What Should be Considered While Designing Hole-Transporting Material for Perovskite Solar Cells? A Special Attention to Thiophene-Based Hole-Transporting Materials.

The molecular design and conformations of hole-transporting materials (HTM) have unravelled a strategy to enhance the performance of environmentally sustainable perovskite solar cells (PSC). Several attempts have been made and several are underway for improving the efficiency of PSCs by designing an efficient HTM, which is crucial to preventing corrosion, facilitating effective hole transportation, and preventing charge recombination. There is a need for a potential alternative to the current market-dominating HTM due to its high cost of production, dopant requirements, moisture sensitivity, and low stability. Among several proposed HTMs, molecules derived from thiophene exhibit unique behaviour, such as the interaction with under-coordinated Pb2+, thereby facilitating the passivation of surface defects in the perovskite layer. In addition, coupling a suitable side chain imparts a hydrophobic character, eventually leading to the development of a moisture-sensitive and highly stable PSC. Furthermore, thiophene-backboned polymers with ionic pendants have been employed as an interfacial layer between PSC layers, with the backbone facilitating efficient charge transfer. This perspective article comprehensively presents the design strategy, characterization, and function of HTMs associated with thiophene-derived molecules. Hence, it is observed that thiophene-formulated HTMs have an enhanced passivation effect, good performance in an open-circuit environment, longevity, humidity resistance, thermostability, good hole extraction, and mobility in a dopant-free condition. For a better understanding, the article provides a comparative description of the activity and function of thiophene-based small molecules and polymers and their effect on device performance.

A PEDOT: PSS/GO fiber microelectrode fabricated by microfluidic spinning for dopamine detection in human serum and PC12 cells.

Rapid and accurate in situ determination of dopamine is of great significance in the study of neurological diseases. In this work, poly (3,4-ethylenedioxythiophene): poly (styrenesulfonic acid) (PEDOT: PSS)/graphene oxide (GO) fibers were fabricated by an effective method based on microfluidic wet spinning technology. The composite microfibers with stratified and dense arrangement were continuously prepared by injecting PEDOT: PSS and GO dispersion solutions into a microfluidic chip. PEDOT: PSS/GO fiber microelectrodes with high electrochemical activity and enhanced electrochemical oxidation activity of dopamine were constructed by controlling the structure composition of the microfibers with varying flow rate. The fabricated fiber microelectrode had a low detection limit (4.56 nM) and wide detection range (0.01-8.0 µM) for dopamine detection with excellent stability, repeatability, and reproducibility. In addition, the PEDOT: PSS/GO fiber microelectrode prepared was successfully used for the detection of dopamine in human serum and PC12 cells. The strategy for the fabrication of multi-component fiber microelectrodes is a new and effective approach for monitoring the intercellular neurotransmitter dopamine and has high potential as an implantable neural microelectrode.

Erdosteine in children and adults with bronchiectasis (BETTER trial): study protocol for a multicentre, double-blind, randomised controlled trial.

INTRODUCTION: Bronchiectasis is a worldwide chronic lung disorder where exacerbations are common. It affects people of all ages, but especially Indigenous populations in high-income nations. Despite being a major contributor to chronic lung disease, there are no licensed therapies for bronchiectasis and there remain relatively few randomised controlled trials (RCTs) conducted in children and adults. Our RCT will address some of these unmet needs by evaluating whether the novel mucoactive agent, erdosteine, has a therapeutic role in children and adults with bronchiectasis.Our primary aim is to determine in children and adults aged 2-49 years with bronchiectasis whether regular erdosteine over a 12-month period reduces acute respiratory exacerbations compared with placebo. Our primary hypothesis is that people with bronchiectasis who regularly use erdosteine will have fewer exacerbations than those receiving placebo.Our secondary aims are to determine the effect of the trial medications on quality of life (QoL) and other clinical outcomes (exacerbation duration, time-to-next exacerbation, hospitalisations, lung function, adverse events). We will also assess the cost-effectiveness of the intervention. METHODS AND ANALYSIS: We are undertaking an international multicentre, double-blind, placebo-RCT to evaluate whether 12 months of erdosteine is beneficial for children and adults with bronchiectasis. We will recruit 194 children and adults with bronchiectasis to a parallel, superiority RCT at eight sites across Australia, Malaysia and Philippines. Our primary endpoint is the rate of exacerbations over 12 months. Our main secondary outcomes are QoL, exacerbation duration, time-to-next exacerbation, hospitalisations and lung function. ETHICS AND DISSEMINATION: The Human Research Ethics Committees (HREC) of Children's Health Queensland (for all Australian sites), University of Malaya Medical Centre (Malaysia) and St. Luke's Medical Centre (Philippines) approved the study. We will publish the results and share the outcomes with the academic and medical community, funding and relevant patient organisations. TRIAL REGISTRATION NUMBER: ACTRN12621000315819.

Brexpiprazole Prevents the Malignant Progression of Human Colorectal Cancer Cells and Increases Its Sensitivity to EGFR Inhibition.

BACKGROUND: Colorectal cancer (CRC) is a major cause of mortality and morbidity. A study proved that brexpiprazole, as a novel dopamine receptor partial agonist, can also prevent CRC cell proliferation. Therefore, clarifying the molecular mechanism of brexpiprazole is vital to developing a novel therapeutic strategy for CRC. METHODS: The effect of brexpiprazole on human colorectal cancer cell proliferation was measured with Cell Counting Kit-8 (CCK-8) kits. Cell migration capability was measured using wound healing and transwell. Cell apoptosis was evaluated with a flow cytometer. Western blots and immunohistochemical staining were used to evaluate protein expression. The effects observed in vitro were also confirmed in xenograft models. RESULTS: Brexpiprazole remarkably inhibited the proliferation, suppressed the migration ability, and induced apoptosis of colorectal cancer cells. Mechanism study showed that brexpiprazole exerted these effects by inhibiting the EGFR pathway. Brexpiprazole enhanced HCT116 cells' sensitivity to cetuximab, and a combination of brexpiprazole and cetuximab inhibited xenograft tumor growth in vivo. CONCLUSIONS: Our finding suggested that brexpiprazole inhibits proliferation, promotes apoptosis, and enhances CRC cells' sensitivity to cetuximab by regulating the EGFR pathway and it might be an efficacious treatment strategy for CRC.

The Promising Effects of Erdosteine and Vitamin B in the Liver Ischemia/Reperfusion Model in Anesthetized Rats.

Background and Objectives: Erdosteine (Erd) is an antioxidant and anti-inflammatory drug. Vitamin B has been reported to exert anti-inflammatory and antioxidant effects. In this study, we investigated the effect of erdosteine and vitamin B complex on a liver ischemia/reperfusion (I/R) model. Materials and Methods: Thirty-two Wistar Albino male rats weighing 350-400 g were used. The animals were randomly selected and divided into four groups. The groups are as follows: first group (Sham), second group (I/R), third group (I/R + vit B), and fourth group (I/R + vit B + Erd). Rats were subjected to 45 min of hepatic ischemia, followed by a 45 min reperfusion period in the I/R and Vitamin B + Erd groups. An amount of 150 mg/kg/day of erdosteine was given orally for 2 days, and 0.05 mL/kg of i.p. vitamin B complex was given 30 min before the reperfusion. Serum biochemical parameters were measured. Serum Total Antioxidant Status (TAS) and Total Oxidant Status (TOS) were measured, and the Oxidative Stress Index (OSI) was calculated. Hepatic tissue samples were taken for the evaluation of histopathological features. Results: In terms of all histopathological parameters, there were significant differences in the I/R + vit B group and I/R + vit B + Erd group compared with the I/R group (p < 0.01). In terms of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), TNF-alpha, and IL-6 levels, there were significant differences between the I/R group and treatment groups (p < 0.01). The lowest TOS and OSI levels were obtained in the treatment groups, and these groups had statistically significantly higher TAS levels compared with the sham and I/R groups (p < 0.01). Conclusions: As a preliminary experimental study, our study suggests that these agents may have potential diagnostic and therapeutic implications for both ischemic conditions and liver-related diseases. These results suggest that the combination of vit B + Erd may be used to protect against the devastating effects of I/R injury. Our study needs to be confirmed by clinical studies with large participation.

Chemiresistors Based on Hybrid Nanostructures Obtained from Graphene and Conducting Polymers with Potential Use in Breath Methane Detection Associated with Irritable Bowel Syndrome.

This paper describes the process of producing chemiresistors based on hybrid nanostructures obtained from graphene and conducting polymers. The technology of graphene presumed the following: dispersion and support stabilization based on the chemical vapor deposition technique; transfer of the graphene to the substrate by spin-coating of polymethyl methacrylate; and thermal treatment and electrochemical delamination. For the process at T = 950 °C, a better settlement of the grains was noticed, with the formation of layers predominantly characterized by peaks and not by depressions. The technology for obtaining hybrid nanostructures from graphene and conducting polymers was drop-casting, with solutions of Poly(3-hexylthiophene (P3HT) and Poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-bithiophene] (F8T2). In the case of F8T2, compared to P3HT, a 10 times larger dimension of grain size and about 7 times larger distances between the peak clusters were noticed. To generate chemiresistors from graphene-polymer structures, an ink-jet printer was used, and the metallization was made with commercial copper ink for printed electronics, leading to a structure of a resistor with an active surface of about 1 cm2. Experimental calibration curves were plotted for both sensing structures, for a domain of CH4 of up to 1000 ppm concentration in air. A linearity of the curve for the low concentration of CH4 was noticed for the graphene structure with F8T2, presenting a sensitivity of about 6 times higher compared with the graphene structure with P3HT, which makes the sensing structure of graphene with F8T2 more feasible and reliable for the medical application of irritable bowel syndrome evaluation.

Activation of SIRT1/Nrf2/HO-1 and Beclin-1/AMPK/mTOR autophagy pathways by eprosartan ameliorates testicular dysfunction induced by testicular torsion in rats.

Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical intervention to reinstate vital testicular perfusion, notwithstanding the paradoxical detrimental impact of reperfusion. Although no drugs have secured approval for this urgent circumstance, antioxidants emerge as promising candidates. This study aspires to illustrate the influence of eprosartan, an AT1R antagonist, on testicular torsion in rats. Wistar albino rats were meticulously separated into five groups, (n = 6): sham group, eprosartan group, testicular torsion-detorsion (T/D) group, and two groups of T/D treated with two oral doses of eprosartan (30 or 60 mg/kg). Serum testosterone, sperm analysis and histopathological examination were done to evaluate spermatogenesis. Oxidative stress markers were assessed. Bax, BCL-2, SIRT1, Nrf2, HO-1 besides cleaved caspase-3 testicular contents were estimated using ELISA or qRT-PCR. As autophagy markers, SQSTM-1/p62, Beclin-1, mTOR and AMPK were investigated. Our findings highlight that eprosartan effectively improved serum testosterone levels, testicular weight, and sperm count/motility/viability, while mitigating histological irregularities and sperm abnormalities induced by T/D. This recovery in testicular function was underpinned by the activation of the cytoprotective SIRT1/Nrf2/HO-1 axis, which curtailed testicular oxidative stress, indicated by lowering the MDA content and increasing GSH content. In terms of apoptosis, eprosartan effectively countered apoptotic processes by decreasing cleaved caspase-3 content, suppressing Bax and stimulating Bcl-2 gene expression. Simultaneously, it reactivated impaired autophagy by increasing Beclin-1 expression, decreasing the expression of SQSTM-1/p62 and modulate the phosphorylation of AMPK and mTOR proteins. Eprosartan hold promise for managing testicular dysfunction arising from testicular torsion exerting antioxidant, pro-autophagic and anti-apoptotic effect via the activation of SIRT1/Nrf2/HO-1 as well as Beclin-1/AMPK/mTOR pathways.

The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.

Carboxymethyl cellulose-based rotigotine nanocrystals-loaded hydrogel for increased transdermal delivery with alleviated skin irritation.

Transdermal rotigotine (RTG) therapy is prescribed to manage Parkinson's disease (Neupro® patch). However, its use is suffered from application site reactions. Herein, drug nanocrystalline suspension (NS)-loaded hydrogel (NS-HG) employing polysaccharides simultaneously as suspending agent and hydrogel matrix was constructed for transdermal delivery, with alleviated skin irritation. RTG-loaded NS-HG was prepared using a bead-milling technique, employing sodium carboxylmethyl cellulose (Na.CMC) as nano-suspending agent (molecular weight 90,000 g/mol) and hydrogel matrix (700,000 g/mol), respectively. NS-HG was embodied as follows: drug loading: ≤100 mg/mL; shape: rectangular crystalline; crystal size: <286.7 nm; zeta potential: -61 mV; viscosity: <2.16 Pa·s; and dissolution rate: >90 % within 15 min. Nuclear magnetic resonance analysis revealed that the anionic polymers bind to RTG nanocrystals via charge interaction, affording uniform dispersion in the matrix. Rodent transdermal absorption of RTG from NS-HG was comparable to that from microemulsions, and proportional to drug loading. Moreover, NS-HG was skin-friendly; erythema and epidermal swelling were absent after repeated application. Further, NS-HG was chemically stable; >95 % of the drug was preserved up to 4 weeks under long term (25 °C/RH60%), accelerated (40 °C/RH75%), and stress (50 °C) storage conditions. Therefore, this novel cellulose derivative-based nanoformulation presents a promising approach for effective transdermal RTG delivery with improved tolerability.

Effect of cevimeline and different concentration of gum arabic on parotid salivary gland function in methotrexate-induced xerostomia: a comparative study.

OBJECTIVE: This study assessed the effect of cevimeline and different concentrations of gum arabic on the parotid gland of rats being given xerostomia-inducing methotrexate. METHODS: One hundred twenty-five rats were divided into five equal groups of twenty-five each. The rats in Group I received basic diets, while those in Groups II, III, IV, and V received 20 mg/kg MTX as a single intraperitoneal dose on day one. Group III received 10 mg/kg CVM dissolved in saline orally and daily, and the other two groups received a 10% W/V aqueous suspension of GA. Therefore, Group IV received 2 ml/kg suspension orally and daily, while Group V received 3 ml/kg suspension orally and daily. After 9 days, the parotid glands were dissected carefully and prepared for hematoxylin and eosin (H&E) staining as a routine histological stain and caspase-3 and Ki67 immunohistochemical staining. Quantitative data from α-Caspase-3 staining and Ki67 staining were statistically analysed using one-way ANOVA followed by Tukey's multiple comparisons post hoc test. RESULTS: Regarding caspase-3 and Ki67 immunohistochemical staining, one-way ANOVA revealed a significant difference among the five groups. For Caspase-3, the highest mean value was for group II (54.21 ± 6.90), and the lowest mean value was for group I (15.75 ± 3.67). The other three groups had mean values of 31.09 ± 5.90, 30.76 ± 5.82, and 20.65 ± 3.47 for groups III, IV, and V, respectively. For Ki67, the highest mean value was for group I (61.70 ± 6.58), and the lowest value was for group II (18.14a ± 5.16). The other three groups had mean values of 34.4 ± 9.27, 48.03 ± 8.40, and 50.63 ± 8.27 for groups III, IV, and V, respectively. CONCLUSION: GA, rather than the normally used drug CVM, had a desirable effect on the salivary glands of patients with xerostomia.

Brexpiprazole toxicity in a paediatric patient.

Brexpiprazole is a relatively new drug that has no published research or applications within the paediatric population. Brexpiprazole targets multiple receptors and can manifest as multisystem symptoms when ingested in supratherapeutic quantities. In this report, we discuss the case of a child in early childhood who presented with delayed neurological and cardiac symptoms 24 hours after accidental ingestion of brexpiprazole. Due to delayed onset, this case highlights that a high index of suspicion and prolonged observation are necessary to appropriately manage brexpiprazole overdose or accidental ingestion.

Data mining and safety analysis of avatrombopag: a retrospective pharmacovigilance study based on the US food and drug administration's adverse event reporting system.

With its increasing use in the treatment of thrombocytopenia, avatrombopag's associated adverse events (AEs) pose a major challenge to its clinical application. This study aims to comprehensively study AEs associated with avatrombopag by using real-world evidence. We curated AE reports for avatrombopag from the first quarter of 2018 to the fourth quarter of 2023 in the US Food and Drug Administration's Adverse Event Reporting System (FAERS) database. AEs were coded using the Medical Dictionary for Regulatory Activities of Preferred Terms and System Organ Classes. The reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item Gamma-Poisson Shrinker were used to investigate the relationship between avatrombopag and AE reports. Among 9,060,312 reported cases in the FAERS database, 1211 reports listed avatrombopag as "primary suspected" drug. Disproportionality analysis identified 44 preferred terms across 17 organ systems met the criteria for at least one of the four algorithms. The most commonly reported AEs were platelet count decreased (20.2%), headache (16.7%), platelet count increased (11.9%), platelet count abnormal (6.3%), contusion (2.7%), pulmonary embolism (2.3%), and deep vein thrombosis (2.1%). Unexpected AEs such as seasonal allergy, rhinorrhea, antiphospholipid syndrome, ear discomfort, and photopsia were also observed. Excluding the other serious outcomes, hospitalization (34.6%) was the most frequently reported serious outcome, followed by death (15.4%). Most reported AEs occurred within the first 2 days of initiating avatrombopag therapy, and the median onset time was 60 days. We identified new and unexpected AEs with clinical use of avatrombopag, and our results may provide valuable information for clinical monitoring and identifying risks associated with avatrombopag.

Rapid prototyping and facile customization of conductive hydrogel bioelectronics based on all laser process.

Proper customization in size and shape is essential in implantable bioelectronics for stable bio-signal recording. Over the past decades, many researchers have heavily relied on conventional photolithography processes to fabricate implantable bioelectronics. Therefore, they could not avoid the critical limitation of high cost and complex processing steps to optimize bioelectronic devices for target organs with various sizes and shapes. Here, we propose rapid prototyping using all laser processes to fabricate customized bioelectronics. PEDOT:PSS is selectively irradiated by an ultraviolet (UV) pulse laser to form wet-stable conductive hydrogels that can softly interact with biological tissues (50 µm line width). The encapsulation layer is selectively patterned using the same laser source by UV-curing polymer networks (110 µm line width). For high stretchability (over 100%), mesh structures are made by the selective laser cutting process. Our rapid prototyping strategy minimizes the use of high-cost equipment, using only a single UV laser source to process the electrodes, encapsulation, and substrates that constitute bioelectronics without a photomask, enabling the prototyping stretchable microelectrode array with an area of 1 cm2 less than 10 min. We fabricated an optimized stretchable microelectrode array with low impedances (∼1.1 kΩ at 1 kHz) that can effectively record rat's cardiac signals with various health states.

Conjugated Polymer/Recombinant Escherichia coli Biohybrid Systems for Photobiocatalytic Hydrogen Production.

Biohybrid photocatalysts are composite materials that combine the efficient light-absorbing properties of synthetic materials with the highly evolved metabolic pathways and self-repair mechanisms of biological systems. Here, we show the potential of conjugated polymers as photosensitizers in biohybrid systems by combining a series of polymer nanoparticles with engineered Escherichia coli cells. Under simulated solar light irradiation, the biohybrid system consisting of fluorene/dibenzo [b,d]thiophene sulfone copolymer (LP41) and recombinant E. coli (i.e., a LP41/HydA BL21 biohybrid) shows a sacrificial hydrogen evolution rate of 3.442 mmol g-1 h-1 (normalized to polymer amount). It is over 30 times higher than the polymer photocatalyst alone (0.105 mmol g-1 h-1), while no detectable hydrogen was generated from the E. coli cells alone, demonstrating the strong synergy between the polymer nanoparticles and bacterial cells. The differences in the physical interactions between synthetic materials and microorganisms, as well as redox energy level alignment, elucidate the trends in photochemical activity. Our results suggest that organic semiconductors may offer advantages, such as solution processability, low toxicity, and more tunable surface interactions with the biological components over inorganic materials.

Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Charge Transfer-Promoted Excited State of a Heavy-Atom-Free Photosensitizer for Efficient Application of Mitochondria-Targeted Fluorescence Imaging and Hypoxia Photodynamic Therapy.

Conventional photosensitizers (PSs) used in photodynamic therapy (PDT) have shown preliminary success; however, they are often associated with several limitations including potential dark toxicity in healthy tissues, limited efficacy under acidic and hypoxic conditions, suboptimal fluorescence imaging capabilities, and nonspecific targeting during treatment. In response to these challenges, we developed a heavy-atom-free PS, denoted as Cz-SB, by incorporating ethyl carbazole into a thiophene-fused BODIPY core. A comprehensive investigation into the photophysical properties of Cz-SB was conducted through a synergistic approach involving experimental and computational investigations. The enhancement of intersystem crossing (kISC) and fluorescence emission (kfl) rate constants was achieved through a donor-acceptor pair-mediated charge transfer mechanism. Consequently, Cz-SB demonstrated remarkable efficiency in generating reactive oxygen species (ROS) under acidic and low-oxygen conditions, making it particularly effective for hypoxic cancer PDT. Furthermore, Cz-SB exhibited good biocompatibility, fluorescence imaging capabilities, and a high degree of localization within the mitochondria of living cells. We posit that Cz-SB holds substantial prospects as a versatile PS with innovative molecular design, representing a potential "one-for-all" solution in the realm of cancer phototheranostics.

Discovery of 2-Amide-3-methylester Thiophenes that Target SARS-CoV-2 Mac1 and Repress Coronavirus Replication, Validating Mac1 as an Antiviral Target.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has made it clear that further development of antiviral therapies will be needed. Here, we describe small-molecule inhibitors for SARS-CoV-2 Mac1, which counters ADP-ribosylation-mediated innate immune responses. Three high-throughput screening hits had the same 2-amide-3-methylester thiophene scaffold. We studied the compound binding mode using X-ray crystallography, allowing us to design analogues. Compound 27 (MDOLL-0229) had an IC50 of 2.1 µM and was selective for CoV Mac1 proteins after profiling for activity against a panel of viral and human proteins. The improved potency allowed testing of its effect on virus replication, and indeed, 27 inhibited replication of both murine hepatitis virus (MHV) prototypes CoV and SARS-CoV-2. Sequencing of a drug-resistant MHV identified mutations in Mac1, further demonstrating the specificity of 27. Compound 27 is the first Mac1-targeted small molecule demonstrated to inhibit coronavirus replication in a cell model.

Jolkinolide B synergistically potentiates the antitumor activity of GPX4 inhibitors via inhibiting TrxR1 in cisplatin-resistant bladder cancer cells.

Glutathione peroxidase 4 (GPX4) is a promising anticancer therapeutic target; however, the application of GPX4 inhibitors (GPX4i) is limited owing to intrinsic or acquired drug resistance. Hence, understanding the mechanisms underlying drug resistance and discovering molecules that can overcome drug resistance are crucial. Herein, we demonstrated that GPX4i killed bladder cancer cells by inducing lipid reactive oxygen species-mediated ferroptosis and apoptosis, and cisplatin-resistant bladder cancer cells were also resistant to GPX4i, representing a higher half-maximal inhibitory concentration value than that of parent bladder cancer cells. In addition, thioredoxin reductase 1 (TrxR1) overexpression was responsible for GPX4i resistance in cisplatin-resistant bladder cancer cells, and inhibiting TrxR1 restored the sensitivity of these cells to GPX4i. In vitro and in vivo studies revealed that Jolkinolide B (JB), a natural diterpenoid and previously identified as a TrxR1 inhibitor, potentiated the antiproliferative efficacy of GPX4i (RSL3 and ML162) against cisplatin-resistant bladder cancer cells. Furthermore, GPX4 knockdown and inhibition could augment JB-induced paraptosis and apoptosis. Our results suggest that inhibiting TrxR1 can effectively improve GPX4 inhibition-based anticancer therapy. A combination of JB and GPX4i, which is well-tolerated and has several anticancer mechanisms, may serve as a promising therapy for treating bladder cancer.