Carboxylesterase Activatable Molecular Probe for Personalized Treatment Guidance by Analyte-Induced Molecular Transformation.

Accurate visualization of tumor microenvironment is of great significance for personalized medicine. Here, we develop a near-infrared (NIR) fluorescence/photoacoustic (FL/PA) dual-mode molecular probe (denoted as NIR-CE) for distinguishing tumors based on carboxylesterase (CE) level by an analyte-induced molecular transformation (AIMT) strategy. The recognition moiety for CE activity is the acetyl unit of NIR-CE, generating the pre-product, NIR-CE-OH, which undergoes spontaneous hydrogen atom exchange between the nitrogen atoms in the indole group and the phenol hydroxyl group, eventually transforming into NIR-CE-H. In cellular experiments and in vivo blind studies, the human hepatoma cells and tumors with high level of CE were successfully distinguished by both NIR FL and PA imaging. Our findings provide a new molecular imaging strategy for personalized treatment guidance.

Metformin rejuvenates Nap1l2-impaired immunomodulation of bone marrow mesenchymal stem cells via metabolic reprogramming.

Ageing and cell senescence of mesenchymal stem cells (MSCs) limited their immunomodulation properties and therapeutic application. We previously reported that nucleosome assembly protein 1-like 2 (Nap1l2) contributes to MSCs senescence and osteogenic differentiation. Here, we sought to evaluate whether Nap1l2 impairs the immunomodulatory properties of MSCs and find a way to rescue the deficient properties. We demonstrated that metformin could rescue the impaired migration properties and T cell regulation properties of OE-Nap1l2 BMSCs. Moreover, metformin could improve the impaired therapeutic efficacy of OE-Nap1l2 BMSCs in the treatment of colitis and experimental autoimmune encephalomyelitis in mice. Mechanistically, metformin was capable of upregulating the activation of AMPK, synthesis of l-arginine and expression of inducible nitric oxide synthase in OE-Nap1l2 BMSCs, leading to an increasing level of nitric oxide. This study indicated that Nap1l2 negatively regulated the immunomodulatory properties of BMSCs and that the impaired functions could be rescued by metformin pretreatment via metabolic reprogramming. This strategy might serve as a practical therapeutic option to rescue impaired MSCs functions for further application.

Programmably Controllable Delivery of Metastable Ferrous Ions for Multiscale Dynamic Imaging Guided Photothermal Primed Chemodynamic Therapy.

Metallomodulation cell death strategies are extensively investigated for antitumor therapy, such as cuproptosis, ferroptosis, and chemodynamic therapy (CDT). Undoubtedly, the accurate and specific elevation of metal ions levels in cancer cells is key to boosting their therapeutic index. Herein, a programmably controllable delivery system based on croconium dye (Croc)-ferrous ion (Fe2+ ) nanoprobes (CFNPs) is developed for multiscale dynamic imaging guided photothermal primed CDT. The Croc, with kinds of electron-rich iron-chelating groups, can form the Croc-Fe2+ complex with a precise stoichiometry of 1:1 to steadily maintain the valence state of Fe2+ . The CFNPs can achieve pH-responsive visualization and accurate Fe2+ release in cancerous tissues under the coactivation of "dual-key" stimulation of "acidity and near-infrared (NIR) light". The acidic tumor microenvironment actuates NIR fluorescence/photoacoustic imaging and photothermal properties of CFNPs. Sequentially, under exogenous NIR light, the CFNPs enable in vivo accurate visualization of Croc-Fe2+ complex delivery for photothermal primed Fe2+ release, thus achieving CDT of tumors. By leveraging multiscale dynamic imaging technologies, the complicated spatiotemporal release of Fe2+ is sketched in a programmably controllable manner, and the domino effect of tumor pH level, photothermal effect, and CDT is also revealed, endowing customized feedback of the therapeutic panorama within the disease microenvironment.

CYLD inhibits osteoclastogenesis to ameliorate alveolar bone loss in mice with periodontitis.

Periodontitis is a chronic immune inflammatory disease that can lead to the destruction and loss of the tooth-supporting apparatus. During this process, the balance between bone absorption mediated by osteoclasts and bone formation mediated by osteoblasts is damaged. Consistent with previous studies, we observed that depletion of cylindromatosis (CYLD) resulted in an osteoporotic bone phenotype. However, the effect of CYLD deficiency on periodontitis is undetermined. Here, we investigated whether CYLD affects periodontal tissue homeostasis in experimental periodontitis in Cyld knockout (KO) mice, and we explored the underlying mechanisms. Interestingly, we discovered significant alveolar bone density loss and severely reduced alveolar bone height in Cyld KO mice with experimentally induced periodontitis. We observed increased osteoclast number and activity in both the femurs and alveolar bones, accompanied by the downregulation of osteogenesis genes and upregulation of osteoclastogenesis genes of alveolar bones in ligatured Cyld KO mice. Taken together, our findings demonstrate that the deletion of CYLD in mice plays a vital role in the pathogenesis of periodontal bone loss and suggest that CYLD might exert an ameliorative effect on periodontal inflammatory responses.

Maximum Emission Peak Over 1500 nm of Organic Assembly for Blood-Brain Barrier-Crossing NIR-IIb Phototheranostics of Orthotopic Glioblastoma.

The development of blood-brain barrier (BBB)-crossing phototheranostic agents in second near-infrared window (NIR-II), especially in the range of 1500-1700 nm (NIR-IIb), affords great opportunities for glioblastoma (GBM) management. Herein, an organic assembly (denoted as LET-12) with the maximum absorption peak at 1400 nm and emission peak at 1512 nm with trailing over 1700 nm through the self-assembly of organic small molecule IR-1064 is designed and subsequently decorated with choline and acetylcholine analogs. The LET-12 can effectively cross BBB through the brain's choline-like receptors-mediated transcytosis and accumulated in tumor tissues, thus achieving fluorescence/photoacoustic (FL/PA) duplex imaging of orthotopic GBM with ≈3.0 mm depth and a superior tumor-to-normal tissue signal ratio (20.93 ± 0.59 for FL imaging and 32.63 ± 1.16 for PA imaging, respectively). Owing to its good photothermal conversion ability, the LET-12 also can serve as a photothermal conversion agent, achieving obvious tumor repression of orthotopic murine GBM model after once treatment. The findings indicate that the LET-12 holds great potential for BBB-crossing NIR-IIb phototheranostics of orthotopic GBM. This self-assembly strategy of organic small molecules opens a new avenue for the construction of NIR-IIb phototheranostics.

EGFR-targeted hybrid lipid nanoparticles for chemo-photothermal therapy against colorectal cancer cells.

Antibody-functionalized targeted nanocarriers have shown great-potential for minimizing the chemoresistance and systemic toxicity of cancer chemotherapies. The combination of chemotherapy and photothermal therapy has great potential in improving therapeutic effect. However, cetuximab-modified nanoparticles based lipids for chemo-phototherapy of EGFR overexpressing colorectal carcinoma (CRC) have seldom been investigated. Hence, this study aimed to fabricate cetuximab-conjugated and near infrared (NIR) light-responsive hybrid lipid-polymer nanoparticles (abbreviated as Cet-CINPs) for targeted delivery of irinotecan. Cet-CINPs were prepared with copolymer PLGA and various lipids DSPE-PEG, DSPE-PEG-Mal, lecithin as carriers. Cetuximab was conjugated on the surface of nanoparticles to achieve targeting anti-tumor efficacy. Cet-CINPs were characterized in terms of morphology (spherical), size (119 nm), charge (-27.2 mV), drug entrapment efficiency (43.27 %), and antibody conjugation efficiency (70.87 %). Cet-CINPs showed preferable photothermal response, pH/NIR-triggered drug release behavior, enhanced cellular uptake and ROS level compared with free ICG and CINPs. Meanwhile, in vitro cytotoxicity assay showed that Cet-CINPs with NIR irradiation had a higher cytotoxicity against Lovo cells than non-targeted or non-NIR activated nanoparticles. The IC50 values of Cet-CINPs with NIR irradiation was 22.84 ± 1.11 µM for 24 h and 5.01 ± 1.06 µM for 48 h, respectively. These investigations demonstrate that Cet-CINPs with good tumor-targeting ability and enhanced antitumor activity, are a promising multifunctional nanoplatform for CRC therapy.

Genome-Wide mRNA and Long Non-Coding RNA Analysis of Porcine Trophoblast Cells Infected with Porcine Reproductive and Respiratory Syndrome Virus Associated with Reproductive Failure.

Porcine reproductive and respiratory syndrome (PRRS) is a vertically transmitted reproductive disorder that is typically characterized by miscarriage, premature birth, and stillbirth in pregnant sows after infection. Such characteristics indicate that PRRSV can infect and penetrate the porcine placental barrier to infect fetus piglets. The porcine trophoblast is an important component of the placental barrier, and secretes various hormones, including estrogen and progesterone, to maintain normal pregnancy and embryonic development during pregnancy. It is conceivable that the pathogenic effects of PRRSV infection on porcine trophoblast cells may lead to reproductive failure; however, the underlying detailed mechanism of the interaction between porcine trophoblast (PTR2) cells and PRRSV is unknown. Therefore, we conducted genome-wide mRNA and long non-coding RNA (lncRNA) analysis profiling in PRRSV-infected PTR2. The results showed that 672 mRNAs and 476 lncRNAs were significantly different from the control group after viral infection. Target genes of the co-expression and co-location of differential mRNAs and lncRNAs were enriched by GO (gene ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis, revealing that most of the pathways were involved in cell nutrient metabolism, cell proliferation, and differentiation. Specifically, the estrogen signaling pathway, the PI3K (PhosphoInositide-3 Kinase)-Akt (serine/threonine kinase) signaling pathway, and the insulin secretion related to embryonic development were selected for analysis. Further research found that PRRSV inhibits the expression of G-protein-coupled estrogen receptor 1 (GPER1), thereby reducing estrogen-induced phosphorylation of AKT and the mammalian target of rapamycin (mTOR). The reduction in the phosphorylation of AKT and mTOR blocks the activation of the GPER1- PI3K-AKT-mTOR signaling pathway, consequently restraining insulin secretion, impacting PTR2 cell proliferation, differentiation, and nutrient metabolism. We also found that PRRSV triggered trophoblast cell apoptosis, interrupting the integrity of the placental villus barrier. Furthermore, the interaction network diagram of lncRNA, regulating GPER1 and apoptosis-related genes, was constructed, providing a reference for enriching the functions of these lncRNA in the future. In summary, this article elucidated the differential expression of mRNA and lncRNA in trophoblast cells infected with PRRSV. This infection could inhibit the PI3K-AKT-mTOR pathway and trigger apoptosis, providing insight into the mechanism of the vertical transmission of PRRSV and the manifestation of reproductive failure.

In Vivo Near-Infrared Fluorescence/Ratiometric Photoacoustic Duplex Imaging of Lung Cancer-Specific hNQO1.

Overexpressing human NAD(P)H:quinone oxidoreductase 1 (hNQO1) in lung cancer tissues is deemed to be an attractive biomarker, which is directly connected to cancerous pathological processes. Monitoring of hNQO1 activity is crucial to early diagnosis and prognosis of lung cancer. In this study, an activatable hemi-cyanine dye-based probe (denoted as the LET-10 probe) was synthesized for near-infrared fluorescence (NIRF) and ratiometric photoacoustic (RPA) imaging of hNQO1. LET-10 can realize the NIRF and PA signal opening in the presence of hNQO1. Taking the octabutoxy naphthalocyanine in the LET-10 probe as a built-in reference signal, the LET-10 probe further demonstrated a double-signal self-calibration process for RPA imaging. Finally, the LET-10 probe was successfully applied for NIRF/RPA duplex imaging in the hNQO1-positive A549 lung cancer model, which suggests that the LET-10 probe is a promising tool for in vivo hNQO1 detection, especially for lung cancer diagnosis.

Engineering Molecular Probes for In Vivo Near-Infrared Fluorescence/Photoacoustic Duplex Imaging of Human Neutrophil Elastase.

Early detection of human neutrophil elastase (HNE), the potential biomarker of lung cancer, is crucial for the accurate diagnosis and evaluation of lung cancer. Currently, little progress of HNE-activated probes has been made for in vivo imaging. Herein, assisted by probe-active pocket match engineering, we synthesized a series of near-infrared fluorescence (NIRF) and photoacoustic (PA) duplex imaging probes by conjugating diverse fluorinated amide chains onto hemi-cyanine. Finally, we identified that probe 2 (denoted as LET-8), with the pentafluoroethyl group, is a superior probe to detect HNE with the best selectivity as well as good response ability and thus successfully realized NIRF/PA duplex imaging of HNE activity both in vitro and in vivo.

Cetuximab-decorated and NIR-activated Nanoparticles Based on Platinum(IV)-prodrug: Preparation, Characterization and In-vitro Anticancer Activity in Epidermoid Carcinoma Cells.

Platinum-based drugs are the mainstay of chemotherapy regimens in a clinic, but their use is seriously limited by severe side effects and drug resistance. A cetuximab-decorated drug delivery system can selectively deliver drugs into EGFR-highexpressing cancer cells to prevent the shortcomings of platinum-based chemotherapy. Here, cetuximab-decorated and near-infrared (NIR)-activated nanoparticles based on Pt(IV)-prodrug (abbreviated as Cetuximab-Pt-INPs) was constructed. First, PEGylated Pt(IV)-prodrug was synthesized by a condensation reaction between c,c,t-[Pt(NH3)2Cl2(OOCCH2CH2COOH)(OH)] and MPEG-PLA. Then, Pt(IV)-prodrug and indocyanine green co-encapsulated nanoparticles (Pt-INPs) were prepared through an ultrasonic emulsification method. Finally, Cetuximab-Pt-INPs were obtained by decorating Pt-INPs with cetuximab as a targeting vector. The optimized Cetuximab-Pt-INPs exhibited a spherical core-shell shape of 138.5 ± 0.96 nm. In-vitro cellular uptake and cytotoxicity assays revealed that more Cetuximab-Pt-INPs with NIR irradiation were selectively taken up by A431 cells, thereby leading to higher cytotoxicity. These multifunctional nanoparticles may have promising potential for targeted and effective therapy against EGFR-highexpressing cells of epidermoid carcinoma.

Expression of the CLCA4 Gene in Esophageal Carcinoma and Its Impact on the Biologic Function of Esophageal Carcinoma Cells.

BACKGROUND: Esophageal carcinoma (ESCA) is one of the malignant tumors with a high mortality rate worldwide, which seriously affects people's health. Calcium-activated chloride channel 4 (CLCA4) was reported to be a tumor inhibitor in hepatocellular carcinoma. Nevertheless, the role of CLCA4 in ESCA is still unclear. METHODS: RT-qPCR and western blot assay were used to test the expression pattern of CLCA4 in ESCA tissues and cells. CCK-8 assay was performed to detect the effect of CLCA4 overexpression on cell proliferation in ESCA cells. Transwell assay was used to measure the effect of CLCA4 upregulation on migration and invasion abilities of ESCA cells. Animal experiments were conducted to investigate the role of CLCA4 upregulation in tumor growth in vivo. RESULTS: CLCA4 was significantly reduced in ESCA tissues and correlated with T stage, differentiation, and lymph node metastasis. CLCA4 overexpression was found to inhibit cell proliferation, migration, invasion, and EMT progression in ESCA cells. Moreover, CLCA4 overexpression suppressed tumor growth in vivo. CONCLUSION: CLCA4 was suggested to act as a tumor inhibitor in ESCA and might be a therapeutic target gene for the treatment of patients with ESCA.

Porcine circovirus type 3 capsid protein induces NF-κB activation and upregulates pro-inflammatory cytokine expression in HEK-293T cells.

Porcine circovirus type 3 (PCV3) has been widely detected throughout the world since it was first discovered on pig farms in 2015. PCV3 is closely associated with cardiac and multisystem inflammation, respiratory disease, congenital tremors, myocarditis, diarrhea, encephalitis and neurologic disease, and periarteritis. However, there have been few reports on the relationship between PCV3 and inflammatory pathways. The NF-κB signaling pathway plays an important role in the defense against viral infection. Here, we demonstrate that the capsid protein (Cap) of PCV3 plays a key role in the activation of NF-κB signaling in HEK-293T cells. Furthermore, PCV3 Cap promotes the mRNA expression of the pro-inflammatory cytokines IL6 and TNFα. In addition, PCV3 Cap promotes RIG-I and MDA5 mRNA expression in RIG-like receptor (RLR) signaling and MyD88 mRNA expression in Toll-like receptor (TLR) signaling but does not influence TRIF mRNA expression in TLR signaling. These results show that PCV3 Cap activates NF-κB signaling, possibly through the RLR and the TLR signaling pathways. This work illustrates that PCV3 Cap activates NF-κB signaling and thus may provide a basis for the pathogenesis of PCV3 and the innate immunity of the host.

Survival analysis of patients with tuberculosis and risk factors for multidrug-resistant tuberculosis in Monrovia, Liberia.

We reviewed the records of 337 confirmed cases of tuberculosis patients in Monrovia, the capital of Liberia, 2015. The risk factors affecting the survival and multidrug-resistance of tuberculosis patients were examined. Kaplan-Meier analysis and the log-rank test were used to assess the differences in survival among the patients, while Cox regression model was used for multivariate analysis. The qualitative data was tested with chi-square test in the single factor analysis of multidrug-resistant TB. Multivariate analysis was performed using binary logistic regression analysis. The significance level for all the tests were set at 0.05. The mean period of the follow-up of patients was 10 months. In the 337 patients, 33 (9.8%) died, the 21-month survival rate was 90.2%. The results of multivariate Cox regression analysis show that overcrowding (HR = 7.942, 95% CI 3.258-19.356), former smoking (HR = 3.773, 95% CI 1.601-8.889), current smoking (HR = 3.546, 95% CI 1.195-10.521), multidrug-resistance tuberculosis (HR = 4.632, 95% CI 1.913-11.217) were risk factors for death during anti-tuberculosis treatment in TB patients in Liberia. The results of binary logistic regression analysis show that extra-pulmonary (OR = 2.032, 95% CI 1.133-3.644), family history of TB (OR = 2.387, 95% CI 1.186-4.807) and current smoking (OR = 3.436, 95% CI 1.681-7.027) were risk factors for multidrug-resistant tuberculosis. These results can provide insights on local tuberculosis early intervention, increase public health awareness, and strengthen the control of factors that may affect the survival and multidrug-resistance of tuberculosis patients.

A GdW10@PDA-CAT Sensitizer with High-Z Effect and Self-Supplied Oxygen for Hypoxic-Tumor Radiotherapy.

Anticancer treatment is largely affected by the hypoxic tumor microenvironment (TME), which causes the resistance of the tumor to radiotherapy. Combining radiosensitizer compounds and O2 self-enriched moieties is an emerging strategy in hypoxic-tumor treatments. Herein, we engineered GdW10@PDA-CAT (K3Na4H2GdW10O36·2H2O, GdW10, polydopamine, PDA, catalase, CAT) composites as a radiosensitizer for the TME-manipulated enhancement of radiotherapy. In the composites, Gd (Z = 64) and W (Z = 74), as the high Z elements, make X-ray gather in tumor cells, thereby enhancing DNA damage induced by radiation. CAT can convert H2O2 to O2 and H2O to enhance the X-ray effect under hypoxic TME. CAT and PDA modification enhances the biocompatibility of the composites. Our results showed that GdW10@PDA-CAT composites increased the efficiency of radiotherapy in HT29 cells in culture. This polyoxometalates and O2 self-supplement composites provide a promising radiosensitizer for the radiotherapy field.

Mechanism of Precipitate Microstructure Affecting Fatigue Behavior of 7020 Aluminum Alloy.

The effect of different precipitate microstructures obtained by different heat treatments on fatigue behavior of 7020 aluminum alloy was investigated. The fine Guinier Preston I (GPI) zones in the under-aged alloy can be repeatedly sheared by dislocations produced in cyclic loading, making the fatigue crack initiate difficultly and fatigue crack path propagate tortuously. Fatigue strength and fatigue crack propagation resistance of the alloy with shearable precipitates are much higher than those of the alloy with unshearable precipitates. The peak-aged alloy with continuous grain boundary precipitate (GBP) and narrow precipitate free zone (PFZ) is prone to initiate fatigue cracks and reduce fatigue strength. With the growth of unshearable precipitates, the fatigue strength of the alloy firstly increases and then decreases. Precipitates with moderate size in the over-aged alloy improve the roughness-induced crack closure (RICC) effect. Soft matrix with appropriate width between the precipitates can promote the slip reversibility and relax the crack tip stress. The fatigue strength of the moderately over-aged alloy reaches to 122.1 MPa at 107 cycles of loading, and the fatigue crack growth rate (FCGR) is 35.6% slower than that of the peak-aged alloy at ΔK of 10 MPa·m1/2.

Copious Irrigation Versus Suction Alone During Laparoscopic Appendectomy for Complicated Appendicitis in Adults.

OBJECTIVE: The objective of this study was to determine whether copious irrigation of peritoneal cavity during laparoscopic appendectomy for complicated appendicitis effectively reduces the incidence of postoperative complications and improves the postoperative recovery in adults compared with suction alone. METHODS: In this prospective randomized trial, adult patients with complicated appendicitis were randomized to "irrigation and suction"(IS) group or "suction only"(SO) group. All surgery was performed with a standardized 3-port laparoscopic approach. The IS group received peritoneal irrigation with a minimum of 2000 mL sterile normal saline. The study primary outcomes included wound infection and postoperative intra-abdominal abscess. The study secondary outcomes included duration of operation, first anal exsufflation time, duration of hospital stay and hospital charges. Chi-squared and t-tests were used to analyze the study data. RESULTS: Between January 2015 and June 2016, a total of 260 patients with complicated appendicitis were enrolled in the study. The peritoneal irrigation resulted in a longer operation time (51.6 ± 16.1 vs. 41.5 ± 15.2 min, p <0.001). There was no significant difference in the rate of wound infection between the two groups. However, the patients who received irrigation had a lower postoperative intra-abdominal abscess rate (3.1% vs. 9.2%, p = 0.039), earlier anal exsufflation (25.2 ± 16.5 vs. 30.7 ± 18.1 hr, p = 0.011), shorter hospital stay (10.2 ± 2.5 vs. 12.5 ± 2.8 days, p <0.001) and lower hospital charges (¥14,592 ± 2,251 vs. 16,674 ± 2,163, p <0.001) compared to those received suction alone. CONCLUSIONS: The study findings revealed that copious irrigation of peritoneal cavity during laparoscopic appendectomy could decrease the incidence of postoperative intra-abdominal abscess in adult patients with complicated appendicitis. These patients also had faster postoperative recovery and lower hospital charges.

Greater Omental Milky Spot Examination for Diagnosis of Peritoneal Metastasis in Gastric Cancer Patients.

OBJECTIVE: To evaluate the diagnostic value of cytological greater omental milky spot examination for the diagnosis of peritoneal metastasis in gastric cancer patients. METHODS: A total of 136 patients diagnosed with gastric cancer and without distant metastasis were enrolled in our study. All patients underwent laparoscopy and CH40 suspension liquid dye of peritoneal lymph nodes preoperatively as well as ascites or peritoneal lavage fluid collections and excisions of marked greater omental milky spot tissues perioperatively. RESULTS: According to the laparoscopic results, the patients were divided into T1-T2 stage (n = 56) without and into T3-T4 stage (n = 80) with tumor invasion into the serosal layer. Among the T1-T2-stage patients, tumor cells could be detected in peritoneal lavage fluids in 2 cases, whereas with greater omental milky spot examination, peritoneal metastasis was detected in 8 cases. Among the 80 cases in the T3-T4 stage, tumor cells could be detected in 28 cases via peritoneal lavage cytology and in 43 cases by greater omental milky spot examinations, and 4 cases had cancer cell infiltration also in nonmilky spot omental areas. The statistical analysis showed that the staging accuracy rate of exfoliative cytology examination was superior to that of the laparoscopic exploration (P < .05), but its sensitivity was significantly lower than that obtained with cytological greater omental milky spot examinations (P < .05). CONCLUSIONS: The laparoscopic exploration could make a preliminary diagnosis of peritoneal metastasis via serosal layer invasion detection. For further analyses, cytological examinations of greater omental milky spots were more sensitive than exfoliative cytology.

A propensity score-matched case-control comparative study of laparoscopic and open gastrectomy for locally advanced gastric carcinoma.

PURPOSE: The aim of this study was to compare the surgical and long-term outcomes of laparoscopic and open gastrectomy with radical intent for locally advanced gastric carcinoma in case-controlled patient groups using the propensity score. METHODS: Between January 2009 and December 2014, 389 patients who underwent gastrectomy with radical intent for locally advanced gastric carcinoma were enrolled. These patients were divided into two groups according to the method of operation: the laparoscopy group (patients who underwent laparoscopic gastrectomy) and the open group (patients who underwent open gastrectomy). To correct different demographic and clinical factors in the two groups, a propensity score matching was used at a 1:1 ratio, and, finally, 184 patients were enrolled in this study, 92 patients in each group. Preoperative characteristics, surgical results, and long-term results were analyzed. RESULTS: Preoperative baseline variables were well balanced in both groups. There were no differences of the extent of surgery between the two groups. With the exception of shorter postoperative hospital stay and less blood loss in the laparoscopy group as compared with the open group, there were no significant differences in surgical, pathological, and long-term outcomes. The 5-year overall survival rates were 57% in the laparoscopy group and 50% in the open group (p=0.606). The 5-year disease-free survival rates were 48% in the laparoscopy group and 42% in the open group (p=0.515). CONCLUSION: Laparoscopic gastrectomy for locally advanced gastric carcinoma is safe, and long-term outcomes were comparable to those who underwent open resection.

Identification of early myeloid progenitors as immunosuppressive cells.

Growing evidence suggests that hematopoietic stem/progenitor cells (HSPCs), precursors of mature immune cells, may play a direct role in immunosurveillance. Early myeloid progenitors are the major components of HSPCs and they often undergo extensive expansion in stress as a result of myeloid-biased hematopoiesis. Yet, the precise function of early myeloid progenitors remains unclear. Here we show that during tumor progression, mouse granulocyte/macrophage progenitors (GMPs) but not common myeloid progenitors (CMPs) are markedly expanded within the bone marrow and blood of mice. Interestingly, both GMPs and CMPs freshly isolated from either tumor-bearing or naïve animals are capable of inhibiting polyclonal stimuli- and alloantigen-induced T cell proliferation, with tumor host-derived cells having elevated activities. Strikingly, these early myeloid progenitor cells even display much stronger suppressive capacity than the classical myeloid-derived suppressive cells. Analysis of GMPs indicates that they express iNOS and can secrete high levels of NO. Further studies unusing iNOS specific inhibitors reveal that the immunosuppression of GMPs is, to a large extent, NO-dependent. GMPs can also efficiently induce regulatory T cell development. These studies demonstrate that early myeloid progenitors can act as immunosuppressive cells. This finding provides novel insights into the functional diversity and plasticity of early myeloid progenitor cells.

TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth.

Androgen receptor (AR), a steroid hormone receptor, is critical for prostate cancer growth. However, activation of AR by androgens can also lead to growth suppression and differentiation. Transcriptional cofactors play an important role in this switch between proliferative and anti-proliferative AR target gene programs. Transducin ß-like-related protein 1 (TBLR1), a core component of the nuclear receptor corepressor complex, shows both corepressor and coactivator activities on nuclear receptors, but little is known about its effects on AR and prostate cancer. We characterized TBLR1 as a coactivator of AR in prostate cancer cells and determined that the activation is dependent on both phosphorylation and 19S proteosome. We showed that TBLR1 physically interacts with AR and directly occupies the androgen-response elements of the affected AR target genes in an androgen-dependent manner. TBLR1 is primarily localized in the nucleus in benign prostate cells and nuclear expression is significantly reduced in prostate cancer cells in culture. Similarly, in human tumor samples, the expression of TBLR1 in the nucleus is significantly reduced in the malignant glands compared with the surrounding benign prostatic glands (P<0.005). Stable ectopic expression of nuclear TBLR1 leads to androgen-dependent growth suppression of prostate cancer cells in vitro and in vivo by selective activation of androgen-regulated genes associated with differentiation (e.g. KRT18) and growth suppression (e.g. NKX3-1), but not cell proliferation of the prostate cancer. Understanding the molecular switches involved in the transition from AR-dependent growth promotion to AR-dependent growth suppression will lead to more successful treatments for prostate cancer.