Midbrain dopamine neurons arbiter OCD-like behavior.

The neurobiological understanding of obsessive-compulsive disorder (OCD) includes dysregulated frontostriatal circuitry and altered monoamine transmission. Repetitive stereotyped behavior (e.g., grooming), a featured symptom in OCD, has been proposed to be associated with perturbed dopamine (DA) signaling. However, the precise brain circuits participating in DA's control over this behavioral phenotype remain elusive. Here, we identified that DA neurons in substantia nigra pars compacta (SNc) orchestrate ventromedial striatum (VMS) microcircuits as well as lateral orbitofrontal cortex (lOFC) during self-grooming behavior. SNc-VMS and SNc-lOFC dopaminergic projections modulate grooming behaviors and striatal microcircuit function differentially. Specifically, the activity of the SNc-VMS pathway promotes grooming via D1 receptors, whereas the activity of the SNc-lOFC pathway suppresses grooming via D2 receptors. SNc DA neuron activity thus controls the OCD-like behaviors via both striatal and cortical projections as dual gating. These results support both pharmacological and brain-stimulation treatments for OCD.

Greatly isolated heterogeneous circulating tumor cells using hybrid engineered cell membrane-camouflaged magnetic nanoparticles.

BACKGROUND: Circulating tumor cells (CTCs) are considered as a useful biomarker for early cancer diagnosis, which play a crucial role in metastatic process. Unfortunately, the tumor heterogeneity and extremely rare occurrence rate of CTCs among billions of interfering leukocytes seriously hamper the sensitivity and purity of CTCs isolation. METHODS: To address these, we firstly used microfluidic chips to detect the broad-spectrum of triple target combination biomarkers in CTCs of 10 types of cancer patients, including EpCAM, EGFR and Her2. Then, we constructed hybrid engineered cell membrane-camouflaged magnetic nanoparticles (HE-CM-MNs) for efficient capture of heterogeneous CTCs with high-purity, which was enabled by inheriting the recognition ability of HE-CM for various CTCs and reducing homologous cell interaction with leukocytes. Compared with single E-CM-MNs, HE-CM-MNs showed a significant improvement in the capture efficiency for a cell mixture, with an efficiency of 90%. And the capture efficiency of HE-CM-MNs toward 12 subpopulations of tumor cells was ranged from 70 to 85%. Furthermore, by using HE-CM-MNs, we successfully isolated heterogeneous CTCs with high purity from clinical blood samples. Finally, the captured CTCs by HE-CM-MNs could be used for gene mutation analysis. CONCLUSIONS: This study demonstrated the promising potential of HE-CM-MNs for heterogeneous CTCs detection and downstream analysis.

Exposure to disinfection by-products and risk of cancer: A systematic review and dose-response meta-analysis.

Disinfection by-products (DBPs), including trihalomethanes (THMs) and haloacetic acids (HAAs), have attracted attention due to their carcinogenic properties, leading to varying conclusions. This meta-analysis aimed to evaluate the dose-response relationship and the dose-dependent effect of DBPs on cancer risk. We performed a selective search in PubMed, Web of Science, and Embase databases for articles published up to September 15th, 2023. Our meta-analysis eventually included 25 articles, encompassing 8 cohort studies with 6038,525 participants and 10,668 cases, and 17 case-control studies with 10,847 cases and 20,702 controls. We observed a positive correlation between increased cancer risk and higher concentrations of total trihalomethanes (TTHM) in water, longer exposure durations, and higher cumulative TTHM intake. These associations showed a linear trend, with relative risks (RRs) and 95 % confidence intervals (CIs) being 1.02 (1.01-1.03), 1.04 (1.02-1.06), and 1.02 (1.00-1.03), respectively. Gender-specific analyses revealed slightly U-shaped relationships in both males and females, with males exhibiting higher risks. The threshold dose for TTHM in relation to cancer risk was determined to be 55 µg/L for females and 40 µg/L for males. A linear association was also identified between bladder cancer risk and TTHM exposure, with an RR and 95 % CI of 1.08 (1.05-1.11). Positive linear associations were observed between cancer risk and exposure to chloroform, bromodichloromethane (BDCM), and HAA5, with RRs and 95 % CIs of 1.02 (1.01-1.03), 1.33 (1.18-1.50), and 1.07 (1.03-1.12), respectively. Positive dose-dependent effects were noted for brominated THMs above 35 µg/L and chloroform above 75 µg/L. While heterogeneity was observed in the studies for quantitative synthesis, no publication bias was detected. Exposure to TTHM, chloroform, BDCM, or HAA5 may contribute to carcinogenesis, and the risk of cancer appears to be dose-dependent on DBP exposure levels. A cumulative effect is suggested by the positive correlation between TTHM exposure and cancer risk. Bladder cancer and endocrine-related cancers show dose-dependent and positive associations with TTHM exposure. Males may be more susceptible to TTHM compared to females.

Integrated metabolomics and network pharmacology to reveal the lipid-lowering mechanisms of Qizha Shuangye granules in hyperlipidemic rats.

BACKGROUND: Qizha Shuangye granules (QSG) comprise six traditional Chinese herbal medicines (TCHMs), which have a long history of treating hyperlipidemia (HLP) in China. This study aimed to evaluate the potential lipid-lowering effects of QSG in an HLP rat model and investigate possible mechanisms. The HLP rat model was induced by a high-fat diet. Lipid-related indicators in serum were detected. Serum and liver metabolites were investigated using a liquid chromatography-mass spectrometry-based metabolomics approach. A herb-compound-target-metabolite (H-C-T-M) network was further constructed to reveal the possible molecular mechanism of QSG to alleviate HLP. RESULTS: The administration of QSG inhibited the HLP-induced changes in total cholesterol, triglyceride, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and non-esterified fatty acid (NEFA) levels. Additionally, QSG significantly attenuated the liver histopathological changes induced by HLP. Metabolomic analysis showed the serum and liver metabolic disorders presented in HLP rats. QSG can reverse the abnormal metabolism caused by HLP. Through network pharmacology analysis, key proteins such as androgen receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and peroxisome proliferator-activated receptor-α were screened out, and they were speculated to be possible therapeutic targets for QSG to treat HLP. CONCLUSION: The present study integrated metabolomics and network pharmacology analysis to reveal the efficacy and possible mechanism of QSG in treating HLP, which provides a new reference for the research and development of QSG as a functional food. © 2023 Society of Chemical Industry.

A Conjugated Phenylene Nanocage with a Guest-Adaptive Deformable Cavity.

The highly strained, phenylene-derived organic cages are typically regarded as very rigid entities, yet their deformation potential and supramolecular properties remain underexplored. Herein, we report a pliable conjugated phenylene nanocage by synergistically merging rigid and flexible building blocks. The anisotropic cage molecule contains branched phenylene chains capped by a calix[6]arene moiety, the delicate conformational changes of which endow the cage with a remarkably deformable cavity. When complexing with fullerene guests, the cage showcases excellent guest-adaptivity, with its cavity volume capable of swelling by as much as 85 %.

Acetyl-Coenzyme A Synthetase 2 Potentiates Macropinocytosis and Muscle Wasting Through Metabolic Reprogramming in Pancreatic Cancer.

BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. Acetyl-coenzyme A synthetase short-chain family member 2 (ACSS2) is an acetyl-enzyme A synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the nonselective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer. METHODS: Clinical significance of ACSS2 was analyzed using samples from patients with pancreatic cancer. ACSS2-knockout cells were established using the clustered regularly interspaced short palindromic repeats-associated protein 9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. The macropinocytotic index was evaluated by dextran uptake assay. Chromatin immunoprecipitation assay was performed to validate transcriptional activation. ACSS2-mediated tumor progression and muscle wasting were examined in orthotopic xenograft models. RESULTS: Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2-dimensional and 3-dimensional models. Macropinocytosis-associated genes are upregulated in tumor tissues and are correlated with worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified Zrt- and Irt-like protein 4 (ZIP4) as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2-induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4-mediated transcriptional activation. ZIP4 induces macropinocytosis through cyclic adenosine monophosphate response element-binding protein-activated syndecan 1 (SDC1) and dynamin 2 (DNM2). Meanwhile, ZIP4 drives muscle wasting and cachexia via glycogen synthase kinase-ß (GSK3ß)-mediated secretion of tumor necrosis factor superfamily member 10 (TRAIL or TNFSF10). ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models. CONCLUSIONS: ACSS2-mediated metabolic reprogramming activates the ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through the GSK3ß/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.

Circular RNA ANAPC7 Inhibits Tumor Growth and Muscle Wasting via PHLPP2-AKT-TGF-ß Signaling Axis in Pancreatic Cancer.

BACKGROUND & AIMS: Pancreatic cancer has the highest prevalence of cancer-associated cachexia among all cancers. ZIP4 promotes pancreatic cancer progression by regulating oncogenic miR-373, and perturbation of circular RNAs (circRNAs) is associated with cancer aggressiveness. This study aimed to identify circRNAs involved in ZIP4/miR-373-driven cancer growth and cachexia and decipher the underlying mechanism. METHODS: Differentially expressed circRNAs and potential targets of microRNA were identified through in silico analysis. The RNA interactions were determined by means of biotinylated microRNA pulldown, RNA immunoprecipitation, and luciferase reporter assays. The function of circRNA in ZIP4-miR-373 signaling axis were examined in human pancreatic cancer cells, 3-dimensional spheroids and organoids, mouse models, and clinical specimens. Mouse skeletal muscles were analyzed by means of histology. RESULTS: We identified circANAPC7 as a sponge for miR-373, which inhibited tumor growth and muscle wasting in vitro and in vivo. Mechanistic studies showed that PHLPP2 is a downstream target of ZIP4/miR-373. CircANAPC7 functions through PHLPP2-mediated dephosphorylation of AKT, thus suppressing cancer cell proliferation by down-regulating cyclin D1 and inhibiting muscle wasting via decreasing the secretion of transforming growth factor-ß through STAT5. We further demonstrated that PHLPP2 induced dephosphorylation of CREB, a zinc-dependent transcription factor activated by ZIP4, thereby forming a CREB-miR-373-PHLPP2 feed-forward loop to regulate tumor progression and cancer cachexia. CONCLUSION: This study identified circANAPC7 as a novel tumor suppressor, which functions through the CREB-miR-373-PHLPP2 axis, leading to AKT dephosphorylation, and cyclin D1 and transforming growth factor-ß down-regulation to suppress tumor growth and muscle wasting in pancreatic cancer.

Exploring the in vitro anti-inflammatory activity of gross saponins of Tribulus terrestris L. fruit by using liquid chromatography-mass spectrometry-based cell metabolomics approach.

Our previous studies confirmed the efficacy of gross saponins of Tribulus terrestris L. fruit in treating cerebral ischemia. This study aimed to investigate the related mechanisms in vitro. The lipopolysaccharide-induced BV2 cells model was constructed and treated with gross saponins at different concentrations to explore its anti-inflammatory activity. The cell metabolite changes were tracked by liquid chromatography-mass spectrometry (LC-MS)-based metabolomics, and the metabolic biomarkers and related metabolic pathways were analyzed. Molecular biochemistry analysis was further used to verify the relevant inflammatory pathways. The results showed that the saponins reduced nitric oxide release and the secretion of tumor necrosis factor-alpha, interleukin-1ß, and interleukin-6 from lipopolysaccharide-induced BV2 cells. Metabolic perturbations occurred in lipopolysaccharide-treated BV2 cells, which could be reversed by drug treatment via mainly regulating glycerophospholipid metabolism, tryptophan metabolism, purine metabolism pathways, etc. The western blot analysis demonstrated that saponin could suppress the activation of the inflammatory-related signaling pathway. The present study explored the in vitro anti-inflammatory mechanism of gross saponins of Tribulus terrestris L. fruit using an LC-MS-based cell metabolomics approach, which confirms the great potential of LC-MS for drug efficacy evaluation and can be applied in other herbal medicine-related analyses.

The Association of Hypertension with Perfluoroalkyl and Polyfluoroalkyl Substances.

Perfluoroalkyl and polyfluoroalkyl substance (PFAS) is a large group of fluorinated synthetic chemicals, e.g., perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluorononanoic acid (PFNA). Many epidemiological studies have found that PFAS exposure is associated with hypertension risk, but others possess a different opinion. Overall, the relationship between PFASs and hypertension risk remains controversial. We sought to conduct a systematic review and meta-analysis to clarify the association between PFAS exposure and human risk of hypertension.We conducted a meta-analysis based on population-involving studies published from 1975 to 2023, which we collected from Web of Science, PubMed, and Embase databases. The odds ratio (OR) and standardized mean difference (SMD), with their 95% confidence interval (CI), were used to assess the risk of hypertension with PFAS exposure. The statistical heterogeneity among studies was assessed with the Q-test and I2 statistics. Research publications related to our meta-analysis topic were systematically reviewed.Fourteen studies involving 71,663 participants, in which 26,281 suffered hypertension, met the inclusion criteria. Our analyses suggest that exposure to general PFAS (OR = 1.09, 95% CI = 1.04-1.14) or PFOS (OR = 1.17, 95% CI = 1.05-1.30) is associated with hypertension risk. Specifically, elevated levels of general PFAS (SMD = 0.25, 95% CI = 0.08-0.42), PFHxS (SMD = 0.17, 95% CI = 0.07-0.27), and PFDA (SMD = 0.08, 95% CI = 0.02-0.13) are associated with a high risk of hypertension.Our meta-analysis indicates that PFAS exposure is a risk factor for hypertension, and increased hypertension risk is associated with higher PFAS levels. Further study may eventually provide a better and more comprehensive elucidation of the potential mechanism of this association.

Zinc-Dependent Regulation of ZEB1 and YAP1 Coactivation Promotes Epithelial-Mesenchymal Transition Plasticity and Metastasis in Pancreatic Cancer.

BACKGROUND: Pancreatic cancer is characterized by extensive metastasis. Epithelial-mesenchymal transition (EMT) plasticity plays a critical role in tumor progression and metastasis by maintaining the transition between EMT and mesenchymal-epithelial transition states. Our aim is to understand the molecular events regulating metastasis and EMT plasticity in pancreatic cancer. METHODS: The interactions between a cancer-promoting zinc transporter ZIP4, a zinc-dependent EMT transcriptional factor ZEB1, a coactivator YAP1, and integrin α3 (ITGA3) were examined in human pancreatic cancer cells, clinical specimens, spontaneous mouse models (KPC and KPCZ) and orthotopic xenografts, and 3-dimensional spheroid and organoid models. Correlations between ZIP4, miR-373, and its downstream targets were assessed by RNA in situ hybridization and immunohistochemical staining. The transcriptional regulation of ZEB1, YAP1, and ITGA3 by ZIP4 was determined by chromatin immunoprecipitation, co-immunoprecipitation, and luciferase reporter assays. RESULTS: The Hippo pathway effector YAP1 is a potent transcriptional coactivator and forms a complex with ZEB1 to activate ITGA3 transcription through the YAP1/transcriptional enhanced associate domain (TEAD) binding sites in human pancreatic cancer cells and KPC-derived mouse cells. ZIP4 upregulated YAP1 expression via activation of miR-373 and inhibition of the YAP1 repressor large tumor suppressor 2 kinase (LATS2). Furthermore, upregulation of ZIP4 promoted EMT plasticity, cell adhesion, spheroid formation, and organogenesis both in human pancreatic cancer cells, 3-dimensional spheroid model, xenograft model, and spontaneous mouse models (KPC and KPCZ) through ZEB1/YAP1-ITGA3 signaling axis. CONCLUSION: We demonstrated that ZIP4 activates ZEB1 and YAP1 through distinct mechanisms. The ZIP4-miR-373-LATS2-ZEB1/YAP1-ITGA3 signaling axis has a significant impact on pancreatic cancer metastasis and EMT plasticity.

Perturbation of Wnt/ß-catenin signaling and sexual dimorphism in non-alcoholic fatty liver disease.

AIMS: The prevalence of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) is higher in postmenopausal women than men. The aim of this study was to determine the molecular mechanisms underlying this sexual dimorphism in NAFLD. METHODS: A total of 24 frozen liver samples of both sexes (normal and NAFLD/NASH) were used in this study. Total RNAseq was first used to identify differentially expressed genes (DEGs) between samples. Enrichment analysis of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome were used to analyze biological pathways. RT2 profiler polymerase chain reaction (PCR) arrays were used to identify genes associated with the biological pathways. Immunoblotting was used to validate protein expression of certain genes. RESULTS: We identified 4362 genes that are differentially expressed between NAFLD/NASH and normal samples; of those 745 genes were characterized as sex specific in NAFLD/NASH. Multiple pathway analysis platforms showed that Wnt-signaling is a candidate shared for a common biological pathway-associated with NAFLD/NASH. Using Wnt pathway focused PCR array we identified many genes involved in canonical pathway (Wnt/ß-catenin activation) such as CTNNB1, c-Myc and CCND2 are overexpressed in female cases, whereas these genes are either not detected or downregulated in male cases. Immunoblot analysis validated the expression of CTNNB1 in female cases but not in male protein samples. CONCLUSIONS: Our study suggests, for the first time, that the activation of canonical Wnt signaling could be one of the main pathways associated with sexual dimorphism in NAFLD and NASH.

ZIP4 Increases Expression of Transcription Factor ZEB1 to Promote Integrin α3ß1 Signaling and Inhibit Expression of the Gemcitabine Transporter ENT1 in Pancreatic Cancer Cells.

BACKGROUND & AIMS: Pancreatic tumors undergo rapid growth and progression, become resistant to chemotherapy, and recur after surgery. We studied the functions of the solute carrier family 39 member 4 (SLC39A4, also called ZIP4), which regulates concentrations of intracellular zinc and is increased in pancreatic cancer cells, in cell lines and mice. METHODS: We obtained 93 pancreatic cancer specimens (tumor and adjacent nontumor tissues) from patients who underwent surgery and gemcitabine chemotherapy and analyzed them by immunohistochemistry. ZIP4 and/or ITGA3 or ITGB1 were overexpressed or knocked down with short hairpin RNAs in AsPC-1 and MIA PaCa-2 pancreatic cancer cells lines, and in pancreatic cells from KPC and KPC-ZEB1-knockout mice, and pancreatic spheroids were established; cells and spheroids were analyzed by immunoblots, reverse transcription polymerase chain reaction, and liquid chromatography tandem mass spectrometry. We studied transcriptional regulation of ZEB1, ITGA3, ITGB1, JNK, and ENT1 by ZIP4 using chromatin precipitation and luciferase reporter assays. Nude mice were given injections of genetically manipulated AsPC-1 and MIA PaCa-2 cells, and growth of xenograft tumors and metastases was measured. RESULTS: In pancreatic cancer specimens from patients, increased levels of ZIP4 were associated with shorter survival times. MIA PaCa-2 cells that overexpressed ZIP4 had increased resistance to gemcitabine, 5-fluorouracil, and cisplatin, whereas AsPC-1 cells with ZIP4 knockdown had increased sensitivity to these drugs. In mice, xenograft tumors grown from AsPC-1 cells with ZIP4 knockdown were smaller and more sensitive to gemcitabine. ZIP4 overexpression significantly reduced accumulation of gemcitabine in pancreatic cancer cells, increased growth of xenograft tumors in mice, and increased expression of the integrin subunits ITGA3 and ITGB1; expression levels of ITGA3 and ITGB1 were reduced in cells with ZIP4 knockdown. Pancreatic cancer cells with ITGA3 or ITGB1 knockdown had reduced proliferation and formed smaller tumors in mice, despite overexpression of ZIP4; spheroids established from these cells had increased sensitivity to gemcitabine. We found ZIP4 to activate STAT3 to induce expression of ZEB1, which induced expression of ITGA3 and ITGB1 in KPC cells. Increased ITGA3 and ITGB1 expression and subsequent integrin α3ß1 signaling, via c-Jun-N-terminal kinase (JNK), inhibited expression of the gemcitabine transporter ENT1, which reduced gemcitabine uptake by pancreatic cancer cells. ZEB1-knockdown cells had increased sensitivity to gemcitabine. CONCLUSIONS: In studies of pancreatic cancer cell lines and mice, we found that ZIP4 increases expression of the transcription factor ZEB1, which activates expression of ITGA3 and ITGB1. The subsequent increase in integrin α3ß1 signaling, via JNK, inhibits expression of the gemcitabine transporter ENT1, so that cells take up smaller amounts of the drug. Activation of this pathway might help mediate resistance of pancreatic tumors to chemotherapeutic agents.

Shaping Magnetite by Hydroxyl Group Numbers of Small Molecules.

Despite numerous reports on magnetite formation with the assistance of various additives, the role of hydroxyl group (-OH) numbers in small polyol molecules has not yet been understood well. We selected small molecules containing different -OH numbers, such as ethanol, ethylene glycol, propanetriol, butanetetrol, pentitol, hexanehexol, and cyclohexanehexol, as additives in coprecipitation. By increasing the -OH number in these small polyol molecules, the formation of crystallization was slowed, and the size and shape of magnetite were regulated as well possibly due to the changed complexation strength and the stability of the precursor. The increase in temperature and the Fe2+/Fe3+ ratio can reduce the complexation strength. The nucleation and growth of magnetite proceed possibly through the aggregation of polyol-stabilized amorphous complexes and two-line ferrihydrite with low crystallinity based on the -OH numbers, suggesting a nonclassical pathway. The as-prepared magnetite showed a r2/r1 ratio after in vitro MRI measurement as follows: Fe3O4@He-6OH rod < Fe3O4@Pr-3OH sheet < Fe3O4@Pe-5OH cube. The Fe3O4@He-6OH rod and Fe3O4@Pr-3OH sheet displayed T1-T2 dual modal contrast ability, while the Fe3O4@Pe-5OH cube can be T2-dominated. This research provides a simple but an essential approach for designing MRI contrast agents.

ZIP4 Promotes Muscle Wasting and Cachexia in Mice With Orthotopic Pancreatic Tumors by Stimulating RAB27B-Regulated Release of Extracellular Vesicles From Cancer Cells.

BACKGROUND & AIMS: Cachexia, which includes muscle wasting, is a frequent complication of pancreatic cancer. There are no therapies that reduce cachexia and increase patient survival, so it is important to learn more about its mechanisms. The zinc transporter ZIP4 promotes growth and metastasis of pancreatic tumors. We investigated its effects on muscle catabolism via extracellular vesicle (EV)-mediated stimulation of mitogen-activated protein kinase 14 (p38 MAPK). METHODS: We studied nude mice with orthotopic tumors grown from human pancreatic cancer cell lines (AsPC-1 and BxPC-3); tumors were removed 8 days after cell injection and analyzed by histology. Mouse survival was analyzed by Kaplan-Meier curves. ZIP4 was knocked down in AsPC-1 and BxPC-3 cells with small hairpin RNAs; cells with empty vectors were used as controls. Muscle tissues were collected from mice and analyzed by histology and immunohistochemistry. Conditioned media from cell lines and 3-dimensional spheroid/organoid cultures of cancer cells were applied to C2C12 myotubes. The myotubes and the media were analyzed by immunoblots, enzyme-linked immunosorbent assays, and immunofluorescence microscopy. EVs were isolated from conditioned media and analyzed by immunoblots. RESULTS: Mice with orthotopic tumors grown from pancreatic cancer cells with knockdown of ZIP4 survived longer and lost less body weight and muscle mass than mice with control tumors. Conditioned media from cancer cells activated p38 MAPK, induced expression of F-box protein 32 and UBR2 in C2C12 myotubes, and also led to loss of myofibrillar protein myosin heavy chain and myotube thinning. Knockdown of ZIP4 in cancer cells reduced these effects. ZIP4 knockdown also reduced pancreatic cancer cell release of heat shock protein (HSP) 70 and HSP90, which are associated with EVs, by decreasing CREB-regulated expression of RAB27B. CONCLUSIONS: ZIP4 promotes growth of orthotopic pancreatic tumors in mice and loss of muscle mass by activating CREB-regulated expression of RAB27B, required for release of EVs from pancreatic cancer cells. These EVs activate p38 MAPK and induce expression of F-box protein 32 and UBR2 in myotubes, leading to loss of myofibrillar myosin heavy chain and myotube thinning. Strategies to disrupt these pathways might be developed to reduce pancreatic cancer progression and accompanying cachexia.

Symmetric spin splitting of elliptically polarized vortex beams reflected at air-gold interface via pseudo-Brewster angle.

A simple expression of the transverse spatial spin splitting of light-carrying intrinsic orbital angular momentum (IOAM) is theoretically derived for reflections at strong absorbing media surfaces. By introducing an asymmetric spin splitting (ASS) factor, the transverse spatial symmetric spin splitting (SSS) and ASS of an arbitrary polarized vortex beam can be distinguished. Here, the transverse spatial SSS of an elliptically polarized vortex beam with a phase difference of 90° is predicted when the incident angle is close to the pseudo-Brewster angle. Remarkably, the larger transverse spatial SSS reaches 1100 nm for the incident circularly polarized LG beam with l=3. It is noteworthy that the transverse spatial SSS can be flexibly manipulated by changing the polarized angle, meaning it is theoretically possible to realize fully polarization-controllable transverse spatial SSS for elliptically polarized incident vortex beams. These results could potentially be applied to precision polarization metrology and edge-enhanced imaging.

CFIm25 links alternative polyadenylation to glioblastoma tumour suppression.

The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3' UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3' UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.

A preoperative serum signature of CEA+/CA125+/CA19-9 ≥ 1000 U/mL indicates poor outcome to pancreatectomy for pancreatic cancer.

Pancreatectomy is associated with significant morbidity and unpredictable outcome, with few diagnostic tools to determine, which patients gain the most benefit from this treatment, especially before the operation. This study aimed to define a preoperative signature panel of serum markers to indicate response to pancreatectomy for pancreatic cancer. Over 1000 patients with pancreatic cancer treated at two independent high-volume institutions were included in this study and were divided into three groups, including resected, locally advanced and metastatic. Eight serum tumor markers most commonly used in gastrointestinal cancers were analyzed for patient outcome. Preoperative CA19-9 independently indicated surgical response in pancreatic cancer. Patients with CA19-9 ≥1000 U/mL generally had a poor surgical benefit. However, a subset of these patients still achieved a survival advantage when CA19-9 levels decreased postoperatively. CEA and CA125 in the presence of CA19-9 ≥1000 U/mL could independently predict the non-decrease of CA19-9 postoperatively. The combination of the three markers was useful for predicting a worse surgical outcome with a median survival of 5.1 months vs. 23.0 months (p < 0.001) for the training cohort and 7.0 months vs. 18.2 months (p < 0.001) for the validation cohort and also suggested a higher prevalence of early distant metastasis after surgery. Resected patients with this proposed signature showed no survival advantage over patients in the locally advanced group who did not receive pancreatectomy. Therefore, a preoperative serum signature of CEA(+)/CA125(+)/CA19-9 ≥1000 U/mL is associated with poor surgical outcome and can be used to select appropriate patients with pancreatic cancer for pancreatectomy.

Vertebrate animal models of glioma: understanding the mechanisms and developing new therapies.

Glioblastoma Multiforme (GBM) is recognized as one of the most deadly cancers characterized by cellular atypia, severe necrosis, and high rate of angiogenesis. In this review, we discuss a diversified group of GBM xenograft models and compare them with the genetically engineered mouse (GEM) model systems. Next, we describe common genetic defects observed in GBM and numerous GEM models that recapitulate these abnormalities. Finally, we focus on the clinical value of other vertebrate animal models such as the canine model by examining their contributions to GBM research.