Search

Background: Although PD-1 blockade has significantly improved the survival of metastatic colorectal cancer with DNA Mismatch Repair-Deficient/Microsatellite Instability-High (MSI-H), the data on neoadjuvant setting is limited. Methods: In this retrospective study, we enrolled eight patients with advanced MSI-H colorectal cancer from three hospitals. Four patients are locally advanced and four are metastatic. All the patients received at least two doses of PD-1 antibody with or without chemotherapy as neoadjuvant therapy. The aim of the present study was to evaluate the short-term efficacy and toxicities of this strategy. Results: All the enrolled eight patients had a major response in imaging and/or pathological evaluation. Five of the seven resected patients were evaluated as pathological complete response. One patient without surgery has a clinical complete response (cCR) tumor response. Conclusions: Neoadjuvant PD-1 blockade induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H colorectal cancer. Further studies are required to evaluate the long-term effect of this strategy.

Through activity-guided fractionation, a new triterpene (asperflagin, 1) was isolated as a PPAR-γ agonist from the jellyfish-derived fungus Aspergillus flavus. Asperflagin displayed selective and moderate transactivation effects on PPAR-γ in Ac2F rat liver cells. Based on further biological evaluation and molecular docking analysis, we postulated that asperflagin might function as a PPAR-γ partial agonist. This compound was calculated to display a typical PPAR-γ ligand–receptor interaction that is distinct from that of full agonistic antidiabetics such as rosiglitazone, and may retain the antidiabetic effect without accompanying weight gain. Weight gain and obesity are typical side effects of the PPAR-γ full agonist rosiglitazone, and lead to suboptimal outcomes in diabetic patients. Compared to rosiglitazone, asperflagin showed higher glucose uptake in HepG2 human liver cells at concentrations of 20 and 40 μM but induced markedly lower adipogenesis and lipid accumulation in 3T3-L1 preadipocytes. These results suggest that asperflagin may be utilized for further study on advanced antidiabetic leads.

AIM: To investigate the effect of tissue factor targeting peptide (TF-TP) on retinal pigment epithelium (RPE) cells tight junctions. METHODS: Cell counting kit-8 (CCK-8) was used to measure the proliferation of ARPE-19 cells. Expression of tight junction, ZO-1 in ARPE-19 cells was measured by Western blot and immunofluorescent staining. Western blot was also used to detect the expression of tissue factor (TF). CEC Transmigration Assay was used to measure the migration of ARPE-19 cells. The transport of fluorescent markers [fluorescein isothiocyanate dextrans of 4, 10, 20 (FD4, FD10, FD20)] and the transepithelial electrical resistance (TEER) were used to measure in ARPE-19 cell. RESULTS: CCK-8 assay showed that 5 μmol/L TF-TP can inhibit ARPE-19 cells abnormally proliferation stimulated by lipopolysaccharide (LPS; P

Phosphorus-solubilizing microbes play key roles in improving phosphorus availability and in alleviating phosphorus nutrient limitation in soils. However, we did not have a comprehensive understanding of the overall research progress and development trend of phosphorus solubilizing microorganisms. In this study, we obtain documents from the Web of Science (WOS) core collection between 2002 and 2022, and a comprehensive review of the progress of global research on soil phosphate solubilizing microorganisms was conducted by using the VOSviewer bibliometric analysis tool. The results showed an increasing trend in the number of published articles from 2002 to 2022. India, accounting for 28% of the total number of published articles, became the most productive country. However, Canada was the country with the highest average citation frequency of articles. Chinese Academy of Sciences (CAS) was the greatest contributor with the most publications. Among the published journals, Frontiers in Microbiology, Applied Soil Ecology and Plant and Soil were the top three core journals in this field. Based on the keyword analysis, the assessment of the mechanisms between phosphorus solubilizing microbes and the soil carbon cycles with the different management practices became the new research trend among the scientific communities. These findings would provide an important reference value for future in-depth research on soil phosphate solubilizing microorganisms. [ABSTRACT FROM AUTHOR]

Objective: To provide novel insights into the aetiology of non-syndromic cleft lip with or without cleft palate (NSCL/P) by integrating multi-omics data and exploring susceptibility genes associated with NSCL/P. Methods: A two-stage genome-wide association study (GWAS) of NSCL/P was performed, involving a total of 1,069 cases and 1,724 controls. Using promoter capture Hi-C (pCHi-C) datasets in human embryonic stem cells (hESC) and chromatin immunoprecipitation sequencing (ChIP-seq) in craniofacial tissues, we filtered out single nucleotide polymorphisms (SNPs) with active cis-regulation and their target genes. Additionally, we employed expression quantitative trait loci (eQTL) analysis to identify candidate genes. Results: Thirteen SNPs were identified as cis-regulation units associated with the risk of NSCL/P. Five of these were proven to be active in chromatin states in early human craniofacial development (rs7218002: odds ratio [OR] 1.50, P = 8.14E-08; rs835367: OR 0.78, P = 3.48E05; rs77022994: OR 0.55, P = 1.05E-04; rs961470: OR 0.73, P = 1.38E-04; rs17314727: OR 0.73, P = 1.85E-04). Additionally, pCHi-C and eQTL analysis prioritised three candidate genes (rs7218002: NTN1, rs835367: FGGY, LINC01135). NTN1 and FGGY were expressed in mouse orofacial development. Deficiencies in NTN1, FGGY and LINC01135 were associated with cleft palate and cleft lip, abnormal facial shape and bifid uvula, and abnormality of the face, respectively. Conclusion: Our study identified five SNPs (rs7218002, rs835367, rs77022994, rs961470 and rs17314727) and three susceptibility genes (NTN1, FGGY and LINC01135) associated with NSCL/P. These findings contribute to a better understanding of the genetic factors involved. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor (PPAR) expression has been implicated in pathological states such as cancer, inflammation, diabetes, and neurodegeneration. We isolated natural PPAR agonists—eight 2,5-diketopiperazines—from the jellyfish-derived fungus Aspergillus flavus. Cyclo-(L-Pro-L-Phe) was the most potent PPAR-γ activator among the eight 2,5-DKPs identified. Cyclo-(L-Pro-L-Phe) activated PPAR-γ in Ac2F rat liver cells and SH-SY5Y human neuroblastoma cells. The neuroprotective effect of this partial PPAR-γ agonist was examined using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, lactate dehydrogenase release, and the Hoechst 33342 staining assay in SH-SY5Y cells. Our findings revealed that cyclo-(L-Pro-L-Phe) reduced hydrogen peroxide-induced apoptosis as well as the generation of reactive oxygen species. Rhodamine 123 staining and western blotting revealed that cyclo-(L-Pro-L-Phe) prevented the loss of mitochondrial membrane potential and inhibited the activation of mitochondria-related apoptotic proteins, such as caspase 3 and poly (ADP-ribose) polymerase. Moreover, cyclo-(L-Pro-L-Phe) inhibited the activation and translocation of nuclear factor-kappa B. Thus, the partial PPAR-γ agonist cyclo-(L-Pro-L-Phe) demonstrated potential neuroprotective activity against oxidative stress-induced neurodegeneration in SH-SY5Y cells.

Neuroblastoma cell differentiation is regulated by Id proteins. Here, the authors show that CaMKII-mediated phosphorylation of Beclin 1 can activate K63-linked ubiquitination and autophagic degradation of Id proteins uncovering a role for autophagy in cell differentiation.

Abstract This study aimed to identify the associated factors for quality measurement (QM) of shear wave speed (SWS) imaging and to validate the additional value of QM in the diagnosis of breast lesions. From September 2014 to February 2015, conventional ultrasound and SWS imaging were performed in 338 women with 361 breast lesions. Binary logistic regression was used to identify associated factors for QM. Sensitivity, specificity and the area under receiver operating characteristic (ROC) curve (AUC) among maximum SWS (SWS max ), QM and SWS max plus QM (SWS max +QM) were compared to validate additional value of QM. Pathology confirmed 263 (72.9%) benign lesions and 98 (27.1%) malignancies. Maximum depth (Odds ratio [OR]: 1.398) and posterior features (OR: 1.206) were identified as independent associated factors for QM. Compared with SWS max and QM, the sensitivity of SWS max +QM increased from 67.3%, 64.3% to 83.7% whereas the specificity decreased from 90.5%, 72.6% to 65.4% (all P

Abstract To develop a risk model for predicting axillary lymph node metastasis (LNM) in patients with breast invasive ductal carcinoma (IDCs) using ultrasound (US), US elastography of virtual touch tissue imaging (VTI) and virtual touch tissue imaging & quantification (VTIQ), and histologic parameters. This study included 162 breast IDCs in 162 patients. Univariate and multivariate analyses were used to identify the risk factors and a risk model was created. The results found that 64 (39.5%) of 162 patients had axillary LNMs. The risk score (RS) for axillary LNM was defined as following: RS = 1.3 × (if lesion size ≥20 mm) + 2.6 × (if taller than wide shape) + 2.2 × (if VTI score ≥5) + 3.9 × (if histological grade III) + 1.9 × (if positive C-erbB-2). The rating system was divided into 6 stages (i.e. Stage I, Stage II, Stage III, Stage IV, Stage V, and Stage VI) and the associated risk rates in terms of axillary LNM were 0% (0/19), 6.1% (2/33), 7.7% (3/39), 65.5% (19/29), 92.3% (24/26), and 100% (16/16), respectively. The risk model for axillary LNM established in the study may facilitate subsequent treatment planning and management in patients with breast IDCs.

Immune checkpoint blockade of programmed cell death protein 1 (PD-1) had an impressive long-lasting effect in a portion of advanced-stage melanoma patients, however, this therapy failed to induce responses in several patients; how to increase the objective response rate is very important. Cellular FLICE-inhibitory protein (c-FLIP) could inhibit apoptosis directly at the death-inducing signaling complex of death receptors and is also considered to be the main cause of immune escape. The overexpression of c-FLIPL occurs frequently in melanoma and its expression is associated with the prognosis. We found that the level of c-FLIPL expression was associated with the PD-1 blockade response rate in melanoma patients. Thus, we performed this research to investigate how c-FLIPL regulates immunotherapy in melanoma. We demonstrate that down regulation of c-FLIPL enhances the PD-1 blockade efficacy in B16 melanoma tumor model. Down regulation of c-FLIPL could increase the tumor apoptosis and enhance the antitumor response of T cells in the lymphocyte tumor cells co-culture system. Moreover, knockdown of c-FLIPL could decrease the expression of PD-L1 and recruit more effector T cells in the tumor microenvironment. Our results may provide a new combined therapeutic target for further improving the efficacy of PD-1 blockade in melanoma.

The hypothesis of the present study is that apoptosis through an intrinsic mitochondrial pathway may mediate high fat diet (HFD)-induced changes in the metabolism of Pelteobagrus fulvidraco. To this end, we cloned the full-length cDNA sequences of Cycs, Apaf1, Casp9, Casp3a, and Casp3b involved in the mitochondria apoptotic pathway, and explored their mRNA tissue expressions and transcriptional responses to HFD. All of these members shared similar domains to their orthologous vertebrate genes. They were constitutively expressed in all analyzed tissues but varied from tissue to tissue. Compared to the control, HFD up-regulated the mRNA expression of partial genes among these five key genes (Cycs, Apaf1, Casp9, Casp3a, and Casp3b) in mesenteric fat, intestine, ovary and the kidney, indicating the induction of apoptosis in these tissues; in contrast, HFD down-regulated mRNA levels of partial genes among the five key genes (Cycs, Apaf1, Casp9, Casp3a, and Casp3b) in the heart, spleen and gill tissues, indicating the inhibition of apoptosis in these tissues. The present study will facilitate further exploration into the functions of these genes at the molecular level and disclose the critical involvement of these genes against nutrient changes, indicating that processes of apoptosis in various tissues may differentially be modified by HFD.

Objective: To observe the protective role of hapatopoietin Cn (HPPcn) on acute liver injury.Methods: Six hours after 10 mmol/L CCl4, 150 mmol/L ethanol, or 0.6 mmol/L H2O2 treatment, SMMC7721 human hepatoma cells were incubated with 10, 100, or 200 ng/ml recombinant human HPPCn protein (rhHPPCn) for an additional 24 h. The cell survival rate was analyzed using the CCK-8 assay. The CCl4-induced apoptosis of SMMC7721 cells was detected by flow cytometry. Then, the levels of glutamic oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) in SMMC7721 cell lysates and cell culture supernatant were detected. SMMC7721 cells were treated with different concentrations of rhHPPCn (0, 10, and 100 ng/ml). The cell proliferation indexes (BrdU incorporation and PCNA expression) were detected by immunohistochemistry (IHC). An acute liver injury mouse model was established by a one-time intraperitoneal injection of 20% CCl4 at a volume of 5 ml/kg body weight. One hour after CCl4 injection, 1.25 or 2.5 mg rhHPPCn/12 h/kg body weight was injected via the tail vein. The serum levels of GOT and GPT were detected at different time points. Pathological changes in the liver were evaluated. PCNA expression levels were observed by IHC.Results: rhHPPCn increased the survival rate of SMMC7721 cells and inhibited chemical toxicity-induced cell apoptosis. The levels of GOT, GPT, MDA, and LDH in the cell supernatant were significantly reduced, while GSH-PX and SOD were significantly increased after rhHPPCn treatment in the CCl4-treated SMMC7721 cells. BrdU incorporation and PCNA expression increased in a concentration-dependent manner, indicating that rhHPPCn promotes cell proliferation. The results showed that rhHPPCn significantly reduced the serum levels of GOT and GPT in CCl4-induced acute liver injury mice. rhHPPCn alleviated the tissue damage and increased PCNA expression, indicating the promotion of proliferation after acute injury.Conclusion: rhHPPCn protects hepatocytes from chemical toxins by promoting proliferation and inhibiting apoptosis in vivo and in vitro. Our study provides new insights for the clinical treatment of acute liver injury.

To study the impact of donepezil, rivastigmine, galantamine, and memantine on cognitive, functional, behavioral, global changes and adverse effects in patients with mild, moderate and severe Alzheimer’s disease (AD), we screened the literature published before September 2017 in the Pubmed, Embase, Cochrane library and Web of Science Electronic databases according to the inclusion criteria. Thirty-six studies were finally determined from 1560 preliminary screened articles. The AD Assessment Scale-cognitive Subscale (ADAS-cog), AD Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI), and Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+) were used as valid endpoints. Of the 36 trials included, meta-analyses of these placebo-control trials showed that there were significant differences between the donepezil, rivastigmine and placebo groups using ADAS-cog, ADCS-ADL, and CIBIC+. Meta-analyses of these placebo-controlled trials showed that there were significant differences between the galantamine and placebo groups using ADAS-cog, ADCS-ADL, NPI, and CIBIC+. These observations suggest that memantine is beneficial for stabilizing or slowing the decline in ADAS-cog and ADCS-ADL19 changes in AD patients. However, there was no significant effect according to the ADCS-ADL23, NPI, and CIBIC+ tests, which indicated that memantine treatment has no significant effect on these cognitive aspects of AD patients. Different effects of donepezil, rivastigmine, galantamine, or memantine on AD were found in this study. According to the results, we conclude that galantamine is effective in treating all aspects of AD and is the first choice for the treatment of AD. However, due to limited data, we should consider additional data to obtain more stable results.

The electrocaloric effect (ECE) in lead-free BaSnxTi1−xO3 (BSnT, x=0.05, 0.10 and 0.15) ceramics were investigated using a direct ECE measurement. Results indicate that the maximum ECE occurs near the Curie temperature and it slightly shifts towards high temperatures. The directly measured ECE is larger than that calculated using the Maxwell relation and P-E loops. A maximum electrocaloric efficiency ΔT∕ΔE=0.49×10−6KmV−1 was procured for the composition with x=0.15 at T=299.2K. And it also shows a broad peak in the temperature range of 250–320K.

Cytokine-induced killer (CIK) cells that are stimulated using mature dendritic cells (DCs), referred to as (DC-CIK cells) exhibit superior anti-tumor potency. Anti-programmed death-1 (PD-1) antibodies reinvigorate T cell-mediated antitumor immunity. This phase I study aimed to assess the safety and clinical activity of immunotherapy with PD-1 blockade (pembrolizumab)-activated autologous DC-CIK cells in patients with advanced solid tumors. Patients with selected types of advanced solid tumors received a single intravenous infusion of activated autologous DC-CIK cells weekly for the first month and every 2 weeks thereafter. The primary end points were safety and adverse event (AE) profiles. Antitumor responses, overall survival (OS), progression-free survival (PFS) and cytolytic activity were secondary end points. Treatment-related AEs occurred in 20/31 patients. Grade 3 or 4 toxicities, including fever and chills, were observed in two patients. All treatment-related AEs were reversible or controllable. The cytotoxicity of DC-CIK cells induced up-regulation of PD-L1 expression on autologous tumor cells. When activated using pembrolizumab ex vivo, DC-CIK cells exerted superior antitumor properties and elevated IFN-γ secretion. Objective responses (complete or partial responses) were observed in 7 of the 31patients.These responses were durable, with 6 of 7 responses lasting more than 5 months. The overall disease control rate in the patients was 64.5%. At the time of this report, the median OS and PFS were 270 and 162 days, respectively. In conclusions, treatment with pembrolizumab-activated autologous DC-CIK cells was safe and exerted encouraging antitumor activity in advanced solid tumors. A larger phase II trial is warranted.

Wheat stem rust, caused by Puccinia granimis f. sp. tritici, severely affects wheat production, but it has been effectively controlled in China since the 1970s. However, the appearance and spread of wheat stem rust races Ug99 (TTKSK, virulence to Sr31), TKTTF (virulence to SrTmp) and TTTTF (virulence to the cultivars carrying Sr9e and Sr13) have received attention. It is important to clarify the effectiveness of resistance genes in a timely manner, especially for the purpose of using new resistance genes in wheat cultivars for durable-resistance. However, little is known about the stem rust resistance genes present in widely used wheat cultivars from Gansu. This study aimed to determine the resistance level at the seedling stage of the main wheat cultivars in Gansu Province. A secondary objective was to assess the prevalence of Sr2, Sr24, Sr25, Sr26, Sr31, and Sr38 using molecular markers. The results of the present study indicated that 38 (50.7%) wheat varieties displayed resistance to all the tested races of Puccinia graminis f. sp. tritici. The molecular marker analysis showed that 13 out of 75 major wheat cultivars likely carried Sr2; 25 wheat cultivars likely carried Sr31; and nine wheat cultivars likely carried Sr38. No cultivar was found to have Sr25 and Sr26, as expected. Surprisingly, no wheat cultivars carried Sr24. The wheat lines with known stem rust resistance genes could be used as donor parent for further breeding programs.

In flowering plants, male gametophyte development occurs in the anther. Tapetum, the innermost of the four anther somatic layers, surrounds the developing reproductive cells to provide materials for pollen development. A genetic pathway of DYT1-TDF1-AMS-MS188 in regulating tapetum development has been proven. Here we used laser microdissection and pressure catapulting to capture and analyze the transcriptome data for the Arabidopsis tapetum at two stages. With a comprehensive analysis by the microarray data of dyt1, tdf1, ams, and ms188 mutants, we identified possible downstream genes for each transcription factor. These transcription factors regulate many biological processes in addition to activating the expression of the other transcription factor. Briefly, DYT1 may also regulate early tapetum development via E3 ubiquitin ligases and many other transcription factors. TDF1 is likely involved in redox and cell degradation. AMS probably regulates lipid transfer proteins, which are involved in pollen wall formation, and other E3 ubiquitin ligases, functioning in degradating proteins produced in previous processes. MS188 is responsible for most cell wall-related genes, functioning both in tapetum cell wall degradation and pollen wall formation. These results propose a more complex gene regulatory network for tapetum development and function.

Background: Many publications have investigated the association between metal ions and the risk of Alzheimer's disease (AD), but the results were ambiguous.Aims: The objective of this study was to assess the association between the serum levels of metals (copper/zinc/iron) and the risk of AD via meta-analysis of case-control studies.Methods: We screened literatures published after 1978 in the Pubmed, Embase, Cochrane library, Web of Science and ClinicalTrials.gov. Electronic databases. By using Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the 407 publications, there are 44 of these publications met all inclusion criteria. The Review Manager 5.3 software was used to calculate available data from each study.Results: Consistent with the conclusions of other meta-analysis, our results demonstrated serum copper levels were significantly higher [MD = 9.27, 95% CI (5.02–13.52); p < 0.0001], and the serum zinc levels were significantly lower in AD patients than in healthy controls [MD = −6.12, 95% CI (−9.55, −2.69); p = 0.0005]. Serum iron levels were significantly lower in AD patients than in healthy controls after excluded two studies [MD = −13.01, 95% CI (−20.75, −5.27); p = 0.001].Conclusion: The results of our meta-analysis provided rigorous statistical support for the association of the serum levels of metals and the risk of AD, suggesting a positive relationship between the serum copper levels and AD risk, and a negative relationship between the serum zinc/iron levels and AD risk.