Bone marrow stromal cell antigen 2: Tumor biology, signaling pathway and therapeutic targeting (Review).

Bone marrow stromal cell antigen 2 (BST2) is a type II transmembrane protein that serves critical roles in antiretroviral defense in the innate immune response. In addition, it has been suggested that BST2 is highly expressed in various types of human cancer and high BST2 expression is related to different clinicopathological parameters in cancer. The molecular mechanism underlying BST2 as a potential tumor biomarker in human solid tumors has been reported on; however, to the best of our knowledge, there has been no review published on the molecular mechanism of BST2 in human solid tumors. The present review focuses on human BST2 expression, structure and functions; the molecular mechanisms of BST2 in breast cancer, hepatocellular carcinoma, gastrointestinal tumor and other solid tumors; the therapeutic potential of BST2; and the possibility of BST2 as a potential marker. BST2 is involved in cell membrane integrity and lipid raft formation, which can activate epidermal growth factor receptor signaling pathways, providing a potential mechanistic link between BST2 and tumorigenesis. Notably, BST2 may be considered a universal tumor biomarker and a potential therapeutical target.

Nitrogen vacancy-rich carbon nitride anchored with iron atoms for efficient redox dyshomeostasis under ultrasound actuation.

Traditional Fe-based Fenton reaction for inducing oxidative stress is restricted by random charge transfer without oriental delivery, and the resultant generation of reactive oxygen species (ROS) is always too simplistic to realize a satisfactory therapeutic outcome. Herein, FeNv/CN nanosheets rich in nitrogen vacancies are developed for high-performance redox dyshomeostasis therapy after surface conjugation with polyethylene glycol (PEG) and cyclic Arg-Gly-Asp (cRGD). Surface defects in FeNv/CN serve as electron traps to drive the directional transfer of the excited electrons to Fe atom sites under ultrasound (US) actuation, and the highly elevated electron density promote the catalytic conversion of H2O2 into ·OH. Meanwhile, energy band edges of FeNv/CN favor the production of 1O2 upon interfacial redox chemistry, which is enhanced by the optimal separation/recombination dynamics of electron/hole pairs. Moreover, intrinsic peroxidase-like activity of FeNv/CN contributes to the depletion of reductant glutathione (GSH). Under the anchoring effect of cRGD, PEGylated FeNv/CN can be efficiently enriched in the tumorous region, which is ultrasonically activated for concurrent ROS accumulation and GSH consumption in cytosolic region. The deleterious redox dyshomeostasis not only eradicates primary tumor but also suppresses distant metastasis via antitumor immunity elicitation. Collectively, this study could inspire more facile designs of chalybeates for medical applications.

Molecular pathogenesis, mechanism and therapy of Cav1 in prostate cancer.

Prostate cancer is the second incidence of malignant tumors in men worldwide. Its incidence and mortality are increasing year by year. Enhanced expression of Cav1 in prostate cancer has been linked to both proliferation and metastasis of cancer cells, influencing disease progression. Dysregulation of the Cav1 gene shows a notable association with prostate cancer. Nevertheless, there is no systematic review to report about molecular signal mechanism of Cav1 and drug treatment in prostate cancer. This article reviews the structure, physiological and pathological functions of Cav1, the pathogenic signaling pathways involved in prostate cancer, and the current drug treatment of prostate cancer. Cav1 mainly affects the occurrence of prostate cancer through AKT/mTOR, H-RAS/PLCε, CD147/MMPs and other pathways, as well as substance metabolism including lipid metabolism and aerobic glycolysis. Baicalein, simvastatin, triptolide and other drugs can effectively inhibit the growth of prostate cancer. As a biomarker of prostate cancer, Cav1 may provide a potential therapeutic target for the treatment of prostate cancer.

Molecular mechanisms of syncytin-1 in tumors and placental development related diseases.

Human endogenous retroviruses (HERVs) have evolved from exogenous retroviruses and account for approximately 8% of the human genome. A growing number of findings suggest that the abnormal expression of HERV genes is associated with schizophrenia, multiple sclerosis, endometriosis, breast cancer, bladder cancer and other diseases. HERV-W env (syncytin-1) is a membrane glycoprotein which plays an important role in placental development. It includes embryo implantation, fusion of syncytiotrophoblasts and of fertilized eggs, and immune response. The abnormal expression of syncytin-1 is related to placental development-related diseases such as preeclampsia, infertility, and intrauterine growth restriction, as well as tumors such as neuroblastoma, endometrial cancer, and endometriosis. This review mainly focused on the molecular interactions of syncytin-1 in placental development-related diseases and tumors, to explore whether syncytin-1 can be an emerging biological marker and potential therapeutic target.

Application of role reversal and standardized patient simulation (SPS) in the training of new nurses.

PURPOSE: To explore the effect of role reversal and standardized patient simulation on the training of new nurses. METHOD: This study was conducted in a territory hospital in China between August 2021 and August 2022. The selected staff were all newly recruited and trained nurses, with a total of 58 cases. This study is a randomised controlled trial. The selected nurses were randomly divided into two groups. One group of 29 nurses (the control group) received routine training and assessment; the other group (the experimental group) was given role reversal combined with a standardized vertebral patient training examination. The implementation effects of different training and assessment methods were compared and analysed. RESULTS: Before the training, the core competence scores of nurses in the two groups were lower, and there was no significant data difference (P > 0.05). After training, the core competence scores of nurses were improved, and the score of nurses in the experimental group was 165.49 ± 22.34. The difference was statistically significant when compared with the score of nurses in the control group (P < 0.05), indicating that nurses in the experimental group had better abilities. At the same time, the satisfaction of the two groups of nurses with the training was 96.55% (experimental group) and 75.86% (control group), and the difference in data was significant (P < 0.05). The satisfaction of the experimental group of nurses was higher, and the training effect was better. CONCLUSION: In the training of new nurses, the combined application of role interchange and standardized patient training and assessment methods has significant effects, which can improve the core competency of nurses and improve the training satisfaction of nurses, which is significant.

The Role of Fascin-1 in Human Urologic Cancers: A Promising Biomarker or Therapeutic Target?

Human cancer statistics show that an increased incidence of urologic cancers such as bladder cancer, prostate cancer, and renal cell carcinoma. Due to the lack of early markers and effective therapeutic targets, their prognosis is poor. Fascin-1 is an actin-binding protein, which functions in the formation of cell protrusions by cross-linking with actin filaments. Studies have found that fascin-1 expression is elevated in most human cancers and is related to outcomes such as neoplasm metastasis, reduced survival, and increased aggressiveness. Fascin-1 has been considered as a potential therapeutic target for urologic cancers, but there is no comprehensive review to evaluate these studies. This review aimed to provide an enhanced literature review, outline, and summarize the mechanism of fascin-1 in urologic cancers and discuss the therapeutic potential of fascin-1 and the possibility of its use as a potential marker. We also focused on the correlation between the overexpression of fascin-1 and clinicopathological parameters. Mechanistically, fascin-1 is regulated by several regulators and signaling pathways (such as long noncoding RNA, microRNA, c-Jun N-terminal kinase, and extracellular regulated protein kinases). The overexpression of fascin-1 is related to clinicopathologic parameters such as pathological stage, bone or lymph node metastasis, and reduced disease-free survival. Several fascin-1 inhibitors (G2, NP-G2-044) have been evaluated in vitro and in preclinical models. The study proved the promising potential of fascin-1 as a newly developing biomarker and a potential therapeutic target that needs further investigation. The data also highlight the inadequacy of fascin-1 to serve as a novel biomarker for prostate cancer.

Ultrasound-Activatable g-C3 N4 -Anchored Titania Heterojunction as an Intracellular Redox Homeostasis Perturbator for Augmented Oncotherapy.

Energy band structure of inorganic nano-sonosensitizers is usually optimized by surface decoration with noble metals or metal oxide semiconductors, aiming to enhance interfacial charge transfer, augment spin-flip and promote radical generation. To avoid potential biohazards of metallic elements, herein, metal-free graphitic carbon nitride quantum dots (g-C3 N4 QDs) are anchored onto hollow mesoporous TiO2 nanostructure to formulate TiO2 @g-C3 N4 heterojunction. The direct Z-scheme charge transfer significantly improves the separation/recombination dynamics of electron/hole (e- /h+ ) pairs upon ultrasound (US) stimulation, which promotes the yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH). The conjugated g-C3 N4 QDs with peroxidase-mimic activity further react with the elevated endogenous H2 O2 and aggravate oxidative stress. After loading prodrug romidepsin (RMD) in TiO2 @g-C3 N4 , stimulus-responsive drug delivery can be realized by US irradiation. The disulfide bridge of the released RMD tends to be reduced by glutathione (GSH) into a monocyclic dithiol, which arrests cell cycle in G2/M phase and evokes apoptosis through enhanced histone acetylation. Importantly, reactive oxygen species accumulation accompanied by GSH depletion is devoted to deleterious redox dyshomeostasis, leading to augmented systemic oncotherapy by eliciting antitumor immunity. Collectively, this paradigm provides useful insights in optimizing the performance of TiO2 -based nano-sonosensitizers for tackling critical diseases.

A robust Au@Cu2-xS nanoreactor assembled by silk fibroin for enhanced intratumoral glucose depletion and redox dyshomeostasis.

Intracellular redox dyshomeostasis promoted by tumor microenvironment (TME) modulation has become an appealing therapeutic target for cancer management. Herein, a dual plasmonic Au/SF@Cu2-xS nanoreactor (abbreviation as ASC) is elaborately developed by covalent immobilization of sulfur defective Cu2-xS nanodots onto the surface of silk fibroin (SF)-capped Au nanoparticles. Tumor hypoxia can be effectively alleviated by ASC-mediated local oxygenation, owing to the newfound catalase-mimic activity of Cu2-xS. The semiconductor of Cu2-xS with narrow bandgap energy of 2.54 eV enables a more rapid dissociation of electron-hole (e-/h+) pair for a promoted US-triggered singlet oxygen (1O2) generation, in the presence of Au as electron scavenger. Moreover, Cu2-xS is devote to Fenton-like reaction to catalyze H2O2 into ·OH under mild acidity and simultaneously deplete glutathione to aggravate intracellular oxidative stress. In another aspect, Au nanoparticles with glucose oxidase-mimic activity consumes intrinsic glucose, which contributes to a higher degree of oxidative damage and energy exhaustion of cancer cells. Importantly, such tumor starvation and 1O2 yield can be enhanced by Cu2-xS-catalyzed O2 self-replenishment in H2O2-rich TME. ASC-initiated M1 macrophage activation and therapy-triggered immunogenetic cell death (ICD) favors the systematic tumor elimination by eliciting antitumor immunity. This study undoubtedly enriches the rational design of SF-based nanocatalysts for medical utilizations.

Comparison of short interval and low dose (SILD) with high dose of cyclophosphamide in the susceptibility to infection in SLE: a multicentrereal-world study.

OBJECTIVE: Infection is a major cause of death in patients with SLE. This study aimed to explore the infection rate in patients with SLE receiving a low dose of intravenous cyclophosphamide (IV-CYC). METHODS: Clinical parameters of 1022 patients with SLE from 24 hospitals in China were collected. Patients were divided into the short-interval and lower-dose (SILD, 400 mg every 2 weeks) IV-CYC group and the high-dose (HD, 500 mg/m2 of body surface area every month) IV-CYC group. The clinical data and infection rate between the two groups were compared. RESULTS: Compared with HD IV-CYC, the infection rate of the SILD IV-CYC group was significantly lower (13.04% vs 22.27%, p=0.001). Respiratory tract infection (10.28% vs 15.23%, p=0.046) and skin/soft tissue infection (1.78% vs 4.3%, p=0.040) were significantly decreased in the SILD IV-CYC group. Moreover, infections occurred most likely in patients with SLE with leucopenia (OR 2.266, 95% CI 1.322 to 3.887, p=0.003), pulmonary arterial hypertension (OR 2.756, 95% CI 1.249 to 6.080, p=0.012) and >15 mg/day of glucocorticoid (OR 2.220, 95% CI 1.097 to 4.489, p=0.027). CONCLUSIONS: SILD IV-CYC showed a lower frequency of infection events than high-dose IV-CYC in patients with SLE.

The role of fascin-1 in the pathogenesis, diagnosis and management of respiratory related cancers.

Human cancer statistics report that respiratory related cancers such as lung, laryngeal, oral and nasopharyngeal cancers account for a large proportion of tumors, and tumor metastasis remains the major reason for patient death. The metastasis of tumor cells requires actin cytoskeleton remodeling, in which fascin-1 plays an important role. Fascin-1 can cross-link F-actin microfilaments into bundles and form finger-like cell protrusions. Some studies have shown that fascin-1 is overexpressed in human tumors and is associated with tumor growth, migration and invasion. The role of fascin-1 in respiratory related cancers is not very clear. The main purpose of this study was to provide an updated literature review on the role of fascin-1 in the pathogenesis, diagnosis and management of respiratory related cancers. These studies suggested that fascin-1 can serve as an emerging biomarker and potential therapeutic target, and has attracted widespread attention.

Zirconia-Platinum Nanohybrids for Ultrasound-Activated Sonodynamic-Thermodynamic Bimodal Therapy by Inducing Intense Intracellular Oxidative Stress.

The therapeutic exploration of nano-zirconia semiconductor largely remains untouched in the field of fundamental science to date. Here, a robust nano-sonosensitizer of ZrO2- x @Pt is strategically formulated by in situ growth of Pt nanocrystal onto the surface of oxygen-deficient ZrO2- x . Compared to 3.09 eV of nano-ZrO2- x , the bandgap of ZrO2- x @Pt Schottky junction is narrowed down to 2.74 eV. The band bending and bandgap narrowing enables an enhanced e- /h+ separation in the presence of aPt electron sink, which facilitates a high yield of singlet oxygen (1 O2 ) and hydroxyl radicals (·OH) under ultrasound (US) irradiation. Moreover, nanozyme Pt with catalase-mimic activity can promote 1 O2  generation by relieving the hypoxic tumor microenvironment. Upon further modification of 2,2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH), US-stimulated local thermal shock can disintegrate AIPH to create cytotoxic alkyl radicals (• R). US-triggered reactive oxygen species generation and hyperthermia-induced alkyl radical production lead to severe and irreversible tumor cell death. Such combinatorial sonodynamic-thermodynamic therapy benefits the tumor eradication and metastasis inhibition at the animal level, with the aid of immunogenetic cell death and immune checkpoint blockade. Taken together, this proof-of-concept paradigm expands the medical use of nano-zirconia and provides useful insights for its therapeutic perspectives.

Recent Insight on Regulations of FBXW7 and Its Role in Immunotherapy.

SCFFBXW7 E3 ubiquitin ligase complex is a crucial enzyme of the ubiquitin proteasome system that participates in variant activities of cell process, and its component FBXW7 (F-box and WD repeat domain-containing 7) is responsible for recognizing and binding to substrates. The expression of FBXW7 is controlled by multiple pathways at different levels. FBXW7 facilitates the maturity and function maintenance of immune cells via functioning as a mediator of ubiquitination-dependent degradation of substrate proteins. FBXW7 deficiency or mutation results in the growth disturbance and dysfunction of immune cell, leads to the resistance against immunotherapy, and participates in multiple illnesses. It is likely that FBXW7 coordinating with its regulators and substrates could offer potential targets to improve the sensitivity and effects of immunotherapy. Here, we review the mechanisms of the regulation on FBXW7 and its tumor suppression role in immune filed among various diseases (mostly cancers) to explore novel immune targets and treatments.

The Biocompatibility of Multi-Source Stem Cells and Gelatin-Carboxymethyl Chitosan-Sodium Alginate Hybrid Biomaterials.

BACKGROUND: Nowadays, biological tissue engineering is a growing field of research. Biocompatibility is a key indicator for measuring tissue engineering biomaterials, which is of great significance for the replacement and repair of damaged tissues. METHODS: In this study, using gelatin, carboxymethyl chitosan, and sodium alginate, a tissue engineering material scaffold that can carry cells was successfully prepared. The material was characterized by Fourier transforms infrared spectroscopy. In addition, the prepared scaffolds have physicochemical properties, such as swelling ratio, biodegradability. we observed the biocompatibility of the hydrogel to different adult stem cells (BMSCs and ADSCs) in vivo and in vitro. Adult stem cells were planted on gelatin-carboxymethyl chitosan-sodium alginate (Gel/SA/CMCS) hydrogels for 7 days in vitro, and the survival of stem cells in vitro was observed by live/died staining. Gel/SA/CMCS hydrogels loaded with stem cells were subcutaneously transplanted into nude mice for 14 days of in vivo culture observation. The survival of adult stem cells was observed by staining for stem cell surface markers (CD29, CD90) and Ki67. RESULTS: The scaffolds had a microporous structure with an appropriate pore size (about 80 µm). Live/died staining showed that adult stem cells could stably survive in Gel/SA/CMCS hydrogels for at least 7 days. After 14 days of culture in nude mice, Ki67 staining showed that the stem cells supported by Gel/SA/CMCS hydrogel still had high proliferation activity. CONCLUSION: Gel/SA/CMCSs hydrogel has a stable interpenetrating porous structure, suitable swelling performance and degradation rate, can promote and support the survival of adult stem cells in vivo and in vitro, and has good biocompatibility. Therefore, Gel/SA/CMCS hydrogel is a strong candidate for biological tissue engineering materials.

Silk fibroin-capped metal-organic framework for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy.

Disturbance in redox homeostasis always leads to oxidative damages to cellular components, which inhibits cancer cell proliferation and causes tumor regression. Therefore, synergistic effects arising from cellular redox imbalance together with other treatment modalities are worth further investigation. Herein, a metal-organic framework nanosystem (NMOF) based on coordination between Fe (III) and 4,4,4,4-(porphine-5,10,15,20-tetrayl) tetrakis (benzoic acid) (TCPP) was synthesized through a one-pot method. After surface capping of silk fibroin (SF) to form NMOF@SF nanoparticles (NPs), this nanoplatform can serve as an eligible nanocarrier to deliver tirapazamine (TPZ), a hypoxia-activated precursor. As-developed NS@TPZ (NST) NPs remained inactive in the normal tissue, whereas became highly active upon endocytosis by tumor cells via glutathione (GSH)-mediated reduction of Fe (III) into Fe (II), further enabling Fe (II)-mediated chemodynamic therapy (CDT). Upon optical laser irradiation, TCPP-mediated photodynamic therapy (PDT) coordinated with CDT to aggravate intracellular oxidative stress. Thus, such reactive oxygen species accumulation and GSH deprivation contributed to a deleterious redox dyshomeostasis. On the other hand, local deoxygenation caused by PDT can increase the cytotoxicity of released TPZ, which significantly improved the integral therapeutic effectiveness relying on the combined redox balance disruption and bioreductive chemotherapy. More importantly, severe immunogenic cell death can be triggered by the combinatorial treatment modalities and the presence of SF, which facilitated an almost complete tumor eradication in vivo. Taken together, this paradigm provides an insightful strategy for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy, which can remarkably enhance antitumor efficacy with negligible adverse effects. STATEMENT OF SIGNIFICANCE: Recently, silk fibroin (SF) has been demonstrated to be effective in activating antitumor immune system through polarization tumor-associated macrophages into M1 subtype. However, engineering SF into multifunctional nanocomposites is seldom reported for combination tumor therapy. In another aspect, disruption of redox homeostasis becomes increasingly attractive for tumor suppression with high clinical-relevance. Herein, we established a newfashioned NMOF nanosystem, named as NST, for tumor-specific redox dyshomeostasis treatment synergized by deoxygenation-driven chemotherapy. This platform takes advantages of Fe2+/Fe3+ coupled Fenton-like reaction and GSH depletion, as well as TCPP-mediated photosensitization for admirable redox unbalancing, which further initiates hypoxia-relevant toxin of TPZ for chemotherapy. Finally, combinatorial treatments and the presence of SF could trigger ICD for rendering a complete tumor eradication in vivo.

Acidic TME-Responsive Nano-Bi2 Se3 @MnCaP as a NIR-II-Triggered Free Radical Generator for Hypoxia-Irrelevant Phototherapy with High Specificity and Immunogenicity.

Here, acidic tumor microenvironment (TME)-responsive nano-Bi2 Se3 @MnCaP, as a near-infrared-II (NIR-II) biowindow-triggered free radical generator for hypoxia-irrelevant phototherapy, is elaborately developed by biomimetic mineralization of MnCaP onto 2, 2'-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride (AIPH)-loaded mesoporous nano-Bi2 Se3 to form Bi2 Se3 /AIPH@MnCaP (BAM). Surface mineral of MnCaP can be degraded under mild acidity, leading to the release of both Mn2+ and AIPH. The leached Mn2+ not only facilitates chemodynamic therapy (CDT) via hydroxyl radicals (• OH) from Mn2+ -mediated Fenton-like reaction but also acts as contrast agent for magnetic resonance imaging. In another aspect, the splendid photothermal conversion capacity of BAM enables a rapid hyperthermia generation under NIR-II laser irradiation for photothermal therapy (PTT). Simultaneously, the local thermal shock can induce the disintegration of AIPH to generate alkyl radicals (• R) for thermodynamic therapy (TDT) and accelerate Fenton-like reaction rate to augment CDT efficacy. The strong synergistic effects from cooperative CDT/PTT/TDT are applied to 4T1 tumor suppression with minimal side effects. Importantly, the combination therapy can effectively trigger immunogenetic cell death and enhance antitumor immunity for systemic tumor eradication. Collectively, this proof-of-concept study demonstrates a more efficacious and safer strategy for oxygenation-independent phototherapy, which holds a good potential for clinical translation in cancer management.

Implication of human endogenous retrovirus W family envelope in hepatocellular carcinoma promotes MEK/ERK-mediated metastatic invasiveness and doxorubicin resistance.

Human endogenous retrovirus (HERVs), originating from exogenous retroviral infections of germ cells millions of years ago, have the potential for human diseases. Syncytin-1, an envelope protein encoded by the HERV W family, participates in the contexts of schizophrenia, multiple sclerosis, diabetes, and several types of cancers. Nevertheless, there is no report on the expression pattern and potential mechanism of Syncytin-1 in HCC. Here we found Syncytin-1 expression was up-regulated in HCC compared to adjacent non-tumorous tissues, especially in advanced HCC. Syncytin-1 was an independent risk factor to predict vascular invasion, metastasis, larger tumor size, and poor prognosis in HCC patients. Further analysis discovered that Syncytin-1 overexpression positively associated with HCC patients with serum HBsAg positive. Functional experiments in vitro and in vivo demonstrated that Syncytin-1 enhanced cell proliferation, metastasis, and tumorigenicity in HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the mitogen-activated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK) pathway was involved in HCC. Our clinical data indicated that the levels of phosphorylation MEK1/2 and ERK1/2 were increased in HCC comparing with adjacent non-tumorous tissues. It showed the linear correlation between Syncytin-1 expression and upregulated MEK1/2 and ERK1/2 phosphorylation levels in HCC. Furthermore, Syncytin-1 activated MEK/ERK pathway in HCC cells. In-depth research showed that the inflammation-activated MEK/ERK pathway was essential in Syncytin-1 promoted hepatocarcinogenesis. Syncytin-1 suppressed doxorubicin-induced apoptosis via MEK/ERK cascade. In conclusion, Syncytin-1 promoted HCC progression and doxorubicin resistance via the inflammation-activated MEK/ERK pathway. Our findings revealed that Syncytin-1 was a potential prognostic biomarker and therapeutic target for HCC.

Lacrimal gland budding requires PI3K-dependent suppression of EGF signaling.

The patterning of epithelial buds is determined by the underlying signaling network. Here, we study the cross-talk between phosphoinositide 3-kinase (PI3K) and Ras signaling during lacrimal gland budding morphogenesis. Our results show that PI3K is activated by both the p85-mediated insulin-like growth factor (IGF) and Ras-mediated fibroblast growth factor (FGF) signaling. On the other hand, PI3K also promotes extracellular signal-regulated kinase (ERK) signaling via a direct interaction with Ras. Both PI3K and ERK are upstream regulators of mammalian target of rapamycin (mTOR), and, together, they prevent expansion of epidermal growth factor (EGF) receptor expression from the lacrimal gland stalk to the bud region. We further show that this suppression of EGF signaling is necessary for induction of lacrimal gland buds. These results reveal that the interplay between PI3K, mitogen-activated protein kinase, and mTOR mediates the cross-talk among FGF, IGF, and EGF signaling in support of lacrimal gland development.