Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

PURPOSE: Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. METHODS: This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). RESULTS: The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CONCLUSION: CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Prognostic significance of SASP-related gene signature of radiation therapy in head and neck squamous cell carcinoma.

In this study,we developed and validated the clinical significance of senescence SASP related gene signature and explored its association with radiation therapy (RT) in patients with head and neck squamous cell carcinoma (HNSCC). First, we searched the three published review literature associated with senescence associated secretory phenotype (SASP) and selected all 81 genes to develop SASP related gene signature. Then, 81 SASP related genes were adapted to gene expression dataset from TCGA. HNSCC patients of TCGA were classified into clusters 1 and 2 via unsupervised clustering according to SASP related gene signature. Kaplan-Meier plot survival analysis showed that cluster 1 had a poorer prognosis than cluster 2 in 5-years overall survival and recurrence-free survival. Similarly, cluster 1 showed a worse prognosis than cluster 2 in three validation cohorts. (E-MTAB-8588, FHCRC and KHU). Cox proportional hazards regression observed that the senescence SASP related signature was an independent prognostic factor for HNSCC patients. We also established a nomogram using a relevant clinical parameter and a risk score. Time-dependent receiver operating characteristic (ROC) analysis was carried out to assess the accuracy of the prognostic risk model and nomogram. Senescence SASP related gene signature was associated with the response to RT. Therefore, subsequent, in vitro experiments further validated the association between senescence SASP related gene signature and RT in HNSCC. In conclusion, we developed a senescence SASP related gene signature, which could predict survival of HNSCC patients, and this gene signature provides new clinical evidence for the accurate diagnosis and targeted RT of HNSCC.

Attenuated adenomatous polyposis with MSH6 variation: Two case reports.

RATIONALE: Adenomatous polyposis (AP) is a genetic disorder characterized by the occurrence of numerous adenomatous polyps in the colon and rectum and can be classified into classical AP and attenuated AP (AAP). AAP is diagnosed when the number of observed adenomas is between 10 and 99. The detection of AAP is significantly increasing mainly due to the improvement of the imaging technique and application of the screening program for colorectal cancer detection. Currently, the germline variations of the APC and MUTYH genes are reported as the main cause of classical AP. However, the underlying genetic basis of AAP is not well understood. In this study, we report 2 cases of AAP with MSH6 variations. PATIENT CONCERNS: Both patients visited the hospital after multiple polyps were detected during colonoscopies conducted as part of their health checkups. DIAGNOSES: The 2 patients were diagnosed with AAP through colonoscopic examination at our hospital. INTERVENTIONS: The 2 received genetic consultation; and, for follow-up purposes, both patients agreed to be tested for an underlying genetic condition through next generation sequencing. And germline MSH6 variations were detected in both AAP patients. OUTCOMES: There was no recurrence for both patients for 3 years follow-up. LESSONS: Minor portion of AAP can cause by genetic mutation in MSH6, and further research is needed.

Local Ablation Therapy for Hepatocellular Carcinoma: Clinical Significance of Tumor Size, Location, and Biology.

ABSTRACT: Local ablation therapy, encompassing radiofrequency ablation (RFA), microwave ablation, and cryoablation, has emerged as a crucial strategy for managing small hepatocellular carcinomas (HCCs), complementing liver resection and transplantation. This review delves into the clinical significance of tumor size, location, and biology in guiding treatment decisions for HCCs undergoing local ablation therapy, with a focus on tumors smaller than 3 cm. Tumor size significantly influences treatment outcomes, with larger tumors associated with poorer local tumor control due to challenges in creating sufficient ablative margins and the likelihood of microvascular invasion and peritumoral satellite nodules. Advanced ablation techniques such as centripetal or no-touch RFA using multiple electrodes, cryoablation using multiple cryoprobes, and microwave ablation offer diverse options for HCC treatment. Notably, no-touch RFA demonstrates superior local tumor control compared with conventional RFA by achieving sufficient ablative margins, making it particularly promising for hepatic dome lesions or tumors with aggressive biology. Laparoscopic RFA proves beneficial for treating anterior subphrenic HCCs, whereas artificial pleural effusion-assisted RFA is effective for controlling posterior subphrenic HCCs. However, surgical resection generally offers better survival outcomes for periportal HCCs compared with RFA. Cryoablation exhibits a lower incidence of vascular or biliary complications than RFA for HCCs adjacent to perivascular or periductal regions. Additionally, aggressive tumor biology, such as microvascular invasion, can be predicted using magnetic resonance imaging findings and serum tumor markers. Aggressive HCC subtypes frequently exhibit Liver Imaging Reporting and Data System M features on magnetic resonance imaging, aiding in prognosis. A comprehensive understanding of tumor size, location, and biology is imperative for optimizing the benefits of local ablation therapy in managing HCCs.

Lavandula angustifolia Mill. inhibits high glucose and nicotine-induced Ca2+ influx in microglia and neuron-like cells via two distinct mechanisms.

Smoking remains a significant health problem in patients with type 2 diabetes mellitus. This study compared intracellular Ca2+ ([Ca2+]i) in microglia, neurons, and astrocytes in the presence of high glucose (HG) and nicotine and evaluated the effects of Lavandula angustifolia Mill. essential oil (LEO) on this process. [Ca2+]i concentrations were measured by monitoring the fluorescence of Fura-2 acetoxymethyl ester. Treatment with HG and nicotine significantly increased [Ca2+]i in both microglia and neurons through Ca2+ influx from extracellular sources. This increased Ca2+ influx in microglia, however, was significantly reduced by LEO, an effect partially inhibited by the Na+/Ca2+ exchanger (NCX) inhibitor Ni2+. Ca2+ influx in neuron-like cells pretreated with HG plus nicotine was also significantly decreased by LEO, an effect partially inhibited by the L-type Ca2+ channel blocker nifedipine and the T-type Ca2+ channel blocker mibefradil. LEO or a two-fold increase in the applied number of astrocytes attenuated Ca2+ influx caused by high glucose and nicotine in the mixed cells of the microglia, neuron-like cells and astrocytes. These findings suggest that LEO can regulate HG and nicotine-induced Ca2+ influx into microglia and neurons through two distinct mechanisms.

Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers.

Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression.

Pan AMPK Activation Protects Tubules in Rat Ischemic Acute Kidney Injury.

Acute Kidney Injury (AKI) is characterized by an abrupt decline in kidney function and has been associated with excess risks of death, kidney disease progression, and cardiovascular events. The kidney has a high energetic demand with mitochondrial health being essential to renal function and damaged mitochondria has been reported across AKI subtypes. 5' adenosine monophosphate-activated protein kinase (AMPK) activation preserves cellular energetics through improvement of mitochondrial function and biogenesis when ATP levels are low such as under ischemia-induced AKI. We developed a selective potent small molecule pan AMPK activator, compound 1, and tested its ability to increase AMPK activity and preserve kidney function during ischemia/reperfusion injury in rats. A single administration of 1 caused sustained activation of AMPK for at least 24 hours, protected against acute tubular necrosis, and reduced clinical markers of tubular injury such as NephroCheck and Fractional Excretion of Sodium (FENa). Reduction in plasma creatinine and increased Glomerular Filtration Rate (GFR) indicated preservation of kidney function. Surprisingly, we observed a strong diuretic effect of AMPK activation associated with natriuresis both with and without AKI. Our findings demonstrate that activation of AMPK leads to protection of tubular function under hypoxic/ischemic conditions which holds promise as a potential novel therapeutic approach for AKI. Significance Statement No approved pharmacological therapies currently exist for acute kidney injury. We developed Compound 1 which dose-dependently activated AMPK in the kidney and protected kidney function and tubules after ischemic renal injury in the rat. This was accompanied by natriuresis in injured as well as uninjured rats.

Immunomethylomic profiles of long-term head and neck squamous cell carcinoma survivors on immune checkpoint inhibitors.

Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.

[Box: see text].

A Divergent Sequela of Scleral Buckle Removal.

Scleral buckle (SB) removal is done for a variety of reasons following treatment of rhegmatogenous retinal detachments (RRD), such as buckle exposure, migration, and infection. The most worrying complication of SB removal is retinal redetachment. We report a unique case of a patient developing strabismus about one month after scleral buckle removal for anterior migration and exposure of the scleral buckle. We also share a successful strabismus surgery which had a main aim of relieving diplopia in the patient's primary gaze.

The Comparison of Efficacy and Safety between Radiofrequency Ablation Alone and Ethanol Ablation Followed by Radiofrequency Ablation in the Treatment of Mixed Cystic and Solid Thyroid Nodule.

Purpose: To compare the efficacy and safety of radiofrequency ablation (RFA) and ethanol ablation (EA) followed by RFA in treating mixed cystic and solid thyroid nodules. Materials and Methods: We included 243 nodules from 243 patients who underwent RFA for mixed cystic and solid benign nodules. The nodules were divided into two groups (RFA alone and EA + RFA). We evaluated volume reduction rate (VRR), therapeutic success rate, improvement in symptomatic and cosmetic issues, complications, and adverse effects. Results: The RFA group included 204 patients, and the EA + RFA group included 39 patients. The long-term success rates in the RFA only and EA + RFA groups were 90.2% and 97.4%, respectively. The mean VRR at the last follow-up in the RFA and EA + RFA groups were 81.6% and 87.2%, respectively. Therapeutic results were similar in both groups at the last follow-up. Cosmetic and symptomatic problems markedly improved in both groups. No major complications were observed. Conclusion: Both RFA alone and EA + RA are safe and effective methods for treating mixed cystic and solid thyroid nodules, although EA + RFA is slightly more effective.

[Pleural Metastasis of Lung Cancer Combined with Pleuroparenchymal Fibroelastosis: A Case Report]. / 흉막폐실질 íƒ„ë ¥ì„¬ìœ ì¦ê³¼ 동반된 폐암의 흉막 ì „ì´: 증례 ë³´ê³ .

Pleural metastasis is the most common cause of malignant diseases involving the pleura, and characterized by pleural effusion, nodules, and thickening. Pleuroparenchymal fibroelastosis (PPFE) is a disease characterized by apical pleural thickening and subjacent parenchymal fibrosis. We report a case of a 60-year-old male with lung cancer in the left lower lobe and underlying PPFE combined with left apical pleural metastasis. Initially, asymmetric left apical pleural thickening due to pleural metastasis was mistaken for PPFE. Additionally, we describe the imaging and histopathological findings of PPFE, including MRI findings.

Gastrointestinal tract perforation after radiofrequency ablation for hepatic tumor: Incidence and risk factors.

OBJECTIVE: We analyzed the incidence and mortality rate of gastrointestinal (GI) tract perforation after radiofrequency ablation (RFA) for hepatic tumors and assess its risk factors. METHODS: This retrospective cohort study included 4799 patients with malignant tumors who underwent RFA (n = 7206). Sixty-nine cases of thermal injury to the GI tract were identified via a search of the electronic medical record system using index terms and divided into two groups according to the thermal injury with (n = 8) or without (n = 61) GI tract perforation based on follow-up CT reports. The risk factors for GI tract perforation were identified via multivariable logistic regression analysis using clinical, technical, and follow-up CT findings. RESULTS: The incidence of thermal injury to the GI tract and GI tract perforation was 0.96 % (69/7206) and 0.11 % (8/7206), respectively. The type of adjacent GI tract and history of diabetes mellitus differed significantly between the two groups (p < 0.05). The index tumor being located around the small intestine was the only significant risk factor for GI tract perforation after ablation (Odds ratio, 22.69; 95 % confidence interval, 2.59-198.34; p = 0.005 [reference standard, stomach]). All perforations were not identified on CT images immediately after RFA. The median time to detection was 20 days (range, 13-41 days). Two patients (25 %, 2/8) died due to perforation-related complications. CONCLUSION: GI tract perforation after RFA for hepatic tumors is rare; however, it is associated with high mortality. Thus, careful follow-up is required after RFA if the index tumor is located around the small intestine.

Ultrathin and Smooth Pheomelanin-like Photoconductive Film.

This study introduces a facile method for the substrate-independent deposition of pheomelanin-like films, revealing unique and promising electrical characteristics. The conventional darkening of a dopamine solution at a basic pH was significantly delayed by the addition of l-cysteine, resulting in a distinctive temporal pattern: an initial quiescent period without apparent color change followed by an abrupt and explosive burst. Surprisingly, within the quiescent period, the deposition of ultrathin and smooth pheomelanin-like films was observed, in addition to rough and thick films formed after the burst. Regardless of thickness or texture, these films exhibited common chemical properties, including moisture-capturing capability and dark- and bright-state conductivities. Particularly noteworthy were consistent photocurrent responses under bias voltage across various pheomelanin-like films, which were not observed in polydopamine films, highlighting the influential role of l-cysteine addition. These findings present a novel avenue for the potential application of pheomelanin-like films in bioelectronics, emphasizing their distinct electrical characteristics and prompting further exploration into their intricate conductive mechanisms. The study contributes to advancing our understanding of melanin-based materials and their potential in diverse scientific and technological domains.

Determining the Optimal Dosage of Dexmedetomidine for Smooth Emergence in Older Patients Undergoing Spinal Surgery: A Study of 44 Cases.

BACKGROUND Emergence agitation, or delirium, occurs during early recovery from general anesthesia and involves disorientation, excitation, and uncontrolled physical movements. Dexmedetomidine is an alpha agonist that has sedative, anxiolytic, analgesic, and sympatholytic activities and is used as a continuous infusion to prevent emergence agitation. This study aimed to evaluate patients aged 65 years and older undergoing general anesthesia to determine the 90% effective dose (ED90) of dexmedetomidine continuous intraoperative infusion to prevent emergence agitation. MATERIAL AND METHODS We enrolled 44 patients aged 65 years and older undergoing spinal surgery under general anesthesia. Dexmedetomidine administration commenced 30 minutes before surgery completion, with a predetermined infusion dose (µg/kg/h), without a loading dose. The initial dose was 0.2 µg/kg/h, and subsequent step size was ±0.05 µg/kg/h. We tried to find ED90 of dexmedetomidine using the biased-coin design. Vital signs, extubation quality scores, extubation-related complications, and postoperative outcomes were monitored. RESULTS Dexmedetomidine ED90 for smooth emergence in older patients was 0.34 µg/kg/h. Peri-extubation vital signs remained within 20% of baseline values, without requiring pharmacological intervention. No hypoxia, hypoventilation, or post-extubation agitation occurred. In the recovery room, 1 patient briefly exhibited excitement but quickly calmed. Nine patients initially unresponsive in the recovery room fully awoke and were promptly discharged. CONCLUSIONS For older patients who are vulnerable to adverse effects of anesthetics and opioids, dexmedetomidine enables gentle awakening without adverse vital sign changes, respiratory depression, excessive sedation, or emergence agitation (ED90=0.34 µg/kg/h). Further studies should involve a larger patient cohort, considering diverse medical conditions in older individuals.

Quantification of tire wear particles in road dust based on synthetic/natural rubber ratio using pyrolysis-gas chromatography-mass spectrometry across diverse tire types.

Increase in road traffic leads to increased concentrations of tire-wear particles (TWPs), a prominent source of microplastics from vehicles, in road dust. These particles can re-enter the atmosphere or move into aquatic ecosystems via runoff, impacting the environment. Consequently, accurately assessing and managing TWP levels in road dust is crucial. However, the ISO method (ISO/TS 20593 and 21396) uses a constant ratio of styrene-butadiene rubber (SBR) to natural rubber (NR) for all tires, disregarding the variability in tire composition across different types and brands. Our study found substantial SBR content (15.7 %) in heavyweight truck tires, traditionally believed to be predominantly NR. We evaluated the SBR/NR content in 15 tire types and proposed a method to more accurately evaluate TWP concentrations in road dust from five different locations. Our findings suggest that the conventional ISO method may underestimate the concentrations of TWP due to its reliance on a static ratio of SBR/NR. This study underscores the necessity for a more flexible approach that can adapt to the variability in SBR and NR content across different tire types. By delineating the limitations inherent in current assessment methods, our research contributes to a more adaptable understanding of TWP concentrations in road dust. This advancement prompts the development of a revised methodology that more accurately reflects the diverse compositions of tire rubber in environmental samples.

An update on the status of HSP90 inhibitors in cancer clinical trials.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

In Vitro Metabolism and Transport Characteristics of Zastaprazan.

Zastaprazan (JP-1366), a novel potassium-competitive acid blocker, is a new drug for the treatment of erosive esophagitis. JP-1366 is highly metabolized in human, mouse, and dog hepatocytes but moderately metabolized in rat and monkey hepatocytes when estimated from the metabolic stability of this compound in hepatocyte suspension and when 18 phase I metabolites and 5 phase II metabolites [i.e., N-dearylation (M6), hydroxylation (M1, M19, M21), dihydroxylation (M7, M8, M14, M22), trihydroxylation (M13, M18), hydroxylation and reduction (M20), dihydroxylation and reduction (M9, M16), hydrolysis (M23), hydroxylation and glucuronidation (M11, M15), hydroxylation and sulfation (M17), dihydroxylation and sulfation (M10, M12), N-dearylation and hydroxylation (M3, M4), N-dearylation and dihydroxylation (M5), and N-dearylation and trihydroxylation (M2)] were identified from JP-1366 incubation with the hepatocytes from humans, mice, rats, dogs, and monkeys. Based on the cytochrome P450 (CYP) screening test and immune-inhibition analysis with CYP antibodies, CYP3A4 and CYP3A5 played major roles in the metabolism of JP-1366 to M1, M3, M4, M6, M8, M9, M13, M14, M16, M18, M19, M21, and M22. CYP1A2, 2C8, 2C9, 2C19, and 2D6 played minor roles in the metabolism of JP-1366. UDP-glucuronosyltransferase (UGT) 2B7 and UGT2B17 were responsible for the glucuronidation of M1 to M15. However, JP-1366 and active metabolite M1 were not substrates for drug transporters such as organic cation transporter (OCT) 1/2, organic anion transporter (OAT) 1/3, organic anion transporting polypeptide (OATP)1B1/1B3, multidrug and toxic compound extrusion (MATE)1/2K, P-glycoprotein (P-gp), and breast cancer-resistant protein (BCRP). Only M1 showed substrate specificity for P-gp. The findings indicated that drug-metabolizing enzymes, particularly CYP3A4/3A5, may have a significant role in determining the pharmacokinetics of zastaprazan while drug transporters may only have a small impact on the absorption, distribution, and excretion of this compound.

Dual-Emissive Detection of ATP and Hypochlorite Ions for Monitoring Inflammation-Driven Liver Injury In Vitro and In Vivo.

Reactive oxygen species play a pivotal role in liver disease, contributing to severe liver damage and chronic inflammation. In liver injury driven by inflammation, adenosine-5'-triphosphate (ATP) and hypochlorite ion (ClO-) emerge as novel biomarkers, reflecting mitochondrial dysfunction and amplified oxidative stress, respectively. However, the dynamic fluctuations of ATP and ClO- in hepatocytes and mouse livers remain unclear, and multidetection techniques for these biomarkers are yet to be developed. This study presents RATP-NClO, a dual-channel fluorescent bioprobe capable of synchronously detecting ATP and ClO- ions. RATP-NClO exhibits excellent selectivity and sensitivity for ATP and ClO- ions, demonstrating a dual-channel fluorescence response in a murine hepatocyte cell line. Upon intravenous administration, RATP-NClO reveals synchronized ATP depletion and ClO- amplification in the livers of mice with experimental metabolic dysfunction-associated steatohepatitis (MASH). Through a comprehensive analysis of the principal mechanism of the developed bioprobe and the verification of its reliable detection ability in both in vitro and in vivo settings, we propose it as a unique tool for monitoring changes in intracellular ATP and ClO- level. These findings underscore its potential for practical image-based monitoring and functional phenotyping of MASH pathogenesis.

Evaluating micronized adipose tissue niche and artificial dermis grafts following nonmelanoma skin cancer excision: a pilot study.

BACKGROUND: Recently, micronized adipose tissue (MAT) grafts have shown promising results in wound healing, including diabetic ulcers. OBJECTIVE: To assess the possibility of using 3D printed MAT niche grafts in the management of skin and soft tissue defects resulting from non-melanoma skin cancer (NMSC) resections. MATERIALS AND METHODS: A retrospective feasibility study was conducted on patients with skin and soft tissue defects resulting from NMSC resections. Twenty-one patients were treated using either artificial dermis (n = 11) or MAT niche (n = 10) grafting. Healing time and POSAS scores were compared. The Mann-Whitney U test and the Pearson chi-square test were used in statistical analysis to compare between and within groups based on preoperative and postoperative measurements. RESULTS: Wounds in the MAT niche group reepithelialized significantly faster than those in the artificial dermis group (mean [SD] 39.2 [11.4] days vs 63.7 [34.8] days; P = .04). In the 21 scar parameters evaluated, the MAT niche group demonstrated significantly superior outcomes in only 2 parameters based on operator assessment scores: relief (mean [SD] 1.6 [0.7] vs 2.2 [0.6]; P = .047) and scar contracture (mean [SD] 1.3 [0.5] vs 2.5 [1.0]; P = .011). CONCLUSION: This study proves the feasibility of exploring the effects of MAT niche grafting following NMSC excision on healing time and specific parameters of scarring, including scar relief and scar contracture.

Particulate matter exposure induces adverse effects on endometrium and fertility via aberrant inflammatory and apoptotic pathways in vitro and in vivo.

This study aimed to evaluate the adverse effects of particulate matter (PM) exposure on endometrial cells and fertility and to identify possible underlying mechanisms. Thirteen women (aged 15-52 years) were included in this study. Enrolled patients underwent laparoscopic surgery at Gangnam Severance Hospital between 1 January and 31 December 2021. For in vivo experiments, 36 female and nine male C57BL/6 mice were randomly divided into control(vehicle), low-dose(10 mg/kg/d), and high-dose exposure groups(20 mg/kg/d). PM was inhaled nasally for four weeks and natural mating was performed. NIST® SRM® 1648a was used for PM exposure. qRT-PCR, western blotting and Masson's trichrome staining were performed. PM treatment in human endometrial stromal cells induced inflammation with significant upregulation of IL-1ß, p-NF-kB, and p-c-Jun compared to those of controls. Additionally, PM treatment significantly increased apoptosis in human endometrial stromal cells by downregulating p-AKT and upregulating p-p53/p53, Cas-3, BAX/Bcl-2, p-AMPK, and p-ERK. After PM treatment, the relative expression of IL-1ß, IL-6, TNF-α, p-NF-κB, p-c-Jun, and p-Nrf2/Nrf2 significantly increased in murine endometrium compared to those of the controls. Expression of apoptotic proteins p53, p27, and Cas-3, was also significantly elevated in murine endometrium of the PM exposure group compared to that of the controls. A significant increase in expression of procollagen Ⅰ, and Masson's trichrome staining scores in the murine endometrium was noted after PM treatment. PM treatment significantly decreased ERα expression. After natural mating, all 3 female mice in the control group gave birth to 25 offspring (mean 8.1), whereas in the low-dose PM treatment group, two of three female mice gave birth to nine offspring (mean 4.5). No pregnant mice or offspring was present in the high-dose PM treatment group. PM exposure induces adverse effects on the endometrium through aberrant activation of inflammatory and apoptotic pathways and is associated with detrimental effects on murine fertility.