Synthesis and Mechanistic Investigation of an Amphiphilic Polymer in Enhancing Extra-Heavy Oil Recovery via Viscosity Reduction.

When applied to extra-heavy oil, conventional polymer surfactants exhibit poor efficacy in reducing viscosity and have limited adaptability. In this work, a novel amphiphilic polymer named PAADB was prepared by incorporating 2-acryloylamino-2-methyl-1-propanesulfonic acid (AMPS), benzyldimethyl [2-[(1-oxoallyl) zoxy] propyl] ammonium chloride (DML), and poly(ethylene glycol) methyl ether acrylate (BEM) into the main chain of acrylamide through free radical polymerization. PAADB exhibited outstanding interfacial activity, water-phase thickening ability, and emulsifying performance. The critical micelle concentration of PAADB was approximately 2500 mg/L, with a viscosity of 84.69 mPa·s at 50 °C. Additionally, interfacial tension experienced a notable decrease from 46.53 to 14.56 mN/m. At an optimal concentration of 4000 mg/L, PAADB reduced the viscosity of extra-heavy oil by over 92% across various temperatures and by more than 93% for different types of extra-heavy oil. PAADB demonstrated excellent emulsification ability and emulsion stability, effectively dispersing crude oil to create water-in-oil droplets measuring 35.33 µm in size. Meanwhile, molecular dynamics simulations further unveiled the viscosity reduction mechanism of PAADB. The hydrophilic groups within PAADB molecules are regularly distributed on the water interface, while the hydrophobic groups infiltrate the oil molecules to form a stable interfacial film. PAADB and asphaltene spontaneously form a sandwich structure, reducing intermolecular forces and disrupting the interlayer structure of asphaltene molecules. In general, this novel amphiphilic polymer demonstrates broad applicability and potential in extra-heavy oil recovery, providing valuable insights for the development of new heavy oil viscosity reducers (HOVRs).

A new mechanism of antibody diversity: formation of the natural antibodies containing LAIR1 and LILRB1 extracellular domains.

The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with P. falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system's response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.

Analysis of blood methylation quantitative trait loci in East Asians reveals ancestry-specific impacts on complex traits.

Methylation quantitative trait loci (mQTLs) are essential for understanding the role of DNA methylation changes in genetic predisposition, yet they have not been fully characterized in East Asians (EAs). Here we identified mQTLs in whole blood from 3,523 Chinese individuals and replicated them in additional 1,858 Chinese individuals from two cohorts. Over 9% of mQTLs displayed specificity to EAs, facilitating the fine-mapping of EA-specific genetic associations, as shown for variants associated with height. Trans-mQTL hotspots revealed biological pathways contributing to EA-specific genetic associations, including an ERG-mediated 233 trans-mCpG network, implicated in hematopoietic cell differentiation, which likely reflects binding efficiency modulation of the ERG protein complex. More than 90% of mQTLs were shared between different blood cell lineages, with a smaller fraction of lineage-specific mQTLs displaying preferential hypomethylation in the respective lineages. Our study provides new insights into the mQTL landscape across genetic ancestries and their downstream effects on cellular processes and diseases/traits.

Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption.

Inflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.

A pancreatic cancer organoid-in-matrix platform shows distinct sensitivities to T cell killing.

Poor treatment responses of pancreatic ductal adenocarcinoma (PDAC) are in large part due to tumor heterogeneity and an immunosuppressive desmoplastic tumor stroma that impacts interactions with cells in the tumor microenvironment (TME). Thus, there is a pressing need for models to probe the contributions of cellular and noncellular crosstalk. Organoids are promising model systems with the potential to generate a plethora of data including phenotypic, transcriptomic and genomic characterization but still require improvements in culture conditions mimicking the TME. Here, we describe an INTERaction with Organoid-in-MatriX ("InterOMaX") model system, that presents a 3D co-culture-based platform for investigating matrix-dependent cellular crosstalk. We describe its potential to uncover new molecular mechanisms of T cell responses to murine KPC (LSL-KrasG12D/+27/Trp53tm1Tyj/J/p48Cre/+) PDAC cells as well as PDAC patient-derived organoids (PDOs). For this, a customizable matrix and homogenously sized organoid-in-matrix positioning of cancer cells were designed based on a standardized agarose microwell chip array system and established for co-culture with T cells and inclusion of stromal cells. We describe the detection and orthogonal analysis of murine and human PDAC cell populations with distinct sensitivity to T cell killing that is corroborated in vivo. By enabling both identification and validation of gene candidates for T cell resistance, this platform sets the stage for better mechanistic understanding of cancer cell-intrinsic resistance phenotypes in PDAC.

The Role of High Mobility Group Box B-1 in the Prognosis of Colorectal Cancer Based on the Changes in the Intestinal Mucosal Barrier.

Background: To investigate the expression of high mobility group box B-1 (HMGB-1) in patients with colorectal cancer (CRC) and its association with clinicopathological features and prognosis in colorectal carcinoma by combining bioinformatics and clinical data analysis, and to clarify the role of HMGB-1. To examine whether HMGB-1 expression is related to the damage of the intestinal mucosal barrier, and then explore the potential HMGB-1-dependent mechanisms affecting the progression of CRC. Methods: CRC datasets of GSE12945, GSE17536, and GSE17537 from the public gene chip database were screened and downloaded. Clinical information and CRC tissue samples from patients with stage I-III CRC from the hospital were collected. Serum samples of patients were applied by enzyme-linked immunosorbent assay on HMGB-1, and were divided into high and low HMGB-1 expression, which was examined by 16S rDNA sequencing. Immunohistochemistry was performed to examine the relationship between the expression of HMGB-1 and tight junction protein, occludin, tumor necrosis factor-α, and interferon-γ. Results: Based on the Cutoff value of 10.24 ng/mL, the CRC patients were divided into high and low expression groups. In the HMGB-1H patient group, the TNM staging, overall survival, disease-free survival, recurrence, and metastasis were inferior to the HMGB-1L group. The results of 16S rDNA sequencing demonstrated that the Providencia genus was found to be enriched in the HMGB-1L group. Immunohistochemical results showed that HMGB-1 expression was negatively correlated with the expression of ZO-1 and occludin (R = 0.035, R = 0.003, P < .05), but was positively correlated with the expression of TNF-α and IFN-γ (R = 0.016, R = 0.001, P < .05). Conclusion: The survival of CRC patients with positive HMGB-1 expression was significantly shortened, which may be related to the decrease of Rovitensis content, the decreased expression of ZO-1 and occludin, and the increased levels of TNF-α and IFN-γ, which in turn damage the intestinal mucosal barrier, leading to the development of CRC.

Identification of prognostic and diagnostic signatures for cancer and acute myocardial infarction: multi-omics approaches for deciphering heterogeneity to enhance patient management.

Patients diagnosed with cancer face an increased risk of cardiovascular events in the short term, while those experiencing acute myocardial infarction (AMI) have a higher incidence of cancer. Given limitations in clinical resources, identifying shared biomarkers offers a cost-effective approach to risk assessment by minimizing the need for multiple tests and screenings. Hence, it is crucial to identify common biomarkers for both cancer survival and AMI prediction. Our study suggests that monocyte-derived biomarkers, specifically WEE1, PYHIN1, SEC61A2, and HAL, hold potential as predictors for cancer prognosis and AMI. We employed a novel formula to analyze mRNA levels in clinical samples from patients with AMI and cancer, resulting in the development of a new risk score based on expression profiles. By categorizing patients into high-risk and low-risk groups based on the median risk score, we observed significantly poorer overall survival among high-risk patients in cancer cohorts using Kaplan-Meier analysis. Furthermore, calibration curves, decision curve analysis (DCA), and clinical impact curve analyses provided additional evidence supporting the robust diagnostic capacity of the risk score for AMI. Noteworthy is the shared activation of the Notch Signaling pathway, which may shed light on common high-risk factors underlying both AMI and cancer. Additionally, we validated the differential expression of these genes in cell lines and clinical samples, respectively, reinforcing their potential as meaningful biomarkers. In conclusion, our study demonstrates the promise of mRNA levels as biomarkers and emphasizes the significance of further research for validation and refinement.

Comparison of the clinical effects of lamina replantation and screw fixation after laminectomy in the treatment of intraspinal tumours.

INTRODUCTION: Intraspinal tumours are common diseases in neurosurgery and spinal surgery. Due to the fact that most of them are benign tumours, surgical resection is usually effective, and it is also the main treatment for these tumours. To maintain the stability of the spine and to reduce the incidence of kyphosis, pedicle screw fixation is required after traditional laminectomy, but there are many complications. In recent years, tumour resection and laminectomy have become increasingly favoured by clinicians. However, the comparison of the clinical effects of lamina complex replantation and pedicle screw fixation after laminectomy in the treatment of intraspinal tumours is still unknown. This paper systematically compared the two methods from many aspects and discussed their advantages and disadvantages to obtain better clinical guidance. MATERIALS AND METHODS: In this study, a retrospective analysis was conducted to select 58 patients who underwent posterior approach tumour resection in the spinal surgery department of our hospital from January 2017 to January 2020. Among them, 32 patients underwent tumour resection and laminoplasty, and 26 patients underwent tumour resection and screw internal fixation. The age, sex, body mass index (BMI), smoking status, duration of symptoms, operation time, length of hospital stay, postoperative complications, amount of bleeding and other data were summarized, calculated and compared. RESULTS: 1. The age, sex, BMI, smoking status and symptom duration of the two groups were compared. The abovementioned results were not statistically significant. 2. The operation time, hospital stay, postoperative complications, intraoperative bleeding and adjacent segment degeneration (ASD) were counted and compared between the two groups. There was no significant difference in hospital stay or intraoperative bleeding between the two groups; in addition, the operation time, postoperative complications and incidence of ASD were statistically significant. 3. The visual analog scale (VAS) score, Oswestry Disability Index (ODI) score of thoracic and lumbar spines and Neck Disability Index (NDI) score of cervical spine patients in the two groups were counted, and the preoperative and postoperative data, as well as their changes, were counted and compared between groups and within groups. There was no statistical significance between the two groups; moreover, the postoperative scores were all significantly lower than preoperative in the group. 4. According to the spinal cord function ASIA grade, the preoperative, final follow-up and change values of the two groups were counted, and intragroup and intergroup comparisons were made. There was no significant difference between the two groups; in addition, the scores of the final follow-up were significantly higher than preoperative in the group. 5. The spinal mobility was measured and recorded before the operation and at the final follow-up. There was no significant difference between preoperative and postoperative cervical mobility, and there was no statistical significance observed; furthermore, the range of flexion, extension, rotation and lateral bending of the thoracic and lumbar spines in the screw fixation group was significantly lower than that in the lamina replantation group. CONCLUSIONS: Lamina replantation can be used as splendid methods for the treatment of Intraspinal tumour. Lamina replantation can reduce the operation time, as well as reduce the occurrence of postoperative cerebrospinal fluid leakage, iatrogenic spinal stenosis, posterior soft tissue adhesion and ASD. These complications are reduced in comparison to the other mode of management and better preserve the mobility of the spine.

Acupuncture combined with moxibustion mitigates spinal cord injury-induced motor dysfunction in mice by NLRP3-IL-18 signaling pathway inhibition.

BACKGROUND: Spinal cord injury (SCI), which reportedly induces severe motor dysfunction, imposes a significant social and financial burden on affected individuals, families, communities, and nations. Acupuncture combined with moxibustion (AM) therapy has been widely used for motor dysfunction treatment, but the underlying mechanisms remain unknown. In this work, we aimed to determine whether AM therapy could alleviate motor impairment post-SCI and, if so, the potential mechanism. METHODS: A SCI model was established in mice through impact methods. AM treatment was performed in SCI model mice at Dazhui (GV14) and Jiaji points (T7-T12), Mingmen (GV4), Zusanli (ST36), and Ciliao (BL32) on both sides for 30 min once per day for 28 days. The Basso-Beattie-Bresnahan score was used to assess motor function in mice. A series of experiments including astrocytes activation detected by immunofluorescence, the roles of NOD-like receptor pyrin domain-containing-3 (NLRP3)-IL-18 signaling pathway with the application of astrocyte-specific NLRP3 knockout mice, and western blot were performed to explore the specific mechanism of AM treatment in SCI. RESULTS: Our data indicated that mice with SCI exposure exhibited motor dysfunction, a significant decrease of neuronal cells, a remarkable activation of astrocytes and microglia, an increase of IL-6, TNF-α, IL-18 expression, and an elevation of IL-18 colocalized with astrocytes, while astrocytes-specific NLRP3 knockout heavily reversed these changes. Besides, AM treatment simulated the neuroprotective effects of astrocyte-specific NLRP3 knockout, whereas an activator of NLRP3 nigericin partially reversed the AM neuroprotective effects. CONCLUSION: AM treatment mitigates SCI-induced motor dysfunction in mice; this protective mechanism may be related to the NLRP3-IL18 signaling pathway inhibition in astrocytes.

Young donor hematopoietic stem cells revitalize aged or damaged bone marrow niche by transdifferentiating into functional niche cells.

The bone marrow niche maintains hematopoietic stem cell (HSC) homeostasis and declines in function in the physiologically aging population and in patients with hematological malignancies. A fundamental question is now whether and how HSCs are able to renew or repair their niche. Here, we show that disabling HSCs based on disrupting autophagy accelerated niche aging in mice, whereas transplantation of young, but not aged or impaired, donor HSCs normalized niche cell populations and restored niche factors in host mice carrying an artificially harassed niche and in physiologically aged host mice, as well as in leukemia patients. Mechanistically, HSCs, identified using a donor lineage fluorescence-tracing system, transdifferentiate in an autophagy-dependent manner into functional niche cells in the host that include mesenchymal stromal cells and endothelial cells, previously regarded as "nonhematopoietic" sources. Our findings thus identify young donor HSCs as a primary parental source of the niche, thereby suggesting a clinical solution to revitalizing aged or damaged bone marrow hematopoietic niche.

N, N'-methylene bisacrylamide/divinyl benzene based-highly cross-linked hybrid monolithic column: Production and its applications for powerful capture of four chlorophenols.

In this paper, the role of the halogen bond in capillary monolithic column microextraction was explored for the first time. Benzene-1,3,5-tricarbohydrazide (BTH) was synthesized as a functional monomer, N, N'-methylene bisacrylamide (MBA) and divinyl benzene (DVB) were used as cross-linking agents, the hybrid monolithic column of poly (BTH-co-DVB-co-MBA) was prepared using methanol and polyethylene glycol as pore-forming agents and azodiisobutyronitrile as the initiator. Due to the existence of BTH, a large number of nitrogen atoms (Lewis base) were introduced into the monolithic column, which could form a halogen bond with chlorine-containing organic pollutants and enhance its adsorption performance. Based on the monolithic column, a sensitive and environment-friendly solid-phase microextraction technology was studied. The monolithic column was integrated with high-performance liquid chromatography (HPLC) to extract and detect four kinds of chlorophenol in real water samples. Under best conditions, the method showed excellent extraction ability and linearity, with a linear correlation coefficient of 0.9958-0.9987, a low detection limit (LOD) of 0.04-0.23 µg L-1 (S/N = 3), and relative standard deviation (RSD) less than 3.09%. The recovery rate was kept between 87.30% and 123.00%, and the RSD was less than 3.83%, which indicated that the column had powerful capture performance, high precision, and strong anti-matrix interference ability in the real sample, and had potential application value in practical work.

Stellate ganglion block relieves acute lung injury induced by severe acute pancreatitis via the miR-155-5p/SOCS5/JAK2/STAT3 axis.

Acute lung injury (ALI), a prevalent complication of severe acute pancreatitis (SAP), is also a leading contributor to respiratory failure and even death of SAP patients. Here, we intended to investigate the function and mechanism of stellate ganglion block (SGB) in ameliorating SAP-induced ALI (SAP-ALI). We engineered an SAP-ALI model in rats and treated them with SGB. HE staining and the dry and wet method were implemented to evaluate pathological alterations in the tissues and pulmonary edema. The rats serum changes of the profiles of TNF-α, IL-6, IL-1ß, and IL-10 were examined. The profiles of miR-155-5p and SOCS5/JAK2/STAT3 were detected. Functional assays were performed for confirming the role of miR-155-5p in modulating the SOCS5/JAK2/STAT3 pathway in pulmonary epithelial cells. Our findings revealed that SGB vigorously alleviated SAP rat lung tissue damage and lung edema and lessened the generation of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. SGB enhanced SOCS5 expression, hampered miR-155-5p, and suppressed JAK2/STAT3 pathway activation. As evidenced by mechanism studies, miR-155-5p targeted the 3'UTR of SOCS5 and repressed its expression, hence resulting in JAK2/STAT3 pathway activation. During animal trials, we discovered that SGB ameliorated SAP-ALI, boosted SOCS5 expression, and mitigated the levels of pro-inflammatory factors and miR-155-5p in the plasma. In vitro, miR-155-5p overexpression substantially facilitated pulmonary epithelial cell apoptosis, inflammation, and JAK2/STAT3 pathway activation and restrained SOCS5 expression. All in all, our work hinted that SGB could modulate the miR-155-5p/SOCS5/JAK2/STAT3 axis to alleviate SAP-ALI.

Dynamic Trajectory of a Patient-Reported Outcome and Its Associated Factors for Patients with Chronic Heart Failure: A Growth Mixture Model Approach.

Purpose: This study aimed to identify subgroups of chronic heart failure (CHF) patients with distinct trajectories of quality of life (QOL) and to identify baseline characteristics associated with the trajectories. Patients and methods: Two-year, prospective, cohort study including 315 patients with CHF was conducted from July 2017. Information on QOL assessed by CHF-patient-reported outcomes measure (CHF-PROM) was collected at baseline, 6, 12, 18, and 24 months. Demographic and clinical variables were recorded at baseline. Growth mixture model was used to identify distinct trajectories of CHF-PROM and its physical, psychological, social, and therapeutic domains. Single factor analysis was employed to assess the factors associated with development of CHF-PROM over time. Results: Two classes of overall score of CHF-PROM were identified: poorer (14.0%) and better (86.0%). Poorer class tended to be aged, have low diastolic blood pressure, have concomitant atrial fibrillation, diabetes, chronic obstructive pulmonary disease, cancers, and central nervous system diseases, and used nitrates. Three classes of physical scores were identified: unstable-poorer (5.2%), stable-poorer (29.4%) and better (65.4%). Age, NYHA grade, chronic obstructive pulmonary disease, combined with cancers and central nervous system diseases were related to the grouping. Poorer (8.6%) and better (91.4%) classes of psychological scores were identified. Poorer class tended to be female and had concomitant atrial fibrillation. Degenerate class (34.6%) and meliorate class (65.4%) of therapeutic scores were identified. Degenerate class tended to have concomitant chronic obstructive pulmonary disease and use less angiotensin converting enzyme inhibitors. Conclusion: We identified different classes with distinct trajectories of QOL that may help proper evaluate QOL and further improve its status for patients CHF.

Gut Microbiota Alteration Influences Colorectal Cancer Metastasis to the Liver by Remodeling the Liver Immune Microenvironment.

Background/Aims: This study aimed to explore the effect of gut microbiota-regulated Kupffer cells (KCs) on colorectal cancer (CRC) liver metastasis. Methods: A series of in vivo and in vitro researches were showed to demonstrate the gut microbiota and its possible mechanism in CRC liver metastasis. Results: Fewer liver metastases were identified in the ampicillin-streptomycin-colistin and colistin groups. Increased proportions of Parabacteroides goldsteinii, Bacteroides vulgatus, Bacteroides thetaiotaomicron, and Bacteroides uniformis were observed in the colistin group. The significant expansion of KCs was identified in the ampicillin-streptomycin-colistin and colistin groups. B. vulgatus levels were positively correlated with KC levels. More liver metastases were observed in the vancomycin group. An increased abundance of Parabacteroides distasonis and Proteus mirabilis and an obvious reduction of KCs were noted in the vancomycin group. P. mirabilis levels were negatively related to KC levels. The number of liver metastatic nodules was increased in the P. mirabilis group and decreased in the B. vulgatus group. The number of KCs decreased in the P. mirabilis group and increased in the B. vulgatus group. In vitro, as P. mirabilis or B. vulgatus doses increased, there was an opposite effect on KC proliferation in dose- and time-dependent manners. P. mirabilis induced CT26 cell migration by controlling KC proliferation, whereas B. vulgatus prevented this migration. Conclusions: An increased abundance of P. mirabilis and decreased amount of B. vulgatus play key roles in CRC liver metastasis, which might be related to KC reductions in the liver.

ITGA7, CD133, ALDH1 are inter-correlated, and linked with poor differentiation, lymph node metastasis as well as worse survival in surgical cervical cancer.

AIM: Integrin alpha 7 (ITGA7) regulates cancer stemness and metastasis in several malignancies, while its role in cervical cancer is obscure. Therefore, the current study aimed to investigate the correlation among ITGA7, cluster of differentiation 133 (CD133), and aldehyde dehydrogenase isoform 1 (ALDH1), as well as their relation to tumor features and survival in cervical cancer patients. METHODS: A total of 133 surgical cervical cancer patients were enrolled. Tumor ITGA7, CD133, and ALDH1 expressions were determined by immunohistochemistry (IHC). Furthermore, the clinicopathological features, disease-free survival (DFS), and overall survival (OS) were collected. RESULTS: ITGA7 expression positively related to CD133 expression (p = 0.040) and ALDH1 expression (p < 0.001). Besides, ITGA7 (p = 0.001), CD133 (p = 0.016), and ALDH1 (p = 0.009) high expressions linked with poor tumor differentiation; meanwhile, ITGA7 (p = 0.010) and ALDH1 (p = 0.004) high expressions correlated with more prevalence of lymph node metastasis. However, ITGA7, CD133, or ALDH1 expression was not associated with other clinicopathological features. Inspiringly, it was worth noting that ITGA7 (p = 0.009), CD133 (p = 0.041), and ALDH1 (p = 0.035) high expressions predicted unfavorable DFS; meanwhile, both ITGA7 (p = 0.021) and ALDH1 (p = 0.023) high expressions but not CD133 expression (p = 0.169) forecasted exasperated OS. CONCLUSION: ITGA7, CD133, ALDH1 are inter-correlated, and linked with poor differentiation, lymph node metastasis as well as worse survival in surgical cervical cancer.

Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity.

Pancreatic cancer remains largely unresponsive to immune modulatory therapy attributable in part to an immunosuppressive, desmoplastic tumor microenvironment. Here, we analyze mechanisms of cancer cell-autonomous resistance to T cells. We used a 3D co-culture model of cancer cell spheroids from the KPC (LSL-KrasG12D/+ /LSL-Trp53R172H/+ /p48-Cre) pancreatic ductal adenocarcinoma (PDAC) model, to examine interactions with tumor-educated T cells isolated from draining lymph nodes of PDAC-bearing mice. Subpopulations of cancer cells resistant to these tumor-educated T cells were isolated from the in vitro co-culture and their properties compared with sensitive cancer cells. In co-culture with resistant cancer cell subpopulations, tumor-educated T cells showed reduced effector T cell functionality, reduced infiltration into tumor cell spheroids and decreased induction of apoptosis. A combination of comparative transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to dissect the role of differential gene expression and signaling pathways between sensitive and resistant cells. A decreased expression of the chemokine CXCL12 (SDF-1) was revealed as a common feature in the resistant cell subpopulations. Adding back CXCL12 reversed the resistant phenotype and was inhibited by the CXCR4 inhibitor AMD3100 (plerixafor). We conclude that reduced CXCL12 signaling contributes to PDAC subpopulation resistance to T cell-mediated attack.

miR-186-3p attenuates the tumorigenesis of cervical cancer via targeting insulin-like growth factor 1 to suppress PI3K-Akt signaling pathway.

miR-186-3p acts as a tumor suppressor in various cancers. This study aimed to explore the expression levels of miR-186-3p and its role in cervical cancer. We analyzed the effects of miR-186-3p and insulin-like growth factor 1 (IGF1) on the proliferation, invasion, and apoptosis of cervical cancer cells in vitro by regulating the PI3K/Akt signaling pathway. In cervical cancer tissues and cells, miR-186-3p was downregulated, and IGF1 was upregulated. In addition, miR-186-3p inhibited cell proliferation and invasion and enhanced apoptosis of cervical cancer cells. Moreover, our results showed that miR-186-3p inversely regulated the mRNA expression of IGF1 through direct contact. Knockdown of IGF1 reversed the results of miR-186-3p inhibitor in cervical cancer cells. In addition, the PI3K/Akt signaling pathway was activated by the miR-186-3p inhibitor, although partially arrested by IGF1 knockdown. The PI3K/Akt signaling pathway inhibitor suppressed miR-186-3p inhibitor-stimulated cell proliferation in cervical cancer. In conclusion, miR-186-3p inhibits tumorigenesis of cervical cancer by repressing IGF1, which inactivates the PI3K/Akt signaling pathway, implicating miR-186-3p as a potential new target for the treatment of cervical cancer.

Aberrant expression of HIF3A in plasma of patients with non-small cell lung cancer and its clinical significance.

BACKGROUND: Hypoxia-inducible factors (HIFs) have been evaluated in various cancers and diseases. However, the specific role of hypoxia-inducible factor 3 alpha (HIF3A) in non-small cell lung cancer (NSCLC) remains controversial. MATERIALS AND METHODS: We investigated HIF3A mRNA expression in the plasma and tumor tissues of patients with NSCLC and explored its clinical significance. Plasma samples from 103 cases of lung adenocarcinoma (LUAD) and 96 cases of lung squamous cell carcinoma (LUSC), and tumor-adjacent normal tissues from 58 LUAD and 62 LUSC cases were retrospectively evaluated at the No.8 People's Hospital of Qing Dao. HIF3A expression was explored using RT-qPCR. The clinical significance of HIF3A was evaluated in the plasma and tumor tissues using the receiver operating curve (ROC) and the area under the curve (AUC). RESULTS: Hypoxia-inducible factor 3 alpha expression was notably downregulated in the plasma or tumor tissues of patients with LUAD and LUSC, compared with the healthy control group or adjacent normal tissues. Furthermore, HIF3A expression had a significant positive correlation in the plasma and tumor tissues of LUAD and LUSC patients. Meanwhile, the ROC-AUCs achieved a significantly higher range, from 0.84 to 0.93, with the plasma or tumor tissues of NSCLC patients. Thus, HIF3A expression was not only correlated with plasma and tumor tissues, but also showed potential significance in NSCLC. CONCLUSION: Hypoxia-inducible factor 3 alpha is aberrantly detectable in NSCLC patients in the plasma and tumor tissues. HIF3A may be involved in hypoxic responses during the development and occurrence of NSCLC.

MiR-186-3p attenuates tumorigenesis of cervical cancer by targeting IGF1.

BACKGROUND: Mounting evidence in the cancer literature suggests that microRNAs (miRNAs) influence the progression of human cancer cells by targeting protein-coding genes. How insulin-like growth factor 1(IGF1) and miR-186-3p contribute to the development of cervical cancer (CC) remains unclear. This study examined the regulatory roles of miR-186-3p and IGF1 in CC development. METHODS: Gene expression levels were determined by qRT-PCR. Proliferation, migration, and apoptosis of CC and normal cells were determined by MTT, Transwell, and caspase-3 activity assays, respectively. Dual-luciferase reporter activity and RNA pull-down assays were performed to identify the target gene of miR-186-3p. RESULTS: IGF1 was the target of miR-186-3p. The expression of miR-186-3p inhibited cell proliferation and migration abilities of CC cell lines, but induced the apoptosis rate of CC cells. IGF1 could restore the inhibitory effects of miR-186-3p on the proliferation, migration, and apoptosis abilities of CC cells. Experimental results revealed that miR-186-3p could inhibit IGF1 expression, thereby reducing the viability of CC cells. CONCLUSIONS: The data suggest that targeting of IGF1 by miR-186-3p could be crucial in regulating the progression of CC.