Search

Abstract Osteosarcoma is the most common primary bone cancer in children and young adults. Limited progress has been made in improving the survival outcomes in patients with osteosarcoma over the past four decades. Especially in metastatic or recurrent osteosarcoma, the survival rate is extremely unsatisfactory. The treatment of osteosarcoma urgently needs breakthroughs. In recent years, immunotherapy has achieved good therapeutic effects in various solid tumors. Due to the low immunogenicity and immunosuppressive microenvironment of osteosarcoma, immunotherapy has not yet been approved in osteosarcoma patients. However, immune-based therapies, including immune checkpoint inhibitors, chimeric antigen receptor T cells, and bispecfic antibodies are in active clinical development. In addition, other immunotherapy strategies including modified-NK cells/macrophages, DC vaccines, and cytokines are still in the early stages of research, but they will be hot topics for future study. In this review, we showed the functions of cell components including tumor-promoting and tumor-suppressing cells in the tumor microenvironment of osteosarcoma, and summarized the preclinical and clinical research results of various immunotherapy strategies in osteosarcoma, hoping to provide new ideas for future research in this field.

Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40 μg/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben’s regulation of the STAT3 signaling pathway.

Abstract Limited information is available on the cardiovascular health (CVH) index and risk of high-normal blood pressure (HNBP) in elderly people. Randomized cluster sampling, multivariate logistic regression, and mediating effects analysis were used in this study analyze the relationship between CVH index and HNBP in the elderly. 1089 non-hypertensive residents aged 65 years or older completed the study. The positive rate of HNBP was 75.85% (male vs. female: 76.13% vs. 75.64%, P = 0.852); The ideal rate of CVH (ideal CVH index ≥ 5 items) was 14.51% (male vs. female: 15.91% vs. 13.46%, P = 0.256). Compared with people with 0–2 ideal CVH index, the risk of HNBP in people with 4 ideal indexes and ≥ 5 ideal indexes decreased by 50% and 63%, respectively, and their OR (95% CI) were 0.50 (0.31, 0.81) and 0.37 (0.21, 0.66), respectively. The results of the trend test showed that the risk of HNBP decreased by 32% for every increase in the ideal CVH index (trend P

NiTi alloys exhibit significant potential for biological applications, and the fabrication of customized NiTi geometries is greatly facilitated by the use of laser powder bed fusion (LPBF) processing. However, there are several challenges with post-processing NiTi specimens processed via LPBF, such as uneven, loosely packed, weakly corrosive surfaces, and low dimensional precision. Therefore, solving the surface problem of metals prepared by LPBF has become the key to the application. In this paper, the influence of the solution and parameters on surface roughness, surface shape and size, composition, and corrosion resistance was studied by adjusting the composition of the polishing solution and polishing parameters. The results show that polishing for 2 h in S2 solution (HNO3: HF: H2O = 40:10:50) produces the smoothest surface with the roughness characteristics Sa is 10.41 ± 0.63 μm and Ra is 0.39 ± 0.30 μm. At the same time, the corrosion resistance of polished samples has been significantly improved in simulated body fluids (SBF), and the corrosion current density (Icorr) reduced by up to one order of magnitude, reaching 5.38 ± 0.24 × 10−8. By altering the polishing process duration, it is possible to achieve a micron-level roughness surface while maintaining dimensional accuracy, making LPBF-NiTi more suitable for implant applications. Ultimately, we conclude with a brief discussion of how chemical polishing affects the handling of materials with complex structures. Between 30 and 1 h, LPBF-NiTi scaffolds were polished in S2 solution to provide porosities and dimensional accuracy that best matched the design parameters.

BackgroundHemorrhagic Fever with Renal Syndrome (HFRS) continues to pose a significant public health threat to the well-being of the population. Given that the spread of HFRS is susceptible to meteorological factors, we aim to probe into the meteorological drivers of HFRS. Thus, novel techniques that can discern time-delayed non-linear relationships from nonlinear dynamical systems are compulsory.MethodsWe analyze the epidemiological features of HFRS in Weifang City, 2011-2020, via the employment of the Empirical Dynamic Modeling (EDM) method. Our analysis delves into the intricate web of time-delayed non-linear associations between meteorological factors and HFRS. Additionally, we investigate the repercussions of minor perturbations in meteorological variables on future HFRS incidence.ResultsA total of 2515 HFRS cases were reported in Weifang from 2011 to 2020. The number of cases per week was 4.81, and the average weekly incidence was 0.52 per 1,000,000. The propagation of HFRS is significantly impacted by the mean weekly temperature, relative humidity, cumulative rainfall, and wind speed, and the ρCCM converges to 0.55,0.48,0.38 and 0.39, respectively. The graphical representation of the relationship between temperature (lagged by 2 weeks) and the incidence of HFRS exhibits an inverted U-shaped curve, whereby the incidence of HFRS culminates as the temperature reaches 10 °C. Moreover, temperature, relative humidity, cumulative rainfall, and wind speed exhibit a positive correlation with HFRS incidence, with a time lag of 4-6 months.ConclusionsOur discoveries suggest that meteorological factors can drive the transmission of HFRS both at a macroscopic and microscopic scale. Prospective alterations in meteorological conditions, for instance, elevations in temperature, relative humidity, and precipitation will instigate an upsurge in the incidence of HFRS after 4-6 months, and thus, timely public health measures should be taken to mitigate these changes.

As a characteristic representative of the new generation of vehicles, autonomous driving is expected to improve people's driving experience. The study on traffic accident of autonomous vehicles (AVs) helps provide suggestions for autonomous driving safety from multiple disciplines and perspectives, and provide support for formulating traffic accident treatment schemes. Knowledge mapping, as a cutting-edge research method in bibliometrics, scientifically and objectively displays the relevant research status using visual means. This paper uses CiteSpace 6.1.r3 to analyze 5068 related literature on the Web of Science database from 1991 to 2022 and finds out major thematic clusters, important documents and representative journals according to citation frequency. The results show that research on traffic accidents involving AVs focuses on accident preventing technologies, including how to avoid collisions, track lane-position, and enhance vehicle-to-everything (V2X) communication. This paper extracts the mean research topics and key points involved in the field and illustrates journals related to AVs and traffic accidents, which provides guidance for subsequent researchers to carry out in-depth research and contribute their papers. Popular journals are in disciplines of mathematics, systems, computer, economics, and social science. This paper also suggests scholars to consider the aspects of scene reconstruction, cause analysis, and injury of vulnerable road users, so as to investigate traffic accidents and put forward effective treatment schemes to reduce AV accidents, and ultimately improve road safety.

Abstract Objective To generate an image‐driven biomarker (Rad_score) to predict tumor‐infiltrating regulatory T lymphocytes (Treg) in breast cancer (BC). Methods Overall, 928 BC patients were enrolled from the Cancer Genome Atlas (TCGA) for survival analysis; MRI (n = 71 and n = 30 in the training and validation sets, respectively) from the Cancer Imaging Archive (TCIA) were retrieved and subjected to repeat least absolute shrinkage and selection operator for feature reduction. The radiomic scores (rad_score) for Treg infiltration estimation were calculated via support vector machine (SVM) and logistic regression (LR) algorithms, and validated on the remaining patients. Results Landmark analysis indicated Treg infiltration was a risk factor for BC patients in the first 5 years and after 10 years of diagnosis (p = 0.007 and 0.018, respectively). Altogether, 108 radiomic features were extracted from MRI images, 4 of which remained for model construction. Areas under curves (AUCs) of the SVM model were 0.744 (95% CI 0.622–0.867) and 0.733 (95% CI 0.535–0.931) for training and validation sets, respectively, while for the LR model, AUCs were 0.771 (95% CI 0.657–0.885) and 0.724 (95% CI 0.522–0.926). The calibration curves indicated good agreement between prediction and true value (p > 0.05), and DCA shows the high clinical utility of the radiomic model. Rad_score was significantly correlated with immune inhibitory genes like CTLA4 and PDCD1. Conclusions High Treg infiltration is a risk factor for patients with BC. The Rad_score formulated on radiomic features is a novel tool to predict Treg abundance in the tumor microenvironment.

Elucidating the temporal process of immune remodeling under immunosuppressive treatment after liver transplantation (LT) is critical for precise clinical management strategies. Here, we performed a single-cell multi-omics analysis of peripheral blood mononuclear cells (PBMCs) collected from LT patients (with and without acute cellular rejection [ACR]) at 13 time points. Validation was performed in two independent cohorts with additional LT patients and healthy controls. Our study revealed a four-phase recovery process after LT and delineated changes in immune cell composition, expression programs, and interactions along this process. The intensity of the immune response differs between the ACR and non-ACR patients. Notably, the newly identified inflamed NK cells, CD14+RNASE2+ monocytes, and FOS-expressing monocytes emerged as predictive indicators of ACR. This study illuminates the longitudinal evolution of the immune cell landscape under tacrolimus-based immunosuppressive treatment during LT recovery, providing a four-phase framework that aids the clinical management of LT patients.

In this study, oral supplementation of stachyose significantly improved HFD-induced MetS symptom, including overweight, hyperlipidemia, hepatic steatosis and system-wide inflammation. The subsequent analysis revealed that stachyose supplement significantly enhanced the integrity of the intestinal epithelial barrier and effectively reversed the gut microbiota dysbiosis, as evidenced by improvements in gut microbial gene richness, microbiota composition, and functional characteristics. The abundance of butyrate-producing strains, such as Bacteroides faecis, Butyomonas faecalis, Parabacteroides distasonis and Phocaeicola coprophilus is significantly increased, concurrently with the activation of the PPAR-γ signaling pathway. The findings of our study suggest that stachyose exhibits potential as a prebiotic agent for the prevention of gut microbiota dysbiosis and the intestinal epithelial barrier disruption in obese. The results of our study suggest that stachyose demonstrates potential as a prebiotic agent for mitigating gut microbiota dysbiosis and preserving the integrity of the intestinal epithelial barrier in individuals with MetS.

Existing research suggested 300∼600 μm as the optimal pore size range for metallic bone implants. The human bones, however, have numerous pores smaller than 300 μm for bone ingrowth, cell growth and migration, fluid flow, and so forth. The bone implant with such small-sized pores has been rarely manufactured and its property is unclear. In the paper, biodegradable Fe scaffolds of different pore sizes (50 μm, 100 μm, 150 μm, 200 μm, and 300 μm) were fabricated by direct ink writing (DIW) with subsequent sintering. The interconnected pores of all scaffolds are highly precise and have no residual powders. The in-vitro degradation and compression tests were conducted on the scaffolds to evaluate the effect of pore size on degradation and mechanical behaviors, respectively. The results indicate that a decrease in pore size leads to an increase in degradation rate, from 0.0423 ± 0.0014 to 0.0433 ± 0.0035 mm/year, with the exception of the 50 μm scaffolds which exhibit the lowest value of 0.0052 ± 0.0018 mm/year due to clogging by degradation products; meanwhile, both elastic modulus and yield strength rise from 344.8 ± 18.6 MPa to 625.0 ± 52.5 MPa and from 9.5 ± 0.9 MPa to 15.1 ± 0.8 MPa, respectively. The pore size of 100 μm shows the most significant potential for use in Fe bone implants regarding its good degradation and mechanical behaviors. Our work provides new insight into the preferable pore size of metallic bone implants produced by additive manufacturing.

Cervical cancer is a serious threat to women's health globally. Therefore, identifying key molecules associated with cervical cancer progression is essential for drug development, disease monitoring, and precision therapy. Recently, TGF-β (transforming growth factor-beta) has been identified as a promising target for cervical cancer treatment. For advanced cervical cancer, TGF-β participates in tumor development by improving metastasis, stemness, drug resistance, and immune evasion. Accumulating evidence demonstrates that TGF-β blockade effectively improves the therapeutic effects, especially immunotherapy. Currently, agents targeting TGF-β and immune checkpoints such as PD-L1 have been developed and tested in clinical studies. These bispecific antibodies might have the potential as therapeutic agents for cervical cancer treatment in the future.

Background & Aims: Phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the de novo serine synthesis pathway (SSP), has been implicated in the carcinogenesis and metastasis of hepatocellular carcinoma (HCC) because of its excessive expression and promotion of SSP. In previous experiments we found that SSP flux was diminished by knockdown of zinc finger E-box binding homeobox 1 (ZEB1), a stimulator of HCC metastasis, but the underlying mechanism remains largely unknown. Here, we aimed to determine how SSP flux is regulated by ZEB1 and the contribution of such regulation to carcinogenesis and progression of HCC. Methods: We used genetic mice with Zeb1 knockout in liver specifically to determine whether Zeb1 deficiency impacts HCC induced by the carcinogen diethylnitrosamine plus CCl4. We explored the regulatory mechanism of ZEB1 in SSP flux using uniformly-labeled [13C]-glucose tracing analyses, liquid chromatography–mass spectrometry, real-time quantitative polymerase chain reaction, luciferase report assay, and chromatin immunoprecipitation assay. We determined the contribution of the ZEB1–PHGDH regulatory axis to carcinogenesis and metastasis of HCC by cell counting assay, methyl thiazolyl tetrazolium (MTT) assay, scratch wound assay, Transwell assay, and soft agar assay in vitro, orthotopic xenograft, bioluminescence, and H&E assays in vivo. We investigated the clinical relevance of ZEB1 and PHGDH by analyzing publicly available data sets and 48 pairs of HCC clinical specimens. Results: We identified that ZEB1 activates PHGDH transcription by binding to a nonclassic binding site within its promoter region. Up-regulated PHGDH augments SSP flux to enable HCC cells to be more invasive, proliferative, and resistant to reactive oxygen species and sorafenib. Orthotopic xenograft and bioluminescence assays have shown that ZEB1 deficiency significantly impairs the tumorigenesis and metastasis of HCC, and such impairments can be rescued to a large extent by exogenous expression of PHGDH. These results were confirmed by the observation that conditional knockout of ZEB1 in mouse liver dramatically impedes carcinogenesis and progression of HCC induced by diethylnitrosamine/CCl4, as well as PHGDH expression. In addition, analysis of The Cancer Genome Atlas database and clinical HCC samples showed that the ZEB1–PHGDH regulatory axis predicts poor prognosis of HCC. Conclusions: ZEB1 plays a crucial role in stimulating carcinogenesis and progression of HCC by activating PHGDH transcription and subsequent SSP flux, deepening our knowledge of ZEB1 as a transcriptional factor in fostering the development of HCC via reprogramming the metabolic pathway.

Abstract Background Iron overload plays a critical role in the pathogenesis of diabetic nephropathy. Non-invasive evaluation of renal iron overload in diabetes in the management and intervention of diabetic nephropathy is of great significance. This study aimed to explore the feasibility of blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in evaluating renal iron overload in diabetes using a rabbit model. Methods The rabbits were randomly divided into control, iron-overload (I), diabetes (D), and diabetes with iron-overload (DI) groups (each n = 19). The diabetes models were generated by injecting intravenous alloxan solution, and the iron-overload models were generated by injecting intramuscular iron-dextran. BOLD MRI was performed immediately (week 0) and at week 4, 8, and 12 following modeling. The differences in renal cortex (CR2 *) and outer medulla R2 * (MR2 *) and the ratio of MR2 *–CR2 * (MCR) across the different time points were compared. Results Iron was first deposited in glomeruli in the I group and in proximal tubular cells in renal cortex in the D group. In the DI group, there was iron deposition in both glomeruli and proximal tubular cells at week 4, and the accumulation increased subsequently. The degree of kidney injury and iron overload was more severe in the DI group than those in the I and D groups at week 12. At week 8 and 12, the CR2 * and MR2 * in the DI group were higher than those in the I and D groups (all P

Sustained swimming induces beneficial effects on growth and energy metabolism in some fish species. However, the absence of a standardized exercise regimen that guarantees an optimal response to physical activity is due to the anatomical, behavioral, and physiological differences among species, and the different conditions of tests applied, which are especially notable for the early stages of cultured species. The objective of this study was to assess the growth and metabolic responses of European sea bass submitted to continuous and moderate exercise exposure, selecting a practical swimming speed from swimming tests of groups of five fingerlings. The exercise-effects trial was carried out with 600 sea bass fingerlings (3–5 g body weight) distributed in two groups (control: voluntary swimming; exercised: under sustained swimming at 1.5 body lengths·s−1). After 6 weeks, growth parameters and proximal composition of both muscles were not altered by sustained swimming, but an increased synthetic capacity (increased RNA/DNA ratio) and more efficient use of proteins (decreased ΔN15) were observed in white muscle. The gene expression of mitochondrial proteins in white and red muscle was not affected by exercise, except for ucp3, which increased. The increase of UCP3 and Cox4 protein expression, as well as the higher COX/CS ratio of enzyme activity in white muscle, pointed out an enhanced oxidative capacity in this tissue during sustained swimming. In the protein expression of red muscle, only CS increased. All these metabolic adaptations to sustained exercise were also reflected in an enhanced maximum metabolic rate (MMR) with higher aerobic scope (AMS) of exercised fish in comparison to the non-trained fish, during a swimming test. These results demonstrated that moderate sustained swimming applied to sea bass fingerlings can improve the physical fitness of individuals through the enhancement of their aerobic capacities.

Due to technological limitations and budget constraints, spatiotemporal image fusion uses the complementarity of high temporal–low spatial resolution (HTLS) and high spatial–low temporal resolution (HSLT) data to obtain high temporal and spatial resolution (HTHS) fusion data, which can effectively satisfy the demand for HTHS data. However, some existing spatiotemporal image fusion models ignore the large difference in spatial resolution, which yields worse results for spatial information under the same conditions. Based on the flexible spatiotemporal data fusion (FSDAF) framework, this paper proposes a multilevel single-image super-resolution (SISR) method to solve this issue under the large difference in spatial resolution. The following are the advantages of the proposed method. First, multilevel super-resolution (SR) can effectively avoid the limitation of a single SR method for a large spatial resolution difference. In addition, the issue of noise accumulation caused by multilevel SR can be alleviated by learning-based SR (the cross-scale internal graph neural network (IGNN)) and then interpolation-based SR (the thin plate spline (TPS)). Finally, we add the reference information to the super-resolution, which can effectively control the noise generation. This method has been subjected to comprehensive experimentation using two authentic datasets, affirming that our proposed method surpasses the current state-of-the-art spatiotemporal image fusion methodologies in terms of performance and effectiveness.

Abstract Background We aimed to appraise the impact of the changing national childbirth policy since 2002, currently allowing two children per family, on obstetric workload in a regional referral center in China. Methods In a retrospective cohort study, temporal changes were examined in relation with maternal demographics, incidence of women with high risk pregnancies and resource statistics in our hospital in managing singleton viable pregnancies (birth from 28 weeks gestational age onwards) for the period 2005–2017. Results During this 13-year period, the number of singleton livebirths from 28 weeks gestational age onwards was 49,479. Annual numbers of births increased from 1,941 to 2005 to 5,777 in 2017. There were concomitant and significant increases in the incidence of multiparous women (10.6–50.8 %), of age ≥35 years (6.5–24.3 %), with prior caesarean Sec. (2.6–23.6 %), with ≥3 previous pregnancy terminations (1.0–4.9 %), with pre-gestational diabetes (0.2–0.9 %), and with chronic hypertension (0.2–1.2 %). There were associated increases in beds and staff complement and reduced average hospital stay. Nevertheless, while the workload of medical staff remained stable with increasing staff complement, that of midwives increased significantly as reflected by the total births: midwife ratio which increased from 194.1:1 to 320.9:1 (p

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD). Its etiology is unclear. Much evidence suggests that the death of abnormal intestinal epithelial cells (IECs) leads to intestinal barrier disruption, and the subsequent inflammatory response plays a vital role in UC. Pyroptosis is a form of programmed inflammatory cell death, and the role of pyroptosis in UC etiology remains to be explored. This study identified 10 hub genes in pyroptosis by gene expression profiles obtained from the GSE87466 dataset. Meanwhile, the biomarkers were screened based on gene significance (GS) and module membership (MM) through the Weighted Gene Co-Expression Network Analysis (WGCNA). The following analysis indicated that hub genes were closely associated with the UC progression and therapeutic drug response. The single-cell RNA (scRNA) sequencing data from UC patients within the GSE162335 dataset indicated that macrophages were most related to pyroptosis. Finally, the expression of hub genes and response to the therapeutic drug [5-aminosalicylic acid (5-ASA)] were verified in dextran sulfate sodium (DSS)-induced colitis mice. Our study identified IL1B as the critical pyroptosis-related biomarker in UC. The crosstalk between macrophage pyroptosis and IEC pyroptosis may play an essential role in UC, deserving further exploration.

Ulcerative colitis (UC) is an inflammatory bowel disease caused by mucosal immune system disorder, which has increased steadily all over the world. Previous studies have shown that collagen peptide (CP) has various beneficial biological activities, it is not clear whether the effect of CP on UC is positive or negative. In this study, 2.5% dextran sulfate sodium (DSS) was used to establish acute colitis in mice. Our results suggested that CP supplementation (200, 400 mg/kg/day) promoted the progression of colitis, increased the expression of inflammatory factors and the infiltration of colonic lamina propria macrophages. Gut microbiota analysis showed the composition changed significantly and inflammation promoted bacteria was after CP treatment. Meanwhile, the effect of CP on macrophage polarization was further determined in Raw264.7 cell line. The results showed that CP treatment could increase the polarization of M1 macrophages and promote the expression of inflammatory factors. In conclusion, our results showed that CP treatment could disrupt the gut microbiota of host, promote macrophage activation and aggravate DSS-induced colitis. This may suggest that patients with intestinal inflammation should not take marine derived CP.

Cordyceps exopolysaccharide (CEP) has shown emerging potential in adjustment of gut microbiota and immune cell function. In this study, a water-soluble CEP with a molecular weight of 58.14 kDa was extracted from the fermentation broth of Paecilomyces hepiali, an endophytic fungus of Cordyceps sinensis. Our results indicated that Paecilomyces hepiali polysaccharide (PHP) showed significantly preventive potential on dextran sulfate sodium (DSS)-induced colitis in mice, which can prevent colon shortening, reduce intestinal epithelial cell (IEC) destruction, suppress inflammatory cell infiltration, and regulate the balance between regulatory T (Treg) cells and T helper type 17 (Th17) cells. Meanwhile, the disturbed gut microbiota was partially restored after PHP treatment. Further Pearson correlation coefficient analyses exhibited that the alteration of the gut microbiota was significantly related to adjustment of the IEC barrier and Treg/Th17 balance. In conclusion, all findings proposed that purified PHP has the potential to develop into a promising agent for colitis prevention and adjuvant therapy via maintaining intestinal homeostasis of gut microbiota and immune system.

Abstract Background Chinese population has a high prevalence of chronic hepatitis B virus (HBV) infection, the impact of which on pregnancy outcome remains controversial. A single-center retrospective cohort study was performed in Kunming, a multi-ethnic city in south-western China to examine this issue. Methods The singleton pregnancies delivering at ≥28 weeks gestation under our care in 2005–2017 constituted the study cohort. Maternal characteristics and pregnancy outcome were compared between mothers with and without seropositivity for hepatitis B surface antigen (HBsAg) determined at routine antenatal screening. Results Among the 49,479 gravidae in the cohort, the 1624 (3.3%) HBsAg seropositive gravidae had a lower incidence of nulliparity (RR 0.963, 95% CI 0.935–0.992) and having received tertiary education (RR 0.829, 95% CI 0.784–0.827). There was no significant difference in the medical history, pregnancy complications, or labor or perinatal outcome, except that HBV carriers had significantly lower incidence of labor induction (RR 0.827, 95% CI 0.714–0.958) and of small-for-gestational age (SGA) infants (RR 0.854, 95% CI 0.734–0.994). On regression analysis, maternal HBV carriage was independently associated with spontaneous labor (aRR 1.231, 95% CI 1.044–1.451) and reduced SGA infants (aRR 0.842, 95% CI 0.712–0.997). Conclusions Our 3.3% prevalence of maternal HBV infection was around the lower range determined in the Chinese population. The association with spontaneous labor and reduced SGA infants could have helped to promote the perpetuation of the infection through enhanced survival of the offspring infected at birth, thus explaining the high prevalence in the Chinese population.

Summary: Background: Osteoarthritis (OA) is a complex process comprised of mechanical load, inflammation, and metabolic factors. It is still unknown that if chondrocytes undergo ferroptosis during OA and if ferroptosis contribute to the progression of OA. Materials and methods: In our study, we use Interleukin-1 Beta (IL-1β) to simulate inflammation and ferric ammonium citrate (FAC) to simulate the iron overload in vitro. Also, we used the surgery-induced destabilized medial meniscus (DMM) mouse model to induce OA in vivo. We verify ferroptosis by its definition that defined by the Nomenclature Committee on Cell Death with both in vitro and in vivo model. Results: We observed that both IL-1β and FAC induced reactive oxygen species (ROS), and lipid ROS accumulation and ferroptosis related protein expression changes in chondrocytes. Ferrostatin-1, a ferroptosis specific inhibitor, attenuated the cytotoxicity, ROS and lipid-ROS accumulation and ferroptosis related protein expression changes induced by IL-1β and FAC and facilitated the activation of Nrf2 antioxidant system. Moreover, erastin, the most classic inducer of ferroptosis, promoted matrix metalloproteinase 13 (MMP13) expression while inhibited type II collagen (collagen II) expression in chondrocytes. At last, we proved that intraarticular injection of ferrostatin-1 rescued the collagen II expression and attenuated the cartilage degradation and OA progression in mice OA model. Conclusions: In summary, our study firstly proved that chondrocytes underwent ferroptosis under inflammation and iron overload condition. Induction of ferroptosis caused increased MMP13 expression and decreased collagen II expression in chondrocytes. Furthermore, inhibition of ferroptosis, by intraarticular injection of ferrostatin-1, in our case, seems to be a novel and promising option for the prevention of OA. The translational potential of this article: The translation potential of this article is that we first indicated that chondrocyte ferroptosis contribute to the progression of osteoarthritis which provides a novel strategy in the prevention of OA.

Abstract Background Glucocorticoid (GC)-associated osteonecrosis of the femoral head (ONFH) is the most common in non-traumatic ONFH. Despite a strong relationship between GC and ONFH, the detailed mechanisms have remained elusive. Recent studies have shown that GC could directly injure the blood vessels and reduce blood supply in the femoral head. Endothelial progenitor cells (EPCs), which were inhibited quantitatively and functionally during ONFH, play an important role in maintaining the normal structure and function of vascular endothelium. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene that promotes cell apoptosis, and its expression was found to be elevated in GC-associated ONFH patients. However, whether direct inhibition of PTEN attenuates GC-associated apoptosis and dysfunction of the EPCs remains largely unknown. Methods We investigated the effect of, VO-OHpic, a potent inhibitor of PTEN, in attenuating GC-associated apoptosis and dysfunction of EPCs and the molecular mechanism. SD rats were used to study the effect of VO-OHpic on angiogenesis and osteonecrosis in vivo. Results The results revealed that methylprednisolone (MPS) obviously inhibit angiogenesis of EPCs by inducing apoptosis, destroying the normal mitochondrial structure, and disrupting function of mitochondria. VO-OHpic treatment is able to reverse the harmful effects by inhibiting the mitochondrial apoptosis pathway and activating the NF-E2-related factor 2 (Nrf2) signaling. Si-Nrf2 transfection significantly reduced the protective effects of VO-OHpic on EPCs. Our in vivo studies also showed that intraperitoneal injection of VO-OHpic obviously attenuates the osteonecrosis of the femoral head induced by MPS and potently increases the blood supply in the femoral head. Conclusion Taken together, the data suggests that inhibition of PTEN with VO-OHpic attenuates apoptosis and promotes angiogenesis of EPCs in vitro via activating Nrf2 signaling pathway and inhibiting the mitochondrial apoptosis pathway. Moreover, VO-OHpic also mitigates GC-associated ONFH and potentiates angiogenesis in the femoral head.

Over fertilization has resulted in serious soil compaction and acidification, as well as nonpoint pollution. A strategy for variable fertilization according to Site-Specific Management Zones (SSMZ) is urgently needed. We developed an object-oriented method using image segmentation for SSMZ delineation for a farming cooperative founded in 2013 in northeastern China. The method is based on Normalized Difference Vegetation Index (NDVI) during the crop growth period from 2011 to 2016. We analyzed and validated SSMZ results with plant sampling data, NDVI, soil temperature and moisture. The results indicated that (i) SSMZs derived from NDVI and image segmentation enhanced the difference between SSMZs and the homogeneity within SSMZs; (ii) crop dry biomass was consistent with NDVI, and NDVI showed a clear change in the regular SSMZ pattern with terrain variation after 2013; and (iii) SSMZ patterns were mainly affected by different farming practices or by topographic factors before and after the cooperative was founded. This new approach for SSMZ delineation will accelerate the application of precision agriculture in relief areas. If the study results are applied to other areas, the main factors of SSMZ need to be determined because of climate differences as well as specific soil and terrain conditions.

Abstract The emergence of immune checkpoint inhibitors (ICIs), mainly including anti-programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies (mAbs), has shaped therapeutic landscape of some type of cancers. Despite some ICIs have manifested compelling clinical effectiveness in certain tumor types, the majority of patients still showed de novo or adaptive resistance. At present, the overall efficiency of immune checkpoint therapy remains unsatisfactory. Exploring additional immune checkpoint molecules is a hot research topic. Recent studies have identified several new immune checkpoint targets, like lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), and so on. The investigations about these molecules have generated promising results in preclinical studies and/or clinical trials. In this review, we discussed the structure and expression of these newly-characterized immune checkpoints molecules, presented the current progress and understanding of them. Moreover, we summarized the clinical data pertinent to these recent immune checkpoint molecules as well as their application prospects.

Abstract Chimeric antigen receptor T (CAR-T) cell therapy is an emerging and effective cancer immunotherapy. Especially in hematological malignancies, CAR-T cells have achieved exciting results. Two Anti-CD19 CAR-T therapies have been approved for the treatment of CD19-positive leukemia or lymphoma. However, the application of CAR-T cells is obviously hampered by the adverse effects, such as cytokines release syndrome and on-target off-tumor toxicity. In some clinical trials, patients quitted the treatment of CAR-T cells due to life-threatening toxicity. Seeking to alleviate these toxicities or prevent the occurrence, researchers have developed a number of safety strategies of CAR-T cells, including suicide genes, synthetic Notch receptor, on-switch CAR, combinatorial target-antigen recognition, bispecific T cell engager and inhibitory CAR. This review summarized the preclinical studies and clinical trials of the safety strategies of CAR-T cells and their respective strengths and weaknesses.

Abstract Background Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers, which is associated with poor prognosis. Herceptin and other agents targeting HER2 have potent antitumor efficacy in patients with HER2-positive cancers. However, the development of drug resistance adversely impacts the efficacy of these treatments. It is therefore urgent to develop new HER2-targeted therapies. Bispecific antibodies (BsAbs) could guide immune cells toward tumor cells, and produced remarkable effects in some cancers. Methods A BsAb named M802 that targets HER2 and CD3 was produced by introducing a salt bridge and knobs-into-holes (KIHs) packing into the structure. Flow cytometry was performed to determine its binding activity and cytotoxicity. CCK-8, Annexin V/PI staining, western blotting, and ELISA were utilized to study its effect on cell proliferation, apoptosis, the signaling pathways of tumor cells, and the secretion of cytokines by immune cells. Subcutaneous tumor mouse models were used to analyze the in vivo antitumor effects of M802. Results We generated a new format of BsAb, M802, consisting of a monovalent unit against HER2 and a single chain unit against CD3. Our in vitro and in vivo experiments indicated that M802 recruited CD3-positive immune cells and was more cytotoxic than Herceptin in cells with high expression of HER2, low expression of HER2, and Herceptin resistance. Although M802 showed weaker effects than Herceptin on the PI3K/AKT and MAPK pathways, it was more cytotoxic due to its specific recognition of HER2 and its ability to recruit effector cells via its anti-CD3 moiety. Conclusions Our results indicated that M802 exhibited potent antitumor efficacy in vitro and in vivo. M802 retained the function of Herceptin in antitumor signaling pathways, and also recruited CD3-positive immune cells to eliminate HER2-positive tumor cells. Therefore, M802 might be a promising HER2 targeted agent.

Abstract Angiogenesis has always been the topic of major scientific interest in the field of malignant tumors. Nowadays, targeting angiogenesis has achieved success in various carcinomas by several mechanisms, including the use of anti-angiogenic small molecule receptor tyrosine kinase inhibitors (TKIs). The development of TKIs targeting pro-angiogenic receptors, mainly vascular endothelial growth factor receptor (VEGFR) family, have significantly improved the outcome of certain types of cancers, like renal cell carcinoma, hepatocellular carcinoma, and colorectal carcinoma. However, the general response rate is not very satisfactory. The particular toxicity profile and resistance to anti-angiogenic targeted agents are unavoidable, and no specific marker is available to screen responsive patients to TKIs for precision therapy. To date, about 11 anti-angiogenic TKIs with different binding capacities to angiogenic receptor tyrosine kinase have been approved for the treatment of patients with advanced cancers. This review presents all approved anti-angiogenic small molecule receptor TKIs so far with an emphasis on their indications and clinical efficacy. We also discuss the combination between TKIs and immune checkpoint blockade inhibitors based on the most recent exciting outcome in immunotherapy.

The present work aims to study the thermal stability and thermodynamics in the process of synthesizing 1, 3-dimethylurea. The HPLC spectrograms were used to study the impacts of reaction time and temperature on the thermal behaviour of the ammonolysis reaction system. Rate equation of the ammonolysis reaction can be summed up as c(t) = 1016.24*e-(t/47.9403) +16.1935. Thermal stability curve also can be determined. Experimental results revealed that the process of synthesizing 1, 3-dimethylurea was of pseudo-first-order reaction kinetics and k value was 0.0163 min-1. Thermodynamics results indicated that enthalpy was -1.92 kJ/mol, Gibbs free energy was -8.51 J/mol, and entropy was 15.96 J/mol*K. The reaction was an exothermic, spontaneous and entropy increasing process. Based on thermal stability and thermodynamics study, synthesis of 1, 3-dimethylurea was unfavourable at higher temperature as well as long reaction time.

Dye wastewater has complex structures and is difficult to be biodegraded. Three-dimensional electrolysis is advantageous in mass transfer and oxidation degradation ability. In this paper, a continuous flow three-dimensional electrolytic reactor with coconut shell activated carbon as the filling material is established to treat methyl blue dye wastewater. The influence on the dye wastewater treatment by the pH value of the system, the impressed voltage, the concentration of electrolyte, the aeration rate, the electrolysis time and the interactions of the five factors on COD degradation are investigated in the experimental part, and the optimal degradation condition is finally determined. Results show that it not only improved the degradation efficiency of dye wastewater, but also help to energy conservation, emission reduction and sustainable development.

Three-dimensional electrolysis treatment of wastewater has unique advantages in cleanliness and efficiency. This work was aimed at investigating the application of three-dimensional electrolysis in treatment of Crystal Violet (CV) wastewater. Firstly, the five single factors which consist of applied voltage, electrolysis time, electrolyte concentration, pH value in the system and the aeration rate for the impact on reduction efficiency of COD were systematically studied. The influence of these factors on COD degradation and the optimum operation conditions of electrolysis were found. The orthogonal test was carried out to determine the interaction effect of five single factors: electrolysis time > pH > external voltage > electrolyte concentration > aeration rate. The optimal experimental electrolysis conditions were determined: the pH was 5, the voltage was 14 V, aeration rate was 50 L/h, Na2SO4 electrolyte concentration was 0.15 mol/L, and the electrolysis time was 120 min. Since CV wastewater is common in printing and dyeing industry, this study highlights the potential of the three-dimensional treatment in wastewater treatment. This method has great advantages in both energy saving and high efficiency.

Background: Interaction between cancer cells with microenvironment is essential for cancer progression, therapeutic resistance and prognosis. Chemokine CXCL1 shows variable roles in the development of cancers. DACH1 has been considered as a tumor suppressor and represses the expressions of several chemokines. The relationship between CXCL1 and DACH1 in non-small cell lung cancer (SCLC) deserves further investigation.Methods: Immunohistochemistry staining was performed on tumor tissue microarrays from lung cancer patients to detect CXCL1 protein. The CXCL1 concentration in the serum of adenocarcinoma patients was measured by ELISA. The CXCL1 protein secreted by cancer cell lines was detected by SearchLight proteome array and human cytokine antibody array. The meta-analysis of CXCL1 expression form public databases was performed and correlation between CXCL1 and DACH1 was analyzed. Moreover, the association between clinicopathological features and prognosis with CXCL1 and DACH1 was analyzed by tissue array and KM-plotter from public database.Results: The protein abundance of CXCL1 in lung cancer tissues was significantly higher than that in adjacent normal tissues. CXCL1 was closely related to TNM stage, tumor size, and lymph node metastasis and predicted worse overall survival in adenocarcinoma. The level of CXCL1 in the peripheral blood of adenocarcinoma patients also significantly elevated and positively related with clinical stage. The meta-analysis demonstrated that CXCL1 mRNA level was increased in lung cancer tissues and high level of CXCL1 indicated tumor progression in lung adenocarcinoma. In addition, public database analyses showed that CXCL1 negatively correlated with DACH1. Stable overexpressing DACH1 in cultured lung cancer cells remarkably decreased CXCL1 protein. Moreover, ectopic expression of DACH1 significantly inhibited the expression of CXCL1, Ki67, and cyclin D1 in tumor tissues compared with A549 cells with empty vector. Survival analysis showed that high CXCL1 and low DACH1 indicated poor overall survival and progression-free survival.Conclusion: CXCL1 is closely associated with tumor progression and poor survival. DACH1 significantly inhibits the expression of CXCL1 and indicates good prognosis. Therefore, combined detection of CXCL1 and DACH1 could more precisely predict prognosis of lung adenocarcinoma.

Accurate and timely crop type mapping and rotation monitoring play a critical role in crop yield estimation, soil management, and food supplies. To date, to our knowledge, accurate mapping of crop types remains challenging due to the intra-class variability of crops and labyrinthine natural conditions. The challenge is further complicated for smallholder farming systems in mountainous areas where field sizes are small and crop types are very diverse. This bottleneck issue makes it difficult and sometimes impossible to use remote sensing in monitoring crop rotation, a desired and required farm management policy in parts of China. This study integrated Sentinel-1 and Sentinel-2 images for crop type mapping and rotation monitoring in Inner Mongolia, China, with an extensive field-based survey dataset. We accomplished this work on the Google Earth Engine (GEE) platform. The results indicated that most crop types were mapped fairly accurately with an F1-score around 0.9 and a clear separation of crop types from one another. Sentinel-1 polarization achieved a better performance in wheat and rapeseed classification among different feature combinations, and Sentinel-2 spectral bands exhibited superiority in soybean and corn identification. Using the accurate crop type classification results, we identified crop fields, changed or unchanged, from 2017 to 2018. These findings suggest that the combination of Sentinel-1 and Sentinel-2 proved effective in crop type mapping and crop rotation monitoring of smallholder farms in labyrinthine mountain areas, allowing practical monitoring of crop rotations.

Abstract Immune checkpoint inhibitor induces tumor rejection by activated host immune system. The anti-tumor immune response consists of capture, presentation, recognition of neoantigen, as well as subsequent killing of tumor cell. Due to the interdependence among this series of stepwise events, neoantigen profoundly influences the efficacy of anti-immune checkpoint therapy. Moreover, the neoantigen-specific T cell reactivity is the cornerstone of multiple immunotherapies. In fact, several strategies targeting neoantigen have been attempted for synergetic effect with immune checkpoint inhibitor. Increasing neoantigen presentation to immune system by oncolytic virus, radiotherapy, or cancer vaccine is feasible to enhance neoantigen-specific T cell reactivity in theory. However, some obstacles have not been overcome in practice such as dynamic variation of neoantigen landscape, identification of potential neoantigen, maintenance of high T cell titer post vaccination. In addition, adoptive T cell transfer is another approach to enhance neoantigen-specific T cell reactivity, especially for patients with severe immunosuppression. In this review, we highlighted the advancements of neoantigen and innovative explorations of utilization of neoantigen repertoire in immune checkpoint blockade therapy.

Abstract Background C-X-C motif ligand 8 (CXCL8), known as a proinflammatory chemokine, exerts multiple effects on the proliferation, invasion, and migration of tumor cells via the autocrine or paracrine manner. Conversely, the human Dachshund homologue 1 (DACH1) is recognized as a tumor suppressor which retards the progression of various cancers. In prostate cancer, it has been demonstrated that DACH1 was negatively correlated with the expression of CXCL8 and able to antagonize the effects of CXCL8 on cellular migration. Herein, we explored the mechanisms by which DACH1 regulated the CXCL8 in non-small cell lung cancer (NSCLC). Methods Public microarray and Kaplan-Meier plotter datasets were analyzed. Blood serum samples from lung adenocarcinoma (ADC) patients were collected for enzyme-linked immunosorbent assay (ELISA) analysis. Immunohistochemical staining was conducted on tissue microarray. Cell lines with stable expression of DACH1 were established, and relative gene expression was measured by Western blot, ELISA, real-time PCR, and human cytokine array. Correspondingly, cell lines transfected with shDACH1 were established, and relative gene expression was measured by real-time PCR and immunofluorescence array. Functional studies were performed by transwell and xenograft mice models. Luciferase reporter gene assay was applied to measure the regulation of DACH1 on CXCL8. Results Our study indicated that CXCL8 both at the mRNA and protein level was associated with the high tumor burden of ADC. Correlational analyses in ADC cell lines and ADC tissues showed that DACH1 was inversely correlated with CXCL8. Meanwhile, patients with high DACH1 expression and low CXCL8 expression had prolonged time to death and recurrence. Moreover, we verified the inhibitory effects of DACH1 on CXCL8 both in vitro and in vivo. Mechanism studies proved that DACH1 transcriptionally repressed CXCL8 promoter activity through activator protein-1 (AP-1) and nuclear transcription factor-kappa B (NF-κB) sites. Conclusions Our study proved that CXCL8 acted as an unfavorable factor promoting to tumor progression and poor prognosis of ADC, while DACH1 antagonized CXCL8 to provide a favorable survival of ADC patients. Double detection of DACH1 and CXCL8 may provide a precise information for further evaluating the prognosis of ADC patients.

Abstract Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.

Abstract Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.

Abstract HER2-targeted immunotherapy consists of monoclonal antibodies (e.g. trastuzumab, pertuzumab), bispecific antibodies (e.g. MM-111, ertumaxomab) and activated T cells armed with anti-HER2 bispecific antibody (HER2Bi-aATC). Trastuzumab is a classic drug for the treatment of HER2 positive metastatic breast cancer. The combined application of pertuzumab, trastuzumab and paclitaxel has been suggested as a standard therapy for HER2 positive advanced breast cancer. The resistance to anti-HER2 antibody has resulted in disease progression. HER2-directed bispecific antibody may be a promising therapeutic approach for these patients. Ertumaxomab enhanced the interaction of immune effector cells and tumor cells. MM-111 simultaneously binds to HER2 and HER3 and blocks downstream signaling. Besides, HER2Bi-aATC is also an alternative therapeutic approach for HER2 positive cancers. In this review, we summarized the recent advancement of HER2-targeted monoclonal antibodies (trastuzumab, pertuzumab and T-DM1) and bispecific antibodies (MM-111, ertumaxomab and HER2Bi-aATC), especially focus on clinical trial results.

Abstract Cancer immunotherapy is the most exciting advancement in cancer therapy. Similar to immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T), bispecific antibody (BsAb) is attracting more and more attention as a novel strategy of antitumor immunotherapy. BsAb not only offers an effective linkage between therapeutics (e.g., immune effector cells, radionuclides) and targets (e.g., tumor cells) but also simultaneously blocks two different oncogenic mediators. In recent decades, a variety of BsAb formats have been generated. According to the structure of Fc domain, BsAb can be classified into two types: IgG-like format and Fc-free format. Among these formats, bispecific T cell engagers (BiTEs) and triomabs are commonly investigated. BsAb has achieved an exciting breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. In this review, we focus on the preclinical experiments and clinical studies of epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor (HER) family, carcinoembryonic antigen (CEA), and prostate-specific membrane antigen (PSMA) related BsAbs in solid tumors, as well as discuss the challenges and corresponding approaches in clinical application.

Abstract Dachshund homolog 1 (DACH1), a key cell fate determination factor, contributes to tumorigenesis, invasion, metastasis of human breast neoplasm. However, the exact molecular mechanisms for the anti-tumor roles of DACH1 in breast carcinoma are still lack of extensive understanding. Herein, we utilized immunohistochemistry (IHC) staining and public microarray data analysis showing that DACH1 was higher in normal breast, low-grade and luminal-type cancer in comparison with breast carcinoma, high-grade and basal-like tumors respectively. Additionally, both correlation analysis of public databases of human breast carcinoma and IHC analysis of mice xenograft tumors demonstrated that DACH1 inversely related to cancer stem cells (CSCs) markers, epithelial-mesenchymal transition (EMT) inducers and basal-enriched molecules, while cluster of differentiation 44 (CD44) behaved in an opposite manner. Furthermore, mice transplanted tumor model indicated that breast cancer cells Met-1 with up-regulation of DACH1 were endowed with remarkably reduced potential of tumorigenesis. Importantly, meta-analysis of 19 Gene Expression Omnibus (GEO) databases of breast cancer implicated that patients with higher DACH1 expression had prolonged time to death, recurrence and metastasis, while CD44 was a promising biomarker predicting worse overall survival (OS) and metastasis-free survival (MFS). Collectively, our study indicated that CD44 might be a novel target of DACH1 in breast carcinoma.

Abstract Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.

Abstract The chimeric antigen receptor T (CAR-T) cell therapy is a newly developed adoptive antitumor treatment. Theoretically, CAR-T cells can specifically localize and eliminate tumor cells by interacting with the tumor-associated antigens (TAAs) expressing on tumor cell surface. Current studies demonstrated that various TAAs could act as target antigens for CAR-T cells, for instance, the type III variant epidermal growth factor receptor (EGFRvIII) was considered as an ideal target for its aberrant expression on the cell surface of several tumor types. CAR-T cell therapy has achieved gratifying breakthrough in hematological malignancies and promising outcome in solid tumor as showed in various clinical trials. The third generation of CAR-T demonstrates increased antitumor cytotoxicity and persistence through modification of CAR structure. In this review, we summarized the preclinical and clinical progress of CAR-T cells targeting EGFR, human epidermal growth factor receptor 2 (HER2), and mesothelin (MSLN), as well as the challenges for CAR-T cell therapy.

While most land use and land cover (LULC) studies have focused on modeling, change detection and driving forces at the class or categorical level, few have focused on the subclass level, especially regarding the quality change within a class such as farmland. The concept of nondominant farmland area (NAF) is proposed in this study to assess within class variability and quantify farmland areas where poor environmental conditions, unsuitable natural factors, natural disasters or unsustainable management practices lead to poor crop growth and thus low yield. A 17-year (2000–2016) time series of the Normalized Difference Vegetation Index (NDVI) was used to develop a NAF extraction model with abnormal features in the NDVI curves and subsequently applied to Heilongjiang province in China. The NAF model was analyzed and assessed from three aspects: agricultural disasters, soil types and medium- and low-yield fields, to determine dominant factors of the NAF patterns. The results suggested that: (1) the NAF model was able to extract a variety of NAF types with an overall accuracy of ~80%. The NAF area accumulated more than 8 years in 17 years is 6.20 thousand km2 in Heilongjiang Province, accounting for 3.75% of the total cultivated land area; (2) the NAF had significant spatial clustering characteristics and temporal variability. 53.24% of the NAF accumulated more than 8 years in 17 years is mainly concentrated in the west of Heilongjiang Province. The inter-annual NAF variability was related with meteorological variations, topography and soil properties; and (3) the spatial and temporal NAF patterns seem to reflect a cumulative impact of meteorological disasters, poor farmland quality, and soil degradation on crop growth. The determinant factors of the observed NAF patterns differed across regions, and must be interpreted in the local context of topography, soil properties and meteorological environment. Spatial and temporal NAF variability could provide useful, diagnostic information for precision farmland management.

Objective To evaluate the associations between dietary fiber intake and ovarian cancer risk. Methods A literature survey was conducted by searching the PubMed, Web of Science, and Wanfang Med Online databases up to March 1st, 2018. The effect of dietary fiber intake on ovarian cancer risk was evaluated by calculating relative risks with 95% confidence intervals (95%CI) using Stata 12.0 software. Results A total of 17 articles with 149,177 participants including 7609 ovarian cancer patients were included in this analysis. The summarized relative risk for ovarian cancer in participants with the highest compared with the lowest fiber intake was 0.760 (95%CI=0.702–0.823), with no significant between-study heterogeneity ( I 2 =12.4%). Subgroup analysis according to study design demonstrated positive associations in both cohort studies and case-control studies. Moreover, the results were consistent among populations from America, Europe, and Asia. No publication bias was found by Egger’s test or funnel plots. Conclusion This meta-analysis concluded that a high intake of dietary fiber could significantly reduce the risk of ovarian cancer compared with a low fiber intake.

Immunotolerance is one of the hallmarks of malignant tumors. Tumor cells escape from host immune surveillance through various mechanisms resulting in tumor progression and therapeutic resistance. Interlukin-6 is a proinflammatory cytokine involved in many physiological and pathological processes by integrating with multiple intracellular signaling pathways. Aberrant expression of interlukin-6 is associated with the growth, metastasis, and chemotherapeutic resistance in a wide range of cancers. Interlukin-6 exerts immunosuppressive capacity mostly by stimulating the infiltrations of myeloid-derived suppressor cells, tumor-associated neutrophils, and cancer stem-like cells via Janus-activated kinase/signal transducer and activator of transcription 3 pathway in tumor microenvironment. On this foundation, blockage of interlukin-6 signal may provide potential approaches to novel therapies. In this review, we introduced interlukin-6 pathways and summarized molecular mechanisms related to interlukin-6-induced immunosuppression of tumor cell. We also concluded recent clinical studies targeting interlukin-6 as an immune-based therapeutic intervention in patients with cancer.

OBJECTIVE: To retrospectively evaluate whether T2*-weighted imaging can be used to grade clear cell renal cell carcinomas (ccRCC) based on intratumoral susceptibility signals (ISSs). MATERIALS AND METHODS: MR imaging from 37 patients with pathologically-proven ccRCCs was evaluated. ISSs on T2*WI were classified as linear or conglomerated linear structures (type I) and dot-like or patchy foci (type II). Two radiologists assessed the likelihood of the presence of ISS, dominant structure of ISS and ratio of ISS area to tumor area. Results were analyzed by nonparametric Mann-Whitney test. RESULTS: ISSs were seen in all patients except for four patients with low-grade ccRCCs and two patients with high-grade ccRCCs. There was no significant difference of the likelihood of the presence of ISS between low- and high-grade ccRCCs. More type I ISSs and less type II ISSs were predictive of low-grade tumors, whereas more conspicuity type II ISSs correlated with higher occurrence of high-grade tumors (P