Role of INPP4B in the proliferation, migration, invasion, and survival of human endometrial cancer cells.

BACKGROUND: Inositol polyphosphate 4-phosphatase type II (INPP4B) has been identified as a tumor repressor in several human cancers while its role in endometrial cancer has not been investigated yet. Therefore, the current study was designed to determine whether INPP4B participates in the progression of endometrial cancer by utilizing clinical data and experimental determination. MATERIALS AND METHODS: We first include six chemotherapy-treated patients with recurrent and metastatic endometrioid carcinoma to determine the relationship between INPP4B mutation and relative tumor burden. By using siRNA-mediated gene silencing and vector-mediated gene overexpression, we further determined the effect of manipulating INPP4B expression on the proliferation, invasion, and survival of endometrial cancer cells. Furthermore, the repressing effect of INPP4B together with its role in chemotherapy was further validated by xenograft tumor-bearing mice models. Western blot analysis was used to explore further downstream signaling modulated by INPP4B expression manipulation. RESULTS: Two of the patients were found to have INPP4B mutations and the mutation frequency of INPP4B increased during the progression of chemotherapy resistance. Endometrial cancer cells with silenced INPP4B expression were found to have promoted tumor cell proliferation, invasion, and survival. Endometrial cancer cells overexpressing INPP4B were found to have decreased tumor cell proliferation, invasion, and survival. An in vivo study using six xenograft tumor-bearing mice in each group revealed that INPP4B overexpression could suppress tumor progression and enhance chemosensitivity. Furthermore, INPP4B overexpression was found to modulate the activation of Wnt3a signaling. CONCLUSION: The current study suggested that INPP4B could be a suppressor in endometrial cancer progression and might be a target for endometrial cancer treatment. Also, INPP4B might serve as a predictor of chemosensitivity determination.

Left ventricular concentric hypertrophy with cardiac magnetic resonance imaging improves risk stratification in patients with Duchenne muscular dystrophy: a prospective cohort study.

BACKGROUND: The development of left ventricular (LV) remodeling has been associated with an increased cardiovascular risk and cardiogenic death, and different patterns of remodeling result in varying levels of prognosis. OBJECTIVE: To investigate the association between different patterns of LV remodeling and clinical outcomes in the preclinical stage of patients with Duchenne muscular dystrophy (DMD). MATERIALS AND METHODS: A total of 148 patients with DMD and 43 sex- and age-matched healthy participants were enrolled. We used the four-quadrant analysis method to investigate LV remodeling based on cardiac magnetic resonance (MR) imaging. Kaplan-Meier curves were generated to illustrate the event-free survival probability stratified by the LV remodeling pattern. Cox regression models were constructed and compared to evaluate the incremental predictive value of the LV remodeling pattern. RESULTS: During the median follow-up period of 2.2 years, all-cause death, cardiomyopathy, and ventricular arrhythmia occurred in 5, 35, and 7 patients, respectively. LV concentric hypertrophy (hazard ratio 2.91, 95% confidence interval 1.47-5.75, P=0.002) was an independent predictor of composite endpoint events. Compared to the model without LV concentric hypertrophy, the model with LV concentric hypertrophy had significant incremental predictive value (chi-square value 33.5 vs. 25.2, P=0.004). CONCLUSION: Age and late gadolinium enhancement positivity were positively correlated with clinical outcomes according to the prediction models. LV concentric hypertrophy was also an independent predictor for risk stratification and provided incremental value for predicting clinical outcomes in the preclinical stage of patients with DMD.

Derivation and validation of diagnostic models for myocardial fibrosis in duchenne muscular dystrophy: assessed by multi-parameter cardiovascular magnetic resonance.

BACKGROUND: Gadolinium-enhanced cardiovascular magnetic resonance (CMR) is the most widely used approach for diagnosing myocardial fibrosis with late gadolinium enhancement (LGE) in cardiomyopathy associated with Duchenne muscular dystrophy. Given the limitations and safety of gadolinium use, we wanted to develop and evaluate multi-parametric pre-contrast CMR models for the diagnosis of LGE and investigate whether they could be utilised as surrogates for LGE in DMD patients. METHODS: A total of 136 DMD patients were prospectively recruited and separated into LGE - and LGE + groups. In the first subset of patients (derivation cohort), regression models for the diagnosis of LGE were built by logistic regression using pre-contrast sequence parameters. In a validation cohort of other patients, the models' performances were evaluated. RESULTS: EF, native T1 and longitudinal strain alone, as well as their combinations form seven models. The model that included EF, native T1 and longitudinal strain had the best diagnostic value, but there was no significant difference in diagnostic accuracy among the other models except EF. In the validation cohort, the diagnosis outcomes of models were moderate consistent with the existence of LGE. The longitudinal strain outperformed the other models in terms of diagnostic value (sensitivity: 83.33%, specificity: 54.55%). CONCLUSIONS: Pre-contrast sequences have a moderate predictive value for LGE. Thus, pre-contrast parameters may be considered only in a specific subset of DMD patients who cannot cooperate for long-time examinations and have contradiction of contrast agent to help predict the presence of LGE. TRIAL REGISTRATION NUMBER (TRN): ChiCTR1800018340 DATE OF REGISTRATION: 20180107.

Longitudinal changes in magnetic resonance imaging biomarkers of the gluteal muscle groups and functional ability in Duchenne muscular dystrophy: a 12-month cohort study.

BACKGROUND: Quantitative magnetic resonance imaging (MRI) is considered an objective biomarker of Duchenne muscular dystrophy (DMD), but the longitudinal progression of MRI biomarkers in gluteal muscle groups and their predictive value for future motor function have not been described. OBJECTIVE: To explore MRI biomarkers of the gluteal muscle groups as predictors of motor function decline in DMD by characterizing the progression over 12 months. MATERIALS AND METHODS: A total of 112 participants with DMD were enrolled and underwent MRI examination of the gluteal muscles to determine fat fraction and longitudinal relaxation time (T1). Investigations were based on gluteal muscle groups including flexors, extensors, adductors, and abductors. The North Star Ambulatory Assessment and timed functional tests were performed. All participants returned for follow-up at an average of 12 months and were divided into two subgroups (functional stability/decline groups) based on changes in timed functional tests. Univariable and multivariable logistic regression methods were used to explore the risk factors associated with future motor function decline. RESULTS: For the functional decline group, all T1 values decreased, while fat fraction values increased significantly over 12 months (P<0.05). For the functional stability group, only the fat fraction of the flexors and abductors increased significantly over 12 months (P<0.05). The baseline T1 value was positively correlated with North Star Ambulatory Assessment and negatively correlated with timed functional tests at the 12-month follow-up (P<0.001), while the baseline fat fraction value was negatively correlated with North Star Ambulatory Assessment and positively correlated with timed functional tests at the 12-month follow-up (P<0.001). Multivariate regression showed that increased fat fraction of the abductors was associated with future motor function decline (model 1: odds ratio [OR]=1.104, 95% confidence interval [CI]: 1.026~1.187, P=0.008; model 2: OR=1.085, 95% CI: 1.013~1.161, P=0.019), with an area under the curve of 0.874. CONCLUSION: Fat fraction of the abductors is a powerful predictor of future motor functional decline in DMD patients at 12 months, underscoring the importance of focusing early on this parameter in patients with DMD.

The induction of ferroptosis by KLF11/NCOA4 axis: the inhibitory role in clear cell renal cell carcinoma.

Ferroptosis is a form of cell death and has great potential application in the treatment of many cancers, including clear cell renal cell carcinoma (ccRCC). Herein, we identified the essential roles of Krüppel-like factor 11 (KLF11) in suppressing the progression of ccRCC. By analyzing mRNA expression data from the Gene Expression Omnibus (GEO) database, we found that KLF11 was a significantly downregulated gene in ccRCC tissues. The results of subsequent functional assays verified that KLF11 played an antiproliferative role in ccRCC cells and xenograft tumors. Furthermore, gene set enrichment analysis indicated that ferroptosis was involved in ccRCC development, and correlation analysis revealed that KLF11 was positively related to ferroptosis drivers. We also found that KLF11 promoted ferroptosis in ccRCC by downregulating the protein expression of ferritin, system xc (-) cystine/glutamate antiporter (xCT), and glutathione peroxidase 4 (GPX4), acting as the inhibitory factors of ferroptosis and increasing the intracellular levels of lipid reactive oxygen species (ROS). As a transcriptional regulator, KLF11 significantly increased the promoter activity of nuclear receptor coactivator 4 (NCOA4), a gene significantly downregulated in ccRCC and whose low expression is associated with poor survival. The characteristics of ccRCC cells caused by KLF11 overexpression were reversed after NCOA4 silencing. In summary, the present study suggests that KLF11 suppresses the progression of ccRCC by increasing NCOA4 transcription. Therefore, the KLF11/NCOA4 axis may serve as a novel therapeutic target for human ccRCC.

Polyhydroxyalkanoates: the natural biopolyester for future medical innovations.

Polyhydroxyalkanoates (PHAs) are a family of natural microbial biopolyesters with the same basic chemical structure and diverse side chain groups. Based on their excellent biodegradability, biocompatibility, thermoplastic properties and diversity, PHAs are highly promising medical biomaterials and elements of medical devices for applications in tissue engineering and drug delivery. However, due to the high cost of biotechnological production, most PHAs have yet to be applied in the clinic and have only been studied at laboratory scale. This review focuses on the biosynthesis, diversity, physical properties, biodegradability and biosafety of PHAs. We also discuss optimization strategies for improved microbial production of commercial PHAs via novel synthetic biology tools. Moreover, we also systematically summarize various medical devices based on PHAs and related design approaches for medical applications, including tissue repair and drug delivery. The main degradation product of PHAs, 3-hydroxybutyrate (3HB), is recognized as a new functional molecule for cancer therapy and immune regulation. Although PHAs still account for only a small percentage of medical polymers, up-and-coming novel medical PHA devices will enter the clinical translation stage in the next few years.

[Mechanism of electroacupuncture penetration needling for relieving synovial inflammation of knee osteoarthritis through TLR4/MyD88/NF-κB signal pathway].

OBJECTIVE: To observe the effects of electroacupuncture (EA) penetration needling on Toll-like receptors 4/myeloid differentiation factor 88/nuclear factor-kappa B (TLR4/MyD88/NF-κB) signaling pathway in rat synovium and the serum-related inflammatory factors, so as to explore the mechanism of EA penetration needling on synovial inflammation in rats with knee osteoarthritis (KOA). METHODS: SD male rats were randomly divided into sham-operation group, model group, EA+penetration needling group, and conventional EA group, with 16 rats in each group. The rats model was prepared by anterior cruciate ligment transection and these rats were forced to exercise for 8 weeks after operation. After successful modeling, in the EA+penetration needling group, the needles were inserted at "Dubi" (ST35) "Neixiyan" (EX-LE4), and at "Xuehai"(SP10) "Liangqiu"(ST34) on the right hind limb, towards each other, 5-8 mm in depth, respectively. In the conventional EA group, the needles were inserted at ST35 and EX-LE4 on the right hind limb, obliquely, at 30° angle to the skin, 3-5 mm in depth; and were inserted at SP10 and ST34 on the right hind limb perpendicularly, 3-5 mm in depth. In these two groups, electric stimulation was operated with dense-disperse wave, 2 Hz/10 Hz in frequency and 0.5-1.5 mA in intensity, retained for 20 min in each treatment. The treatment was given once daily, 10 days as 1 course of treatment, and 2 courses were required at the interval of 2 days. After the intervention, the knee joint effusion was observed by musculoskeletal ultrasound; the contents of IL-1ß, IL-6 and TNF-α in serum were determined by ELISA; the morphological changes in the synovium were observed after H.E. staining; the positive expression of NF-κB p65 in the synovial membrane was detected by immunohistochemical method; the expression levels of TLR4, MyD88, TRAF-6 and NF-κB p65 proteins in the synovial membrane were determined by Western blot. RESULTS: Compared with the sham-operation group, in the model group, the knee joint effusion was obviously increased, the synovial lining cells were distributed irregularly, the cells were disarranged, the pannus was formed largely, and a great number of the inflammatory cells were infiltrated; the contents of serum IL-1ß, IL-6 and TNF-α, the positive expression of NF-κB p65, the protein expression levels of TLR4, MyD88, TRAF-6 and NF-κB p65 in the synovial tissue were increased (P<0.05). Compared with the model group, the knee joint effusion was reduced, the synovial lining cells were proliferated, a small number of the inflammatory cells were infiltrated, and the pannus was formed lightly; the contents of serum IL-1ß, IL-6 and TNF-α, the positive expression of NF-κB p65, the protein expression levels of TLR4, MyD88, TRAF-6 and NF-κB p65 in the synovial tissue were lower (P<0.05) in the EA+penetration needling group and the conventional EA group. In the conventional EA group, the knee joint effusion was increased, the synovial lining cells were proliferated, the inflammatory cells were infiltrated largely, and the pannus was formed increasingly; the contents of serum IL-1ß, IL-6 and TNF-α, and the protein expression levels of TLR4, MyD88 and NF-κB p65 in the synovial tissue were increased when compared with the EA+penetration needling group (P<0.05). CONCLUSION: The EA+penetration needling can significantly relieve the synovial inflammatory reaction and the knee joint effusion in KOA rats. The mechanism is probably related to down-regulating the downstream inflammatory cascade through inhibiting the transduction of TLR4/MyD88/NF-κB signaling pathway.

Clinical utilisation of multimodal quantitative magnetic resonance imaging in investigating muscular damage in Duchenne muscular dystrophy: a study on the association between gluteal muscle groups and motor function.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a neuromuscular disease characterised by progressive muscular weakness and atrophy. Currently, studies on DMD muscle function mostly focus on individual muscles; little is known regarding the effect of gluteal muscle group damage on motor function. OBJECTIVE: To explore potential imaging biomarkers of hip and pelvic muscle groups for measuring muscular fat replacement and inflammatory oedema in DMD with multimodal quantitative magnetic resonance imaging (MRI). MATERIALS AND METHODS: One hundred fifty-nine DMD boys and 32 healthy male controls were prospectively included. All subjects underwent MRI examination of the hip and pelvic muscles with T1 mapping, T2 mapping and Dixon sequences. Quantitatively measured parameters included longitudinal relaxation time (T1), transverse relaxation time (T2) and fat fraction. Investigations were all based on hip and pelvic muscle groups covering flexors, extensors, adductors and abductors. The North Star Ambulatory Assessment and stair climbing tests were used to measure motor function in DMD. RESULTS: T1 of the extensors (r = 0.720, P < 0.01), flexors (r = 0.558, P < 0.01) and abductors (r = 0.697, P < 0.001) were positively correlated with the North Star Ambulatory Assessment score. In contrast, T2 of the adductors (r = -0.711, P < 0.01) and fat fraction of the extensors (r = -0.753, P < 0.01) were negatively correlated with the North Star Ambulatory Assessment score. Among them, T1 of the abductors (b = 0.013, t = 2.052, P = 0.042), T2 of the adductors (b = -0.234, t = -2.554, P = 0.012) and fat fraction of the extensors (b = -0.637, t = - 4.096, P < 0.001) significantly affected the North Star Ambulatory Assessment score. Moreover, T1 of the abductors was highly predictive for identifying motor dysfunction in DMD, with an area under the curve of 0.925. CONCLUSION: Magnetic resonance biomarkers of hip and pelvic muscle groups (particularly T1 values of the abductor muscles) have the potential to be used as independent risk factors for motor dysfunction in DMD.

Selection of suitable reference genes for qPCR normalization in different developmental stages of Oenanthe javanica.

Gene expression analysis is widely used to unravel molecular regulatory mechanisms and identify key genes in plants. Appropriate reference gene is an important prerequisite to ensure the accuracy and reliability of qPCR analysis results. Water dropwort is a plant of the Oenanthe genus in the Apiaceae family, which has high economic benefits. However, the underlying molecular regulatory mechanisms in the growth and development of water dropwort have not been fully understood and the appropriate reference genes in different developmental stages of water dropwort not yet reported. In this study, 10 candidate reference genes (ACTIN, PP2A, SAND, EF-1α, GAPDH, UBQ, MIP, TBP, RPS-18, eIF-4α) were identified and cloned from Oenanthe javanica. The qPCR primers of candidate reference genes were designed and verified. Four statistical algorithms, geNorm, NormFinder, BestKeeper and RefFinder were used to evaluate the expression stability of 10 candidate reference genes in different developmental stages of water dropwort. The results showed that TBP and UBQ were the most stable genes in different developmental stages of water dropwort, while GAPDH was the most unstable gene. The normalization of EXP1 genes at different developmental stages further confirmed the reliability of internal reference genes. The results of this study provide a theoretical basis for selecting appropriate internal reference genes in different developmental stages of water dropwort. This study also provides technical support and reliable basis for the expression analysis of key genes in different developmental stages of water dropwort.

Comparison of cardiovascular magnetic resonance features and clinical consequences in patients with left ventricular non-compaction with and without mitral regurgitation-a multi-institutional study of the retrospective cohort study.

Background: Mitral regurgitation (MR) is common in patients with ischemic or idiopathic cardiomyopathies and may be associated with a poor prognosis; however, the impact of different degrees of MR on cardiovascular magnetic resonance images, left ventricular features, and clinical outcomes of left ventricular noncompaction are unknown. We aimed to investigate and compare cardiovascular magnetic resonance characteristics and clinical consequences in patients with left ventricular non-compaction (LVNC) with and without MR. Methods: A cohort of 75 patients with left ventricular noncompaction were retrospectively studied from three institutions; all had undergone cardiovascular magnetic resonance examination with subsequent clinical follow-up. MR was evaluated by echocardiography. Left ventricular myocardial strains including global radial, circumferential, and longitudinal peak strains and left ventricular geometric and functional parameters, including left ventricular ejection fraction, end-diastolic volume, end-systolic volume, left ventricular mass, left ventricular sphericity index, longitudinal shorten, and late gadolinium enhancement (LGE) were measured and compared among groups. The primary endpoint was a composite of heart transplantation, implantable cardioverter-defibrillator insertion, and cardiac death. Results: Compared with the no MR group, the MR groups showed significant deterioration in left ventricular myocardial strains (all P<0.05), and impaired left ventricular geometry and function, including lower left ventricular ejection fraction and greater left ventricular end-systolic volume and left ventricular mass (P<0.05). In the subgroup of moderate-severe MR, patients showed more impaired cardiovascular magnetic resonance features, including left ventricular sphericity index, left ventricular end-diastolic volume, and longitudinal shorten (P<0.05). In this subgroup, Kaplan-Meier analysis showed a significant difference in clinical outcomes (log-rank χ2=4.516, P=0.034; log-rank χ2=4.419, P=0.036, respectively). Additionally, multivariate analyses showed a 6.5-fold higher [hazard ratio, 6.5 (95% CI, 1.015-41.881)] risk of cardiac death with LGE in the moderate-severe MR cohort. Conclusions: In patients with left ventricular noncompaction, MR induced more maladaptive left ventricular remodeling. The incidence of adverse outcomes may be related to the degree of MR. In moderate-severe MR patients, coexisting of LGE may have an additive deleterious effect on clinical outcomes.

Comparison of cardiovascular magnetic resonance characteristics and clinical prognosis in left ventricular noncompaction patients with and without arrhythmia.

BACKGROUND: Left ventricular noncompaction (LVNC) is a rare type of cardiomyopathy, and one of its clinical manifestations is arrhythmia. Cardiovascular magnetic resonance (CMR) is valuable for the diagnosis and prognosis of LVNC. However, studies are lacking on the use of CMR for LVNC patients with arrhythmia. This study aimed to characterize and compare CMR features and prognosis in LVNC patients with and without arrhythmia. METHODS: Eighty-four LVNC patients diagnosed by CMR were enrolled retrospectively in this study. Clinical data, arrhythmia characteristics, and CMR parameters were collected. Patients were divided into different groups according to the arrhythmia characteristics and CMR manifestations for statistical analysis and comparison. Ventricular tachycardia (VT), ventricular fibrillation (Vf), ventricular flutter (VFL), III° atrioventricular block (III° AVB), Wolff-Parkinson-White syndrome (WPW) and ventricular escape (VE) were defined as malignant arrhythmias and benign arrhythmias included premature ventricular contraction, atrial premature beats, atrial fibrillation, supraventricular tachycardia, supraventricular premature beat, bundle branch block, atrial flutter and sinus tachycardia. The outcome events were defined as a composition event of cardiac death, rehospitalization for heart failure, heart transplantation, and implantation of an implantable cardioverter defibrillator (ICD). RESULTS: Sixty-seven LVNC patients (79.76%) mainly presented with arrhythmia, including premature ventricular beat (33 patients [27.73%]), bundle branch block (14 patients [11.77%]), electrocardiogram waveform changes (18 patients [15.13%]), and ventricular tachycardia (11 patients [9.24%]). The cardiac function and structure parameters had no significant difference among the nonarrhythmia group, benign arrhythmia group, and malignant arrhythmia group. However, the presence of late gadolinium enhancement (LGE) was higher in the malignant arrhythmia group than in the other two groups (p = 0.023). At a mean follow-up of 46 months, cardiac events occurred in twenty-three patients (46.94%). Kaplan-Meier analysis showed that there was no statistically significant difference in prognosis among the nonarrhythmia, benign, and malignant arrhythmia groups, but the patients with arrhythmia and association with LGE + or left ventricular ejection fraction (LVEF) < 30% had a higher risk than patients with LGE- or LVEF > 30% (LGE +, HR = 4.035, 95% CI 1.475-11.035; LVEF < 30%, HR = 8.131, 95% CI 1.805-36.636; P < 0.05). CONCLUSIONS: In LVNC patients, the types of arrhythmias are numerous and unrepresentative, and arrhythmia is not the prognostic factor. Arrhythmia combined with presence of LGE or LVEF < 30% is associated with poor prognosis in LVNC patients.

New lead-iodide formates with a strong second-harmonic generation response and suitable birefringence obtained by the substitution strategy.

Nonlinear optical (NLO) crystals featuring a strong second-harmonic generation (SHG) response and suitable birefringence to achieve phase-matching are in urgent demand in industrial and commercial applications. Based on the substitution strategy, two new NLO lead-iodide formates, K2[PbI2(HCOO)2] and Rb2[PbI2(HCOO)2], have been successfully synthesized using a moderate mixed-solvothermal method. K2[PbI2(HCOO)2] and Rb2[PbI2(HCOO)2] exhibit strong phase-matching SHG responses of 8 and 6.8 × KDP, respectively, a suitable birefringence and transparent window covering most of the visible light and mid-IR region. Crystal structures and theoretical calculations unveil that the origins of the strong SHG response and suitable birefringence can be credibly attributed to the oriented arrangement of the highly distorted [PbI2O4] hexa-coordinated polyhedra, which are consistent in their local dipole moments, as well. This research provides a new strategy to explore high-performance NLO crystals.

A Lead Mixed Halide with Three Different Coordinated Anions and Strong Second-Harmonic Generation Response.

Nonlinear optical (NLO) crystals are widely applied in information technology, micro-manufacturing and medical treatment. Herein, a new lead mixed halide with strong second-harmonic generation (SHG) response, Cs3 Pb2 (CH3 COO)2 Br3 I2 , has been designed and rationally synthesized. Cs3 Pb2 (CH3 COO)2 Br3 I2 represents the rare NLO crystal featuring that three different anions (I- , Br- and O2- ) simultaneously coordinate the Pb(II) atom to form a severely distorted [PbBr2 I2 O2 ] polyhedron with a large polarizability. Remarkably, Cs3 Pb2 (CH3 COO)2 Br3 I2 not only exhibits a very strong phase-matching SHG response of 9×KH2 PO4 (KDP), but also possesses a large birefringence (0.27@1064 nm) and high laser damage threshold (LDT). The strong SHG effect of Cs3 Pb2 (CH3 COO)2 Br3 I2 mainly originates from the oriented arrangement of [Pb2 Br3 I2 ] chains. This study points out an effective strategy to develop new NLO crystals with strong SHG response.

KCs2 [Pb2 Br5 (HCOO)2 ]: A Polar 3D Lead-Bromide Framework Exhibiting Strong Second-Harmonic Generation Response.

The discovery of new nonlinear optical (NLO) crystals with excellent properties is in urgently demand because of their ability to generate coherent light. Herein, we report an unique NLO lead bromide formate, KCs2 [Pb2 Br5 (HCOO)2 ], which has been synthesized by a mix-solvothermal method. KCs2 [Pb2 Br5 (HCOO)2 ] exhibits strong phase-matching second-harmonic generation (SHG) response (6.5×KDP), large birefringence (0.16@ 1064 nm), and a wide transparent window in most visible light and mid-IR region. Interestingly, KCs2 [Pb2 Br5 (HCOO)2 ] features a polar 3D lead-bromide framework in which adjacent Pb-Br layers containing coplanar Pb6 Br6 rings are not only parallel to each other, but also orient in the same direction. These oriented arrangements are responsible for the strong SHG response and large birefringence that are elucidated by both local dipole moment and theoretical calculations. This research provides a new strategy to explore subsequent NLO crystals.

Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression.

BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis. APPROACH AND RESULTS: In the HCC-TME, CAF-derived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif) ligand 6 (CXCL6) and TGF-ß secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF-ß secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1-CXCL6/TGF-ß axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis. CONCLUSIONS: This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1-CXCL6/TGF-ß axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.

The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study.

OBJECTIVES: Although axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab-activated autologous dendritic cells-co-cultured cytokine-induced killer cells in patients with advanced RCC. METHODS: All adult patients, including treatment-naive or pretreated with VEGF-targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab-activated dendritic cells-co-cultured cytokine-induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter. RESULTS: The 43 patients (22 untreated and 21 previously treated) showed a median progression-free survival (mPFS) of 14.7 months (95% CI, 11.16-18.30). mPFS in treatment-naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log-rank P-value = 0.07). Overall response rates were 25.6% (95% CI, 13.5-41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar-plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long-term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum-level immunostimulatory cytokine profile. CONCLUSIONS: The combination therapy was active and well tolerated for treatment of advanced RCC, either as first- or second-line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.

The Effect of Posture on Maximum Grip Strength Measurements.

INTRODUCTION/BACKGROUND: The purpose of this study was to compare the grip strength values obtained under 4 postures, and to identify the position providing the maximum grip strength value. We also explored the effects of different body positions on grip strength measurements and the significance of the selection of measurement position for guiding the screening and diagnosis of sarcopenia. METHODOLOGY: A total of 764 people (409 males and 355 females) participated in this study. Grip strength was measured in 4 positions: (1) standing with the elbow fully extended; (2) standing with arms raised; (3) sitting with the elbow flexed 90°; and (4) sitting with the elbow extended. Multiple linear regression model was used to compare the grip strength measurements obtained from these 4 positions by each hand when considering the influence of age, gender, body mass index, and other factors. RESULTS: Both male and female grip strength values in the standing position with the elbow fully extended were significantly greater than those in other positions. In addition, the grip strength measured by standing posture was generally greater than measured by sitting posture. In contrast, grip strength values in the 2 sitting positions did not differ significantly. The grip strength of men was generally greater than that of women. CONCLUSIONS: The findings reveal that grip strength measured while standing with the elbow fully extended is greater than that measured while sitting, which is the posture currently recommended in clinical practice. Clinicians and researchers should choose the appropriate and optimal postures to measure grip strength.

Screening and identification of hub genes in bladder cancer by bioinformatics analysis and KIF11 is a potential prognostic biomarker.

Bladder cancer (BC) is the ninth most common lethal malignancy worldwide. Great efforts have been devoted to clarify the pathogenesis of BC, but the underlying molecular mechanisms remain unclear. To screen for the genes associated with the progression and carcinogenesis of BC, three datasets were obtained from the Gene Expression Omnibus. A total of 37 tumor and 16 non-cancerous samples were analyzed to identify differentially expressed genes (DEGs). Subsequently, 141 genes were identified, including 55 upregulated and 86 downregulated genes. The protein-protein interaction network was established using the Search Tool for Retrieval of Interacting Genes database. Hub gene identification and module analysis were performed using Cytoscape software. Hierarchical clustering of hub genes was conducted using the University of California, Santa Cruz Cancer Genomics Browser. Among the hub genes, kinesin family member 11 (KIF11) was identified as one of the most significant prognostic biomarkers among all the candidates. The Kaplan Meier Plotter database was used for survival analysis of KIF11. The expression profile of KIF11 was analyzed using the ONCOMINE database. The expression levels of KIF11 in BC samples and bladder cells were measured using reverse transcription-quantitative pCR, immunohistochemistry and western blotting. In summary, KIF11 was significantly upregulated in BC and might act as a potential prognostic biomarker. The present identification of DEGs and hub genes in BC may provide novel insight for investigating the molecular mechanisms of BC.

Protective effects of Coenzyme Q10 against acute pancreatitis.

Acute pancreatitis (AP) refers to inflammation in the pancreas, which may lead to death in severe cases. Coenzyme Q10 (Q10), generally known to generate energy, plays an important role as an anti-oxidant and anti-inflammatory effector. Here, we showed the effect of Q10 on inflammatory response in murine AP model. For this study, we induced AP by injection of cerulein intraperitoneally or pancreatic duct ligation (PDL) in mice. The level of cytokines and digestive enzymes were measured in pancreas, and blood. All pancreatic tissues were excised for investigation such as histological changes, infiltration of immune cells. Administration of Q10 attenuated the severity of AP and its associated pulmonary complication as shown by reduction of acinar cell death, parenchymal edema, inflammatory cell infiltration and alveolar thickening in both cerulein-induced AP and PDL-induced AP. Moreover, reduction of the cytokines such as interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α were observed in pancreas and pancreatic acinar cells by Q10. Furthermore, Q10 reduced the infiltration of immune cells such as monocytes and neutrophils and augmentation of chemokines such as CC chemokine-2 (CCL2) and C-X-C chemokine-2 (CXCL2) in pancreas of AP mice. In addition, Q10 deactivates the phosphorylation of extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) in pancreas. In conclusion, these observations suggest that Q10 could attenuate the pancreatic damage and its associated pulmonary complications via inhibition of inflammatory cytokines and inflammatory cell infiltration and that the deactivation of ERK and JNK by Q10 might contribute to the attenuation of AP.