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Objective: To construct a prognostic model based on MR features and clinical data to evaluate the progression free survival (PFS), overall survival (OS) and objective response rate (ORR) of pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy. Methods: 105 pancreatic cancer patients with hepatic metastases who received chemoimmunotherapy were assigned to the training set (n = 52), validation set (n = 22), and testing set (n = 31). Multi-lesion volume of interest were delineated, multi-sequence radiomics features were extracted, and the radiomics models for predicting PFS, OS and ORR were constructed, respectively. Clinical variables were extracted, and the clinical models for predicting PFS, OS and ORR were constructed, respectively. The nomogram was jointly constructed by radiomics model and clinical model. Result: The ORR exhibits no significant correlation with either PFS or OS. The area under the curve (AUC) of nomogram for predicting 6-month PFS reached 0.847 (0.737–0.957), 0.786 (0.566–1.000) and 0.864 (0.735–0.994) in the training set, validation set and testing set, respectively. The AUC of nomogram for predicting 1-year OS reached 0.770 (0.635–0.906), 0.743 (0.479–1.000) and 0.818 (0.630–1.000), respectively. The AUC of nomogram for predicting ORR reached 0.914 (0.828–1.00), 0.938 (0.840–1.00) and 0.846 (0.689–1.00), respectively. Conclusion: The prognostic models based on MR imaging features and clinical data are effective in predicting the PFS, OS and ORR of chemoimmunotherapy in pancreatic cancer patients with hepatic metastasis, and can be used to evaluate the prognosis of patients. [ABSTRACT FROM AUTHOR]

The design and synthesis of economy and efficiency materials for oxygen evolution reaction (OER) have been a continuous hot spot in the field of scientific study. Herein, a high-valence-state two-dimension (2D) NiFe phosphonate-based (NiFeP) nanoribbons catalyst has been constructed through a one-step solvothermal process. The NiFeP nanoribbons exhibit highly active in both photocatalytic and electrocatalytic water oxidation due to the 2D nanoribbons and high-valence Ni3+ sites. The 2D nanoribbons not only provide more reactive sites for OER but also shorten bulk diffusion distance with better photoexcited carrier transport from the interior to the surface. Meanwhile, the existence of high-valence Ni3+ could be acted as an efficient redox site to reduce the overpotential and facilitate the catalytic reaction. In consequence, the NiFeP nanoribbons catalyst demonstrates a superior O2 yield of 65.7% and O2 production rate of 25.97 umol s−1 g−1, which are comparable or even much higher than those other reported transition metal oxide photocatalysts. At last, the possible proton-coupled electron transfer mechanism is also proposed. This study not only demonstrates the potential of a low-cost metal phosphonate OER catalyst but also provides a referential system for the fabrication of high activity and stability catalysts toward replacing noble metals for energy storage and conversion. High-valence-state 2D NiFe phosphonate-based nanoribbons catalyst has been constructed for the first time through a one-step solvothermal process without any organic additives or template agent. The as-prepared catalyst of NiFeP nanoribbons exhibits highly active in both photocatalytic and electrocatalytic water oxidation. [ABSTRACT FROM AUTHOR]

A universal platform with Mn doping and hyaluronic acid (HA) modification, based on mesoporous silica (mSiO), was designed and used as a basic multifunctional material with magnetic resonance (MR) imaging. Furthermore, we added flexible functions through the addition of functional molecules. Specially, two typical compounds, hydrophobic perfluorooctyl bromide (PFOB) and hydrophilic doxorubicin (DOX), were loaded into the channels to obtain PFOB@Mn@mSiO@HA (PMMH) or DOX@Mn@mSiO@HA (DMMH) nanoparticles for dual-mode imaging or imaging and therapy, respectively. The PMMH and DMMH nanoparticles were highly targeted to the lymph system in vitro and in vivo. MR and ultrasound imaging of PMMH nanoparticles were performed in the lymph system, while MR imaging and chemotherapy of DMMH nanoparticles was used to detect cancer. These results showed that both PMMH and DMMH nanoparticles can be designed with high lymph targeting efficiency. PMMH nanoparticles are a dual-mode contrast agent for both ultrasound and MR imaging for the lymph system and DMMH nanoparticles are powerful agents for the combined diagnosis and therapy of cancer in vivo. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation. [ABSTRACT FROM AUTHOR]

Loss of cardiomyocytes through programmed cell death is a key event in the development of heart failure, but the inciting molecular mechanisms are largely unknown. We used microarray analysis to identify a genetic program for myocardial apoptosis in Gq-mediated and pressure-overload cardiac hypertrophy. A critical component of this apoptotic program was Nix/Bnip3L. Nix localized to mitochondria and caused release of cytochrome c, activation of caspase-3 and apoptotic cell death, when expressed in HEK293 fibroblasts. A previously undescribed truncated Nix isoform, termed sNix, was not targeted to mitochondria but heterodimerized with Nix and protected against Nix-mediated apoptosis. Forced in vivo myocardial expression of Nix resulted in apoptotic cardiomyopathy and rapid death. Conversely, sNix protected against apoptotic peripartum cardiomyopathy in Gαq-overexpressors. Thus, Nix/Bnip3L is upregulated in myocardial hypertrophy, and is both necessary and sufficient for Gq-mediated apoptosis of cardiomyocytes and resulting hypertrophy decompensation. [ABSTRACT FROM AUTHOR]

The regulatory mechanisms of cell surface targeting of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum through the Golgi remain poorly understood. We have recently demonstrated that three Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins (GGAs) mediate the post-Golgi export of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and directly interact with the receptor. In particular, GGA1 interaction with α2B-AR is mediated via its hinge domain. Here we determined the role of a naturally occurring truncated form of GGA1 (GGA1t) which lacks the N-terminal portion of the hinge domain in α2B-AR trafficking and elucidated the underlying mechanisms. We demonstrated that both GGA1 and GGA1t were colocalized and mainly expressed at the Golgi. In marked contrast to GGA1, the expression of GGA1t significantly attenuated the cell surface export of newly synthesized α2B-AR from the Golgi and in parallel receptor-mediated signaling. Furthermore, we found that GGA1t formed homodimers and heterodimers with GGA1. More interestingly, GGA1t was unable to bind the cargo α2B-AR and to recruit clathrin onto the trans-Golgi network. These data provide evidence implicating that the truncated form of GGA1 behaviors as a dominant-negative regulator for the cell surface export of α2B-AR and this function of GGA1t is attributed to its abilities to dimerize with its wide type counterpart and to inhibit cargo interaction and clathrin recruitment to form specialized transport vesicles. [ABSTRACT FROM AUTHOR]

Resistant starch (RS) has been reported to reduce body fat in obese mice. However, this effect has not been demonstrated in humans. In this study, we tested the effects of RS in 19 volunteers with normal body weights. A randomized, double-blinded and crossover design clinical trial was conducted. The study subjects were given either 40 g high amylose RS2 or energy-matched control starch with three identical diets per day throughout the study. The effect of RS was evaluated by monitoring body fat, glucose metabolism, gut hormones, gut microbiota, short-chain fatty acids (SCFAs) and metabolites. The visceral and subcutaneous fat areas were significantly reduced following RS intake. Acetate and early-phase insulin, C-peptide and glucagon-like peptide-1 (GLP-1) secretion were increased, and the low-density lipoprotein cholesterol (LDL-C) and blood urea nitrogen (BUN) levels were decreased after the RS intervention. Based on 16S rRNA sequencing, certain gut microbes were significantly decreased after RS supplementation, whereas the genus Ruminococcaceae_UCG-005 showed an increase in abundance. Other potential signatures of the RS intervention included Akkermansia, Ruminococcus_2, Victivallis, and Comamonas. Moreover, the baseline abundance of the genera Streptococcus, Ruminococcus_torques_group, Eubacterium_hallii_group, and Eubacterium_eligens_group was significantly associated with the hormonal and metabolic effects of RS. These observations suggest that a daily intake of 40 g of RS is effective in modulating body fat, SCFAs, early-phase insulin and GLP-1 secretion and the gut microbiota in normal-weight subjects. [ABSTRACT FROM AUTHOR]

The molecular mechanisms that control the targeting of newly synthesized G protein-coupled receptors (GPCRs) to the functional destinations remain poorly elucidated. Here, we have determined the role of Golgi-localized, γ-adaptin ear domain homology, ADP ribosylation factor-binding proteins 1 and 2 (GGA1 and GGA2) in the cell surface transport of α2B-adrenergic receptor (α2B-AR), a prototypic GPCR, and studied the underlying mechanisms. We demonstrated that knockdown of GGA1 and GGA2 by shRNA and siRNA significantly reduced the cell surface expression of inducibly expressed α2B-AR and arrested the receptor in the perinuclear region. Knockdown of each GGA markedly inhibited the dendritic expression of α2B-AR in primary cortical neurons. Consistently, depleting GGA1 and GGA2 attenuated receptor-mediated signal transduction measured as ERK1/2 activation and cAMP inhibition. Although full length α2B-AR associated with GGA2 but not GGA1, its third intracellular loop was found to directly interact with both GGA1 and GGA2. More interestingly, further mapping of interaction domains showed that the GGA1 hinge region and the GGA2 GAE domain bound to multiple subdomains of the loop. These studies have identified an important function and revealed novel mechanisms of the GGA family proteins in the forward trafficking of a cell surface GPCR. [ABSTRACT FROM AUTHOR]

Bioluminescence resonance energy transfer (BRET) is often used to study association of membrane proteins, and in particular oligomerization of G protein-coupled receptors (GPCRs). Oligomerization of class A GPCRs is controversial, in part because the methods used to study this question are not completely understood. Here we reconsider oligomerization of the class A β2 adrenergic receptor (β2AR), and reevaluate BRET titration as a method to study membrane protein association. Using inducible expression of the energy acceptor at multiple levels of donor expression we find that BRET between β2AR protomers is directly proportional to the density of the acceptor up to ~3,000 acceptors μm−2, and does not depend on the density of the donor or on the acceptor:donor (A:D) stoichiometry. In contrast, BRET between tightly-associating control proteins does not depend on the density of the acceptor, but does depend on the density of the donor and on the A:D ratio. We also find that the standard frameworks used to interpret BRET titration experiments rely on simplifying assumptions that are frequently invalid. These results suggest that β2ARs do not oligomerize in cells, and demonstrate a reliable method of assessing membrane protein association with BRET. [ABSTRACT FROM AUTHOR]

Background: To evaluate the performance of diffusion-relaxation correlation spectrum imaging (DR-CSI) with support vector machine (SVM) in detecting prostate cancer (PCa)., Methods: In total, 114 patients (mean age, 66 years, range, 48-87 years) who received a prostate MRI and underwent biopsy were enrolled in three stages. Thirty-nine were assigned for the exploration stage to establish the model, 18 for the validation stage to choose the appropriate scale for mapping and 57 for the test stage to compare the diagnostic performance of the DR-CSI and PI-RADS., Results: In the exploration stage, the DR-CSI model was established and performed better than the ADC and T 2 values (both P < 0.001). The validation result shows that at least 2 pixels were required for both the long-axis and short-axis in the mapping procedure. In the test stage, DR-CSI had higher accuracy than PI-RADS ≥ 3 as a positive finding based on patient (84.2% vs. 63.2%, P = 0.004) and lesion (78.8% vs. 57.6%, P = 0.001) as well as PI-RADS ≥ 4 on lesion (76.5% vs. 64.7%, P = 0.029), while there was no significant difference between DR-CSI and PI-RADS ≥ 4 based on patient (P = 0.508). For clinically significant PCa, DR-CSI had higher accuracy than PI-RADS ≥ 3 based on patients (84.2% vs. 63.2%, P = 0.004) and lesions (62.4% vs. 48.2%, P = 0.036). There was no significant difference between DR-CSI and PI-RADS ≥ 4 (P = 1.000 and 0.845 for the patient and lesion levels, respectively)., Conclusions: DR-CSI combined with the SVM model may improve the diagnostic accuracy of PCa., Trial Registration: This study was approved by the Ethics Committee of our institute (Approval No. KY2018-213). Written informed consent was obtained from all participants., (© 2022. The Author(s).)