Natural Killer Cell Dysfunction in Premenopausal BRCA1 Mutation Carriers: A Potential Mechanism for Ovarian Carcinogenesis.

BACKGROUND: Tissue-specificity for fimbrial fallopian tube ovarian carcinogenesis remains largely unknown in BRCA1 mutation carriers. We aimed to assess the cell autonomous and cell-nonautonomous implications of a germline BRCA1 mutation in the context of cancer immunosurveillance of CD3- CD56+ natural killer (NK) cells. METHODS: Premenopausal BRCA1 mutation carriers versus age-matched non-carriers were compared. Daily urinary 5ß-pregnanediol levels were used to determine progesterone metabolomics across an ovarian cycle. Using peripherally acquired NK cells the cell-mediated cytotoxicity of tumor targets (OVCAR-3, K-562) was determined using live cellular impedance (xCELLigence®) and multicolor flow cytometry. Hypoxia-inducible factor 1-alpha (HIF-1α) immunohistochemistry of cancer-free fallopian tube specimens allowed a comparison of proximal versus distal portions. Utilizing these findings the role of environmental factors relevant to the fimbrial fallopian tube (progesterone, hypoxia) on NK cell functional activity were studied in an ovarian phase-specific manner. RESULTS: BRCA1 mutation carriers demonstrate a differential progesterone metabolome with a phase-specific reduction of peripheral NK cell functional activity. Progesterone exposure further impairs NK cell-mediated cytotoxicity in a dose-dependent manner, which is reversed with the addition of mifepristone (1.25 µM). The fimbrial fallopian tube demonstrated significantly higher HIF-1α staining, particularly in BRCA1 mutation carriers, reflecting a site-specific 'hypoxic niche'. Exposure to hypoxic conditions (1% O2) can further impair tumor cytotoxicity in high-risk carriers. CONCLUSIONS: Phase-specific differential NK cell activity in BRCA1 mutation carriers, either systemically or locally, may favor site-specific pre-invasive carcinogenesis. These cumulative effects across a reproductive lifecycle in high-risk carriers can have a detrimental effect further supporting epidemiological evidence for ovulation inhibition.

Beyond Dollars and Scars: The Influence of Wealth Inequality on Total Expenditure on Cosmetic Procedures in the United States.

The present study delves into the "beauty paradox," a multifaceted phenomenon influenced by wealth inequality, societal norms, and consumer behaviors, specifically regarding spending on cosmetic procedures. Relying on data from the United States Census Bureau and the American Society of Plastic Surgeons, the research primarily focuses on the Gini coefficient, Mean Logarithmic Deviation (MLD), and income data for the lowest and top 5% quintiles of mean household income over a 15-year span. The analysis uncovers a significant correlation between Total Expenditures on Cosmetic Surgery and minimally invasive procedures and the wealth of the top 5% income quintile. The "Cosmetic Enhancement Cycle (CEC)" is proposed, indicating a symbiotic growth between wealth accumulation among the affluent and the plastic surgery industry. As such, the "beauty paradox" lays bare the multifaceted consequences of wealth inequality, necessitating a comprehensive approach that addresses socioeconomic dynamics, accessibility of cosmetic procedures, societal norms, and perceptions. This investigation underscores the imperative for further exploration into the myriad ways that wealth inequality sculpts societies and influences behaviors, including within the context of the CEC.

Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women.

BACKGROUND: Distinguishing ovarian cancer (OC) from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of OC pathogenesis. Accumulating evidence suggests a link between OC and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved OC diagnosis and prevention. METHODS: Here, we profiled the serum lipidome of 208 OC, including 93 patients with early-stage OC, and 117 non-OC (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning approaches. RESULTS: We found lipidome alterations unique to OC were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in OC in comparison to other gynecological diseases. Machine learning methods selected a panel of 17 lipids that discriminated OC from non-OC cases with an AUC of 0.85 for an independent test set. CONCLUSIONS: This study provides a systemic analysis of lipidome alterations in human OC, specifically in Korean women. IMPACT: Here, we show the potential of circulating lipids in distinguishing OC from non-OC conditions.

Forced eruption in impacted teeth: analysis of failed cases and outcome of re-operation.

BACKGROUND: Forced eruption of an impacted tooth usually requires surgical and orthodontic interventions to successfully bring the tooth into the dental arch. The clinical time required for a forced eruption is difficult to predict before treatment begins and success rates are affected by several factors before and after an eruption. This study was conducted to identify factors that affect the success of forced eruption, the duration of orthodontic treatment of impacted teeth, and the reasons for re-operation and forced eruption failure in a various teeth and cases. METHODS: In this retrospective study, the records regarding the forced eruption of 468 teeth in 371 patients from June 2006 to May 2020 at the Advanced General Dentistry Department of Yonsei University Dental Hospital were initially examined. The records of 214 teeth in 178 patients who completed orthodontic treatment were included in the analysis. Data on patient demographics, tooth characteristics, orthodontic treatment duration, re-operations, and failures were collected from electronic medical records. RESULTS: There was a significant difference in age between the success and failure forced eruption. Factors significantly affecting treatment duration were apex formation, position, rotation, and re-operation. Re-operation had a 96% success rate. The average orthodontic treatment duration was 29.99 ± 16.93 months, but the average orthodontic treatment duration for teeth that undergone re-operation was 20.36 ± 11.05 months, which was approximately 9 months shorter. Additionally, there was an interaction effect between rotation and re-operation on the duration of orthodontic treatment. The causes for failure of forced eruption in 6 cases were ankyloses (3 cases), incomplete alignment with the normal dental arch (2 cases), and a significant deviation in the impacted tooth's location (1 case). CONCLUSIONS: To increase the success rate of forced eruption, age should be considered as a priority, and in order to predict the treatment period, the apex formation status, position in the arch, and rotation should be considered in addition to age. When determining re-operation, considering factors such as ankylosis, root curvature, and apex formation can help in the success of orthodontic treatment.

The assessment of halitosis with a new screening tool in medication-related osteonecrosis of the jaw.

OBJECTIVES: This study aimed to identify the levels of halitosis in patients with Medication-related osteonecrosis of the jaw (MRONJ) and osteoporosis and to suggest a new MRONJ screening method using halitosis measurement. MATERIALS AND METHODS: From October 2019 to April 2023, participants aged 19 years or older without periodontal disease were selected. Seventy-five participants, 25 in each group, were divided into an MRONJ group, an osteoporosis group without MRONJ, and a control group without osteoporosis and not taking osteoporosis drugs or antibiotics. Each participant underwent halitosis assessment twice using an exhaled breath analyzer to measure halitosis twice by blowing a straw for 1 min. Measured concentrations of hydrogen, hydrogen sulfide, and methyl mercaptan were compared between groups. RESULTS: Data from 22 patients in the MRONJ group, 25 in the osteoporosis group, and 25 in the control group were analyzed. The concentrations of hydrogen sulfide and methyl mercaptan were significantly higher in the MRONJ group than in the other groups, but the concentrations of hydrogen did not differ between the groups. When comparing the concentrations of hydrogen sulfide and methyl mercaptan in osteoporosis patients and solid cancer patients in the MRONJ group, there was a significant difference in hydrogen sulfide concentration, but there was no significant difference in methyl mercaptan. CONCLUSIONS: Quantifying the level of halitosis can be used to screen for MRONJ in patients taking bisphosphonates, such as patients with osteoporosis, prostate cancer, and breast cancer. CLINICAL RELEVANCE: MRONJ is accompanied by bad breath, and the concentrations of hydrogen sulfide and methyl mercaptan are associated with MRONJ.

First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations.

BACKGROUND: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. METHODS: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety. RESULTS: A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively. CONCLUSIONS: Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Ultrahigh Resolution Lipid Mass Spectrometry Imaging of High-Grade Serous Ovarian Cancer Mouse Models.

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights on how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and a triple mutant mouse models (n = 4) of high-grade serous ovarian cancer (HGSC). Lipids belonging to a total of 15 different classes were annotated and their abundance changes compared to those in healthy mouse reproductive tissue (n = 4), mapping onto major lipid pathways involved in OC progression. From intermediate-stage OC to advanced HGSC, we provide a direct visualization of lipid distributions and their biological links to inflammatory response, cellular stress, cell proliferation, and other processes. We also show the ability to distinguish tumors at different stages from healthy tissues via a number of highly specific lipid biomarkers, providing targets for future panels that could be useful in diagnosis.

Preventive effect of teriparatide on medication-related osteonecrosis of the jaw in rats.

This study aimed to investigate the preventive effect of teriparatide (TPD) administration on medication-related osteonecrosis of the jaw (MRONJ) before tooth extraction due to periodontal lesions in bilaterally ovariectomized female rats treated with zoledronic acid. Thirty skeletally mature Sprague-Dawley rats were randomly divided into three groups: control (CONT, n = 10), zoledronic acid (ZA, n = 10), and zoledronic acid and teriparatide (ZA-TPD, n = 10). The rats were sacrificed 8 weeks after tooth extraction. Micro-computed tomography analysis of the tibia showed that bone mineral density was highest in the CONT, followed by that in the ZA and ZA-TPD groups (CONT/ZA, p = 0.009; CONT/ZA-TPD, p < 0.001; ZA/ZA-TPD, p < 0.001). In the trabecular bone analysis of the extraction site, significant differences in specific bone surface (CONT/ZA, p = 0.010; CONT/ZA-TPD, p = 0.007; ZA/ZA-TPD, p = 0.002) and trabecular thickness (CONT/ZA-TPD, p = 0.002; ZA/ZA-TPD, p = 0.002) were observed. Histological analyses of the extraction sites revealed characteristic MRONJ lesions in the ZA group. Osteonecrosis, inflammatory cells, and sequestrum were less frequently observed in the ZA-TPD group than in the ZA group. In conclusion, TPD administration before tooth extraction helped reduce the occurrence of MRONJ in rats treated with zoledronic acid, confirming its preventative effects.

Reset-First and Multibit-Level Resistive-Switching Behavior of Lanthanum Nickel Oxide (LaNiO3-x) Thin Films.

The resistive random-access memory (RRAM) with multi-level storage capability has been considered one of the most promising emerging devices to mimic synaptic behavior and accelerate analog computations. In this study, we investigated the reset-first bipolar resistive switching (RS) and multi-level characteristics of a LaNiO3-x thin film deposited using a reactive magnetron co-sputtering method. Polycrystalline phases of LaNiO3 (LNO), without La2O3 and NiO phases, were observed at similar fractions of Ni and La at a constant partial pressure of oxygen. The relative chemical proportions of Ni3+ and Ni2+ ions in LaNiO3-x indicated that it was an oxygen-deficient LaNiO3-x thin film, exhibiting RS behavior, compared to LNO without Ni2+ ions. The TiN/LaNiO3-x/Pt devices exhibited gradual resistance changes under various DC/AC voltage sweeps and consecutive pulse modes. The nonlinearity values of the conductance, measured via constant-pulse programming, were 0.15 for potentiation and 0.35 for depression, indicating the potential of the as-fabricated devices as analog computing devices. The LaNiO3-x-based device could reach multi-level states without an electroforming step and is a promising candidate for state-of-the-art RS memory and synaptic devices for neuromorphic computing.

Seasonal effects on hydrochemistry, microbial diversity, and human health risks in radon-contaminated groundwater areas.

Groundwater is an important human resource. Daejeon in South Korea faces severe water quality issues, including radon, uranium, and fluoride pollution, all of which pose health risks to humans. With climate change, threats to potable water, such as heavy rain and typhoons, have become common. Therefore, examining the seasonal effects on groundwater quality and resultant health risks is important for understanding the mechanisms of different hydroclimatological conditions to enable the implementation of sustainable management plans in radon-contaminated groundwater areas. However, this issue has not yet been studied. To bridge this gap, in this study, major ions and microbial community structures were employed and groundwater quality index (GWQI) were calculated with hazard index based on limits set by the World Health Organization (WHO) to investigate the hydrochemical characterization and to assess pollution levels. The results showed that the rainy season had distinct hydrochemical characteristics with high correlations between radon and fluoride, and most groundwater samples collected after the typhoon had characteristics similar to those collected during the dry season, owing to the flow path. Furthermore, the microbial diversity and hazard quotient (HQ) values of fluoride revealed that pollution worsened during the dry season. All of the calculated effective dose values of radon exceeded the threshold limit set by the WHO, despite the low GWQI. Infants and children were particularly susceptible to radon-contaminated groundwater. The statistical results of self-organizing map (SOM) suggested that radon analysis was sufficient for public health intervention in the rainy season; however, in the dry season, combined analyses of radon, fluoride, and microbial diversity played important roles in health risk assessment. Our study presents a comprehensive understanding of radon-contaminated groundwater characteristics under seasonal effects and can serve as a reference for other similar zones to provide significant insights into the effective management of radon contamination.

Incidence and risk factors for pressure injury in hospitalized non-small cell lung cancer patients: A retrospective observational study.

AIM: This study aimed to identify the incidence and risk factors for pressure injury in patients hospitalized for non-small cell lung cancer (NSCLC). METHODS: This retrospective observational study was conducted in 645 adults who were hospitalized for NSCLC. Clinicopathological characteristics were compared between NSCLC patients with pressure injury and those without pressure injury. RESULTS: Among total 645 patients, 180 patients showed pressure injury with an incidence of 27.9%. Patients with pressure injury showed increased serum C-reactive protein (CRP) levels (P < 0.001), increased neutrophil-lymphocyte ratio (P = 0.002), and increased platelet-lymphocyte ratio (P = 0.001) more often. Increase in serum CRP levels at the time of admission was the major risk factor for development of pressure injury in NSCLC patients (OR = 2.20; 95% CI [1.40-3.45]; P = 0.001). Also, among major inflammatory markers, serum CRP levels at the time of admission showed weak negative correlation with the period from admission to the development of pressure injury (r = -0.216, P = 0.004). CONCLUSION: By checking serum CRP levels at the time of admission, the NSCLC patients at high risk for the development of pressure injury can be identified in advance and the occurrence of pressure injury can be reduced by applying more active preventive nursing care. CLINICAL TRIAL REGISTRATION NUMBER: KCT0006570.

Developing and Establishing a Wound Dressing Team: Experience and Recommendations.

BACKGROUND: The existing literature has comprehensively examined the benefits of specialized wound-care services and multidisciplinary team care. However, information on the development and integration of wound-dressing teams for patients who do not require specialized wound care is scarce. Therefore, the present study aimed to elucidate the benefits of a wound-dressing team by reporting our experiences with the establishment of a wound-dressing team. METHODS: The wound-dressing team was established at Korea University Guro Hospital. Between July 2018 and June 2022, 180,872 cases were managed for wounds at the wound-dressing team. The data were analyzed to assess the types of wounds and their outcomes. In addition, questionnaires assessing the satisfaction with the service were administered to patients, ward nurses, residents/internists, and team members. RESULTS: Regarding the wound type, 80,297 (45.3%) were catheter-related, while 48,036 (27.1%), 26,056 (14.7%), and 20,739 (11.7%) were pressure ulcers, dirty wounds, and simple wounds, respectively. In the satisfaction survey, the scores of the patient, ward nurse, dressing team nurse, and physician groups were 8.9, 8.1, 8.2, and 9.1, respectively. Additionally, 136 dressing-related complications (0.08%) were reported. CONCLUSION: The wound dressing team can enhance satisfaction among patients and healthcare providers with low complications. Our findings may provide a potential framework for establishing similar service models.

Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipid alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer.

Mechanistically Weighted Metric to Predict In Vivo Antibody-Receptor Occupancy: An Analytical Approach.

In situ clinical measurement of receptor occupancy (RO) is challenging, particularly for solid tumors, necessitating the use of mathematical models that predict tumor receptor occupancy to guide dose decisions. A potency metric, average free tissue target to initial target ratio (AFTIR), was previously described based on a mechanistic compartmental model and is informative for near-saturating dose regimens. However, the metric fails at clinically relevant subsaturating antibody doses, as compartmental models cannot capture the spatial heterogeneity of distribution faced by some antibodies in solid tumors. Here we employ a partial differential equation (PDE) Krogh cylinder model to simulate spatiotemporal receptor occupancy and derive an analytical solution, a mechanistically weighted global AFTIR, that can better predict receptor occupancy regardless of dosing regimen. In addition to the four key parameters previously identified, a fifth key parameter, the absolute receptor density (targets/cell), is incorporated into the mechanistic AFTIR metric. Receptor density can influence equilibrium intratumoral drug concentration relative to whether the dose is saturating or not, thereby influencing the tumor penetration depth of the antibody. We derive mechanistic RO predictions based on distinct patterns of antibody tumor penetration, presented as a global AFTIR metric guided by a Thiele Modulus and a local saturation potential (drug equivalent of binding potential for positron emissions tomography imaging) and validate the results using rigorous global and local sensitivity analysis. This generalized AFTIR serves as a more accurate analytical metric to aid clinical dose decisions and rational design of antibody-based therapeutics without the need for extensive PDE simulations. SIGNIFICANCE STATEMENT: Determining antibody-receptor occupancy (RO) is critical for dosing decisions in pharmaceutical development, but direct clinical measurement of RO is often challenging and invasive, particularly for solid tumors. Significant efforts have been made to develop mathematical models and simplified analytical metrics of RO, but these often require complex computer simulations. Here we present a mathematically rigorous but simplified analytical model to accurately predict RO across a range of affinities, doses, drug, and tumor properties.

Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study.

PURPOSE: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available. PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

[A Case of Epiploic Appendagitis after COVID-19].

Acute epiploic appendagitis is an uncommon cause of abdominal pain resulting from appendageal ischemia caused by torsion or thrombosis of the draining vein. It is frequently misdiagnosed as acute appendicitis or diverticulitis. The coronavirus disease 2019 (COVID-19) pandemic has changed how this rare disease is diagnosed. There was a report of a young men diagnosed with COVID-19 and epiploic appendagitis as a rare cause of abdominal pain. In addition, a 50-year-old men was diagnosed with epiploic appendagitis during the treatment of COVID-19. This paper reports the case of a 53-year-old men who presented with right lower quadrant abdominal pain after COVID-19 and was diagnosed with acute epiploic appendagitis by computed tomography image findings. The thrombotic condition of COVID-19 may contribute to acute appendagitis, but more studies are needed to confirm this hypothesis.

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development.

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g., optimal dose, frequency of administration, dose adjustments for special populations). This white paper is the output of an industry-government collaboration among scientists with broad experience in E-R modeling as part of regulatory submissions. The goal of this white paper is to provide guidance on what the preferred methods for E-R analysis in oncology clinical drug development are and what metrics of exposure should be considered.

Machine Learning Reveals Lipidome Remodeling Dynamics in a Mouse Model of Ovarian Cancer.

Ovarian cancer (OC) is one of the deadliest cancers affecting the female reproductive system. It may present little or no symptoms at the early stages, and typically unspecific symptoms at later stages. High-grade serous ovarian cancer (HGSC) is the subtype responsible for most ovarian cancer deaths. However, very little is known about the metabolic course of this disease, particularly in its early stages. In this longitudinal study, we examined the temporal course of serum lipidome changes using a robust HGSC mouse model and machine learning data analysis. Early progression of HGSC was marked by increased levels of phosphatidylcholines and phosphatidylethanolamines. In contrast, later stages featured more diverse lipids alterations, including fatty acids and their derivatives, triglycerides, ceramides, hexosylceramides, sphingomyelins, lysophosphatidylcholines, and phosphatidylinositols. These alterations underscored unique perturbations in cell membrane stability, proliferation, and survival during cancer development and progression, offering potential targets for early detection and prognosis of human ovarian cancer. Teaser: Time-resolved lipidome remodeling in an ovarian cancer model is studied through lipidomics and machine learning.

Ultrahigh resolution lipid mass spectrometry imaging of high-grade serous ovarian cancer mouse models.

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering that little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights into how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and triple mutant mouse models (n = 4) of high-grade serous ovarian cancer (HGSOC). Lipids belonging to a total of 15 different classes were annotated and their abundance changes were compared to those in healthy mouse reproductive tissue (n = 4), mapping onto major lipid pathways involved in OC progression. From intermediate-stage OC to advanced HGSC, we provide direct visualization of lipid distributions and their biological links to inflammatory response, cellular stress, cell proliferation, and other processes. We also show the ability to distinguish tumors at different stages from healthy tissues via a number of highly specific lipid biomarkers, providing targets for future panels that could be useful in diagnosis.

Comparison of detection performance of soft tissue calcifications using artificial intelligence in panoramic radiography.

Artificial intelligence (AI) is limited to teeth and periodontal disease in the dental field, and is used for diagnosis assistance or data analysis, and there has been no research conducted in actual clinical situations. So, we created an environment similar to actual clinical practice and conducted research by selecting three of the soft tissue diseases (carotid artery calcification, lymph node calcification, and sialolith) that are difficult for general dentists to see. Therefore, in this study, the accuracy and reading time are evaluated using panoramic images and AI. A total of 20,000 panoramic images including three diseases were used to develop and train a fast R-CNN model. To compare the performance of the developed model, two oral and maxillofacial radiologists (OMRs) and two general dentists (GDs) read 352 images, excluding the panoramic images used in development for soft tissue calcification diagnosis. On the first visit, the observers read images without AI; on the second visit, the same observers used AI to read the same image. The diagnostic accuracy and specificity for soft tissue calcification of AI were high from 0.727 to 0.926 and from 0.171 to 1.000, whereas the sensitivity for lymph node calcification and sialolith were low at 0.250 and 0.188, respectively. The reading time of AI increased in the GD group (619 to 1049) and decreased in the OMR group (1347 to 1372). In addition, reading scores increased in both groups (GD from 11.4 to 39.8 and OMR from 3.4 to 10.8). Using AI, although the detection sensitivity of sialolith and lymph node calcification was lower than that of carotid artery calcification, the total reading time of the OMR specialists was reduced and the GDs reading accuracy was improved. The AI used in this study helped to improve the diagnostic accuracy of the GD group, who were not familiar with the soft tissue calcification diagnosis, but more data sets are needed to improve the detection performance of the two diseases with low sensitivity of AI.