Novel WRN Helicase Inhibitors Selectively Target Microsatellite Unstable Cancer Cells.

Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n-dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumours, and WRN inhibitors are in development. Here, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth In vitro and In vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA-repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair (MMR) alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft (PDX) models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic-lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.

Microfluidic Platform Enables Shearless Aerosolization of Lipid Nanoparticles for mRNA Inhalation.

Leveraging the extensive surface area of the lungs for gene therapy, the inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient delivery of mRNA to the respiratory system. Our results demonstrated the superiority of the MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of the nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful lung-specific mRNA transfection without observable signs of toxicity. This MAP may represent an advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.

US oil and gas system emissions from nearly one million aerial site measurements.

As airborne methane surveys of oil and gas systems continue to discover large emissions that are missing from official estimates1-4, the true scope of methane emissions from energy production has yet to be quantified. We integrate approximately one million aerial site measurements into regional emissions inventories for six regions in the USA, comprising 52% of onshore oil and 29% of gas production over 15 aerial campaigns. We construct complete emissions distributions for each, employing empirically grounded simulations to estimate small emissions. Total estimated emissions range from 0.75% (95% confidence interval (CI) 0.65%, 0.84%) of covered natural gas production in a high-productivity, gas-rich region to 9.63% (95% CI 9.04%, 10.39%) in a rapidly expanding, oil-focused region. The six-region weighted average is 2.95% (95% CI 2.79%, 3.14%), or roughly three times the national government inventory estimate5. Only 0.05-1.66% of well sites contribute the majority (50-79%) of well site emissions in 11 out of 15 surveys. Ancillary midstream facilities, including pipelines, contribute 18-57% of estimated regional emissions, similarly concentrated in a small number of point sources. Together, the emissions quantified here represent an annual loss of roughly US$1 billion in commercial gas value and a US$9.3 billion annual social cost6. Repeated, comprehensive, regional remote-sensing surveys offer a path to detect these low-frequency, high-consequence emissions for rapid mitigation, incorporation into official emissions inventories and a clear-eyed assessment of the most effective emission-finding technologies for a given region.

Development of a Novel DNA Mono-alkylator Platform for Antibody-Drug Conjugates.

Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.

Microfluidic platform enables shear-less aerosolization of lipid nanoparticles for messenger RNA inhalation.

Leveraging the extensive surface area of the lungs for gene therapy, inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a novel microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient mRNA delivery to the respiratory system. Our results demonstrated the superiority of the novel MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful, lung-specific mRNA transfection without observable signs of toxicity. This pioneering MAP represents a significant advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.

The Point-of-Care Peritoneal Dialysis System Early Evaluation Study (POC-PDEE): A pilot proof-of-principal study of the Ellen Medical Devices Point-of-Care affordable peritoneal dialysis system.

The global unmet need for kidney replacement therapy means that millions of people die every year as they cannot afford treatment. Peritoneal dialysis (PD) offers comparable survival to haemodialysis and is often more affordable, but one barrier to increasing access is that conventional manufacturing and distribution of PD fluid is costly. Here we report the results from a pilot proof-of-principal study demonstrating for the first time that the Ellen Medical Devices Point-of-Care system can be used by patients to produce sterile PD fluid at the point-of-care. With further development, this low-cost system could offer a solution to the many millions of people around the world who currently cannot afford treatment for kidney failure.

Central Venous Access Devices for the Delivery of Systemic Anticancer Therapy: An Economic Evaluation.

OBJECTIVES: Patients undergoing long-term anticancer therapy typically require one of 3 venous access devices: Hickman-type device (HICK), peripherally inserted central catheter (PICC), or implantable chest wall port (PORT). Recent evidence has shown PORT is safer and improves patient satisfaction. However, PORT did not show improvement in quality-adjusted life-years and was more expensive. Decisions regarding cost-effectiveness in the United Kingdom are typically informed by a cost-per-quality-adjusted life-year metric. However, this approach is limited in its ability to capture the full range of relevant outcomes, especially in the context of medical devices. This study assessed the potential cost-effectiveness of HICK, PICC, and PORT in routine clinical practice. METHODS: This is a cost-consequence analysis to determine the trade-offs between the following outcomes: complication, infection, noninfection, chemotherapy interruption, unplanned device removals, health utilities, device insertion cost, follow-up cost, and total cost, using data from the Cancer and Venous Access clinical trial. We conducted value of implementation analysis of a PORT service. RESULTS: PORT was superior in terms of overall complication rate compared with both HICK (incidence rate ratio 0.422; 95% CI 0.286-0.622) and PICC (incidence rate ratio 0.295; 95% CI 0.189-0.458) and less likely to lead to an unplanned device removal. There was no difference in chemotherapy interruption or health utilities. Total cost with device in situ was lower on PORT than HICK (-£98.86; 95% CI -189.20 to -8.53) and comparable with PICC -£48.57 (95% CI -164.99 to 67.86). Value of implementation analysis found that PORT was likely to be considered cost-effective within the National Health Service. CONCLUSION: Decision makers should consider including PORT within the suite of venous access devices available within in the National Health Service.

Topical Application of Skin Biome Care Regimen Containing Live Cultures and Ferments of Cutibacterium acnes defendens strain XYCM42 and the Impact on Clinical Outcomes Following Microneedle-induced Skin Remodeling.

Background: The skin, our body's largest organ, hosts a complex microbiome that plays a pivotal role in maintaining health and protecting against pathogens. Even slight disruptions to this delicate balance can influence skin health and disease. Among the diverse microbial community, Cutibacterium acnes (C. acnes) subspecies defendens is known for its positive contribution to skin health. However, the interaction between living microbe probiotics and wound healing after aesthetic procedures, such as microneedling, remains unexplored. Methods: Our study included 40 participants with acne scars who underwent four microneedling sessions spaced three weeks apart. They were randomly assigned to Group 1, receiving a regimen with live C. acnes defendens strain XYCM42, or Group 2, following a conventional skincare routine with a cleanser, moisturizer, and sunscreen. Our study assessed various endpoints, including the Clinician's Global Aesthetic Improvement Scale (CGAIS), clinical safety, improvement in acne scars using Goodman and Baron's Qualitative and Quantitative Acne Scars Grading Scale and Subject's Global Aesthetic Improvement Scale (SGAIS). Results: Our analysis of live and photo grading data for CGAIS unveiled a statistically significant difference between the two groups, with Group 1 (XYCM42-based regimen) showing remarkable improvement. A similar positive trend was observed in the photo grading for CGAIS. Additionally, participant diaries indicated that Group 1 experienced a faster decline in posttreatment parameters, including erythema, swelling, burning/tingling, and itching. Conclusion: Integrating a microbiome-optimized, probiotic XYCM42-based regimen with microneedling demonstrated a high safety profile and enhanced treatment outcomes. These findings mark a milestone in aesthetic dermatology, supporting innovative microbiome-based approaches to improve skin health and aesthetics.

Study to determine the safety and efficacy of microneedling as an effective treatment for acne vulgaris.

Background: Acne is an inflammatory disease of the pilosebaceous unit that occurs primarily in adolescents. There is no current ideal treatment for acne vulgaris, as many mainstay prescription treatment modalities can compromise the skin microbiome or have deleterious health effects. Further research is needed to investigate novel treatment modalities that account for the importance of the skin microbiome. Other developing treatment modalities for acne are still taking a similar mode of action as current treatments by trying to eliminate Cutibacterium acnes despite growing evidence that some C. acnes strains may be symbiotic in nature. The perception that microneedling will exacerbate the disease state and trigger more acneic lesions via the spread of acne-associated microbes has hindered research investigating whether microneedling is a safe and effective treatment. This pilot clinical study challenges such perceptions by clinical assessment to determine if microneedling may produce beneficial treatment outcomes without disrupting critical skin structure or skin microbiome. Objectives: Test the safety and efficacy of microneedling as an effective treatment modality for acne vulgaris. Methods: Subjects were split into two groups, one group received three treatments 4 weeks apart, and the second group received four treatments 2 weeks apart. Subjects received an acne assessment by an expert clinical grader at all clinical visits. Results: There was a statistically significant reduction in both non-inflammatory and inflammatory lesions at the 2-month follow-up compared to the baseline for Group 1. Group 1 and Group 2 saw a decline of 48.20% and 54.00% in non-inflammatory lesions and 57.97% and 36.67% in inflammatory lesions, respectively, at their last visit compared to baseline. Conclusion: This study expands the utility of microneedling into a potential therapeutic modality for acne vulgaris. The data generated during the duration of this clinical study demonstrates that there is no scientific reason for microneedling to be contraindicated for acne. In this pilot, microneedling did not cause post-treatment complications and was seen to reduce acne lesions effectively. Thus, microneedling may have the potential to be a well-tolerated option for those suffering from acne, being a treatment that neither damages the sebaceous glands nor disrupts the skin microbiome.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

Controlling the surface silanol density in capillary columns and planar silicon via the self-limiting, gas-phase deposition of tris(dimethylamino)methylsilane, and quantification of surface silanols after silanization by low energy ion scattering.

Surface silanols (Si-OH) play a vital role on fused silica surfaces in chromatography. Here, we used an atmospheric-pressure, gas-phase reactor to modify the inner surface of a gas chromatography, fused silica capillary column (0.53 mm ID) with a small, reactive silane (tris(dimethylamino)methylsilane, TDMAMS). The deposition of TDMAMS on planar witness samples around the capillary was confirmed with X-ray photoelectron spectroscopy (XPS), ex situ spectroscopic ellipsometry (SE), and wetting. The number of surface silanols on unmodified and TDMAMS-modified native oxide-terminated silicon were quantified by tagging with dimethylzinc (DMZ) via atomic layer deposition (ALD) and counting the resulting zinc atoms with high sensitivity-low energy ion scattering (HS-LEIS). A bare, clean native oxide - terminated silicon wafer has 3.66 OH/nm2, which agrees with density functional theory (DFT) calculations from the literature. After TDMAMS modification of native oxide-terminated silicon, the number of surface silanols decreases by a factor of ca. 10 (to 0.31 OH/nm2). Intermediate surface testing (IST) was used to characterize the surface activities of functionalized capillaries. It suggested a significant deactivation/passivation of the capillary with some surface silanols remaining; the modified capillary shows significant deactivation compared to the native/unmodified fused silica tubing. We believe that this methodology for determining the number of residual silanols on silanized fused silica will be enabling for chromatography.

Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates.

While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.

Infection responsive coatings to reduce biofilm formation and encrustation of urinary catheters.

AIMS: The care of patients undergoing long-term urethral catheterization is frequently complicated by Proteus mirabilis infection. This organism forms dense, crystalline biofilms, which block catheters leading to serious clinical conditions. However, there are currently no truly effective approaches to control this problem. Here, we describe the development of a novel theranostic catheter coating, to simultaneously provide early warning of blockage, and actively delay crystalline biofilm formation. METHODS AND RESULTS: The coating comprises of a pH sensitive upper polymer layer (poly(methyl methacrylate-co-methacrylic acid); Eudragit S 100®) and a hydrogel base layer of poly(vinyl alcohol), which is loaded with therapeutic agents (acetohydroxamic acid or ciprofloxacin hydrochloride) and a fluorescent dye, 5(6)-carboxyfluorescein (CF). The elevation of urinary pH due to P. mirabilis urease activity results in the dissolution of the upper layer and release of cargo agents contained in the base layer. Experiments using in vitro models, which were representative of P. mirabilis catheter-associated urinary tract infections, demonstrated that these coatings significantly delay time taken for catheters to block. Coatings containing both CF dye and ciprofloxacin HCl were able to provide an average of ca. 79 h advanced warning of blockage and extend catheter lifespan ca. 3.40-fold. CONCLUSIONS: This study has demonstrated the potential for theranostic, infection-responsive coatings to form a promising approach to combat catheter encrustation and actively delay blockage.

Rotational stability and refractive outcomes of the DFT/DATx15 toric, extended depth of focus intraocular lens.

PURPOSE: To quantitatively assess postoperative rotational stability and visual acuity with the DFT/DATx15 extended depth of focus (EDOF) toric intraocular lens (IOL). METHODS: In this prospective case series, thirty-five patients with a calculated IOL power between + 15.0 D and + 25.0 D, corneal astigmatism between 0.75 D and 2.25 D, and no significant ocular pathology underwent cataract surgery. Primary outcome was rotational stability of the IOL at 1 month post-operatively. Secondary outcomes included residual refractive astigmatism, absolute residual astigmatism prediction error, and monocular distance and intermediate visual acuities. RESULTS: Mean absolute postoperative IOL rotation was 1.1 ± 0.2 degrees, with no rotation of more than 3 degrees at the final visit. Monocular mean best spectacle-corrected distance visual acuity (BSCDVA) improved from logMAR 0.27 ± 0.030 to 0.078 ± 0.017 (P < .001). Monocular uncorrected distance visual acuity (UCDVA) improved from 0.93 ± 0.096 to 0.18 ± 0.022 (P < .001). Best spectacle-corrected intermediate visual acuity (DSCIVA) was 0.17 ± 0.025, and uncorrected intermediate visual acuity (UCIVA) was 0.27 ± 0.040. Residual regular astigmatic refractive error was 0.21 ± 0.047 D. CONCLUSIONS: The toric DFT/DATx15 EDOF lens showed excellent rotational stability and effective and predictable correction of astigmatism. Its refractive outcomes and safety profile were similar to those identified in prior studies of the non-toric DFT/DAT015 EDOF IOL. A small difference in monocular BSCDVA, of uncertain clinical significance, was found when comparing these outcomes with prior DFT/DAT015 data. The trial was retrospectively registered on November 5, 2021 (TRN ​​NCT05119127).

In cataract surgery, the natural lens of the eye is replaced with an artificial lens implant. In many cases, the patient's glasses prescription in the operated eye can be reduced or eliminated through careful choice of a lens implant. There are many types of lens implants available. Toric lens implants are used to reduce one component of the glasses prescription, called regular astigmatism (or often just "astigmatism"). To maintain the full astigmatism-reducing effect of the toric lens, the lens implant must not rotate significantly within the eye after the surgery. The DFT/DATx15 (Vivity™) is a relatively new type of lens implant designed to offer patients good spectacle-free vision at far distances and improved glasses-free vision at arm's length ("intermediate") compared to a more traditional lens implant that is designed to maximize spectacle-free distance vision only. This study reports one surgeon's experience with measuring the amount of rotation of DFT/DATx15 lenses after surgery. This study also assessed the ability of the DFT/DATx15 to reduce regular astigmatism and improve glasses-free vision at far and intermediate distances. The results show that this lens did not rotate significantly within the eye and was effective at reducing the regular astigmatism as intended.

Characterization of a live Cutibacterium acnes subspecies defendens strain XYCM42 and clinical assessment as a topical regimen for general skin health and cosmesis.

BACKGROUND: When formulating topical products to treat skin diseases and addressing general skin health and cosmesis, most of the focus has traditionally been placed on how any given ingredient may impact the structure, function, and health of human skin elements. However, recent research is beginning to highlight the importance of the skin microbiome in relation to certain skin conditions and general cosmesis. Cutibacterium acnes is one of the most prolific skin-specific bacterial species. Research has shown that the species is divided into subspecies, some of which are thought to be beneficial to the skin. This paper aims to determine the efficacy of strainXYCM42, a C. acnes subspecies defendens derived strain designed to improve the health and appearance of the skin. METHODS: In vitro studies were performed on human keratinocyte and fibroblast monolayers, human peripheral blood mononuclear cells (PBMC), and skin explants to elucidate the effects of live XYCM42 cells and their ferment on human skin cells and tissues. Subsequently, clinical studies were performed using XYCM42-based topical regimens designed to deliver and support the engraftment of live XYCM42 cells onto subjects' skin. Two studies were performed, a 3-week pilot study (n = 10) and a 8-week pivotal study (n = 121). In the latter, 32 subjects were enrolled for an in-clinic portion for efficacy evaluation, with clinic visits occurring at Baseline, Week 1, Week 4, and Week 8. RESULTS: In vitro data suggest that XYCM42 and its ferment filtrate have potential to provide benefits to the skin via antioxidant, anti-inflammatory, and select antimicrobial activities. Clinical observation demonstrated that a XYCM42-containing regimen supports a healthy skin environment, promotes increased skin hydration, decreases erythema, calms the skin, and regulates sebum production. CONCLUSION: These studies provide further evidence that specific strains of C. acnes, such as XYCM42, have a more beneficial function regarding skin health and appearance than was previously thought. Appropriate use of formulations derived from symbiotic strains within the skin microbiome can support the development of novel, beneficial topicals.

Comprehension, Utility, and Acceptability of a Multidomain Physical Functioning Report for Systemic Lupus Erythematosus Patients and Their Providers.

OBJECTIVE: Patient-provider discussions about functioning are often outside the scope of usual care for systemic lupus erythematosus (SLE), and tools to facilitate such discussions are lacking. The present study was undertaken to assess the comprehension, utility, and acceptability of a novel, individualized functioning report, the purpose of which is to facilitate patient-provider communication about functioning, in a predominantly Black SLE patient population. METHODS: Individualized reports (including sections with pictorial representations of participants' measured activities of daily living, falls, physical performance, perceived physical functioning, and community mobility from a previous pilot study visit) and surveys were emailed or mailed to 59 SLE patients. Ease of interpretation was dichotomized ("very easy" versus all other responses). Utility and acceptability were assessed by items relating to usefulness for care planning and comfort with discussing the report. RESULTS: Among 47 (79.7%) SLE patients who completed the survey (78.7% Black, 91.5% female, mean age 49.6 years), the reported ease of interpretation ranged from 70.2% to 85.1% across the report sections. Ease of interpretation was lower among those who were older, Black, and female and who had lower cognitive scores (P > 0.05 for all). Most reported that physical functioning domains of the report were useful for treatment or other care planning (70.2-80.5%) and that they felt comfortable discussing the report with a health care provider (93.2-100%). CONCLUSION: We found that a novel functioning report for SLE patients was associated with high comprehension, utility, and acceptability. Future studies can help determine how an individualized functioning report could improve patient-provider communication in the clinic setting.

Efficacy and tolerability of a microneedling device for treating wrinkles on the face.

OBJECTIVES: A microneedling pen has been cleared by the US Food and Drug Administration, indicated for improving the appearance of adult facial acne scars. The objective of this study was to assess the device's effectiveness for treating wrinkles of the face area. MATERIALS AND METHODS: Healthy adults seeking to improve the appearance of face wrinkles were enrolled (N = 35), receiving four monthly microneedling procedures by a trained aesthetician who treated the face skin per manufacturer instructions. Wrinkle assessments were performed by two trained blinded raters by comparing baseline images of each subject with images obtained at 90 days post-procedure. Subsequently, the two raters were unblinded for the Clinician's Global Aesthetic Improvement Scale (CGAIS) assessment. Subjects completed the Subject's Global Aesthetic Improvement Scale (SGAIS) and a Satisfaction Questionnaire at 30 and 90 days post-treatment. RESULTS: The study was completed by 32 subjects with a mean (SD) age of 56.3 (5.0) years. Wrinkle assessments demonstrated significant improvement in the face areas (p < 0.001). The SGAIS scores showed significant improvements after 30 and 90 days post-treatment (for each, p < 0.001). The CGAIS scores also showed significant improvements at 90 days post-treatment (p < 0.001). Most subjects reported some level of improvement in their appearance at 30 days (73.3%) and 90 days (68.8%) post-treatment. The satisfaction questionnaire showed high levels of improvement in wrinkles (93.8%), satisfaction with the treatment procedure (87.5%) and would recommend microneedling to friends and family members (80.6%) on the face and neck. CONCLUSION: Microneedling is a viable, minimally invasive option for treating wrinkles of the face. CLINICALTRIALS: gov Identifier: NCT03803059.