Effects of Curcumin C3 Complex® on Physical Function in Moderately Functioning Older Adults with Low-Grade Inflammation - A Pilot Trial.

BACKGROUND: Natural dietary compounds that can modulate the inflammation process have the potential to improve physical function through a number of biological pathways, and thus may represent an alternative approach to avert functional decline compared to more time-burdening lifestyle interventions. In this pilot trial, we tested the feasibility and explored the effect of a nutritional compound, Curcumin C3 Complex® for improving physical function and muscle strength in moderately functioning older adults with low-grade inflammation. METHODS: Moderately functioning (short physical performance battery, SPPB <10) and sedentary older adults (>65 years) with low-grade systemic inflammation (c-reactive protein >1mg/dL) were randomized to receive Curcumin C3 Complex® (n=9) (1000mg/day) or placebo (n=8) groups for 12 weeks. All participants (age range: 66-94 years, 8 females and 9 males) underwent functional testing (SPPB and walking speed by the 400-meter walk test) and lower-limb strength (knee flexion and extension peak torque by the Biodex test) at baseline and 12 weeks. Venous blood was collected at baseline, 4, 8 and 12 weeks for safety blood chemistry analyses and biomarkers of inflammation. RESULTS: A total of 17 participants were randomized and completed the study. Adherence was high (> 90%) and there were no adverse events reported or abnormal blood chemistries reported. Based on effect sizes, participants in the Curcumin C3 Complex® group demonstrated large effect sizes in the SPPB (Cohen's effect size d=0.75) and measures of knee extension (d=0.69) and flexion peak torque (d=0.82). Effect sizes for galectin-3 (d=-0.31) (larger decrease) and interleukin-6 (d=0.38) (smaller increase) were small in the Curcumin C3 Complex® group compared to placebo. CONCLUSION: This pilot trial suggests that there were no difficulties with recruitment, adherence and safety specific to the study protocol. Preliminary findings warrant a Phase IIb clinical trial to test the effect of Curcumin C3 Complex® on physical function and muscle strength in older adults at risk for mobility disability.

Benign submandibular gland tumours: outcomes of gland-preserving excision by endoscopic or conventional approach.

Endoscope-assisted surgery is becoming a preferred technique in salivary gland surgery. However, this technique has not yet been applied in submandibular gland (SMG) preservation surgery. This retrospective study was performed to evaluate the outcomes of endoscope-assisted gland-preserving surgery through a hairline incision in patients with benign SMG tumours. The study included 38 patients with benign SMG tumours who underwent tumour excision with gland preservation: 19 who underwent local excision of the tumour through an endoscope-assisted hairline approach and 19 who received the conventional cervical approach. The feasibility of the surgical procedure, perioperative patient variables, and postoperative appearance and functional outcomes were evaluated. Patients in both groups had their tumours removed successfully with tumour-free margins. The intraoperative blood loss, postoperative amount of drainage, mean length of the incision, and unstimulated saliva flow rate did not differ between the two groups. There was no difference in the stimulated saliva flow rate between the preserved gland and unaffected SMG. The aesthetic result was better in the endoscope-assisted hairline incision group. No tumour recurrence occurred during follow-up (range 12-52 months). Thus, gland-preserving tumour dissection appears to be a safe method for benign SMG tumours, with good functional results. Furthermore, the endoscope-assisted hairline incision is a feasible method with excellent cosmetic results.

[Talin1 is highly expressed in the fallopian tube and chorionic villi to promote trophoblast invasion in tubal pregnancy].

OBJECTIVE: To investigate the expression of Talin1 in the fallopian tube and chorionic villi in patients with tubal pregnancy and its role in regulating invasion and migration of trophoblasts. METHODS: Immunohistochemistry and Western blotting were used to detect the localization and expression level of Talin1 in the fallopian tube and chorionic villi in patients with tubal pregnancy and in women with normal pregnancy. In the cell experiment, HTR-8/SVneo cells was transfected with Talin1 siRNA and the changes in cell invasion and migration were assessed using scratch assay and Transwell assay. The expressions of MMP-2, MMP-9, N-cadherin and Snail in the transfected cells were detected by qRT-PCR and Western blotting. RESULTS: Positive expression of Talin1 was detected in both normal fallopian tube tissues and tissues from women tubal pregnancy, and its expression was localized mainly in the cytoplasm of cilia cells. The expression level of Talin1 was significantly higher in both the fallopian tube and chorionic villi in women with tubal pregnancy than in normal fallopian tube and chorionic villi samples (P < 0.01). In HTR-8/SVneo cells, transfection with Talin1 siRNA significantly inhibited cell invasion (P < 0.01) and migration (P < 0.05), down-regulated the expression of N-cadherin, MMP-2 and Snail (P < 0.05), and up-regulated the expression of MMP-9 in the cells (P < 0.05). CONCLUSION: The expression of Talin1 in the fallopian tube and chorionic villi is significantly increased in women with tubal pregnancy, suggesting the association of Talin1-regulated trophoblast cell invasion with the occurrence of tubal pregnancy.

Vitamin D Supplementation Is Associated with a Reduction in Self-Reported Falls among Older Adults with Previous Fall History - Feasibility Study.

BACKGROUND: Vitamin D insufficiency contributes to muscle weakness and a higher risk of falls in older adults. OBJECTIVES: This study explored the impact of vitamin D supplementation on self-reported falls and physical function in older adults with low vitamin D levels and a recent fall history. MATERIALS AND METHODS: Twenty-five older adults ≥ 70 years with two or more falls during the past year, low vitamin D blood levels (≥10 ng/ml and < 30 ng/mL), and slow gait speed (1.2 m/s) participated in a 6-month vitamin D supplementation (800 IU/day) study. A modified version of the Morse Fall Scale questionnaire was used to assess frequency of falls over one-year prior to study enrollment. Functional outcomes (short physical performance battery, handgrip strength, gait Timed Up and Go, and six-minute walk), and vitamin D levels were assessed at baseline and 6-month follow-up. RESULTS: Based on diaries and pill counts, participants were generally adherent to the intervention (6 of 7 days per week). Supplementation with 800 IU/day of vitamin D for 6 months increased blood vitamin D levels from 23.25±4.8 ng/ml to 29.13±6.9 ng/ml (p<0.001). Self-reported number of falls decreased from an average of 3.76 ± 2.2 falls in one-year to 0.76 plusmn; 1.4 falls (p <0.0001) over the 6-month intervention. No changes in functional outcome measures were observed. CONCLUSIONS: Vitamin D supplementation at the currently recommended dose of 800 IU/day increased blood vitamin D levels and reduced frequency of falls in older adults with low vitamin D levels and a recent fall history.

The spatial form periosteal-bone complex promotes bone regeneration by coordinating macrophage polarization and osteogenic-angiogenic events.

Bone defects associated with soft tissue injuries are an important cause of deformity that threatens people's health and quality of life. Although bone substitutes have been extensively explored, effective biomaterials that can coordinate early inflammation regulation and subsequent repair events are still lacking. We prepared a spatial form periosteal bone extracellular matrix (ECM) scaffold, which has advantages in terms of low immunogenicity, good retention of bioactive ingredients, and a natural spatial structure. The periosteal bone ECM scaffold with the relatively low-stiffness periosteum (41.6 ± 3.7 kPa) could inhibit iNOS and IL-1ß expression, which might be related to actin-mediated YAP translocation. It also helped to promote CD206 expression with the potential influence of proteins related to immune regulation. Moreover, the scaffold combined the excellent properties of decalcified bone and periosteum, promoted the formation of blood vessels, and good osteogenic differentiation (RUNX2, Col 1α1, ALP, OPN, and OCN), and achieved good repair of a cranial defect in rats. This scaffold, with its natural structural and biological advantages, provides a new idea for bone healing treatment that is aligned with bone physiology.

Harnessing lipid signaling pathways to target specialized pro-angiogenic neutrophil subsets for regenerative immunotherapy.

To gain insights into neutrophil heterogeneity dynamics in the context of sterile inflammation and wound healing, we performed a pseudotime analysis of single-cell flow cytometry data using the spanning-tree progression analysis of density-normalized events algorithm. This enables us to view neutrophil transitional subsets along a pseudotime trajectory and identify distinct VEGFR1, VEGFR2, and CXCR4 high-expressing pro-angiogenic neutrophils. While the proresolving lipid mediator aspirin-triggered resolvin D1 (AT-RvD1) has a known ability to limit neutrophil infiltration, our analysis uncovers a mode of action in which AT-RvD1 leads to inflammation resolution through the selective reprogramming toward a therapeutic neutrophil subset. This accumulation leads to enhanced vascular remodeling in the skinfold window chamber and a proregenerative shift in macrophage and dendritic cell phenotype, resulting in improved wound closure after skin transplantation. As the targeting of functional immune subsets becomes the key to regenerative immunotherapies, single-cell pseudotime analysis tools will be vital in this field.

Long non-coding RNA TTN-AS1 promotes the metastasis in breast cancer by epigenetically activating DGCR8.

Since this article has been suspected of research misconduct and the corresponding authors did not respond to our request to prove originality of data and figures, "Long non-coding RNA TTN-AS1 promotes the metastasis in breast cancer by epigenetically activating DGCR8, by P. Qiu, Y. Dou, L.-Z. Ma, X.-X. Tang, X.-L. Liu, J.-W. Chen, published in Eur Rev Med Pharmacol Sci 2019; 23 (24): 10835-10841-DOI: 10.26355/eurrev_201912_19787-PMID: 31858552" has been withdrawn. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19787.

[Study on the role and possible mechanism of hemeoxygenase-1/carbon monoxide system in protection of quercetin against ethanol-induced hepatocytes oxidative injury].

Objective: To study the protective effect and potential mechanism of heme oxygenase (HO-1)/carbon monoxide (CO)-mediated quercetin on alcoholic oxidative damage of primary rat hepatocytes. Methods: Primary rat hepatocytes were isolated and cultured by two-step collagenase technique. Ethanol exposed primary rat hepatocytes were simultaneously added with quercetin (100 µmol/L) and/or hemoglobin (100 µmol/L) or different doses of CO-releasing molecules (CORM-2, 5-50 µmol/L) for their combined action. After polling, LDH, AST activities and MDA and GSH levels were measured in the supernatant of cell culture. The alone or combined effects of quercetin, CORM-2, hemoglobin and zinc protoporphyrin IX exposed to ethanol were detected by the activity of CYP2E1 in liver microsomes. Statistical analysis of data was performed by analysis of variance (ANOVA) and intergroup comparison was done by SNK-test. Results: Simultaneous addition of 100 µmol/L quercetin had significantly reduced ethanol-induced AST and LDH release, and GSH consumption and MDA elevation extent. Moreover, quercetin had not only lost the hemoglobin (CO blocker) protective effect but also had further exacerbated ethanol-induced lipid peroxidation. CORM-2 had reduced ethanol-induced AST and LDH release, and GSH consumption and MDA production in liver cells, and thus had dose-dependent protective effect. Ethanol had increased significantly CYP2E1 activity. Quercetin or CORM-2 had inhibited CYP2E1 activity, while hemoglobin or protoporphyrin IX had eliminated quercetin inhibitory effect and had increased the CYP2E1 activity. Quercetin, and CYP2E1 activity was constant as compared to ethanol group when CORM-2, zinc protoporphyrin IX and ethanol were incubated with hepatocytes, but the CYP2E1 activity was significantly decreased (P < 0.05), and the differences were statistically significant. Conclusion: CO/HO-1 metabolite mediates the protective effect of quercetin on alcoholic oxidative damage of hepatocytes, which may be related to the inhibition of CYP2E1 activity.

LINC00675 suppresses proliferative, migration and invasion of clear cell renal cell carcinoma via the Wnt/ß-catenin pathway.

OBJECTIVE: To clarify the role of LINC00675 in affecting the progression of clear cell renal cell carcinoma (ccRCC) and its potential mechanism, thus providing effective hallmarks and therapeutic targets for the clinical treatment of ccRCC. MATERIALS AND METHODS: Differentially expressed long non-coding RNAs (lncRNAs) in renal epithelial tissues and ccRCC tissues were searched by analyzing the dataset downloaded from The Cancer Genome Atlas (TCGA) and LINC00675 was selected. LINC00675 level in ccRCC cell lines was determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Overexpression model of LINC00675 model in 786-O and 769-P cells was constructed by the transfection of pcDNA3.1(+)-LINC00675 (LV-LINC00675). Changes in proliferative, migratory, and invasive capacities of 786-O and 769-P cells overexpressing LINC00675 were assessed. At last, relative levels of ß-catenin, Vimentin, and N-cadherin in ccRCC cells overexpressing LINC00675 were detected by qRT-PCR and Western blot. RESULTS: LINC00675 was downregulated in ccRCC tissues and cell lines. Overexpression of LINC00675 attenuated proliferative, migratory, and invasive capacities of 786-O and 769-P cells. Downregulation in ß-catenin after overexpression of LINC00675, while Vimentin and N-cadherin levels did not change. CONCLUSIONS: LINC00675 is downregulated in ccRCC. Overexpression of LINC00675 attenuates ccRCC to proliferate, migrate, and invade by activating the Wnt/ß-catenin pathway.

Higher dose of resveratrol elevated cardiovascular disease risk biomarker levels in overweight older adults - A pilot study.

Older adults are at high risk of developing cardiovascular disease (CVD). Pre-clinical studies indicate that resveratrol (RSV), a polyphenol commonly found in grapes and red wine, may help prevent development of CVD. Based on our previous reports where the 300 mg and 1000 mg doses appeared safe and improved psychomotor function in a dose-dependent manner, our hypothesis was that RSV would reduce biomarkers of CVD risk in overweight, but otherwise healthy older adults and that 1000 mg would lower CVD biomarkers >300 mg. This analysis was performed on samples from older participants (65 years and older) who were randomized to a 90 day RSV treatment with 300 mg (n = 10), 1000 mg (n = 9) or placebo (n = 10). We measured levels of CVD risk biomarkers i.e. oxidized low-density lipoprotein (oxLDL), soluble E-selectin-1 (sE-selectin), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), total plasminogen activator inhibitor (tPAI-1). Statistical significance was set at p < 0.05. Both sVCAM-1 and tPAI increased significantly more in the 1000 mg vs. 300 mg and placebo groups. Other biomarkers (300 mg vs. 1000 mg vs. placebo: oxLDL, sEselectin-1 and sICAM-1) followed the same trend toward higher levels in the 1000 mg group compared to the 300 mg and placebo groups, without reaching statistical significance. This pilot project suggests that a higher dose of RSV may increase the levels of CVD risk biomarkers in overweight older adults. Given no change in the CVD risk biomarkers in response to a lower dose, future studies should test the effects of different doses of RSV to evaluate potential detrimental effects of higher doses on CVD biomarkers and measures of cardiovascular function in older adults at risk for CVD.

Association of SNPs in PLA2R1 with idiopathic and secondary membranous nephropathy in two Chinese cohorts.

Objectives: Specific single-nucleotide polymorphisms (SNPs) in the M-type phospholipase A2 receptor-1 (PLA2R1) are associated with increased risk of idiopathic membranous nephropathy (IMN) in European populations. We hypothesized links between IMN and SMN with these SNPs in two Chinese cohorts.Methods: A cohort of 166 IMN patients and 144 controls from southern China (Group A) and a cohort of 212 IMN patients, 118 SMN patients, and 162 controls from northwestern China (Group B) were recruited. SNPs within PLA2R1 (rs3749119, rs3749117, rs35771982, rs3828323, and rs4664308) were identified and the frequencies of genotypes and alleles were determined for the different groups.Results: Relative to controls, IMN patients had a greater prevalence of rs35771982, rs3749117, and rs4664308 in Group A (OR = 1.61, 95% CI = 1.13-2.31, P = 0.011; OR = 1.62 (1.15-2.29), P = 0.006 and OR = 1.17 (1.06-1.28), P = 0.001, respectively) and in Group B (OR = 1.58 (1.13-2.22), P = 0.009; OR = 1.68 (1.22-2.33), P = 0.002 and OR = 1.15 (1.06-1.25), P < 0.001, respectively). Genotype and allele distributions of rs4664308 differed significantly between SMN patients and controls in Group B (OR = 1.58 (1.10-2.26), P = 0.012). Genotype and allele distribution of rs35771982 and rs4664308 differed significantly between PLA2R-Ab(+) and PLA2R-Ab(-) IMN patients in Group B (OR = 1.59 (1.09-2.31), P = 0.018 and OR = 1.15 (1.03-1.29), P = 0.005, respectively).Conclusion: This study of two cohorts from different regions of China indicate that specific PLA2R1 polymorphisms are associated with IMN and SMN.

Long non-coding RNA TTN-AS1 promotes the metastasis in breast cancer by epigenetically activating DGCR8.

OBJECTIVE: Breast cancer (BC) is one of the most common fatal cancers. Recent studies have identified the vital roles of long non-coding RNAs (lncRNAs) in the development and progression of BC. This research aimed to investigate the underlying mechanisms of lncRNA TTN-AS1 in the metastasis of BC. PATIENTS AND METHODS: TTN-AS1 expression of tissues was detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) in 50 BC patients. Wound healing assay and transwell assay were used to observe the phenotypic alteration of BC cells after knockdown or overexpression of TTN-AS1. Moreover, RT-qPCR and Western blot assay were performed to discover the potential targets of TTN-AS1 in BC. RESULTS: TTN-AS1 expression in BC samples was significantly higher than that of the adjacent tissues. Besides, the migration and invasion of BC cells were markedly inhibited after TTN-AS1 was silenced, while promoted after TTN-AS1 overexpression. In addition, a remarkable decrease of DGCR8 was observed after TTN-AS1 was inhibited in BC cells, while DGCR8 was upregulated after overexpression of TTN-AS1. Furthermore, DGCR8 expression showed significant enhancement in BC tissues and was positively associated with TTN-AS1 level. CONCLUSIONS: Our study uncovered a new oncogene in BC and suggested that TTN-AS1 could enhance BC cell migration and invasion via sponging DGCR8, which provided a novel therapeutic target for the treatment of breast cancer.

[Discussion on the indications of internal mammary sentinel lymph node biopsy in breast cancer in the era of precision medicine].

Objective: To determine the clinical benefits of internal mammary sentinel lymph node biopsy (IM-SLNB) acquired by breast cancer patients with clinically positive axillary lymph node (ALN), and further optimize the IM-SLNB indications. Methods: All primary breast cancer patients with clinically positive ALN from February 2014 to September 2017 were prospectively recruited in this study. IM-SLNB was performed under the guidance of the modified injection technique. The success rate and visualization rate of IM-SLNB, metastatic rate of internal mammary sentinel lymph node (IMSLN) and its related factors were analyzed, and the clinical benefits were accessed according to the current guidelines. Results: Among 126 patients, all of 94 patients (74.6%) who showed internal mammary drainage successfully underwent IM-SLNB. The incidence of internal mammary artery bleeding and pleural lesion were 4.3%(4/94) and 9.6%(9/94), respectively. The metastatic rate of IMSLN was 38.3% (36/94), which was significantly associated with the number of positive ALN (P<0.001) and tumor size (P=0.024). The lymph node staging of 94 patients who underwent IM-SLNB was more accurate. Among them, 36 cases with positive IMSLN underwent internal mammary radiotherapy (IMRT), while the other 58 cases with negative IMSLN avoided radiotherapy. Conclusions: IM-SLNB should be routinely performed in patients with positive ALN. IM-SLNB can provide more accurate staging and guide tailored IMRT to benefit more breast cancer patients.

Expression of programmed death ligand-1 and programmed death 1 in hepatocellular carcinoma and its clinical significance.

OBJECTIVE: To investigate the correlation between the expression of programmed death 1 (PD-1) and PD ligand-1 (PD-L1) in hepatocellular carcinoma (HCC) and clinical parameters. MATERIALS AND METHODS: The study comprised tumor sections from 45 HCC patients treated with curative resection, which were evaluated for PD-1 and PD-L1 protein expression by immunohistochemistry. RESULTS: PD-1 and PD-L1 expression was increased in cancers compared to adjacent normal tissues, with a positive rate of 37.78% (17/45) and 62.22% (28/45), respectively, which was positively correlated with the tumor stage and lymph node metastasis, negatively with postoperative prognosis. PD-1 positivity was most frequently observed in stromal tumor-infiltrating lymphocytes. The number of PD-1 positive lymphocyte was correlated with PD-L1 positive expression. CONCLUSION: PD-L1 and PD-1 are overexpressed in HCC tissues. PD-L1 expression plays a critical role in the pathogenesis of human HCC, suggesting that it might be used as a new biomarker to predict the disease progression and prognosis.

DNAH6 is a novel candidate gene associated with sperm head anomaly.

Globozoospermia and acephalic spermatozoa are two rare sperm head anomalies associated with male infertility. Combination of the two phenotypes in the same patient is extremely rare, so the underlying pathogenesis of this disorder remains unclear. Here, we report a 35-year-old infertile male, who presented with 30% of sperm-lacked heads and 69% of sperm round-headed or small-headed with neck thickening in his ejaculate. Subsequent whole-exome sequencing (WES) analysis identified compound heterozygous variants within the DNAH6 gene. DNAH6 is a testis-specific-expressed protein that was localised to the neck region in the spermatozoa of normal control; however, immunofluorescent staining failed to detect DNAH6 protein in the patient's spermatozoa. Quantitative real-time PCR analysis also showed the complete absence of DNAH6 mRNA in the patient's spermatozoa. Moreover, two cycles of in vitro fertilisation (IVF)-assisted reproduction were carried out, but pregnancy was not achieved after embryo transfer. Therefore, rare sequence variants in DNAH6 might be susceptibility risks for human sperm head anomaly.

TSGA10 is a novel candidate gene associated with acephalic spermatozoa.

Acephalic spermatozoa is a rare teratozoospermia associated with male infertility. However, the pathogenesis of this disorder remains unclear. Here, we report a 27 years old infertile male from a consanguineous family, who presented with 99% headless sperm in his ejaculate. Electron microscopic and immunofluorescence analysis suggested breakage at the midpiece of the patient's sperm cells. Subsequent whole-exome sequencing analysis identified a homozygous deletion within TSGA10 (c.211delG; p.A71Hfs*12), which resulted in the production of truncated TSGA10 protein. TSGA10 is a testis-specific protein that localized to the midpiece in the spermatozoa of a normal control; however, immunostaining failed to detect TSGA10 protein in the patient's sperm. Western blot analysis also showed complete absence of TSGA10 protein in the patient. One cycle of in vitro fertilization-assisted reproduction was conducted, but pregnancy was not achieved after embryo transfer, possibly due to poor embryo quality. Therefore, we speculate that the presence of rare sequence variants within TSGA10 may be associated with acephalic spermatozoa in humans.

A familial study of twins with severe asthenozoospermia identified a homozygous SPAG17 mutation by whole-exome sequencing.

Asthenozoospermia (AZS) is a common cause of male infertility, characterized by abnormal reduction in the motility of ejaculated spermatozoa. Here, in a patient from a consanguineous family, we identified a homozygous mutation (c.G4343A, p.R1448Q) in SPAG17 by whole-exome sequencing. The encoded protein, SPAG17, localizes to the axonemal central apparatus and is considered essential for flagellar waveform. In silico analysis revealed that R1448Q is a potential pathogenic mutation. Immunostaining and western blot assays showed that the R1448Q mutation may exert a negative effect on the steady-state of the SPAG17 protein. Therefore, SPAG17 may be a new pathogenic gene causing AZS.

Biphasic hierarchical extracellular matrix scaffold for osteochondral defect regeneration.

OBJECTIVE: To investigate the effect of decellularized osteochondral extracellular matrix (ECM) scaffold for osteochondral defect regeneration. DESIGN: We compared the histological features and microstructure of degenerated cartilage to normal articular cartilage. We also generated and evaluated osteochondral ECM scaffolds through decellularization technology. Then scaffolds were implanted to osteochondral defect in rabbit model. After 12 weeks surgery, regeneration tissues were analyzed by histology, immunohistochemistry evaluation. And possible mechanisms of angiogenesis and cell migration were explored. RESULTS: We demonstrated decreased cell numbers, formation of fibrous cartilage, lost microstructure and worse permeability in degenerated cartilage compared to normal cartilage. We also generated an osteochondral ECM scaffold with a hierarchical structure that exhibited low immunogenicity, high bioactivity, and well biocompatibility. We found that the ECM scaffold promoted tissue regeneration in osteochondral defects, which was dependent on the scaffold constituents and stratified three-dimensional microstructure as well as on its ability to inhibit angiogenesis and stimulate cell migration. CONCLUSIONS: Our findings demonstrated that the biphasic hierarchical ECM scaffold represents a novel and effective biomaterial that can be used in the treatment of osteochondral defect.

Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells.

The PROTAC (proteolysis-targeting chimera) ARV-825 recruits bromodomain and extraterminal (BET) proteins to the E3 ubiquitin ligase cereblon, leading to degradation of BET proteins, including BRD4. Although the BET-protein inhibitor (BETi) OTX015 caused accumulation of BRD4, treatment with equimolar concentrations of ARV-825 caused sustained and profound depletion (>90%) of BRD4 and induced significantly more apoptosis in cultured and patient-derived (PD) CD34+ post-MPN sAML cells, while relatively sparing the CD34+ normal hematopoietic progenitor cells. RNA-Seq, Reverse Phase Protein Array and mass cytometry 'CyTOF' analyses demonstrated that ARV-825 caused greater perturbations in messenger RNA (mRNA) and protein expressions than OTX015 in sAML cells. Specifically, compared with OTX015, ARV-825 treatment caused more robust and sustained depletion of c-Myc, CDK4/6, JAK2, p-STAT3/5, PIM1 and Bcl-xL, while increasing the levels of p21 and p27. Compared with OTX015, PROTAC ARV-771 treatment caused greater reduction in leukemia burden and further improved survival of NSG mice engrafted with luciferase-expressing HEL92.1.7 cells. Co-treatment with ARV-825 and JAK inhibitor ruxolitinib was synergistically lethal against established and PD CD34+ sAML cells. Notably, ARV-825 induced high levels of apoptosis in the in vitro generated ruxolitinib-persister or ruxolitinib-resistant sAML cells. These findings strongly support the in vivo testing of the BRD4-PROTAC based combinations against post-MPN sAML.

Correlation analysis of genetic diversity and population structure of Houttuynia cordata Thunb with regard to environment.

To study the levels of genetic diversity, and population structure, of Houttuynia cordata Thunb, the genetic background and relationships of populations were analyzed in terms of environmental factors. The genetic diversity and population structure of H. cordata were investigated using sequence-related amplified polymorphisms and correlation with environmental factors was analyzed using the SPSS software. Two thousand one hundred sixty-three sites were amplified from 41 pairs of primers, 1825 of which were polymorphic, and the percentage of polymorphic loci was 84.37%; the percentage of polymorphic sites was 72.14 and 67.77% at the species and population level, respectively. The observed number of alleles was 1.52 and 1.30 at species and population level, respectively. The effective number of alleles was 1.38 and 1.24 at species and population level, respectively. The Nei's diversity was 0.26 and 0.15 at species and population level, respectively. The Shannon's information index was 0.87 and 0.63 at species and population level, respectively. The genetic differentiation coefficient of populations was 0.51, and 12 populations were divided into three classes based on D = 0.20; the genetic diversities of different populations are correlated at different significance levels (P < 0.05) with environmental factors. Genetic differentiation existed among populations and the populations exhibited heteroplasmy.