Prediction of response to promising first-line chemotherapy in ovarian cancer patients with residual peritoneal tumors: practical biomarkers and robust multiplex models.

BACKGROUND: Platinum/taxane (TC) chemotherapy with debulking surgery stays the mainstay of the treatment in ovarian cancer patients with peritoneal metastasis, and recently its novel modality, intraperitoneal carboplatin with dose-dense paclitaxel (ddTCip), was shown to have greater therapeutic impact. Nevertheless, the response varies among patients and consequent recurrence, or relapse often occurs. Discovery of therapeutic response predictor to ddTCip and/or TC therapy is eagerly awaited to improve the treatment outcome. METHODS: Using datasets in 76 participants in our ddTCip study and published databases on patients received TC therapy, we first validated a total of 75 previously suggested markers, sought out more active biomarkers through the association analyses of genome-wide transcriptome and genotyping data with progression-free survival (PFS) and adverse events, and then developed multiplex statistical prediction models for PFS and toxicity by mainly using multiple regression analysis and the classification and regression tree (CART) algorithm. RESULTS: The association analyses revealed that SPINK1 could be a possible biomarker of ddTCip efficacy, while ABCB1 rs1045642 and ERCC1 rs11615 would be a predictor of hematologic toxicity and peripheral neuropathy, respectively. Multiple regression analyses and CART algorithm finally provided a potent efficacy prediction model using 5 gene expression data and robust multiplex toxicity prediction models-CART models using a total of 4 genotype combinations and multiple regression models using 15 polymorphisms on 12 genes. CONCLUSION: Biomarkers and multiplex models composed here could work well in the response prediction of ddTCip and/or TC therapy, which might contribute to realize optimal selection of the key therapy.

Relationship between mortality and vitality in patients with mild cognitive impairment/dementia: An 8-year retrospective study.

AIM: The study aimed to investigate the association of vitality, as measured using the vitality index (Vix), with the survival outcomes of older adults with mild cognitive impairment (MCI) or dementia. METHODS: We analyzed data from 3731 patients in the National Center for Geriatrics and Gerontology - Life Stories of Individuals with Dementia cohort from July 2010 to September 2018. The main focus was to correlate Vix scores with the time from the initial visit to death. Vix was categorized into "moderately to severely impaired" (0-7 points), "mildly impaired" (8-9 points), and "normal" (10 points) groups. Survival outcomes were assessed using a Cox proportional hazards model, adjusted for various factors. We conducted a mediation analysis to evaluate the effect of body mass index (BMI), instrumental activities of daily living (IADL), and basic activities of daily living (BADL) on the association between vitality and mortality. Stratified analysis was also conducted for the Mini-Mental State Examination groups. RESULTS: We included 2740 patients with an average follow-up of 1315 days. The mortality rate was 15.7%. The Vix distribution was 16% at 0-7 points; 40%, 8-9 points; and 44%, 10 points. Patients in the "moderately to severely impaired" category, characterized by lower Vix scores, exhibited notably higher mortality rates. Mediation effects emphasized the significant roles of BMI, IADL, and BADL in influencing survival outcomes. CONCLUSIONS: Vitality significantly influences patient survival rates. The association between vitality and mortality seems to be mediated by IADL and BADL, which has significant clinical implications. Geriatr Gerontol Int 2024; 24: 221-228.

Factors Associated with Behavioral and Psychological Symptoms of Dementia during COVID-19.

(1) Background: Preventive measures to control the spread of COVID-19 are essential, but they often cause social isolation and diminish the physical and mental health of older adults. In cognitively impaired individuals, the pandemic has worsened behavioral and psychological symptoms of dementia (BPSD). Here, we explored the factors contributing to the worsening of BPSD during the COVID-19 pandemic. (2) Methods: Potential patients were identified at a memory clinic in Japan between June 2017 and June 2021. Eligible patients had a diagnosis of mild cognitive impairment (MCI) or dementia during the study period. The outcome was BPSD, as assessed by using the Dementia Behavioral Disorders Scale. Information on patients' lifestyle habits and use of care services was obtained for use as primary explanatory variables; multiple regression analysis was performed to examine the relationship between BPSD and care services use or lifestyle habits. The model was adjusted for sociodemographic factors, and the interaction terms of the pandemic period with lifestyle and service use were included to evaluate the effects of COVID-19. (3) Results: We identified 977 participants with MCI and 1380 with dementia (MCI group: 69.8% age 75 years or older, 54.2% female; dementia group: 79.8% age 75 years or older, 64.8% female). After adjustment for possible confounders, significantly worse BPSD was demonstrated in those who used daycare services during COVID-19 (both MCI and dementia patients; p = 0.007 and p = 0.025 respectively) and in those with poor nutritional function (dementia patients; p = 0.040). (4) Conclusions and Implications: During COVID-19, poor nutritional status and use of daycare services were associated with BPSD in those with cognitive decline. These findings indicate the need to fully examine the quantity and quality of care services for people with cognitive decline during emergencies and to continue to provide effective services.

Risk factors associated with hospitalization in patients with asymptomatic or mild COVID-19 in public accommodation facilities in Tokyo.

INTRODUCTION: In Japan, patients with coronavirus disease 2019 (COVID-19) who do not require medical intervention are provided care in recovery accommodation facilities (RAFs). However, some patients may require hospitalization if their symptoms become more severe during their stay. We conducted an observational study using epidemiological data of patients with COVID-19 admitted to RAFs in Tokyo. METHODS: This was an observational cohort study using data from COVID-19 patients admitted to one of the RAFs in Tokyo from December 2020 to November 2021. Admissions to the facilities were limited to patients with asymptomatic or mild COVID-19 with no underlying disease or at least stable underlying disease at the time of admission. Patients were hospitalized when they required oxygen administration or when they had, or persistent fever, or severe respiratory symptoms. We evaluated the association between hospitalization and the risk factors for hospitalization using a Cox regression model. RESULTS: The number of patients with COVID-19 admitted to the RAF was 6176. The number of hospitalized patients was 393 (6.4%), and the median length of stay was 5.50 days (IQR: 4.50, 6.50). In the Cox regression analysis, the hazard ratio increased with age and was significantly higher among patients aged >60 years (HR = 10.23, 95% CI: 6.72-15.57) than those in other age groups. This trend is similar to that observed in the sensitivity analysis. CONCLUSION: Patients with diabetes, the elderly, obesity, and medications for gout and psychiatric diseases may be at a high risk of hospitalization. In particular, an age over 60 years was strongly associated with hospitalization.

Contribution of radiation education to anxiety reduction among Fukushima Daiichi Nuclear Power Plant workers: a cross sectional study using a text mining method.

The purpose of this study is to investigate the frequency of education, knowledge of radiation and workplace anxiety of Fukushima Daiichi Nuclear Power Plant (FDNPP) workers and to analyze what type of words are used for anxiety with a text mining method. An original questionnaire survey was given to FDNPP workers, and a text mining method was used to extract information from free-entry fields. The questionnaires were collected from 1135 workers (response rate: 70.8%). It was found that when workers receive education on radiation, the increased knowledge helps to reduce their anxiety. Among the 1135 workers, 92 of 127 completed the free-entry field with valid entries. Seventy-one words were extracted by the text mining method. The words used differed depending on the degree of anxiety. The text mining method revealed information about the presence or absence of radiation anxiety and the subjects' working environment and background.

[Questionnaire Survey of Fukushima Daiichi Nuclear Power Plant Workers in 2016 on Knowledge and Anxiety About Radiation].

The results of a survey of radiation workers suggest that they are worried about the effects of radiation exposure on health, and approximately 30% of Fukushima Daiichi Nuclear Power Plant (FDNPP) workers have anxiety. This questionnaire survey reveals that the higher the frequency of radiation education, the higher the knowledge of radiation the workers will have, and that the higher the level of knowledge, the lower the anxiety. To reduce anxiety, it is important to increase knowledge about radiation through radiation education. However, even those workers who had radiation education several times still had anxiety. According to the Ordinance on the Prevention of Ionizing Radiation Hazards, the time spent on education about the effects of radiation on the human body is only about 30 minutes. This education is not enough to reduce anxiety. FDNPP workers needed more effective education to increase their knowledge and to reduce their anxiety.

Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel CaV3.1 caused by a mutation responsible for spinocerebellar ataxia.

Spinocerebellar ataxia (SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel CaV3.1 (T-type). Patients with SCA42 exhibit a pure form of cerebellar ataxia. We encountered a patient with the p.Arg1715His mutation, suffering from intractable resting tremor, particularly head tremor. This symptom improved with the administration of low-dose of zonisamide (ZNS), a T-type calcium channel blocker effective for treating Parkinson's disease and epilepsy. Previous electrophysiological studies showed that the voltage dependence of this mutant CaV3.1 was shifted toward the positive potential. This abnormal shift was considered a factor related to disease onset and symptoms. In this study, we performed whole-cell recordings of GFP-expressing HEK293T cells that expressed wild-type or mutant CaV3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant CaV3.1. The results showed that ZNS in an amount equivalent to the patient's internal dose significantly ameliorated the abnormal shift in the mutant CaV3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type CaV3.1. Because CaV3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant CaV3.1 by ZNS might have contributed to improvement in the intractable tremor of our patient with SCA42. Moreover, efonidipine, another T-type calcium channel blocker, had no effect on tremors in our patient with SCA42 and did not improve the abnormal shift in the voltage dependence of the mutant CaV3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant CaV3.1.

Prospective, randomized, cross-over pilot study of the effects of Rikkunshito, a Japanese traditional herbal medicine, on anorexia and plasma-acylated ghrelin levels in lung cancer patients undergoing cisplatin-based chemotherapy.

Purpose Anorexia induced by cytotoxic chemotherapy on delayed phase is a highly frequent adverse event. We aimed to determine the effects of rikkunshito (RKT) on chemotherapy-induced anorexia (CIA) in patients with lung cancer. Methods This prospective, randomized, cross-over pilot trial included 40 lung cancer patients scheduled to undergo cisplatin-based chemotherapy and randomized to either a group given RKT 7.5 g/day for 14 days (Group A, N = 20) or not (Group B, N = 20), then the treatments were switched. All patients received dexamethasone, palonosetron hydrochloride and aprepitant regardless of group assignment. Rescue drugs were allowed as required. The primary and key secondary endpoints were changes in caloric intake and in plasma acylated ghrelin (AG) levels, respectively. Average daily caloric intake during days 3 to 5 was compared with that on day 1 of each course. Results The primary and key secondary endpoints were analyzed in 31 patients (per protocol population) completing the study. Reduction rate of caloric intake was lower in RKT, than in control courses (18% vs. 25%, P = 0.025). Plasma AG levels significantly declined between days 1 and 3 in RKT (12.3 vs. 7.5 fmol/mL, P < 0.001) and control (10.8 vs. 8.6 fmol/mL, P < 0.001) courses. However, those obviously increased to 8.5 fmol/mL (P = 0.025) by day 5 in RKT course but not in control course (7.7 fmol/mL, P = 0.28). Conclusions Rikkunshito could mitigate CIA and ameliorate plasma AG levels during the delayed phase of CDDP-based chemotherapy in lung cancer patients. Clinical trial registration numbers: UMIN000010748.

Computerized data mining analysis of keywords as indicators of the concepts in AHA-BLS guideline updates.

INTRODUCTION: Cardiopulmonary resuscitation (CPR) guidelines have been updated every 5 years since 2000. Significant changes have been made in each update, and every time a guideline is changed, the instructors of each country that ratify the American Heart Association (AHA) must review the contents of the revised guideline to understand the changes made in the concept of CPR. The purpose of this study was to use a computerized data mining method to identify and characterize the changes in the key concepts of the AHA-Basic Life Support (BLS) updates between 2000 and 2015. METHODS: We analyzed the guidelines of the AHA-BLS provider manual of 2000, 2005, 2010, and 2015 using a computerized data mining method and attempted to identify the changes in keywords along with changes in the guideline. RESULTS: In particular, the 2000 guideline has focused on the detailed BLS technique of an individual health care provider, whereas the 2005 and 2010 guidelines have focused on changing the ratio of chest compressions and breathing and changing the BLS sequence, respectively. In the most recent 2015 guideline, the CPR team was the central topic. We observed that as the guidelines were updated over the years, keywords related to CPR and automated external defibrillators (AED) associated with co-occurrence network continued to appear. CONCLUSIONS: Analysis revealed that keywords related to CPR and AED associated with the co-occurrence network continued to appear. We believe that the results of this study will ultimately contribute to optimizing AHA's educational strategies for health care providers.

[Thrombocytopenia in pregnancy: a single-center retrospective analysis of 91 cases].

Thrombocytopenia is a relatively common complication in pregnancy, with a reported frequency of 7%-11%. The causes of this condition are diverse, although the most common etiology is gestational thrombocytopenia (GT) (70%-80%), followed by HELLP syndrome and immune thrombocytopenia (ITP). To investigate the clinical features of thrombocytopenia during pregnancy, we conducted a retrospective analysis of 69 women at our center with 91 pregnancies in which the platelet count was below 100×109/l. There were 38 cases in women with a prior diagnosis of thrombocytopenic diseases such as ITP or an inherited platelet disorder. In the remaining 53 cases, a diagnosis could be made only after delivery. We analyzed the disease course, maternal and perinatal characteristics, platelet count fluctuations, and pregnancy outcomes. The final diagnosis was GT in 38, ITP in 14, and other causes in 1. To distinguish between GT and ITP is not always feasible and can sometimes only be performed based on postpartum changes in the platelet count. In pregnant women with thrombocytopenia, careful follow-up of platelet count fluctuations after delivery is crucial to distinguish ITP from GT.

Identification of ApoA4 as a sphingosine 1-phosphate chaperone in ApoM- and albumin-deficient mice.

HDL-bound ApoM and albumin are protein chaperones for the circulating bioactive lipid, sphingosine 1-phosphate (S1P); in this role, they support essential extracellular S1P signaling functions in the vascular and immune systems. We previously showed that ApoM- and albumin-bound S1P exhibit differences in receptor activation and biological functions. Whether the physiological functions of S1P require chaperones is not clear. We examined ApoM-deficient, albumin-deficient, and double-KO (DKO) mice for circulatory S1P and its biological functions. In albumin-deficient mice, ApoM was upregulated, thus enabling S1P functions in embryonic development and postnatal adult life. The Apom:Alb DKO mice reproduced, were viable, and exhibited largely normal vascular and immune functions, which suggested sufficient extracellular S1P signaling. However, Apom:Alb DKO mice had reduced levels (∼25%) of plasma S1P, suggesting that novel S1P chaperones exist to mediate S1P functions. In this study, we report the identification of ApoA4 as a novel S1P binding protein. Recombinant ApoA4 bound to S1P, activated multiple S1P receptors, and promoted vascular endothelial barrier function, all reflective of its function as a S1P chaperone in the absence of ApoM and albumin. We suggest that multiple S1P chaperones evolved to support complex and essential extracellular signaling functions of this lysolipid mediator in a redundant manner.

Chromosomal Abnormalities in Human Lymphocytes after Computed Tomography Scan Procedure.

The incidence of chromosomal abnormalities and cancer risk correlates well with the radiation dose after exposure to moderate- to high-dose ionizing radiation. However, the biological effects and health risks at less than 100 mGy, e.g., from computed tomography (CT) have not been ascertained. To investigate the biological effects of low-dose exposure from a CT procedure, we examined chromosomal aberrations, dicentric and ring chromosomes (dic+ring), in peripheral blood lymphocytes (PBLs), using FISH assays with telomere and centromere PNA probes. In 60 non-cancer patients exposed to CT scans, the numbers of dicentric and ring chromosomes were significantly increased with individual variation. The individual variations in the increment of dicentric and ring chromosomes after CT procedures were confirmed using PNA-FISH analysis of PBLs from 15 healthy volunteers after in vitro low-dose exposure using a 137Cs radiation device. These findings strongly suggest that appropriate medical use of low-dose radiation should consider individual differences in radiation sensitivity.

IL­1ß and TNF­α suppress TGF­ß­promoted NGF expression in periodontal ligament­derived fibroblasts through inactivation of TGF­ß­induced Smad2/3­ and p38 MAPK­mediated signals.

Mechanosensitive (MS) neurons in the periodontal ligament (PDL) pass information to the trigeminal ganglion when excited by mechanical stimulation of the tooth. During occlusal tooth trauma of PDL tissues, MS neurons are injured, resulting in atrophic neurites and eventual degeneration of MS neurons. Nerve growth factor (NGF), a neurotrophic factor, serves important roles in the regeneration of injured sensory neurons. In the present study, the effect of pro­inflammatory cytokines, including interleukin 1ß (IL­1ß) and tumor necrosis factor α (TNF­α), on transforming growth factor ß1 (TGF­ß1)­induced NGF expression was evaluated in rat PDL­derived SCDC2 cells. It was observed that TGF­ß1 promoted NGF expression via Smad2/3 and p38 mitogen­activated protein kinase (MAPK) activation. IL­1ß and TNF­α suppressed the TGF­ß1­induced activation of Smad2/3 and p38 MAPK, resulting in the abrogation of NGF expression. NGF secreted by TGF­ß1­treated SCDC2 cells promoted neurite extension and the expression of tyrosine hydroxylase, a rate­limiting enzyme in dopamine synthesis in rat pheochromocytoma PC12 cells. These results suggested that pro­inflammatory cytokines suppressed the TGF­ß­mediated expression of NGF in PDL­derived fibroblasts through the inactivation of TGF­ß­induced Smad2/3 and p38 MAPK signaling, possibly resulting in the disturbance of the regeneration of injured PDL neurons.

Lexical analysis suggests differences between subgroups in anxieties over radiation exposure in Fukushima.

Although many experts have attempted communication about radiation risk, fears about radiation exposure stemming from the Fukushima Daiichi Nuclear Power Plant accident remain deeply rooted. The characteristics of the anxiety vary with social background, which makes it difficult to alleviate with one approach. Our ultimate goal is therefore to create risk-communication materials tailored to various groups with differing social backgrounds. Towards that end, the purpose of the present study was to clarify potential factors associated with radiation-related anxieties within these groups. After obtaining informed consent, we conducted focus group interviews (FGIs) with Fukushima residents from various social groups, including evacuees, emergency responders, government personnel, medical staff, and decontamination workers. We obtained narrative comments specifically related to the following two themes: (i) lessons learned (at work or home) in light of one's position in society, and (ii) health issues. After transcribing the comments, we examined potential factors associated with radiation-related anxieties using both quantitative and qualitative study methods simultaneously, using the KH Coder software and the Steps for Coding and Theorization (SCAT) method respectively. FGIs were undertaken with 141 persons. Categories, words and storylines extracted in this study might indicate potential anxieties that are unique to each group, but our analysis also suggested that some anxieties were common to all groups. We expect to continue the analyses and, ultimately, to establish group-tailored risk-communication materials for achieving our final goal of adapting and better managing risk-communication efforts to help people deal more effectively with the scientific, technological and societal changes that came about after the disaster.

RELATIVE BIOLOGICAL EFFECTIVENESS OF NEUTRONS DERIVED FROM THE EXCESS RELATIVE RISK MODEL WITH THE ATOMIC BOMB SURVIVORS DATA MANAGED BY HIROSHIMA UNIVERSITY.

According to an analysis of the Life Span Study cohort data conducted by the Radiation Effects Research Foundation in Hiroshima and Nagasaki, the sex-averaged excess relative risk (ERR) of all solid cancers was 0.42 Gy-Eq-1. On the other hand, analysis of the atomic bomb survivors (ABS) cohort data at Hiroshima University indicated the ERR value was 0.28 Gy-Eq-1 in Hiroshima. In both cases, initial radiation doses were derived from the dosimetry system DS02, in which the relative biological effectiveness (RBE) of neutrons was assumed to be a constant value of 10. To clarify the validity of the RBE, the authors investigated the possibility of different contributions of neutrons by using the ABS. Although there were no statistically significant differences among the estimated value of RBE (=65) and the ordinal value (=10), the corresponding ERR decreased by 30%, which might affect the interpretation of radiation health assessments.

[A case of metastatic uveal melanoma of the liver and digestive tract].

Metastasis of uveal melanoma of the digestive tract is rare. We report a case of a patient with metastatic uveal melanoma of the liver and digestive tract. A 68-year-old man was admitted with primary complaint of appetite loss and fatigue. Abdominal computed tomography revealed a 13-cm diameter tumor in the right lobe of the liver. We diagnosed him with metastatic uveal melanoma. We performed a liver tumor biopsy and diagnosed metastatic melanoma;we found distant metastases in the stomach, duodenum, and rectum on endoscopic biopsy. We administered systemic chemotherapy [DACa-Tam therapy (Dacarbazine, 220mg/m2×3 days;Nimustine, 60mg/m2×1 day;Carboplatin area under the curve (AUC) =4×1 day;Tamoxifen, 40mg/day×3 days)]. Prognosis is unfavorable in approximately half of the patients with liver metastases that occur through blood circulation. The patient died of liver failure two months after the diagnosis.

Protective Effects of Japanese Soybean Paste (Miso) on Stroke in Stroke-Prone Spontaneously Hypertensive Rats (SHRSP).

BACKGROUND AND HYPOSESIS: Soybean isoflavones have been shown to reduce the risk of cerebral infarction in humans according to epidemiological studies. However, whether intake of miso can reduce the incidence of stroke in animal models remains unknown. In this study, we investigated the effects of soybean paste (miso) in an animal model of stroke. METHODS: Stroke-prone spontaneously hypertensive rats (SHRSP) were fed a miso diet (normal diet 90%, miso 10%; final NaCl content 2.8%), a high salt diet (normal diet and NaCl 2.5%; final NaCl content 2.8%), or a low salt diet (normal diet; final NaCl content 0.3%). RESULTS: Kaplan-Meier survival curves revealed a significantly lower survival rate in the high salt group compared to the miso group (P = 0.002) and the low salt group (P ≤ 0.001). Large hemorrhagic macules were found in the cerebrum in the high salt group, whereas none were found in the other 2 groups. There were also fewer histological and immunohistochemical changes in the brain and kidneys in the miso group compared to the high salt group. CONCLUSION: Our results suggest that miso may have protective effects against stroke despite its high salt content.

Impact of interferon-free antivirus therapy on lipid profiles in patients with chronic hepatitis C genotype 1b.

AIM: To investigate the influence of interferon-free antivirus therapy on lipid profiles in chronic hepatitis C virus genotype 1b (HCV1b) infection. METHODS: Interferon-free antiviral agents were used to treat 276 patients with chronic HCV1b infection, and changes in serum lipids of those who achieved sustained virologic response (SVR) were examined. The treatment regimen included 24 wk of daclatasvir plus asunaprevir (DCV + ASV) or 12 wk of sofosbuvir plus ledipasvir (SOF + LDV). SVR was achieved in 121 (85.8%) of 141 patients treated with DCV + ASV and 132 (97.8%) of 135 patients treated with SOF + LDV. In the two patient groups (DCV + ASV-SVR and SOF + LDV-SVR), serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured at baseline during treatment and at 4 and 12 wk after treatment. Then, longitudinal changes in lipid profiles were analyzed. RESULTS: Serum levels of TC, LDL-C, and HDL-C were significantly increased throughout the observation period in both the DCV + ASV-SVR and SOF + LDV-SVR groups. During antivirus treatment, the increases in TC and LDL-C were significantly greater in the SOF + LDV-SVR group than in the DCV + ASV-SVR group (P < 0.001). At 4 and 12 wk after the therapy, serum levels of TC and LDL-C were similar between the two groups and were significantly greater than those at baseline. Approximately 75%-80% of the increase in TC was derived from an increased LDL-C. In multiple regression analysis, the difference in therapy protocol (DCA + ASV or SOF + LDV) was an independent predictor that was significantly associated with the increase in TC and LDL-C at 4 wk of therapy. CONCLUSION: Serum cholesterol significantly increased during SOF + LDV treatment. After treatment, HCV elimination was associated with a similar increase in cholesterol regardless of the therapy protocol.