Inhibition of lysine acetyltransferase KAT6 in ER+HER2- metastatic breast cancer: a phase 1 trial.

Inhibition of histone lysine acetyltransferases (KATs) KAT6A and KAT6B has shown antitumor activity in estrogen receptor-positive (ER+) breast cancer preclinical models. PF-07248144 is a selective catalytic inhibitor of KAT6A and KAT6B. In the present study, we report the safety, pharmacokinetics (PK), pharmacodynamics, efficacy and biomarker results from the first-in-human, phase 1 dose escalation and dose expansion study (n = 107) of PF-07248144 monotherapy and fulvestrant combination in heavily pretreated ER+ human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (mBC). The primary objectives of assessing the safety and tolerability and determining the recommended dose for expansion of PF-07248144, as monotherapy and in combination with fulvestrant, were met. Secondary endpoints included characterization of PK and evaluation of antitumor activity, including objective response rate (ORR) and progression-free survival (PFS). Common treatment-related adverse events (any grade; grades 3-4) included dysgeusia (83.2%, 0%), neutropenia (59.8%, 35.5%) and anemia (48.6%, 13.1%). Exposure was approximately dose proportional. Antitumor activity was observed as monotherapy. For the PF-07248144-fulvestrant combination (n = 43), the ORR (95% confidence interval (CI)) was 30.2% (95% CI = 17.2-46.1%) and the median PFS was 10.7 (5.3-not evaluable) months. PF-07248144 demonstrated a tolerable safety profile and durable antitumor activity in heavily pretreated ER+HER2- mBC. These findings establish KAT6A and KAT6B as druggable cancer targets, provide clinical proof of concept and reveal a potential avenue to treat mBC. clinicaltrial.gov registration: NCT04606446 .

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial.

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .

A Standardized Approach To Evaluation And Reporting of Synovial Histopathology In Two Surgically Induced Murine Models Of Osteoarthritis.

OBJECTIVE: Synovial pathology has been linked to osteoarthritis (OA) pain in patients. Microscopic grading systems for synovial changes in human OA have been described, but a standardized approach for murine models of OA is needed. We sought to develop a reproducible approach and set of minimum recommendations for reporting of synovial histopathology in mouse models of OA. METHODS: Coronal and sagittal sections from male mouse knee joints subjected to destabilization of medial meniscus (DMM) or partial meniscectomy (PMX) were collected as part of other studies. Stains included Hematoxylin and Eosin (H&E), Toluidine Blue (T-Blue) and Safranin O/Fast Green (Saf-O). Four blinded readers graded pathological features (hyperplasia, cellularity, and fibrosis) at specific anatomic locations. Inter-reader agreement of each feature score was determined. RESULTS: There was acceptable to very good agreement when using 3-4 individual readers. After DMM and PMX, expected medial predominant changes in hyperplasia and cellularity were observed, with fibrosis noted at 12 weeks post-PMX. Synovial changes were consistent from section to section in the mid-joint area. When comparing stains, H&E and T-blue resulted in better agreement compared to Saf-O stain. CONCLUSIONS: To account for the pathologic and anatomic variability in synovial pathology and allow for a more standardized evaluation that can be compared across studies, we recommend evaluating a minimum set of 3 pathological features at standardized anatomic areas. Further, we suggest reporting individual feature scores separately before relying on a single summed "synovitis" score. H&E or T-blue are preferred, inter-reader agreement for each feature should be considered.

Effects of particle size on toxicity, bioaccumulation, and translocation of zinc oxide nanoparticles to bok choy (Brassica chinensis L.) in garden soil.

The indiscriminate use of zinc oxide nanoparticles (ZnO NPs) in daily life can lead to their release into soil environment. These ZnO NPs can be taken up by crops and translocated to their edible part, potentially causing risks to the ecosystem and human health. In this study, we conducted pot experiments to determine phytotoxicity, bioaccumulation and translocation depending on the size (10 - 30 nm, 80 - 200 nm and 300 nm diameter) and concentration (0, 100, 500 and 1000 mg Zn/kg) of ZnO NPs and Zn ion (Zn2+) in bok choy, a leafy green vegetable crop. After 14 days of exposure, our results showed that large-sized ZnO NPs (i.e., 300 nm) at the highest concentration exhibited greater phytotoxicity, including obstruction of leaf and root weight (42.5 % and 33.8 %, respectively) and reduction of chlorophyll a and b content (50.2 % and 85.2 %, respectively), as well as changes in the activities of oxidative stress responses compared to those of small-sized ZnO NPs, although their translocation ability was relatively lower than that of smaller ones. The translocation factor (TF) values decreased as the size of ZnO NPs increased, with TF values of 0.68 for 10 - 30 nm, 0.55 for 80 - 200 nm, and 0.27 for 300 nm ZnO NPs, all at the highest exposure concentration. Both the results of micro X-ray fluorescence (µ-XRF) spectrometer and bio-transmission electron microscopy (bio-TEM) showed that the Zn elements were mainly localized at the edges of leaves exposed to small-sized ZnO NPs. However, the Zn elements upon exposure to large-sized ZnO NP were primarily observed in the primary veins of leaves in the µ-XRF data, indicating a limitation in their ability to translocate from roots to leaves. This study not only advances our comprehension of the environmental impact of nanotechnology but also holds considerable implications for the future of sustainable agriculture and food safety.

Extracellular fluid excess linked to reduced choroidal vascularity index in patients with chronic kidney disease.

Extracellular fluid (ECF) excess is common in patients with chronic kidney disease (CKD). This study (involving 284 patients with CKD) explored the association between choroidal vascularity index (CVI) and ECF excess. We categorised patients into three groups based on extracellular water/total body water: normal, mildly overhydrated, and severely overhydrated. The more severe ECF status was associated with a lower CVI after adjustment (B = - 0.902, p = 0.001). In non-diabetic patients, both vascular luminal (LA, p < 0.001) and stromal areas (SA, p = 0.003) were significantly reduced in patients with severe ECF excess compared to others, whereas diabetic patients showed no significant differences in LA (p = 0.96) and SA (p = 0.86) based on ECF excess status. These findings suggest that ECF status may influence CVI in patients with CKD, underscoring the need for further research to clarify its direct impact on choroidal changes.

Asymmetric allostery in estrogen receptor-α homodimers drives responses to the ensemble of estrogens in the hormonal milieu.

The estrogen receptor-α (ER) is thought to function only as a homodimer but responds to a variety of environmental, metazoan, and therapeutic estrogens at subsaturating doses, supporting binding mixtures of ligands as well as dimers that are only partially occupied. Here, we present a series of flexible ER ligands that bind to receptor dimers with individual ligand poses favoring distinct receptor conformations-receptor conformational heterodimers-mimicking the binding of two different ligands. Molecular dynamics simulations showed that the pairs of different ligand poses changed the correlated motion across the dimer interface to generate asymmetric communication between the dimer interface, the ligands, and the surface binding sites for epigenetic regulatory proteins. By examining the binding of the same ligand in crystal structures of ER in the agonist vs. antagonist conformers, we also showed that these allosteric signals are bidirectional. The receptor conformer can drive different ligand binding modes to support agonist vs. antagonist activity profiles, a revision of ligand binding theory that has focused on unidirectional signaling from the ligand to the coregulator binding site. We also observed differences in the allosteric signals between ligand and coregulator binding sites in the monomeric vs. dimeric receptor, and when bound by two different ligands, states that are physiologically relevant. Thus, ER conformational heterodimers integrate two different ligand-regulated activity profiles, representing different modes for ligand-dependent regulation of ER activity.

Immunosuppressive therapy in elderly patients with neuromyelitis optica spectrum disorder: a retrospective multicentre study.

BACKGROUND: The risk-benefit relationship of immunosuppressive therapies (ISTs) for elderly patients with neuromyelitis optica spectrum disorder (NMOSD) is not well established. This study aimed to investigate the safety and efficacy of IST in elderly patients with NMOSD. METHODS: This retrospective study analysed IST efficacy and safety in 101 patients with aquaporin-4 antibody-positive NMOSD aged over 65 years, treated for at least 6 months at five Korean referral centres, focusing on relapse rates, infection events and discontinuation due to adverse outcomes. RESULTS: The mean age at disease onset was 59.8 years, and female-to-male ratio was 4:1. Concomitant comorbidities at NMOSD diagnosis were found in 87 patients (86%). The median Expanded Disability Status Scale score at the initiation of IST was 3.5. The administered ISTs included azathioprine (n=61, 60%), mycophenolate mofetil (MMF) (n=48, 48%) and rituximab (n=41, 41%). Over a median of 5.8 years of IST, 58% of patients were relapse-free. The median annualised relapse rate decreased from 0.76 to 0 (p<0.001), and 81% experienced improved or stabilised disability. Patients treated with rituximab had a higher relapse-free rate than those treated with azathioprine or MMF (p=0.022). During IST, 21 patients experienced 25 severe infection events (SIEs) over the age of 65 years, and 3 died from pneumonia. 14 patients (14%) experienced 17 adverse events that led to switching or discontinuation of IST. When comparing the incidence rates of SIEs and adverse events, no differences were observed among patients receiving azathioprine, MMF and rituximab. CONCLUSION: In elderly patients with NMOSD, IST offers potential benefits in reducing relapse rates alongside a tolerable risk of adverse events.

Prediction of TKI response in EGFR-mutant lung cancer patients-derived organoids using malignant pleural effusion.

Patient-derived organoids (PDOs) are valuable in predicting response to cancer therapy. PDOs are ideal models for precision oncologists. However, their practical application in guiding timely clinical decisions remains challenging. This study focused on patients with advanced EGFR-mutated non-small cell lung cancer and employed a cancer organoid-based diagnosis reactivity prediction (CODRP)-based precision oncology platform to assess the efficacy of EGFR inhibitor treatments. CODRP was employed to evaluate EGFR-tyrosine kinase inhibitors (TKI) drug sensitivity. The results were compared to those obtained using area under the curve index. This study validated this index by testing lung cancer-derived organoids in 14 patients with lung cancer. The CODRP index-based drug sensitivity test reliably classified patient responses to EGFR-TKI treatment within a clinically suitable 10-day timeline, which aligned with clinical drug treatment responses. This approach is promising for predicting and analyzing the efficacy of anticancer, ultimately contributing to the development of a precision medicine platform.

Primary cutaneous mucinous carcinoma in a periorbital lesion: two case reports and literature review.

Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy of the sweat glands that most commonly affects the periorbital area. It is characterized by slow growth over a prolonged period, and its morphology can be easily confused with a benign tumor, such as an epidermal cyst. Consequently, many patients experience recurrence after undergoing multiple resections. However, there are few reports concerning the surgical management of PCMC. We present two cases of PCMC originating in the periorbital area. The first case involved a 76-year-old man with a mass measuring 3.0× 1.5 cm that had been increasing in size. The second case was a 61-year-old man with two masses, each measuring 1.0× 1.0 cm, that were also growing. Both patients underwent wide excision with a 5-mm safety margin, which was determined based on the widest view of the cross-section of the mass on the magnetic resonance imaging. Subsequently, based on the intraoperative frozen biopsy results, both patients underwent additional excision with a 5-mm safety margin in only one direction. This report shows that, when determining the surgical margin of PCMC in periorbital area, employing imaging modalities and intraoperative frozen biopsies can be helpful for narrowing the surgical margin.

Usefulness of Impulse Oscillometry in Predicting the Severity of Bronchiectasis.

Background: : Bronchiectasis is a chronic respiratory disease that leads to airway inflammation, destruction, and airflow limitation, which reflects its severity. Impulse oscillometry (IOS) is a non-invasive method that uses sound waves to estimate lung function and airway resistance. The aim of this study was to assess the usefulness of IOS in predicting the severity of bronchiectasis. Methods: : We retrospectively reviewed the IOS parameters and clinical characteristics in 145 patients diagnosed with bronchiectasis between March 2020 and May 2021. Disease severity was evaluated using the FACED score, and patients were divided into mild and moderate/severe groups. Results: : Forty-four patients (30.3%) were in the moderate/severe group, and 101 (69.7%) were in the mild group. Patients with moderate/severe bronchiectasis had a higher airway resistance at 5 Hz (R5), a higher difference between the resistance at 5 and 20 Hz (R5-R20), a higher resonant frequency (Fres), and a higher area of reactance (AX) than patients with mild bronchiectasis. R5 ≥0.43, resistance at 20 Hz (R20) ≥0.234, R5-R20 ≥28.3, AX ≥1.02, reactance at 5 Hz (X5) ≤-0.238, and Fres ≥20.88 revealed significant univariable relationships with bronchiectasis severity (p<0.05). Among these, only X5 ≤-0.238 exhibited a significant multivariable relationship with bronchiectasis severity (p=0.039). The receiver operating characteristic curve for predicting moderate- to-severe bronchiectasis of FACED score based on IOS parameters exhibited an area under the curve of 0.809. Conclusion: : The IOS assessed by the disease severity of FACED score can effectively reflect airway resistance and elasticity in bronchiectasis patients and serve as valuable tools for predicting bronchiectasis severity.

Factors predicting redislocation or suture-break in eyes after scleral-fixated intraocular lens.

PURPOSE: To investigate predictive factors for redislocation in patients with recurrent intraocular lens (IOL) dislocation following secondary scleral-fixated IOL (SFIOL) surgery. SETTING: Two tertiary referral hospitals. DESIGN: Retrospective case series. METHODS: Patients undergoing SFIOL surgery were grouped into redislocation and no-redislocation groups. Medical records of consecutive patients who underwent SFIOL surgery between June 2014 and December 2019 at two tertiary referral centers were reviewed. Data regarding patient demographics, treatment factors, anatomical and functional outcomes, and postoperative complications were recorded. RESULTS: We included 237 eyes of 225 patients (169 [75.1%] men). The redislocation group was more likely to have a younger mean age at the initial SFIOL surgery (redislocation vs no-redislocation, 55.4 vs 62.0 years, respectively; P=0.008), have a prior history of a previous suture-break (23 eyes, 52.3% vs 1 eye, 0.5%; P<0.001), and have undergone the initial SFIOL surgery using <1 mm-sized side-port incisions (17 eyes, 38.6% vs 32 eyes, 16.5%; P=0.002) than was the no-redislocation group. Additionally, the redislocation group had a higher occurrence of complications (P<0.001). Multivariable regression revealed that younger age, left eye involvement, aphakic status prior to the surgery, unremarkable primary IOL dislocation cause, need for ocular hypertension treatment and glaucoma surgery, and no large incision during the initial surgery were significantly (all P<0.05) associated with redislocation. CONCLUSION: Younger age, left eye involvement, postoperative complications like ocular hypertension and glaucoma, and techniques without large incisions increase the risk of redislocation. Conversely, lower risk factors include unremarkable surgery causes and a history of aphakic conditions.

A method to find temporal structure of neuronal coactivity patterns with across-trial correlations.

BACKGROUND: The across-trial correlation of neurons' coactivity patterns emerges to be important for information coding, but methods for finding their temporal structures remain largely unexplored. NEW METHOD: In the present study, we propose a method to find time clusters in which coactivity patterns of neurons are correlated across trials. We transform the multidimensional neural activity at each timing into a coactivity pattern of binary states, and predict the coactivity patterns at different timings. We devise a method suitable for these coactivity pattern predictions, call general event prediction. Cross-temporal prediction accuracy is then used to estimate across-trial correlations between coactivity patterns at two timings. We extract time clusters from the cross-temporal prediction accuracy by a modified k-means algorithm. RESULTS: The feasibility of the proposed method is verified through simulations based on ground truth. We apply the proposed method to a calcium imaging dataset recorded from the motor cortex of mice, and demonstrate time clusters of motor cortical coactivity patterns during a motor task. COMPARISON WITH EXISTING METHODS: While the existing cosine similarity method, which does not account for across-trial correlation, shows temporal structures only for contralateral neural responses, the proposed method reveals those for both contralateral and ipsilateral neural responses, demonstrating the effect of across-trial correlations. CONCLUSIONS: This study introduces a novel method for measuring the temporal structure of neuronal ensemble activity.

Impact of Infection Prevention Programs on Catheter-Associated Urinary Tract Infections Analyzed in Multicenter Study.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) account for a large proportion of healthcare-associated infections and have a significant impact on morbidity, length of hospital stay, and mortality. Adherence to the recommended infection prevention practices can effectively reduce the incidence of CAUTIs. This study aimed to assess the characteristics of CAUTIs and the efficacy of prevention programs across hospitals of various sizes. METHODS: Intervention programs, including training, surveillance, and monitoring, were implemented. Data on the microorganisms responsible for CAUTIs, urinary catheter utilization ratio, rate of CAUTIs per 1,000 device days, and factors associated with the use of indwelling catheters were collected from 2017 to 2019. The incidence of CAUTIs and associated data were compared between university hospitals and small- and medium-sized hospitals. RESULTS: Thirty-two hospitals participated in the study, including 21 university hospitals and 11 small- and medium-sized hospitals. The microorganisms responsible for CAUTIs and their resistance rates did not differ between the two groups. In the first quarter of 2018, the incidence rate was 2.05 infections/1,000 device-days in university hospitals and 1.44 infections/1,000 device-days in small- and medium-sized hospitals. After implementing interventions, the rate gradually decreased in the first quarter of 2019, with 1.18 infections/1,000 device-days in university hospitals and 0.79 infections/1,000 device-days in small- and medium-sized hospitals. However, by the end of the study, the infection rate increased to 1.74 infections/1,000 device-days in university hospitals and 1.80 infections/1,000 device-days in small- and medium-sized hospitals. CONCLUSION: We implemented interventions to prevent CAUTIs and evaluated their outcomes. The incidence of these infections decreased in the initial phases of the intervention when adequate support and personnel were present. The rate of these infections may be reduced by implementing active interventions such as consistent monitoring and adherence to guidelines for preventing infections.

Effects of post-exercise intake of exogenous lactate on energy substrate utilization at rest.

PURPOSE: This study investigated the effects of exogenous lactate intake on energy metabolism during 1 h of rest after acute exercise. METHODS: Eight-week-old ICR mice were randomly divided into four groups: SED (no treatment), EXE (exercise only), LAC (post-exercise oral lactate administration), and SAL (post-exercise saline administration) (n=8 per group). The exercise intensity was at VO2max 80% at 25 m/min and 15° slope for 50 min. After acute exercise, the LAC and SAL groups ingested lactate and saline orally, respectively, and were allowed to rest in a chamber. Energy metabolism was measured for 1 h during the resting period. RESULTS: LAC and SAL group mice ingested lactate and saline, respectively, after exercise and the blood lactate concentration was measured 1 h later through tail blood sampling. Blood lactate concentration was not significantly different between the two groups. Energy metabolism measurements under stable conditions revealed that the respiratory exchange ratio in the LAC group was significantly lower than that in the SAL group. Additionally, carbohydrate oxidation in the LAC group was significantly lower than that in the SAL group at 10-25 min. No significant difference was observed in the fat oxidation level between the two groups. CONCLUSION: We found that post-exercise lactate intake modified the respiratory exchange ratio after 1 h of rest. In addition, acute lactate ingestion inhibits carbohydrate oxidation during the post-exercise recovery period.

Effects of public transportation use on non-exercise activity thermogenesis and health promotion: a mini-review.

PURPOSE: Public transportation (PT) systems significantly shape urban mobility and have garnered attention owing to their potential impact on public health, particularly the promotion of physical activity. Beyond their transportation functions, PT systems also affect daily energy expenditure through non-exercise activity thermogenesis (NEAT). This mini-review surveys the existing literature to explore the effects of PT use on NEAT levels and subsequent health outcomes. METHODS: A comprehensive literature search was conducted using the electronic databases PubMed, Google Scholar, and Web of Science. Keywords including "public transportation," "non-exercise activity thermogenesis," "physical activity," "health promotion," and related terms were used to identify relevant studies. RESULTS: This review highlights the multifaceted relationship between PT use and health promotion, emphasizing the potential benefits and challenges of increasing NEAT through public transit utilization. Overall, the findings suggest that PT use contributes positively to NEAT levels, and thus improves health outcomes. However, the extent of this impact may vary depending on individual and contextual factors. CONCLUSION: Interventions promoting active transportation modes, including public transit, hold promise for addressing sedentary behavior and fostering healthier lifestyles at the population level.

Quintic refractive index profile-based funnel-shaped silicon antireflective structures for enhanced photodetector performance.

Antireflection, vital in optoelectronics devices such as solar cells and photodetectors, reduces light reflection and increases absorption. Antireflective structures (ARS), a primary method by which to realize this effect, control the refractive index (RI) profile based on their shape. The antireflection efficiency depends on the refractive index profile, with the quintic RI profile being recognized as ideal for superior antireflection. However, fabricating nano-sized structures with a desired shape, particularly in silicon with a quintic RI profile, has been a challenge. In this study, we introduce a funnel-shaped silicon (Si) ARS with a quintic RI profile. Its antireflective properties are demonstrated through reflectance measurements and by an application to a photodetector surface. Compared to the film Si and cone-shaped ARS types, which are common structures to achieve antireflection, the funnel-shaped ARS showed reflectance of 4.24% at 760 nm, whereas those of the film Si and cone-shaped ARS were 32.8% and 10.6%, respectively. Photodetectors with the funnel-shaped ARS showed responsivity of 0.077 A/W at 950 nm, which is 19.54 times higher than that with the film Si and 2.45 times higher than that with the cone-shaped ARS.

Molecular Packing Topology and Interactions to Decipher Mechanical Compliances in Dicyano-distyrylbenzene Derivatives.

Flexible optoelectronics is the need of the hour as the market moves toward wearable and conformable devices. Crystalline π-conjugated materials offer high performance as active materials compared to their amorphous counterpart, but they are typically brittle. This poses a significant challenge that needs to be overcome to unfold their potential in optoelectronic devices. Unveiling the molecular packing topology and identifying interaction descriptors that can seamlessly accommodate strain offers essential guiding principles for developing conjugated materials as active components in flexible optoelectronics. The molecular packing and interaction topology of eight crystal systems of dicyano-distyrylbenzene derivatives are investigated. Face-to-face π-stacks in an inclined orientation relative to the bending surface can accommodate expansion and compression with minimal molecular motion from their equilibrium positions. This configuration exhibits good compliance towards mechanical strain, while a similar structure with a criss-cross arrangement capable of distributing applied strain equally in opposite directions enhances the flexibility. Molecular arrangements that cannot reversibly undergo expansion and compression exhibit brittleness. In the isometric CT crystals, the disproportionate strength of the interactions along the bending plane and orthogonal directions makes these materials sustain a moderate bending strain. These results provide an updated explanation for the elastic bending in semiconducting π-conjugated crystals.

Rapid Surface Reconstruction of In2S3 Photoanode via Flame Treatment for Enhanced Photoelectrochemical Performance.

Surface reconstruction, reorganizing the surface atoms or structure, is a promising strategy to manipulate materials' electrical, electrochemical, and surface catalytic properties. Herein, a rapid surface reconstruction of indium sulfide (In2S3) is demonstrated via a high-temperature flame treatment to improve its charge collection properties. The flame process selectively transforms the In2S3 surface into a diffusionless In2O3 layer with high crystallinity. Additionally, it controllably generates bulk sulfur vacancies within a few seconds, leading to surface-reconstructed In2S3 (sr-In2S3). When using those sr-In2S3 as photoanode for photoelectrochemical water splitting devices, these dual functions of surface In2O3/bulk In2S3 reduce the charge recombination in the surface and bulk region, thus improving photocurrent density and stability. With optimized surface reconstruction, the sr-In2S3 photoanode demonstrates a significant photocurrent density of 8.5 mA cm-2 at 1.23 V versus a reversible hydrogen electrode (RHE), marking a 2.5-fold increase compared to pristine In2S3 (3.5 mA cm-2). More importantly, the sr-In2S3 photoanode exhibits an impressive photocurrent density of 7.3 mA cm-2 at 0.6 V versus RHE for iodide oxidation reaction. A practical and scalable surface reconstruction is also showcased via flame treatment. This work provides new insights for surface reconstruction engineering in sulfide-based semiconductors, making a breakthrough in developing efficient solar-fuel energy devices.

Polyhexamethylene guanidine phosphate induces pyroptosis via reactive oxygen species-regulated mitochondrial dysfunction in bronchial epithelial cells.

Pyroptosis is a form of programmed cell death characterized by gasdermin (GSDM)-mediated pore formation in the cell membrane, resulting in the release of pro-inflammatory cytokines and cellular lysis. Increasing evidence has shown that pyroptosis is responsible for the progression of various pulmonary disorders. The inhalation of polyhexamethylene guanidine (PHMG) causes severe lung inflammation and pulmonary toxicity; however, the underlying mechanisms are unknown. Therefore, in this study, we investigate the role of pyroptosis in PHMG-induced pulmonary toxicity. We exposed bronchial epithelial cells, BEAS-2B, to PHMG phosphate (PHMG-p) and evaluated cell death type, reactive oxygen species (ROS) levels, and relative expression levels of pyroptosis-related proteins. Our data revealed that PHMG-p reduced viability and induced morphological alterations in BEAS-2B cells. Exposure to PHMG-p induced excessive accumulation of mitochondrial ROS (mtROS) in BEAS-2B cells. PHMG-p activated caspase-dependent apoptosis as well as NLRP3/caspase-1/GSDMD-mediated- and caspase-3/GSDME-mediated pyroptosis through mitochondrial oxidative stress in BEAS-2B cells. Notably, PHMG-p reduced mitochondrial respiratory function and induced the translocation of Bax and cleaved GSDM into the mitochondria, leading to mitochondrial dysfunction. Our results enhanced our understanding of PHMG-p-induced lung toxicity by demonstrating that PHMG-p induces pyroptosis via mtROS-induced mitochondrial dysfunction in bronchial epithelial cells.

Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell-derived multi-cellular heart organoids.

Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches to non-clinical animal research. However, most of these approaches struggle to accurately replicate adult human heart conditions, such as myocardial infarction and ventricular remodeling pathology. The intricate interplay between various cell types within the adult heart, including cardiomyocytes, fibroblasts, and endothelial cells, contributes to the complexity of most heart diseases. Consequently, the mechanisms behind heart disease induction cannot be attributed to a single-cell type. Thus, the use of multi-cellular models becomes essential for creating clinically relevant in vitro cell models. This study focuses on generating self-organizing heart organoids (HOs) using human-induced pluripotent stem cells (hiPSCs). These organoids consist of cardiomyocytes, fibroblasts, and endothelial cells, mimicking the cellular composition of the human heart. The multi-cellular composition of HOs was confirmed through various techniques, including immunohistochemistry, flow cytometry, q-PCR, and single-cell RNA sequencing. Subsequently, HOs were subjected to hypoxia-induced ischemia and ischemia-reperfusion (IR) injuries within controlled culture conditions. The resulting phenotypes resembled those of acute myocardial infarction (AMI), characterized by cardiac cell death, biomarker secretion, functional deficits, alterations in calcium ion handling, and changes in beating properties. Additionally, the HOs subjected to IR efficiently exhibited cardiac fibrosis, displaying collagen deposition, disrupted calcium ion handling, and electrophysiological anomalies that emulate heart disease. These findings hold significant implications for the advancement of in vivo-like 3D heart and disease modeling. These disease models present a promising alternative to animal experimentation for studying cardiac diseases, and they also serve as a platform for drug screening to identify potential therapeutic targets.