Dual-energy computed tomography in the early evaluation of acute radiation pneumonia.

OBJECTIVE: To investigate the value of dual-energy dual-source computed tomography (DSCT) in evaluating pulmonary perfusion changes before and after radiotherapy for esophageal cancer, and its clinical use in the early diagnosis of acute radiation pneumonia (ARP). METHODS: We selected 45 patients with pathologically confirmed esophageal cancer who received radiotherapy (total irradiation dose of 60 Gy). Dual-energy DSCT scans were performed before and after radiotherapy and the normalized iodine concentrations (NIC) in the lung fields of the areas irradiated with doses of > 20 Gy, 10-20 Gy, 5-10 Gy, and < 5 Gy were measured. We also checked for the occurrence of ARP in the patients, and the differences in NIC values and NIC reduction rates before and after radiotherapy were calculated and statistically analyzed. RESULTS: A total of 16 of the 45 patients developed ARP. The NIC values in the lung fields of all patients decreased at different degrees after radiotherapy, and the NIC values in the area where ARP developed, decreased significantly. The rate of NIC reduction and incidence rate of ARP increased gradually with the increasing irradiation dose, and the inter-group difference in NIC reduction rate was statistically significant (P < 0.05). Based on the receiver operating characteristic (ROC) curve analysis, the areas under the curves of NIC reduction rate versus ARP occurrence in the V5-10 Gy, V10-20 Gy, and V> 20 Gy groups were 0.780, 0.808, and 0.772, respectively. Sensitivity of diagnosis was 81.3%, 75.0%, and 68.8% and the specificity was 65.5%, 82.8%, and 79.3%, when taking 12.50%, 16.50%, and 26.0% as the diagnostic thresholds, respectively. The difference in NIC values in the lung fields of V<5 Gy before and after radiotherapy was not statistically significant (P > 0.05). CONCLUSION: The dual-energy DSCT could effectively evaluate pulmonary perfusion changes after radiotherapy for esophageal cancer, and the NIC reduction rate was useful as a reference index to predict ARP and provide further reference for decisions in clinical practice.

Clerodane diterpenoids from the Uygur medicine Salvia deserta with immunosuppressive activity.

Six undescribed clerodane diterpenoids along with five known ones were isolated from the aerial parts of Salvia deserta, a traditional Uygur medicine. Their chemical structures including absolute configurations were elucidated by extensive spectroscopic analysis (including 1D and 2D NMR, HRESIMS, and IR), combined with calculated ECD method and single-crystal X-ray diffraction analysis. All the compounds possessed a terminal α,ß-unsaturated-γ-lactone moiety, and were assayed for their immunosuppressive activity via inhibiting the secretion of cytokines TNF-α and IL-6 in macrophages RAW264.7. Among them, (5R,8R,9S,10R)-18-nor-cleroda-2,13-dien-16,15-olide-4-one obviously suppressed the secretion of TNF-α and IL-6 with IC50 values of 8.55 and 13.65 µM, respectively.

The value, diagnostic efficacy and clinical significance of functional magnetic resonance imaging in evaluating the efficacy of neoadjuvant chemotherapy in patients with triple negative breast cancer.

Background: Breast cancer (BC) is a common malignant tumor in female. In recent years, with the change of fertility pattern and lifestyle, the incidence of breast cancer is increasing year by year, seriously endangering the health and life of women. MRI is suitable for follow-up evaluation of the course of neoadjuvant chemotherapy in LABC, but there are few related studies and reports. Based on the above background, it is necessary to further evaluate the value of functional magnetic resonance imaging in neoadjuvant chemotherapy in patients with triple negative breast cancer, so as to lay a theoretical foundation for the popularization and application of this detection method. Based on this, this study was to explore the value, diagnostic efficacy and clinical importance of functional magnetic resonance imaging in evaluating the efficacy of neoadjuvant chemotherapy in patients with triple negative breast cancer. Methods: A total of 62 patients with triple-negative breast cancer who received neoadjuvant chemotherapy in our hospital from September 2017 to September 2022 were selected. To compare the differences of functional magnetic resonance imaging (fMRI) between effective and ineffective patients with neoadjuvant chemotherapy, the related data were statistically analyzed. Results: There was no significant difference between the mode of tumor withdrawal and the pathological complete remission of tumor tissue (P>0.05). There was no significant difference in anti-Trop-2 antibody-drug conjugates (ADC) data before and after chemotherapy between over-expressed patients with human epidermal growth factor receptor-2 (HER-2) and non-over-expressed patients with HER-2 (P>0.05). The levels of ADC and Δ ADC in pathological complete remission patients after chemotherapy were significantly higher than those in non-pathological complete remission patients (P<0.05). Using the ΔADC value as the evaluation parameter, the pathological response of tumor tissue was classified as the "gold standard" to draw the ROC curve, the area under curve (AUC) was 0.673, the cut-off of ΔADC to evaluate the significant response of tumor tissue after chemotherapy was 1.418, the sensitivity of evaluating the efficacy was 71.9%, and the specificity was 55.0%. Conclusion: Functional magnetic resonance imaging (fMRI) has diagnostic value for neoadjuvant chemotherapy in patients with triple negative breast cancer. According to the change of ADC value, the curative effect can be predicted early and the treatment strategy can be adjusted in time.

Development of an icIEF assay for monitoring AAV capsid proteins and application to gene therapy products.

Adeno-associated virus (AAV) gene therapy vectors, which contain a DNA transgene packaged into a protein capsid, have shown tremendous therapeutic potential in recent years. Methods traditionally used in quality control labs, such as high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE), do not provide a complete understanding of capsid viral protein (VP) charge heterogeneity. In the present study, we developed simple, one-step sample preparation and charge-based VP separation using imaged capillary isoelectric focusing (icIEF) for monitoring AAV products. The robustness of the method was confirmed through a design of experiments (DoE) exercise. An orthogonal reverse-phase (RP) HPLC method coupled with mass spectrometry was developed to separate and identify charge species. Additionally, capsid point mutants demonstrate the capability of the method to resolve deamidation at a single site on the viral proteins. Finally, case studies using two different AAV serotype vectors establish the icIEF method as stability indicating and demonstrate that increases in acidic species measured by icIEF correlate with increased deamidation, which, we show, results in decreased transduction efficiency. The addition of a rapid and robust icIEF method to the AAV capsid analytical toolkit enables development and consistent manufacturing of well-characterized gene therapy products.

LncRNA BBOX1-AS1 targets miR-361-3p/COL1A1 axis to drive the progression of oesophageal carcinoma.

BACKGROUND: Oesophageal carcinoma (EC) is one of the types of prevalent malignant cancer in the globe. Many researchers reported the vital role played by long-coding RNAs in EC. In the current research, we investigated the mechanisms of the action of lncRNA BBOX1-AS1 in EC progression. METHODS: In EC tissues and EC cells, the expression levels of miR-361-3p along with COL1A1 and BBOX1-AS1 were detected through RT-qPCR or western blotting. MiR-361-3p interactions with BBOX1-AS1 or COL1A1 were verified through Luciferase reporter and RIP tests. Loss of function combined with caspase-3 activity, CCK-8 and Transwell assays was performed to investigate cell apoptosis, proliferation and migration, respectively. Knockdown of BBOX1-AS1 was used for evaluating BBOX1-AS1 effects on tumour development in vivo. RESULTS: BBOX1-AS1 was remarkably elevated in EC tissues and cells. In addition, the silencing of BBOX1-AS1 attenuated the cell viability, cell migration and enhanced cell apoptosis of EC, as well as suppressed EC tumour formation in vivo. Moreover, BBOX1-AS1 was found to be a sponge of miR-361-3p, which downregulated miR-361-3p expression. MiR-361-3p inhibitor rescued the anti-tumour effect of BBOX1-AS1 knockdown on the progression of EC. Furthermore, we discovered that miR-361-3p specially bound to COL1A1 3'UTR and downregulated COL1A1 and COL1A1 reduction declined the promoting effect of silencing miR-361-3p on EC cell malignant phenotypes. CONCLUSION: BBOX1-AS1 facilitated the EC development and malignancy via miR-361-3p/COL1A1 axis, indicating BBOX1-AS1 could be a novel therapy target for the diagnostic of EC.

EGFR inhibition reverses resistance to lenvatinib in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Lenvatinib is approved as a first-line treatment for unresectable HCC. The therapeutic duration of lenvatinib is limited by resistance, but the underlying mechanism is unclear. To establish lenvatinib-resistant cells, Hep3B cells were initially treated with 3 µM lenvatinib. The concentration was gradually increased by 1 µM or 0.5 µM per week and it reached to 7.5 µM 2 months after the initial exposure to lenvatinib. The biological characteristics of these cells were analyzed by ERK activation in the MAPK signaling pathway and a human phospho-receptor tyrosine kinase (RTK) antibody array. Factors possibly related to lenvatinib resistance were analyzed using inhibitors, and cell proliferation was analyzed. We established lenvatinib-resistant HCC cells (LR cells) by long-term exposure to lenvatinib. Lenvatinib reduced ERK activation in the parent cells, but not in the LR cells. RTK array analysis showed that the activities of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR) were significantly increased in LR cells, whereas the activities of other RTKs were unchanged. Erlotinib, a widely used EGFR inhibitor, downregulated ERK activation in LR cells. The proliferation of LR cells will also be affected when lenvatinib is combined with erlotinib to treat LR cells. In contrast, inhibition of IGFR/INSR did not affect ERK activation or cell proliferation. Scavenging of reactive oxygen species (ROS) ameliorated the enhanced EGFR activation in LR cells. Lenvatinib resistance was induced by enhanced EGFR activation, possibly via ROS accumulation, in lenvatinib- resistant cells. These findings may enable the development of lenvatinib combination therapies for HCC.

Paraneptunicella aestuarii gen. nov., sp. nov., a member of the family Alteromonadaceae isolated from seawater in East China Sea.

An aerobic Gram-stain-negative, curved rod-shaped and non-spore-forming bacterial strain (NBU2194T) was isolated from seawater collected in an intertidal zone in Ningbo, Zhejiang Province, PR China. It was motile though a single polar flagellum and grew at 20-42 °C (optimum, 30 °C), in 0-2.0 % NaCl (0 %, w/v) and at pH 5.0-9.0 (pH 6.0-7.0). The sole respiratory quinone was ubiquinone-8. The major cellular fatty acids were C16 : 0, C16 : 1 ω7c and/or C16 : 1 ω6c. The polar lipids contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unidentified phospholipid and two unidentified aminophosphoglycolipids. A phylogenetic analysis based on 16S rRNA gene sequences and 65 genomic core genes showed that strain NBU2194T formed a distinct lineage in the family Alteromonadaceae. The genome of strain NBU2194T was 4 913 533 bp with a DNA G+C content of 43.9 mol% and coded 3895 genes, 12 rRNA genes and 47 tRNA genes. The average nucleotide identity, amino acid identity and digital DNA-DNA hybridization values between strain NBU2194T and related species of Alteromonadaceae were below the threshold limit for prokaryotic species delineation. NBU2194T could be distinguished from other genera in the family Alteromonadaceae based on phenotypic, chemotaxonomic and genomic characteristics. On the basis of the polyphasic taxonomic evidence collected in this study, strain NBU2194T is considered to represent a novel genus and species in the family Alteromonadaceae, for which the name Paraneptunicella aestuarii is proposed. The type strain is NBU2194T (=KCTC 82442T=GDMCC 1.2217T).

[Effect of active component compound of Epimedii Folium,Astragali Radix,and Puerariae Lobatae Radix on expression of ADAM17 in HT22 cells by mediating hepcidin].

Alzheimer's disease(AD) patients in China have been surging, and the resultant medical burden and care demand have a huge impact on the development of individuals, families, and the society. The active component compound of Epimedii Folium, Astragali Radix, and Puerariae Lobatae Radix(YHG) can regulate the expression of iron metabolism-related proteins to inhibit brain iron overload and relieve hypofunction of central nervous system in AD patients. Hepcidin is an important target regulating iron metabolism. This study investigated the effect of YHG on the expression of a disintegrin and metalloprotease-17(ADAM17), a key enzyme in the hydrolysis of ß amyloid precursor protein(APP) in HT22 cells, by mediating hepcidin. To be specific, HT22 cells were cultured in vitro, followed by liposome-mediated siRNA transfection to silence the expression of hepcidin. Real-time PCR and Western blot were performed to examine the silencing result and the effect of YHG on hepcidin in AD cell model. HT22 cells were randomized into 7 groups: control group, Aß25-35 induction(Aß) group, hepcidin-siRNA(siRNA) group, Aß25-35 + hepcidin-siRNA(Aß + siRNA) group, Aß25-35+YHG(Aß+YHG) group, hepcidin-siRNA+YHG(siRNA+YHG) group, Aß25-35+hepcidin-siRNA+YHG(Aß+siRNA+YHG) group. The expression of ADAM17 mRNA in cells was detected by real-time PCR, and the expression of ADAM17 protein by immunofluorescence and Western blot. Immunofluorescence showed that the ADAM17 protein expression was lower in the Aß group, siRNA group, and Aß+siRNA group than in the control group(P<0.05) and the expression was lower in the Aß+siRNA group(P<0.05) and higher in the Aß+YHG group(P<0.05) than in the Aß group. Moreover, the ADAM17 protein expression was lower in the Aß+siRNA group(P<0.05) and higher in the siRNA+YHG group(P< 0.05) than in the siRNA group. The expression was higher in the Aß+siRNA+YHG group than in the Aß+siRNA group(P<0.05). The results of Western blot and real-time PCR were consistent with those of immunofluorescence. The experiment showed that YHG induced hepcidin to up-regulate the expression of ADAM17 in AD cell model and promote the activation of non-starch metabolic pathways, which might be the internal mechanism of YHG in preventing and treating AD.

N­acetyl cysteine inhibits the lipopolysaccharide­induced inflammatory response in bone marrow mesenchymal stem cells by suppressing the TXNIP/NLRP3/IL­1ß signaling pathway.

N-acetyl cysteine (NAC) has been used to inhibit lipopolysaccharide (LPS)-induced inflammation. However, the molecular mechanism underlying its anti­inflammatory effects remains to be elucidated. The present study aimed to determine the effect of NAC on the LPS­induced inflammatory response in bone marrow mesenchymal stem cells (BMSCs) and elucidate the underlying molecular mechanism. First, BMSCs were stimulated by LPS following pretreatment with NAC (0, 0.1, 0.5, 1 or 2 mM). A Cell Counting Kit 8 assay was used to determine the number of viable cells and 1 mM NAC was selected as the experimental concentration. Then, the secretion of inflammatory factors, including interleukin (IL)­1ß, IL­6 and tumor necrosis factor­α was evaluated by enzyme­linked immunosorbent assay. Finally, the expression levels of mRNA and proteins, including apoptosis­associated speck­like protein containing a CARD (ASC), nucleotide­binding oligomerization domain­like receptor protein 3 (NLRP3), caspase­1, thioredoxin­interacting protein (TXNIP), and thioredoxin (TRX), were evaluated by reverse transcription­quantitative PCR and western blot analysis, respectively. The results demonstrated that the secretion of inflammatory factors, which was increased by the administration of LPS, was reduced by pretreatment with NAC. Furthermore, NAC reduced the expression of ASC, NLRP3, caspase­1 and TXNIP, but enhanced that of TRX. To conclude, NAC had anti­inflammatory effects on LPS­stimulated BMSCs, which was closely associated with the TXNIP/NLRP3/IL­1ß signaling pathway. Thus, NAC may be a promising treatment to attenuate the inflammatory response in LPS­induced BMSCs.

Lin28 enhances de novo fatty acid synthesis to promote cancer progression via SREBP-1.

Lin28 plays an important role in promoting tumor development, whereas its exact functions and underlying mechanisms are largely unknown. Here, we show that both human homologs of Lin28 accelerate de novo fatty acid synthesis and promote the conversion from saturated to unsaturated fatty acids via the regulation of SREBP-1. By directly binding to the mRNAs of both SREBP-1 and SCAP, Lin28A/B enhance the translation and maturation of SREBP-1, and protect cancer cells from lipotoxicity. Lin28A/B-stimulated tumor growth is abrogated by SREBP-1 inhibition and by the impairment of the RNA binding properties of Lin28A/B, respectively. Collectively, our findings uncover that post-transcriptional regulation by Lin28A/B enhances de novo fatty acid synthesis and metabolic conversion of saturated and unsaturated fatty acids via SREBP-1, which is critical for cancer progression.

DIS3L2 Promotes Progression of Hepatocellular Carcinoma via hnRNP U-Mediated Alternative Splicing.

DIS3-like 3'-5' exoribonuclease 2 (DIS3L2) degrades aberrant RNAs, however, its function in tumorigenesis remains largely unexplored. Here, aberrant DIS3L2 expression promoted human hepatocellular carcinoma (HCC) progression via heterogeneous nuclear ribonucleoproteins (hnRNP) U-mediated alternative splicing. DIS3L2 directly interacted with hnRNP U through its cold-shock domains and promoted inclusion of exon 3b during splicing of pre-Rac1 independent of its exonuclease activity, yielding an oncogenic splicing variant, Rac1b, which is known to stimulate cellular transformation and tumorigenesis. DIS3L2 regulated alternative splicing by recruiting hnRNP U to pre-Rac1. Rac1b was critical for DIS3L2 promotion of liver cancer development both in vitro and in vivo. Importantly, DIS3L2 and Rac1b expression highly correlated with HCC progression and patient survival. Taken together, our findings uncover an oncogenic role of DIS3L2, in which it promotes liver cancer progression through a previously unappreciated mechanism of regulating hnRNP U-mediated alterative splicing. SIGNIFICANCE: These findings establish the role and mechanism of the 3'-5' exoribonuclease DIS3L2 in hepatocellular carcinoma carcinogenesis.

Rv1075c of Mycobacterium tuberculosis is a GDSL-Like Esterase and Is Important for Intracellular Survival.

Mycobacterium tuberculosis lipid metabolism pathways facilitate access to carbon and energy sources during infection. M. tuberculosis gene Rv1075c was annotated as a conserved hypothetical protein. We identified that Rv1075c amino acid sequence shares similarities with other bacterial lipase/esterases and we demonstrated that it has esterase activity, with preference for short-chain fatty acids, particularly acetate, with highest activity at 45°C, pH 9. Site-direct mutagenesis revealed its activity triad as Ser80, Asp244, and His247. We further determined that rRv1075c hydrolyzed triacetin and tributyrin, and it was mainly distributed in cell wall and membrane. Its expression was induced at pH 4.5, mimicking the acidic phagosome of macrophages. Mutation of Rv1075c led to reduced bacterial growth in THP-1 cells and human peripheral blood mononuclear cell-derived macrophages, and attenuated M. tuberculosis infection in mice. Our data suggest that Rv1075c is involved in ester and fatty acid metabolism inside host cells.

The ignored emission of volatile organic compounds from iron ore sinter process.

Iron ore sintering is a major source of gaseous and particulate pollutants emission in iron smelt plant. The aim of present study is to characterize the volatile organic compounds (VOCs) emission profiles from iron ore sintering process. Both sinter pot test and sinter simulation experiment were conducted and compared. Out results showed that sinter process produced large quantity of VOCs together with NOx and SO2. VOCs and NO were produced simultaneously in sinter pot test from 3 to 24 min after ignition, flowed by SO2 production from 15 min to the end of sintering. Total VOCs (TVOC) concentration in sinter flue gas was affected by the coal and coke ratio in sinter raw material. The maximum TVOC concentration was 34.5 ppm when using 100% coal as fuel. Sinter simulation experiments found that the number of VOCs species and their concentrations were found by sinter temperature. The largest VOCs species varieties were obtained at 500 °C. Benzene, toluene, xylene and ethylbenzene were major VOCs in sinter flue gas based on the results from both simulation test and sinter pot. It thus demonstrated that in addition to NOx, SO2 and metal oxide particles, sinter flue gas also contained significant amount of VOCs whose environmental impact cannot be ignored. Based on our work, it is timely needed to establish a new VOC emission standard for sinter flue gas and develop advanced techniques to simultaneously eliminate multi-pollutants in iron ore sinter process.

Author Correction: Menin enhances c-Myc-mediated transcription to promote cancer progression.

This corrects the article DOI: 10.1038/ncomms15278.

Monocular diplopia-associated migraine-like headache induced by nicotine withdrawal.

We describe an extremely rare case of migraine-associated monocular diplopia developed in a 23-year-old man after sudden cessation of smoking. The physical examination and brain MRI scan were unremarkable. The symptoms resolved after starting nicotine patch. We reviewed the literature and discussed the diagnosis and possible mechanism of this phenomenon.

Menin enhances c-Myc-mediated transcription to promote cancer progression.

Menin is an enigmatic protein that displays unique ability to either suppress or promote tumorigenesis in a context-dependent manner. The role for Menin to promote oncogenic functions has been largely attributed to its essential role in forming the MLL methyltransferase complex, which mediates H3K4me3. Here, we identify an unexpected role of Menin in enhancing the transactivity of oncogene MYC in a way independent of H3K4me3 activity. Intriguingly, we find that Menin interacts directly with the TAD domain of MYC and co-localizes with MYC to E-Box to enhance the transcription of MYC target genes in a P-TEFb-dependent manner. We further demonstrate that, by transcriptionally promoting the expression of MYC target genes in cancer cells, Menin stimulates cell proliferation and cellular metabolism both in vitro and in vivo. Our results uncover a previously unappreciated mechanism by which Menin functions as an oncogenic regulatory factor that is critical for MYC-mediated gene transcription.

Quinacrine in endometrial cancer: Repurposing an old antimalarial drug.

OBJECTIVE: Generate preclinical data on the effect of quinacrine (QC) in inhibiting tumorigenesis in endometrial cancer (EC) in vitro and explore its role as an adjunct to standard chemotherapy in an EC mouse model. METHODS: Five different EC cell lines (Ishikawa, Hec-1B, KLE, ARK-2, and SPEC-2) representing different histologies, grades of EC, sensitivity to cisplatin and p53 status were used for the in vitro studies. MTT and colony formation assays were used to examine QC's ability to inhibit cell viability in vitro. The Chou-Talalay methodology was used to examine synergism between QC and cisplatin, carboplatin or paclitaxel. A cisplatin-resistant EC subcutaneous mouse model (Hec-1B) was used to examine QC's role as maintenance therapy. RESULTS: QC exhibited strong synergism in vitro when combined with cisplatin, carboplatin or paclitaxel with the highest level of synergism in the most chemo-resistant cell line. Neither QC monotherapy nor carboplatin/paclitaxel significantly delayed tumor growth in xenografts. Combination treatment (QC plus carboplatin/paclitaxel) significantly augmented the antiproliferative ability of these agents and was associated with a 14-week survival prolongation compared to carboplatin/paclitaxel. Maintenance with QC resulted in further delay in tumor progression and survival prolongation compared to carboplatin/paclitaxel. QC was not associated with weight loss and the yellow skin discoloration noted during treatment was reversible upon discontinuation. CONCLUSIONS: QC exhibited significant antitumor activity against EC in vitro and was successful as maintenance therapy in chemo-resistant EC mouse xenografts. This preclinical data suggest that QC may be an important adjunct to standard chemotherapy for patients with chemo-resistant EC.

CUE domain-containing protein 2 promotes the Warburg effect and tumorigenesis.

Cancer progression depends on cellular metabolic reprogramming as both direct and indirect consequence of oncogenic lesions; however, the underlying mechanisms are still poorly understood. Here, we report that CUEDC2 (CUE domain-containing protein 2) plays a vital role in facilitating aerobic glycolysis, or Warburg effect, in cancer cells. Mechanistically, we show that CUEDC2 upregulates the two key glycolytic proteins GLUT3 and LDHA via interacting with the glucocorticoid receptor (GR) or 14-3-3ζ, respectively. We further demonstrate that enhanced aerobic glycolysis is essential for the role of CUEDC2 to drive cancer progression. Moreover, using tissue microarray analysis, we show a correlation between the aberrant expression of CUEDC2, and GLUT3 and LDHA in clinical HCC samples, further demonstrating a link between CUEDC2 and the Warburg effect during cancer development. Taken together, our findings reveal a previously unappreciated function of CUEDC2 in cancer cell metabolism and tumorigenesis, illustrating how close oncogenic lesions are intertwined with metabolic alterations promoting cancer progression.

Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2S505 phosphorylation. Conversely, HSulf-1 expression in SKOV3 cells reduced the number of LDs and increased the number of AVs compared to vector controls. Furthermore, pharmacological (AACOCF3) and ShRNA mediated downregulation of cPLA2 resulted in reduced LDs, and increased autophagy. Finally, in vivo experiment using OV202 Sh1 derived xenograft show that AACOCF3 treatment effectively attenuated tumor growth and LD biogenesis. Collectively, these results show a reciprocal regulation of autophagy and lipid biogenesis by HSulf-1 in ovarian cancer.

Fibroblast Activation Protein-α-Positive Fibroblasts Promote Gastric Cancer Progression and Resistance to Immune Checkpoint Blockade.

Gastric cancer (GC) is one of the main causes of cancer death. The tumor microenvironment has a profound effect on inducing tumor growth, metastasis, and immunosuppression. Fibroblast activation protein-α (FAP) is a protein that is usually expressed in fibroblasts, such as cancer-associated fibroblasts, which are major components of the tumor microenvironment. However, the role of FAP in GC progression and treatment is still unknown. In this study, we explored these problems based on GC patient samples and experimental models. We found that high FAP expression was an independent prognosticator of poor survival in GC patients. FAP+ cancer-associated fibroblasts (CAFs) promoted the survival, proliferation, and migration of GC cell lines in vitro. Moreover, they also induced drug resistance of the GC cell lines and inhibited the antitumor functions of T cells in the GC tumor microenvironment. More importantly, we found that targeting FAP+ CAFs substantially enhanced the antitumor effects of immune checkpoint blockades in GC xenograft models. This evidence highly suggested that FAP is a potential prognosticator of GC patients and a target for synergizing with other treatments, especially immune checkpoint blockades in GC.