[Concentration of gilteritinib in the cerebrospinal fluid of a patient with relapsed FLT3-ITD positive acute myeloid leukemia with optic nerve involvement].

A 72-year-old woman with relapsed FLT3-ITD-positive acute myeloid leukemia was treated with gilteritinib and achieved complete remission with incomplete hematological recovery. However, two months later, she developed optic nerve infiltration and lost vision in her right eye while maintaining hematological remission on gilteritinib. Intrathecal injection of cytotoxic drugs reduced the number of blasts in the cerebrospinal fluid (CSF), but her vision did not recover. At the onset of optic nerve infiltration, at a dose of 80 mg/day gilteritinib, the plasma trough and CSF levels of gilteritinib were 151.9 ng/ml and 1.9 ng/ml, respectively, with a central nervous system (CNS) penetration rate of 1.3%. Hematologic progressive disease (PD) was detected after 40 days, and the patient died one month later. Target sequencing at the time of hematologic PD revealed the FLT3 F691L mutation, which is known to confer resistance to gilteritinib. In this patient, pharmacokinetic (low CNS penetration of gilteritinib) and pharmacodynamic (acquisition of a drug resistance mutation) mechanisms were thought to be responsible for the CNS relapse and hematologic PD, respectively. We believe this is a valuable case to report considering the scarcity of data on CNS penetration of FLT3 inhibitors and their effects on CNS disease in the literature.

Intrinsic impacts of the expression of PD-L1 on postoperative recurrence in EGFR-mutated lung adenocarcinoma.

Objectives: This study aimed to assess the intrinsic impacts of the expression of PD-L1 on postoperative recurrence and the prognosis in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinomas. Patients and methods: Data from 221 surgically resected pathological stage IA-IIIA lung adenocarcinomas, collected between 2017 and 2019, were analyzed. This included measurements of EGFR mutations and the PD-L1 expression. Recurrence-free survival (RFS) and overall survival (OS) were estimated using a Kaplan-Meier analysis and log-rank test. The independent risk factors for RFS were assessed using univariate and multivariate analyses. Results: Among the patients, 140 were PD-L1-negative (<1%), while 81 were PD-L1-positive (≥1%). PD-L1 positivity was significantly associated with male sex (p=0.038), smoking habit (p=0.005), ND2 lymph node dissection (p=0.013), higher malignant subtype (p=0.003), higher histological grade (p=0.001), and advanced pathological stage (p=0.004). Conversely, EGFR mutations were more common in the PD-L1-negative group than in the PD-L1-positive group (p=0.006). Patients were categorized into four groups based on their EGFR mutation status and PD-L1 expression status: PD-L1-positive (≥1%) with or without EGFR mutations (EGFR(+)/PD-L1≥1% or EGFR (-)/PD-L1≥1%), and PD-L1-negative (<1%) with or without EGFR mutations (EGFR(+)/PD-L1<1% or EGFR (-)/PD-L1<1%). Among these groups, EGFR(+)/PD-L1≥1% cases exhibited the worst 5-year RFS (log-rank, p=0.010), while there was no significant difference in 5-year OS (log-rank, p=0.122). Furthermore, a multivariate analysis revealed that PD-L1 positivity was an independent significant factor for RFS in EGFR-mutated lung adenocarcinoma (p=0.013). Conclusion: PD-L1 positivity emerged as an independent risk factor for RFS in patients with EGFR-mutant resected lung adenocarcinoma. These findings may provide valuable insights into the prognostic impact of PD-L1 expression and guide the implementation of postoperative adjuvant therapy in this patient population.

Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis.

Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male gpt delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione S-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co-expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.

Current Status and Future Perspective of Onco-Hypertension.

Hypertension and cancer are both increasing with age. Recently, the new concept of "Onco-Hypertension" has been proposed to address the mutual risks posed by hypertension and cancer and to provide comprehensive care for patients with these two conditions in an aging society. Hypertension and cancer share common risk factors and may be interrelated in pathogenesis: hypertension is involved in the development of certain cancers, and cancer survivors have a higher incidence of hypertension. With recent advances in cancer therapy, the number of cancer survivors has increased. Cancer survivors not only have a higher risk of incident hypertension but also an increased risk of future cardiovascular events, highlighting the growing importance of comprehensive care. In this review, we provide an overview of the current status and future perspective of the "Onco-Hypertension," including our research findings.

BP classification using the 2017 ACC/AHA BP guidelines with risk of cardiovascular events in older individuals.

BACKGROUND: The association between stage 1 hypertension and the risk of cardiovascular disease (CVD) has not been established in older adults. Furthermore, little is known about whether lowering blood pressure (BP) is beneficial in older adults with stage 1 hypertension. METHODS: This cohort study analyzed nationwide data collected from the Japanese DeSC database, including 476,654 individuals aged ≥60 years. Individuals were categorized into four groups according to the 2017 ACC/AHA BP guidelines: normal BP, elevated BP, stage 1 hypertension, and stage 2 hypertension. The primary outcome was a composite CVD event, including myocardial infarction, angina pectoris, stroke, and heart failure. RESULTS: During a mean follow-up of 3.1 years, 53,946 composite CVD events were recorded. Hazard ratios of stage 1 hypertension for composite CVD events, myocardial infarction, angina pectoris, stroke, and heart failure were 1.10 (95 % CI, 1.07-1.13), 1.16 (95 % CI, 1.03-1.31), 1.06 (95 % CI, 1.01-1.10), 1.13 (95 % CI, 1.08-1.18), and 1.13 (95 % CI, 1.09-1.16), respectively. Individuals with a ≥5 mmHg decrease in systolic BP over one year had a lower risk of stroke among individuals with stage 1 hypertension. The positive association between stage 1 hypertension and composite CVD events was attenuated in individuals aged ≥75 years. CONCLUSIONS: Stage 1 hypertension is associated with a higher risk of developing CVD events among older adults. The 2017 ACC/AHA BP guidelines could be applied to older populations; however, the applicability of these guidelines to older adults aged ≥75 years requires further investigations.

Differences in the Association of Lifestyle-Related Modifiable Risk Factors with Incident Cardiovascular Disease Between Individuals with and without Diabetes.

AIMS: Individuals with diabetes have a high risk of developing cardiovascular disease (CVD). Little was known whether the association between modifiable risk factors and incident CVD would change according to the presence of diabetes. METHODS: In this study, we analyzed 4,132,006 individuals including 173,262 individuals (4.2%) with diabetes registered in the JMDC Claims Database, and compared the association between modifiable risk factors and risk of CVD between individuals with and without diabetes. RESULTS: The median age was 44 years, and 57.5% were men. Multivariable Cox regression analyses showed that the relationship of obesity, hypertension, and dyslipidemia with incident CVD was attenuated in individuals with diabetes, whereas that of non-ideal eating habits, smoking, and physical inactivity with incident CVD was pronounced in those with diabetes. The hazard ratio per 1-point increase in non-ideal lifestyle-related factors was 1.03 [95% confidence interval (CI) 1.03-1.04] in individuals with non-diabetes, whereas 1.09 [95% CI 1.07-1.11] in individuals with diabetes (p-value for interaction < 0.001). Further, hazard ratios for developing CVD were 1.02 [95% 1.01-1.04] in individuals not having diabetes, whereas 1.09 [95% CI 1.04-1.13] in individuals having diabetes for the increase of lifestyle-related factor after 1-year follow-up (p-value for interaction 0.007). CONCLUSION: Our analysis utilizing a nationwide epidemiological dataset presented that the relationship of lifestyle-related factors with incident CVD would be pronounced in people having diabetes, suggesting that the maintenance of a healthy lifestyle would play a more important role in the development of CVD in individuals having diabetes. (244 words).

Our investigation utilizing a nationwide epidemiological cohort showed a pronounced relationship of lifestyle-related factors with incident CVD in individuals with diabetes. The HRs (95% CI) for the occurrence of CVD events showed a progressive increase with each additional lifestyle-related factor. This trend was more prominent among individuals with diabetes than those without diabetes. The association between changes in the number of lifestyle-related factors over a year and the risk of developing CVD was also more pronounced in individuals with diabetes. These results suggest that maintaining healthy lifestyle habits would be more important for the CVD prevention in individuals having diabetes.

Kidney outcomes with SGLT2 inhibitor vs. DPP4 inhibitor use in older adults with diabetes.

BACKGROUND AND HYPOTHESIS: While the kidney protective effects of sodium glucose co-transporter-2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes. METHODS: Using a nationwide claims database, we studied 6 354 older adults (≥ 60 years of age) who had diabetes and newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in eGFR between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decline in the rate of estimated glomerular filtration rate (eGFR), which was obtained using a linear mixed-effects model with an unstructured covariance. RESULTS: Following propensity score matching, 6 354 individuals including 1 271 SGLT2 inhibitor users and 5 083 DPP4 inhibitor users (median age: 68 [65-70] years); men, 60.4%; median eGFR:69.0 [59.1-79.0] ml/min/1.73 m2, median hemoglobin A1c [HbA1c]:6.9 [6.5-7.4]%) were analyzed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users (-0.97 [95% CI, -1.24 to -0.70] ml/min/1.73m2 vs. -1.83 [95% CI, -1.97 to -1.69] ml/min/1.73m2 per year; p for interaction < 0.001). This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use, and baseline eGFR. Additionally, the risk of a ≥ 20%, ≥ 30%, and ≥ 40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than that in DPP4 inhibitor users. CONCLUSIONS: Our analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decline in eGFR was slower in individuals aged ≥ 60 years with diabetes who were prescribed SGLT2 inhibitors compared to those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

Body weight change associated kidney outcomes of sodium-glucose cotransporter new users.

AIM: To investigate the clinical significance of body weight changes on kidney outcomes among individuals with diabetes using sodium-glucose cotransporter-2 (SGLT2) inhibitors. MATERIALS AND METHODS: This is a retrospective cohort study using a nationwide epidemiological database, and we conducted an analysis involving 11 569 individuals with diabetes who were newly prescribed SGLT2 inhibitors. The main outcome was the rate of decline in estimated glomerular filtration rate (eGFR), determined through a linear mixed-effects model with an unstructured covariance structure. RESULTS: The median age of the patients was 52 (Q1-Q3: 47-58) years, and the median fasting plasma glucose and glycated haemoglobin (HbA1c) levels were 144 (Q1-Q3: 124-175) mg/dL and 7.4 (Q1-Q3: 6.8-8.3)%, respectively. The median estimated eGFR was 77.7 (Q1-Q3: 67.2-89.1) mL/min/1.73 m2. The median follow-up period was 1.7 (Q1-Q3: 1.0-2.6) years. Participants were stratified into three groups based on the body mass index change rate tertiles between baseline and 1 year after (tertile 1: <-4.55%, tertile 2: -4.55% to -1.43%, tertile 3: >-1.43%). The annual change in eGFR was -0.78 (-0.94 to -0.63) mL/min/1.73 m2 in tertile 1, -0.95 (-1.09 to -0.81) mL/min/1.73 m2 in tertile 2, and -1.65 mL/min/1.73 m2 (-1.84 to -1.47) in tertile 3 (pinteraction < 0.001). A variety of sensitivity analyses confirmed the relationship between the 1-year body mass index decrease and favourable kidney outcomes after SGLT2 inhibitor administration. CONCLUSIONS: Our analysis of a nationwide epidemiological cohort revealed that kidney outcomes following the initiation of SGLT2 inhibitors would be more favourable, with greater body weight loss observed after the initiation of SGLT2 inhibitors.

Understanding the Manufacturing Process of Lipid Nanoparticles for mRNA Delivery Using Machine Learning.

Lipid nanoparticles (LNPs), used for mRNA vaccines against severe acute respiratory syndrome coronavirus 2, protect mRNA and deliver it into cells, making them an essential delivery technology for RNA medicine. The LNPs manufacturing process consists of two steps, the upstream process of preparing LNPs and the downstream process of removing ethyl alcohol (EtOH) and exchanging buffers. Generally, a microfluidic device is used in the upstream process, and a dialysis membrane is used in the downstream process. However, there are many parameters in the upstream and downstream processes, and it is difficult to determine the effects of variations in the manufacturing parameters on the quality of the LNPs and establish a manufacturing process to obtain high-quality LNPs. This study focused on manufacturing mRNA-LNPs using a microfluidic device. Extreme gradient boosting (XGBoost), which is a machine learning technique, identified EtOH concentration (flow rate ratio), buffer pH, and total flow rate as the process parameters that significantly affected the particle size and encapsulation efficiency. Based on these results, we derived the manufacturing conditions for different particle sizes (approximately 80 and 200 nm) of LNPs using Bayesian optimization. In addition, the particle size of the LNPs significantly affected the protein expression level of mRNA in cells. The findings of this study are expected to provide useful information that will enable the rapid and efficient development of mRNA-LNPs manufacturing processes using microfluidic devices.

Serum interleukin-6 levels at the start of the second course of atezolizumab plus bevacizumab therapy predict therapeutic efficacy in patients with advanced hepatocellular carcinoma: a multicenter analysis.

BACKGROUND AND AIM: Serum interleukin-6 (IL-6) before the administration of atezolizumab plus bevacizumab (Atez + Bev) is a prognostic biomarker in patients with hepatocellular carcinoma (HCC) treated with Atez + Bev. We previously revealed that the neutrophil-to-lymphocyte ratio and serum chemokine levels during treatment with Atez + Bev were more useful as prognostic biomarkers. Therefore, we examined the predictive ability of serum IL-6 for the efficacy of Atez + Bev in patients with HCC. METHODS: We enrolled 94 patients with HCC who received treatment with Atez + Bev. Initial responses were assessed through dynamic computed tomography or magnetic resonance imaging. The levels of IL-6 in serum were measured before and at the initiation of the second course of Atez + Bev. Subsequently, the relationship of IL-6 levels with treatment efficacy was evaluated. RESULTS: IL-6 levels at the initiation of the second course tended to be higher in patients with progressive disease versus those with non-progressive disease in the initial evaluation (P = 0.054). Moreover, the cutoff value (7.4 pg/mL) was useful in stratifying patients by overall survival (i.e. low vs high: not reached vs 21.4 months, respectively, P = 0.001) and progression-free survival (low vs high: 11.9 vs 5.2 months, respectively, P = 0.004). This result was reproduced in patients with HCC who received Atez + Bev as first-line therapy. In the multivariate analyses, IL-6 levels at the initiation of the second course were independent predictive factors for progression-free and overall survival. CONCLUSIONS: Serum levels of IL-6 at the initiation of the second course of treatment may predict Atez + Bev efficacy and prognosis in HCC.

Age-Dependent Relationship of Physical Inactivity With Incident Cardiovascular Disease: Analysis of a Large Japanese Cohort.

BACKGROUND: There have been limited studies examining age-dependent associations between physical inactivity and cardiovascular disease (CVD). We aimed to clarify the age-dependent relationship of physical inactivity with incident CVD. METHODS: We analyzed 1,097,424 participants, aged 18 to 105 years, without histories of CVD, enrolled in the DeSC database (median age, 63 years; 46.4% men). We categorized participants into the following 4 groups based on age: ≤ 44 years (n = 203,835); 45 to 64 years (n = 403,619); 65 to 79 years (n = 437,236); and ≥ 80 years (n = 52,734). We used 3 physical inactivity components gained from the self-reported questionnaire during a health checkup. The outcomes were composite CVD events including myocardial infarction, stroke, heart failure, and each CVD event. RESULTS: During a mean follow-up of 3.2 ± 1.9 years, 81,649 CVD events were observed. The hazard ratios of 3 physical inactivity components for CVD events increased with age category (P for interaction < 0.001). For example, the hazard ratio (95% confidence interval) of physical inactivity defined as not doing light sweaty exercise for 30 minutes at least twice a week for incident CVD in the groups aged ≤ 44 years, 45 to 64 years, 65 to 79 years, and ≥ 80 years were 0.97 (0.88-1.05), 1.08 (1.05-1.12), 1.12 (1.10-1.15), and 1.17 (1.12-1.21), respectively (P for interaction < 0.001). This association was consistent across subtypes of CVD including heart failure, myocardial infarction, and stroke. CONCLUSIONS: The association of physical inactivity with a higher risk of developing CVD increased with age. Preventive efforts for physical activity optimization may be more valuable in older people.

Chronic Tonsillitis and IgA Nephropathy: Findings From a Nationwide Japanese Cohort Study.

RATIONALE & OBJECTIVE: Little is known regarding the association between chronic tonsillitis and the onset of IgA nephropathy (IgAN). In the present study, we examined the potential relationship between chronic tonsillitis and a subsequent risk of developing IgAN. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 4,311,393 individuals without a history of IgAN identified between January 2005 and May 2022 within a Japanese nationwide epidemiological database, the JMDC Claims Database, representing health claims to over 60 insurers. EXPOSURE: Comorbid chronic tonsillitis based on diagnosis codes. OUTCOME: IgAN occurrence. ANALYTICAL APPROACH: Cause-specific Cox proportional hazards analysis adjusting for potential confounding factors was employed to estimate hazard ratios (HRs). RESULTS: Comorbid chronic tonsillitis was identified in 12,842 individuals, constituting 0.3% of the cohort. The cohort had a median age of 44 years (IQR, 36-53), and males accounted for 57.9%, with a follow-up of 1,089 days (IQR, 532-1,797), during which 2,653 cases of IgAN developed. Cumulative incidence curve showed a higher cumulative incidence of IgAN in individuals with chronic tonsillitis compared with their counterparts without this condition. Multivariable cause-specific analysis further demonstrated that individuals with chronic tonsillitis had an elevated risk of developing IgAN, with HR of 2.72 (95% CI, 1.79-4.14). LIMITATIONS: Potential residual confounders, and lack of consideration for ethnic distinctions. CONCLUSIONS: Using a large-scale epidemiological dataset, these findings suggest a relationship between chronic tonsillitis and an elevated risk of IgAN development in the general Japanese population. PLAIN-LANGUAGE SUMMARY: IgA nephropathy (IgAN), the most prevalent form of primary glomerulonephritis worldwide, is associated with unfavorable long-term kidney survival and life expectancy. Despite the substantial implications, the early detection of IgAN still remains challenging due to its commonly asymptomatic clinical presentation. Consequently, the exploration of risk factors assumes a critical research priority. Prior studies have reported the potential role of tonsilitis in the pathogenesis of IgAN. In this study, we assessed whether chronic tonsillitis was associated with the subsequent development of IgAN using a nationwide epidemiological dataset incorporating over 4,000,000 individuals. Within this large-scale cohort, our findings revealed an association between a history of tonsillitis and a greater risk of developing IgAN. These findings should heighten awareness of the potential susceptibility of people with chronic tonsilitis to IgAN.

Significance of eGFR and proteinuria for cardiovascular disease in individuals beyond 85 years.

BACKGROUND: There are limited data on how advancing age influences prediction of CVD risk based on the estimated glomerular filtration rate (eGFR) and proteinuria, especially in older adults, including those aged ≥ 85 years. This study aimed to clarify the association of eGFR and proteinuria with CVD outcomes and the impact of age on this association. METHODS: The distribution of eGFR and urine protein in Japan was assessed retrospectively using real-world administrative claims and health checkup data collected between April 2014 and November 2022. We investigated the associations of these two parameters with the incidence of CVD, with an emphasis on the impact of aging. RESULTS: We assessed 1 829 020 individuals for distribution of eGFR and proteinuria; after excluding those with known CVD, their association with CVD risk was examined in 1 040 101 individuals aged ≥ 40 years. The prevalence of impaired kidney function (eGFR <60 mL/min/1.73 m2) increased with age, being 0.7%, 9.2%, 21.9%, 40.2%, and 60.2% at the ages of 18-39, 40-64, 65-74, 75-84, and ≥ 85 years (P for trend < 0.001); similarly, the proportion with positive proteinuria increased with age, being 2.7%, 4.3%, 5.6%, 9.2%, and 15.8%, respectively (P for trend < 0.001). Both eGFR and urine protein were identified to be independent risk factors for CVD. Hazard ratios for CVD increased significantly when eGFR was <45 mL/min/1.73 m2 at the ages of 40-64, 65-74, and 75-84 and <30 mL/min/1.73 m2 at ≥ 85 years, while proteinuria remained significantly associated with a high CVD risk regardless of age. These findings were consistent even when analyzed separately by sex. CONCLUSIONS: This study identified eGFR and urine dipstick proteinuria to be independent risk factors for CVD, even among individuals aged ≥ 85 years. However, the contribution of eGFR to the CVD risk was attenuated by aging, whereas proteinuria remained less affected by advancing age.

Relationship between the Thermodynamic Quantities and Coordination Structure of Oxide Ions in CaCl2-Based Chloride Melts.

Measuring the thermodynamic quantities and coordination structure of oxide ions in CaCl2-based melts is essential for comprehensively understanding the relationship between the thermodynamic and microscopic behaviors of high-temperature molten salts. In this study, the standard formal chemical potentials of oxide ion, µO2- o', and activity coefficient, γO2- , in NaCl-CaCl2, NaCl-KCl-CaCl2, and LiCl-KCl-CaCl2 melts at 873 K, were evaluated by measuring the dependence of potential of O2/O2- on the oxygen partial pressure by using non-consumable ceramic electrodes; the µO2- o' was -527 ± 0.3, - 535 ± 0.1, and -538 ± 0.2 kJ mol-1 and the γO2- was 0.10, 0.30, and 0.45 for each melt. In addition, the coordination structure of oxide ions in each melt was investigated by combining high-temperature Raman spectroscopy and density functional theory calculations. The coordination structures of oxide ions were identified as [NaO2]3- and [CaOCl3]3- in the NaCl-CaCl2 melt, [CaOCl2]2- in the NaCl-KCl-CaCl2 melt, and [LiCaO]+ and [Li3KO]2+ in the LiCl-KCl-CaCl2 melt, revealing that the stable structure was significantly different depending on the melt composition. The activity coefficients showed a tendency to depend on the nearest-neighbor cation coordinated with the oxide ion. The reported data will provide insights into the physicochemical properties of high-temperature melts and contribute to controlling the compatibility of materials and melts in pyrochemical engineering processes.

Integration of Computational Pipeline to Streamline Efficacious Drug Nomination and Biomarker Discovery in Glioblastoma.

Glioblastoma multiforme (GBM) is the deadliest, most heterogeneous, and most common brain cancer in adults. Not only is there an urgent need to identify efficacious therapeutics, but there is also a great need to pair these therapeutics with biomarkers that can help tailor treatment to the right patient populations. We built patient drug response models by integrating patient tumor transcriptome data with high-throughput cell line drug screening data as well as Bayesian networks to infer relationships between patient gene expression and drug response. Through these discovery pipelines, we identified agents of interest for GBM to be effective across five independent patient cohorts and in a mouse avatar model: among them are a number of MEK inhibitors (MEKis). We also predicted phosphoglycerate dehydrogenase enzyme (PHGDH) gene expression levels to be causally associated with MEKi efficacy, where knockdown of this gene increased tumor sensitivity to MEKi and overexpression led to MEKi resistance. Overall, our work demonstrated the power of integrating computational approaches. In doing so, we quickly nominated several drugs with varying known mechanisms of action that can efficaciously target GBM. By simultaneously identifying biomarkers with these drugs, we also provide tools to select the right patient populations for subsequent evaluation.

The Current Achievements of Multi-Gene Panel Tests in Clinical Settings for Patients with Non-Small-Cell Lung Cancer.

Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings.

A polygenic score method boosted by non-additive models.

Dominance heritability in complex traits has received increasing recognition. However, most polygenic score (PGS) approaches do not incorporate non-additive effects. Here, we present GenoBoost, a flexible PGS modeling framework capable of considering both additive and non-additive effects, specifically focusing on genetic dominance. Building on statistical boosting theory, we derive provably optimal GenoBoost scores and provide its efficient implementation for analyzing large-scale cohorts. We benchmark it against seven commonly used PGS methods and demonstrate its competitive predictive performance. GenoBoost is ranked the best for four traits and second-best for three traits among twelve tested disease outcomes in UK Biobank. We reveal that GenoBoost improves prediction for autoimmune diseases by incorporating non-additive effects localized in the MHC locus and, more broadly, works best in less polygenic traits. We further demonstrate that GenoBoost can infer the mode of genetic inheritance without requiring prior knowledge. For example, GenoBoost finds non-zero genetic dominance effects for 602 of 900 selected genetic variants, resulting in 2.5% improvements in predicting psoriasis cases. Lastly, we show that GenoBoost can prioritize genetic loci with genetic dominance not previously reported in the GWAS catalog. Our results highlight the increased accuracy and biological insights from incorporating non-additive effects in PGS models.

Change in Body Mass Index and Cardiovascular Outcomes in Patients With Cancer.

OBJECTIVE: To investigate the association between body mass index (BMI) changes and the risk of cardiovascular disease (CVD) in patients with cancer. PATIENTS AND METHODS: This retrospective observational study used data from the JMDC Claims Database obtained between January 2005, and April 2021. We included 52,344 individuals (median [IQR] age, 53 years [46 to 60 years]; 23,584 [45.1%] men) with cancer and no prior CVD. Patients were classified into 3 groups based on the percentage change in BMI from the initial health checkup to the checkup 1 year later: -5.0% or less (BMI loss), -5.0% to 5.0% (stable BMI), and 5.0% or more (BMI gain). The primary end point was composite CVD events including heart failure, atrial fibrillation, ischemic heart disease, and stroke. RESULTS: During a median follow-up period of 763 days (IQR, 369 to 1274 days), 3124 composite CVD events were observed. Compared with stable BMI, the hazard ratios (HRs) of BMI loss and gain for CVD events were 1.16 (95% CI, 1.00 to 1.34) and 1.10 (95% CI, 0.96 to 1.25), respectively. A U-shaped association was observed between the BMI changes and CVD events, particularly for nonatherosclerotic CVD outcomes including heart failure and atrial fibrillation. Compared with stable BMI, both BMI loss and gain increased the risk of heart failure (HR, 1.30; 95% CI, 1.08 to 1.57 and HR, 1.22; 95% CI, 1.02 to 1.47, respectively) and atrial fibrillation (HR, 1.70; 95% CI, 1.18 to 2.45 and HR, 1.55; 95% CI, 1.07 to 2.24, respectively). CONCLUSION: Cancer survivors with BMI loss and gain were at greater risk of CVD. Body mass index loss is associated with a higher risk of CVD.