Impact of Smoking and Chronic Obstructive Pulmonary Disease on All-Cause, Respiratory, and Cardio-Cerebrovascular Mortality.

Introduction: Mortality differences in chronic obstructive pulmonary disease (COPD) between nonsmokers and smokers remain unclear. We compared the risk of death associated with smoking and COPD on mortality. Methods: The study included participants aged ≥40 years who visited pulmonary clinics and were categorised into COPD or non-COPD and smoker or nonsmoker on the basis of spirometry results and cigarette consumption. Mortality rates were compared between groups using statistical analysis for all-cause mortality, respiratory disease-related mortality, and cardiocerebrovascular disease-related mortality. Results: Among 5811 participants, smokers with COPD had a higher risk of all-cause (adjusted hazard ratio (aHR), 1.69; 95% confidence interval (CI), 1.23-2.33) and respiratory disease-related mortality (aHR, 2.14; 95% CI, 1.20-3.79) than nonsmokers with COPD. Non-smokers with and without COPD had comparable risks of all-cause mortality (aHR, 1.39; 95% CI, 0.98-1.97) and respiratory disease-related mortality (aHR, 1.77; 95% CI, 0.85-3.68). However, nonsmokers with COPD had a higher risk of cardiocerebrovascular disease-related mortality than nonsmokers without COPD (aHR, 2.25; 95% CI, 1.15-4.40). Conclusion: The study found that smokers with COPD had higher risks of all-cause mortality and respiratory disease-related mortality compared to nonsmokers with and without COPD. Meanwhile, nonsmokers with COPD showed comparable risks of all-cause and respiratory mortality but had a higher risk of cardiocerebrovascular disease-related mortality compared to nonsmokers without COPD.

High vegetable consumption and regular exercise are associated with better quality of life in patients with gout.

Background/Aims: The Gout Impact Scale (GIS), a part of the Gout Assessment Questionnaire 2.0, is used to measure gout-specific health-related quality of life (HRQOL). Although several studies have been conducted on the factors affecting the HRQOL of patients with gout, few have focused on lifestyle factors. This study aimed to investigate the correlation between lifestyle habits and HRQOL using the GIS in patients with gout. Methods: We used data from the Urate-Lowering TheRApy in Gout (ULTRA) registry, a prospective cohort of Korean patients with gout treated at multiple centers nationwide. The patients were aged ≥18 years and met the 2015 American College of Rheumatology/European League Against Rheumatism gout classification criteria. They were asked to complete a GIS and questions regarding their lifestyle habits at enrollment. Results: The study included 232 patients. 'Gout concern overall' scores in the GIS were significantly lower in patients who exercised more frequently and consumed soft drinks and meat less, and 'well-being during attack' scores were significantly lower in patients who consumed vegetables and exercised more frequently. The frequency of vegetable consumption had a negative linear relationship with the 'well-being during attack' and 'gout concern during attack' scores (p = 0.01, p = 0.001, respectively). The frequency of exercise had a negative linear relationship with the 'gout concern overall' and 'gout concern during attack' scores (p = 0.04 and p = 0.002, respectively). Conclusions: Patients with gout who frequently consumed vegetables and exercised regularly experienced less impact of gout, exhibiting a better GIS that represented HRQOL.

The Influence of Environmental Factors on Site Selection Augment Breeding Success in Honey Bees: An Insight of Honey Bee Genetic Resource Conservation.

Honey bee reproductive behavior involves a complicated mating system that embodies a number of factors, including environmental and human-induced factors. Controlled breeding in isolated mating stations is a prerequisite to maintain the genetic resources of honey bees through natural mating. The concept of controlled mating is a challenge in most beekeeping operations due to its low mating success rate. Therefore, a detailed investigation into the suitability of isolated mating stations is of interest. Thus, we bred two subspecies of honey bees (Apis cerana koreana and Apis mellifera L.) in isolated mating stations (island) from 2021 to 2023 and in an open breeding station in 2023. Our results demonstrate that the highest percentage of the mating success rate in isolated mating stations was recorded in the Wido Island, which had the highest percentage of bare land, coniferous forests, deciduous forests, fields, and mixed forests. The mating success rate was higher in the summer and spring for A. cerana and A. mellifera, respectively. The mating success rate was higher in open mating compared to controlled mating (Island) and did not vary between pure-breeding and cross-breeding lines. Our findings suggested that mating stations with mixed forest and fields are potential sites for the successful breeding of honey bees.

Eosinophilia is a favorable marker for pneumonia in chronic obstructive pulmonary disease.

Background: Patients with chronic obstructive pulmonary disease (COPD) expressing eosinophilia experience slightly fewer episodes of community-acquired pneumonia (CAP) than those without eosinophilia. However, the severity and burden of hospitalized pneumonia patients with COPD concerning eosinophilia have not been assessed. Methods: We evaluated the differences in clinical characteristics between patients with CAP and COPD with or without eosinophilia by a post-hoc analysis of a prospective, multi-center, cohort study data. Results: Of 349 CAP patients with COPD, 45 (12.9%) had eosinophilia (blood eosinophil ≥ 300 cells/µL). Patients with eosinophilia had a lower sputum culture percentile (8.1% vs. 23.4%, P < 0.05), a lower percentile of neutrophils (70.3% vs 80.2%, P<0.05), reduced C-reactive protein levels (30.6 mg/L vs 86.6 mg/L, P<0.05), and a lower pneumonia severity index score (82.5 vs. 90.0, P < 0.05) than those without eosinophilia. The duration of antibiotic treatment (8.0 days vs. 10.0 days, P < 0.05) and hospitalization (7.0 days vs. 9.0 days, P < 0.05) were shorter in eosinophilic patients. The cost of medical care per day (256.4 US$ vs. 291.0 US$, P < 0.05), cost for the medication (276.4 US$ vs. 349.9 US$, P < 0.05), and cost for examination (685.5 US$ vs 958.1 US$, P<0.05) were lower in patients with eosinophilia than those without eosinophilia. Conclusion: Eosinophilia serves as a favorable marker for severity of pneumonia, health-care consumption, and cost of medical care in patients with CAP and COPD.

Saururus chinensis (Lour.) Baill. extract promotes skeletal muscle cell differentiation by positively regulating mitochondrial biogenesis and AKT/mTOR signaling in vitro.

Promotion of myoblast differentiation by activating mitochondrial biogenesis and protein synthesis signaling pathways provides a potential alternative strategy to balance energy and overcome muscle loss and muscle disorders. Saururus chinensis (Lour.) Baill. extract (SCE) has been used extensively as a traditional herbal medicine and has several physiological activities, including anti­asthmatic, anti­oxidant, anti­inflammatory, anti­atopic, anticancer and hepatoprotective properties. However, the effects and mechanisms of action of SCE on muscle differentiation have not yet been clarified. In the present study, it was investigated whether SCE affects skeletal muscle cell differentiation through the regulation of mitochondrial biogenesis and protein synthesis in murine C2C12 myoblasts. The XTT colorimetric assay was used to determine cell viability, and myosin heavy chain (MyHC) levels were determined using immunocytochemistry. SCE was applied to C2C12 myotube at different concentrations (1, 5, or 10 ng/ml) and times (1,3, or 5 days). Reverse transcription­quantitative PCR and western blotting were used to analyze the mRNA and protein expression change of factors related to differentiation, mitochondrial biogenesis and protein synthesis. Treatment of C2C12 cells with SCE at 1,5, and 10 ng/ml did not affect cell viability. SCE promoted C2C12 myotube formation and significantly increased MyHC expression in a concentration­ and time­dependent manner. SCE significantly increased the mRNA and protein expression of muscle differentiation­specific markers, such as MyHC, myogenic differentiation 1, myogenin, Myogenic Factor 5, and ß­catenin, mitochondrial biosynthesis­related factors, such as peroxisome proliferator­activated receptor­gamma coactivator­1α, nuclear respirator factor­1, AMP­activated protein kinase phosphorylation, and histone deacetylase 5 and AKT/mTOR signaling factors related to protein synthesis. SCE may prevent skeletal muscle dysfunction by enhancing myoblast differentiation through the promotion of mitochondrial biogenesis and protein synthesis.

Vigeo attenuates cartilage and bone destruction in a collagen­induced arthritis mouse model by reducing production of pro­inflammatory cytokines.

Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by articular cartilage destruction, bone destruction and synovial hyperplasia. It has been suggested that Vigeo, a mixture of Eleutherococcus senticosus, Achyranthes japonica and Atractylodes japonica fermented with Korean nuruk, has an anti-osteoporotic effect in a mouse model of inflammation-mediated bone loss. The present study evaluated the therapeutic effects of Vigeo in RA using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen on days 0 and 21 and Vigeo was administered daily for 20 days beginning the day after the second type II collagen injection. The mice were sacrificed on day 42 and the joint tissues were anatomically separated and subjected to micro computed tomography and histological analyses. In addition, the serum levels of TNF-α, IL-6 and IL-1ß were determined by enzyme-linked immunosorbent assays. CIA in DBA/1J mice caused symptoms of RA, such as joint inflammation, cartilage destruction and bone erosion. Treatment of CIA mice with Vigeo markedly decreased the symptoms and cartilage pathology. In addition, radiological and histological analyses showed that Vigeo attenuated bone and cartilage destruction. The serum TNF-α, IL-6 and IL-1ß levels following oral Vigeo administration were also reduced when compared with those in CIA mice. The present study revealed that Vigeo suppressed arthritis symptoms in a CIA-RA mouse model, including bone loss and serum levels of TNF-α, IL-6 and IL-1ß.

Dihydrostilbenes and flavonoids from whole plants of Jacobaea vulgaris.

The isolation of previously undescribed 12 compounds from the MeOH extract of Jacobaea vulgaris whole plants is disclosed, comprising 11 dihydrostilbenes (1-11) and one flavanone (12), and eight known compounds (six flavonoids, one dihydrostilbene, and one caffeoylquinic acid). Structural elucidation employed spectroscopic methods, including 1D and 2D NMR spectroscopy, HRESIMS, and ECD calculations. Evaluation of the compounds' effects on PCSK9 and LDLR mRNA expression revealed that compounds 1 and 3 downregulated PCSK9 mRNA while increasing LDLR mRNA expression, suggesting potential cholesterol-lowering properties.

Association between statin use and the risk for idiopathic pulmonary fibrosis and its prognosis: a nationwide, population-based study.

Given the pleiotropic effects of statins beyond their lipid-lowering effects, there have been attempts to evaluate the role of statin therapy in IPF, but they have shown inconclusive results. Data from the National Health Insurance Service (NHIS) database of South Korea were used to investigate the effects of statin therapy on IPF. The IPF cohort consisted of a total of 10,568 patients who were newly diagnosed with IPF between 2010 and 2017. These patients were then matched in a 1:3 ratio to 31,704 subjects from a control cohort without IPF, with matching based on age and sex. A case-control study was performed to evaluate the association between statin use and the risk for IPF, and the multivariable analysis revealed that statin use was associated with a lower risk for IPF (adjusted OR 0.847, 95% CI 0.800-0.898). Using the IPF cohort, we also evaluated whether statin use at the time of diagnosis was associated with future clinical outcomes. The statin use at the time of IPF diagnosis was associated with improved overall survival (adjusted HR 0.779, 95% CI 0.709-0.856). Further prospective studies are needed to clarify the role of statin therapy in IPF.

Hierarchical channel morphology in O-rings after two cycling exposures to 70 MPa hydrogen gas: a case study of sealing failure.

This study investigates the impact of high-pressure hydrogen gas exposure on the structural and morphological characteristics of O-ring materials. O-ring specimens undergo two cycles of sealing under 70 MPa hydrogen gas, and their resulting variations are examined using advanced characterization techniques, including powder X-ray diffraction (PXRD), small-angle X-ray scattering (SAXS), scanning electron microscopy (SEM) and atomic force microscopy (AFM). Our findings reveal that the lattice parameters of the O-ring material show no significant changes when exposed to 70 MPa hydrogen gas. However, in the micrometre range, the formation of a hierarchical channel morphology becomes evident. This morphology is accompanied by the separation of carbon black filler from the rubber matrix, contributing to mechanical weakening of the O-ring. These observations can be attributed to the pressure gradient that develops between the inner and outer radii of the O-ring, resulting from compression forces acting perpendicularly to the radial direction due to clamp locking.

Prescribing Patterns and Outcomes of Edoxaban in Atrial Fibrillation Patients From Asia　- One-Year Data From the Global ETNA-AF Program.

Background: This study reports prescribing patterns and the 1-year effectiveness and safety of edoxaban in an Asian cohort of Edoxaban Treatment in routiNe clinical prActice (ETNA)-Atrial Fibrillation (AF) patients. Methods and Results: The Global ETNA-AF program integrates prospective, observational, noninterventional regional studies, collecting data on characteristics and clinical outcomes of patients with AF receiving edoxaban for stroke prevention. Baseline characteristics, medical history, and 1-year clinical event rates were assessed in patients from South Korea, Taiwan, Hong Kong, and Thailand. Clinically relevant events assessed at 12 months included all-cause death, cardiovascular death, ischemic and hemorrhagic stroke, systemic embolic events (SEEs), bleeding, and net clinical outcome (NCO). Overall, 3,359 patients treated with edoxaban 60 or 30 mg once daily completed 1-year follow-up; 70.9% of patients received recommended dosing according to local labels. Baseline mean±standard deviation age was 71.7±9.6 years, CHA2DS2-VASc score was 3.1±1.5, and modified HAS-BLED score was 2.3±1.1. Mean age and sex were similar across countries/regions. The 1-year event rate for all-cause death was 1.8%; major bleeding, 1.3%; ischemic stroke, 1.1%; cardiovascular mortality, 0.7%; hemorrhagic stroke, 0.3%; SEEs, 0%; and NCO, 4.1%; with differences observed between countries/regions and dosing groups. Conclusions: Most Asian patients with AF were prescribed recommended edoxaban dosing in routine care settings. At 1-year follow-up, this analysis supports the effectiveness and safety of edoxaban in these patients.

Dual regulation of NEMO by Nrf2 and miR-125a inhibits ferroptosis and protects liver from endoplasmic reticulum stress-induced injury.

Rationale: The surge of severe liver damage underscores the necessity for identifying new targets and therapeutic agents. Endoplasmic reticulum (ER) stress induces ferroptosis with Gα12 overexpression. NF-κB essential modulator (NEMO) is a regulator of inflammation and necroptosis. Nonetheless, the regulatory basis of NEMO de novo synthesis and its impact on hepatocyte ferroptosis need to be established. This study investigated whether Nrf2 transcriptionally induces IKBKG (the NEMO gene) for ferroptosis inhibition and, if so, how NEMO induction protects hepatocytes against ER stress-induced ferroptosis. Methods: Experiments were conducted using human liver tissues, hepatocytes, and injury models, incorporating NEMO overexpression and Gα12 gene modulations. RNA sequencing, immunoblotting, immunohistochemistry, reporter assays, and mutation analyses were done. Results: NEMO downregulation connects closely to ER and oxidative stress, worsening liver damage via hepatocyte ferroptosis. NEMO overexpression protects hepatocytes from ferroptosis by promoting glutathione peroxidase 4 (GPX4) expression. This protective role extends to oxidative and ER stress. Similar shifts occur in nuclear factor erythroid-2-related factor-2 (Nrf2) expression alongside NEMO changes. Nrf2 is newly identified as an IKBKG (NEMO gene) transactivator. Gα12 changes, apart from Nrf2, impact NEMO expression, pointing to post-transcriptional control. Gα12 reduction lowers miR-125a, an inhibitor of NEMO, while overexpression has the opposite effect. NEMO also counters ER stress, which triggers Gα12 overexpression. Gα12's significance in NEMO-dependent hepatocyte survival is confirmed via ROCK1 inhibition, a Gα12 downstream kinase, and miR-125a. The verified alterations or associations within the targeted entities are validated in human liver specimens and datasets originating from livers subjected to exposure to other injurious agents. Conclusions: Hepatic injury prompted by ER stress leads to the suppression of NEMO, thereby facilitating ferroptosis through the inhibition of GPX4. IKBKG is transactivated by Nrf2 against Gα12 overexpression responsible for the increase of miR-125a, an unprecedented NEMO inhibitor, resulting in GPX4 induction. Accordingly, the induction of NEMO mitigates ferroptotic liver injury.

Gα12 and endoplasmic reticulum stress-mediated pyroptosis in a single cycle of dextran sulfate-induced mouse colitis.

Inflammatory bowel disease (IBD) pathogenesis involves complex inflammatory events and cell death. Although IBD involves mainly necrosis in the digestive tract, pyroptosis has also been recognized. Nonetheless, the underlying basis is elusive. Gα12/13 overexpression may affect endoplasmic reticulum (ER) stress. This study examined how Gα12/13 and ER stress affect pyroptosis using dextran sulfate sodium (DSS)-induced colitis models. Gα12/13 levels were increased in the distal and proximal colons of mice exposed to a single cycle of DSS, as accompanied by increases of IRE1α, ATF6, and p-PERK. Moreover, Il-6, Il-1ß, Ym1, and Arg1 mRNA levels were increased with caspase-1 and IL-1ß activation, supportive of pyroptosis. In the distal colon, RIPK1/3 levels were enhanced to a greater degree, confirming necroptosis. By contrast, the mice subjected to three cycles of DSS treatments showed decreases of Gα12/13, as accompanied by IRE1α and ATF6 suppression, but increases of RIPK1/3 and c-Cas3. AZ2 treatment, which inhibited Gα12, has an anti-pyroptotic effect against a single cycle of colitis. These results show that a single cycle of DSS-induced colitis may cause ER stress-induced pyroptosis as mediated by Gα12 overexpression in addition to necroptosis, but three cycles model induces only necroptosis, and that AZ2 may have an anti-pyroptotic effect.

Case report of hypoglossal nerve stimulation therapy failure due to significant underlying central sleep apnea.

Hypoglossal nerve stimulation is indicated for obstructive sleep apnea but is ineffective in treating central sleep apnea. We describe 2 patients implanted with hypoglossal nerve stimulation after being diagnosed with obstructive sleep apnea at outside sleep laboratories and failing a trial of continuous positive airway pressure therapy. Despite successful hypoglossal nerve stimulation implantation, the patients continued to have persistent symptoms with residual apnea-hypopnea indices above 25 events/h. Although obstructive sleep apnea was the presenting diagnosis, we discovered a significant central sleep apnea component in the original diagnostic sleep data upon careful review. One patient was confirmed to have a central sleep apnea-predominant sleep disorder and improved with adaptive servo-ventilation therapy. The other was diagnosed with central sleep apnea and severe periodic limb movement disorder, and improved with medication. Based on these sleep apnea cases, we propose guidelines emphasizing the importance of reviewing basic clinical information upon treatment failure and initiating multidisciplinary collaboration early in the treatment course. CITATION: Banerjee D, Lee C-H, Im K. Case report of hypoglossal nerve stimulation therapy failure due to significant underlying central sleep apnea. J Clin Sleep Med. 2024;20(6):1003-1007.

Del-1 Plays a Protective Role against COPD Development by Inhibiting Inflammation and Apoptosis.

Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects.

Efficacy of dapagliflozin in improving arrhythmia-related outcomes after ablation for atrial fibrillation: a retrospective single-center study.

BACKGROUND: Atrial fibrillation (AF) is a widespread type of sustained arrhythmia that poses significant health risks. Catheter ablation is the preferred treatment; however, arrhythmia recurrence remains challenging. Sodium-glucose co-transporter 2 inhibitors, particularly dapagliflozin (DAPA), have exhibited cardiovascular benefits. However, to date, the influence of these inhibitors on AF post-ablation remains unclear. METHODS: We analyzed the records of 272 patients who underwent catheter ablation for AF from January 2018 to December 2022. Patients were divided into the control (n = 199) and DAPA (n = 73) groups based on DAPA prescription post-ablation. The primary outcome was total atrial arrhythmia recurrence after a 3-month blanking period. RESULTS: The mean age was 72.19 ± 5.45 years; 86.8% of the patients were men. At 18 months post-ablation, 36.2% and 9.5% of the patients in the control and DAPA groups, respectively, reported atrial arrhythmia. Multivariate analysis revealed that DAPA use was associated with a significantly reduced risk of arrhythmia recurrence (adjusted hazard ratio [aHR]: 0.15, 95% confidence interval [CI]: 0.07-0.32, p < 0.001). After propensity score-matching (PSM) in 65 pairs, arrhythmia recurrence was lower in the DAPA group compared with the control (8.3% versus 30.8%, aHR: 0.17, 95% CI: 0.06-0.51, p = 0.002). Freedom from total arrhythmia recurrence was significantly higher in the DAPA group compared with the control group in both the overall and PSM population (log-rank test p < 0.01). CONCLUSION: DAPA administration post-ablation was associated with significantly reduced atrial arrhythmia recurrence rates, indicating its potential as an adjunct therapy for enhancing the success of AF ablation.

Clonal Hematopoiesis of Indeterminate Potential Is Associated with Current Smoking Status and History of Exacerbation in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: There is limited data regarding the clinical outcomes of clonal hematopoiesis of indeterminate potential (CHIP) in patients with chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the clinical significance of CHIP as a COPD biomarker. METHODS: This retrospective study was conducted on patients with COPD who were enrolled prospectively in the Seoul National University Hospital Airway Registry from January 2013 to December 2019 and underwent pulmonary function and blood tests. We evaluated the CHIP score according to smoking status and severity of airflow obstruction. RESULTS: We analyzed next-generation sequencing data to detect CHIP in 125 patients with COPD. Current smokers had a higher prevalence of CHIP in combination of DNMT3A, TET2, and PPM1D (DTP), DNA methyltransferase 3 alpha (DNMT3A), and protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) genes than in never- or ex-smokers. CHIP of DTP and DNMT3A genes was significantly associated with current smokers (adjusted odds ratio [aOR], 2.80; 95% confidence interval [CI], 1.01 to 7.79) (aOR, 4.03; 95% CI, 1.09 to 14.0). Patients with moderate-to-severe airflow obstruction had a higher prevalence of CHIP in most of the explored genes than those with mild obstruction, although the difference was not statistically significant. CHIP in ASXL transcriptional regulator 1 (ASXL1) genes was significantly associated with history of mild, severe, and total acute exacerbation. CONCLUSION: Given that CHIP in specific genes was significantly associated with current smoking status and acute exacerbation, CHIP can be considered as a candidate biomarker for COPD patients.

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.

Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.

Ultrastrong and ductile steel welds achieved by fine interlocking microstructures with film-like retained austenite.

The degradation of mechanical properties caused by grain coarsening or the formation of brittle phases during welding reduces the longevity of products. Here, we report advances in the weld quality of ultra-high strength steels by utilizing Nb and Cr instead of Ni. Sole addition of Cr, as an alternative to Ni, has limitations in developing fine weld microstructure, while it is revealed that the coupling effects of Nb and Cr additions make a finer interlocking weld microstructures with a higher fraction of retained austenite due to the decrease in austenite to acicular ferrite and bainite transformation temperature and carbon activity. As a result, an alloying design with Nb and Cr creates ultrastrong and ductile steel welds with enhanced tensile properties, impact toughness, and fatigue strength, at 45% lower material costs and lower environmental impact by removing Ni.

Risk stratification for early mortality in newly diagnosed acute promyelocytic leukemia: a multicenter, non-selected, retrospective cohort study.

Introduction: Despite the current effective treatments for acute promyelocytic leukemia (APL), early mortality (EM), defined as death within 30 days of presentation, is a major hurdle to long-term survival. Methods: We performed a multicenter retrospective study to evaluate the incidence and clinical characteristics of EM in patients with newly diagnosed APL and to develop a risk stratification model to predict EM. Results: We identified 313 eligible patients diagnosed between 2000 and 2021 from five academic hospitals. The median age was 50 years (range 19-94), and 250 (79.9%) patients were <65 years. Most patients (n=274, 87.5%) received their first dose of all-trans retinoic acid (ATRA) within 24 hours of presentation. EM occurred in 41 patients, with a cumulative incidence of 13.1%. The most common cause of EM was intracranial hemorrhage (n=22, 53.6%), and most EMs (31/41, 75.6%) occurred within the first seven days of APL presentation. In a multivariable analysis, we identified three independent factors predicting EM: age ≥65 years (HR, 2.56), white blood cell count ≥8.0 x 109/L (HR, 3.30), and ATRA administration >24 hours of presentation (HR, 2.95). Based on these factors, patients were stratified into three categories with a significantly increasing risk of EM: 4.1% for low risk (54.3%; no risk factors; HR 1), 18.5% for intermediate risk (34.5%; 1 factor; HR 4.81), and 40.5% for high risk (11.2%; 2-3 factors; HR 13.16). Discussion: The risk of EM is still not negligible in this era of ATRA-based therapies. Our risk model serves as a clinically useful tool to identify high-risk patients for EM who may be candidates for novel treatments and aggressive supportive strategies.