Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor.

Background: Profiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), a cancer whose aggressive clinical course making it exceedingly challenging to obtain tumor biopsies. Methods: Here, a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC, we study cfDNA low pass whole genome (0.1X coverage) and exome (130X) sequencing in comparison with time-point matched tumor, characterized using exome and transcriptome sequencing. Results: Direct comparison of cfDNA versus tumor biopsy reveals that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not found in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Genomic sequencing coverage of plasma DNA fragments around transcription start sites shows distinct treatment-related changes and captures the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors, allowing prediction of SCLC neuroendocrine phenotypes and treatment responses. Conclusions: These findings have important implications for non-invasive stratification and subtype-specific therapies for patients with SCLC, now treated as a single disease.

A study of correlations between cephalometric measurements in Koreans with normal occlusion by network analysis.

Analyzing the correlation between cephalometric measurements is important for improving our understanding of the anatomy in the oral and maxillofacial region. To minimize bias resulting from the design of the input data and to establish a reference for malocclusion research, the aims of this study were to construct the input set by integrating nine cephalometric analyses and to study the correlation structure of cephalometric variables in Korean adults with normal occlusion. To analyze the complex correlation structure among 65 cephalometric variables, which were based on nine classical cephalometric analyses, network analysis was applied to data obtained from 735 adults (368 males, 367 females) aged 18-25 years with normal occlusion. The structure was better revealed through weighted network analysis and minimum spanning tree. Network analysis revealed cephalometric variable clusters and the inter- and intra-correlation structure. Some metrics were divided based on their geometric interpretation rather than their clinical significance. It was confirmed that various classical cephalometric analyses primarily focus on investigating nine anatomical features. Investigating the correlation between cephalometric variables through network analysis can significantly enhance our understanding of the anatomical characteristics in the oral and maxillofacial region, which is a crucial step in studying malocclusion using artificial intelligence.

Baculovirus Vector-Based Varicella-Zoster Virus Vaccine as a Promising Alternative with Enhanced Safety and Therapeutic Functions.

Varicella-zoster virus (VZV) poses lifelong risks, causing varicella and herpes zoster (HZ, shingles). Currently, varicella and HZ vaccines are predominantly live attenuated vaccines or adjuvanted subunit vaccines utilizing VZV glycoprotein E (gE). Here, we propose our vaccine candidates involving a comparative analysis between recombinant baculoviral vector vaccines (AcHERV) and a live attenuated vaccine strain, vOka. AcHERV vaccine candidates were categorized into groups encoding gE only, VZV glycoprotein B (gB) only, or both gE and gB (gE-gB) as AcHERV-gE, AcHERV-gB, and AcHERV-gE-gB, respectively. Humoral immune responses were evaluated by analyzing total IgG, IgG1, IgG2a, and neutralizing antibodies. Cell-mediated immunity (CMI) responses were evaluated by enzyme-linked immunospot (ELISPOT) assay and Th1/Th2/Th17 cytokine profiling. In the mouse model, AcHERV-gE-gB elicited similar or higher total IgG, IgG2a, and neutralizing antibody levels than vOka and showed robust VZV-specific CMI responses. From the perspective of antigens encoded in vaccines and their relationship with CMI response, both AcHERV-gB and AcHERV-gE-gB demonstrated results equal to or superior to AcHERV-gE, encoding only gE. Taken together, these results suggest that AcHERV-gE-gB can be a novel candidate for alleviating risks of live attenuated vaccine-induced latency and effectively preventing varicella during early stages of life while providing strong CMI for effective resistance against HZ and therapeutic potential in later stages of life.

Preparation of Low-Temperature Solution-Processed High-κ Gate Dielectrics Using Organic-Inorganic TiO2 Hybrid Nanoparticles.

Organic-inorganic hybrid dielectric nanomaterials are vital for OTFT applications due to their unique combination of organic dielectric and inorganic properties. Despite the challenges in preparing stable titania (TiO2) nanoparticles, we successfully synthesized colloidally stable organic-inorganic (O-I) TiO2 hybrid nanoparticles using an amphiphilic polymer as a stabilizer through a low-temperature sol-gel process. The resulting O-I TiO2 hybrid sols exhibited long-term stability and formed a high-quality dielectric layer with a high dielectric constant (κ) and minimal leakage current density. We also addressed the effect of the ethylene oxide chain within the hydrophilic segment of the amphiphilic polymer on the dielectric properties of the coating film derived from O-I TiO2 hybrid sols. Using the O-I TiO2 hybrid dielectric layer with excellent insulating properties enhanced the electrical performance of the gate dielectrics, including superior field-effect mobility and stable operation in OTFT devices. We believe that this study provides a reliable method for the preparation of O-I hybrid TiO2 dielectric materials designed to enhance the operational stability and electrical performance of OTFTs.

Fully printed non-contact touch sensors based on GCN/PDMS composites: enabling over-the-bottom detection, 3D recognition, and wireless transmission.

The rapid advancement in intelligent bionics has elevated electronic skin to a pivotal component in bionic robots, enabling swift responses to diverse external stimuli. Combining wearable touch sensors with IoT technology lays the groundwork for achieving the versatile functionality of electronic skin. However, most current touch sensors rely on capacitive layer deformations induced by pressure, leading to changes in capacitance values. Unfortunately, sensors of this kind often face limitations in practical applications due to their uniform sensing capabilities. This study presents a novel approach by incorporating graphitic carbon nitride (GCN) into polydimethylsiloxane (PDMS) at a low concentration. Surprisingly, this blend of materials with higher dielectric constants yields composite films with lower dielectric constants, contrary to expectations. Unlike traditional capacitive sensors, our non-contact touch sensors exploit electric field interference between the object and the sensor's edge, with enhanced effects from the low dielectric constant GCN/PDMS film. Consequently, we have fabricated touch sensor grids using an array configuration of dispensing printing techniques, facilitating fast response and ultra-low-limit contact detection with finger-to-device distances ranging from 5 to 100 mm. These sensors exhibit excellent resolution in recognizing 3D object shapes and accurately detecting positional motion. Moreover, they enable real-time monitoring of array data with signal transmission over a 4G network. In summary, our proposed approach for fabricating low dielectric constant thin films, as employed in non-contact touch sensors, opens new avenues for advancing electronic skin technology.

We've created 3D recognition sensing arrays using a printed method, enabling remote data transmission. We've identified an intriguing interfacial effect in GCN/PDMS doping, opening new possibilities in smart skin technology.

Comparative Biodistribution Study of Baculoviral and Adenoviral Vector Vaccines against SARS-CoV-2.

Various types of vaccines have been developed against COVID-19, including vector vaccines. Among the COVID-19 vaccines, AstraZeneca's chimpanzee adenoviral vaccine was the first to be commercialized. For viral vector vaccines, biodistribution studies are critical to vaccine safety, gene delivery, and efficacy. This study compared the biodistribution of the baculoviral vector vaccine (AcHERV-COVID19) and the adenoviral vector vaccine (Ad-COVID19). Both vaccines were administered intramuscularly to mice, and the distribution of the SARS-CoV-2 S gene in each tissue was evaluated for up to 30 days. After vaccination, serum and various tissue samples were collected from the mice at each time point, and IgG levels and DNA copy numbers were measured using an enzyme-linked immunosorbent assay and a quantitative real-time polymerase chain reaction. AcHERV-COVID19 and Ad-COVID19 distribution showed that the SARS-CoV-2 spike gene remained predominantly at the injection site in the mouse muscle. In kidney, liver, and spleen tissues, the AcHERV-COVID19 group showed about 2-4 times higher persistence of the SARS-CoV-2 spike gene than the Ad-COVID19 group. The distribution patterns of AcHERV-COVID19 and Ad-COVID19 within various organs highlight their contrasting biodistribution profiles, with AcHERV-COVID19 exhibiting a broader and prolonged presence in the body compared to Ad-COVID19. Understanding the biodistribution profile of AcHERV-COVID19 and Ad-COVID19 could help select viral vectors for future vaccine development.

A Scoping Review of Trauma-Informed Pediatric Interventions in Response to Natural and Biologic Disasters.

A scoping review was performed of trauma-informed psychological interventions to treat anxiety, depression, and posttraumatic stress symptoms in youth in response to natural/biologic disasters. The specific aims were to identify psychosocial interventions used in response to natural/biologic disasters, report the interventions' effectiveness, describe limitations, and provide treatment recommendations and future directions. Of the 45 studies extracted, 28 were on natural disasters and 17 on biologic disasters with the majority related to the COVID-19 pandemic. The most commonly implemented interventions were Cognitive Behavioral Therapy (CBT), Trauma-Focused Cognitive Behavioral Therapy (TF-CBT), and eye movement desensitization and reprocessing (EMDR). The UCLA Posttraumatic Stress Disorder Reaction Index (UCLA PTSD-RI) and the Strengths and Difficulties Questionnaire (SDQ) were the most frequently used measures. Methodological rigor was varied, with 60% randomized, controlled trials. Overall, there was a significant decrease in posttraumatic stress symptoms, distress, anxiety, and depression regardless of whether the participant received CBT, TF-CBT, or EMDR. Generally, there was not a significant decrease in anxiety and depression with yoga, cognitive fear-reduction, emotion-based drawing, and community health education. Recommendations for future directions include larger-scale studies with group and on-line interventions that include younger children with moderation analyses by gender and race/ethnicity.

Effects of three-dimensional image based insole for healthy volunteers: a pilot clinical trial.

Insoles are used to treat various foot diseases, including plantar foot, diabetic foot ulcers, and refractory plantar fasciitis. In this study, we investigated the effects of 3-dimensional image-based (3-D) insole in healthy volunteers with no foot diseases. Additionally, the comfort of the 3-D insole was compared with that of a custom-molded insole. A single-center, randomized, open clinical trial was conducted to address the effectiveness of insole use in a healthy population with no foot or knee disease. Two types of arch support insoles were evaluated for their effectiveness: a 3-D insole and a custom-molded insole. Fifty Korean volunteers participated in the study and were randomly allocated into the "3-D insole" (n = 40) or "custom-molding insole" (n = 10) groups. All subjects wore 3-D insoles or custom-molded insoles for 2 weeks. The sense of wearing shoes (Visual Analog Scale [VAS] and score) and fatigue of the foot were used to assess the insole effects at the end of the 2-week study period. The 3-D insole groups showed significantly improved sense of wearing shoes (VAS, p = 0.0001; score, p = 0.0002) and foot fatigue (p = 0.0005) throughout the study period. Although the number of subjects was different, the custom-molding insole group showed no significant changes in the sense of wearing shoes (VAS, 0.1188; score, p = 0.1483). Foot fatigue in the 3-D insole group improved significantly (p = 0.0005), which shows that a 3-D insole might have favorable effects on foot health in a healthy population. Trial Registration: Clinical Research Information Service Identifier: KCT0008100.

Bioconversion of BIOGF1K, a compound-K-rich fraction from ginseng root and its effect on epidermal barrier function.

BIOGF1K, the ginseng root-based and hydrolyzed ginsenoside-rich fraction, is known to improve skin damage, but there are rare studies on the kinetic of ginsenosides in the epidermis and their effects on epidermal barrier function. The current study investigated the effect of BIOGF1K on epidermal barrier function and its kinetics on epidermal transport. HPLC and LC/MS were used to verify the ginsenosides and the metabolites of BIOGF1K. Human immortalized keratinocytes (HaCaT) and epidermis-dermis artificial skin were treated with BIOGF1K and their metabolites were analyzed by HPLC and LC/MS. The epidermal barrier function was evaluated by transepithelial electrical resistance (TEER). In BIOGF1K, ginsenoside Rg1, Rd, F1, F2, compound Mc, compound Y (CY), and compound K (CK) were detected and CK and CY were the most and second abundant ginsenosides. TEER of HaCaT with 100 and 200 µg/mL BIOGF1K treatment was significantly higher than the control during 600 min of incubation. CK was permeated to the epidermis in a time-dependent manner and its maximum transported rate was observed at 600 min. In the case of artificial skin, CY and CK were permeated to the epidermis-dermis skin as time-dependent. Also, 24 h after treatment of CY, CK was detected as 19.59% of CY. It was proposed that CY was hydrolyzed into CK while permeating the epidermis. Results from the current study suggest that bioconversion of BIOGF1K rich in CK effectively enhances epidermal barrier function and it could be a useful cosmeceutical to exhibit its functionality to the skin.

Rare CIDEC coding variants enriched in age-related macular degeneration patients with small low-luminance deficit cause lipid droplet and fat storage defects.

BACKGROUND: The basis of Age-related macular degeneration (AMD) genetic risk has been well documented; however, few studies have looked at genetic biomarkers of disease progression or treatment response within advanced AMD patients. Here we report the first genome-wide analysis of genetic determinants of low-luminance vision deficit (LLD), which is seen as predictive of visual acuity loss and anti-VEGF treatment response in neovascular AMD patients. METHODS: AMD patients were separated into small- and large-LLD groups for comparison and whole genome sequencing was performed. Genetic determinants of LLD were assessed by common and rare variant genetic analysis. Follow-up functional analysis of rare coding variants identified by the burden test was then performed in vitro. RESULTS: We identified four coding variants in the CIDEC gene. These rare variants were only present in patients with a small LLD, which has been previously shown to indicate better prognosis and better anti-VEGF treatment response. Our in vitro functional characterization of these CIDEC alleles revealed that all decrease the binding affinity between CIDEC and the lipid droplet fusion effectors PLIN1, RAB8A and AS160. The rare CIDEC alleles all cause a hypomorphic defect in lipid droplet fusion and enlargement, resulting in a decreased fat storage capability in adipocytes. CONCLUSIONS: As we did not detect CIDEC expression in the ocular tissue affected by AMD, our results suggest that the CIDEC variants do not play a direct role in the eye and influence low-luminance vision deficit via an indirect and systemic effect related to fat storage capacity.

Bioconversion of retinol and its cell barrier function in human immortalized keratinocytes cells and artificial epidermis-dermis skin.

The current study aimed to characterize cellular uptake and bioconversion of retinol in fully differentiated human immortalized keratinocytes cells (HaCaT) and artificial skin by measuring the cell integrity of skin barriers, time-dependent transport of retinol, and bioconversion to its metabolites. The expression of epidermal differentiation related genes including Keratin 1 (KRT1), Keratin 10 (KRT10), and Involucrin (IVL) significantly increased in differentiated HaCaT. TEER of HaCaT did not decrease after incubating retinol compared to control (p > 0.05), indicating that retinol tends to maintain strength and integrity of epidermal barrier. TEER of artificial skin decreased treatment of retinol for 2 h, but it was recovered after 4 h. During retinol transport, metabolite was eluted at 13.37 and 13.82 min of basal medium of both keratinocytes and artificial skin, which was identified as retinoic acid by product ion of m/z 283.47. Retinol appeared to be accumulated in keratinocytes, but its uptake tends to be reduced in a time-dependent manner. Retinoic acid converted from retinol in keratinocytes was time dependently transported. In case of artificial skin, retinol was mostly found in apical at initial incubation time, but it was reduced during incubation for 24 h. Retinoic acid was time-dependently found in a basal, which was converted via epidermis-dermis. Results from the current study suggest that topical application of retinol to human skin optimal concentration and time exposure could maintain epidermal barrier function and promote skin function due to its remarkable bioconversion to retinoic acid in the epidermis-dermis.

Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier.

Effective delivery of therapeutics to the brain is challenging. Molecular shuttles use receptors expressed on brain endothelial cells to deliver therapeutics. Antibodies targeting transferrin receptor (TfR) have been widely developed as molecular shuttles. However, the TfR-based approach raises concerns about safety and developmental burden. Here, we report insulin-like growth factor 1 receptor (IGF1R) as an ideal target for the molecular shuttle. We also describe Grabody B, an antibody against IGF1R, as a molecular shuttle. Grabody B has broad cross-species reactivity and does not interfere with IGF1R-mediated signaling. We demonstrate that administration of Grabody B-fused anti-alpha-synuclein (α-Syn) antibody induces better improvement in neuropathology and behavior in a Parkinson's disease animal model than the therapeutic antibody alone due to its superior serum pharmacokinetics and enhanced brain exposure. The results indicate that IGF1R is an ideal shuttle target and Grabody B is a safe and efficient molecular shuttle.

Replication stress defines distinct molecular subtypes across cancers.

Endogenous replication stress is a major driver of genomic instability. Current assessments of replication stress are low throughput precluding its comprehensive assessment across tumors. Here we develop and validate a transcriptional profile of replication stress by leveraging established cellular characteristics that portend replication stress. The repstress gene signature defines a subset of tumors across lineages characterized by activated oncogenes, aneuploidy, extrachromosomal DNA amplification, immune evasion, high genomic instability, and poor survival, and importantly predicts response to agents targeting replication stress more robustly than previously reported transcriptomic measures of replication stress. Repstress score profiles the dual roles of replication stress during tumorigenesis and in established cancers and defines distinct molecular subtypes within cancers that may be more vulnerable to drugs targeting this dependency. Altogether, our study provides a molecular profile of replication stress, providing novel biological insights of the replication stress phenotype, with clinical implications.

Evaluation of Spatial Distribution of Three Major Leptocorisa (Hemiptera: Alydidae) Pests Using MaxEnt Model.

We targeted three major Leptocorisa species (L. chinensis, L. acuta, and L. oratoria) and evaluated their potential distributions using MaxEnt. The results showed that most Asian countries and northern Australia would be suitable for at least one of these pest species, and climate change will expand their habitat northward. All of the developed models were evaluated to be excellent with AUC, TSS, and OR10%. Most of the recorded regions of the Leptocorisa species are consistent with the result of potential distributions predicted in this study. The results confirmed that the minimum temperature of the coldest month mainly influences the three Leptocorisa species distributions. The potential distributions of the three species cover major rice cultivation areas regardless of climate change, suggesting that it would be necessary to establish a sustainable control strategy for the pests.

In Vitro and In Vivo Human Body Odor Analysis Method Using GO:PANI/ZNRs/ZIF-8 Adsorbent Followed by GC/MS.

Among various volatile organic compounds (VOCs) emitted from human skin, trans-2-nonenal, benzothiazole, hexyl salicylate, α-hexyl cinnamaldehyde, and isopropyl palmitate are key indicators associated with the degrees of aging. In our study, extraction and determination methods of human body odor are newly developed using headspace-in needle microextraction (HS-INME). The adsorbent was synthesized with graphene oxide:polyaniline/zinc nanorods/zeolitic imidazolate framework-8 (GO:PANI/ZNRs/ZIF-8). Then, a wire coated with the adsorbent was placed into the adsorption kit to be directly exposed to human skin as in vivo sampling and inserted into the needle so that it was able to be desorbed at the GC injector. The adsorption kit was made in-house with a 3D printer. For the in vitro method, the wire coated with the adsorbent was inserted into the needle and exposed to the headspace of the vial. When a cotton T-shirt containing body odor was transferred to a vial, the headspace of the vial was saturated with body odor VOCs. After volatile organic compounds were adsorbed in the dynamic mode, the needle was transferred to the injector for analysis of the volatile organic compounds by gas chromatography/mass spectrometry (GC/MS). The conditions of adsorbent fabrication and extraction for body odor compounds were optimized by response surface methodology (RSM). In conclusion, it was able to synthesize GO:PANI/ZNRs/ZIF-8 at the optimal condition and applicable to both in vivo and in vitro methods for body odor VOCs analysis.

Characterization of scents from Juniperus chinensis by headspace in-needle microextraction using graphene oxide-polyaniline nanocomposite coated wire followed by gas chromatography-mass spectrometry.

Scents released by trees are the secondary metabolites that play various roles, including indirect plant defense against insects, attraction to pollinators, communication, adaptation to heat resistance, environmental stress, and protection from predators. In this study, the scents of three individual trees designated as Korean natural monuments (pair of Chinese junipers, Chinese juniper, and horizontal Chinese juniper tree) were analyzed using headspace in-needle microextraction (HS-INME) method with graphene oxide-polyaniline (GO-PANI) adsorbent followed by gas chromatography-mass spectrometry (GC/MS). GO-PANI layer was coated on a stainless steel wire using cyclic voltammetry (CV). It was characterized through thermogravimetric analysis (TGA), Fourier transform-infrared spectroscopy (FT-IR), and field emission-scanning electron microscope (FE-SEM). As a result, it was confirmed that the GO-PANI coating was successfully prepared. α-Longipinene, α-cedrene, and cedrol, which are representative scent components of common juniper trees, were selected as target compounds through a preliminary test and used in the optimization processes. Response surface methodology (RSM) with Box Behnken Design (BBD) was applied to optimize the experimental conditions. The developed analytical method was validated by checking the limit of detection (LOD), the limit of quantitation (LOQ), recovery rate, sensitivity, and reproducibility. Significant scientific findings from three Korean natural monuments of Juniperus chinensis were characterized by their major scent components such as α-cedrene, γ-cadinene, thujopsene, and cedrol of pungent-woody base note.

The organization and development of cortical interneuron presynaptic circuits are area specific.

Parvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

Ensemble evaluation of the potential risk areas of yellow-legged hornet distribution.

Invasion of alien species facilitated by climate change and human assistant is one of global threats that cause irreversible damages on the local flora and fauna. One of these issued species, Vespa velutina nigrithorax du Buysson, 1905 (Hymenoptera:Vespidae), is a significant threat to entomofauna, including honeybees, in the introduced regions. This wasp is still expanding its habitats, prioritizing the development of a reliable species distribution model based on recently updated occurrence data. Therefore, the aim of this study was to evaluate the potential areas that are climatically exposed to V. v. nigrithorax invasion globally and in South Korea, where the wasp has caused severe damage to local ecosystems and apiculture after its recent introduction. We developed a new global scale ensemble model based on CLIMEX and Maxent models and applied it to South Korea using field survey data. As a result, risky areas were predicted to be temperate and subtropical climate regions, including the eastern USA, western Europe, Far East Asia, and small areas in South America and Australia. In particular, South Korea has a high potential risk throughout the country. We expect that this study would provide fundamental data for monitoring the environmental risks caused by V. v. nigrithorax using advanced species distribution modeling.

Synergistic Effects of Nonmagnetic Carbon Nanotubes on the Performance and Stability of Magnetorheological Fluids Containing Carbon Nanotube-Co0.4Fe0.4Ni0.2 Nanocomposite Particles.

We investigated the magnetorheological (MR) properties of the carbon nanotube (CNT)-Co0.4Fe0.4Ni0.2 composite suspension to find a high-performance MR fluid with excellent stability. The composites were fabricated by chemical reduction of Co0.4Fe0.4Ni0.2 on the surface of amine-functionalized CNTs. A synergistic effect between the high aspect ratio of the CNTs and the strong magnetic polarization of the Co0.4Fe0.4Ni0.2 led to stronger MR performance of the nanocomposite particle suspension. The MR fluid exhibits an unexpected high yield stress value that is 13 times greater than that of a CNT-Fe3O4 suspension at a magnetic field strength of 343 kA/m. Nonmagnetic CNTs form a three-dimensional networklike structure, imparting surprisingly large additional yield stress to the CNT-Co0.4Fe0.4Ni0.2 nanocomposite MR suspension. The low density of the CNTs resulted in much better long-term stability for the CNT-Co0.4Fe0.4Ni0.2 nanocomposite suspension than the MR fluid containing only Co0.4Fe0.4Ni0.2.

Therapeutic targeting of ATR yields durable regressions in small cell lung cancers with high replication stress.

Small cell neuroendocrine cancers (SCNCs) are recalcitrant cancers arising from diverse primary sites that lack effective treatments. Using chemical genetic screens, we identified inhibition of ataxia telangiectasia and rad3 related (ATR), the primary activator of the replication stress response, and topoisomerase I (TOP1), nuclear enzyme that suppresses genomic instability, as synergistically cytotoxic in small cell lung cancer (SCLC). In a proof-of-concept study, we combined M6620 (berzosertib), first-in-class ATR inhibitor, and TOP1 inhibitor topotecan in patients with relapsed SCNCs. Objective response rate among patients with SCLC was 36% (9/25), achieving the primary efficacy endpoint. Durable tumor regressions were observed in patients with platinum-resistant SCNCs, typically fatal within weeks of recurrence. SCNCs with high neuroendocrine differentiation, characterized by enhanced replication stress, were more likely to respond. These findings highlight replication stress as a potentially transformative vulnerability of SCNCs, paving the way for rational patient selection in these cancers, now treated as a single disease.