroscopy demonstrates high charge mobilities exceeding 130 cm2/V ⋅ s in both Ag4TTHQ and Ag4TTBQ

Adherence to High Dietary Diversity and Incident Cognitive Impairment for the Oldest-Old: A Community-Based, Nationwide Cohort Study

Background and aims: Dietary diversity change is associated with cognitive function, however, whether the effect still exists among the oldest-old (80+) is unclear. Our aim was to examine the effect of dietary diversity changes on cognitive impairment for the oldest-old in a large prospective cohort. Methods: Within the Chinese Longitudinal Healthy Longevity Study, 6237 adults older than 80 years were included. The dietary diversity score (DDS) was assessed by a simplified food frequency questionnaire (FFQ). Cognitive impairment was defined as a Mini-Mental State Examination (MMSE) score lower than 18 points. Cognitive decline was defined as a reduction of total MMSE score ≥3 points, and cognitive decline of different subdomains was defined as a reduction of ≥15% in the corresponding cognitive domain. The multivariate-adjusted Cox proportional hazard model evaluated the effects of DDS change on cognitive decline. The linear mixed-effect model was used to test subsequent changes in MMSE over the years. Results: During 32,813 person-years of follow-up, 1829 participants developed cognitive impairment. Relative to the high–high DDS change pattern, participants in the low–low and high–low patterns were associated with an increased risk of cognitive impairment with a hazard ratio (95% confidential interval, CI) of 1.43 (1.25, 1.63) and 1.44 (1.24, 1.67), and a faster decline in the MMSE score over the follow-up year. Participants with the low–high pattern had a similar incidence of cognitive impairment with HRs (95% CI) of 1.03 (0.88, 1.20). Compared with the stable DDS status group (−1–1), the risk of cognitive impairment was higher for those with large declines in DDS (≤−5) and the HR was 1.70 (95% CI: 1.44, 2.01). Conclusions: Even for people older than 80, dietary diversity change is a simple method to identify those who had a high risk of cognitive decline. Keeping high dietary diversity is beneficial for cognitive function and its subdomain even in the final phase of life, especially for females and the illiterate oldest-old