The bone microenvironment invigorates metastatic seeds for further dissemination.

Metastasis has been considered as the terminal step of tumor progression. However, recent genomic studies suggest that many metastases are initiated by further spread of other metastases. Nevertheless, the corresponding pre-clinical models are lacking, and underlying mechanisms are elusive. Using several approaches, including parabiosis and an evolving barcode system, we demonstrated that the bone microenvironment facilitates breast and prostate cancer cells to further metastasize and establish multi-organ secondary metastases. We uncovered that this metastasis-promoting effect is driven by epigenetic reprogramming that confers stem cell-like properties on cancer cells disseminated from bone lesions. Furthermore, we discovered that enhanced EZH2 activity mediates the increased stemness and metastasis capacity. The same findings also apply to single cell-derived populations, indicating mechanisms distinct from clonal selection. Taken together, our work revealed an unappreciated role of the bone microenvironment in metastasis evolution and elucidated an epigenomic reprogramming process driving terminal-stage, multi-organ metastases.

Siglec-15/sialic acid axis as a central glyco-immune checkpoint in breast cancer bone metastasis.

Immunotherapy is a promising approach for treating metastatic breast cancer (MBC), offering new possibilities for therapy. While checkpoint inhibitors have shown great progress in the treatment of metastatic breast cancer, their effectiveness in patients with bone metastases has been disappointing. This lack of efficacy seems to be specific to the bone environment, which exhibits immunosuppressive features. In this study, we elucidate the multiple roles of the sialic acid-binding Ig-like lectin (Siglec)-15/sialic acid glyco-immune checkpoint axis in the bone metastatic niche and explore potential therapeutic strategies targeting this glyco-immune checkpoint. Our research reveals that elevated levels of Siglec-15 in the bone metastatic niche can promote tumor-induced osteoclastogenesis as well as suppress antigen-specific T cell responses. Next, we demonstrate that antibody blockade of the Siglec-15/sialic acid glyco-immune checkpoint axis can act as a potential treatment for breast cancer bone metastasis. By targeting this pathway, we not only aim to treat bone metastasis but also inhibit the spread of metastatic cancer cells from bone lesions to other organs.

Evaluation of altered starch mutants and identification of candidate genes responsible for starch variation in wheat.

BACKGROUND: Induction of mutation through chemical mutagenesis is a novel approach for preparing diverse germplasm. Introduction of functional alleles in the starch biosynthetic genes help in the improvement of the quality and yield of cereals. RESULTS: In the present study, a set of 350 stable mutant lines were used to evaluate dynamic variation of the total starch contents. A megazyme kits were used for measuring the total starch content, resistant starch, amylose, and amylopectin content. Analysis of variance showed significant variation (p < 0.05) in starch content within the population. Furthermore, two high starch mutants (JE0173 and JE0218) and two low starch mutants (JE0089 and JE0418) were selected for studying different traits. A multiple comparison test showed that significant variation in all physiological and morphological traits, with respect to the parent variety (J411) in 2019-2020 and 2020-2021. The quantitative expression of starch metabolic genes revealed that eleven genes of JE0173 and twelve genes of JE0218 had consistent expression in high starch mutant lines. Similarly, in low starch mutant lines, eleven genes of JE0089 and thirteen genes of JE0418 had consistent expression in all stages of seed development. An additional two candidate genes showed over-expression (PHO1, PUL) in the high starch mutant lines, indicating that other starch metabolic genes may also contribute to the starch biosynthesis. The overexpression of SSII, SSIII and SBEI in JE0173 may be due to presence of missense mutations in these genes and SSI also showed overexpression which may be due to 3-primer_UTR variant. These mutations can affect the other starch related genes and help to increase the starch content in this mutant line (JE0173). CONCLUSIONS: This study screened a large scale of mutant population and identified mutants, could provide useful genetic resources for the study of starch biosynthesis and genetic improvement of wheat in the future. Further study will help to understand new genes which are responsible for the fluctuation of total starch.

Transcriptomics and Selection Pressure Analysis Reveals the Influence Mechanism of PLIN1 Protein on the Development of Small Size in Min Pigs.

Body size is an important biological phenotypic trait that has attracted substantial attention. Small domestic pigs can serve as excellent animal models for biomedicine and also help meet sacrificial culture needs in human societies. Although the mechanisms underlying vertebral development regulating body size variation in domestic pigs during the embryonic period have been well described, few studies have examined the genetic basis of body size variation in post embryonic developmental stages. In this study, seven candidate genes-PLIN1, LIPE, PNPLA1, SCD, FABP5, KRT10 and IVL-significantly associated with body size were identified in Min pigs, on the basis of weighted gene co-expression network analysis (WGCNA), and most of their functions were found to be associated with lipid deposition. Six candidate genes except for IVL were found to have been subjected to purifying selection. PLIN1 had the lowest ω value (0.139) and showed heterogeneous selective pressure among domestic pig lineages with different body sizes (p < 0.05). These results suggested that PLIN1 is an important genetic factor regulating lipid deposition and consequently affecting body size variation in pigs. The culture of whole pig sacrifice in Manchu during the Qing Dynasty in China might have contributed to the strong artificial domestication and selection of Hebao pigs.

Identification of RNA-Binding Protein Targets with HyperTRIBE in Saccharomyces cerevisiae.

As a master regulator in cells, RNA-binding protein (RBP) plays critical roles in organismal development, metabolism and various diseases. It regulates gene expression at various levels mostly by specific recognition of target RNA. The traditional CLIP-seq method to detect transcriptome-wide RNA targets of RBP is less efficient in yeast due to the low UV transmissivity of their cell walls. Here, we established an efficient HyperTRIBE (Targets of RNA-binding proteins Identified By Editing) in yeast, by fusing an RBP to the hyper-active catalytic domain of human RNA editing enzyme ADAR2 and expressing the fusion protein in yeast cells. The target transcripts of RBP were marked with new RNA editing events and identified by high-throughput sequencing. We successfully applied HyperTRIBE to identifying the RNA targets of two yeast RBPs, KHD1 and BFR1. The antibody-free HyperTRIBE has competitive advantages including a low background, high sensitivity and reproducibility, as well as a simple library preparation procedure, providing a reliable strategy for RBP target identification in Saccharomyces cerevisiae.

Acute carbohydrate overfeeding: a redox model of insulin action and its impact on metabolic dysfunction in humans.

A role for fat overfeeding in metabolic dysfunction in humans is commonly implied in the literature. Comparatively less is known about acute carbohydrate overfeeding (COF). We tested the hypothesis that COF predisposes to oxidative stress by channeling electrons away from antioxidants to support energy storage. In a study of 24 healthy human subjects with and without obesity, COF was simulated by oral administration of excess carbohydrates; a two-step hyperinsulinemic clamp was used to evaluate insulin action. The distribution of electrons between oxidative and reductive pathways was evaluated by the changes in the reduction potentials (Eh) of cytoplasmic (lactate, pyruvate) and mitochondrial (ß-hydroxybutyrate, acetoacetate) redox couples. Antioxidant redox was measured by the ratio of reduced to oxidized glutathione. We used cross-correlation analysis to evaluate the relationships between the trajectories of Eh, insulin, glucose, and respiratory exchange during COF. DDIT3 and XBP1s/u mRNA were measured as markers of endoplasmic reticulum stress (ER stress) in adipose tissue before and after COF. Here, we show that acute COF is characterized by net transfer of electrons from mitochondria to cytoplasm. Circulating glutathione is oxidized in a manner that significantly cross-correlates with increasing insulin levels and precedes the decrease in cytoplasmic Eh. This effect is more pronounced in overweight individuals (OW). Markers of ER stress in subcutaneous fat are detectable in OW within 4 h. We conclude that acute COF contributes to metabolic dysfunction through insulin-dependent pathways that promote electron transfer to the cytoplasm and decrease antioxidant capacity. Characterization of redox during overfeeding is important for understanding the pathophysiology of obesity and type 2 diabetes.NEW & NOTEWORTHY Current principles assume that conversion of thermic energy to metabolically useful energy follows fixed rules. These principles ignore the possibility of variable proton uncoupling in mitochondria. Our study shows that the net balance of electron distribution between mitochondria and cytoplasm is influenced by insulin in a manner that reduces proton leakage during overfeeding. Characterization of the effects of insulin on redox balance is important for understanding obesity and insulin resistance.

Study on the correlation between vaginal bleeding in first trimester and preterm birth: A birth cohort study in Lanzhou, China.

OBJECTS: To investigate the correlation between first trimester vaginal bleeding and preterm birth (PB), and to offer suggestions on the perinatal health care and preterm birth prevention. METHODS: A birth cohort study was conducted on 10 179 pregnant women. Unconditional logistic regression model was used to evaluate the associations between vaginal bleeding and preterm birth in sub-preterm groups. RESULTS: Of the 10 179 pregnant women included, a total of 1001 women suffered from vaginal bleeding during the first trimester, of which 119 suffered from PB. Any vaginal bleeding increased the risk of PB. Severe bleeding was a high-risk factor of PB, associated with 4.8-fold risk of very PB, 2.7-fold risk of spontaneous PB without PROM (premature rupture of membrane) and 4.6-fold risk of medical induced PB. Bleeding prolonged more than 1 week increased 66% risk of PB and 36% risk of PB on initial episode happened in 5-12 weeks of gestation age, especially in moderate PB, in medical-induced PB and in spontaneous PB with PPROM (preterm premature rupture of membrane which is one cause of PB). Mild bleeding or bleeding within 1 week or initial episode happened within 4 weeks of gestation age possibly had no influence on PB. CONCLUSION: Vaginal bleeding in the first-trimester was an independent risk factor for PB. The severity, duration and initial time of vaginal bleeding had different effects on different subtypes of PB.

Rickettsia japonica Infections in Humans, Zhejiang Province, China, 2015.

We investigated 16 Japanese spotted fever cases that occurred in southeastern China during September-October 2015. Patients had fever, rash, eschar, and lymphadenopathy. We confirmed 9 diagnoses and obtained 2 isolates with high identity to Rickettsia japonica strain YH. R. japonica infection should be considered for febrile patients in China.

Development of 12 microsatellite markers for Bombina orientails based on RNA-Seq and their usefulness in population genetic diversity.

Bombina orientalis is widely used due to bombesin which isolated from its skin. But in recent years, the population of B. orientalis has become declining distinctly because of human activities, environmental pollution, drought climatic conditions and other factors. In order to provide the molecular basis for the proposal of biodiversity conservation, we report the development of 12 microsatellite markers for B. orientalis based on RNA-Seq. We test polymorphism against in 48 B. orientalis individuals which randomly selected from 182 individuals take advantage of polyacrylamide gel electrophoresis (PAGE). These markers will be useful in the research on the genetic diversity, population genetic structure and other studies. For B. orientalis, all of these loci showed polymorphism, and in line with the H-W equilibrium law. The number of alleles per locus ranged from 3 to 21. The observed and expected heterozygosities ranged from 0.0118 to 0.7795 and from 0.1612 to 0.8703, respectively. The polymorphism information content ranged from 0.153 to 0.857. And the genetic diversity of B. orientalis in Lushui Rivers is significantly higher than that in the Maoer Mountains.

Vigorous-intensity physical activity is associated with metabolic syndrome among the Chinese middle-aged population: a cross-sectional study.

OBJECTIVE: To examine the association and relative contribution of different levels of physical activity (PA) with metabolic syndrome (MS). METHODS: The cluster sampling method was used to recruit 8,750 community-based individuals between 40 and 60 years of age. MS was defined according to the International Diabetes Federation, 2005. PA was estimated with the International Physical Activity Questionnaire, and three levels of PA (low, moderate, vigorous) were used to classify the individuals. The risk factors of MS were comprehensively collected, and logistic regression methods were used to measure the association between PA and MS. Population-attributable risks and their 95% confidence intervals (CI) were calculated based on the regression model. RESULTS: Approximately 30.4% (2,661) of the participants were MS patients. The percentage of individuals with vigorous levels of PA was 46.2% and 43.5% and with low levels of PA was 11.3% and 11.3% in non-MS and MS group, respectively. Individuals with vigorous PA had an odds ratio (OR) of 0.78 (95% CI: 0.66, 0.91) for MS compared with those with low PA, and the OR for individuals with moderate PA was 0.85 (95% CI: 0.73, 1.01). Moderate and vigorous PA levels decreased risk of MS by 18.3%, with approximately 11% of that decrease due to vigorous PA. CONCLUSIONS: Vigorous PA levels were consistently associated with a reduced risk of MS; however, a protective role of moderate PA was not found. The population-attributable risk for vigorous PA was about 11% for all MS risk factors.

Laparoscopic surgery for ectopic pregnancy: A comparative study on the clinical benefits and impact on tubal patency and reproductive outcomes.

BACKGROUND: Ectopic pregnancy is a major contributor to maternal morbidity and mortality across the globe. OBJECTIVE: This study aims to investigate the clinical benefits of laparoscopic surgery in treating ectopic pregnancy, and its impact on tubal patency and reproductive outcomes. METHODS: A clinical study was conducted to compare laparoscopic and medical conservative treatment for ectopic pregnancy. A total of 206 patients were treated for ectopic pregnancy at our hospital from January 2018 to June 2020. Among them, 46 underwent laparoscopic ipsilateral salpingectomy, 54 underwent laparoscopic ipsilateral salpingostomy with lesion removal, and 106 were treated conservatively with medication. RESULTS: The age range and average age of each group are provided, with no significant differences in these general demographic characteristics (p> 0.05). Both the salpingostomy and medication groups had higher rates of ectopic pregnancy compared to the salpingectomy group, with statistically significant differences (p< 0.05). The comparison of ectopic pregnancy rates between the salpingostomy and medication groups showed no significant difference. Within three years, the salpingostomy group had 10 cases of recurrent ectopic pregnancy, with 2 cases on the same side, while the medication group had 18 cases, with 8 cases on the same side. At 3 months after the normalization of blood ß-HCG, the salpingostomy group showed 43 cases of tubal patency (patency rate: 79.63%), while the medication group showed 57 cases (patency rate: 53.77%), with a statistically significant difference between the two groups (p= 0.01). CONCLUSION: Laparoscopic surgery for ectopic pregnancy offers significant clinical benefits over conservative medical treatment, including higher rates of tubal patency and improved reproductive outcomes. These findings support laparoscopic surgery as an effective approach for the management of ectopic pregnancy.

Surfactant-assisted preparation of all-gel-state flexible supercapacitor with remarkable electrochemical performance based on polyaniline-polyacrylamide/sodium alginate hydrogels.

The electrochemical performance of polyaniline-based all-gel-state supercapacitor (AGSSC) is significantly depended on the dispersity and mass loaded of polyaniline (PANI). In this manuscript, inspired by the properties of surfactant, sodium dodecylbenzene sulfonate (SDBS) was introduced to prepare various PANI-polyacrylamide/sodium alginate/SDBS (PANIy-PSSx) AGSSCs. With presence of SDBS, the electrochemical performance of PANIy-PSSx AGSSCs was greatly improved, displaying a trend of initial rise and then decrease with increasing concentration of SDBS from 0 to 0.75 wt%. As the content of SDBS was 0.5 wt%, the resulting PANI1.0-PSS0.5 AGSSC displayed the optimum electrochemical properties with area capacitance and energy density of 913.79 mF/cm2 and 81.23 µWh/cm2, respectively. The capacitance rate of PANI1.0-PSS0.5 AGSSC was still more than 93 % after 2000 cycles of sequential CV scans at the scan rate of 200 mV/s. These data were greatly higher than many reported PANI-based AGSSCs. Moreover, the resultant PANI1.0-PSS0.5 AGSSC could maintain high electrochemical performance even after various operations, such as compression, puncture, fluctuating temperature, bending situations and various voltage windows and series-parallel connections. The resultant PANI1.0-PSS0.5 AGSSC had the wide potentials to satisfy the real application requirements. This study offered a facile strategy for design and preparation of flexible supercapacitor with excellent electrochemical performance.

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

[In vitro heart models simulating in vivo cardiac ischemia-reperfusion injury].

The aim of this study was to compare in vivo and several in vitro cardiac ischemia-reperfusion (I-R) myocardial injury models, and choose a superior in vitro cardiac I-R model. Sprague-Dawley (SD) rats were randomly grouped into in vivo, Langendorff, Langendorff + pacing, and working heart groups. Left anterior descending (LAD) coronary artery was ligated for 60 min and then reperfused for 120 min in in vivo and in vitro rat hearts. Cardiac function and myocardial infarct size were measured by using pressure transducer and TTC/Evans blue double staining, respectively. The results showed that heart rate was greater in in vivo model than those in the three in vitro models. Coronary flows were dropped after LAD ligation and could recover at early phase of releasing LAD ligation in I-R models of the isolated working heart, Langendorff and Langendorff with 300 beats/min of electrical stimulation. Left ventricular end-systolic pressure (LVESP) decreased during ischemia, and partially restored during reperfusion in the three in vitro models. Left ventricular end-diastolic pressure (LVEDP) increased during ischemia in the three in vitro models. LVEDP was significantly higher in the isolated working heart than those in Langendorff models during ischemia, whereafter decreased slowly during reperfusion. LVEDP elevated further in the initiation of reperfusion period and then decreased, but did not recover to normal levels during reperfusion in Langendorff and Langendorff + pacing groups. Left ventricular myocardial infarct size was (60.4 ± 5.4)% in in vivo I-R model, which was significantly higher than that in Langendorff model and the isolated working heart. Notably, there was no significant difference in myocardial infarct size between in vivo model and Langendorff model with electrical stimulation. These results suggest that Langendorff I-R model with 300 beats/min of electrical stimulation can simulate the in vivo I-R myocardial injury.

Identification of New Prognostic Genes and Construction of a Prognostic Model for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is a rapidly progressive malignancy, and its mortality rate is very high. In this study, we aimed at finding novel prognosis-related genes and constructing a credible prognostic model to improve the prediction for LUAD patients. Differential gene expression, mutant subtype, and univariate Cox regression analyses were conducted with the dataset from the Cancer Genome Atlas (TCGA) database to screen for prognostic features. These features were employed in the following multivariate Cox regression analysis and the produced prognostic model included the stage and expression of SMCO2, SATB2, HAVCR1, GRIA1, and GALNT4, as well as mutation subtypes of TP53. The exactness of the model was confirmed by an overall survival (OS) analysis and disease-free survival (DFS) analysis, which indicated that patients in the high-risk group had a poorer prognosis compared to those in the low-risk group. The area under the receiver operating characteristic curve (AUC) was 0.793 in the training group and 0.779 in the testing group. The AUC of tumor recurrence was 0.778 in the training group and 0.815 in the testing group. In addition, the number of deceased patients increased as the risk scores raised. Furthermore, the knockdown of prognostic gene HAVCR1 suppressed the proliferation of A549 cells, which supports our prognostic model that the high expression of HAVCR1 predicts poor prognosis. Our work created a reliable prognostic risk score model for LUAD and provided potential prognostic biomarkers.

The enhanced generation of motor neurons from mESCs by MgAl layered double hydroxide nanoparticles.

The committed differentiation of stem cells into neurons is a promising therapeutic strategy for neurological diseases. Predifferentiation of transplanted stem cells into neural precursors could enhance their utilization and control the direction of differentiation. Embryonic stem cells with totipotency can differentiate into specific nerve cells under appropriate external induction conditions. Layered double hydroxide (LDH) nanoparticles have been proven to regulate the pluripotency of mouse ESCs (mESCs), and LDH could be used as carrier in neural stem cells for nerve regeneration. Hence, we sought to study the effects of LDH without loaded factors on mESCs neurogenesis in this work. A series of characteristics analyses indicated the successful construction of LDH nanoparticles. LDH nanoparticles that may adhere to the cell membranes had insignificant effect on cell proliferation and apoptosis. The enhanced differentiation of mESCs into motor neurons by LDH was systematically validated by immunofluorescent staining, quantitative real-time PCR analysis and western blot analysis. In addition, transcriptome sequencing analysis and mechanism verification elucidated the significant regulatory roles of focal adhesion signaling pathway in the enhanced mESCs neurogenesis by LDH. Taken together, the functional validation of inorganic LDH nanoparticles promoting motor neurons differentiation provide a novel strategy and therapeutic prospect for the clinical transition of neural regeneration.

EVs-mediated delivery of CB2 receptor agonist for Alzheimer's disease therapy.

Alzheimer's disease (AD) is a typical neurodegenerative disease that leads to irreversible neuronal degeneration, and effective treatment remains elusive due to the unclear mechanism. We utilized biocompatible mesenchymal stem cell-derived extracellular vesicles as carriers loaded with the CB2 target medicine AM1241 (EVs-AM1241) to protect against neurodegenerative progression and neuronal function in AD model mice. According to the results, EVs-AM1241 were successfully constructed and exhibited better bioavailability and therapeutic effects than bare AM1241. The Morris water maze (MWM) and fear conditioning tests revealed that the learning and memory of EVs-AM1241-treated model mice were significantly improved. In vivo electrophysiological recording of CA1 neurons indicated enhanced response to an auditory conditioned stimulus following fear learning. Immunostaining and Western blot analysis showed that amyloid plaque deposition and amyloid ß (Aß)-induced neuronal apoptosis were significantly suppressed by EVs-AM1241. Moreover, EVs-AM1241 increased the number of neurons and restored the neuronal cytoskeleton, indicating that they enhanced neuronal regeneration. RNA sequencing revealed that EVs-AM1241 facilitated Aß phagocytosis, promoted neurogenesis and ultimately improved learning and memory through the calcium-Erk signaling pathway. Our study showed that EVs-AM1241 efficiently reversed neurodegenerative pathology and enhanced neurogenesis in model mice, indicating that they are very promising particles for treating AD.

Bone Metastasis Initiation Is Coupled with Bone Remodeling through Osteogenic Differentiation of NG2+ Cells.

The bone microenvironment is dynamic and undergoes remodeling in normal and pathologic conditions. Whether such remodeling affects disseminated tumor cells (DTC) and bone metastasis remains poorly understood. Here, we demonstrated that pathologic fractures increase metastatic colonization around the injury. NG2+ cells are a common participant in bone metastasis initiation and bone remodeling in both homeostatic and fractured conditions. NG2+ bone mesenchymal stem/stromal cells (BMSC) often colocalize with DTCs in the perivascular niche. Both DTCs and NG2+ BMSCs are recruited to remodeling sites. Ablation of NG2+ lineage impaired bone remodeling and concurrently diminished metastatic colonization. In cocultures, NG2+ BMSCs, especially when undergoing osteodifferentiation, enhanced cancer cell proliferation and migration. Knockout of N-cadherin in NG2+ cells abolished these effects in vitro and phenocopied NG2+ lineage depletion in vivo. These findings uncover dual roles of NG2+ cells in metastasis and remodeling and indicate that osteodifferentiation of BMSCs promotes metastasis initiation via N-cadherin-mediated cell-cell interaction. SIGNIFICANCE: The bone colonization of cancer cells occurs in an environment that undergoes constant remodeling. Our study provides mechanistic insights into how bone homeostasis and pathologic repair lead to the outgrowth of disseminated cancer cells, thereby opening new directions for further etiologic and epidemiologic studies of tumor recurrences. This article is highlighted in the In This Issue feature, p. 247.

Osteoprogenitor-GMP crosstalk underpins solid tumor-induced systemic immunosuppression and persists after tumor removal.

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting the overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitor (OP) expansion, hematopoietic stem cell dislocation, and CD41- granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41- GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in the hematopoietic program. Importantly, these effects persist post-surgery and continue to impair anti-tumor immunity. Conditional knockout or inhibition of MMP-13 accelerates immune reinstatement and restores the efficacies of immunotherapies. Therefore, tumor-induced systemic effects are initiated by OP-GMP crosstalk that outlasts tumor burden, and additional treatment is required to reverse these effects for optimal therapeutic efficacy.

Dys-psychological Stress Effect on Expressions of P53 and NFκBp65 in Human Ovarian Carcinoma In Vivo.

OBJECTIVE: To investigate the dys-psychological stress effect on the growth of subcutaneous xenotransplanted tumor in nude mice bearing human epithelium ovarian carcinoma, and the influence on P53 and NFκBp65 expressions. METHODS: The subcutaneous tumor xenografts were established by implanting human epithelium ovarian carcinoma tissues into nude mice and the dys-psychological stress model was established with restraint. The mice were randomized into the following four treatment groups with each group six mice respectively: tumor group (group A), normal saline intraperitoneal injection; tumor with stress group (group B), normal saline intraperitoneal injection; tumor therapy group (group C), cisplatin intraperitoneal injection; and tumor therapy with stress group (group D), cisplatin intraperitoneal injection. The expressions of P53 and NFκBp65 in tumor tissues were determined by Western blotting. RESULTS: The expressions of P53 and NFκBp65 in each restraint group were enhanced compared with the control groups (P<0.05). CONCLUSION: The dys-psychological stress may induce the high expressions of P53 and NFκBp65 proteins and further promote tumor growth.