Strongly-Confined CsPbBr3 Perovskite Quantum Dots with Ultralow Trap Density and Narrow Size Distribution for Efficient Pure-Blue Light-Emitting Diodes.

The development of pure-blue perovskite light-emitting diodes (PeLEDs) faces challenges of spectral stability and low external quantum efficiency (EQE) due to phase separation in mixed halide compositions. Perovskite quantum dots (QDs) with strong confinement effects are promising alternatives to achieve high-quality pure-blue PeLEDs, yet their performance is often hindered by the poor size distribution and high trap density. A strategy combining thermodynamic control with a polishing-driven ligand exchange process to produce high-quality QDs is developed. The strongly-confined pure-blue (≈470 nm) CsPbBr3 QDs exhibit narrow size distribution (12% dispersion) and are achieved in Br-rich ion environment based on growth thermodynamic control. Subsequent polishing-driven ligand exchange process removes imperfect surface sites and replaces initial long-chain organic ligands with short-chain benzene ligands. The resulting QDs exhibit high photoluminescence quantum yield (PLQY) to near-unity. The resulting PeLEDs exhibit a pure-blue electroluminescence (EL) emission at 472 nm with narrow full-width at half-maximum (FWHM) of 25 nm, achieving a maximum EQE of 10.7% and a bright maximum luminance of 7697 cd m-2. The pure-blue PeLEDs show ultrahigh spectral stability under high voltage, a low roll-off of EQE, and an operational half-lifetime (T50) of 127 min at an initial luminance of 103 cd m-2 under continuous operation.

The implicated role of GDF15 in gastrointestinal cancer.

BACKGROUND: Growth differentiation factor 15 (GDF15), a stress-responsive cytokine from transforming growth factor superfamily, is highly expressed in mammalian tissues, including pancreas, stomach and intestine under pathological conditions. In particular, elevated levels of GDF15 might play an important role in the development and progression of various gastrointestinal cancers (GCs), suggesting its potential as a promising target for disease prediction and treatment. METHODS: In this review, systematic reviews addressing the role of GDF15 in GCs were updated, along with the latest clinical trials focussing on the GDF15-associated digestive malignancies. RESULTS: The multiple cellular pathways through which GDF15 is involved in the regulation of physiological and pathological conditions were first summarized. Then, GDF15 was also established as a valuable clinical index, functioning as a predictive marker in diverse GCs. Notably, latest clinical treatments targeting GDF15 were also highlighted, demonstrating its promising potential in mitigating and curing digestive malignancies. CONCLUSIONS: This review unveils the pivotal roles of GDF15 and its potential as a promising target in the pathogenesis of GCs, which may provide insightful directions for future investigations.

Glutamine addiction in tumor cell: oncogene regulation and clinical treatment.

After undergoing metabolic reprogramming, tumor cells consume additional glutamine to produce amino acids, nucleotides, fatty acids, and other substances to facilitate their unlimited proliferation. As such, the metabolism of glutamine is intricately linked to the survival and progression of cancer cells. Consequently, targeting the glutamine metabolism presents a promising strategy to inhibit growth of tumor cell and cancer development. This review describes glutamine uptake, metabolism, and transport in tumor cells and its pivotal role in biosynthesis of amino acids, fatty acids, nucleotides, and more. Furthermore, we have also summarized the impact of oncogenes like C-MYC, KRAS, HIF, and p53 on the regulation of glutamine metabolism and the mechanisms through which glutamine triggers mTORC1 activation. In addition, role of different anti-cancer agents in targeting glutamine metabolism has been described and their prospective applications are assessed.

Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To evaluate the diagnostic accuracy of aspartate aminotransferase(AST)/ alanine transaminase (ALT), AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4) and gamma-glutamyl transpeptidase to platelet count ratio (GPR) for hepatic fibrosis in patients with chronic hepatitis B (CHB). METHODS: A total of 1210 CHB patients who underwent liver biopsy were divided into two groups: patients with no significant fibrosis (control group) and patients with significant fibrosis, and routine laboratory tests were retrospectively included. Logistic regression models were used for the prediction, and the area under the receiver operating characteristic (AUROC) was used to assess the diagnostic accuracy. RESULTS: A total of 631 (52.1%) and 275 (22.7%) patients had significant fibrosis (≥ S2) and advanced fibrosis (≥ S3), respectively. The GPR showed significantly higher diagnostic accuracy than that of APRI, FiB-4, and AST/ALT to predict ≥ S2(significant fibrosis) and ≥ S3 fibrosis(advanced fibrosis), with an AUROC was 0.69 (95%CI: 0.66-0.71) and 0.72 (0.69-0.75), respectively. After stratified by the status of HBeAg ( positive or negative), GPR, APRI, and FiB-4 showed improved predicting performance for significant fibrosis and advanced fibrosis in HBeAg positive patients, with the most significant improvement was shown for GPR in predicting significant fibrosis (AUROC = 0.74, 95%CI: 0.70-0.78). CONCLUSIONS: Among the four noninvasive models, GPR has the best performance in the diagnosis of hepatic fibrosis in CHB patients and is more valuable in HBeAg-positive patients.

Natural Product-Based Glycolysis Inhibitors as a Therapeutic Strategy for Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Resistant Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide. Targeted therapy against the epidermal growth factor receptor (EGFR) is a promising treatment approach for NSCLC. However, resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge in its clinical management. EGFR mutation elevates the expression of hypoxia-inducible factor-1 alpha to upregulate the production of glycolytic enzymes, increasing glycolysis and tumor resistance. The inhibition of glycolysis can be a potential strategy for overcoming EGFR-TKI resistance and enhancing the effectiveness of EGFR-TKIs. In this review, we specifically explored the effectiveness of pyruvate dehydrogenase kinase inhibitors and lactate dehydrogenase A inhibitors in combating EGFR-TKI resistance. The aim was to summarize the effects of these natural products in preclinical NSCLC models to provide a comprehensive understanding of the potential therapeutic effects. The study findings suggest that natural products can be promising inhibitors of glycolytic enzymes for the treatment of EGFR-TKI-resistant NSCLC. Further investigations through preclinical and clinical studies are required to validate the efficacy of natural product-based glycolytic inhibitors as innovative therapeutic modalities for NSCLC.

Spatiotemporal geographically weighted regression analysis for runoff variations in the Weihe River Basin.

In order to investigate the effects of vegetation changes on runoff and to obtain recommendations for improving runoff in the Weihe River Basin (. In this study, a spatiotemporal geographic autocorrelation weighted regression analysis (SGAWRA) approach was newly developed based on previous studies. This approach investigates spatial non-stationarity of the dynamic response from vegetation variations to climatic change and human activity. Implications of spatial non-stationarity related to runoff variability were also discussed, which in turn yield the effect that vegetation changes have on runoff. The method systematically analysed the spatial non-stationarity of vegetation variations and its associated effects on runoff. Therefore, more closely related results with less error were produced at each step, and results with more accuracy were obtained. These results indicated that the average trend rates of NDVI in the annual average, each season, and the growing season (Growing season refers to April to September) exceeded 0. Areas where NDVI show a growing trend cover more than 50%, which is greater than the area with a decreasing trend. The GWR regression parameters of precipitation, average temperature, and NDVI are all greater than 0. The GWR regression parameters of human activities and NDVI also have more than 50% of the area greater than 0. Based on the visual analysis of the calculation results, it can be seen that there are obvious spatial trends in the data, and the spatial data are significantly different between different regions. Therefore, WRB can be regarded as spatio-temporally non-stationary. In the WRB, the underlying surface change with vegetation change as the prominent feature is the leading cause (about 60%) of the runoff attenuation. The results showed that WRB has spatial and temporal non-stationarity. The spatial non-stationarity of vegetation has a greater effect on runoff changes. The results of this study support recommendations for improving runoff in the WRB.

Overview of growth differentiation factor 15 in metabolic syndrome.

Growth and differentiation factor 15 (GDF15) is a member of the transforming growth factor-ß (TGF-ß) superfamily. GDF15 has been linked with several metabolic syndrome pathologies such as obesity and cardiovascular diseases. GDF15 is considered to be a metabolic regulator, although its precise mechanisms of action remain to be determined. Glial cell-derived neurotrophic factor family receptor alpha-like (GRAL), located in the hindbrain, has been identified as the receptor for GDF15 and signals through the coreceptor receptor tyrosine kinase (RET). Administration of GDF15 analogues in preclinical studies using various animal models has consistently been shown to induce weight loss through a reduction in food intake. GDF15, therefore, represents an attractive target to combat the current global obesity epidemic. In this article, we review current knowledge on GDF15 and its involvement in metabolic syndrome.

Extracellular vesicle-cell adhesion molecules in tumours: biofunctions and clinical applications.

Cell adhesion molecule (CAM) is an umbrella term for several families of molecules, including the cadherin family, integrin family, selectin family, immunoglobulin superfamily, and some currently unclassified adhesion molecules. Extracellular vesicles (EVs) are important information mediators in cell-to-cell communication. Recent evidence has confirmed that CAMs transported by EVs interact with recipient cells to influence EV distribution in vivo and regulate multiple cellular processes. This review focuses on the loading of CAMs onto EVs, the roles of CAMs in regulating EV distribution, and the known and possible mechanisms of these actions. Moreover, herein, we summarize the impacts of CAMs transported by EVs to the tumour microenvironment (TME) on the malignant behaviour of tumour cells (proliferation, metastasis, immune escape, and so on). In addition, from the standpoint of clinical applications, the significance and challenges of using of EV-CAMs in the diagnosis and therapy of tumours are discussed. Finally, considering recent advances in the understanding of EV-CAMs, we outline significant challenges in this field that require urgent attention to advance research and promote the clinical applications of EV-CAMs. Video Abstract.

Exosomes in the hypoxic TME: from release, uptake and biofunctions to clinical applications.

Hypoxia is a remarkable trait of the tumor microenvironment (TME). When facing selective pressure, tumor cells show various adaptive characteristics, such as changes in the expression of cancer hallmarks (increased proliferation, suppressed apoptosis, immune evasion, and so on) and more frequent cell communication. Because of the adaptation of cancer cells to hypoxia, exploring the association between cell communication mediators and hypoxia has become increasingly important. Exosomes are important information carriers in cell-to-cell communication. Abundant evidence has proven that hypoxia effects in the TME are mediated by exosomes, with the occasional formation of feedback loops. In this review, we equally focus on the biogenesis and heterogeneity of cancer-derived exosomes and their functions under hypoxia and describe the known and potential mechanism ascribed to exosomes and hypoxia. Notably, we call attention to the size change of hypoxic cancer cell-derived exosomes, a characteristic long neglected, and propose some possible effects of this size change. Finally, jointly considering recent developments in the understanding of exosomes and tumors, we describe noteworthy problems in this field that urgently need to be solved for better research and clinical application.

Extracellular vesicle PD-L1 in reshaping tumor immune microenvironment: biological function and potential therapy strategies.

Programmed cell death 1 ligand 1 (PD-L1) is the ligand for programmed death protein-1 (PD-1), is associated with immunosuppression. Signaling via PD-1/PD-L1 will transmits negative regulatory signals to T cells, inducing T-cell inhibition, reducing CD8+ T-cell proliferation, or promoting T-cell apoptosis, which effectively reduces the immune response and leads to large-scale tumor growth. Accordingly, many antibody preparations targeting PD-1 or PD-L1 have been designed to block the binding of these two proteins and restore T-cell proliferation and cytotoxicity of T cells. However, these drugs are ineffective in clinical practice. Recently, numerous of studies have shown that, in addition to the surface of tumor cells, PD-L1 is also found on the surface of extracellular vesicles secreted by these cells. Extracellular vesicle PD-L1 can also interact with PD-1 on the surface of T cells, leading to immunosuppression, and has been proposed as a potential mechanism underlying PD-1/PD-L1-targeted drug resistance. Therefore, it is important to explore the production, regulation and tumor immunosuppression of PD-L1 on the surface of tumor cells and extracellular vesicles, as well as the potential clinical application of extracellular vesicle PD-L1 as tumor biomarkers and therapeutic targets. Video Abstract.

Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.

BACKGROUND: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear. METHODS: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments. RESULTS: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling. CONCLUSION: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.

Extracellular vesicles mediated gastric cancer immune response: tumor cell death or immune escape?

Gastric cancer (GC) is a major global health issue, being the fifth most prevalent cancer and the third highest contributor to cancer-related deaths. Although treatment strategies for GC have diversified, the prognosis for advanced GC remains poor. Hence, there is a critical need to explore new directions for GC treatment to enhance diagnosis, treatment, and patient prognosis. Extracellular vesicles (EVs) have emerged as key players in tumor development and progression. Different sources of EVs carry different molecules, resulting in distinct biological functions. For instance, tumor-derived EVs can promote tumor cell proliferation, alter the tumor microenvironment and immune response, while EVs derived from immune cells carry molecules that regulate immune function and possess tumor-killing capabilities. Numerous studies have demonstrated the crucial role of EVs in the development, immune escape, and immune microenvironment remodeling in GC. In this review, we discuss the role of GC-derived EVs in immune microenvironment remodeling and EVs derived from immune cells in GC development. Furthermore, we provide an overview of the potential uses of EVs in immunotherapy for GC.

Peri-implant epidermoid cyst: A case report and literature analysis.

BACKGROUND: A peri-implant cystic lesion is a rare finding, and to date most investigators have considered that its pathogenesis is caused by trauma and infection related to dental implantation. However, the pathogenesis of these cysts remains unclear and is recognized to have multifactorial origins. CASE PRESENTATION: In February 2021, a 75-year-old male patient underwent implant restoration due to mobility of the left maxillary central incisor. The implant achieved good osseointegration and was successfully restored. However, in March 2023, the patient sought treatment due to mobility of the dental implant. Clinical examination showed that the implant had loosened in three directions (vertical, mesial-distal, and labial-lingual), and the peri-implant mucosa was slightly red and swollen. Radiographic examination (cone beam computed tomography) showed a large radiolucent area with clear boundaries involving the cervical and middle portions of the dental implant, and white bone lines were observed at the edge of the low-density shadow. Intraoperatively, we removed the patient's implant, performed a complete debridement, and conducted bone augmentation surgery in the area of bone defect. Postoperatively, the patient recovered well. The final histopathological result confirmed an epidermoid cyst. CONCLUSIONS: Peri-implant epidermoid cyst is a rare complication that affects the long-term outcome of implant therapy. This case serves as a warning to clinicians to avoid involving epithelial tissue in the implant site during implant surgery, in order to prevent the potential occurrence of a peri-implant epidermoid cyst, thereby creating better conditions for the patient's recovery and the long-term efficacy of the implant.

Ferroptosis and iron metabolism in diabetes: Pathogenesis, associated complications, and therapeutic implications.

Diabetes mellitus is a complex chronic disease, considered as one of the most common metabolic disorders worldwide, posing a major threat to global public health. Ferroptosis emerges as a novel mechanism of programmed cell death, distinct from apoptosis, necrosis, and autophagy, driven by iron-dependent lipid peroxidation accumulation and GPx4 downregulation. A mounting body of evidence highlights the interconnection between iron metabolism, ferroptosis, and diabetes pathogenesis, encompassing complications like diabetic nephropathy, cardiomyopathy, and neuropathy. Moreover, ferroptosis inhibitors hold promise as potential pharmacological targets for mitigating diabetes-related complications. A better understanding of the role of ferroptosis in diabetes may lead to an improvement in global diabetes management. In this review, we delve into the intricate relationship between ferroptosis and diabetes development, exploring associated complications and current pharmacological treatments.

Revisiting the advances and challenges in the clinical applications of extracellular vesicles in cancer.

Extracellular vesicles (EVs) have been the subject of an exponentially growing number of studies covering their biogenesis mechanisms, isolation and analysis techniques, physiological and pathological roles, and clinical applications, such as biomarker and therapeutic uses. Nevertheless, the heterogeneity of EVs both challenges our understanding of them and presents new opportunities for their potential application. Recently, the EV field experienced a wide range of advances. However, the challenges also remain huge. This review focuses on the recent progress and difficulties encountered in the practical use of EVs in clinical settings. In addition, we also explored the concept of EV heterogeneity to acquire a more thorough understanding of EVs and their involvement in cancer, specifically focusing on the fundamental nature of EVs.

Delivery of dental pulp stem cells by an injectable ROS-responsive hydrogel promotes temporomandibular joint cartilage repair via enhancing anti-apoptosis and regulating microenvironment.

Temporomandibular joint (TMJ) cartilage repair poses a considerable clinical challenge, and tissue engineering has emerged as a promising solution. In this study, we developed an injectable reactive oxygen species (ROS)-responsive multifunctional hydrogel (RDGel) to encapsulate dental pulp stem cells (DPSCs/RDGel in short) for the targeted repair of condylar cartilage defect. The DPSCs/RDGel composite exhibited a synergistic effect in the elimination of TMJ OA (osteoarthritis) inflammation via the interaction between the hydrogel component and the DPSCs. We first demonstrated the applicability and biocompatibility of RDGel. RDGel encapsulation could enhance the anti-apoptotic ability of DPSCs by inhibiting P38/P53 mitochondrial apoptotic signal in vitro. We also proved that the utilization of DPSCs/RDGel composite effectively enhanced the expression of TMJOA cartilage matrix and promoted subchondral bone structure in vivo. Subsequently, we observed the synergistic improvement of DPSCs/RDGel composite on the oxidative stress microenvironment of TMJOA and its regulation and promotion of M2 polarization, thereby confirmed that M2 macrophages further promoted the condylar cartilage repair of DPSCs. This is the first time application of DPSCs/RDGel composite for the targeted repair of TMJOA condylar cartilage defects, presenting a novel and promising avenue for cell-based therapy.

Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease.

Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Gut microbiota-generated metabolites: missing puzzles to hosts' health, diseases, and aging.

The gut microbiota, an intricate community of bacteria residing in the gastrointestinal system, assumes a pivotal role in various physiological processes. Beyond its function in food breakdown and nutrient absorption, gut microbiota exerts a profound influence on immune and metabolic modulation by producing diverse gut microbiota-generated metabolites (GMGMs). These small molecules hold potential to impact host health via multiple pathways, which exhibit remarkable diversity, and have gained increasing attention in recent studies. Here, we elucidate the intricate implications and significant impacts of four specific metabolites, Urolithin A (UA), equol, Trimethylamine N-oxide (TMAO), and imidazole propionate, in shaping human health. Meanwhile, we also look into the advanced research on GMGMs, which demonstrate promising curative effects and hold great potential for further clinical therapies. Notably, the emergence of positive outcomes from clinical trials involving GMGMs, typified by UA, emphasizes their promising prospects in the pursuit of improved health and longevity. Collectively, the multifaceted impacts of GMGMs present intriguing avenues for future research and therapeutic interventions. [BMB Reports 2024; 57(5): 207-215].

Prmt7 regulates the JAK/STAT/Socs3 signaling pathway in postmenopausal cardiomyopathy.

Protein arginine methyltransferases (PRMTs) modulate diverse cellular processes, including stress responses. The present study explored the role of Prmt7 in protecting against menopause-associated cardiomyopathy. Mice with cardiac-specific Prmt7 ablation (cKO) exhibited sex-specific cardiomyopathy. Male cKO mice exhibited impaired cardiac function, myocardial hypertrophy, and interstitial fibrosis associated with increased oxidative stress. Interestingly, female cKO mice predominantly exhibited comparable phenotypes only after menopause or ovariectomy (OVX). Prmt7 inhibition in cardiomyocytes exacerbated doxorubicin (DOX)-induced oxidative stress and DNA double-strand breaks, along with apoptosis-related protein expression. Treatment with 17ß-estradiol (E2) attenuated the DOX-induced decrease in Prmt7 expression in cardiomyocytes, and Prmt7 depletion abrogated the protective effect of E2 against DOX-induced cardiotoxicity. Transcriptome analysis of ovariectomized wild-type (WT) or cKO hearts and mechanical analysis of Prmt7-deficient cardiomyocytes demonstrated that Prmt7 is required for the control of the JAK/STAT signaling pathway by regulating the expression of suppressor of cytokine signaling 3 (Socs3), which is a negative feedback inhibitor of the JAK/STAT signaling pathway. These data indicate that Prmt7 has a sex-specific cardioprotective effect by regulating the JAK/STAT signaling pathway and, ultimately, may be a potential therapeutic tool for heart failure treatment depending on sex.

Targeting pyruvate dehydrogenase kinase 1 overcomes EGFR C797S mutation-driven osimertinib resistance in non-small cell lung cancer.

Osimertinib, a selective third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively targets the EGFR T790M mutant in non-small cell lung cancer (NSCLC). However, the newly identified EGFR C797S mutation confers resistance to osimertinib. In this study, we explored the role of pyruvate dehydrogenase kinase 1 (PDK1) in osimertinib resistance. Patients exhibiting osimertinib resistance initially displayed elevated PDK1 expression. Osimertinib-resistant cell lines with the EGFR C797S mutation were established using A549, NCI-H292, PC-9, and NCI-H1975 NSCLC cells for both in vitro and in vivo investigations. These EGFR C797S mutant cells exhibited heightened phosphorylation of EGFR, leading to the activation of downstream oncogenic pathways. The EGFR C797S mutation appeared to increase PDK1-driven glycolysis through the EGFR/AKT/HIF-1α axis. Combining osimertinib with the PDK1 inhibitor leelamine helped successfully overcome osimertinib resistance in allograft models. CRISPR-mediated PDK1 knockout effectively inhibited tumor formation in xenograft models. Our study established a clear link between the EGFR C797S mutation and elevated PDK1 expression, opening new avenues for the discovery of targeted therapies and improving our understanding of the roles of EGFR mutations in cancer progression.