MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

Different diagnostic strategies combining prostate health index and magnetic resonance imaging for predicting prostate cancer: A multicentre study.

OBJECTIVE: To explore how prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) should be used in concert to improve diagnostic capacity for clinically significant prostate cancers (CsCaP) in patients with prostate-specific antigen (PSA) between 4 and 20 ng/ml. METHODS: About 426 patients fulfilling the inclusion criteria were included in this study. Univariable and multivariable logistic analyses were performed to analyze the association between the clinical indicators and CaP/CsCaP. We used the Delong test to compare the differences in the area under the curve (AUC) values of four models for CaP and CsCaP. Decision curve analysis (DCA) and calibration plots were used to assess predictive performance. We compared clinical outcomes of different diagnostic strategies constructed using different combinations of the models by the chi-square test and the McNemar test. RESULTS: The AUC of PHI-MRI (a risk prediction model based on PHI and mpMRI) was 0.859, which was significantly higher than those of PHI (AUC = 0.792, P < 0.001) and mpMRI (AUC = 0.797, P < 0.001). PHI-MRI had a higher net benefit on DCA for predicting CaP and CsCaP in comparison to PHI and mpMRI. Adding the PHI-MRI in diagnostic strategies for CsCaP, such as use PHI-MRI alone or sequential use of PHI followed by PHI-MRI, could reduce the number of biopsies by approximately 20% compared to use PHI followed by mpMRI (256 vs 316, 257 vs 316, respectively). CONCLUSIONS: The PHI-MRI model was superior to PHI and MRI alone. It may reduce the number of biopsies and ensure the detection rate of CsCaP under an appropriate sensitivity at the cost of an increased number of MRI scans.

Corrigendum: Coating of manganese functional polyetheretherketone implants for osseous interface integration.

[This corrects the article DOI: 10.3389/fbioe.2023.1182187.].

Coating of manganese functional polyetheretherketone implants for osseous interface integration.

Polyetheretherketone (PEEK) has been used extensively in biomedical engineering and it is highly desirable for PEEK implant to possess the ability to promote cell growth and significant osteogenic properties and consequently stimulate bone regeneration. In this study, a manganese modified PEEK implant (PEEK-PDA-Mn) was fabricated via polydopamine chemical treatment. The results showed that manganese was successfully immobilized on PEEK surface, and the surface roughness and hydrophilicity significantly improved after surface modification. Cell experiments in vitro demonstrated that the PEEK-PDA-Mn possesses superior cytocompatibility in cell adhesion and spread. Moreover, the osteogenic properties of PEEK-PDA-Mn were proved by the increased expression of osteogenic genes, alkaline phosphatase (ALP), and mineralization in vitro. Further rat femoral condyle defect model was utilized to assess bone formation ability of different PEEK implants in vivo. The results revealed that the PEEK-PDA-Mn group promoted bone tissue regeneration in defect area. Taken together, the simple immersing method can modify the surface of PEEK, giving outstanding biocompatibility and enhanced bone tissue regeneration ability to the modified PEEK, which could be applied as an orthopedic implant in clinical.

The effect of allyl isothiocyanate on chondrocyte phenotype is matrix stiffness-dependent: Possible involvement of TRPA1 activation.

Osteoarthritis (OA) is a chronic joint disease with increasing prevalence. Chondrocytes (CHs) are highly differentiated end-stage cells with a secretory phenotype that keeps the extracellular matrix (ECM) balanced and the cartilage environment stable. Osteoarthritis dedifferentiation causes cartilage matrix breakdown, accounting for one of the key pathogenesis of osteoarthritis. Recently, the activation of transient receptor potential ankyrin 1 (TRPA1) was claimed to be a risk factor in osteoarthritis by causing inflammation and extracellular matrix degradation. However, the underlying mechanism is still unknown. Due to its mechanosensitive property, we speculated that the role of TRPA1 activation during osteoarthritis is matrix stiffness-dependent. In this study, we cultured the chondrocytes from patients with osteoarthritis on stiff vs. soft substrates, treated them with allyl isothiocyanate (AITC), a transient receptor potential ankyrin 1 agonist, and compared the chondrogenic phenotype, containing cell shape, F-actin cytoskeleton, vinculin, synthesized collagen profiles and their transcriptional regulatory factor, and inflammation-related interleukins. The data suggest that allyl isothiocyanate treatment activates transient receptor potential ankyrin 1 and results in both positive and harmful effects on chondrocytes. In addition, a softer matrix could help enhance the positive effects and alleviate the harmful ones. Thus, the effect of allyl isothiocyanate on chondrocytes is conditionally controllable, which could be associated with transient receptor potential ankyrin 1 activation, and is a promising strategy for osteoarthritis treatment.

Androgen Receptor Transcriptionally Inhibits Programmed Death Ligand-1 Expression and Influences Immune Escape in Bladder Cancer.

In multiple clinical trials, immune checkpoint blockade-based immunotherapy has shown significant therapeutic efficacy in bladder cancer (BCa). Sex is closely related to the incidence rate and prognosis of BCa. As one of the sex hormone receptors, the androgen receptor (AR) is a well-known key regulator that promotes the progression of BCa. However, the regulatory mechanism of AR in the immune response of BCa is still unclear. In this study, the expression of AR and programmed death ligand 1 (PD-L1) was negatively correlated in BCa cells, clinical tissues, and tumor data extracted from The Cancer Genome Atlas Bladder Urothelial Carcinoma cohort. A human BCa cell line was transfected to alter the expression of AR. The results show that AR negatively regulated PD-L1 expression by directly binding to AR response elements on the PD-L1 promoter region. In addition, AR overexpression in BCa cells significantly enhanced the antitumor activity of cocultured CD8+ T cells. Injection of anti-PD-L1 monoclonal antibodies into C3H/HeN mice significantly suppressed tumor growth, and stable expression of AR dramatically enhanced the antitumor activity in vivo. In conclusion, this study describes a novel role of AR in regulating the immune response to BCa by targeting PD-L1, thus providing potential therapeutic strategies for immunotherapy in BCa.

Nomograms Combining PHI and PI-RADS in Detecting Prostate Cancer: A Multicenter Prospective Study.

(1) Background: The study aimed to construct nomograms to improve the detection rates of prostate cancer (PCa) and clinically significant prostate cancer (CSPCa) in the Asian population. (2) Methods: This multicenter prospective study included a group of 293 patients from three hospitals. Univariable and multivariable logistic regression analysis was performed to identify potential risk factors and construct nomograms. Discrimination, calibration, and clinical utility were used to assess the performance of the nomogram. The web-based dynamic nomograms were subsequently built based on multivariable logistic analysis. (3) Results: A total of 293 patients were included in our study with 201 negative and 92 positive results in PCa. Four independent predictive factors (age, prostate health index (PHI), prostate volume, and prostate imaging reporting and data system score (PI-RADS)) for PCa were included, and four factors (age, PHI, PI-RADS, and Log PSA Density) for CSPCa were included. The area under the ROC curve (AUC) for PCa was 0.902 in the training cohort and 0.869 in the validation cohort. The AUC for CSPCa was 0.896 in the training cohort and 0.890 in the validation cohort. (4) Conclusions: The combined diagnosis of PHI and PI-RADS can avoid more unnecessary biopsies and improve the detection rate of PCa and CSPCa. The nomogram with the combination of age, PHI, PV, and PI-RADS could improve the detection of PCa, and the nomogram with the combination of age, PHI, PI-RADS, and Log PSAD could improve the detection of CSPCa.

The function of Prostate Health Index in detecting clinically significant prostate cancer in the PI-RADS 3 population: a multicenter prospective study.

PURPOSE: The purpose of this study is to identify patients in the prostate imaging reporting and data system (PI-RADS) 3 population who need biopsy by using prostate health index (PHI) and other clinical parameters in order to avoid unnecessary biopsies. METHODS: A total of 302 patients from four hospital were enrolled, and 92 patients with PI-RADS 3 were included finally. All patients were biopsy-naïve and had suspicion of prostate cancer (PCa) with PSA level in 4-20 ng/ml and a normal digital rectal exam. Univariable and stepwise forward multivariable logistic regression analyses were used to evaluated the risk factors. The sensitivity, specificity, and positive and negative predictive values of different cut-off value of PHI were calculated for the diagnosis of clinically significant prostate cancer (CSPCa). RESULTS: The overall patient's mean age was 65.65 ± 9.55 years, median PSA was 7.68 (5.28-12.07) ng/ml and median PHI was 43.80 (33.09-64.69). PCa was identified in 32.61% (30/92) of PI-RADS 3 and CSPCa was identified in 28.26% (26/92) of PI-RADS 3. The risk factors for detecting PCa and CSPCa in multivariable regression analysis were age and PHI. When the biopsy was restricted to those PHI ≥ 43.5, 42.39% unnecessary biopsied could avoid. The sensitivity, specificity, positive predictive value and negative predictive value for the detection of CSPCa in the PHI ≥ 43.5 were 92.31%, 63.64%, 50% and 95.45% respectively. CONCLUSION: The inclusion of PHI in the diagnosis of the PI-RADS 3 population may avoid many unnecessary biopsies. The multivariable models could increase the detection of cancer.

Abdominal obesity, chronic inflammation and the risk of non-alcoholic fatty liver disease.

INTRODUCTION AND OBJECTIVES: The purpose of this study was to evaluate the effect of abdominal obesity and chronic inflammation on risk of non-alcoholic fatty liver disease (NAFLD) among Chinese population. MATERIALS AND METHODS: Overall, 50776 staff from the Kailuan Group who participated in and finished physical examinations between 2006 and 2007 were included in the cohort study. Their medical information was collected and they were followed after examination. The correlations of waist-to-height ratio (WHtR) or serum high-sensitivity C-reactive protein (hs-crp) with NAFLD were analyzed. Then, we categorized all participants into four groups: non-abdominal obesity and non-chronic inflammation group, abdominal obesity and non-chronic inflammation group, non-abdominal obesity and chronic inflammation group, abdominal obesity and chronic inflammation group, and non-abdominal obesity and non-chronic inflammation group was used as a control group. The combined effects of abdominal obesity and chronic inflammation with NAFLD were analyzed using the Cox proportional hazard regression model. RESULTS: After a mean follow-up of 5.59±1.79 years, a total of 15451 NAFLD cases occurred. We found the WHtR and hs-crp increase the risk for NAFLD, respectively. Compared with the non-abdominal obesity and non-chronic inflammation group, the risk of NAFLD was significantly increased in the abdominal obesity and non-chronic inflammation group (HR 1.21, 95%CI 1.11-1.32), non-abdominal obesity and chronic inflammation group (HR 1.32, 95%CI 1.27-1.38), abdominal obesity and chronic inflammation group (HR 1.60, 95% CI 1.52-1.70). And, a significant interaction effect was found of abdominal obesity and chronic inflammation on NAFLD. CONCLUSIONS: In this study, it was demonstrated in the Chinese population that both abdominal obesity and chronic inflammation increase the risk of NAFLD, and there is an interaction between the two factors in the incidence of NAFLD.

All-sapphire fiber-optic pressure sensors for extreme harsh environments.

In this paper, an all-sapphire fiber-optic Fabry-Perot (F-P) pressure sensor is proposed. The sapphire pressure-sensitive diaphragm with low surface roughness is fabricated by MEMS wet etching. The direct bonding process is adopted to bond the sapphire-sensitive diaphragm and substrate together. And the sapphire fiber is adopted to be the lead-in fiber to ensure the sensor's resistance to high temperature. The performance of the sensor is tested within a pressure range of 0.1∼5 MPa and within the temperature range from room temperature to 1200°C. Experimental results show that the sensor could work stably at the temperature of 1200°C. The pressure sensitivity reaches up to 15nm/MPa. The nonlinearity of the sensor is 0.96% FS (full scale), and the relative resolution reaches 0.12%FS. The all-sapphire F-P sensor could be used for high-pressure testing in a high-temperature environment.

Comparison of the Efficacy of ShuoTong Ureteroscopy and Simple Flexible Ureteroscopy in the Treatment of Unilateral Upper Ureteral Calculi.

Background: ShuoTong ureteroscopy (Sotn-ureteroscopy, ST-URS), a new lithotripsy operation method developed on the basis of ureteroscopy, is widely used to treat ureteral stones in China. Its composition includes rigid ureteral access sheath, standard mirror, lithotripsy mirror, and ShuoTong perfusion aspirator (ST-APM). Here, we compared the efficacy and safety of the ST-URS and the flexible ureteroscope (F-URS) holmium laser lithotripsy in the treatment of unilateral upper ureteral calculi. Methods: Retrospective analysis was conducted on the clinical data of 280 patients who met the inclusion 1) urinary tract CT was diagnosed with unilateral single upper ureteral calculi above the L4 lumbar spine; 2) patient age was from 18 to 80 years old; 3) patients were informed and consented to this study; and 4) patients were approved by the hospital ethics committee (proof number: KY-2019-020) and the exclusion criteria for unilateral upper ureteral calculi in the First Affiliated Hospital of Xiamen University from January 2018 to November 2020, and they were divided into the ST-URS group and the flexible ureteroscopy (F-URS) group. Results: The stone-free rate of 1 day after operation of the ST-URS group was significantly higher than the F-URS group (63.71 vs. 34.62%, P < 0.0001). The operative time (38.45 vs. 46.18 min, P = 0.005) and hospitalization cost (27,203 vs. 33,220 Yuan, P < 0.0001) of the ST-URS group were significantly lower than the F-URS group. There were no significant differences in the success rate of ureteral access sheath placement, operative blood loss, stone-free rate of 1 month after operation, postoperative complications, postoperative hospital stay, and postoperative visual analog scale (VAS) pain score between the two groups (P > 0.05). In subgroups of a diameter of calculi ≥ 1.5 cm, calculi CT numerical value ≥ 1,000 Hounsfield unit and the preoperative hydronephrosis range ≥ 3.0 cm, ST-URS shows more advantages in the operative time, stone-free rate of 1 day after the operation, the hospitalization cost, and the incidence of postoperative complications. Conclusion: In unilateral upper ureteral stones treated with a holmium laser, compared with the simple F-URS, the ST-URS has a shorter operative time, lower hospitalization cost, and a higher stone-free rate of 1 day after the operation, suggesting that the ST-URS could be more widely applied in clinics.

Excellent repeatability, all-sapphire Fabry Perot optical Pressure sensor based on wet etching and direct bonding for Harsh Environment Applications.

In this paper, we proposed an all-sapphire-based extrinsic Fabry-Perot interferometer (EFPI) sensor based on wet etching and the direct bonding process. Temperature measured by the EFPI is used to calibrate pressure measurement. The problem of repeatable measurement of dynamic pressure in a harsh environment is solved. The EFPI sensor can be applied in the temperature range of 25°C to 800°C and the pressure range environment of 0MPa to 5MPa. The pressure sensitivity of 355.8nm/MPa and the temperature sensitivity of 1.64nm/°C are obtained by a cross-correlation function (CCF) algorithm to interrogate the optical sensing system. Therefore, the proposed sensor has a great potential for pressure monitoring, such as jet engines, industrial gas turbine, and so on due to its 8×8mm size and compact structure.

All-sapphire-based fiber-optic pressure sensor for high-temperature applications based on wet etching.

In this paper, we proposed an all-sapphire-based extrinsic Fabry-Perot interferometer (EFPI) pressure sensor based on an optimized wet etching process, aiming to improve the quality of the interference signal. The sapphire pressure sensitive diaphragm (SPSD) was fabricated by wet etching solutions with different mixture ratios of H3PO4 and H2SO4 at 280°C. The differences of mixture ratios affect the surface roughness of SPSD. SPSDs with surface roughness of 3.91nm and 0.39nm are obtained when the mixture ratios of H3PO4 and H2SO4 is 1:1 and 1:3, respectively. We constructed pressure sensing test system adopting these two kinds of SPSD and performed comparative test. The experiment results show that the demodulation jump can be solved and cavity length fluctuation is decreased to ±5nm when the surface roughness of SPSD is 0.39nm.

Perivascular epithelioid cell tumor (PEComa) of the kidney: an overview of its management and outcomes.

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor with unique histological and immunohistochemical characteristics. Malignant renal cell carcinoma is even rarer and its biological behavior is still not clear. We report here a case of malignant PEComa in a male patient. The first symptom of the patient was intermittent hematuria. Ultrasound and computed tomography scan showed a solid mass in the left kidney. Fibrosarcoma was initially diagnosed after radical resection of the tumor. Six years later, the patient had a tumor recurrence and underwent a second operation, through which the diagnosis of renal malignant PEComa was made. Since then, the patient received chemotherapy, a third operation, and interventional treatment because of recurrence and metastasis of the tumor, which prolonged the life of the patient for another 6 years. Malignant PEComa involving the kidney is very rare; it seems to develop slowly but will recur and metastasize. At present, surgical resection remains the best treatment.

Kidney ventrally rotation technique in retroperitoneal robot-assisted partial nephrectomy for posterior hilar tumor: technical feasibility and preliminary results.

PURPOSE: The retroperitoneal robotic assisted partial nephrectomy (RAPN) is suitable for tumors locating on the posterior side of the kidney. However, the posterior hilar tumor poses an additional surgical challenge due to the special location and poor tumor exposure. We developed a novel kidney ventrally rotation technique to overcome this difficulty during retroperitoneal RAPN and evaluated its efficacy in a retrospective case-control comparative study. METHODS: From March 2016 to April 2019, a total of 39 patients with posterior renal hilar tumor underwent retroperitoneal RAPN. The kidney ventrally rotation technique, which improved the tumor exposure by opening the peritoneum and rotating the kidney ventrally, was applied in 24 cases, and the conventional RAPN was performed in the other 15 cases (control group). Perioperative data was analyzed to evaluate the efficacy of the kidney ventrally rotation technique. RESULTS: In kidney rotation group, the 24 patients underwent RAPN successfully without converting to open surgery or radical nephrectomy. The warm ischemia time was 17.4 ± 6.6 min, which was significantly shorter than 24.5 ± 8.3 min in control group. The mean operation time (80 ± 24 min) and estimated blood loss (104 ± 65 ml) were not different from the control group. No sever complications occurred, and no positive surgical margin was found in all the malignant cases. After 14 months follow-up, no recurrence or metastasis occurred in all cases. CONCLUSION: Kidney ventrally rotation technique is safe and feasible for improving the exposure of posterior renal hilar tumor during retroperitoneal RAPN. It could be regarded as an efficient option for the management of posterior hilar tumor.

Laparoscopic nephron-sparing surgery for a tumor near the isthmus of a horseshoe kidney with a complicated blood supply.

A horseshoe kidney is a congenital kidney malformation commonly associated with complications such as hydronephrosis, renal calculi, and infections of the renal pelvis. Renal cell carcinoma is extremely rare in a horseshoe kidney; once it occurs, however, it is intractable because of vascular abnormalities. This is especially true in laparoscopic nephron-sparing surgery, even for tumors of <4 cm in diameter. We herein report a case involving an asymptomatic 65-year-old man with an incidental finding of a 4-cm solid mass near the isthmus of a horseshoe kidney on B-mode ultrasonography. Preoperative computed tomography of the renal artery revealed six arterial vessels supplying the affected kidney. Laparoscopic partial nephrectomy was performed. The outcome of this case suggests that laparoscopic nephron-sparing surgery might be a successful treatment method for a horseshoe kidney but that preoperative vessel evaluation and experienced laparoscopic skills are needed.

Identification of potential therapeutic targets in urothelial bladder carcinoma of Chinese population by targeted next-generation sequencing.

Patients with urothelial carcinoma (UC) of the bladder have a high risk of death in China. However, a lack of comprehensive molecular profiling in Chinese Han population hinders the development of targeted therapies for bladder cancer. In our present study, we collected fresh bladder tumors from low-grade (T1, N0, M0, G1) non-muscle invasive bladder cancer (NMIBC) patients (n = 16) and high-grade (T2-4, N0, M0, Gx) muscle-invasive bladder cancer (MIBC) patients (n = 16) with their paired normal bladder tissues, and subjected the total genomic DNAs to targeted next-generation sequencing (NGS) for 94 cancer-associated genes. NGS results showed that 30.9% of detected genes (29/94) was mutated in 32 urothelial carcinoma bladder tissues. Furthermore, our results and ICGC database showed that FGFR3, KMT2D, TP53, KDM6A, and ARID1A were the most frequently mutated genes in UC patients. Of note, NMIBC and MIBC displayed distinguishable genomic alterations. FGFR3, KMT2D, AKT1, ARID1A, and STAG2 were the most frequently mutated genes in NMIBC patients, whereas mutations of TP53, CREBBP, FGFR3, KDM6A, KMT2D, and ARID1A were frequently detected in MIBC. Intriguingly, gene ontology and clustering analysis revealed that these frequently mutated genes were highly enriched in signaling pathways responsible for cancer development. Taken together, the mutation frequency of genes associated with UC development in NMIBC and MIBC was screened out in Chinese Han population and elucidation of the related mechanisms provides theoretical basis and technical support for the development of early diagnosis and therapeutic strategies in UC.

Antitumor Effect of a DNA Vaccine Harboring Prostate Cancer-Specific Antigen with IL-12 as an Intramolecular Adjuvant.

To improve the lower immune intensity of DNA vaccines, we developed a DNA vaccine based on prostate cancer-specific antigen (PSA), which has been suggested as a potential target for prostate cancer therapy, and enhanced the DNA vaccine potency using interleukin-12 (IL-12) as an intramolecular adjuvant. A series of DNA plasmids encoding human PSA, IL-12, and their conjugates was constructed and injected into female mice intramuscularly, followed by an electric pulse. The humoral and cellular immune responses after immunization were detected by ELISA and ELISPOT, respectively. To evaluate the therapeutic efficacy of these plasmids, a mouse model with a PSA-expressing tumor was constructed. Mice vaccinated with PSA-IL-12 plasmids elicited the strongest PSA-specific humoral and cellular immune responses. Furthermore, these vaccinations inhibited the growth of PSA-expressing tumors and prolonged mouse survival. These observations emphasize the potential of the IL-12 gene as an intramolecular adjuvant for DNA vaccines. Moreover, the vaccine based on PSA and IL-12 may be a promising treatment for prostate cancer.

Matrine inhibits bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway: An experimental study.

OBJECTIVE: To study the inhibitory effect of matrine on bladder cancer cell growth and invasion in vitro through PI3K/AKT signaling pathway. METHODS: Human T24 bladder cancer cell lines were cultured and treated with different doses of matrine (0.25 mg/mL, 0.5 mg/mL and 1.0 mg/mL) as well as 20 µmol/L PI3K inhibitor LY294002 for 24 h, and the cell proliferation activity, the number of invasive cells as well as the expression of p-PI3K, p-AKT, proliferation genes and invasion genes were determined. RESULTS: Different doses of matrine could decrease the cell viability value, the number of invasive cells as well as the expression of p-PI3K, p-AKT, MMP2 and MMP9, and increase the expression of p16, p21 and p27 in dose-dependent manner; p16, p21 and p27 expression in cells of 20 µmol/L LY29002 group were significantly higher than those of 0 µmol/L LY29002 group while MMP2 and MMP9 expression were significantly lower than those of 0 µmol/L LY29002 group (P < 0.05). CONCLUSIONS: Matrine can inhibit bladder cancer cell proliferation and invasion in vitro and regulate the expression of cell cycle-inhibiting molecules and invasion-related genes through PI3K/AKT signaling pathway.