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Background: Breast reconstruction is crucial for patients who have undergone mastectomy for breast cancer. Our bioabsorbable implants comprising an outer poly-l-lactic acid mesh and an inner component filled with collagen sponge promote and retain adipogenesis in vivo without the addition of exogenous cells or growth factors. In this study, we evaluated adipogenesis over time histologically and at the gene expression level using this implant in a rodent model. Methods: The implants were inserted in the inguinal and dorsal regions of the animals. At 1, 3, 6, and 12 months post-operation, the weight, volume, and histological assessment of all newly formed tissue were performed. We analyzed the formation of new adipose tissue using multiphoton microscopy and RNA sequencing. Results: Both in the inguinal and dorsal regions, adipose tissue began to form 1 month post-operation in the peripheral area. Angiogenesis into implants was observed until 3 months. At 6 months, microvessels matured and the amount of newly generated adipose tissue peaked and was uniformly distributed inside implants. The amount of newly generated adipose tissue decreased from 6 to 12 months but at 12 months, adipose tissue was equivalent to the native tissue histologically and in terms of gene expression. Conclusions: Our bioabsorbable implants could induce normal adipogenesis into the implants after subcutaneous implantation. Our implants can serve as a novel and safe material for breast reconstruction without requiring exogenous cells or growth factors.

Abstract The need for the accurate generation of acoustic holograms has increased with the prevalence of the use of acoustophoresis methods such as ultrasonic haptic sensation, acoustic levitation, and displays. However, experimental results have shown that the actual acoustic field may differ from the simulated field owing to uncertainties in the transducer position, power and phase, or from nonlinearity and inhomogeneity in the field. Traditional methods for experimentally optimizing acoustic holograms require prior calibration and do not scale with the number of variables. Here, we propose a digital twin approach that combines feedback from experimental measurements (such as a microphone and an optical camera) in the physical setup with numerically obtained derivatives of the loss function, using automatic differentiation, to optimize the loss function. This approach is number of transducers times faster and more efficient than the classical finite difference approach, making it beneficial for various applications such as acoustophoretic volumetric displays, ultrasonic haptic sensations, and focused ultrasound therapy.

Background: The modified Rankin scale (mRS) is extensively used for premorbid evaluation in patients with stroke; however, its limited capacity to assess functional status highlights the need for additional indicators such as frailty. Aims: This study aimed to assess the impact of the premorbid mRS score and frailty on daily living (ADL) activities at hospital discharge, focusing on varying stroke severities. Methods: This single-centre, prospective cohort study included patients with acute stroke aged ≥60 years. Key metrics included the frailty index for frailty assessment or mRS for functional status premorbid and the functional independence measure of the motor domain (FIM-M) at discharge for ADL outcomes. The patients were categorized into mild (0–4), moderate (5–15), and severe (16–42) groups based on the National Institute of Health Stroke Scale. Multiple hierarchical linear regression analyses were performed for each group to evaluate the influence of mRS and frailty on FIM-M scores. Results: In the mild stroke group, significant associations were observed with premorbid mRS3 (β = −0.183, p = 0.004), mRS4 (β = −0.234, p < 0.001), and frailty status (β = −0.227, p = 0.005) and FIM-M scores. Premorbid frailty did not show a significant association with the FIM-M scores in the moderate or severe stroke group. Frailty status notably contributed to changes in R², particularly in the mild stroke group (R² change = 0.031, p = 0.002). However, such changes were not evident in the other stroke severity groups. Conclusion: This study emphasizes the importance of incorporating frailty assessments into premorbid evaluations, particularly when considering ADL outcomes in patients with mild stroke. Conversely, the significance of frailty in moderate-to-severe stroke was less evident.

Osteoclast stimulatory transmembrane protein (OC-STAMP) plays a pivotal role in the promotion of cell fusion during osteoclast differentiation (osteoclastogenesis) in the context of pathogenic bone resorption. Thus, it is plausible that the suppression of OC-STAMP through a bioengineering approach could lead to the development of an effective treatment for inflammatory bone resorptive diseases with minimum side effects. Here, we synthesized two types of spermine-bearing (Spe) cationic glucan dendrimer (GD) gels (with or without C12) as carriers of short interfering RNA (siRNA) to silence OC-STAMP. The results showed that amphiphilic C12-GD-Spe gel was more efficient in silencing OC-STAMP than GD-Spe gel and that the mixture of anti-OC-STAMP siRNA/C12-GD-Spe significantly downregulated RANKL-induced osteoclastogenesis. Also, local injection of anti-OC-STAMP-siRNA/C12-GD-Spe could attenuate bone resorption induced in a mouse model of periodontitis. These results suggest that OC-STAMP is a promising target for the development of a novel bone regenerative therapy and that C12-GD-Spe gel provides a new nanocarrier platform of gene therapies for osteolytic disease.

Background: No actual data on spinal fusion and management of osteoporosis in Japan have been reported. The aim of the survey was to investigate pre- and post-operative management of osteoporosis, including testing and prescription, in elderly patients undergoing spinal fusion in Japan. Methods: Medical data on patients aged 65 years or older undergoing spinal fusion from April 2018 to March 2022 were extracted from the medical data vision (MDV) database containing health insurance claims data from Japanese acute care hospitals to investigate fusion area, pre- and post-operative osteoporosis tests (bone mineral density and osteoporosis markers), prescriptions of osteoporosis medications, and other information. Results: The analysis set consisted of 26,959 patients. Annual pre-operative BMD testing rates and osteoporosis markers testing rates were higher than the post-operative rates without significant annual changes. The post-operative prescription rate of osteoporosis medications throughout the target period was approximately two times higher than the preoperative rate. The drug with highest pre- and post-operative prescription rates was teriparatide (TPTD) followed by bisphosphonates, showing that the prescription rate of TPTD proportionally increased with the length of fusion area. Conclusions: It was suggested that patients aged 65 years or older undergoing spinal fusion might receive insufficient osteoporosis tests. Despite no trend in the testing rate with the length of fusion area, some tendency was observed in the selection of osteoporosis medications. In patients with osteoporosis undergoing spinal fusion, early examination, diagnosis, and therapeutic intervention may improve the prognoses, and solid testing and prescriptions are therefore expected.

The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab.

Abstract Background Patient motivation is an important determinant of rehabilitation outcomes. Differences in patients’ and clinicians’ perceptions of motivational factors can potentially hinder patient-centered care. Therefore, we aimed to compare patients’ and clinicians’ perceptions of the most important factors in motivating patients for rehabilitation. Methods This multicenter explanatory survey research was conducted from January to March 2022. In 13 hospitals with an intensive inpatient rehabilitation ward, 479 patients with neurological or orthopedic disorders undergoing inpatient rehabilitation and 401 clinicians, including physicians, physical therapists, occupational therapists, and speech-language-hearing therapists, were purposively selected using inclusion criteria. The participants were asked to choose the most important factor motivating patients for rehabilitation from a list of potential motivational factors. Results Here we show that realization of recovery, goal setting, and practice related to the patient’s experience and lifestyle are the three factors most frequently selected as most important by patients and clinicians. Only five factors are rated as most important by 5% of clinicians, whereas nine factors are selected by 5% of patients. Of these nine motivational factors, medical information (p

Abstract Lipid droplets (LDs) have been observed in the nuclei of hepatocytes; however, their significance in liver disease remains unresolved. Our purpose was to explore the pathophysiological features of intranuclear LDs in liver diseases. We included 80 patients who underwent liver biopsies; the specimens were dissected and fixed for electron microscopy analysis. Depending on the presence of adjacent cytoplasmic invagination of the nuclear membrane, LDs in the nuclei were classified into two types: nucleoplasmic LDs (nLDs) and cytoplasmic LD invagination with nucleoplasmic reticulum (cLDs in NR). nLDs were found in 69% liver samples and cLDs in NR were found in 32%; no correlation was observed between the frequencies of the two LD types. nLDs were frequently found in hepatocytes of patients with nonalcoholic steatohepatitis, whereas cLDs in NR were absent from the livers of such patients. Further, cLDs in NR were often found in hepatocytes of patients with lower plasma cholesterol level. This indicates that nLDs do not directly reflect cytoplasmic lipid accumulation and that formation of cLDs in NR is inversely correlated to the secretion of very low-density lipoproteins. Positive correlations were found between the frequencies of nLDs and endoplasmic reticulum (ER) luminal expansion, suggesting that nLDs are formed in the nucleus upon ER stress. This study unveiled the presence of two distinct nuclear LDs in various liver diseases.

Abstract This study aimed to identify the modifiable cardiovascular risk factors associated with longitudinal changes, which are nine functional and structural biological vascular aging indicators (BVAIs), to propose an effective method to prevent biological vascular aging. We conducted a longitudinal study of 697 adults (a maximum of 3636 BVAI measurements) who were, at baseline, aged between 26 and 85 years and whose BVAIs were measured at least twice between 2007 and 2018. The nine BVAIs were measured using vascular testing and an ultrasound device. Covariates were assessed using validated questionnaires and devices. During the mean follow-up period of 6.7 years, the average number of BVAI measurements ranged from 4.3 to 5.3. The longitudinal analysis showed a moderate positive correlation between the common carotid intima-media thickness (IMT) and chronological age in both men (r = 0.53) and women (r = 0.54). In the multivariate analysis, BVAIs were associated with factors such as age, sex, residential area, smoking status, blood clinical chemistry test levels, number of comorbidities, physical fitness, body mass, physical activity, and dietary intake. The IMT is the most useful BVAI. Our findings suggest that modifiable cardiovascular risk factors are associated with longitudinal changes in BVAI as represented by IMT.

Novel functional biomaterials are expected to bring about breakthroughs in developing immunotherapy and regenerative medicine through their application as drug delivery systems and scaffolds. Nanogels are defined as nanoparticles with a particle size of 100 nm or less and as having a gel structure. Nanogels have a three-dimensional network structure of cross-linked polymer chains, which have a high water content, a volume phase transition much faster than that of a macrogel, and a quick response to external stimuli. As it is possible to transmit substances according to the three-dimensional mesh size of the gel, a major feature is that relatively large substances, such as proteins and nucleic acids, can be taken into the gel. Furthermore, by organizing nanogels as a building block, they can be applied as a scaffold material for tissue regeneration. This review provides a brief overview of the current developments in nanogels in general, especially drug delivery, therapeutic applications, and tissue engineering. In particular, polysaccharide-based nanogels are interesting because they have excellent complexation properties and are highly biocompatible.

We investigated the prognostic role of the gut microbiome and clinical factors in chronic liver disease (hepatitis, cirrhosis, and hepatocellular carcinoma [HCC]). Utilizing data from 227 patients whose stool samples were collected over the prior 3 years and a Cox proportional hazards model, we integrated clinical attributes and microbiome composition based on 16S ribosomal RNA sequencing. HCC was the primary cause of mortality, with the Barcelona Clinic Liver Cancer staging system-derived B/C significantly increasing the mortality risk (hazard ratio [HR] = 8.060; 95% confidence interval [CI]: 3.6509–17.793; p < 0.001). Cholesterol levels < 140 mg/dL were associated with higher mortality rates (HR = 4.411; 95% CI: 2.0151–9.6555; p < 0.001). Incertae sedis from Ruminococcaceae showed a protective effect, reducing mortality risk (HR = 0.289; 95% CI: 0.1282 to 0.6538; p = 0.002), whereas increased Veillonella presence was associated with a higher risk (HR = 2.733; 95% CI: 1.1922–6.2664; p = 0.017). The potential of specific bacterial taxa as independent prognostic factors suggests that integrating microbiome data could improve the prognosis and treatment of chronic liver disease. These microbiome-derived markers have prognostic significance independently and in conjunction with clinical factors, suggesting their utility in improving a patient’s prognosis.

Abstract Background Fecal microbiota transplantation (FMT) is a potential treatment for irritable bowel syndrome (IBS), but its efficacy in Japanese IBS patients is unknown. This study aimed to evaluate the efficacy, side effects, and microbiome changes following FMT in Japanese IBS patients. Methods Seventeen Japanese patients with refractory IBS received FMT (4 donors) under colonoscopy. Responders were defined by an improvement in the IBS severity index (IBS-SI) of 50 points or more after 12 weeks. We evaluated the IBS-SI and Bristol Stool Form Scale (BSFS) and compared the diversity and microbiome before and 12 weeks after FMT. For the microbiome, we analyzed the V3–V4 region of the 16S rRNA gene. Results IBS-SI decreased an average of 115.58 points after 12 weeks, and 10 patients (58.8%) were considered responders. Eight patients with diarrhea (66.7%) and three patients with constipation (60.0%) showed improvement in the BSFS. Two patients complained of mild abdominal pain, but there were no cases with severe side-effects. α-diversity was increased only in the responder group (p = 0.017). Patients who closely paralleled the donor microbiome had a higher rate of IBS-SI improvement. The relative abundance of Neisseria and Akkermansia increased and Desulfovibrio and Delftia were decreased in the responder group after FMT. Conclusions Following FMT, about 60% of Japanese patients with IBS showed improvement in both the IBS-SI and BSFS, without severe side effects. Increased α-diversity and similarity to the donor microbiome after FMT may be associated with better treatment effects. Trial registration: This study was registered in the University Hospital Medical Information Network Clinical Trial Registration (UMIN000026363). Registered 31 May 2017, https://rctportal.niph.go.jp/s/detail/um?trial_id=UMIN000026363 . The study was registered prospectively.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic disease for which no effective treatment is available. Transforming growth factor-β (TGF-β) is thought to be involved in the pathogenesis of IC/PBS, and previous studies have suggested that administrations of a TGF-β inhibitor significantly ameliorated IC/PBS in a mouse model. However, the molecular mechanisms underlying the therapeutic effect of a TGF-b inhibitor on IC/PBS has not been comprehensively analyzed. TGF-β has a variety of actions, such as regulation of immune cells and fibrosis. In our study, we induced IC/PBS-like disease in mice by an intravesical administration of hydrogen peroxide (H₂O₂) and examined the effects of three TGF-β inhibitors, Repsox, SB431542, and SB505124, on the urinary functions as well as histological and gene expression profiles in the bladder. TGF-β inhibitor treatment improved urinary function and histological changes in the IC/PBS mouse model, and SB431542 was most effective among the TGF-β inhibitors. In our present study, TGF-β inhibitor treatment improved abnormal enhancement of nociceptive mechanisms, immunity and inflammation, fibrosis, and dysfunction of bladder urothelium. These results show that multiple mechanisms are involved in the improvement of urinary function by TGF-β inhibitor.

Abstract Sarcopenia is thought to be related to the microbiome, but not enough reports in chronic liver disease (CLD) patients. In addition to the differences in microbiome, the role of the microbiome in the gut is also important to be clarified because it has recently been shown that the microbiome may produce branched-chain amino acids (BCAAs) in the body. In this single-center study, sixty-nine CLD patients were divided by skeletal muscle mass index (SMI) into low (L-SMI: n = 25) and normal (N-SMI: n = 44). Microbiome was analyzed from stool samples based on V3-4 region of bacterial 16S rRNA). L-SMI had a lower Firmicutes/Bacteroidetes ratio than N-SMI. At the genus level, Coprobacillus, Catenibacterium and Clostridium were also lower while the Bacteroides was higher. Predictive functional profiling of the L-SMI group showed that genes related to nitrogen metabolism were enriched, but those related to amino acid metabolism, including BCAA biosynthesis, were lower. The genes related to 'LPS biosynthesis' was also higher. The microbiome of CLD patients with low muscle mass is characterized not only by high relative abundance of gram-negative bacteria with LPS, but also by the possibility of low potential for amino acid synthesis including BCAAs.

Abstract The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3–4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

Abstract Background In an effort to increase people’s adherence to active lifestyles, contemporary physical activity (PA) guidelines now include low-dose PA. Methods PA was evaluated in 583 participants of the Nutritional and Physical Activity Intervention Study (NEXIS) cohort (30–65 years old); 349 inactive participants (MVPA, 2.7 ± 1.0 MET-h/day) were randomly assigned to the intervention or control groups, and 235 active participants participated in follow-up visits. The intervention aimed to increase MVPA and comprised five brief counseling sessions over 1 year. The 1-year target for the participant was increasing their step-count to 10,000 steps/d or +3000 steps/d, relative to the baseline score. The counseling sessions were designed to stimulate progressive changes in physical behaviors by recommendations promoting small and/or light-intensity bouts of PA. PA was measured at baseline, the end of the intervention, and 1 year after the intervention ended. Additionally, several nutrition, health, and fitness parameters were measured. Results Participants in the intervention group significantly increased their step-count from 8415 ± 1924 at baseline to 9493 ± 2575 at the end of the 1-year period. During the same period, MVPA significantly increased by 0.9 MET-h. The daily time spent in ≥ 3, ≥ 4 and ≥ 5 MET activities increased by 11, 6, and 3 min, respectively. This increase in PA remained observable 1 year after intervention concluded. The active group maintained higher physical activity levels throughout the two years. The intervention group showed smaller energy intakes at the end of the 2-year period. Significant correlations were noted between the 1-year change in MVPA and the change in resting heart rate (r = − 0.22), and between the 2-year change in MVPA and the change in waist circumference (r = − 0.08) and peak oxygen consumption capacity (r = 0.23) in the intervention group only. Conclusions A prolonged and progressive PA intervention promoting small bouts of light-to-moderate PA may be used in healthy, not-optimally-active people to increase PA beyond the strict period of the intervention. Further studies are necessary to understand whether low-dose PA messages can be effective in initiating a progressive increase toward larger amounts of PA. Trial registration: Clinical Trials.gov, NCT00926744, retrospectively registered.

Abstract Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α , Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.

The gastric H+,K+-ATPase is a proton pump that creates the acidic environment of the stomach lumen, maintaining high proton gradient across the gastric mucosa cell membrane. Here, structural analysis of rationally designed H+,K+-ATPase mutants provides insight into this and other P-type ATPases cation binding stoichiometry and mechanisms.

Previous studies reported that consumers choose a higher number of options in subtractive framing (-OF), which delete the unnecessary options from the full model with all options chosen than in additive framing (+OF), which adds options to a simple base model. The purposes of this study are to examine the effect of age on option framing and the differences of product type on the option framing effect using two product scenarios (travel package and medical examination). Participants were 40 younger and 40 older adults. We measured the number of options chosen, total price, choice difficulty, and choice satisfaction. In addition, cognitive functions (coding, symbol search, digit span, arithmetic, and information) were assessed. Results revealed that older and younger adults chose more options in the -OF condition for both the scenarios. For the medical examination, older adults chose more options than did the younger adults in both -OF and +OF conditions. Developmental shift in goals and motivation related to life-span may explain the differences between the age differences.

Background: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. Method: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. Results: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. Conclusion: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

Abstract Acoustic holograms are the keystone of modern acoustics. They encode three-dimensional acoustic fields in two dimensions, and their quality determines the performance of acoustic systems. Optimisation methods that control only the phase of an acoustic wave are considered inferior to methods that control both the amplitude and phase of the wave. In this paper, we present Diff-PAT, an acoustic hologram optimisation platform with automatic differentiation. We show that in the most fundamental case of optimizing the output amplitude to match the target amplitude; our method with only phase modulation achieves better performance than conventional algorithm with both amplitude and phase modulation. The performance of Diff-PAT was evaluated by randomly generating 1000 sets of up to 32 control points for single-sided arrays and single-axis arrays. This optimisation platform for acoustic hologram can be used in a wide range of applications of PATs without introducing any changes to existing systems that control the PATs. In addition, we applied Diff-PAT to a phase plate and achieved an increase of > 8 dB in the peak noise-to-signal ratio of the acoustic hologram.

Abstract Background Pancreatic exocrine insufficiency (PEI) is associated with the outcome of pancreatic disease. However, there is no method for assessing PEI that can be used noninvasively and easily for outpatient. It has been reported that changes in intestinal bacteria caused by PEI may increase breath hydrogen concentration (BHC) levels during glucose or lactose loading. We have evaluated the usefulness of fasting breath hydrogen concentration (FBHC) measurement without glucose loading for the evaluation of PEI. Methods Sixty patients underwent FBHC measurement, BT-PABA testing, and microbiome analysis. They were classified into PEI group (PABA excretion rate

The mechanics of the migration of T cells into tumours is an important aspect of tumour immunity. Here the authors engineer complex 3D environments to explore functions of microtubules and cell contractility as strategies to enhance T cell migration in tumour microenvironments.

Oral mucositis is a typical adverse effect of chemotherapy, causing oral pain that significantly reduces the patient’s quality of life. β-cryptoxanthin (β-cry) is a carotenoid abundant in citrus fruits with antioxidant and anti-inflammatory effects. However, the β-cry effect on oral mucositis remains unclear. We investigated the effects of 5-fluorouracil (5-FU) and β-cry on human normal oral mucosal keratinocytes (hOMK). hOMK was seeded on a culture plate and cultured with 5-FU and β-cry. The cell number, mRNA expression of inflammatory cytokines and matrix metalloproteinases (MMPs), and production of inflammatory cytokines in hOMK were evaluated. Additionally, the cell count and inflammatory cytokine production were analyzed when hOMK was co-stimulated with Porphyromonas gingivalis lipopolysaccharide (P. gingivalis LPS) in addition to 5-FU. The numbers of hOMK significantly reduced with 5-FU stimulation, whereas it increased with β-cry treatment. mRNA expression of interleukin (IL)-6, IL-8, metalloproteinase (MMP)-2, and MMP-9 and protein production of IL-6 and IL-8 in hOMK were augmented on 5-FU stimulation. Simultaneously, β-cry treatment significantly suppressed IL-8 and MMP-9 mRNA expression, and IL-8 production was induced on 5-FU stimulation. Co-stimulation with P. gingivalis LPS and 5-FU enhanced IL-6 and IL-8 production in hOMK. β-cry could enhance cell proliferation and suppress 5-FU-induced expression of inflammatory cytokines and MMP in hOMK. Thus, β-cry can alleviate the symptoms of chemotherapy-induced oral mucositis, and its combination with oral care is effective in managing oral mucositis.

The impact of a high-fat diet (HFD) on intestinal permeability has been well established. When bacteria and their metabolites from the intestinal tract flow into the portal vein, inflammation in the liver is triggered. However, the exact mechanism behind the development of a leaky gut caused by an HFD is unclear. In this study, we investigated the mechanism underlying the leaky gut related to an HFD. C57BL/6J mice were fed an HFD or control diet for 24 weeks, and their small intestine epithelial cells (IECs) were analyzed using deep quantitative proteomics. A significant increase in fat accumulation in the liver and a trend toward increased intestinal permeability were observed in the HFD group compared to the control group. Proteomics analysis of the upper small intestine epithelial cells identified 3684 proteins, of which 1032 were differentially expressed proteins (DEPs). Functional analysis of DEPs showed significant enrichment of proteins related to endocytosis, protein transport, and tight junctions (TJ). Expression of Cldn7 was inversely correlated with intestinal barrier function and strongly correlated with that of Epcam. This study will make important foundational contributions by providing a comprehensive depiction of protein expression in IECs affected by HFD, including an indication that the Epcam/Cldn7 complex plays a role in leaky gut.

Introduction and objectives: Hepatitis C virus (HCV) infections in patients with hemophilia lead to the development of hepatocellular carcinoma (HCC) at a relatively younger age than that in patients without hemophilia. Although recent progress in direct-acting-antivirals has facilitated a high rate of sustained virological response (SVR), the clinical influence of HCV eradication in hemophilia patients remains unclear. This study aimed to compare the clinical outcomes of SVR against HCV in patients with and without hemophilia. Patients and methods: The study enrolled 699 patients who achieved SVR after HCV antiviral treatment. Patients were divided into two groups: 78 patients with hemophilia (H group) and 621 patients without hemophilia (NH group). We evaluated patient characteristics, clinical outcomes, and the cumulative incidence of HCC after SVR. Results: Compared with the NH group, patients in the H-group were significantly younger and had a lower hepatic fibrosis score. No difference was found in the incidence of liver-related disease or overall death between the two groups over a mean follow-up period of 7 years.Four patients in the H group and 36 patients in the NH group were diagnosed with HCC after SVR. Multivariate analysis showed that male sex, age, and cirrhosis were significant risk factors for HCC incidence. There was no significant difference in the cumulative incidence of HCC after propensity-score matching adjusting for the risk factors of HCC between the two groups. Conclusion: Hemophilia is not a significant risk factor for hepatocarcinogenesis after SVR against HCV.

Phased array transducers (PATs) are used in many applications, from airborne ultrasonic tactile displays to acoustic levitation. Acoustic holograms play a significant role in determining the performance of these applications. Many PATs and optimizers have been developed; however, only the following have been demonstrated in the literature: “phase” and “phase and amplitude” control of transducers and “phase” and “amplitude” only control at target points. Thus, most of the combinations of transducer state and target acoustic field conditions are yet to be explored. Here, we explore such combinations using Diff-PAT, one of the latest acoustic hologram optimizers. Diff-PAT is based on automatic differentiation and stochastic gradient descent. This optimizer achieves higher accuracy than conventional optimizers. We formulated multiple loss functions and wave propagators to enable each combination of the operation mode and quantitatively assessed the performance of each combination. The developed optimizers will offer new opportunities in the field and could allow further simplifications in PAT applications.

Human dermal fibroblasts (HDFs) were converted into osteoblasts using a ALK inhibitor II (inhibitor of transforming growth factor-β signal) on freeze-dried nanogel-cross-linked porous (FD-NanoClip) polysaccharide sheets or fibers. Then, the ability of these directly converted osteoblasts (dOBs) to produce calcified substrates and the expression of osteoblast genes were analyzed in comparison with osteoblasts converted by exactly the same procedure but seeded onto a conventional atelocollagen scaffold. dOBs exposed to FD-NanoClip in both sheet and fiber morphologies produced a significantly higher concentration of calcium deposits as compared to a control cell sample (i.e., unconverted fibroblasts), while there was no statistically significant difference in calcification level between dOBs exposed to atelocollagen sheets and the control group. The observed differences in osteogenic behaviors were interpreted according to Raman spectroscopic analyses comparing different polysaccharide scaffolds and Fourier transform infrared spectroscopy analyses of dOB cultures. This study substantiates a possible new path to repair large bone defects through a simplified transplantation procedure using FD-NanoClip sheets with better osteogenic outputs as compared to the existing atelocollagen scaffolding material.

It is well known that Semaphorin 4D (Sema4D) inhibits IGF-1-mediated osteogenesis by binding with PlexinB1 expressed on osteoblasts. However, its elevated level in the gingival crevice fluid of periodontitis patients and the broader scope of its activities in the context of potential upregulation of osteoclast-mediated periodontal bone-resorption suggest the need for further investigation of this multifaceted molecule. In short, the pathophysiological role of Sema4D in periodontitis requires further study. Accordingly, attachment of the ligature to the maxillary molar of mice for 7 days induced alveolar bone-resorption accompanied by locally elevated, soluble Sema4D (sSema4D), TNF-α and RANKL. Removal of the ligature induced spontaneous bone regeneration during the following 14 days, which was significantly promoted by anti-Sema4D-mAb administration. Anti-Sema4D-mAb was also suppressed in vitro osteoclastogenesis and pit formation by RANKL-stimulated BMMCs. While anti-Sema4D-mAb downmodulated the bone-resorption induced in mouse periodontitis, it neither affected local production of TNF-α and RANKL nor systemic skeletal bone remodeling. RANKL-induced osteoclastogenesis and resorptive activity were also suppressed by blocking of CD72, but not Plexin B2, suggesting that sSema4D released by osteoclasts promotes osteoclastogenesis via ligation to CD72 receptor. Overall, our data indicated that ssSema4D released by osteoclasts may play a dual function by decreasing bone formation, while upregulating bone-resorption.

The present work investigated the effect of Polylactic acid (PLA) fibers produced by centrifugal spinning with incorporated BaTiO3 particles to improve their bacteriostatic behavior. The PLA matrix and three composites, presenting three different amounts of fillers, were subjected to UV/O3 treatment monitoring the possible modifications that occurred over time. The morphological and physical properties of the surfaces were characterized by different microscopic techniques, contact angle, and surface potential measurements. Subsequently, the samples were tested in vitro with human dermal fibroblasts (HDF) to verify the cytotoxicity of the substrates. No significant differences between the PLA matrix and composites emerged; the high hydrophobicity of the fibers, derived by the polymer structure, represented an obstacle limiting the fibroblast attachment. Samples underwent bacterial exposure (Staphylococcus epidermidis) for 12 and 24 h. Increasing the concentration of BT, the number of living bacteria and their distribution decreased in comparison with the PLA matrix suggesting an effect of the inorganic filler, which generates a neutralization effect leading to reactive oxygen species (ROS) generation and subsequently to bacterial damages. These results suggest that the barium titanate (BT) fillers clearly improve the antibacterial properties of PLA fibers after aging tests made before bacterial exposure, representing a potential candidate in the creation of composites for medical applications.

Most Japanese people have had their flexibility tested in childhood physical education classes. Recent studies may provide a retrospective answer as to why those measurements may be important. Flexibility is one of the components of physical fitness along with cardiorespiratory fitness and muscular strength. Although flexibility was originally assumed to correlate with other aspects of physical fitness, recent studies demonstrate that a less flexible body indicates arterial stiffening. Arterial stiffness has been identified as an independent risk factor for mortality and cardiovascular disorders. Therefore, there is a possibility that flexibility is a novel fitness indicator related to cardiovascular disease, which can be easily evaluated over all ages and in any area (e.g., medical check-up). Now, flexibility may no longer be simply viewed as important just for optimizing functional movement in daily life and/or reducing the risk of injury. This article reviews the recent findings on the relationship between flexibility and arterial stiffness, emphasizing “flexibility and arterial stiffness”, “genetics and flexibility”, “stretching and arterial stiffness”, and “flexibility and blood pressure”.

The gastric proton pump (H+,K+-ATPase), a P-type ATPase responsible for gastric acidification, mediates electro-neutral exchange of H+ and K+ coupled with ATP hydrolysis, but with an as yet undetermined transport stoichiometry. Here we show crystal structures at a resolution of 2.5 Å of the pump in the E2-P transition state, in which the counter-transporting cation is occluded. We found a single K+ bound to the cation-binding site of the H+,K+-ATPase, indicating an exchange of 1H+/1K+ per hydrolysis of one ATP molecule. This fulfills the energy requirement for the generation of a six pH unit gradient across the membrane. The structural basis of K+ recognition is resolved and supported by molecular dynamics simulations, establishing how the H+,K+-ATPase overcomes the energetic challenge to generate an H+ gradient of more than a million-fold—one of the highest cation gradients known in mammalian tissue—across the membrane.

Brown adipocytes (BAs) play important roles in body temperature regulation, energy balance, and carbohydrate and lipid metabolism. Activities of BAs are remarkably diminished in obese and diabetic patients, providing possibilities of transplanting functional BAs resulting in therapeutic benefit. Here, we show generation of functional BAs by cellular reprogramming procedures. Transduction of the PRDM16 gene into iPSC-derived embryoid bodies induced BA phenotypes (iBAs). Moreover, normal human fibroblasts were directly converted into BAs (dBAs) by C/EBP-β and C-MYC gene transduction. Approximately 90% of the fibroblasts were successfully converted within 12 days. The dBAs were highly active in mitochondrial biogenesis and oxidative metabolism. Mouse dBAs were induced by Prdm16, C/ebp-β, and L-myc genes, and after transplantation, they significantly reduced diet-induced obesity and insulin resistance in an UCP1-dependent manner. Thus, highly functional BAs can be generated by cellular reprogramming, suggesting a promising tailor-made cell therapy against metabolic disorders including type 2 diabetes mellitus.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky’s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome (international scale (IS)) and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

Purpose: Having a low level of physical fitness, especially cardiorespiratory fitness, appears to accelerate age-related aortic stiffening. Whereas, some studies have reported that trunk flexibility is a component of physical fitness, it is also negatively associated with arterial stiffening independent of cardiorespiratory fitness in cross-sectional studies. However, no long-term longitudinal study has determined whether poor trunk flexibility accelerates the progression of age-related aortic stiffening. We examined trunk flexibility and aortic stiffness progression in a 5-year longitudinal study.Methods and Results: A total of 305 apparently healthy men and women participated in this study (49.6 ± 9.5 years of age). Trunk flexibility was measured using a sit-and-reach test. Aortic stiffness was assessed using carotid-femoral pulse wave velocity (cfPWV) at baseline and after 5 years. Analysis of covariance (ANCOVA) was used to assess the association of the annual rate of cfPWV across flexibility levels (low, middle, high). There were no significant differences in baseline cfPWV among the three groups (835 ± 164, 853 ± 140, 855 ± 2.68 cm/s; P = 0.577). Annual ΔcfPWV was significantly higher in the low-flexibility group than in the high-flexibility group (P = 0.009). ANCOVA revealed an inverse relationship between flexibility level and annual ΔcfPWV (14.41 ± 2.73, 9.79 ± 2.59, 2.62 ± 2.68 cm/s/year; P for trend = 0.011). Multiple regression analysis revealed that baseline sit and reach (β = −0.12, −0.70 to −0.01) was independently correlated with ΔcfPWV following adjustment for baseline peak oxygen uptake, age, sex, body fat, heart rate, and cfPWV. The 5-year change in cfPWV was not significantly correlated with 5-year change in sit-and-reach performance (P = 0.859).Conclusion: Poor trunk flexibility is associated with greater progression of age-related aortic stiffening in healthy adults. However, we failed to confirm a significant association between 5-year change in aortic stiffness and 5-year change in trunk flexibility. The association between increased age-related increase in aortic stiffness and deterioration in flexibility due to age may require observation for more than 5 years.

We synthesized Pd-Fe series nanoparticles in solid solution using pulsed plasma in liquid with Pd-Fe bulk mixture electrodes. The Pd-Fe atomic percent ratios were 1:3, 1:1, and 3:1, and the particle size was measured to be less than 10 nm by high-resolution transmission electron microscopy (HR-TEM). The nanoparticles showed face-centered cubic structure. The lattice parameter increased with increasing Pd content and followed Vegard’s law, and energy-dispersive X-ray spectra were consistent with the ratios of the starting samples, which showed a solid solution state. The solid solution structure and local structure were confirmed by HR-TEM and X-ray absorption fine structure.

Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.