A Method to Reduce Tension Differences in Pull/Push Manipulation for a Robot in Fluorescence Emission-Guided Surgical Microscopy.

MOTIVATION: A fluorescence emission-guided microscope used to monitor the outcome of cancer removal surgery is highly effective when employing a manipulator to motorize and switch the observation direction. It is necessary to minimize the alignment of looper tension between the stands for pull/push to change the direction of the manipulator and reduce the error rate caused by tension differences. This paper presents a method to minimize the error rate of looper tension between the stands. METHODS: \The looper is inserted between the stands of the manipulator to minimize the difference in tension and make the stress on the pull and push of the looper constant. The constant stress allows the manipulator to move stably in left/right, up/down, and left/right movements, which will be effective for full-camera observation and close-up shots of the end effector. RESULTS: Reducing the tolerance for differences in the manipulator's looper tension (angle and tension) is crucial. When the input value of the looper tension angle is 50°, the output should closely match 50°. Consequently, the measured response has a tolerance of ±49.98%, resulting in an error rate of .02% (1/50th level). CONCLUSION: A method is proposed to minimize the error rate of the manipulator's looper tension in a robot-based fluorescence emission-guided microscope used to observe the status of cancer surgery. As a result, a stable manipulator with a minimal error rate can achieve a 3.986x magnification for close-up observation by switching between high and low orientations.

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis.

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.

Design of a Miniature Observation Robot for Light Emitting Diode Irradiation and Indocyanine Green Fluorescence-emission Guided Lymph Node Monitoring in Operating Rooms.

MOTIVATION: Typical surgical microscopes used for fluorescence-based lymph node detection experience limitations such as weight and restricted adjustability of the integrated light emitting diode (LED) and camera. This restricts the capture of detailed images of specific regions within the lesion. RESEARCH GOAL: This study proposes a miniature observation robot design that offers adjustable working distance (WD) and rotational radius, along with zoom-in/zoom-out functionality. METHODS: A five-degree-of-freedom manipulator was designed, with the end effector incorporating an LED and concave lens to widen the beam width for comprehensive lesion illumination. Additionally, a long-pass filter was integrated into the camera system to enhance image resolution. EXPERIMENTAL RESULTS: Experiments were conducted using a fluorescence-expressing phantom to evaluate the performance of the robot. Results demonstrated a captured image resolution of 9600 × 3240 pixels and a zoom-in/zoom-out capacity of up to 3.68 times. CONCLUSION: The proposed robot design is cost-effective and highly adjustable, enabling suitability for rapid and accurate detection of fresh lymph nodes during surgeries. The robot's capability to detect small lesions (<1 cm), as validated by phantom tests, holds promise for the detection of minute lymph nodes.

Bevacizumab and anexelekto inhibitor, TP-0903 inhibits TGF-ß1-induced epithelial-mesenchymal transition of colon cancer cells.

The incidence of colorectal cancer (CRC) is reported to be increasing nowadays, with a large proportion of newly diagnosed CRC patients being affected by metastasis. Epithelial-mesenchymal transition (EMT) is an important event in the development of metastasis of CRC. In this study, we investigated whether the anticancer drug bevacizumab and anexelekto inhibitor, TP-0903, regulate EMT of colon cancer cells induced by transforming growth factor-beta 1 (TGF-ß1). Using quantitative real-time PCR and western blot analysis, we found that bevacizumab and TP-0903 decreased the expression levels of fibronectin, alpha-smooth muscle actin, and vimentin, whereas they restored E-cadherin expression in TGF-ß1-exposed SW480 and HCT116 cells. In addition, we elucidated that bevacizumab and TP-0903 inhibited the migration and invasion of TGF-ß1-exposed colon cancer cells using scratched wound healing, transwell migration, and Matrigel-coated invasion assays. Finally, we discovered that bevacizumab and TP-0903 inactivated the Smad 2/3 signaling pathway in TGF-ß1-exposed SW480 and HCT116 cells. Therefore, we suggest that treatment of bevacizumab and TP-0903 inhibits TGF-ß1-induced EMT of colon cancer cells through inactivation of the Smad 2/3 signaling pathway.

Clip-Detector Using a Neodymium Magnet to Locate Malignant Tumors during Laparoscopic Surgery.

During laparoscopic surgery for colorectal or gastric cancers, locating the tumor for excision is difficult owing to it being obscured by mucous membranes. Therefore, a clip can be installed around the tumor, which can be located using a sensor. Most of the clip-detectors developed thus far can only detect tumors in either the colon or stomach and require a wire to connect the clip and detector. This study designs a clip and detector that can locate a tumor in the stomach and colon. The clip contains a neodymium magnet that generates a magnetic field, and the detector includes a Colpitts oscillator that allows magnetic coupling of the clip and detector. After installing the prepared clip at the tumor location, the detector is used to locate the clip. To test the clip and detector, we conducted animal experiments, during which four clips were installed in the colon and stomach of a mini pig. We succeeded in locating the clips within 2.17 and 3.14 s in the stomach and colon, respectively, which were shorter than the detection times reported in previous studies. The demand for laparoscopic surgery and endoscopes is predicted to increase owing to this method.

Imaging and Deep Learning Based Approach to Leaf Wetness Detection in Strawberry.

The Strawberry Advisory System (SAS) is a tool developed to help Florida strawberry growers determine the risk of common fungal diseases and the need for fungicide applications. Leaf wetness duration (LWD) is one of the important parameters in SAS disease risk modeling. By accurately measuring the LWD, disease risk can be better assessed, leading to less fungicide use and more economic benefits to the farmers. This research aimed to develop and test a more accurate leaf wetness detection system than traditional leaf wetness sensors. In this research, a leaf wetness detection system was developed and tested using color imaging of a reference surface and a convolutional neural network (CNN), which is one of the artificial-intelligence-based learning methods. The system was placed at two separate field locations during the 2021-2022 strawberry-growing season. The results from the developed system were compared against manual observation to determine the accuracy of the system. It was found that the AI- and imaging-based system had high accuracy in detecting wetness on a reference surface. The developed system can be used in SAS for determining accurate disease risks and fungicide recommendations for strawberry production and allows the expansion of the system to multiple locations.

Clinical Impact of PD-L1 Expression for Survival in Curatively Resected Colon Cancer.

BACKGROUND: Programmed death 1 (PD-1) and its ligand PD-L1 play a key dysfunction of T lymphocytes. The purpose of this study was to assess and compare the prognostic role of tumor- TILs and its relationship with PD-L1 expression in stage II and III colon cancer. METHODS: Immunohistochemisty was used to assess the densities of CD8+, CD4+, and FOXP3+ cells, and PD-L1 expression in intraepithelial tumor site from 58 stage II and III colon cancers. These were evaluated for association with histopathologic features and overall survival. RESULTS: PD-L1-positive tumors contained a higher number of CD8+ TILs with statistical significance (p = 0.001). CD4+ TILs showed positive correlation with PD-L1 expression (p = 0.034). There were no associations between PD-L1 expression and FOXP3+ TILs. Microsatellite instability (MSI)-high status (p = 0.001; Odd ration 18.0; 95% CI = 4.3-74.8) was the strongest prognostic factor along with mucinous/poor cell differentiation, CD8 and right tumor location was associated with PD-L1 expression (p = 0.024, 0.035 and 0.033, respectively). CONCLUSION: This study demonstrated that PD-L1 expression was associated with MSI-high, increased CD8+ TILs, mucinous and poor cell differentiation, and right-sided tumor location.

Beam shaping for ultra-compact waveguide crossings on monolithic silicon photonics platform.

A beam shaping approach has been implemented to realize high-performance waveguide crossings based on cosine tapers. Devices with a compact footprint of 4.7µm×4.7µm were fabricated on the GLOBALFOUNDRIES 45 nm monolithic silicon photonics platform (45 CLO technology). Fabricated devices are found to be nearly wavelength independent (±0.035dB for 1260nm≤λ≤1360nm) with low insertion loss (∼0.2dB) and crosstalk (-35dB). The measured response of the devices is consistent with the three-dimensional finite-difference time-domain simulation results. The design stability is validated by measuring the device insertion loss on eight chips, which is found to be 0.197±0.017dB at the designed center wavelength of 1310 nm.

Autologous blood, a novel agent for preoperative colonic localization: a safety and efficacy comparison study.

BACKGROUND: Preoperative localization is essential for minimally invasive colorectal surgery. However, conventional endoscopic tattooing agents such as India ink have safety issues. The availability of new endoscopic markers such as non-India-ink-based agent is limited. We assessed the efficacy and safety of preoperative endoscopic tattooing using autologous blood in colorectal surgery. METHODS: From February 2016, all patients who required localization of a target lesion before colorectal surgery underwent endoscopic tattooing using autologous blood, and the outcomes were collected prospectively. As a comparison, we retrospectively reviewed the medical records of a further 51 consecutive patients who underwent endoscopic tattooing using India ink before February 2016. A total of 102 patients who underwent endoscopic tattooing using either India ink or autologous blood were included in this study. The primary outcomes were the visibility of the tattooing in the peritoneal cavity and related adverse events. RESULTS: Endoscopic tattoos produced using India ink were visible in 49 (96.1%) patients, and tattoos created using autologous blood were visible in 47 (92.2%) patients. In the autologous blood group, the tattoo could not be identified in four patients due to excessive peritoneal fat, bleeding tendency, congenital anomaly, and suboptimal tattooing. Seven (13.7%) patients in the India ink group and three (5.9%) patients in the autologous blood group experienced endoscopic tattooing-related adverse events. CONCLUSIONS: Autologous blood is a feasible and safe tattooing agent for preoperative endoscopic localization of colorectal lesions within maximal interval of 5 days.

Risk Factors for Recurrence of Right Colonic Diverticulitis.

BACKGROUND: Right colonic diverticulitis (RCD) is more common in Asian countries than in Western countries, and the risk factors for recurrence of RCD are not fully understood. The objective of this study was to assess the risk factors for recurrence of RCD. METHODS: We analyzed 296 patients admitted for treatment of RCD in the Gachon University Gil Medical Center from December 2001 to October 2014. Gender, age, BMI, obesity, hypertension, diabetes mellitus, alcohol consumption, smoking, Hinchey classification, and hospital stay were investigated as risk factors for recurrence. RESULTS: Of the 296 patients with RCD, 31 patients recurred after conservative treatment. The median time interval between the initial episode and recurrence of diverticulitis was 10.4 months. In the univariate analysis, a high recurrence rate was observed in patients with a history of alcohol consumption, smoking, and long hospital stay. In the multivariate analysis, the recurrence rate was much higher (p < 0.001) in patients who stayed in the hospital for more than 10 days after the first attack. Smoking also elevated the recurrence rate (p = 0.011). CONCLUSION: Factors associated with recurrence of RCD may include smoking and the long hospital stay due to complexity when first diverticulitis occurs. Further prospective large-scale studies are needed to draw a definite conclusion.

Caffeic acid phenethyl ester protects against photothrombotic cortical ischemic injury in mice.

In this study, we aimed to investigate the neuroprotective effects of caffeic acid phenethyl ester (CAPE), an active component of propolis purified from honeybee hives, on photothrombotic cortical ischemic injury in mice. Permanent focal ischemia was achieved in the medial frontal and somatosensory cortices of anesthetized male C57BL/6 mice by irradiation of the skull with cold light laser in combination with systemic administration of rose bengal. The animals were treated with CAPE (0.5-5 mg/kg, i.p.) twice 1 and 6 h after ischemic insult. CAPE significantly reduced the infarct size as well as the expression of tumor necrosis factor-α, hypoxiainducible factor-1α, monocyte chemoattractant protein-1, interleukin-1α, and indoleamine 2,3-dioxygenase in the cerebral cortex ipsilateral to the photothrombosis. Moreover, it induced an increase in heme oxygenase-1 immunoreactivity and interleukin-10 expression. These results suggest that CAPE exerts a remarkable neuroprotective effect on ischemic brain injury via its anti-inflammatory properties, thereby providing a benefit to the therapy of cerebral infarction.

Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition.

Osteoclasts are bone-specific multinucleated cells generated by differentiation of monocyte/macrophage hematopoietic lineages and degrade bone matrix by secretion of lytic enzymes. The regulation of osteoclast differentiation provides a potential strategy for treatment of bone-lytic damage. In this study, cilostazol, an inhibitor of type III phosphodiesterase, inhibited RANKL [receptor activator of nuclear factor kappa B (RANK) ligand]-induced RANK expression in bone marrow-derived monocyte/macrophage precursors (BMMs) and Raw 264.7 cells by inhibiting PU.1 via SIRT1 activation. RANKL-induced RANK expression was attenuated by cilostazol and rSIRT1 in Raw 264.7 cells, and these were blocked by sirtinol. In line with these, cilostazol elevated SIRT1 mRNA and protein levels in 12-24h and increased SIRT1 activity, and these effects were inhibited by sirtinol. Furthermore, the RANKL-induced nuclear expression of PU.1, a transcription factor required for macrophage differentiation, was suppressed by cilostazol. Additionally, marked RANKL-induced RANK immunofluorescence staining in Raw 264.7 cells was attenuated by cilostazol and rSIRT1, and both attenuations were prevented by sirtinol. Extensive RANK staining of knee synovial tissues in a mouse model of collagen-induced arthritis (CIA) was markedly reduced by cilostazol (30mg/kg/day). In line with these results, both RANKL- and M-CSF-induced differentiation of BMMs to multinucleated TRAP(+) giant cells and resorption pit formation were inhibited by cilostazol associated with a decrease in TRAP (a marker enzyme of osteoclasts) activity. In conclusion, cilostazol activates SIRT1, which suppresses the nuclear translocation of PU.1, and thus, inhibits RANKL-stimulated RANK expression and causes anti-osteoclast formation in BMMs in vitro and in their murine model of CIA.

HMGB1 induces angiogenesis in rheumatoid arthritis via HIF-1α activation.

High-mobility group box protein 1 (HMGB1), a nonhistone nuclear protein and a cytokine mediator, is implicated in the pathogenesis of rheumatoid arthritis (RA). Extracellular HMGB1 binds to its receptors and triggers downstream signal cascade leading to the perpetuation of synovitis and local tissue invasion. Here, we investigated a novel role of HMGB1 in regulating hypoxia-inducible factor (HIF)-1α to mediate angiogenesis in RA synovium. HIF-1α mRNA levels and activities in synovial fibroblasts from RA patients were enhanced by HMGB1. Pharmacological inhibition of TLR4 and NF-kappaB activation blocked the HMGB1-dependent upregulation of HIF-1α mRNA expression and its activity, suggesting the involvement of transcriptional regulation. HMGB1 stimulated expression of vascular endothelial growth factor (VEGF), and inhibition of HIF-1α attenuated HMGB1-induced VEGF. Conditioned media derived from HMGB1-stimulated synovial fibroblasts enhanced tube formation in human microvascular endothelial cells by upregulating HIF-1α. In the joint tissues of mice with collagen-induced arthritis, treatment with anti-HMGB1 neutralizing antibody prevented blood vessel formation in association with decreased expression of HIF-1α. These observations support the idea that increased HMGB1 induces an extension of inflamed synovium by accelerating angiogenesis in RA through enhancement of HIF-1α activation. Therefore, inhibition of HMGB1 could prove beneficial for the treatment of angiogenesis in RA.

Evaluation of anti-tumorigenic activity of BP3B against colon cancer with patient-derived tumor xenograft model.

BACKGROUND: KIOM-CRC#BP3B (BP3B) is a novel herbal prescription that is composed of three plant extracts. Our preliminary study identified that BP3B exhibited potent anti-proliferative activity against various types of cancer cell lines in vitro. Because the in vivo anti-tumor effect of BP3B is not evaluated before clinical trial, we want to test it using patient's samples. METHODS: To confirm the in vivo anti-cancer effect of BP3B, we used genetically characterized patient-derived colon tumor xenograft (PDTX) mouse model. Anti-cancer activity was evaluated with apoptosis, proliferation, angiogenesis and histological analysis. RESULTS: Oral administration of BP3B significantly inhibited the tumor growth in two PDTX models. Furthermore, TUNEL assay showed that BP3B induced apoptosis of tumor tissues, which was associated with degradation of PARP and Caspase 8 and activation of Caspase 3. We also observed that BP3B inhibited cancer cell proliferation by down-regulation of Cyclin D1 and induction of p27 proteins. Inhibition of angiogenesis in BP3B-treated group was observed with immunofluorescence staining using CD31 and Tie-2 antibodies. CONCLUSION: These findings indicated that BP3B has a strong growth-inhibitory activity against colon cancer in in vivo model and will be a good therapeutic candidate for treatment of refractory colon cancer.

Resistin derived from diabetic perivascular adipose tissue up-regulates vascular expression of osteopontin via the AP-1 signalling pathway.

Perivascular adipose tissue (PVAT) is implicated in the development of vascular diseases; however, the roles of PVAT on OPN expression in diabetic vasculature remain to be determined. This study investigated the role of adipokines derived from diabetic PVAT in regulating the vascular expression of OPN and explored the mechanisms involved. Aortic sections of ob/ob and high-fat diet (HFD)-induced obese (DIO) mice showed an increased expression of OPN, which was paralleled by increased amounts of PVAT characterized by enlargement of adipocytes. In the earlier phase of HFD feeding, macrophage infiltration was mainly localized to the area of PVAT at which adipocytes were enlarged, suggesting a potential link of activated adipocytes to macrophage infiltration. PVAT sections of ob/ob and DIO mice revealed a significantly greater number of macrophages with increased expression of adipokines, including resistin and visfatin. The distribution of resistin in PVAT mostly co-localized with macrophages, while visfatin was expressed in macrophages and other cells. In in vitro studies, OPN expression in vascular smooth muscle cells (VSMCs) co-cultured with PVAT of DIO mice was significantly increased, which was attenuated by a resistin-neutralizing antibody. Likewise, resistin up-regulated expression of OPN mRNA and protein in cultured VSMCs and the pivotal role of AP-1 in resistin-induced OPN transcription was demonstrated. Resistin produced by PVAT plays a pivotal role in the up-regulated expression of OPN in the diabetic vasculature via a signalling pathway that involves activation of AP-1.

Comparison of palonosetron, granisetron, and ramosetron for the prevention of postoperative nausea and vomiting after laparoscopic gynecologic surgery: a prospective randomized trial.

BACKGROUND: Selective 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are reported to have potent antiemetic effects for postoperative nausea and vomiting (PONV). The purpose of this study was to prospectively evaluate the efficacy of palonosetron, granisetron, and ramosetron for the prevention of PONV in patients undergoing laparoscopic gynecologic surgery. METHODS: In this prospective, randomized observational study, 105 healthy female patients who were undergoing laparocopic hystectomy under general anaesthesia were enrolled (clinical trial number: NCT01752374, www.clinicaltrials.gov ). Patients were divided into three groups: the palonostron (0.075 mg i.v.; n = 35), the granisetron group (3 mg i.v.; n = 35), and the ramosetron group (0.3 mg i.v.; n = 35). The treatments were given before the end of surgery. The incidence of PONV, severity of nausea/vomiting, and the use of rescue antiemetic requirements during the first 48 h after surgery were evaluated. RESULTS: The overall incidence of PONV was 33.3 % for this series. The number of complete responders at 48 h after the surgery was 21 (60.0 %) for palonosetron, 24 (68.6 %) for granisetron, and 26 (71.4 %) for ramosetron, representing no statistical difference (P = 0.086). CONCLUSIONS: There were no significant differences in the overall incidence of postoperative nausea and vomiting and complete responders for palonosetron, granisetron and ramosetron group. CLINICAL TRIAL NUMBER: NCT01752374 , www.clinicaltrials.gov .

Ingestion of Portland Cement.

BACKGROUND: The common toxicities of cement are allergic dermatitis, abrasions, and chemical burns, but reports of cement ingestion are rare. In this study, we report a case of successful treatment of cement ingestion using emergency gastrointestinal endoscopy. CASE REPORT: An 83-year-old female was admitted to the emergency department with altered mental state and abdominal pain. We assumed that she ingested cement based on her medical history and radiologic examination. A previous report recommended surgical removal with gastric lavage. However, we thought that wet cement is highly alkaline, and gastric lavage is contraindicated. We performed emergency gastrointestinal endoscopy, instead of gastric lavage. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: If a patient ingests cement, the recommendation is to check the status of the upper gastrointestinal tract and remove the cement by emergency gastrointestinal endoscopy as soon as possible.

Attenuation of ß-amyloid-induced tauopathy via activation of CK2α/SIRT1: targeting for cilostazol.

ß-Amyloid (Aß) deposits and hyperphosphorylated tau aggregates are the chief hallmarks in the Alzheimer's disease (AD) brains, but the strategies for controlling these pathological events remain elusive. We hypothesized that CK2-coupled SIRT1 activation stimulated by cilostazol suppresses tau acetylation (Ac-tau) and tau phosphorylation (P-tau) by inhibiting activation of P300 and GSK3ß. Aß was endogenously overproduced in N2a cells expressing human APP Swedish mutation (N2aSwe) by exposure to medium containing 1% fetal bovine serum for 24 hr. Increased Aß accumulation was accompanied by increased Ac-tau and P-tau levels. Concomitantly, these cells showed increased P300 and GSK3ß P-Tyr216 expression; their expressions were significantly reduced by treatment with cilostazol (3-30 µM) and resveratrol (20 µM). Moreover, decreased expression of SIRT1 and its activity by Aß were significantly reversed by cilostazol as by resveratrol. In addition, cilostazol strongly stimulated CK2α phosphorylation and its activity, and then stimulated SIRT1 phosphorylation. These effects were confirmed by using the pharmacological inhibitors KT5720 (1 µM, PKA inhibitor), TBCA (20 µM, inhibitor of CK2), and sirtinol (20 µM, SIRT1 inhibitor) as well as by SIRT1 gene silencing and overexpression techniques. In conclusion, increased cAMP-dependent protein kinase-linked CK2/SIRT1 expression by cilostazol can be a therapeutic strategy to suppress the tau-related neurodegeneration in the AD brain.

Cilostazol suppresses ß-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-ß.

The accumulation of plaques of ß-amyloid (Aß) peptides, a hallmark of Alzheimer's disease, results from the sequential cleavage of amyloid precursor protein (APP) by activation of ß- and γ-secretases. However, the production of Aß can be avoided by alternate cleavage of APP by α-and γ-secretases. We hypothesized that cilostazol attenuates Aß production by increasing a disintegrin and metalloproteinase 10 (ADAM10)/α-secretase activity via SIRT1-coupled retinoic acid receptor-ß (RARß) activation in N2a cells expressing human APP Swedish mutation (N2aSwe). To evoke endogenous Aß overproduction, the culture medium was switched from medium containing 10% fetal bovine serum (FBS) to medium containing 1% FBS, and cells were cultured for 3∼24 hr. After depletion of FBS in media, N2aSwe cells showed increased accumulations of full-length APP (FL-APP) and Aß in a time-dependent manner (3-24 hr) in association with decreased ADAM10 protein expression. When pretreated with cilostazol (10-30 µM), FL-APP and Aß levels were significantly reduced, and ADAM10 and α-secretase activities were restored. Furthermore, the effect of cilostazol on ADAM10 expression was antagonized by pretreating Rp-cAMPS and sirtinol and by SIRT1-gene silencing. In the N2aSwe cells overexpressing the SIRT1 gene, ADAM10, and sAPPα levels were significantly elevated. In addition, like all-trans retinoic acid, cilostazol enhanced the protein expressions of RARß and ADAM10, and the cilostazol-stimulated ADAM10 elevation was significantly attenuated by LE135 (a RARß inhibitor), sirtinol, and RARß-gene silencing. In conclusion, cilostazol suppresses the accumulations of FL-APP and Aß by activating ADAM10 via the upregulation of SIRT1-coupled RARß.