A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7 days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 120 mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150 mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80 mg/m2; oxaliplatin, 85 mg/m2; and irinotecan, 150 mg/m2).

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Stratified choroidal vascular structure in treatment-naïve diabetic retinopathy.

OBJECTIVE: To analyze the anatomical choroidal vascular layers in topical treatment-naïve diabetic retinopathy (DR) eyes. DESIGN: A retrospective, clinical case-control study. METHODS: A total of 328 eyes from 228 patients with treatment-naive DR and 192 eyes matched for axial length from 174 healthy controls were enrolled in the study. Choroidal structure was quantitatively analyzed using enhanced depth imaging optical coherence tomography (EDI-OCT). Each choroidal vascular layer was divided into the choriocapillaris, Sattler's layer, and Haller's layer, and then the choroidal area (CA), luminal area (LA), stromal area (SA), and central choroidal thickness (CCT) were calculated using binarization techniques. The ratio of LA to CA was defined as the L/C ratio. RESULTS: In the choriocapillaris, CA was significantly lower in the mild/moderate non-proliferative DR (mNPDR) group than in the control group, and SA was significantly higher in all DR groups (each P < 0.01). The L/C ratio was significantly lower in all DR groups than controls (P < 0.01). In Sattler's layer, CA, LA, and SA were significantly higher in the severe NPDR (sNPDR) and PDR groups than in the control group (P < 0.01). In Haller's layer, the L/C ratio was significantly high among the PDR groups (P < 0.05). CONCLUSIONS: The choroidal parameters of DR patients by the binarization method were associated with the stage of DR, in which the choriocapillaris lumen decreased in all the DR stages. The expansion of CA seen in more advanced DR eyes mainly resulted from changes in the Sattler's and Haller's layers.

Mechanism of Stent Failure in Patients with Eruptive Calcified Nodule Treated with Rotational Atherectomy.

BACKGROUND: Percutaneous coronary intervention (PCI) for lesions with eruptive calcified nodules (CNs) is associated with worse outcomes compared with that for other calcified lesions. We aimed to clarify the relationship between eruptive CNs at index PCI, optical coherence tomography (OCT) findings at the 8-month follow-up, and clinical outcomes using serial OCT. METHODS: This retrospective observational study utilized data from a prospective, single-center registry. We conducted consecutive PCI for calcified lesions requiring rotational atherectomy (RA) with OCT guidance. We categorized 51 patients (54 lesions) into those with (16 patients [16 lesions]) and without eruptive CNs (35 patients [38 lesions]). RESULTS: Post-PCI, stent expansion was comparable between the two groups, and CN-like protrusion was found in 75% of lesions with eruptive CNs. Follow-up OCT at 8 months revealed in-stent CNs in 54% of treated eruptive CN lesions, whereas lesions without eruptive CNs lacked in-stent CNs. Multivariate linear regression analysis demonstrated that eruptive CN was associated with maximum neointimal tissue (NIT) thickness (regression coefficient 0.303; 95% confidence interval: 0.057-0.549, p=0.02). Consequently, patients with eruptive CNs exhibited a higher clinically-driven target lesion revascularization (TLR) rate than did those without at 1 year (31.3% vs. 2.9%, p=0.009) and 5 years (43.8% vs. 11.4%, p=0.02). TLR primarily occurred in lesions with maximum eruptive CN arc angles>180°. CONCLUSIONS: Following RA treatment with acceptable stent expansion, eruptive CNs before PCI correlated with greater NIT formation with in-stent CNs, resulting in a higher TLR rate, particularly in lesions with maximum eruptive CN arc angles exceeding 180°.

Risedronate-Induced Chronic Drug Fever in a Case of Parkinson's Disease.

We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had been administered an analgesic/antipyretic drug, acetaminophen, at a rate of 600 mg/day for treatment of a vertebral fracture that occurred relatively frequently, which might have masked the fever caused by risedronate. We noted two clinically significant indications. Firstly, blood test results do not necessarily show the cause of risedronate-induced fever, as white blood cell counts and C-reactive protein levels vary. A simple way to diagnose risedronate-induced fever is to suspend risedronate for a certain period and observe if the patient's fever lowers. Secondly, in general, cases receiving polypharmacy tend to include an analgesic antipyretic agent, which may mask the drug-induced fever. Even in patients with Parkinson's disease whose body temperature is generally unstable due to autonomic nerve system disorder, if they are administered risedronate and experience chronic fever of unknown cause, the possibility of drug fever may be considered. This study concludes that risedronate-induced chronic fever, as observed in our case, represents a rare phenomenon, and it may be necessary to reconsider treatment methods for osteoporosis.

Combination of crystal growth with optical floating zone and evaluation of Nd3+:LaAlO3 crystals with the dynamic nuclear polarization of 139La and 27Al.

Producing a polarized lanthanum (La) target with high polarization and long relaxation time is crucial for realizing time-reversal violation experiments using polarized neutron beams. We use a LaAlO3 crystal doped with a small amount of Nd3+ ions for the polarized lanthanum target. Optimizing the amount of Nd3+ ions is considerably important because the achievable polarization and relaxation time strongly depend on this amount. We established a fundamental method to grow single crystals of Nd3+:LaAlO3 using an optical floating zone method that employs halogen lamps and evaluated the crystals with the dynamic nuclear polarization (DNP) method for polarizing nuclear spins. Two crystal samples were grown by ourselves and evaluated with the DNP at 1.3 K and 2.3 T for the first time, except for the target materials of protons. The enhancement of nuclear magnetic resonance signals for 139La and 27Al was successfully observed, and the enhancement factors were eventually 3.5 ± 0.3 and 13 ± 3 for the samples with Nd3+ ions of 0.05 and 0.01 mol. %, respectively. These enhancement factors correspond to absolute vector polarizations of 0.27% ± 0.02% (Nd3+ 0.05 mol. %) and 1.4% ± 0.3% (Nd3+ 0.01 mol. %). Although the obtained polarizations are still low, they are acceptable as a first step. The combination scheme of the crystal growth and the evaluation of the crystals is found to be effectively applicable for optimizing the amount of Nd3+ ions for improving the performance of the polarized target.

Synaptic proteomics decode novel molecular landscape in the brain.

Synapses play a pivotal role in forming neural circuits, with critical implications for brain functions such as learning, memory, and emotions. Several advances in synaptic research have demonstrated the diversity of synaptic structure and function, which can form thousands of connections depending on the neuronal cell types. Moreover, synapses not only interconnect neurons but also establish connections with glial cells such as astrocytes, which play a key role in the architecture and function of neuronal circuits in the brain. Emerging evidence suggests that dysfunction of synaptic proteins contributes to a variety of neurological and psychiatric disorders. Therefore, it is crucial to determine the molecular networks within synapses in various neuronal cell types to gain a deeper understanding of how the nervous system regulates brain function. Recent advances in synaptic proteome approaches, such as fluorescence-activated synaptosome sorting (FASS) and proximity labeling, have allowed for a detailed and spatial analysis of many cell-type-specific synaptic molecules in vivo. In this brief review, we highlight these novel spatial proteomic approaches and discuss the regulation of synaptic formation and function in the brain. This knowledge of molecular networks provides new insight into the understanding of many neurological and psychiatric disorders.

Clinical course and genetic analysis of a case of the amniocentesis showing chromosome 6 trisomy mosaicism.

OBJECTIVE: Herein, we present a case of mosaic trisomy 6 detected by amniocentesis. CASE REPORT: Amniocentesis (G-banding) was performed at 17 weeks of gestation; the results were 47,XY,+6[3]/46,XY[12]. Fetal screening ultrasonography showed no morphological abnormalities, and the parents desired to continue the pregnancy. The infant was delivered vaginally at 39 weeks' gestation. The male infant weighed 3002 g at birth with no morphological abnormalities. G-banding karyotype analysis performed on the infant's peripheral blood revealed 46,XY[20]. FISH analysis revealed trisomy signals on chromosome 6 in 1-4 out of 100 cells from the placenta. The single nucleotide polymorphism microarray of the umbilical cord blood revealed no abnormalities. Methylation analysis of umbilical cord blood revealed no abnormalities in PLAGL1. No disorders were observed at one year of age. CONCLUSION: When amniocentesis reveals chromosomal mosaicism, it is essential to provide a thorough fetal ultrasound examination and careful genetic counseling to support the couples' decision-making.

Rituximab and pericardiectomy with waffle procedure in constrictive pericarditis due to IgG4-related disease: A case report.

We should consider IgG4-related disease (IGRD) as one of the potential causes of constrictive pericarditis. In patients with constrictive pericarditis due to IGRD, the combination of surgical treatment and immunosuppressive therapy may be an effective strategy.

Relationship between texture perception and oral function: A preliminary study in young, healthy adults.

BACKGROUND: Oral frailty, characterised by reduced oral function, is associated with systemic health issues in older adults. Although the criteria for diminished oral function often focus on motor and secretory abilities, texture perception also plays a crucial role in health due to its impact on food intake and palatability. OBJECTIVE: This study aimed to explore the relationship between thickness discrimination ability (TDA) and oral motor and secretory functions in healthy young individuals. METHODS: Twenty-eight adults were assessed for texture perception using eight concentrations of aqueous xanthan gum solutions to determine TDA scores. Measurements of occlusal force, masticatory performance, tongue pressure, stimulated salivary flow rate and tongue-lip motor function were conducted. Spearman's correlation analysis was used to evaluate the relationship between TDA scores and oral functions. Participants were divided into high-sensitivity and low-sensitivity groups based on their TDA scores to compare oral function test results. RESULTS: The TDA scores varied among the participants, with higher scores correlating with higher masticatory performance (r = 0.41, p < .05). Masticatory performance in the high-sensitivity group was significantly higher than in the low-sensitivity group (211.9 ± 59.2 mg/dL vs. 157.9 ± 43.0 mg/dL, p = .013), with no significant differences in other oral functions. CONCLUSION: Masticatory performance was correlated with TDA, suggesting a link between the selection function of mastication and thickness discrimination. These findings highlight the potential relevance of texture perception in oral function and indicate the need for further exploration, particularly in older adults with declining oral health.

Rhodium-catalysed additive-free alkoxycarbonylation of indoles: 2,4,6-trimethylbenzoic acid-based carbonate anhydrides as a versatile alkoxycarboxyl source.

We report a CO-free approach to indole-2-carboxylic esters: rhodium-catalysed C(2)-alkoxycarbonylation of indoles with 2,4,6-trimethylbenzoic acid-based carbonate anhydrides. Selective C-O bond cleavage of the anhydrides facilitates the introduction of various alkoxycarbonyl groups. Control experiments suggest that merging a rhodium catalyst and KI promotes the in situ formation of the RhI species.

Morphogenesis of a chiral liquid crystalline droplet with topological reconnection and Lehmann rotation.

Morphogenesis is a hierarchical phenomenon that produces various macroscopic structures in living organisms, with high reproducibility. This study demonstrates that such structural formation can also be observed in a chiral liquid crystalline droplet under a temperature gradient. Through specific control of the temperature change process, we were able to switch the final structure obtained as a result of the formation via the appearance and reconnection of loop defects in the transient state during structure formation. Simultaneously, the existence of the gradient resulted in a characteristic rotational phenomenon called Lehmann rotation, which was prominently induced in the transient state. By demonstrating three-dimensional measurements of the flow field, we revealed the existence of Marangoni convection in the state. Consequently, it is indicated that the convection results in high-speed Lehmann rotation and large structural deformation with topological changes, thereby playing a significant role in the structure formation.

Loeys-Dietz syndrome with a novel in-frame SMAD3 deletion diagnosed as a result of postpartum aortic dissection: A case report.

OBJECTIVE: Loeys-Dietz syndrome (LDS) is a rare, autosomal dominant connective tissue disorder which can aggressively affect the aortic vasculature. Limited information is available regarding its impact on pregnancy and postpartum outcomes. CASE REPORT: A pregnant 38-year-old nulliparous woman with mild aortic regurgitation and family history of aortic aneurysms presented with an aortic root measuring 49 mm. Despite concerns of an underlying connective tissue disorder, a definitive diagnosis was not reached. She delivered under strict blood pressure control, developed intractable uterine atony, and underwent uterine artery embolization. On the second postpartum day, aortic dissection was incidentally diagnosed, and aortic root replacement surgery was performed. Genetic testing revealed a novel in-frame SMAD3 deletion [NM_005902.4: c.703_708del, (p.Ile235_Ser236del)], leading to a diagnosis of LDS type 3. CONCLUSION: This case highlights the high postpartum aortic dissection risk in women with LDS, emphasizing the importance of early diagnosis in pregnant women with few clinical symptoms.

Effects of continuous supplementation of Acanthopanax senticosus Harms on the cardiac autonomic function of community-dwelling elderly individuals during resting and standing tests: a randomized controlled trial.

Background: Cardiac autonomic function (CAF) decreases with aging, and Acanthopanax senticosus Harms (ASH) consumption reportedly induces anti-stress effects. This study aimed to assess the effect of continuous supplementation of ASH on CAF during resting and standing tests in the elderly population. Methods: This double-blind, randomized controlled trial was conducted in the morning in a laboratory setting and was carried out between June 2017 and July 2017 at Kambaikan, Doshisha University (Karasuma-higashi-iru, Imadegawa-dori, Kamigyo-ku, Kyoto 602-8580, Japan). In total, 28 community-dwelling elderly individuals (mean ± standard deviation = 72.5 ± 4.5 years) were included. Each subject was instructed to consume ASH or placebo supplements twice daily for 4 weeks. An autonomic reflex orthostatic tolerance recorder was used to measure CAF in pre- and post-intervention phases. Parameters were measured in a seated position and included coefficient of variation of R-R intervals (CVRR), low frequency (LF), high frequency (HF), LF/HF ratio, blood pressure, and heart rate (HR). Changes in each parameter were evaluated before and after standing. All parameters were defined as the difference between the mean value obtained in a standing position for 2 min and that obtained in a 2-min seated position. Results: A two-way analysis of variance revealed a significant group-time interaction effect on CVRR, HF, and ΔLF/HF ratio. Following the intervention, CVRR, HF, LF/HF ratio, systolic blood pressure (SBP), HR, ΔLF/HF ratio, ΔSBP, and ΔHR improved significantly in the ASH group only. Conclusions: Four-week supplementation of ASH improved CAF in community-dwelling elderly individuals during resting and standing tests. Clinical Trial Registration: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000031218, UMIN Clinical Trials Registry (UMIN000027251).

Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways.

BACKGROUND: Advanced gastric cancer (GC) has a poor prognosis. This study aimed to identify novel GC-related genes as potential therapeutic targets. METHODS: Killer cell lectin-like receptor G2 (KLRG2) was identified as a candidate gene by transcriptome analysis of metastatic GC tissues. Small interfering RNA-mediated KLRG2 knockdown in human GC cell lines was used to investigate KLRG2 involvement in signaling pathways and functional behaviors in vitro and in vivo. Clinicopathological data were analyzed in patients stratified according to tumor KLRG2 mRNA expression. RESULTS: KLRG2 knockdown in GC cells decreased cell proliferation, migration, and invasion; caused cell cycle arrest in G2/M phase; induced apoptosis via caspase activation; suppressed JAK/STAT and MAPK-ERK1/2 pathway activities; and upregulated p53 and p38 MAPK activities. In mouse xenograft models of peritoneal metastasis, the number and weight of disseminated GC nodules were decreased by KLRG2 knockdown. High tumor levels of KLRG2 mRNA were significantly associated with lower 5-year overall survival (OS) and relapse-free survival (RFS) rates in patients with Stage I-III GC (5-year OS rate: 64.4% vs. 80.0%, P = 0.009; 5-year RFS rate: 62.8% vs. 78.1%, P = 0.030). CONCLUSIONS: KLRG2 knockdown attenuated the malignant phenotypes of GC cells via downregulation of JAK/STAT and MAPK-ERK1/2 pathway activity and upregulation of p38 MAPK and p53. Targeted suppression of KLRG2 may serve as a new treatment approach for GC.

Effects of age and axial length on choroidal stratified structure in normal eyes.

To quantify the choroidal structures of normal eyes by optical coherence tomography (OCT)-based binarization and evaluate the relationships among age, refractive power, and ocular axial length. This was a retrospective observational study. One hundred and eighty nine eyes of 189 subjects without ocular diseases were examined by enhanced depth imaging (EDI)-OCT. A choroidal OCT horizontal image with a width of 1500 µm centered on the fovea was binarized. The lumen, stroma, and total choroidal area in the choriocapillaris (CC), Sattler's layer (SL), and Haller's layer (HL) were measured, and the ratio of the luminal area to total choroidal area (L/C ratio) was calculated. Multiple regression analysis was performed for choroidal parameters in each choroidal layer and for age, refractive power, and ocular axial length. Multiple regression analysis showed that an older age was significantly correlated with a lower choroidal area and the L/C ratio in all choroidal layers (each P < 0.05). A Long axial length was significantly associated with lower SL and HL (P < 0.05), but not with refractive power. In the choroid of normal eyes, age-related decreases in the choroidal area and L/C ratio were associated with all choroidal layers, and elongation of the axial length was associated with thinning of SL and HL.

Prevalence of Non-alcoholic Fatty Liver Disease Detected by Computed Tomography in the General Population Compared with Ultrasonography.

Objective To assess the prevalence and clinical correlates of non-alcoholic fatty liver disease (NAFLD) identified by computed tomography (CT) in the general population compared with ultrasonography (US). Methods Four hundred and fifty-eight subjects who received health checkups at Meijo Hospital in 2021 and underwent CT within a year of US in the past decade were analyzed. The mean age was 52.3±10.1 years old, and 304 were men. Results NAFLD was diagnosed in 20.3% by CT and in 40.4% by the US. The NAFLD prevalence in men was considerably greater in subjects 40-59 years old than in those ≤39 years old and in those ≥60 years old by both CT and US. The NAFLD prevalence in women was substantially higher in the subjects 50-59 years old than in those ≤49 years old or those ≥60 years old on US, while no significant differences were observed on CT. The abdominal circumference, hemoglobin value, high-density lipoprotein cholesterol level, albumin level, and diabetes mellitus were independent predictors of NAFLD diagnosed by CT. The body mass index, abdominal circumference, and triglyceride level were independent predictors of NAFLD diagnosed by the US. Conclusion NAFLD was found in 20.3% of CT cases and 40.4% of US cases among recipients of health checkups. An "inverted U curve" in which the NAFLD prevalence rose with age and dropped in late adulthood was reported. NAFLD was associated with obesity, the lipid profile, diabetes mellitus, hemoglobin values, and albumin levels. Our research is the first in the world to compare the NAFLD prevalence in the general population simultaneously by CT and US.

Renal Immune-related Adverse Event of Pembrolizumab Masked by Pemetrexed.

A Japanese woman in her 60s developed a kidney injury 9 weeks after treatment with pemetrexed, carboplatin, and pembrolizumab for stage IV lung adenocarcinoma. A renal biopsy showed chronic tubulointerstitial damage with minimal focal interstitial inflammation, consistent with pemetrexed-induced nephropathy; thus, pemetrexed was withdrawn. However, the kidney injury continued to worsen. A repeated biopsy showed severe acute tubulointerstitial nephritis, suggestive of a pembrolizumab-induced immune-related adverse event (irAE). The worsening after pemetrexed discontinuation suggested that the irAE had already begun, as the first biopsy showed focal inflammation. This case suggests thatcombining immune checkpoints and chemotherapy requires considering concurrent drug-induced nephrotoxicity.

Effect of beta-blockers and exercise restriction on the prevention of sudden cardiac death in pediatric hypertrophic cardiomyopathy.

BACKGROUND: Risk assessment tools and effective prevention strategies for sudden cardiac death (SCD) in pediatric patients with hypertrophic cardiomyopathy (HCM) have not been established. This study aimed to evaluate the efficacy of beta-blockers and exercise restriction for SCD prevention in this population. METHODS: We retrospectively reviewed the medical records of patients aged <18 years who were diagnosed with HCM at our center between January 1996 and December 2021. SCD and aborted SCD were defined as SCD equivalents. We divided patients based on whether they were prescribed beta-blockers or exercise restriction and compared the outcomes among the groups. The primary outcome was the overall survival (OS), and the secondary outcome was the cumulative SCD equivalent rate. Outcomes were analyzed using Kaplan-Meier curves and Cox proportional hazard analysis. We also compared patients according to the occurrence of SCD equivalents to identify SCD risk predictors. RESULTS: Among the 43 included patients [mean age, 7.7 (1.6-12.1) years; 23 male individuals], SCD equivalents occurred in 13 patients over 11.2 (4.5-15.6) years of follow-up, among whom 12 were resuscitated and 1 died. The OS rate was significantly higher in the beta-blocker and exercise restriction groups than in the non-beta-blocker and non-exercise restriction groups (81.3 % vs. 19.1 %, p < 0.01 and 57.4 % vs. 12.7 %, p < 0.01, respectively). Among the 13 patients with SCD equivalents, 5 had 9 recurrent SCD equivalents. A significant difference was observed between the SCD equivalent and non-SCD equivalent groups in the history of suspected arrhythmogenic syncope (p < 0.01) in the univariable but not in the multivariable analysis. CONCLUSIONS: Beta-blockers and exercise restriction may decrease the risk of SCD in pediatric patients with HCM and should be considered for SCD prevention in this population, particularly because predicting SCD in these patients remains challenging.