Imidazolyl Lipids Enhanced LNP Endosomal Escape for Ferroptosis RNAi Treatment of Cancer.

Treatments for cancer that incorporate small interfering RNA (siRNA) to target iron-dependent ferroptosis are thought to be highly promising. However, creating a reliable and clinically feasible siRNA delivery system continues to be a major obstacle in the field of cancer treatment. Here, three imidazole-based ionizable lipid nanoparticles (LNPs) with pH-sensitive effects are rationally designed and synthesized for siRNA delivery. LNPs formulated with the top-performing lipid (O12-D3-I3) encapsulating FVII siRNA (FVII@O-LNP) elicited greater gene silencing than those with the benchmark Onpattro lipid DLin-MC3-DMA (MC3) due to its stronger endosomal escape. Moreover, Fc-siRNA@O-LNPs encapsulated with ferrocene (Fc) and SLC7A11/Nrf2-targeted siRNA is formulated. The outcomes demonstrate optimal safety profiles and a significant anti-tumor effect by inducing long-lasting and efficient ferroptosis through a synergistic action in vivo. In summary, this work shows that imidazolyl lipid-prepared LNPs are efficient delivery vehicles for cancer therapy and ferroptosis-targeting siRNA administration, both of which have extensive clinical application potential.

Macrocyclic Neutralizer to Polybrene via Direct Host-Guest Complexation.

Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host-guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 107 M-1. Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.

Tumor Microenvironment-Responsive Polymer-Based RNA Delivery Systems for Cancer Treatment.

Ribonucleic acid (RNA) therapeutics offer a broad prospect in cancer treatment. However, their successful application requires overcoming various physiological barriers to effectively deliver RNAs to the target sites. Currently, a number of RNA delivery systems based on polymeric nanoparticles are developed to overcome these barriers in RNA delivery. This work provides an overview of the existing RNA therapeutics for cancer gene therapy, and particularly summarizes those that are entering the clinical phase. This work then discusses the core features and latest research developments of tumor microenvironment-responsive polymer-based RNA delivery carriers which are designed based on the pathological characteristics of the tumor microenvironment. Finally, this work also proposes opportunities for the transformation of RNA therapies into cancer immunotherapy methods in clinical applications.

Real-world experience quantifying access to JAK inhibitor care for alopecia areata patients: a patient-centered survey study.

Background: Janus kinase inhibitor (JAKi) therapy has revolutionized the treatment landscape for alopecia areata (AA); however, access may be limited by a lack of insurance coverage and high out-of-pocket costs. Objective: We aimed to evaluate real-world patient experiences regarding access to JAKi therapy. Methods: We conducted an online patient-centered survey using the National Alopecia Areata Foundation listserv. Results: In total 784 individuals initiated our survey, and 600 completed it in full (76.5%). While more non-White patients considered obtaining JAKi therapy, more White patients reported the use of this medication class. In total, 74.2% lacked insurance coverage or had partial coverage for JAKi, and 52% expressed dissatisfaction with available coverage. However, 52.9% reported delays in starting medication due to insurance approval processes, contributing to worsened AA and related stress. In total, 35% of patients did not try to obtain JAKi therapy due to concerns about costs, and 18.2% discontinued therapy due to financial barriers. Also, 19.8% of patients reported utilizing financial savings to pay for medication, and 55.2% reported using a copay assistance card. Further, 12.2% reported forgoing other necessities to pay for AA expenses. Limitations: Our results are limited by the subjective nature of survey studies. The recency of FDA approval for JAKi therapy may also influence patients' perceptions of access to care. Conclusion: Patients with AA face significant barriers when trying to obtain JAKi therapy, and existing racial inequities may be exacerbated by these barriers. Further advocacy work is needed to improve access to care.

Opioid Prescribing and Outcomes in Patients With Sickle Cell Disease Post-2016 CDC Guideline.

Importance: Although the intention of the 2016 US Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain was not to limit pain treatment for patients with sickle cell disease (SCD), clinicians and patients have recognized the possibility that the guideline may have altered outcomes for this population. However, the outcomes of the 2016 guideline for this patient population are unknown. Objective: To examine changes in opioid prescribing patterns and health outcomes among patients with SCD before and after the release of the 2016 CDC guideline. Design, Setting, and Participants: This retrospective cohort study conducted interrupted time series analysis of claims data from the Merative MarketScan Commercial Database from January 1, 2011, to December 31, 2019. In this population-based study in the US, individuals with SCD who were at least 1 year of age, had no cancer diagnosis, and had pharmacy coverage for the month of measurement were included. The data were analyzed from January 2021 to November 2023. Exposure: The CDC Guideline for Prescribing Opioids for Chronic Pain released in March 2016. Main Outcomes and Measures: The main variables measured in this study included the practice of opioid prescribing among patients with SCD (ie, rate of opioid prescriptions dispensed, mean number of days supplied, mean total morphine milligram equivalents [MME] per patient, and mean daily MME per opioid prescription) and pain-related health outcomes (rates of emergency department visits related to vaso-occlusive crises [VOC] and hospitalizations related to VOC). Results: The cohort included 14 979 patients with SCD (mean [SD] age, 25.9 [16.9] years; 8520 [56.9%] female). Compared with the preguideline trends, the following changes were observed after the guideline was released: significant decreases in the coefficient for change in slope of the opioid dispensing rate (-0.29 [95% CI, -0.39 to -0.20] prescriptions per 100 person-month; P < .001), the number of days supplied per prescription (-0.05 [95% CI, -0.06 to -0.04] days per prescription-month; P < .001), and opioid dosage (-141.0 [95% CI, -219.5 to -62.5] MME per person-month; P = .001; -10.1 [95% CI, -14.6 to -5.6] MME/prescription-month; P < .001). Conversely, a significant increase in VOC-related hospitalizations occurred after the guideline release (0.16 [95% CI, 0.07-0.25] hospitalizations per 100 person-month; P = .001). These changes were observed to a greater extent among adult patients, but pediatric patients experienced similar changes in several measures, even though the guideline focused exclusively on adult patients. Conclusions and Relevance: This retrospective cohort study showed that the 2016 CDC guideline may have had unintended negative outcomes on the patient population living with SCD.

A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3.

BACKGROUND: Triple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. ß-tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure. PURPOSE: In this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated. STUDY DESIGN/METHODS: This study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments. RESULTS: Herein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression. CONCLUSION: The findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC.

Platelet-Derived Growth Factor Nanocapsules with Tunable Controlled Release for Chronic Wound Healing.

Chronic wounds have emerged as an increasingly critical clinical challenge over the past few decades, due to their increasing incidence and socioeconomic burdens. Platelet-derived growth factor (PDGF) plays a pivotal role in regulating processes such as fibroblast migration, proliferation, and vascular formation during the wound healing process. The delivery of PDGF offers great potential for expediting the healing of chronic wounds. However, the clinical effectiveness of PDGF in chronic wound healing is significantly hampered by its inability to maintain a stable concentration at the wound site over an extended period. In this study, a controlled PDGF delivery system based on nanocapsules is proposed. In this system, PDGF is encapsulated within a degradable polymer shell. The release rate of PDGF from these nanocapsules can be precisely adjusted by controlling the ratios of two crosslinkers with different degradation rates within the shells. As demonstrated in a diabetic wound model, improved therapeutic outcomes with PDGF nanocapsules (nPDGF) treatment are observed. This research introduces a novel PDGF delivery platform that holds promise for enhancing the effectiveness of chronic wound healing.

Biochemical and microstructural determinants of the development of serous retinal detachment secondary to retinal vein occlusion.

Purpose: To study the alteration of cytokine factors in aqueous humor and retinal microstructure in the formation of serous retinal detachment (SRD) secondary to retinal vein occlusion. Methods: The subjects were 39 patients with RVO, of whom 31 patients had SRD (RVO-SRD). Spectral Domain Optical Coherence Tomography (SD-OCT) was used to measure the completeness of photoreceptor inner segment/outer segment (IS/OS) and the external limiting membrane (ELM) as well as the structure of RVO-SRD, including the height and shape of SRD. The aqueous humor was collected before intravitreal injection of Ranibizumab. The concentrations of VEGF, MCP-1, IL-8, IL-6, b-FGF and TNF-α in the aqueous humor were measured. All patients participated in the 6-month follow-up examinations, which included visual acuity, intraocular pressure, ophthalmologic examination, and SD-OCT. The time of recurrence of RVO-SRD was recorded. Results: The formation of SRD was associated with the area of congested vein, disrupted IS/OS, ELM layers and high VEGF, MCP-1, IL-8, IL-6 levels. However, the height and shape of SRD were not relevant to any inflammatory factors. Moreover, high levels of MCP-1, IL-8 and IL-6 were found in large areas of congested veins. High levels of MCP-1 and IL-6 were observed in the patients with incomplete IS/OS and ELM. The recurrence of SRD was related to the high MCP-1 level. Conclusion: High concentrations of cytokine factors in aqueous humor could induce vascular leakage, exacerbate the extent of macular edema, disrupt the structure of ELM and IS/OS, and develop SRD in RVO.

Research Advances in the High-Value Utilization of Peanut Meal Resources and Its Hydrolysates: A Review.

Peanut meal (PM) is a by-product of extracting oil from peanut kernels. Although peanut meal contains protein, carbohydrates, minerals, vitamins, and small amounts of polyphenols and fiber, it has long been used as a feed in the poultry and livestock industries due to its coarse texture and unpleasant taste. It is less commonly utilized in the food processing industry. In recent years, there has been an increasing amount of research conducted on the deep processing of by-products from oil crops, resulting in the high-value processing and utilization of by-products from various oil crops. These include peanut meal, which undergoes treatments such as enzymatic hydrolysis in industries like food, chemical, and aquaculture. The proteins, lipids, polyphenols, fibers, and other components present in these by-products and hydrolysates can be incorporated into products for further utilization. This review focuses on the research progress in various fields, such as the food processing, breeding, and industrial fields, regarding the high-value utilization of peanut meal and its hydrolysates. The aim is to provide valuable insights and strategies for maximizing the utilization of peanut meal resources.

Case Report: Primary low-grade dedifferentiated liposarcoma of the urinary bladder with molecular confirmation.

Liposarcomas originating in the urinary bladder are extremely rare. Only six cases of bladder liposarcoma have been reported, and all have been described as myxoid liposarcomas. Notably, none of the patients underwent molecular testing. Here, we report a dedifferentiated liposarcoma (DDL) that occurred in the urinary bladder, primarily in a 69-year-old Chinese woman, with infrequent low-grade dedifferentiation. Computed tomography (CT) revealed an ill-defined solid mass in the anterior bladder wall. The patient underwent a partial bladder resection. Histologically, the tumor cells with mild-to-moderate nuclear atypia were arranged in fascicular and storiform patterns, mimicking a low-grade fibroblastic tumor. In addition, scattered small foci of typical lipoma-like well-differentiated components were identified. Immunohistochemically, the tumor tested positivity for MDM2, CDK4, and p16. Fluorescence in situ hybridization revealed MDM2 gene amplification in the neoplastic cells. Whole-exome sequencing showed that this tumor also harbored CDK4, TSPAN31, and JUN amplification. At the latest follow-up (85 months after surgery), the patient was alive, with no evidence of disease. To the best of our knowledge, this is the first example of a molecularly confirmed primary bladder liposarcoma and the first case of DDL at this site.

Selective Fluorescent Sensing for Iron in Aqueous Solution by A Novel Functionalized Pillar[5]arene.

Iron ion is one of the most physiologically important elements in metabolic processes, indispensable for all living systems. Since its excess can lead to severe diseases, new approaches for its monitoring in water samples are urgently needed to meet requirements. Here, we firstly report a novel and universal route for the synthesis of a series of pillar[n]arene derivates containing one benzoquinone unit by photocatalysis. With this in hand, an anthracene - appended water - soluble pillar[5]arene (H) with excellent fluorescence sensing potency was prepared. H enabled the ultrasensitive detection of iron ions in aqueous solution with limits of detection of 10-8  M. Over a wide range of metal ions, H exhibited specific selectivity toward Fe3+ . More importantly, H could still properly operate in a simulated sewage sample, coexisting with multiple interference ions.

Host-Guest Formulation of Carboxylatopillar[6]arene with Ergothioneine as a New Antidote for Combinational Detoxification of Paraquat.

Paraquat (PQ) is exceptionally toxic to the human body. PQ ingestion can cause severe organ damage with a mortality rate of 50-80%, resulting from the absence of effective antidotes and detoxification solutions. Herein, a host-guest formulation is proposed, in which ergothioneine (EGT), an antioxidant drug, was encapsulated by carboxylatopillar[6]arene (CP6A) to achieve a combinational therapy for PQ poisoning. Nuclear magnetic resonance (NMR) and fluorescence titration were employed to confirm the complexation between CP6A and EGT as well as PQ with robust affinities. In vitro studies proved that EGT/CP6A significantly reduced PQ toxicity. Treatment with EGT/CP6A could effectively relieve organ damage caused by PQ ingestion and enhance the normalization of hematological and biochemical parameters. The host-guest formulation EGT/CP6A also improved the survival ratio in PQ-poisoned mice. These favorable outcomes originated from synergistic effects that PQ triggered the release of EGT to combat peroxidation damage and excess PQ was engulfed within the cavity of CP6A.

Assessment of Vigilance Level during Work: Fitting a Hidden Markov Model to Heart Rate Variability.

This study aimed to enhance the real-time performance and accuracy of vigilance assessment by developing a hidden Markov model (HMM). Electrocardiogram (ECG) signals were collected and processed to remove noise and baseline drift. A group of 20 volunteers participated in the study. Their heart rate variability (HRV) was measured to train parameters of the modified hidden Markov model for a vigilance assessment. The data were collected to train the model using the Baum-Welch algorithm and to obtain the state transition probability matrix A^ and the observation probability matrix B^. Finally, the data of three volunteers with different transition patterns of mental state were selected randomly and the Viterbi algorithm was used to find the optimal state, which was compared with the actual state. The constructed vigilance assessment model had a high accuracy rate, and the accuracy rate of data prediction for these three volunteers exceeded 80%. Our approach can be used in wearable products to improve their vigilance level assessment functionality or in other fields that have key positions with high concentration requirements and monotonous repetitive work.

Synthesis of Cationic Biphen[4, 5]arenes as Biofilm Disruptors.

Since bacteria in biofilms are inherently resistant to antibiotics and biofilm-associated infections pose a serious threat to global public health, new therapeutic agents and schemes are urgently needed to meet clinical requirements. Here two quaternary ammonium-functionalized biphen[n]arenes (WBPn, n=4, 5) were designed and synthesized with excellent anti-biofilm potency. Not only could they inhibit the assembly of biofilms, but also eradicate intractable mature biofilms formed by Gram-positive S. aureus and Gram-negative E. coli bacterial strains. Moreover, they could strongly complex a conventional antibiotic, cefazolin sodium (CFZ) with complex stability constants of (7.41±0.29)×104  M-1 for CFZ/WBP4 and (4.98±0.49)×103  M-1 for CFZ/WBP5. Combination of CFZ by WBP4 and WBP5 synergistically enhanced biofilm eradication performance in vitro and statistically improved healing efficacy on E. coli-infected mice models, providing a novel supramolecular strategy for combating biofilm-associated infections.

Patients' comfort with and receipt of health risk assessments during routine dental visits: Results from the South Atlantic region of the US National Dental Practice-Based Research Network.

OBJECTIVES: To understand patients' comfort with health risk assessments (HRAs) and patient and dentist factors associated with the provision of HRAs. METHODS: In this cross-sectional study, 857 patients seen by 30 dental practitioners in the United States National Dental Practice-Based Research Network reported their comfort receiving HRA for six risk factors (tobacco use, alcohol use, dietary sugar intake, human immunodeficiency virus risks, human papillomavirus risks and existing medical conditions) and whether they discussed any of the risk factors during their visits. Multi-level logistic models were used to examine the impacts of patient, practitioner, practice characteristics on the (1) number of risk factors patients were comfortable discussing and (2) number of risk factors assessed in the current dental visit. RESULTS: Only a small percentage (4%) of patients reported being uncomfortable receiving any HRA during their dental visits. However, over half of the patients (53%) reported that they did not receive any HRAs during the current visit. In the regression analyses, patients who were older, male and from the suburban were more likely to be comfortable with more HRAs. Dentists were more likely to provide HRA if they were younger, not non-Hispanic white, less likely to feel that providing HRAs was beyond their scope of practice, yet more likely to feel occasional discomfort in providing HRA. CONCLUSIONS: Interventions should focus on reducing dental practitioner perception that conducting HRAs is beyond their scope of practice and standardizing screening assessments for multiple risk factors.

Changes in Cyclic Guanosine Monophosphate Channel of 661w Cells In vitro with Excessive Light Time.

Purpose: To determine the response time and protective mechanism of the cyclic guanosine monophosphate (cGMP) channel in 661w cells. Methods: 661w cells were exposed to 4500Lux visible light for three and four days at the following exposure time periods per day: 20, 30, 60, 90, 120, and 180. Cells were incubated for the rest of the time without any other treatment. Cell activity and cell death rates were measured with Hoechst/PI (diphenylmethane/propidium iodide) staining. Western Blot was used to detect the levels of guanylate cyclase-activating proteins 1 (GCAP1), cGMP, and phosphodiesterase (PDE)6 in the cGMP-gated channel. Results: 661w cells showed low mortality within three days. The mortality rate increased from the fourth day, especially during the longer times (120 and 180 min) of light exposure. After three-day illumination, the level of cGMP increased after 20 and 90 min and the level of GCAP1 increased after 60 and 90 min. After four days of illumination, the level of GCAP1 upregulated after a time of 20 and 60 min, while the cGMP level decreased from 30 min. The expression of PDE6 upregulated at each light period. Conclusion: The survival rate of 661w cells was relevant to the time of light exposure. The changes in GCAP1, cGMP, and PDE6 levels over time were possibly related to cell metabolism and restoration after light-induced damage.

Patient-Defined Goals and Preferences Among Adults With Advanced Neuroendocrine Tumors.

BACKGROUND: Patient preferences (quantity vs quality of life; present vs future health) have not been investigated in patients with neuroendocrine tumors (NETs). The goal of this cross-sectional study was to evaluate patient values toward treatment goals and competing health outcomes among adults with NETs. PATIENTS AND METHODS: Patients with well-differentiated, grade 1 or 2, advanced NETs starting a new systemic therapy completed 4 tools: (1) Health Outcomes Tool, which ranks the importance of 4 outcomes (survival, function/independence, freedom from pain, freedom from symptoms); (2) Attitude Scale, which identifies the extent to which patients agree with statements related to health outcomes; (3) Now versus Later Tool, which ranks the relative importance of quality of life (QoL) now versus 1 and 5 years from now; and (4) Prognosis and Treatment Perceptions Questionnaire, which identifies the amount of information the patient prefers to receive about their disease and treatment, the patient's treatment goal, the patient's perception of the physician's treatment goal, and self-reported health status. RESULTS: We recruited 60 patients with NETs (50.0% aged ≥65 years; 96.7% with stage IV disease). Primary tumor locations included the gastrointestinal tract (41.7%), pancreas (30.0%), and lung (21.7%). A plurality of patients reported maintaining independence as their most important health outcome (46.7%), followed by survival (30.0%), freedom from pain (11.7%), and freedom from symptoms (11.7%). A total of 67% of patients agreed with the statement, "I would rather live a shorter life than lose my ability to take care of myself"; 85.0% agreed with the statement, "It is more important to me to maintain my thinking ability than to live as long as possible." When asked to choose between current QoL versus QoL 1 year or 5 years in the future as more important, 48.3% and 40.0% of patients valued their QoL 1 year and 5 years in the future, respectively, more than their current QoL. Only 51.7% of patients believed their physician's treatment goals aligned with their own. CONCLUSIONS: Adult patients with NETs strongly value independence over survival. More communication between patients with NETs and their physicians is needed to ensure that patient preferences are incorporated into treatment plans.

A Biocompatible Liquid Pillar[n]arene-Based Drug Reservoir for Topical Drug Delivery.

Advanced external preparations that possess a sustained-release effect and integrate few irritant elements are urgently needed to satisfy the special requirements of topical administration in the clinic. Here, a series of liquid pillar[n]arene-bearing varying-length oligoethylene oxide chains (OEPns) were designed and synthesized. Following rheological property and biocompatibility investigations, pillar[6]arene with triethylene oxide substituents (TEP6) with satisfactory cavity size were screened as optimal candidate compounds. Then, a supramolecular liquid reservoir was constructed from host-guest complexes between TEP6 and econazole nitrate (ECN), an external antimicrobial agent without additional solvents. In vitro drug-release studies revealed that complexation by TEP6 could regulate the release rate of ECN and afford effective cumulative amounts. In vivo pharmacodynamic studies confirmed the formation of a supramolecular liquid reservoir contributed to the accelerated healing rate of a S. aureus-infected mouse wound model. Overall, these findings have provided the first insights into the construction of a supramolecular liquid reservoir for topical administration.