Capturing Coherent Magnons by Tip-Assisted Terahertz Spectroscopy.

Our study highlights the versatility of tip-assisted terahertz spectroscopy in probing coherent magnons, the elementary quanta of spin waves in magnetic materials. We identify two distinct coherent magnon types in canted antiferromagnet YFeO3. The remarkable consistency with far-field terahertz spectroscopy in crucial magnon parameters, such as coherence time and resonance frequency, firmly establishes the credibility of tip-assisted terahertz spectroscopy. Notably, we capture more coherent ferromagnetic magnons near the sample surface, underscoring the strength of the technique. This approach paves the way for local, free-standing, and real-space investigations of spin waves in solid magnets.

Interaction between p21-activated kinase 4 and ß-catenin as a novel pathway for PTH-dependent osteoblast activation.

Parathyroid hormone (PTH) serves dual roles in bone metabolism, exhibiting both anabolic and catabolic effects. The anabolic properties of PTH have been utilized in the treatment of osteoporosis with proven efficacy in preventing fractures. Despite these benefits, PTH can be administered therapeutically for up to 2 years, and its use in patients with underlying malignancies remains a subject of ongoing debate. These considerations underscore the need for a more comprehensive understanding of the underlying mechanisms. p21-activated kinase 4 (PAK4) is involved in bone resorption and cancer-associated osteolysis; however, its role in osteoblast function and PTH action remains unknown. Therefore, in this study, we aimed to clarify the role of PAK4 in osteoblast function and its effects on PTH-induced anabolic activity. PAK4 enhanced MC3T3-E1 osteoblast viability and proliferation and upregulated cyclin D1 expression. PAK4 also augmented osteoblast differentiation, as indicated by increased mineralization found by alkaline phosphatase and Alizarin Red staining. Treatment with PTH (1-34), an active PTH fragment, stimulated PAK4 expression and phosphorylation in a protein kinase A-dependent manner. In addition, bone morphogenetic protein-2 (which is known to promote bone formation) increased phosphorylated PAK4 (p-PAK4) and PAK4 levels. PAK4 regulated the expression of both phosphorylated and total ß-catenin, which are critical for osteoblast proliferation and differentiation. Moreover, p-PAK4 directly interacted with ß-catenin, and disruption of ß-catenin's binding to T-cell factor impaired PAK4- and PTH-induced osteoblast differentiation. Our findings elucidate the effect of PAK4 on enhancing bone formation in osteoblasts and its pivotal role in the anabolic activity of PTH mediated through its interaction with ß-catenin. These insights improve the understanding of the mechanisms underlying PTH activity and should inform the development of more effective and safer osteoporosis treatments.

Polyamine and EIF5A hypusination downstream of c-Myc confers targeted therapy resistance in BRAF mutant melanoma.

BACKGROUND: BRAF inhibitors are widely employed in the treatment of melanoma with the BRAF V600E mutation. However, the development of resistance compromises their therapeutic efficacy. Diverse genomic and transcriptomic alterations are found in BRAF inhibitor resistant melanoma, posing a pressing need for convergent, druggable target that reverse therapy resistant tumor with different resistance mechanisms. METHODS: CRISPR-Cas9 screens were performed to identify novel target gene whose inhibition selectively targets A375VR, a BRAF V600E mutant cell line with acquired resistance to vemurafenib. Various in vitro and in vivo assays, including cell competition assay, water soluble tetrazolium (WST) assay, live-dead assay and xenograft assay were performed to confirm synergistic cell death. Liquid Chromatography-Mass Spectrometry analyses quantified polyamine biosynthesis and changes in proteome in vemurafenib resistant melanoma. EIF5A hypusination dependent protein translation and subsequent changes in mitochondrial biogenesis and activity were assayed by O-propargyl-puromycin labeling assay, mitotracker, mitoSOX labeling and seahorse assay. Bioinformatics analyses were used to identify the association of polyamine biosynthesis with BRAF inhibitor resistance and poor prognosis in melanoma patient cohorts. RESULTS: We elucidate the role of polyamine biosynthesis and its regulatory mechanisms in promoting BRAF inhibitor resistance. Leveraging CRISPR-Cas9 screens, we identify AMD1 (S-adenosylmethionine decarboxylase 1), a critical enzyme for polyamine biosynthesis, as a druggable target whose inhibition reduces vemurafenib resistance. Metabolomic and proteomic analyses reveal that polyamine biosynthesis is upregulated in vemurafenib-resistant cancer, resulting in enhanced EIF5A hypusination, translation of mitochondrial proteins and oxidative phosphorylation. We also identify that sustained c-Myc levels in vemurafenib-resistant cancer are responsible for elevated polyamine biosynthesis. Inhibition of polyamine biosynthesis or c-Myc reversed vemurafenib resistance both in vitro cell line models and in vivo in a xenograft model. Polyamine biosynthesis signature is associated with poor prognosis and shorter progression free survival after BRAF/MAPK inhibitor treatment in melanoma cohorts, highlighting the clinical relevance of our findings. CONCLUSIONS: Our findings delineate the molecular mechanisms involving polyamine-EIF5A hypusination-mitochondrial respiration pathway conferring BRAF inhibitor resistance in melanoma. These targets will serve as effective therapeutic targets that can maximize the therapeutic efficacy of existing BRAF inhibitors.

Systematic review of fatigue severity in ME/CFS patients: insights from randomized controlled trials.

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness medically unexplained, affecting approximately 1% of the global population. Due to the subjective complaint, assessing the exact severity of fatigue is a clinical challenge, thus, this study aimed to produce comprehensive features of fatigue severity in ME/CFS patients. METHODS: We systematically extracted the data for fatigue levels of participants in randomized controlled trials (RCTs) targeting ME/CFS from PubMed, Cochrane Library, Web of Science, and CINAHL throughout January 31, 2024. We normalized each different measurement to a maximum 100-point scale and performed a meta-analysis to assess fatigue severity by subgroups of age, fatigue domain, intervention, case definition, and assessment tool, respectively. RESULTS: Among the total of 497 relevant studies, 60 RCTs finally met our eligibility criteria, which included a total of 7088 ME/CFS patients (males 1815, females 4532, and no information 741). The fatigue severity of the whole 7,088 patients was 77.9 (95% CI 74.7-81.0), showing 77.7 (95% CI 74.3-81.0) from 54 RCTs in 6,706 adults and 79.6 (95% CI 69.8-89.3) from 6 RCTs in 382 adolescents. Regarding the domain of fatigue, 'cognitive' (74.2, 95% CI 65.4-83.0) and 'physical' fatigue (74.3, 95% CI 68.3-80.3) were a little higher than 'mental' fatigue (70.1, 95% CI 64.4-75.8). The ME/CFS participants for non-pharmacological intervention (79.1, 95% CI 75.2-83.0) showed a higher fatigue level than those for pharmacological intervention (75.5, 95% CI 70.0-81.0). The fatigue levels of ME/CFS patients varied according to diagnostic criteria and assessment tools adapted in RCTs, likely from 54.2 by ICC (International Consensus Criteria) to 83.6 by Canadian criteria and 54.2 by MFS (Mental Fatigue Scale) to 88.6 by CIS (Checklist Individual Strength), respectively. CONCLUSIONS: This systematic review firstly produced comprehensive features of fatigue severity in patients with ME/CFS. Our data will provide insights for clinicians in diagnosis, therapeutic assessment, and patient management, as well as for researchers in fatigue-related investigations.

Completely Resectable (cT1-2) Esophageal Squamous Cell Carcinoma with Minimal Lymph Node Involvement (cN1): Is Neoadjuvant Chemoradiation Therapy the Only Viable Treatment Option?

BACKGROUND: Neoadjuvant chemoradiation therapy (nCRT) is recommended when lymph node metastasis is evident or strongly suspected on preoperative imaging studies, even for a completely resectable (cT1-2) tumor with minimal lymph node involvement (cN1). We evaluated the validity of upfront surgical approach in this patient group. METHODS: We retrospectively reviewed data from 247 patients with cT1-2 esophageal squamous cell carcinoma (ESCC) who underwent upfront radical esophagectomy followed by the pathology-based adjuvant treatment. Oncologic outcomes of cN1 patients were compared with those of cN0 patients. RESULTS: There were 203 cN0 and 44 cN1 patients. The lymph node yield was 62.0 (interquartile range [IQR], 51.0-76.0) in cN0 and 65.5 (IQR, 57.5-85.0) in cN1 patients (p = 0.033). The size of metastatic node was 0.6 cm (IQR, 0.4-0.9 cm) in cN0 and 0.8 cm (IQR, 0.5-1.3 cm) in cN1 patients (p = 0.001). Nodal upstaging was identified in 29.1% of cN0 and 40.9% of cN1 patients, whereas 18.2% of the cN1 had no actual lymph node metastasis (pN0). The 5-year disease-free survival rate was not significantly different between the groups (cN0, 74.4%; cN1, 71.8%; p = 0.529). Survival rates were closely correlated with pN stage, and a multivariate analysis revealed that pN2-3 stage was a risk factor for poor disease-free survival. CONCLUSIONS: Upfront radical surgery provided accurate nodal staging information, potentially sparing some cN1 patients from unnecessary nCRT while demonstrating comparable survival rates. It might be a valid option for the treatment of cT1-2N1 ESCC.

Aberrant glucose metabolism underlies impaired macrophage differentiation in glycogen storage disease type Ib.

Glycogen storage disease type Ib (GSD-Ib) is an autosomal recessive disorder caused by a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD-Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD-Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte-to-macrophage differentiation using bone marrow-derived monocytes from G6pt-/- mice as well as G6PT-deficient human THP-1 monocytes. Our findings revealed that G6PT-deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT-deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT-deficient THP-1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte-to-macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD-Ib. These findings may contribute to a better understanding of the pathogenesis of GSD-Ib and potentially pave the way for the development of targeted therapeutic interventions.

Germinal centers are associated with postthymectomy myasthenia gravis in patients with thymoma.

BACKGROUND AND PURPOSE: Germinal centers (GCs) can be observed in the thymic tissues of patients with thymoma-associated myasthenia gravis (MG). Although an association between thymic GCs and MG has been suggested, it is unknown whether the presence of GCs could predict the development of MG after the resection of thymoma, known as postthymectomy MG. METHODS: We conducted a retrospective analysis of previously nonmyasthenic patients who underwent surgical removal of the thymoma. All available thymic tissue slides were rereviewed by a pathologist to assess for GCs. Patients were classified into GC-positive and GC-negative groups based on the presence of GCs. The incidence of postthymectomy MG was compared between the two groups, and the risk factors for postthymectomy MG were assessed. RESULTS: Of the 196 previously nonmyasthenic patients who underwent thymoma resection, 21 were GC-positive, whereas 175 were GC-negative. Postthymectomy MG developed in 11 (5.6%) patients and showed a higher incidence in the GC-positive group than in the GC-negative group (33.3% vs. 2.3%, p < 0.001). No postoperative radiotherapy and the presence of GCs were risk factors for postthymectomy MG in the univariate analysis. In multivariate analysis, invasive thymoma (hazard ratio [HR] = 9.835, 95% confidence interval [CI] = 1.358-105.372), postoperative radiotherapy (HR = 0.160, 95% CI = 0.029-0.893), and presence of GCs (HR = 15.834, 95% CI = 3.742-67.000) were significantly associated with postthymectomy MG. CONCLUSIONS: Thymic GCs may be a significant risk factor for postthymectomy MG. Even in patients with thymoma who do not show clinical symptoms of MG, postthymectomy MG should be considered, especially if thymic GCs are observed.

Whole-exome sequencing analysis of patent ductus arteriosus in a Japanese macaque (Macaca fuscata).

We performed whole-exome sequencing using a human exome capture kit to analyze the potential genetic factors related to patent ductus arteriosus in Japanese macaques. Compared with the reference sequences of other primates, we identified potential missense variants in five genes: ADAM15, AZGP1, CSPG4, TNFRSF13B, and EPOR.

Sextant Systematic Biopsy Versus Extended 12-Core Systematic Biopsy in Combined Biopsy for Prostate Cancer.

BACKGROUND: This study assessed the comparative effectiveness of sextant and extended 12-core systematic biopsy within combined biopsy for the detection of prostate cancer. METHODS: Patients who underwent combined biopsy targeting lesions with a Prostate Imaging Reporting and Data System (PI-RADS) score of 3-5 were assessed. Two specialists performed all combined cognitive biopsies. Both specialists performed target biopsies with five or more cores. One performed sextant systematic biopsies, and the other performed extended 12-core systematic biopsies. A total of 550 patients were analyzed. RESULTS: Cases requiring systematic biopsy in combined biopsy exhibited a significant association with age ≥ 65 years (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.25-4.32; P = 0.008), PI-RADS score (OR, 2.32; 95% CI, 1.25-4.32; P = 0.008), and the number of systematic biopsy cores (OR, 3.69; 95% CI, 2.11-6.44; P < 0.001). In patients with an index lesion of PI-RADS 4, an extended 12-core systematic biopsy was required (target-negative/systematic-positive or a greater Gleason score in the systematic biopsy than in the targeted biopsy) (P < 0.001). CONCLUSION: During combined biopsy for prostate cancer in patients with PI-RADS 3 or 5, sextant systematic biopsy should be recommended over extended 12-core systematic biopsy when an effective targeted biopsy is performed.

A framework for inferring and analyzing pharmacotherapy treatment patterns.

BACKGROUND: To discover pharmacotherapy prescription patterns and their statistical associations with outcomes through a clinical pathway inference framework applied to real-world data. METHODS: We apply machine learning steps in our framework using a 2006 to 2020 cohort of veterans with major depressive disorder (MDD). Outpatient antidepressant pharmacy fills, dispensed inpatient antidepressant medications, emergency department visits, self-harm, and all-cause mortality data were extracted from the Department of Veterans Affairs Corporate Data Warehouse. RESULTS: Our MDD cohort consisted of 252,179 individuals. During the study period there were 98,417 emergency department visits, 1,016 cases of self-harm, and 1,507 deaths from all causes. The top ten prescription patterns accounted for 69.3% of the data for individuals starting antidepressants at the fluoxetine equivalent of 20-39 mg. Additionally, we found associations between outcomes and dosage change. CONCLUSIONS: For 252,179 Veterans who served in Iraq and Afghanistan with subsequent MDD noted in their electronic medical records, we documented and described the major pharmacotherapy prescription patterns implemented by Veterans Health Administration providers. Ten patterns accounted for almost 70% of the data. Associations between antidepressant usage and outcomes in observational data may be confounded. The low numbers of adverse events, especially those associated with all-cause mortality, make our calculations imprecise. Furthermore, our outcomes are also indications for both disease and treatment. Despite these limitations, we demonstrate the usefulness of our framework in providing operational insight into clinical practice, and our results underscore the need for increased monitoring during critical points of treatment.

Comparison of laser and traditional lancing devices for capillary blood sampling in patients with diabetes mellitus and high bleeding risk.

PURPOSE: Despite the importance of self-monitoring blood glucose (SMBG) for management of diabetes mellitus (DM), frequent blood sampling is discouraged by bleeding risk due to dual-antiplatelet agent therapy (DAPT) or thrombocytopenia. METHODS: We compared the bleeding time (BT) of sampling by using a laser-lancing-device (LMT-1000) and a conventional lancet in patients with DM and thrombocytopenia or patients undergoing DAPT. BT was measured using the Duke method, and pain and satisfaction scores were assessed using numeric rating scale (NRS) and visual analog scale (VAS). The consistency in the values of glucose and glycated-hemoglobin (HbA1c) sampled using the LMT-1000 or lancet were compared. RESULTS: The BT of sampling with the LMT-1000 was shorter than that with the lancet in patients with thrombocytopenia (60s vs. 85s, P = 0.024). The NRS was lower and the VAS was higher in laser-applied-sampling than lancet-applied sampling in the DAPT-user group (NRS: 1 vs. 2, P = 0.010; VAS: 7 vs. 6, P = 0.003), whereas the group with thrombocytopenia only showed improvement in the VAS score (8 vs. 7, P = 0.049). Glucose and HbA1c sampled by the LMT-1000 and lancet were significantly correlated in both the DAPT-user and the thrombocytopenia groups. CONCLUSION: The LMT-1000 can promote SMBG by shortening BT in subject with thrombocytopenia and by increasing satisfaction score, as well as by showing reliable glucose and HbA1c value.

Efficient prioritization of CRISPR screen hits by accounting for targeting efficiency of guide RNA.

BACKGROUND: CRISPR-based screens are revolutionizing drug discovery as tools to identify genes whose ablation induces a phenotype of interest. For instance, CRISPR-Cas9 screening has been successfully used to identify novel therapeutic targets in cancer where disruption of genes leads to decreased viability of malignant cells. However, low-activity guide RNAs may give rise to variable changes in phenotype, preventing easy identification of hits and leading to false negative results. Therefore, correcting the effects of bias due to differences in guide RNA efficiency in CRISPR screening data can improve the efficiency of prioritizing hits for further validation. Here, we developed an approach to identify hits from negative CRISPR screens by correcting the fold changes (FC) in gRNA frequency by the actual, observed frequency of indel mutations generated by gRNA. RESULTS: Each gRNA was coupled with the "reporter sequence" that can be targeted by the same gRNA so that the frequency of mutations in the reporter sequence can be used as a proxy for the endogenous target gene. The measured gRNA activity was used to correct the FC. We identified indel generation efficiency as the dominant factor contributing significant bias to screening results, and our method significantly removed such bias and was better at identifying essential genes when compared to conventional fold change analysis. We successfully applied our gRNA activity data to previously published gRNA screening data, and identified novel genes whose ablation could synergize with vemurafenib in the A375 melanoma cell line. Our method identified nicotinamide N-methyltransferase, lactate dehydrogenase B, and polypyrimidine tract-binding protein 1 as synergistic targets whose ablation sensitized A375 cells to vemurafenib. CONCLUSIONS: We identified the variations in target cleavage efficiency, even in optimized sgRNA libraries, that pose a strong bias in phenotype and developed an analysis method that corrects phenotype score by the measured differences in the targeting efficiency among sgRNAs. Collectively, we expect that our new analysis method will more accurately identify genes that confer the phenotype of interest.

Severe COVID-19 post pregnancy complicated by acute thromboemboli resulting in ST-elevation myocardial infarction - A case report.

Introduction: It has been shown that pregnancy can cause alterations in the severity of COVID-19 infection. We demonstrate an immediate post-partum patient diagnosed with severe COVID-19 and subsequently developed acute thrombosis of coronary artery.Case Summary: 35-year-old female unvaccinated for COVID-19 presented in labor and delivered on the same day. Several hours later, she was found to be in respiratory distress and tested positive for COVID-19. On day 7, computerized tomography (CT) of chest revealed bilateral pneumonia and pneumomediastinum. On day 8, she developed chest pain with electrocardiogram (EKG) showing inferior STelevations with troponin I of 0.6 ng/mL. She was intubated for airway protection and emergent diagnostic angiogram revealed thrombus occlusion of the third right posterolateral segment that resulted in thrombolysis in myocardial infarction (TIMI) 0 flow without evidence of underlying atherosclerotic disease in the remaining vessels. Intracoronary IIb/IIIa inhibitor was administered. Arterial blood gas in the lab revealed profound hypoxia despite being on 100% inspired oxygen. Multidisciplinary decision was made to cannulate patient for venovenous extracorporeal membrane oxygenation (ECMO) to treat severe COVID-19 pneumonia. She was finally decannulated from ECMO on day 65. After prolonged hospital stay, she eventually recovered and was discharged to rehabilitation.Conclusions: The center for disease control (CDC) surveillance has reported that pregnant patients with COVID-19 are more likely to require invasive ventilation and ECMO, and die given the immunological changes during pregnancy. Hypercoagulable state caused by combination of pregnancy and COVID-19 resulting in coronary thrombosis is rarely described in literature, our case demonstrated the paucity of this phenomenon.

The Skin-Whitening and Antioxidant Effects of Protocatechuic Acid (PCA) Derivatives in Melanoma and Fibroblast Cell Lines.

The skin is the most voluminous organ of the human body and is exposed to the outer environment. Such exposed skin suffers from the effects of various intrinsic and extrinsic aging factors. Skin aging is characterized by features such as wrinkling, loss of elasticity, and skin pigmentation. Skin pigmentation occurs in skin aging and is caused by hyper-melanogenesis and oxidative stress. Protocatechuic acid (PCA) is a natural secondary metabolite from a plant-based source widely used as a cosmetic ingredient. We chemically designed and synthesized PCA derivatives conjugated with alkyl esters to develop effective chemicals that have skin-whitening and antioxidant effects and enhance the pharmacological activities of PCA. We identified that melanin biosynthesis in B16 melanoma cells treated with alpha-melanocyte-stimulating hormone (α-MSH) is decreased by PCA derivatives. We also found that PCA derivatives effectively have antioxidant effects in HS68 fibroblast cells. In this study, we suggest that our PCA derivatives are potent ingredients for developing cosmetics with skin-whitening and antioxidant effects.

Importance of Local Ablative Therapies for Lung Metastases in Patients With Colorectal Cancer.

OBJECTIVE: To assess the effect of local ablative therapy (LAT) on overall survival in patients with lung metastases from colorectal cancer (CRC) compared with patients treated with systemic therapy. SUMMARY BACKGROUND DATA: CRC affects approximately 1.4 million individuals worldwide every year. The lungs are commonly affected by CRC, and there is no treatment standard for a secondary lung metastasis from CRC. METHODS: This longitudinal, retrospective cohort study (2010-2018) quantified the pulmonary and extrapulmonary tumor burden of 1143 patients by retrospectively reviewing computed tomography images captured at diagnosis. A comprehensive multidisciplinary approach informed how and when surgery and/or stereotactic body radiotherapy was administered. RESULTS: Among 1143 patients, 473 patients (41%) received LAT, with surgery first (n = 421) or stereotactic ablative radiation therapy first (n = 52) either at the time of diagnosis (n = 288), within 1 year (n = 132), or after 1 year (n = 53). LAT was repeated in 158 patients (33.4%, 384 total sessions) when new lung metastases were detected. The 5- and 10-year survival rates for patients treated with LAT (71.2% and 64.0%, respectively) were significantly higher than those of patients treated with systemic therapy alone (14.2% and 10.0%, respectively; P <0.001). The overall survival of patients who received LAT intervention increased as the total tumor burden decreased. CONCLUSIONS: A high long-term survival rate was achievable in a significant portion of patients with lung metastasis from CRC by the timely administrations of LAT to standard systemic therapy. The tumor burden and LAT feasibility should be included in a discussion during the follow-up period.

Melatonin inhibits Japanese encephalitis virus replication and neurotoxicity via calcineurin-autophagy pathways.

BACKGROUND: Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that has no specific treatment except for supportive medical care. JEV is a neurotropic virus that affects the nervous system and triggers inflammation in the brain. METHODS: Melatonin is used as a sleep-inducing agent in neurophysiology and may serve as a protective agent against neurological and neurodegenerative diseases. Herein, we investigated the effects of melatonin and the critical roles of the serine/threonine protein phosphatase calcineurin during JEV infection in SK-N-SH neuroblastoma cells. RESULTS: Melatonin treatment decreased JEV replication and JEV-mediated neurotoxicity. Calcineurin activity was increased by JEV infection and inhibited by melatonin treatment. Through calcineurin regulation, melatonin decreased the JEV-mediated neuroinflammatory response and attenuated JEV-induced autophagy. CONCLUSIONS: Calcineurin inactivation has a protective effect in JEV-infected neuronal cells, and melatonin is a novel resource for the development of anti-JEV agents.

p21-activated kinase 4 inhibition protects against liver ischemia/reperfusion injury: Role of nuclear factor erythroid 2-related factor 2 phosphorylation.

BACKGROUND AND AIMS: p21-activated kinase 4 (PAK4), an oncogenic protein, has emerged as a promising target for anticancer drug development. Its role in oxidative stress conditions, however, remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. APPROACH AND RESULTS: Hepatocyte- and myeloid-specific Pak4 knockout (KO) mice and their littermate controls were subjected to a partial hepatic I/R (HIR) injury. We manipulated the catalytic activity of PAK4, either through genetic engineering (gene knockout, overexpression of wild-type [WT] or dominant-negative kinase) or pharmacological inhibitor, coupled with a readout of nuclear factor erythroid 2-related factor 2 (Nrf2) activity, to test the potential function of PAK4 on HIR injury. PAK4 expression was markedly up-regulated in liver during HIR injury in mice and humans. Deletion of PAK4 in hepatocytes, but not in myeloid cells, ameliorated liver damages, as demonstrated in the decrease in hepatocellular necrosis and inflammatory responses. Conversely, the forced expression of WT PAK4 aggravated the pathological changes. PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. Nrf2 silencing in liver abolished the protective effects of PAK4 deficiency. A PAK4 inhibitor protected mice from HIR injury. CONCLUSIONS: PAK4 phosphorylates Nrf2 and suppresses its transcriptional activity. Genetic or pharmacological suppression of PAK4 alleviates HIR injury. Thus, PAK4 inhibition may represent a promising intervention against I/R-induced liver injury.

Immediate Postoperative High Syndecan-1 is Associated with Short-Term Morbidity and Mortality After Robot-Assisted Esophagectomy: A Prospective Observational Study.

BACKGROUND: Disruption of the endothelial glycocalyx (EG) is associated with a poor prognosis in various clinical settings. This study aimed to determine the association between immediate postoperative serum syndecan-1 levels, a representative marker for EG degradation, and major postoperative morbidity and mortality in patients undergoing robot-assisted esophagectomy. METHODS: Patients who underwent robot-assisted esophagectomy between 2018 and 2022 were prospectively enrolled. The primary outcome was the association between immediate postoperative syndecan-1 levels and the occurrence of major postoperative morbidity and mortality within 30 days of surgery. Patients were classified into low and high syndecan-1 groups based on the optimal cut-off value of syndecan-1 for predicting major morbidity and mortality. A multivariable logistic regression analysis was performed to investigate the risk factors for major morbidity and mortality. RESULTS: A total of 207 patients were analyzed. Patients with high syndecan-1 levels (≥48 ng/mL) showed a significantly greater incidence of unexpected returns to the operating room and anastomotic leaks and longer durations of hospital and intensive care unit stays than patients with low syndecan-1 levels (<48 ng/mL). Immediate postoperative syndecan-1 levels ≥48 ng/mL (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.23-4.76), American Society of Anesthesiologists physical status ≥III (OR 3.36, 95% CI 1.56-7.22), and current smoker (OR 4.02, 95% CI 1.52-10.61) were independently associated with major morbidity and mortality within 30 days of esophagectomy. CONCLUSIONS: Immediate postoperative syndecan-1 levels ≥48 ng/mL could be used for the early detection of patients at high risk of complications after robot-assisted esophagectomy.

Risk of pancreatic cancer after acute pancreatitis: A population-based matched cohort study.

BACKGROUND: We investigated the short- and long-term risks of pancreatic cancer after the diagnosis of acute pancreatitis. METHODS: This population-based matched-cohort study used data from the Korean National Health Insurance Service database. Patients with acute pancreatitis (n = 25,488) were matched with the control group (n = 127,440) based on age, sex, body mass index, smoking status, and diabetes. We estimated the hazard ratios for developing pancreatic cancer in both groups using Cox regression analysis. RESULTS: During a median follow-up of 5.4 years, pancreatic cancer developed in 479 patients (1.9%) in the acute pancreatitis group and 317 patients (0.2%) in the control group. Compared with the control group, the risk of pancreatic cancer in the acute pancreatitis group was very high within the first 2 years, which gradually decreased over time. The hazard ratio for the risk of developing pancreatitis was 8.46 (95% confidence interval, 5.57-12.84) at 1-2 years, and then decreased to 3.62 (95% confidence interval, 2.26-4.91) at 2-4 years. However, even after 8-10 years, the hazard ratio was still statistically significantly increased to 2.80 (95% confidence interval, 1.42-5.53). After 10 years, there was no significant difference in the risk of pancreatic cancer between the two groups. CONCLUSIONS: The risk of pancreatic cancer increases rapidly after acute pancreatitis diagnosis, gradually declines after 2 years, and remains elevated for up to 10 years. Further studies are needed to determine the long-term effects of acute pancreatitis on the risk of pancreatic cancer.

Antidepressants and the Risk of Ischemic Stroke in Older Adults According to the Degree of Serotonin Reuptake Inhibition: A Retrospective Cohort Study.

OBJECTIVE: The effects of serotonin reuptake inhibition induced by antidepressants on ischemic stroke and its pathophysiology remain unclear despite the frequent use of antidepressants and high fatality of ischemic stroke. We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition. DESIGN: Retrospective cohort study. PARTICIPANTS: The cohort consisted of older adult patients who were treated with antidepressants. MEASUREMENTS: We estimated the risk of ischemic stroke associated with antidepressant use in older adults according to the degree of serotonin reuptake inhibition using Korea's National Health Insurance System-Senior Cohort. Exposure to antidepressants was categorized by type (strong, intermediate, or weak serotonin reuptake inhibitors [SRIs]) and by the mean prescribed dose per day and treatment duration. The risk for the strong and intermediate SRIs group was compared with that of the weak SRIs group using a Cox proportional hazards regression model. RESULTS: Of 97,411 were weak SRIs users, and 107,152 and 18,783 were users of strong and intermediate SRIs. The risk of ischemic stroke was 1.192- and 1.057-fold higher in strong and intermediate SRI users, respectively than in weak SRI users. Hazard ratios were increased in higher dose and shorter duration user groups. The risk increased 1.753-fold in strong SRI users with anticonvulsants and 1.387-fold in intermediate SRI users with PPIs. CONCLUSION: The use of strong and intermediate SRIs should be considered carefully in older adult patients, especially when high-dose antidepressants are prescribed even for a short duration.