Proton pump inhibitors enhance macropinocytosis-mediated extracellular vesicle endocytosis by inducing membrane v-ATPase assembly.

Besides participating in diverse pathological and physiological processes, extracellular vesicles (EVs) are also excellent drug-delivery vehicles. However, clinical drugs modulating EV levels are still lacking. Here, we show that proton pump inhibitors (PPIs) reduce EVs by enhancing macropinocytosis-mediated EV uptake. PPIs accelerate intestinal cell endocytosis of autocrine immunosuppressive EVs through macropinocytosis, thereby aggravating inflammatory bowel disease. PPI-induced macropinocytosis facilitates the clearance of immunosuppressive EVs from tumour cells, improving antitumor immunity. PPI-induced macropinocytosis also increases doxorubicin and antisense oligonucleotides of microRNA-155 delivery efficiency by EVs, leading to enhanced therapeutic effects of drug-loaded EVs on tumours and acute liver failure. Mechanistically, PPIs reduce cytosolic pH, promote ATP6V1A (v-ATPase subunit) disassembly from the vacuolar membrane and enhance the assembly of plasma membrane v-ATPases, thereby inducing macropinocytosis. Altogether, our results reveal a mechanism for macropinocytic regulation and PPIs as potential modulators of EV levels, thus regulating their functions.

Blockade of CD93 in pleural mesothelial cells fuels anti-lung tumor immune responses.

Background: CD93 reportedly facilitates tumor angiogenesis. However, whether CD93 regulates antitumor immunity remains undeciphered. Methods: Lung tumor tissues, malignant pleural effusions (MPEs) were obtained from lung cancer patients. Blood was obtained from healthy volunteers and lung cancer patients with anti-PD-1 therapy. Furthermore, p53fl/flLSL-KrasG12D, Ccr7-/-, Cd93-/- mice and CD11c-DTR mice were generated. Specifically, EM, NTA and western blotting were utilized to identify Tumor extracellular vesicles (TEVs). EV labeling, detection of EV uptake in vitro and in vivo, degradation of EV proteins and RNAs were performed to detect the role of TEVs in tumor progression. Pleural mesothelial cells (pMCs) were isolated to investigate related signaling pathways. Recombinant proteins and antibodies were generated to test which antibody was the most effective one to increase CCL21a in p-pMCs. RNA-Seq, MiRNA array, luciferase reporter assay, endothelial tube formation assay, protein labeling and detection, transfection of siRNAs and the miRNA mimic and inhibitor, chemotaxis assay, immunohistochemical staining, flow cytometry, Real-time PCR, and ELISA experiments were performed. Results: We show that CD93 of pMCs reduced lung tumor migration of dendritic cells by preventing pMCs from secreting CCL21, thereby suppressing systemic anti-lung tumor T-cell responses. TEV-derived miR-5110 promotes CCL21 secretion by downregulating pMC CD93, whereas C1q, increasing in tumor individuals, suppresses CD93-mediated CCL21 secretion. CD93-blocking antibodies (anti-CD93) inhibit lung tumor growth better than VEGF receptor-blocking antibodies because anti-CD93 inhibit tumor angiogenesis and promote CCL21 secretion from pMCs. Anti-CD93 also overcome lung tumor resistance to anti-PD-1 therapy. Furthermore, lung cancer patients with higher serum EV-derived miR-5193 (human miR-5110 homolog) are more sensitive to anti-PD-1 therapy, while patients with higher serum C1q are less sensitive, consistent with their regulatory functions on CD93. Conclusions: Our study identifies a crucial role of CD93 in controlling anti-lung tumor immunity and suggests a promising approach for lung tumor therapy.

Labor induction in term gravidas with prelabor rupture of membranes and unfavorable cervixes: Oxytocin versus vaginal misoprostol.

OBJECTIVE: To compare maternal and neonatal outcomes between oxytocin and vaginal misoprostol induction in women with term prelabor rupture of membranes (PROM) and unfavorable cervixes. METHODS: In this retrospective study, 589 pregnant women with term singleton fetuses in cephalic presentation, reactive nonstress tests, PROM of 2-24 h duration, Bishop score <6, and no previous uterine surgery were reviewed and divided into oxytocin (n = 301) and misoprostol (n = 288) groups. The primary outcomes were the rate of vaginal delivery and delivery within 24 h. RESULTS: After 24 h of induction, the misoprostol group showed a significantly higher proportion of vaginal delivery (64.6% vs. 49.5%, P < 0.001) and a lower cesarean section delivery rate (11.5% vs. 25.2%, P < 0.001) than the oxytocin group. More primiparas in the misoprostol group achieved vaginal delivery within 24 h than in the oxytocin group (60.5% vs. 45.4%, P = 0.001). Among primiparas, the misoprostol group had a significantly lower cesarean delivery rate (12.6% vs. 27.5%, P < 0.001). CONCLUSION: Vaginal misoprostol induction in term PROM gravidas with unfavorable cervixes was associated with lower cesarean section and higher vaginal delivery rates within 24 h than oxytocin infusion. Vaginal misoprostol and oxytocin infusion had similar maternal and neonatal outcomes.

Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1+ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.

Ursodeoxycholic acid reduces antitumor immunosuppression by inducing CHIP-mediated TGF-ß degradation.

TGF-ß is essential for inducing systemic tumor immunosuppression; thus, blocking TGF-ß can greatly enhance antitumor immunity. However, there are still no effective TGF-ß inhibitors in clinical use. Here, we show that the clinically approved compound ursodeoxycholic acid (UDCA), by degrading TGF-ß, enhances antitumor immunity through restraining Treg cell differentiation and activation in tumor-bearing mice. Furthermore, UDCA synergizes with anti-PD-1 to enhance antitumor immunity and tumor-specific immune memory in tumor-bearing mice. UDCA phosphorylates TGF-ß at T282 site via TGR5-cAMP-PKA axis, causing increased binding of TGF-ß to carboxyl terminus of Hsc70-interacting protein (CHIP). Then, CHIP ubiquitinates TGF-ß at the K315 site, initiating p62-dependent autophagic sorting and subsequent degradation of TGF-ß. Notably, results of retrospective analysis shows that combination therapy with anti-PD-1 or anti-PD-L1 and UDCA has better efficacy in tumor patients than anti-PD-1 or anti-PD-L1 alone. Thus, our results show a mechanism for TGF-ß regulation and implicate UDCA as a potential TGF-ß inhibitor to enhance antitumor immunity.

XELOX doublet regimen versus EOX triplet regimen as first-line treatment for advanced gastric cancer: An open-labeled, multicenter, randomized, prospective phase III trial (EXELOX).

BACKGROUND: There is no consensus on whether triplet regimen is better than doublet regimen in the first-line treatment of advanced gastric cancer (AGC). We aimed to compare the efficacy and safety of oxaliplatin plus capecitabine (XELOX) and epirubicin, oxaliplatin, plus capecitabine (EOX) regimens in treating AGC. METHODS: This phase III trial enrolled previously untreated patients with AGC who were randomly assigned to receive the XELOX or EOX regimen. The primary endpoint was non-inferiority in progression-free survival (PFS) for XELOX as compared with EOX on an intention-to-treat basis. RESULTS: Between April 10, 2015 and August 20, 2020, 448 AGC patients were randomized to receive XELOX (n = 222) or EOX (n = 226). The median PFS (mPFS) was 5.0 months (95% confidence interval [CI] = 4.5-6.0 months) in the XELOX arm and 5.5 months (95% CI = 5.0-6.0 months) in the EOX arm (hazard ratio [HR] = 0.989, 95% CI = 0.812-1.203; Pnon-inferiority = 0.003). There was no significant difference in median overall survival (mOS) (12.0 vs. 12.0 months, P = 0.384) or objective response rate (37.4% vs. 45.1%, P = 0.291) between the two groups. In patients with poorly differentiated adenocarcinoma and liver metastasis, the EOX arm had a significantly longer mOS (P = 0.021) and a trend of longer mPFS (P = 0.073) than the XELOX arm. The rate of grade 3/4 adverse events (AEs) was 42.2% (90/213) in the XELOX arm and 72.5% (156/215) in the EOX arm (P = 0.001). The global health-related quality of life (QoL) score was significantly higher in the XELOX arm than in the EOX arm during chemotherapy. CONCLUSIONS: This non-inferiority trial demonstrated that the doublet regimen was as effective as the triplet regimen and had a better safety profile and QoL as a first-line treatment for AGC patients. However, the triplet regimen might have a survival advantage in patients with poorly differentiated adenocarcinoma and liver metastasis.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastasis from breast cancer: a preliminary report of 4 cases.

BACKGROUND: Breast cancer (BC) has the highest morbidity and the fifth-highest mortality rate among women in China. Peritoneal metastases from BC are rare, and presently, there are no guidelines or international consensus on its treatment. Patients with a prognosis of peritoneal carcinomatosis (PC) have poorer survival rates than patients with other regional metastases from BC. METHODS: Four BC PC patients, who had undergone cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC), participated in this study. Clinicopathologic characteristics and overall survival (OS) data were collected and analyzed. RESULTS: Patients' average age when they underwent CRS + HIPEC was 59.8 years. The average time of CRS + HIPEC was 8.8 h. The median number of resected organ areas was 7. Following CRS + HIPEC, each of the 4 patients survived for 31, 28, 16 and 52 months, respectively. There were no serious adverse events during the perioperative period. CONCLUSIONS: The study examined the detailed process of CRS + HIPEC and found that patients with BC PC may benefit from this treatment. The 4 cases provided evidence that the integrated therapy of CRS + HIPEC is a promising strategy that could improve outcomes for BC PC patients. Further, no serious adverse events (SAEs) occurred during the CRS + HIPEC perioperative period.

Placenta percreta after Strassman metroplasty of complete bicornuate uterus: a case report.

BACKGROUND: A bicornuate uterus often results in infertility. While reconstructive procedures may facilitate pregnancy, spontaneous abortion or serious pregnancy complications may occur. We present a case of a bicornuate uterus with spontaneous conception after Strassman metroplasty; however, life-threatening complications during pregnancy occurred. CASE PRESENTATION: A 38-year-old woman with a history of infertility presented for prenatal care at 6 weeks of gestation. She had conceived spontaneously after four failed in vitro fertilization and embryo transfer (IVF-ET) procedures, Strassman metroplasty for a complete bicornuate uterus, and two postoperative IVF-ET pregnancies that ended in embryo arrest. This pregnancy was uneventful until the patient presented with massive vaginal bleeding at 28 weeks of gestation and was diagnosed with placenta previa and placenta percreta. Bleeding was controlled after emergency Caesarean section and delivery of a healthy neonate. However, severe adhesions were noted as well as a rupture along the metroplasty scar. Two days later, on removal of the intrauterine gauze packing, severe hemorrhage resumed, and the uterus did not respond to oxytocin, hemabate, or carbetocin. Emergency hysterectomy was required. CONCLUSIONS: Reconstructive surgical procedures for complete bicornuate uterus may allow patients to achieve spontaneous pregnancies. However, potential intrapartum complications include placenta implantation and postpartum hemorrhage, and the latter may be exacerbated as the uterus does not contract or respond to oxytocin or prostaglandin drugs. Patients should be counseled on the risks associated with pregnancy after Strassman metroplasty, and clinicians must be aware of potential severe complications.

Emerging Blood-Based Biomarkers for Predicting Response to Checkpoint Immunotherapy in Non-Small-Cell Lung Cancer.

Immune checkpoint inhibitors (ICIs) have brought impressive clinical benefits in a variety of malignancies over the past years, which dramatically revolutionized the cancer treatment paradigm. Monotherapy or in combination with chemotherapy of ICIs targeting programmed death 1/programmed death ligand 1 (PD-L1) has emerged as an alternative treatment for patients with advanced non-small-cell lung cancer (NSCLC). However, constrained by primary or acquired resistance, most patients obtain limited benefits from ICIs and occasionally suffer from severe immune-related adverse events. Moreover, owing to the complexity of the tumor microenvironment and the technical limitations, clinical application of PD-L1 and tumor mutation burden as biomarkers shows many deficiencies. Thus, additional predictive biomarkers are required to further advance the precision of proper patient selection, avoiding the exposure of potential non-responders to unnecessary immunotoxicity. Nowadays, an increasing number of investigations are focusing on peripheral blood as a noninvasive alternative to tissue biopsy in predicting and monitoring treatment outcomes. Herein, we summarize the emerging blood-based biomarkers that could predict the clinical response to checkpoint immunotherapy, specifically in patients with NSCLC.

LncRNA DLX6-AS1 aggravates the development of ovarian cancer via modulating FHL2 by sponging miR-195-5p.

BACKGROUND: Ovarian cancer (OC) is a huge burden on women's lives. Recently, the implication of long non-coding RNAs (lncRNAs) in cancers, including OC, has aroused much attention. The objective of this study was to explore the role and functional mechanism of lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) in OC. METHODS: The expression of DLX6-AS1, miR-195-5p, and four and a half LIM domains protein 2 (FHL2) was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The cell proliferation, apoptosis, migration, and invasion were assessed by cell count kit 8 (CCK-8), flow cytometry and transwell assays, respectively. The protein levels of proliferating cell nuclear antigen (PCNA), cleaved-caspase-3 (C-caspase 3), N-cadherin, Vimentin, E-cadherin and FHL2 were quantified by western blot. The relationship between miR-195-5p and DLX6-AS1 or FHL2 was predicted by bioinformatics tool starBase and verified by luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Xenograft tumor model was established to observe the role of DLX6-AS1 in vivo. RESULTS: DLX6-AS1 and FHL2 were up-regulated in OC tissues and cells, while miR-195-5p was down-regulated. DLX6-AS1 knockdown inhibited proliferation, migration, and invasion but induced apoptosis of OC cells. However, miR-195-5p inhibition reversed these effects. Overexpression of miR-195-5p also depleted proliferation, migration, and invasion but promoted apoptosis of OC cells, while FHL2 overexpression overturned these influences. DLX6-AS1 knockdown blocked tumor growth in vivo. CONCLUSION: DLX6-AS1, as an oncogene in OC, accelerated tumor progression by up-regulating FHL2 via mediating miR-195-5p, suggesting that DLX6-AS1 was a hopeful target for the lncRNA-targeted therapy in OC.

Highly flexible reduced graphene oxide@polypyrrole-polyethylene glycol foam for supercapacitors.

A flexible and free-standing 3D reduced graphene oxide@polypyrrole-polyethylene glycol (RGO@PPy-PEG) foam was developed for wearable supercapacitors. The device was fabricated sequentially, beginning with the electrodeposition of PPy in the presence of a PEG-borate on a sacrificial Ni foam template, followed by a subsequent GO wrapping and chemical reduction process. The 3D RGO@PPy-PEG foam electrode showed excellent electrochemical properties with a large specific capacitance of 415 F g-1 and excellent long-term stability (96% capacitance retention after 8000 charge-discharge cycles) in a three electrode configuration. An assembled (two-electrode configuration) symmetric supercapacitor using RGO@PPy-PEG electrodes exhibited a remarkable specific capacitance of 1019 mF cm-2 at 2 mV s-1 and 95% capacitance retention over 4000 cycles. The device exhibits extraordinary mechanical flexibility and showed negligable capacitance loss during or after 1000 bending cycles, highlighting its great potential in wearable energy devices.

Clinical efficacy and safety of apatinib combined with S-1 in advanced esophageal squamous cell carcinoma.

Background Esophageal cancer is a very common malignant tumor in China, especially esophageal squamous cell carcinoma (ESCC), but there is currently no effective treatment for patients after first-line chemotherapy failure. Apatinib has shown promising outcomes in treatment with various solid tumors. Objectives To evaluate the clinical efficacy and safety of apatinib combined with S-1 in the treatment of advanced ESCC patients after first-line chemotherapy failure. Methods In this prospective study, fifteen patients with advanced ESCC who failed first-line chemotherapy were enrolled from Nov 2016 to Apr 2019. Patients received the combination therapy with apatinib (250-500 mg, once daily) plus S-1 (40-60 mg based on body surface area, twice daily). Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), disease control rate (DCR) and objective response rate (ORR). Adverse events (AEs) were recorded to evaluate the safety. Results A total of 12 patients were included in the efficacy analysis. The median PFS was 6.23 months, and the median OS was 8.83 months. Two (16.67%) patients achieved partial remission, 9 patients (75.00%) achieved stable disease and 1 (8.33%) patient achieved progressive disease. DCR and ORR was 91.67%and 16.67%, respectively. Most frequent AEs were hypertension, myelosuppression, weakness, hemorrhage, hand-foot syndrome, total bilirubin elevation, sick, proteinuria, oral ulcer, loss of appetite, and transaminase elevation. The most AEs were in grade I~II. Conclusion The combination therapy of apatinib plus S-1 was effective and well tolerated in the treatment of advanced ESCC patients after first-line chemotherapy failure. The combination therapy has the potential to be a potent therapeutic option for advanced ESCC patients after first-line chemotherapy failure.

Preoperative Risk Assessment of Lymph Node Metastasis in cT1 Lung Cancer: A Retrospective Study from Eastern China.

BACKGROUND: Lymph node status of clinical T1 (diameter ≤ 3 cm) lung cancer largely affects the treatment strategies in the clinic. In order to assess lymph node status before operation, we aim to develop a noninvasive predictive model using preoperative clinical information. METHODS: We retrospectively reviewed 924 patients (development group) and 380 patients (validation group) of clinical T1 lung cancer. Univariate analysis followed by polytomous logistic regression was performed to estimate different risk factors of lymph node metastasis between N1 and N2 diseases. A predictive model of N2 metastasis was established with dichotomous logistic regression, externally validated and compared with previous models. RESULTS: Consolidation size and clinical N stage based on CT were two common independent risk factors for both N1 and N2 metastases, with different odds ratios. For N2 metastasis, we identified five independent predictors by dichotomous logistic regression: peripheral location, larger consolidation size, lymph node enlargement on CT, no smoking history, and higher levels of serum CEA. The model showed good calibration and discrimination ability in the development data, with the reasonable Hosmer-Lemeshow test (p = 0.839) and the area under the ROC being 0.931 (95% CI: 0.906-0.955). When externally validated, the model showed a great negative predictive value of 97.6% and the AUC of our model was better than other models. CONCLUSION: In this study, we analyzed risk factors for both N1 and N2 metastases and built a predictive model to evaluate possibilities of N2 metastasis of clinical T1 lung cancers before the surgery. Our model will help to select patients with low probability of N2 metastasis and assist in clinical decision to further management.

Association between PD-L1 expression and driver gene status in non-small-cell lung cancer: a meta-analysis.

OBJECTIVE: To assess the association between PD-L1 expression and driver gene mutations in patients with non-small-cell lung cancer (NSCLC). METHOD: We performed a meta-analysis of 26 studies (7541 patients) which were published from 2015 to 2017. Pooled odds ratios (ORs) with 95% confidence intervals (CI) were calculated to describe the correlation. Subgroup analysis was performed based on population characteristics, types of PD-L1 antibodies and quality of individual studies. RESULTS: A lower frequency of PD-L1 positivity was observed in NSCLCs harboring EGFR mutation (OR: 0.64, 95% CI, 0.45-0.91, p = 0.014). A negative correlation was also found at 1% (OR: 0.35, 95% CI, 0.22-0.55, p = 0.000) and 50% (OR: 0.33, 95% CI, 0.14-0.81, p = 0.015) cutoff for PD-L1 positive, elderly age group (OR: 0.56, 95% CI, 0.35-0.89, p = 0.013), female dominant group (OR: 0.55, 95% CI, 0.29-0.94, p = 0.030) and smoker dominant group (OR: 0.52, 95% CI, 0.29-0.96, p = 0.035). No significant differences in PD-L1 expression were observed among patients with different ALK, BRAF, HER2, PIK3CA status and MET expression level. Higher level of PD-L1 was found in tumors with KRAS mutation (OR: 1.45, 95% CI, 1.18-1.80, p = 0.001). PD-L1 expression level was not significantly different between triple (EGFR/ALK/KRAS) wild type NSCLCs and those with EGFR/ALK/KRAS mutation. CONCLUSIONS: PD-L1 expression in EGFR mutated NSCLCs were lower than those in EGFR wild type NSCLCs, while tumors with KRAS mutation showed higher levels of PD-L1.

Malignant glomus tumor of the ileum mimicking GIST with distant metastasis without BRAF V600E mutation.

Glomus tumors arising in the gastrointestinal tract are rare and generally benign mesenchymal neoplasms that account for approximately 1% of all gastrointestinal soft tissue tumors. We report a unique case of malignant glomus tumor arising in the ileum of an elderly Chinese woman with widespread metastasis. The patient underwent local tumor resection for a presumed gastrointestinal stromal tumor (GIST). However, brain metastasis developed 2 years later, followed by a lesion in colon 6 months later and a subcutaneous mass of abdominal wall 12 months later. Then, local resections of all metastatic tumors were performed. Histopathology and immunohistochemical findings supported the diagnosis of malignant glomus tumor. Microscopic examination revealed that the primary and metastatic tumor cells shared common features: oval to spindle-shaped, with sharply defined cell membranes, round uniform nuclei, atypical mitotic figures, and variable necrosis. Immunohistochemical staining revealed positive expression of vimentin, SMA, caldesmon, MLH1, MSH2, MSH6, PMS2, SDHB and P53. Even with distant metastasis, the patient has been followed up for 28 months after the third operation without any radiotherapy and chemotherapy. To the best of our knowledge, this is the first report of a malignant glomus tumor arising from the ileum that metastasizes to the brain and abdominal wall with relatively favorable prognosis.

Clinical profiles and trend analysis of newly diagnosed lung cancer in a tertiary care hospital of East China during 2011-2015.

BACKGROUND: More than one-third of lung cancer worldwide occurring in China. However, the clinical profiles of lung cancer patients in the mainland of China are rarely reported and largely unknown. The objective of this study is to analyze the characteristics and time trends of newly diagnosed lung cancer cases during the past 5 years in East China. METHODS: The data came from an academic tertiary care hospital of East China. Patients who were newly diagnosed as lung cancer from 2011 to 2015 were enrolled. All new cases got pathological supports by lung biopsy or surgery. Tumor staging was performed according to the seventh edition of the tumor node metastasis (TNM) classification of malignant tumors. The patients' disease information was collected from the database of the hospital information system (HIS). RESULTS: From 2011 to 2015, aggregately 5,779 patients, including 3,719 males and 2,060 females, were diagnosed as lung cancer. The major histologic subtypes of lung cancer were adenocarcinoma (ADC, 60.0%), squamous cell carcinoma (SCC, 25.6%), small cell lung cancer (SCLC, 8.5%), large cell carcinoma (0.6%), adenosquamous carcinoma (1%), other non-small cell carcinoma (1.6%) and unclassified or rare carcinoma (2.8%). ADC proportion of female was much higher than that of male. A higher proportion of advanced stage (stage IIIB, IV) of lung cancer existed in patients who were admitted to hospital due to respiratory or cancer related symptoms (RCRS) than those without RCRS. Smoking rate in male patients reached 80.2%, while it was only 2.7% in females. EGFR mutation existed in 66% of female and 37% of male patients with ADC. CONCLUSIONS: This study demonstrates the clinicopathologic characteristics of lung cancer patients from East China, including histologic composition, staging proportion, smoking prevalence and gene mutation status. During the past 5 years, the proportion of ADC has increased gradually whereas SCC decreased.

Activated cytotoxic lymphocytes promote tumor progression by increasing the ability of 3LL tumor cells to mediate MDSC chemoattraction via Fas signaling.

The Fas/FasL system transmits intracellular apoptotic signaling, inducing cell apoptosis. However, Fas signaling also exerts non-apoptotic functions in addition to inducing tumor cell apoptosis. For example, Fas signaling induces lung cancer tumor cells to produce prostaglandin E2 (PGE2) and recruit myeloid-derived suppressor cells (MDSCs). Activated cytotoxic T lymphocytes (CTLs) induce and express high levels of FasL, but the effects of Fas activation initiated by FasL in CTLs on apoptosis-resistant tumor cells remain largely unclear. We purified activated CD8(+) T cells from OT-1 mice, evaluated the regulatory effects of Fas activation on tumor cell escape and investigated the relevant mechanisms. We found that CTLs induced tumor cells to secrete PGE2 and increase tumor cell-mediated chemoattraction of MDSCs via Fas signaling, which was favorable to tumor growth. Our results indicate that CTLs may participate in the tumor immune evasion process. To the best of our knowledge, this is a novel mechanism by which CTLs play a role in tumor escape. Our findings implicate a strategy to enhance the antitumor immune response via reduction of negative immune responses to tumors promoted by CTLs through Fas signaling.

Elevated levels of gremlin-1 in eutopic endometrium and peripheral serum in patients with endometriosis.

OBJECTIVE: To examine the expression of gremlin-1 (GREM1) on the levels of messenger RNA (mRNA) and protein in eutopic endometrium and its serum level in patients with endometriosis. DESIGN: Prospective, experimental study using reverse-transcription polymerase chain reaction, Western blot, immunofluorescence, and ELISA. SETTING: Gynecological oncology laboratory in a department of obstetrics and gynecology in a medical college in China. PATIENT(S): Thirty-five patients with endometriosis and 23 healthy control women. INTERVENTION(S): During surgery, the eutopic endometria and peripheral serum were obtained from the patients with endometriosis and the control women. MAIN OUTCOME MEASURE(S): The cellular compartment location of GREM1 expression was examined by using immunofluorescent double staining. The expression levels of mRNA and protein for GREM1 were determined by reverse-transcription polymerase chain reaction and Western blot, respectively. The serum level of GREM1 was measured by indirect ELISA. RESULT(S): The expression of GREM1 was defined within endometrial blood vessel endothelium exclusively, with the concomitant expressions of GREM1 and CD146. The expression of GREM1 on the levels of mRNA and protein was significantly higher in eutopic endometria of patients with endometriosis than in those from healthy control women. According to the ELISA established in our laboratory, the concentration of GREM1 in peripheral serum that was collected during the follicular menstrual phase of patients with endometriosis was significantly higher than that in serum from healthy control women. CONCLUSION(S): Gremlin-1 plays a role to some extent in the aberrant angiogenesis of eutopic endometrium in patients with endometriosis. It is possible that the peripheral serum level of GREM1 is a prospective serum biomarker of endometriosis.