Batteryless implantable device with built-in mechanical clock for automated and precisely timed drug administration.

Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.

Molecular mechanism underlying impaired hepatic autophagy in glycogen storage disease type Ib.

Type Ib glycogen storage disease (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that translocates G6P from the cytoplasm into the endoplasmic reticulum lumen, where the intraluminal G6P is hydrolyzed to glucose by glucose-6-phosphatase-α (G6Pase-α). Clinically, GSD-Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and a long-term risk of hepatocellular adenoma/carcinoma (HCA/HCC). Studies have shown that autophagy deficiency contributes to hepatocarcinogenesis. In this study, we show that G6PT deficiency leads to impaired hepatic autophagy evident from attenuated expression of many components of the autophagy network, decreased autophagosome formation and reduced autophagy flux. The G6PT-deficient liver displayed impaired sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK) signaling, along with reduced expression of SIRT1, forkhead boxO3a (FoxO3a), liver kinase B-1 (LKB1) and the active p-AMPK. Importantly, we show that overexpression of either SIRT1 or LKB1 in G6PT-deficient liver restored autophagy and SIRT1/FoxO3a and LKB1/AMPK signaling. The hepatosteatosis in G6PT-deficient liver decreased SIRT1 expression. LKB1 overexpression reduced hepatic triglyceride levels, providing a potential link between LKB1/AMPK signaling upregulation and the increase in SIRT1 expression. In conclusion, downregulation of SIRT1/FoxO3a and LKB1/AMPK signaling underlies impaired hepatic autophagy which may contribute to HCA/HCC development in GSD-Ib. Understanding this mechanism may guide future therapies.

Routine Functional Testing or Standard Care in High-Risk Patients after PCI.

BACKGROUND: There are limited data from randomized trials to guide a specific follow-up surveillance approach after myocardial revascularization. Whether a follow-up strategy that includes routine functional testing improves clinical outcomes among high-risk patients who have undergone percutaneous coronary intervention (PCI) is uncertain. METHODS: We randomly assigned 1706 patients with high-risk anatomical or clinical characteristics who had undergone PCI to a follow-up strategy of routine functional testing (nuclear stress testing, exercise electrocardiography, or stress echocardiography) at 1 year after PCI or to standard care alone. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. Key secondary outcomes included invasive coronary angiography and repeat revascularization. RESULTS: The mean age of the patients was 64.7 years, 21.0% had left main disease, 43.5% had bifurcation disease, 69.8% had multivessel disease, 70.1% had diffuse long lesions, 38.7% had diabetes, and 96.4% had been treated with drug-eluting stents. At 2 years, a primary-outcome event had occurred in 46 of 849 patients (Kaplan-Meier estimate, 5.5%) in the functional-testing group and in 51 of 857 (Kaplan-Meier estimate, 6.0%) in the standard-care group (hazard ratio, 0.90; 95% confidence interval [CI], 0.61 to 1.35; P = 0.62). There were no between-group differences with respect to the components of the primary outcome. At 2 years, 12.3% of the patients in the functional-testing group and 9.3% in the standard-care group had undergone invasive coronary angiography (difference, 2.99 percentage points; 95% CI, -0.01 to 5.99), and 8.1% and 5.8% of patients, respectively, had undergone repeat revascularization (difference, 2.23 percentage points; 95% CI, -0.22 to 4.68). CONCLUSIONS: Among high-risk patients who had undergone PCI, a follow-up strategy of routine functional testing, as compared with standard care alone, did not improve clinical outcomes at 2 years. (Funded by the CardioVascular Research Foundation and Daewoong Pharmaceutical; POST-PCI ClinicalTrials.gov number, NCT03217877.).

Oncogenic Fatty Acid Metabolism Rewires Energy Supply Chain in Gastric Carcinogenesis.

BACKGROUND & AIMS: Gastric carcinogenesis develops within a sequential carcinogenic cascade from precancerous metaplasia to dysplasia and adenocarcinoma, and oncogenic gene activation can drive the process. Metabolic reprogramming is considered a key mechanism for cancer cell growth and proliferation. However, how metabolic changes contribute to the progression of metaplasia to dysplasia remains unclear. We have examined metabolic dynamics during gastric carcinogenesis using a novel mouse model that induces Kras activation in zymogen-secreting chief cells. METHODS: We generated a Gif-rtTA;TetO-Cre;KrasG12D (GCK) mouse model that continuously induces active Kras expression in chief cells after doxycycline treatment. Histologic examination and imaging mass spectrometry were performed in the GCK mouse stomachs at 2 to 14 weeks after doxycycline treatment. Mouse and human gastric organoids were used for metabolic enzyme inhibitor treatment. The GCK mice were treated with a stearoyl- coenzyme A desaturase (SCD) inhibitor to inhibit the fatty acid desaturation. Tissue microarrays were used to assess the SCD expression in human gastrointestinal cancers. RESULTS: The GCK mice developed metaplasia and high-grade dysplasia within 4 months. Metabolic reprogramming from glycolysis to fatty acid metabolism occurred during metaplasia progression to dysplasia. Altered fatty acid desaturation through SCD produces a novel eicosenoic acid, which fuels dysplastic cell hyperproliferation and survival. The SCD inhibitor killed both mouse and human dysplastic organoids and selectively targeted dysplastic cells in vivo. SCD was up-regulated during carcinogenesis in human gastrointestinal cancers. CONCLUSIONS: Active Kras expression only in gastric chief cells drives the full spectrum of gastric carcinogenesis. Also, oncogenic metabolic rewiring is an essential adaptation for high-energy demand in dysplastic cells.

Routine stress testing in diabetic patients after percutaneous coronary intervention: the POST-PCI trial.

BACKGROUND AND AIMS: The optimal follow-up surveillance strategy for high-risk diabetic patients with had undergone percutaneous coronary intervention (PCI) remains unknown. METHODS: The POST-PCI (Pragmatic Trial Comparing Symptom-Oriented versus Routine Stress Testing in High-Risk Patients Undergoing Percutaneous Coronary Intervention) study was a randomized trial comparing a follow-up strategy of routine functional testing at 1 year vs. standard care alone after high-risk PCI. Randomization was stratified according to diabetes status. The primary outcome was a composite of death from any cause, myocardial infarction, or hospitalization for unstable angina at 2 years. RESULTS: Among 1706 randomized patients, participants with diabetes (n = 660, 38.7%) had more frequent comorbidities and a higher prevalence of complex anatomical or procedural characteristics than those without diabetes (n = 1046, 61.3%). Patients with diabetes had a 52% greater risk of primary composite events [hazard ratio (HR) 1.52; 95% confidence interval (CI) 1.02-2.27; P = .039]. The 2-year incidences of the primary composite outcome were similar between strategies of routine functional testing or standard care alone in diabetic patients (7.1% vs. 7.5%; HR 0.94; 95% CI 0.53-1.66; P = .82) and non-diabetic patients (4.6% vs. 5.1%; HR 0.89; 95% CI 0.51-1.55; P = .68) (interaction term for diabetes: P = .91). The incidences of invasive coronary angiography and repeat revascularization after 1 year were higher in the routine functional-testing group than the standard-care group irrespective of diabetes status. CONCLUSIONS: Despite being at higher risk for adverse clinical events, patients with diabetes who had undergone high-risk PCI did not derive incremental benefit from routine surveillance stress testing compared with standard care alone during follow-up.

Optical Coherence Tomography-Guided or Intravascular Ultrasound-Guided Percutaneous Coronary Intervention: The OCTIVUS Randomized Clinical Trial.

BACKGROUND: Intravascular imaging-guided percutaneous coronary intervention (PCI) with intravascular ultrasound (IVUS) or optical coherence tomography (OCT) showed superior clinical outcomes compared with angiography-guided PCI. However, the comparative effectiveness of OCT-guided and IVUS-guided PCI regarding clinical outcomes is unknown. METHODS: In this prospective, multicenter, open-label, pragmatic trial, we randomly assigned 2008 patients with significant coronary artery lesions undergoing PCI in a 1:1 ratio to undergo either an OCT-guided or IVUS-guided PCI. The primary end point was a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at 1 year, which was powered for noninferiority of the OCT group compared with the IVUS group. Safety outcomes were also assessed. RESULTS: At 1 year, primary end point events occurred in 25 of 1005 patients (Kaplan-Meier estimate, 2.5%) in the OCT group and in 31 of 1003 patients (Kaplan-Meier estimate, 3.1%) in the IVUS group (absolute difference, -0.6 percentage points; upper boundary of one-sided 97.5% CI, 0.97 percentage points; P<0.001 for noninferiority). The incidence of contrast-induced nephropathy was similar (14 patients [1.4%] in the OCT group versus 15 patients [1.5%] in the IVUS group; P=0.85). The incidence of major procedural complications was lower in the OCT group than in the IVUS group (22 [2.2%] versus 37 [3.7%]; P=0.047), although imaging procedure-related complications were not observed. CONCLUSIONS: In patients with significant coronary artery lesions, OCT-guided PCI was noninferior to IVUS-guided PCI with respect to the incidence of a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target-vessel revascularization at 1 year. The selected study population and lower-than-expected event rates should be considered in interpreting the trial. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique number: NCT03394079.

Spatial transcriptomic analysis of tumour-immune cell interactions in melanoma arising from congenital melanocytic nevus.

BACKGROUND: Studies on the interaction between tumour-infiltrating immune cells (TIICs) and tumour cells in melanoma arising from congenital melanocytic nevus (CMN) are lacking. OBJECTIVE: The aim of this study was to determine the intratumoral immune landscape of TIICs and tumour cells during invasion and metastasis. METHODS: Tissue specimens were obtained from patients with melanoma originating from CMN. Differential gene expression in melanoma cells and TIICs during invasion and metastasis was determined using spatial transcriptomics. RESULTS: As invasion depth increased, the expression of LGALS3, known to induce tumour-driven immunosuppression, increased in melanoma cells. In T cells, the expression of genes that inhibit T-cell activation increased with increasing invasion depth. In macrophages, the expression of genes related to the anti-inflammatory M2 phenotype was upregulated with increasing invasion depth. Compared to primary tumour cells, melanoma cells in metastatic lesions showed upregulated expression of genes associated with cancer immune evasion, including AXL and EPHA2, which impede T-cell recruitment, and BST2, associated with M2 polarization. Furthermore, T cells showed increased expression of genes related to immunosuppression, and macrophages exhibited increased expression of genes associated with the M2 phenotype. CONCLUSIONS: The interaction between melanomas arising from CMN and TIICs may be important for tumour progression and metastasis.

Induction of Autophagy by Extract from Corydalis heterocarpa for Skin Anti-Aging.

The extracts of Corydalis heterocarpa, a salt-tolerant plant, exhibit diverse physiological properties, including anti-inflammatory, anticancer, and antiadipogenic effects. However, the anti-aging effects of C. heterocarpa extract (CHE) on human skin cells have not yet been investigated. In the present study, we determined that CHE inhibited senescence-associated ß-galactosidase (SA-ß-gal)-stained senescent human dermal fibroblasts (HDFs). Furthermore, CHE markedly suppressed the expression of major regulatory proteins involved in senescence, including p53, p21, and caveolin-1. Interestingly, CHE promoted autophagic flux, as confirmed by the formation of microtubule-associated protein 1 light chain 3B (LC3B) puncta and lysosomal activity. Notably, using RNA sequencing (RNA-seq), we showed that CHE selectively regulated the gene expression of leucine-rich repeat and sterile alpha motif-containing 1 (LRSAM1), an important regulator of autophagy. The adenosine-monophosphate activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) pathway, which is essential for autophagy regulation, was also modulated by CHE. LRSAM1 depletion not only inhibited LC3B expression but also decreased the autophagy flux induced by CHE. Moreover, the knockdown of LRSAM1 suppressed the reversal of CHE-induced senescence in old HDFs. Collectively, our study has revealed the rejuvenating effects and molecular mechanisms of CHE, suggesting that CHE may be a promising anti-aging agent.

The Relationship between Pre-Anesthetic Analgesia and Nociception (ANI) and Propofol Injection Pain among Patients Receiving Remifentanil: A Prospective, Randomized, Controlled Study.

Background and Objectives: The analgesia/nociception index (ANI) potentially monitors nociceptive status during anesthesia, but its link to preoperative pain sensitivity is unclear. We investigated the relationship between pre-anesthetic ANI scores and propofol injection pain (PIP) in patients receiving remifentanil. Materials and Methods: This study included 124 male patients aged 19-60 undergoing general anesthesia (ASA class I or II). Patients were randomized to group R (n = 62, remifentanil 4 ng/mL) or group C (n = 62, saline). The primary outcome was the association between PIP and ANI. Secondary outcomes included the incidence and severity of PIP or rocuronium-induced withdrawal movement (RIWM) and their association with ANI. Results: PIP and RIWM incidence and severity were lower in group R than in group C. A weak negative correlation between PIP and ANI at pre-induction (rpb = -0.21, p = 0.02, rpb = -0.37, p < 0.01) and a moderate negative correlation during propofol injection (rpb = -0.48, p = 0.02) were observed. A significant negative correlation was found between RIWM and ANI during rocuronium injection (τb = -0.61, p < 0.01). AUC, cut-off value, specificity, and sensitivity in ANI at pre-induction for predicting PIP were 0.67 (p = 0.02), 59, 76%, and 55%, respectively. AUC, cut-off value, specificity, and sensitivity in ANI during propofol injection for PIP were 0.77 (p < 0.01), 65, 81%, and 67%, respectively. Conclusions: ANI scores demonstrated significant differences between groups, suggesting potential predictive value for PIP despite the low pre-induction AUC value. This study highlights the potential of using ANI scores to predict and manage PIP in patients receiving remifentanil.

Effect of Remimazolam on Pain Perception and Opioid-Induced Hyperalgesia in Patients Undergoing Laparoscopic Urologic Surgery-A Prospective, Randomized, Controlled Study.

Background and Objectives: The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on opioid-induced hyperalgesia (OIH) in patients undergoing general anesthesia. Materials and Methods: The patients were randomized into three groups: group RHR (6 mg/kg/h initial dose followed by 1 mg/kg/h remimazolam and 0.3 µg /kg/min remifentanil), group DHR (desflurane and 0.3 µg /kg/min remifentanil) or group DLR (desflurane and 0.05 µg/kg /min remifentanil). The primary outcome was a mechanical hyperalgesia threshold, while secondary outcomes included an area of hyperalgesia and clinically relevant pain outcomes. Results: Group RHR had a higher mechanical hyperalgesia threshold, a smaller hyperalgesia postoperative area at 24 h, a longer time to first rescue analgesia (p = 0.04), lower cumulative PCA volume containing morphine postoperatively consumed for 24 h (p < 0.01), and lower pain intensity for 12 h than group DHR (p < 0.001). However, there was no significant difference in OIH between groups RHR and DLR. Conclusions: Group RHR, which received remimazolam, attenuated OIH, including mechanically evoked pain and some clinically relevant pain outcomes caused by a high dose of remifentanil. Further research is essential to determine how clinically meaningful and important the small differences observed between the two groups are.

FPR1 is essential for rapamycin-induced lifespan extension in Saccharomyces cerevisiae.

FK506-sensitive proline rotamase 1 protein (Fpr1p), which is a homologue of the mammalian prolyl isomerase FK506-binding protein of 12 kDa (FKBP12), is known to play important roles in protein folding and prevention of protein aggregation. Although rapamycin is known to bind to Fpr1p to inhibit Tor1p mediated-mechanistic Target Of Rapamycin (mTOR) activity, the physiological functions of Fpr1p on lifespan remain unclear. In this study, we used the eukaryotic model Saccharomyces cerevisiae to demonstrate that deletion of FPR1 reduced yeast chronological lifespan (CLS), and there was no benefit on lifespan upon rapamycin treatment, indicating that lifespan extension mechanism of rapamycin in yeast is exclusively dependent on FPR1. Furthermore, there was a significant increase in CLS of fpr1Δ cells during caloric restriction (CR), suggesting that rapamycin affects lifespan in a different way compared to CR. This study highlights the importance of FPR1 for rapamycin-induced lifespan extension.

Effect of rosuvastatin 20 mg versus rosuvastatin 5 mg plus ezetimibe on statin side-effects in elderly patients with atherosclerotic cardiovascular disease: Rationale and design of a randomized, controlled SaveSAMS trial.

BACKGROUND: Current guidelines recommend that patients with established atherosclerotic cardiovascular disease (ASCVD) use high-intensity statin therapy to lower low-density lipoprotein (LDL)-cholesterol levels by at least 50%, irrespective of age. However, in real-world practice, there is reluctance to maintain statin use in response to side-effects, particularly statin-associated muscle symptoms (SAMS). Moreover, no randomized trial has been conducted on the safety of statin therapy in elderly patients. TRIAL DESIGN: This investigator-initiated, multicenter, randomized clinical trial aimed to investigate the incidence of SAMS and its effect on LDL-cholesterol levels in elderly patients with established ASCVD. Eligible patients were aged 70 years or older with established ASCVD. Consecutive patients who met the inclusion criteria were randomized in a 1:1 fashion to receive either intensive statin monotherapy (rosuvastatin 20 mg) or combination therapy (rosuvastatin/ezetimibe, 5/10 mg). The primary endpoint of the study is SAMS at 6 months with regard to treatment strategy. Positive SAMS results are defined as patients with a proposed statin myalgia index score of 7 or higher. The key secondary end-points are target LDL-cholesterol achievement (LDL < 70 mg/dL), incidence of myopathy, rhabdomyolysis, frequency of drug discontinuation, and creatinine kinase, aspartate transaminase, alanine transaminase, total cholesterol, LDL-cholesterol, high-density lipoprotein-cholesterol, triglyceride, and highly sensitive C-reactive protein levels at 6 months. CONCLUSIONS: The SaveSAMS study is a multicenter, randomized trial that will compare the incidence of SAMS in patients with established ASCVD who are 70 years or older on intensive statin monotherapy to that combination therapy.

Prognostic Impact of the Immunoscore Based on Whole-Slide Image Analysis of CD3+ Tumor-Infiltrating Lymphocytes in Diffuse Large B-Cell Lymphoma.

An Immunoscore based on tumor-infiltrating T-cell density was validated as a prognostic factor in patients with solid tumors. However, the potential utility of the Immunoscore in predicting the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) is unclear. Here, the prognostic value of an Immunoscore based on tumor-infiltrating CD3+ T-cell density was evaluated in 104 patients with DLBCL who underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. Digitally scanned whole-slide images were analyzed using Aperio ImageScope software. CD3+ cell densities in the whole tumor area were quantitated using 3 different methods, including number of CD3+ cells/area (mm2), ratio of CD3+ cells to total cells, and ratio of CD3+ cells to CD20+ cells. There was a high concordance among the 3 methods. Patients with low CD3+ cell density had an elevated serum lactate dehydrogenase level and a high Ki-67 proliferation index (all, P < .05). Patients with low CD3+ cell density, according to all 3 methods, had worse overall survival (OS) and worse progression-free survival (P < .05, all). They also had poor OS, independent of MYC/BCL2 double expression (DE) status, Eastern Cooperative Oncology Group performance status, or Ann Arbor stage (all, P < .05). These results were validated using 2 publicly available data sets. In both validation cohorts, patients with low CD3E mRNA expression had an elevated serum lactate dehydrogenase level, extranodal site involvement, and DE status (P < .05). They also had worse progression-free survival (P = .067 and P = .002, respectively) and OS (both P < .05). A low CD3E mRNA level was predictive of poor OS, independent of DE status. An Immunoscore based on whole-slide image analysis of CD3+ T-cell infiltration was sufficient to predict survival in patients with DLBCL. Low CD3+ cell density was a poor prognostic factor, independent of other prognostic parameters and DE status.

Smoking behavior change and risk of cardiovascular disease incidence and mortality in patients with type 2 diabetes mellitus.

BACKGROUND: We aimed to examine the association between smoking behavior change and risk of cardiovascular disease (CVD) incidence and mortality in patients with type 2 diabetes mellitus (T2DM). METHODS: This study used nationwide data from the Korean National Health Insurance System and included 349,137 T2DM patients who smoked. Smoking behavior changes were defined with five groups: quitters, reducers I (≥ 50% reduction), reducers II (20-50% reduction), sustainers (± 20%), and increasers (≥ 20% increase) from the number of cigarettes/day at the baseline. RESULTS: During a median follow-up of 5.1 years, 6,514 cases of myocardial infarction (MI) (1.9%), 7,837 cases of ischemic stroke (IS) (2.2%), and 14,932 deaths (4.3%) were identified. Quitters had a significantly decreased risk of MI (adjusted hazard ratio [aHR] 0.80, 95% CI 0.75-0.86) and IS (aHR 0.80, 95% CI 0.75-0.85) compared to sustainers, whereas reducers did not have a significant association with the risk of MI (aHR 1.03, 95% CI 0.94-1.13) and IS (aHR 1.00, 95% CI 0.92-1.08) in reducer I. Quitters also had a lower all-cause and CVD mortality than sustainers. CONCLUSIONS: Smoking cessation was associated with decreased CVD incidence, and all-cause and CVD mortality among T2DM patients. However, smoking reduction was not associated with decreased risks for these.

Evaluation of an eight marker-panel including long mononucleotide repeat markers to detect microsatellite instability in colorectal, gastric, and endometrial cancers.

BACKGROUND: Accurate determination of microsatellite instability (MSI) status is critical for optimal treatment in cancer patients. Conventional MSI markers can sometimes display subtle shifts that are difficult to interpret, especially in non-colorectal cases. We evaluated an experimental eight marker-panel including long mononucleotide repeat (LMR) markers for detection of MSI. METHODS: The eight marker-panel was comprised of five conventional markers (BAT-25, BAT-26, NR-21, NR-24, and NR-27) and three LMR markers (BAT-52, BAT-59 and BAT-62). MSI testing was performed against 300 specimens of colorectal, gastric, and endometrial cancers through PCR followed by capillary electrophoresis length analysis. RESULTS: The MSI testing with eight marker-panel showed 99.3% (295/297) concordance with IHC analysis excluding 3 MMR-focal deficient cases. The sensitivity of BAT-59 and BAT-62 was higher than or comparable to that of conventional markers in gastric and endometrial cancer. The mean shift size was larger in LMR markers compared to conventional markers for gastric and endometrial cancers. CONCLUSIONS: The MSI testing with eight maker-panel showed comparable performance with IHC analysis. The LMR markers, especially BAT-59 and BAT-62, showed high sensitivity and large shifts which can contribute to increased confidence in MSI classification, especially in gastric and endometrial cancers. Further study is needed with large number of samples for the validation of these LMR markers.

Prognostic significance of L1CAM expression in addition to ProMisE in endometrial cancer.

OBJECTIVE: To investigate the prognostic significance of L1 cell-adhesion molecule (L1CAM), ß-catenin, and programmed death-ligand 1 (PD-L1) in endometrial cancer (EC) patients, with a focus on p53 wild-type subgroup, for additional risk stratification. METHODS: This retrospective cohort study included EC patients classified according to Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) who underwent primary surgical treatment at the single center between January 2014 and December 2018. Immunohistochemical staining was performed for four mismatch repair (MMR) proteins, p53, L1CAM, ß-catenin, and PD-L1. DNA polymerase epsilon (POLE) mutation was detected by hot spot sequencing via droplet digital polymerase chain reaction. Survival outcome of each subgroup of L1CAM, ß-catenin, and PD-L1 was measured according to their expression. RESULTS: A total of 162 EC patients were included. Endometrioid histologic type and early-stage disease were 140 (86.4%) and 109 (67.3%), respectively. ProMisE classification assigned 48 (29.6%), 16 (9.9%), 72 (44.4%), and 26 (16.0%) patients to MMR-deficient, POLE-mutated, p53 wild-type, and p53 abnormal subgroups, respectively. L1CAM was identified as an independent poor prognostic factor for progression-free survival (PFS; adjusted hazard ratio [aHR], 3.207; 95% confidence interval (CI), 1.432-7.187; P = 0.005), whereas ß-catenin and PD-L1 positivity were not associated with recurrence (P = 0.462 and P = 0.152, respectively). In p53 wild-type subgroup, L1CAM positivity was associated with worse PFS (aHR, 4.906; 95% CI, 1.685-14.287; P = 0.004). CONCLUSION: L1CAM positivity was associated with poor prognosis in EC and further stratified the risk of recurrence in p53 wild-type subgroup, whereas ß-catenin and PD-L1 were not informative for risk stratification.

Clinical implications of histologic subtypes on survival outcomes in primary mucinous ovarian carcinoma.

OBJECTIVE: In 2014, the World Health Organization introduced a new histologic classification by dividing primary mucinous ovarian carcinoma (PMOC) into two: expansile (ES) or infiltrative subtypes (IS). This study investigated the clinical implications of these histological subtypes on survival outcomes. METHODS: Data from 131 patients with PMOC who underwent primary surgery between 2003 and 2021 were analyzed. The patients baseline characteristics, surgical and pathological information were collected. Survival outcomes were calculated, while factors affecting them were also investigated. RESULTS: During 55.9 months of median follow-up, 27 (20.6%) patients experienced recurrence and 20 (15.3%) died. Among 131 patients, 113 patients were classified into 87 (77%) ES and 26 (23%) IS after a slide review. Advanced stage, lymph node involvement, and residual tumors after surgery were more common in the IS, showing poorer prognosis. In multivariate analyses, advanced stage and residual tumors after surgery were associated with worse survival, while the IS showed no statistical significance. In subgroup analysis for stage I disease, survival did not vary between subtypes. Nevertheless, patients in the IS group who underwent fertility-sparing surgeries demonstrated a 5-year progression-free survival (PFS) rate of 83.3%, significantly lower than patients without fertility preservation, irrespective of histologic subtypes (5-year PFS rate: 97.9%; P = 0.002 for the ES, 5-year PFS rate: 100%; P = 0.001 for the IS). CONCLUSIONS: The IS of PMOC had poorer survival outcomes and a higher proportion of advanced-stage tumors. Although its independent prognostic significance remains uncertain, adjuvant chemotherapy should be considered for patients with fertility preservation in the IS group.

Densification effect on field emission characteristics of CNT film emitters for electron emission devices.

Field electron emission characteristics of the carbon nanotube (CNT) film emitters were investigated according to densification conditions such as nitric acid, acetic acid, and salicylic acid. The emission performance of the CNT film emitters was strongly affected by the densification conditions. Salicylic acid exhibits the best field electron emission properties of the CNT film emitters, followed by nitric acid and acetic acid. The efficient densification of the CNT film emitter by salicylic acid is caused by the role of polarity and p orbitals, nitric acid by hydrogen ions, and acetic acid by weak polarity. After the densification with salicylic acid, the turn-on field of the CNT film emitter decreases from 1.94 Vµm-1to 1.86 Vµm-1, the threshold field decreases from 3.41 Vµm-1to 2.95 Vµm-1, the emission current significantly increases from 20.92 mA to 43.98 mA, and the degradation rate from the long-term emission stability decreases from 49.9% to 21%. The improved emission characteristics are attributed to the increased emission sites at the CNT film and the increased electrical conductivity of the CNT film. The densification is a useful way to enhance the field electron emission properties of CNT film emitters.

Machine Learning-Based prediction of Post-Treatment ambulatory blood pressure in patients with hypertension.

Purpose. Pre-treatment prediction of individual blood pressure (BP) response to anti-hypertensive medication is important to determine the specific regimen for promptly and safely achieving a target BP. This study aimed to develop supervised machine learning (ML) models for predicting patient-specific treatment effects using 24-hour ambulatory BP monitoring (ABPM) data.Materials and Methods. A total of 1,129 patients who had both baseline and follow-up ABPM data were randomly assigned into training, validation and test sets in a 3:1:1 ratio. Utilising the features including clinical and laboratory findings, initial ABPM data, and anti-hypertensive medication at baseline and at follow-up, ML models were developed to predict post-treatment individual BP response. Each case was labelled by the mean 24-hour and daytime BPs derived from the follow-up ABPM.Results. At baseline, 616 (55%) patients had been treated using mono or combination therapy with 45 anti-hypertensive drugs and the remaining 513 (45%) patients had been untreated (drug-naïve). By using CatBoost, the difference between predicted vs. measured mean 24-hour systolic BP at follow-up was 8.4 ± 7.0 mm Hg (% difference of 6.6% ± 5.7%). The difference between predicted vs. measured mean 24-hour diastolic BP was 5.3 ± 4.3 mm Hg (% difference of 6.8% ± 5.5%). There were significant correlations between the CatBoost-predicted vs. the ABPM-measured changes in the mean 24-hour Systolic (r = 0.74) and diastolic (r = 0.68) BPs from baseline to follow-up. Even in the patients with renal insufficiency or diabetes, the correlations between CatBoost-predicted vs. ABPM-measured BP changes were significant.Conclusion. ML algorithms accurately predict the post-treatment ambulatory BP levels, which may assist clinicians in personalising anti-hypertensive treatment.

The prediction of post-treatment BP response is essential to plan the appropriate optimal treatment strategy for achieving the target BP level.The poor predictability of the post-treatment BP level is due to the complex pathophysiology of individual BP response, which can partly explain the poor rate to achieve the target systolic BP.In this current study including both treated and untreated patients with hypertension, machine leaning models predicted the post-treatment mean BP levels on 24-hr ABPM even in high-risk patients and patients with a high BP variability.Model-derived selection and optimisation of anti-hypertension drugs may facilitate prompt achievement of adequate BP control without drug-related complications and avoiding repeating 24-hour ABPM or multiple visits for drug readjustment.

FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation.

In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3ß-mediated STAT2 phosphorylation facilitated STAT2-FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.