Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.

Vitamin B6 Competition in the Tumor Microenvironment Hampers Antitumor Functions of NK Cells.

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC. SIGNIFICANCE: The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models. This article is featured in Selected Articles from This Issue, p. 5.

Mechanical properties and crack evolution characteristics of fractured rock with hidden fissures.

Natural defects, such as joints, structural surfaces and voids, significantly affect the mechanical properties and fracture modes of rock mass. Hidden fissures are widely distributed in magmatic rock, while their influences on the mechanical properties and the cracking mechanism are still unclear. Laboratory tests were conducted on prefabricating hidden-fissured rock-like specimens, as well as intact specimens and close-fissured specimens as a comparison. The real-time digital image correlation technology and acoustic emission monitoring technology were synchronously adopted to capture both the external and internal cracking process. The results show that the hidden fissures can weaken the uniaxial compression strength, while the deterioration effect of hidden fissures is weaker than closed fissures due to the internal cohesion among fissure internal particles. What's more, the initiation behavior of the α = 90° hidden-fissured specimen is different from that of ß = 90° closed-fissured specimen. Finally, the cracking mechanism of hidden-fissured specimens was revealed by analyzing the RA-AF relationship. The failure of the close-fissured specimens is mainly the tensile-shear mixed fracture mode, while the failure of the hidden-fissured specimens is mainly the tensile fracture mode and supplemented by the shear. The experimental results contribute to the understanding of cracking properties in hidden-fissured rock.

FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells.

Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by providing the necessary physical support and microenvironment for follicular development, play critical roles in maintaining female fertility. We previously showed that ectopic expression of four and a half LIM domains 2 (FHL2) promoted ovarian granulosa cell tumor progression. However, its function in follicular development and fertility remains unknown. Here, we confirmed that FHL2 is highly expressed in human and mouse ovaries. FHL2 immunosignals were predominantly expressed in ovarian GCs. A Fhl2 knockout (KO) mouse model was generated to examine its roles in follicular development and fertility. Compared with wildtype, knockout of Fhl2 significantly decreased female litter size and offspring number. Furthermore, Fhl2 deficiency reduced ovarian size and impaired follicular development. RNA-sequencing analysis of GCs isolated from either KO or WT mice revealed that, Fhl2 deletion impaired multiple biological functions and signaling pathways, such as Ovarian Putative Early Atresia Granulosa Cell, ErbB, Hippo/YAP, etc. In vitro studies confirmed that FHL2 silencing suppressed GCs growth and EGF-induced GCs proliferation, while its overexpression promoted GC proliferation and decreased apoptosis. Mechanistic studies indicated that FHL2, via forming complexes with transcriptional factors AP-1 or NF-κB, regulated Egf and Egfr expression, respectively. Besides, FHL2 depletion decreased YAP1 expression, especially the active form of YAP1 (nuclear YAP1) in GCs of growing follicles. EGF, serving as an autocrine/paracrine factor, not only induced FHL2 expression and nuclear accumulation, but also stimulated YAP1 expression and activation. Collectively, our study suggests that FHL2 interacts with EGFR and Hippo/YAP signaling to regulate follicular development and maintain fertility. This study illuminates a novel mechanism for follicular development and a potential therapeutic target to address subfertility.

Clinical Application of Individualized 3D-Printed Chest Wall Conformal Device in IMRT for Post-Mastectomy Breast Cancer.

Background Breast cancer is the most common malignant tumour in women. Radical mastectomy with postoperative radiotherapy is now the standard treatment for locally advanced breast cancer. Intensity-modulated radiotherapy (IMRT) has now been developed, which employs linear accelerators to deliver precise radiation to a tumour while minimizing the dose to surrounding normal tissue. It significantly improves the efficacy of breast cancer treatment. However, there are still some flaws that must be addressed. Objective To assess the clinical application of the three-dimensional (3D)-printed chest wall conformal device for breast cancer patients who need to be treated by chest wall intensity modulated radiotherapy (IMRT) after radical mastectomy. Methods The 24 patients were divided into three groups. During a computed tomography (CT) scan, patients in the study group were fixed by a 3D-printed chest wall conformal device, nothing in control group A, and a traditional 1-cm thick silica gel compensatory pad on the chest wall in control group B. The parameters of mean Dmax, Dmean, D2%, D50%, D98%, the conformity index (CI), and the homogeneity index (HI) of the planning target volume (PTV) are compared. Results The study group had the best dose uniformity (HI = 0.092) and the highest conformation (CI = 0.97), the worst in control group A (HI = 0.304, CI = 0.84). The mean Dmax, Dmean, and D2% of the study group were lower than control groups A and B (p<0.05). The mean D50% was higher than control group B (p<0.05), while the mean D98% was higher than control groups A and B (p<0.05). The mean Dmax, Dmean, D2%, and HI of control group A were higher than control group B (p<0.05), whereas the mean D98% and CI were lower than control group B (p<0.05). Conclusion By improving the efficacy of postoperative radiotherapy for breast cancer, using 3D-printed chest wall conformal devices may greatly improve the accuracy of repeating position fixation, increase the dose on the skin surface of the chest wall, optimise the dose distribution of the target area, and thus further reduce tumour recurrence and prolong patients' survival.

ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.

Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in pancreatic cancer.

Identification of DDX60 as a Regulator of MHC-I Class Molecules in Colorectal Cancer.

Immune checkpoint blockade (ICB) therapies induce durable responses in approximately 15% of colorectal cancer (CRC) patients who exhibit microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR). However, more than 80% of CRC patients do not respond to current immunotherapy. The main challenge with these patients is lack of MHC-I signaling to unmask their cancer cells so the immune cells can detect them. Here, we started by comparing IFNγ signature genes and MHC-I correlated gene lists to determine the potential candidates for MHC-I regulators. Then, the protein expression level of listed potential candidates in normal and cancer tissue was compared to select final candidates with enough disparity between the two types of tissues. ISG15 and DDX60 were further tested by wet-lab experiments. Overexpression of DDX60 upregulated the expression of MHC-I, while knockdown of DDX60 reduced the MHC-I expression in CRC cells. Moreover, DDX60 was downregulated in CRC tissues, and lower levels of DDX60 were associated with a poor prognosis. Our data showed that DDX60 could regulate MHC-I expression in CRC; thus, targeting DDX60 may improve the effects of immunotherapy in some patients.

Human papillomavirus targets the YAP1-LATS2 feedback loop to drive cervical cancer development.

Human papillomavirus (HPV) infection is very common in sexually active women, but cervical cancer only develops in a small fraction of HPV-infected women, suggesting that unknown intrinsic factors associated with the unique genetic/genomic background of the high-risk population play a critical role in cervical carcinogenesis. Although our previous studies have identified the hyperactivated YAP1 oncogene as a critical contributor to cervical cancer, the molecular mechanism by which YAP1 drives cervical cancer is unknown. In the present study, we found that although the hyperactivated YAP1 caused a malignant transformation of immortalized cervical epithelial cells, it induced cellular senescence in cultures of primary human cervical epithelial cells (HCvECs). However, the hyperactivated YAP1 induced malignant transformation of HCvECs in the presence of high-risk HPV E6/E7 proteins, suggesting that the hyperactivated YAP1 synergizes with HPV to initiate cervical cancer development. Our mechanistic studies demonstrate that YAP1, via up-regulating LATS2, formed a YAP1-LATS2 negative feedback loop in cervical epithelial cells to maintain homeostasis of cervical tissue. Intriguingly, we found that high-risk HPV targets LATS2 to disrupt the feedback loop leading to the malignant transformation of cervical epithelial cells. Finally, we report that mitomycin C, an FDA-approved drug that could upregulate LATS2 and drive cellular senescence in vitro and in vivo, induced a regression of cervical cancer in a pre-clinial animal model. Thus, high-risk HPV targeting the YAP1-LATS2 feedback loop represents a new mechanism of cervical cancer development.

Pulmonary Delivery of Theranostic Nanoclusters for Lung Cancer Ferroptosis with Enhanced Chemodynamic/Radiation Synergistic Therapy.

Inefficient tumor accumulation and penetration remain as the main challenges to therapy efficacy of lung cancer. Local delivery of smart nanoclusters can increase drug penetration and provide superior antitumor effects than systemic routes. Here, we report self-assembled pH-sensitive superparamagnetic iron oxide nanoclusters (SPIONCs) that enhance in situ ferroptosis and apoptosis with radiotherapy and chemodynamic therapy. After pulmonary delivery in orthotopic lung cancer, SPIONCs disintegrate into smaller nanoparticles and release more iron ions in an acidic microenvironment. Under single-dose X-ray irradiation, endogenous superoxide dismutase converts superoxide radicals produced by mitochondria to hydrogen peroxide, which in turn generates hydroxyl radicals by the Fenton reaction from iron ions accumulated inside the tumor. Finally, irradiation and iron ions enhance tumor lipid peroxidation and induce cell apoptosis and ferroptosis. Thus, rationally designed pulmonary delivered nanoclusters provide a promising strategy for noninvasive imaging of lung cancer and synergistic therapy.

CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.

Metabolic alterations regulate cancer aggressiveness and immune responses. Given the poor response of pancreatic ductal adenocarcinoma (PDAC) to conventional immunotherapies, we investigated the link between metabolic alterations and immunosuppression. Our metabolic enzyme screen indicated that elevated expression of CD73, an ecto-5'-nucleotidase that generates adenosine, correlates with increased aggressiveness. Correspondingly, we observed increased interstitial adenosine levels in tumors from spontaneous PDAC mouse models. Diminishing CD73 by genetic manipulations ablated in vivo tumor growth, and decreased myeloid-derived suppressor cells (MDSC) in orthotopic mouse models of PDAC. A high-throughput cytokine profiling demonstrated decreased GM-CSF in mice implanted with CD73 knockdowns. Furthermore, we noted increased IFN-γ expression by intratumoral CD4+ and CD8+ T cells in pancreatic tumors with CD73 knockdowns. Depletion of CD4+ T cells, but not CD8+ T cells abrogated the beneficial effects of decreased CD73. We also observed that splenic MDSCs from Nt5e knockdown tumor-bearing mice were incompetent in suppressing T cell activation in the ex vivo assays. Replenishing GM-CSF restored tumor growth in Nt5e knockout tumors, which was reverted by MDSC depletion. Finally, anti-CD73 antibody treatment significantly improved gemcitabine efficacy in orthotopic models. Thus, targeting the adenosine axis presents a novel therapeutic opportunity for improving the anti-tumoral immune response against PDAC.

Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.

BACKGROUND & AIMS: SIRT5 plays pleiotropic roles via post-translational modifications, serving as a tumor suppressor, or an oncogene, in different tumors. However, the role SIRT5 plays in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) remains unknown. METHODS: Published datasets and tissue arrays with SIRT5 staining were used to investigate the clinical relevance of SIRT5 in PDAC. Furthermore, to define the role of SIRT5 in the carcinogenesis of PDAC, we generated autochthonous mouse models with conditional Sirt5 knockout. Moreover, to examine the mechanistic role of SIRT5 in PDAC carcinogenesis, SIRT5 was knocked down in PDAC cell lines and organoids, followed by metabolomics and proteomics studies. A novel SIRT5 activator was used for therapeutic studies in organoids and patient-derived xenografts. RESULTS: SIRT5 expression negatively regulated tumor cell proliferation and correlated with a favorable prognosis in patients with PDAC. Genetic ablation of Sirt5 in PDAC mouse models promoted acinar-to-ductal metaplasia, precursor lesions, and pancreatic tumorigenesis, resulting in poor survival. Mechanistically, SIRT5 loss enhanced glutamine and glutathione metabolism via acetylation-mediated activation of GOT1. A selective SIRT5 activator, MC3138, phenocopied the effects of SIRT5 overexpression and exhibited antitumor effects on human PDAC cells. MC3138 also diminished nucleotide pools, sensitizing human PDAC cell lines, organoids, and patient-derived xenografts to gemcitabine. CONCLUSIONS: Collectively, we identify SIRT5 as a key tumor suppressor in PDAC, whose loss promotes tumorigenesis through increased noncanonic use of glutamine via GOT1, and that SIRT5 activation is a novel therapeutic strategy to target PDAC.

MCRT, a multifunctional ligand of opioid and neuropeptide FF receptors, attenuates neuropathic pain in spared nerve injury model.

Chimeric peptide MCRT (YPFPFRTic-NH2 ) was a multifunctional ligand of opioid and neuropeptide FF (NPFF) receptors and reported to be potentially antalgic in acute tail-flick test. Here, we developed spared nerve injury (SNI) model to explore its efficacy in chronic neuropathic pain. Analgesic tolerance, opioid-induced hyperalgesia and gastrointestinal transit were measured for safety evaluation. Intracerebroventricular (i.c.v.) and intraplantar (i.pl.) injections were conducted as central and peripheral routes, respectively. Results demonstrated that MCRT alleviated neuropathic pain effectively and efficiently, with the ED50 values of 4.93 nmol/kg at the central level and 3.11 nmol/kg at the peripheral level. The antagonist blocking study verified the involvement of mu-, delta-opioid and NPFF receptors in MCRT produced anti-allodynia. Moreover, the separation of analgesia from unwanted effects was preliminarily achieved and that MCRT caused neither analgesic tolerance nor hyperalgesia after chronic i.c.v. administration, nor constipation after i.pl. administration. Notably, the local efficacy of MCRT in SNI mice was about one thousandfold higher than morphine and ten thousandfold higher than pregabalin, indicating a great promise in the future treatment of neuropathic pain.

Three-Dimensionally-Precise Breast Conformal Device for IMRT in Breast Cancer Patients Treated With Breast-Conserving Surgery-A Pilot Randomized Controlled Trial.

OBJECTIVE: To examine the accuracy and efficiency of breast radiotherapy after breast-conserving surgery of a novel 3-dimensional (3D) printing tissue compensator technology, the 3D-precise breast conformer, compared with a usual compensator and an unstructured compensator. METHODS: This novel device is patented in China (patent No.: ZL2015 2 0259472.9). Thirty patients with breast cancer after breast-conserving surgery were randomly divided into 2 control groups (no compensator, NST group, and usual compensator, ST group) and 1 study group (3D-precise breast conformer, 3D-BCT group) (n = 10/group). Before radiotherapy, all patients were scanned in the same CT positioning conditions to prepare the treatment plans. RESULTS: The 3D-BCT showed the best homogeneity index (HI) (0.08 ± 0.03) and conformity index (CI) (0.95 ± 0.03), while the NST group showed the worst HI (0.34 ± 0.07) and CI (0.78 ± 0.06), with the ST group between the 2 (HI: 0.15 ± 0.05; CI: 0.87 ± 0.04) (all P < 0.01). The common tissue compensation membrane could lead to 95-100% of the prescription dose covering 85-95% of the target volume, and the uniformity and conformability of the target dose were improved overall compared with the NST group. In the 3D-BCT group, 100% of the prescription dose covered the target volume of 95-100%. CONCLUSION: The 3D-precision breast conformal device had the highest individualization, uniformity, and conformity. The V95, V98, CI, and HI of PTV were optimal in the 3D-BCT group, and an ideal isodose curve distribution of the breast and clavicle upper and lower target areas was achieved. This device could improve the surface dose and the efficacy of radiotherapy after breast-conserving surgery.

Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis.

Epithelial ovarian cancer (EOC) is one of the most lethal gynecologic malignancies. To date, the etiology of this deadly disease remains elusive. FHL2, a member of the four and a half LIM domain family, has been shown to serve either as an oncoprotein or as a tumor suppressor in various cancers. Our previous study showed that FHL2 plays a critical role in the initiation and progression of ovarian granulosa cell tumor via regulating AKT1 transcription. However, direct and systematic evidence of FHL2 in the initiation and progression of EOC remains unclear. In the present study, immunohistochemical analysis from EOC patient tissues showed that positivity and intensity of FHL2 immunosignal were up-regulated in the EOC tissues compared with normal ovary tissues. Knockdown of FHL2 in SKOV-3 cell line reduced cell growth and cell viability, blocked cell cycle progression, and inhibited cell migration. Ectopic expression of FHL2 in IGROV-1 cells which have low endogenous FHL2, promoted cell growth, improved cell viability and enhanced cell migration. Additionally, knock down of FHL2 in the SKOV-3 cell line significantly inhibited anchorage-independent growth indicated by the soft agar assay. In comparison, overexpression of FHL2 in IGROV-1 cell improved the colonies growth in soft agar. Western blot data showed that knockdown of FHL2 downregulated AKT expression level, and upregulated apoptosis related proteins such as cleaved PARP, and cleaved-lamin A. Finally, by employing stable SKOV-3/FHL2 stable knock down cell line, our data clearly showed that knockdown of FHL2 inhibited EOC xenograft initiation in vivo. Taken together, our results showed that FHL2, via regulating cell proliferation, cell cycle, and adhesion, has a critical role in regulating EOC initiation and progression. These results indicate that FHL2 could be a potential target for the therapeutic drugs against EOC.

Long non-coding RNA LINC01116 regulated miR-744-5p/SCN1B axis to exacerbate lung squamous cell carcinoma.

BACKGROUND: Lung squamous cell carcinoma (LUSC) is a kind of lung cancer which possesses high morbidity and mortality. Long non-coding RNAs (lncRNAs) have been abundantly reported to participate in regulating cellular activities of various diseases, including cancers. LINC01116 was reported as a tumor promoter in some cancers, whereas its function has not been clarified in LUSC. OBJECTIVE: This exploration aimed to study the modulatory role of LINC01116 in LUSC. METHODS: The expressions of LINC01116, miR-744-5p and SCN1B were determined by RT-qPCR. CCK-8, EdU and transwell assays were conducted to evaluate the proliferative, migratory and invasive abilities of A549 and H1299 cells. The protein expression of SCN1B or EMT-associated proteins was examined through western blot assay. The interaction between miR-744-5p and LINC01116 (or SCN1B) was confirmed by RNA pull down and luciferase reporter assays. RESULTS: LINC01116 was up-regulated in LUSC tissues and cells, and LINC01116 repression limited the proliferative, migratory, invasive capabilities and EMT process in LUSC cells. In mechanism, LINC01116 directly interacted with miR-744-5p, and its expression was negatively correlated with miR-744-5p expression. SCN1B, overexpressed in LUSC tissues and cells, was proved to be targeted by miR-744-5p. Furthermore, SCN1B expression was in a negative association with miR-744-5p expression. At last, SCN1B amplification recovered the inhibitive effect of LINC01116 knockdown on cell proliferation, migration, invasion and EMT process in LUSC. CONCLUSION: LINC01116 regulated miR-744-5p/SCN1B axis to exacerbate LUSC, providing a helpful theoretic basis for the exploration of LUSC treatment.

Endokinin A/B stimulates rat gastric motility through myogenic NK1 receptors located in the fundus.

Endokinin A/B (EKA/B), the common C-terminal decapeptide in endokinins A and B, is a preferred ligand of the NK1 receptor and regulates pain and itch. The study focused on the effects of EKA/B on rat gastric motility in vivo and in vitro. Gastric emptying was measured to evaluate gastric motility in vivo. Intragastric pressure and the contraction of gastric muscle strips were measured to evaluate gastric motility in vitro. Moreover, various neural blocking agents and neurokinin receptor antagonists were applied to explore the mechanisms. TAC4 and TACR1 mRNAs were expressed throughout rat stomach. EKA/B promoted gastric emptying by intraperitoneal injection in vivo. Correspondingly, EKA/B also increased intragastric pressure in vitro. Additionally, EKA/B contracted the gastric muscle strips from the fundus but not from the corpus or antrum. Further studies revealed that the contraction induced by EKA/B on muscle strips from the fundus could be significantly reduced by NK1 receptor antagonist SR140333 but not by NK2 receptor antagonist, NK3 receptor antagonist, or the neural blocking agents used. Our results suggested that EKA/B might stimulate gastric motility mainly through the direct activation of myogenic NK1 receptors located in the fundus.

Magnetic-activated carbon composites derived from iron sludge and biological sludge for sulfonamide antibiotic removal.

Novel magnetic-activated carbon composites (MACs) were synthesized via coupling of a glucose-assisted hydrothermal pretreatment and subsequent thermal treatment using iron sludge and biological sludge. The adsorption properties of MACs for sulfonamide antibiotic removal from aqueous solution were investigated. Results revealed that the MACs had a high specific surface area with well-distributed magnetic nano-sized Fe3O4/Fe0 particles with a graphitic shell. This finding indicates that the ferric compounds in the iron sludge were not only converted into magnetic ferrite but also worked as activators for graphitization of the surrounding amorphous carbon. The pseudo-second-order kinetics and Langmuir models were shown to well fit sulfonamide antibiotic adsorption on the MACs. There was a high correlation between the kl·qm and physicochemical parameters of the sulfonamides. The three parameters are molecular polarizability, octanol-water partition coefficient, and solubility, respectively. The sulfonamide adsorption by the MACs was highly pH dependent. Hydrophobic interaction, π-π interaction, as well as electrostatic interaction, played dominant roles in the sulfonamide adsorption.

Reprogramming of Ovarian Granulosa Cells by YAP1 Leads to Development of High-Grade Cancer with Mesenchymal Lineage and Serous Features.

Understanding the cell-of-origin of ovarian high grade serous cancer (HGSC) is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological cancer. Recently, a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS studies. The cell-of-origin of this subtype of ovarian cancer is unknown. While pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology, we unexpectedly found that the Yes-associated protein 1 (YAP1), the major effector of the Hippo signaling pathway, induced dedifferentiation and reprogramming of the ovarian granulosa cells, a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity, leading to the development of high grade ovarian cancer with serous features. Our research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development.

Although the role of the Hippo signaling pathway in development and tumorigenesis has been extensively studied in multiple organs, its role in ovarian follicle development remains largely unknown. Here, we report that Yes-Associated Protein 1 (YAP1), the major effector of Hippo signaling, is spatiotemporally expressed in ovarian granulosa cells and plays a critical role in the regulation of follicle development. We found that the active form of YAP1 (nuclear YAP1) was predominantly expressed in proliferative granulosa cells, whereas the inactive form of YAP1 (cytoplasmic YAP1) was mainly detected in luteal cells (terminally differentiated granulosa cells). Pharmacological inhibition of YAP1 activity disrupted mouse ovarian follicle development in vitro and in vivo. Foxl2 promoter-driven knockout of Yap1 in ovarian granulosa cells resulted in increased apoptosis of granulosa cells, decreased number of corpora lutea, reduced ovarian size, and subfertility in transgenic mice. However, Cyp19a1 promoter-driven knockout of Yap1 in differentiated granulosa cells of preovulatory follicles and luteal cells of corpora lutea had no effect on ovarian morphology and fertility. Mechanistic studies demonstrated that YAP1 interacted with epidermal growth factor receptor and TGF-ß signaling pathways to regulate granulosa cell proliferation, differentiation, and survival. Results from this study identify YAP1 as a critical regulator of granulosa cell proliferation and differentiation. Balanced expression and activation of YAP1 is essential for follicle development and successful reproduction. YAP1 is a promising target for treatment of subfertility associated with abnormal granulosa cell function.-Lv, X., He, C., Huang, C., Wang, H., Hua, G., Wang, Z., Zhou, J., Chen, X., Ma, B., Timm, B. K., Maclin, V., Dong, J., Rueda, B. R., Davis, J. S., Wang, C. Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development.