Non-exercise Activity Thermogenesis Correlated With Clinical Parameters in Patients With or At-Risk for Chronic Obstructive Pulmonary Disease (COPD): A Pilot Study.

BACKGROUND: Attention to physical activity has grown in patients with chronic obstructive pulmonary disease (COPD), as it serves as a robust indicator for mortality associated with COPD. Non-exercise activity thermogenesis (NEAT) is the energy expenditure due to physical activities besides active sports-like exercises and resistance training in daily life, and decreased NEAT may be related to physical inactivity in patients with COPD. We examined whether NEAT assessed using a questionnaire reflects clinical parameters in patients with or at risk for COPD. METHODS: The study participants consisted of 36 male patients (COPD=28; stage1=6, stage2=14, stage3/4=8, and at-risk for COPD=8) older than 50 years of age. The participants underwent anthropometric measurements, lung function testing, a six-minute walk test, muscle strength testing, and questionnaires, e.g., the COPD assessment test (CAT), modified Medical Research Council (mMRC) dyspnea scale, and Hospital Anxiety and Depression Scale. Image analysis with chest computed tomography (CT) included the number of trunk muscles, bronchial wall thickening, and emphysema (percentage of the lung field occupied by low attenuation area <-950 HU). We evaluated the relationship between these clinical parameters and NEAT questionnaire scores using Pearson correlation analysis and the Tukey-Kramer test. RESULTS: The NEAT score was correlated with the severity of airflow limitation and airway wall thickness measured by chest CT, symptoms evaluated by the mMRC dyspnea scale and CAT, and inspiratory muscle strength and pectoralis muscle area assessed by CT. CONCLUSION: Our study revealed the significance of NEAT as a valuable indicator in assessing the health status of patients with or at risk for COPD. The NEAT score was correlated with various clinical traits, suggesting that incorporating NEAT assessments using a questionnaire can contribute to a comprehensive understanding of the clinical condition in these patients. Further large-scale studies are warranted to validate and generalize these findings across diverse COPD populations.

Effect of overweight/obesity and metabolic syndrome on frailty in middle-aged and older Japanese adults.

Background: The potential for developing frailty exists in middle-aged and older adults. While obesity and metabolic syndrome (MetS) increase the risk of frailty in older adults, this relationship remains unclear in middle-aged adults, who are prone to developing lifestyle-related diseases. Objective: To examine the effect of overweight/obesity and MetS on frailty development in middle-aged and older Japanese adults using real-world data. Methods: This nationwide cohort study used exhaustive health insurance claims data of 3,958,708 Japanese people from 2015 to 2019 provided by the Japan Health Insurance Association. Participants aged ≥35 and < 70 years who received health checkups in 2015 were included. Multivariate logistic regression was used to assess the effect of body mass index (BMI) and MetS or MetS components (i.e., diabetes, hypertension, and dyslipidemia) in 2015 on frailty risk assessed using the hospital frailty risk score in 2019. Additionally, a subgroup analysis was performed to examine the interaction effects of MetS components and 4-year weight change (%) on frailty risk among participants who were overweight and obese (BMI ≥25 kg/m2). Results: In 2019, 7204 (0.2%) and 253,671 (6.4%) participants were at high and intermediate frailty risks, respectively. Obesity and MetS were independently associated with intermediate/high frailty risk (odds ratio (OR) 1.36, p < 0.05; OR 1.23, p < 0.05, respectively) and high frailty risk (OR 1.80, p < 0.05; OR 1.37, p < 0.05, respectively) in all participants. Although all MetS components were frailty risk factors, these effects diminished with age in both sexes. Subgroup analysis of patients with diabetes revealed that 5%-10% weight loss was associated with reduced frailty risk in both sexes. Conclusions: Obesity, MetS, and MetS components were independent frailty risk factors in middle-aged and older Japanese adults. Weight loss of up to 10% over 4 years prevented frailty in patients with diabetes who were overweight and obese.

Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.

Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.

Antifungal Activity and Molecular Mechanisms of Copper Nanoforms against Colletotrichum gloeosporioides.

In this work, we have synthesized copper nanoforms (Cu NFs) using ascorbic acid as a reducing agent and polyvinylpyrrolidone as a stabilizer. Elemental characterization using EDS has shown the nanostructure to be of high purity and compare well with commercially sourced nanoforms. SEM images of both Cu NFs show some agglomeration. The in-house NFs had a better even distribution and size of the nanostructures. The XRD peaks represented a face-centered cubic structure of Cu2O. The commercially sourced Cu NFs were found to be a mixture of Cu and Cu2O. Both forms had a crystalline structure. Using these two types of Cu NFs, an antimicrobial study against Colletotrichum gloeosporioides, a devastating plant pathogen, showed the in-house Cu NFs to be most effective at inhibiting growth of the pathogen. Interestingly, at low concentrations, both Cu NFs increased fungal growth, although the mycelia appeared thin and less dense than in the control. SEM macrographs showed that the in-house Cu NFs inhibited the fungus by flattening the mycelia and busting some of them. In contrast, the mycelia were short and appeared clustered when exposed to commercial Cu NFs. The difference in effect was related to the size and/or oxidation state of the Cu NFs. Furthermore, the fungus produced a defense mechanism in response to the NFs. The fungus produced melanin, with the degree of melanization directly corresponding to the concentration of the Cu NFs. Localization of aggregated Cu NFs could be clearly observed outside of the model membranes. The large agglomerates may only contribute indirectly by a hit-and-bounce-off effect, while small structures may adhere to the membrane surface and/or internalize. Spatio-temporal membrane dynamics were captured in real time. The dominant dynamics culminated into large fluctuations. Some of the large fluctuations resulted in vesicular transformation. The major transformation was exo-bud/exo-cytosis, which may be a way to excrete the foreign object (Cu NFs).

Web-Based Content on Diet and Nutrition Written in Japanese: Infodemiology Study Based on Google Trends and Google Search.

BACKGROUND: The increased availability of content of uncertain integrity obtained through the internet is a major concern. To date, however, there has been no comprehensive scrutiny of the fitness-for-purpose of web-based content on diet and nutrition. OBJECTIVE: This cross-sectional study aims to describe diet- and nutrition-related web-based content written in Japanese, identified via a systematic extraction strategy using Google Trends and Google Search. METHODS: We first identified keywords relevant for extracting web-based content (eg, blogs) on diet and nutrition written in Japanese using Google Trends. This process included identification of 638 seed terms, identification of approximately 1500 pairs of related queries (top) and search terms, the top 10% of which were extracted to identify 160 relevant pairs of related queries (top) and search terms, and identification of 107 keywords for search. We then extracted relevant web-based content using Google Search. RESULTS: The content (N=1703) examined here was extracted following a search based on 107 keywords. The most common themes included food and beverages (390/1703, 22.9%), weight management (366/1703, 21.49%), health benefits (261/1703, 15.33%), and healthy eating (235/1703, 13.8%). The main disseminators were information technology companies and mass media (474/1703, 27.83%), food manufacturers (246/1703, 14.45%), other (236/1703, 13.86%), and medical institutions (214/1703, 12.57%). Less than half of the content (790/1703, 46.39%) clearly indicated the involvement of editors or writers. More than half of the content (983/1703, 57.72%) was accompanied by one or more types of advertisement. The proportion of content with any type of citation reference was 40.05% (682/1703). The themes and disseminators of content were significantly associated with the involvement of editors or writers, accompaniment with advertisement, and citation of reference. In particular, content focusing on weight management was more likely to clearly indicate the involvement of editors or writers (212/366, 57.9%) and to be accompanied by advertisement (273/366, 74.6%), but less likely to have references cited (128/366, 35%). Content from medical institutions was less likely to have citation references (62/214, 29%). CONCLUSIONS: This study highlights concerns regarding the authorship, conflicts of interest (advertising), and the scientific credibility of web-based diet- and nutrition-related information written in Japanese. Nutrition professionals and experts should take these findings seriously because exposure to nutritional information that lacks context or seems contradictory can lead to confusion and backlash among consumers. However, more research is needed to draw firm conclusions about the accuracy and quality of web-based diet- and nutrition-related content and whether similar results can be obtained in other major mass media or social media outlets and even other languages.

Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias.

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

Multimorbidity patterns in the working age population with the top 10% medical cost from exhaustive insurance claims data of Japan Health Insurance Association.

Although the economic burden of multimorbidity is a growing global challenge, the contribution of multimorbidity in patients with high medical expenses remains unclear. We aimed to clarify multimorbidity patterns that have a large impact on medical costs in the Japanese population. We conducted a cross-sectional study using health insurance claims data provided by the Japan Health Insurance Association. Latent class analysis (LCA) was used to identify multimorbidity patterns in 1,698,902 patients who had the top 10% of total medical costs in 2015. The present parameters of the LCA model included 68 disease labels that were frequent among this population. Moreover, subgroup analysis was performed using a generalized linear model (GLM) to assess the factors influencing annual medical cost and 5-year mortality. As a result of obtaining 30 latent classes, the kidney disease class required the most expensive cost per capita, while the highest portion (28.6%) of the total medical cost was spent on metabolic syndrome (MetS) classes, which were characterized by hypertension, dyslipidemia, and type 2 diabetes. GLM applied to patients with MetS classes showed that cardiovascular diseases or complex conditions, including malignancies, were powerful determinants of medical cost and mortality. MetS was classified into 7 classes based on real-world data and accounts for a large portion of the total medical costs. MetS classes with cardiovascular diseases or complex conditions, including malignancies, have a significant impact on medical costs and mortality.

Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation.

Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.

Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells.

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation.

Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics.

TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53-mutant compared to TP53-wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53-knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53-mutant compared to TP53-WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53-mutant AML and stem/progenitor cells. The BH3 mimetic-driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53-WT and TP53-R248W Molm13 cells suppressed both TP53-WT and TP53-mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53-mutant cells, thus shifting cell fate from survival to death in TP53-deficient and -mutant AML. This concept warrants clinical evaluation.

Tfs1, transcription elongation factor TFIIS, has an impact on chromosome segregation affected by pka1 deletion in Schizosaccharomyces pombe.

The cAMP-dependent protein kinase (PKA) pathway in Schizosaccharomyces pombe plays an important role in microtubule organization and chromosome segregation. Typically, loss of functional Pka1 induces sensitivity to the microtubule-destabilizing drug thiabendazole (TBZ) and chromosome mis-segregation. To determine the mechanism via which Pka1 is involved in these events, we explored the relevance of transcription factors by creating a double-deletion strain of pka1 and 102 individual genes encoding transcription factors. We found that rst2∆, tfs1∆, mca1∆, and moc3∆ suppressed the TBZ-sensitive phenotype of the pka1∆ strain, among which tfs1∆ was the strongest suppressor. All single mutants (rst2∆, tfs1∆, mca1∆, and moc3∆) showed a TBZ-tolerant phenotype. Tfs1 has two transcriptional domains (TFIIS and Zn finger domains), both of which contributed to the suppression of the pka1∆-induced TBZ-sensitive phenotype. pka1∆-induced chromosome mis-segregation was rescued by tfs1∆ in the presence of TBZ. tfs1 overexpression induced the TBZ-sensitive phenotype and a high frequency of chromosome mis-segregation, suggesting that the amount of Tfs1 must be strictly controlled. However, Tfs1-expression levels did not differ between the wild-type and pka1∆ strains, and the Tfs1-GFP protein was localized to the nucleus and cytoplasm in both strains, which excludes the direct regulation of expression and localization of Tfs1 by Pka1. Growth inhibition by TBZ in pka1∆ strains was notably rescued by double deletion of rst2 and tfs1 rather than single deletion of rst2 or tfs1, indicating that Rst2 and Tfs1 contribute independently to counteract TBZ toxicity. Our findings highlight Tfs1 as a key transcription factor for proper chromosome segregation.

[A Case of Medullary Carcinoma of the Colon].

The patient is a 79-year-old woman who visited her local doctor with a chief complaint of abdominal pain. A lower gastrointestinal endoscopy revealed a circumferential type 3 mass in the transverse colon. The patient was diagnosed with transverse colon cancer (cT3N0M0, cStage Ⅱa)and underwent laparoscopic transverse colectomy(D3). The postoperative course was good, and she was discharged on POD 9. Pathological results showed a diagnosis of medullary carcinoma(pT3N0M0, pStage Ⅱa)with MSI-high. The patient was treated with UFT/UZEL for 6 months as postoperative adjuvant chemotherapy. The patient has been recurrence-free for 1 year and 6 months postoperatively and is under outpatient follow-up. Medullary carcinoma is a rare histologic type that is estimated to account for 2-3% of all colorectal cancers. Medullary carcinoma of the colon is more common in elderly patients, women, and the right side of the colon, with a relatively favorable prognosis. We report a case of medullary carcinoma of the transverse colon in which the patient had a relatively long survival, with some discussion of the literature.

Impact of non-exercise activity thermogenesis on physical activity in patients with COPD.

Physical inactivity is associated with comorbidities and mortality in chronic obstructive pulmonary disease (COPD) patients. Although non-exercise activity thermogenesis (NEAT) is important for evaluating the physical activity level (PAL) of patients with chronic diseases, it has not yet been assessed in COPD patients. This study included male patients with COPD (n = 28) and high risk for COPD (n = 8). Total energy expenditure (TEE) and basal metabolic rate (BMR) were measured using the doubly labeled water (DLW) method and indirect calorimetry, respectively. PAL was calculated as TEE/BMR, while the NEAT was obtained from a questionnaire. Physical activity was also assessed using an accelerometer. The total NEAT score was correlated with PAL (r = 0.534, P < 0.001), while PAL was correlated more strongly with the non-locomotive NEAT score (r = 0.548, P < 0.001) than the locomotive NEAT score (r = 0.278, P = 0.10). Regarding accelerometer-obtained data, this questionnaire mainly reflected steps/day and the duration of light locomotive and non-locomotive daily activities. The NEAT score is a possible option for evaluating PAL in daily clinical practice. The present results indicated that non-locomotive activity may have a greater impact on PAL than locomotive activity in COPD patients.

Possible association of high-density lipoprotein cholesterol levels with trunk muscle deficits and decrease in energy expenditure in patients with or at risk for COPD: A pilot study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with low muscle mass and function caused by malnutrition and physical inactivity. We aimed to investigate possible associations between serum biomarkers and clinical traits including computed tomography-derived muscle measurements and energy expenditure indices in COPD. METHODS: Total energy expenditure (TEE) was measured by the doubly labeled water method, while physical activity level (PAL) was calculated as TEE/basal metabolic rate. Cross-sections and densities of pectoralis, rectus abdominis, and erector spinae muscles were measured. Serum biomarkers included adiponectin, insulin-like growth factor-1, and high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol (C). RESULTS: HDL-C levels were significantly correlated with all muscle areas, densities, and TEE. Only LDL-C levels were correlated with PAL. CONCLUSIONS: HDL-C level was a potential biomarker for trunk muscle volumes and functions, as well as total energy expenditure in COPD.

Characterization of Antioxidant Activity of Heated Mycosporine-like Amino Acids from Red Alga Dulse Palmaria palmata in Japan.

We recently demonstrated the monthly variation and antioxidant activity of mycosporine-like amino acids (MAAs) from red alga dulse in Japan. The antioxidant activity of MAAs in acidic conditions was low compared to that in neutral and alkali conditions, but we found strong antioxidant activity from the heated crude MAA fraction in acidic conditions. In this study, we identified and characterized the key compounds involved in the antioxidant activity of this fraction. We first isolated two MAAs, palythine, and porphyra-334, from the fraction and evaluated the activities of the two MAAs when heated. MAAs possess absorption maxima at around 330 nm, while the heated MAAs lost this absorption. The heated MAAs showed a high ABTS radical scavenging activity at pH 5.8-8.0. We then determined the structure of heated palythine via ESI-MS and NMR analyses and speculated about the putative antioxidant mechanism. Finally, a suitable production condition of the heated compounds was determined at 120 °C for 30 min at pH 8.0. We revealed compounds from red algae with antioxidant activities at a wide range of pH values, and this information will be useful for the functional processing of food.

Evaluation of energy intake by brief-type self-administered diet history questionnaire among male patients with stable/at risk for chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Weight loss and reduced fat-free mass are independent risk factors for mortality among patients with chronic obstructive pulmonary disease (COPD). These factors are important for determining diet therapy and examining the validity of assessment for energy intake (EI). We assessed the agreement of EI between a brief-type self-administered diet history questionnaire (BDHQ) and the doubly labelled water (DLW) method among male patients with stable/at risk for COPD. METHOD: In this cross-sectional observational study, data for 33 male patients were analysed. At the first visit, EI was estimated using a BDHQ (EIBDHQ). Total energy expenditure (TEE) was measured during 13-15 days by the DLW method, while corrected EI was calculated using the TEE and weight change during the DLW period (EIDLW). The difference between EIBDHQ and EIDLW was evaluated by the Bland-Altman method. Multiple regression analysis was used to determine the proportion of variance in the difference between EIBDHQ and EIDLW, as determined by the patient's characteristics. RESULTS: EIBDHQ was 2100 (95% CI: 1905 to 2295) kcal/day in the total population. A fixed bias was observed between EIBDHQ and EIDLW as -186 (95% CI: -422 to 50) kcal/day, while a proportional bias was not detected by the Bland-Altman analysis. Age, weight, anxiety and interleukin 6 were responsible for 61.7% of the variance in the difference between both EIs in a multiple regression model. CONCLUSIONS: The BDHQ underestimated EI among male patients with stable/at risk for COPD, but this estimation error was within an acceptable range compared with previous studies. EIBDHQ precision might be improved by considering common COPD traits, including inflammatory condition and mental state.

Impact of walking aids on estimating physical activity using a tri-axial accelerometer in frail older adults.

OBJECTIVES: This study aimed to compare the estimation error of physical activity level (PAL) estimated using a tri-axial accelerometer between an independent walking group and an assisted walking group with walking aids. METHODS: Subjects were 6 older adults who could walk independently and 10 older adults requiring walking assistance during gait. Total energy expenditure (TEE) was measured using the doubly labelled water (DLW) method over 2 weeks and PAL was calculated as the measured TEE divided by the basal metabolic rate measured using indirect calorimetry (PALDLW). The participants wore a tri-axial accelerometer (Active style Pro HJA-750C) on the waist simultaneously as the DLW period, and the estimated PAL was derived from it (PALACC). RESULTS: The median PAL estimation error in the assisted walking group was -0.30 kcal/day (range: -0.77 to -0.01 kcal/day) and more underestimated than that in the independent walking group (p=0.02). The estimation error of PALACC was significantly correlated with PALDLW (r=-0.80, p<0.01). CONCLUSIONS: Using the accelerometer, PAL was underestimated for older adults who used walking aids but not for those who walked independently under free-living conditions.

DNA-PK inhibitor peposertib enhances p53-dependent cytotoxicity of DNA double-strand break inducing therapy in acute leukemia.

Peposertib (M3814) is a potent and selective DNA-PK inhibitor in early clinical development. It effectively blocks non-homologous end-joining repair of DNA double-strand breaks (DSB) and strongly potentiates the antitumor effect of ionizing radiation (IR) and topoisomerase II inhibitors. By suppressing DNA-PK catalytic activity in the presence of DNA DSB, M3814 potentiates ATM/p53 signaling leading to enhanced p53-dependent antitumor activity in tumor cells. Here, we investigated the therapeutic potential of M3814 in combination with DSB-inducing agents in leukemia cells and a patient-derived tumor. We show that in the presence of IR or topoisomerase II inhibitors, M3814 boosts the ATM/p53 response in acute leukemia cells leading to the elevation of p53 protein levels as well as its transcriptional activity. M3814 synergistically sensitized p53 wild-type, but not p53-deficient, AML cells to killing by DSB-inducing agents via p53-dependent apoptosis involving both intrinsic and extrinsic effector pathways. The antileukemic effect was further potentiated by enhancing daunorubicin-induced myeloid cell differentiation. Further, combined with the fixed-ratio liposomal formulation of daunorubicin and cytarabine, CPX-351, M3814 enhanced the efficacy against leukemia cells in vitro and in vivo without increasing hematopoietic toxicity, suggesting that DNA-PK inhibition could offer a novel clinical strategy for harnessing the anticancer potential of p53 in AML therapy.