Dynamic Microcirculation Characteristics of Plantar Skin Under Metatarsal Head of Human Foot in Response to Life-Like Pressure Stimulus.

OBJECTIVE: Diabetic foot ulcer (DFU) is a severe complication with high mortality. High plantar pressure and poor microcirculation are considered main causes of DFU. The specific aims were to provide a novel technique for real-time measurement of plantar skin blood flow (SBF) under walking-like pressure stimulus and delineate the first plantar metatarsal head dynamic microcirculation characteristics because of life-like loading conditions in healthy individuals. METHODS: Twenty young healthy participants (14 male and 6 female) were recruited. The baseline (i.e., unloaded) SBF of soft tissue under the first metatarsal head were measured using laser Doppler flowmetry (LDF). A custom-made machine was utilized to replicate daily walking pressure exertion for 5 min. The exerted plantar force was adjusted from 10 N (127.3 kPa) to 40 N (509.3 kPa) at an increase of 5 N (63.7 kPa). Real-time SBF was acquired using the LDF. After each pressure exertion, postload SBF was measured for comparative purposes. Statistical analysis was performed using the R software. RESULTS: All levels of immediate-load and postload SBF increased significantly compared with baseline values. As the exerted load increased, the postload and immediate-load SBF tended to increase until the exerted load reached 35 N (445.6 kPa). However, in immediate-load data, the increasing trend tended to level off as the exerted pressure increased from 15 N (191.0 kPa) to 25 N (318.3 kPa). For postload and immediate-load SBF, they both peaked at 35 N (445.6 kPa). However, when the exerted force exceeds 35 N (445.6 kPa), both the immediate-load and postload SBF values started to decrease. CONCLUSIONS: Our study offered a novel real-time plantar soft tissue microcirculation measurement technique under dynamic conditions. For the first metatarsal head of healthy people, 20 N (254.6 kPa)-plantar pressure has a fair microcirculation stimulus compared with higher pressure. There might be a pressure threshold at 35 N (445.6 kPa) for the first metatarsal head, and soft tissue microcirculation may decrease when local pressure exceeds it.

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial.

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Asymmetric Organocatalytic 1,3-Dipolar Cycloaddition of Azomethine Ylides with ß-Substituted Cyclic Enones.

The enantioselective and diastereoselective control of 1,3-dipolar cycloaddition reactions to ß-substituted cyclic enones has been developed. The 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with cyclic dienones affords chiral tetrahydropyrrolo[2,1-a]phthalazine derivatives 3 through vinylogous iminium ion activation by combining a cinchona-based primary amine C3 and a chiral camphorsulfonic acid additive. Conversely, with a weaker 3,5-bis(trifluoromethyl)benzoic acid additive, the 1,3-dipolar cycloaddition of phthalazinium dicyanomethanides with ß-substituted cyclic enones leads to chiral hexahydroisoindolo[1,2-a]phthalazin-10(8H)-one derivatives 4 with excellent stereocontrol via endo-dienamine activation.

The establishment of a multiple myeloma clinical registry in the Asia-Pacific region: The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR).

BACKGROUND: Multiple myeloma (MM) is the second most common haematological cancer worldwide. Along with related diseases including monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukaemia (PCL) and plasmacytoma, MM incidence is rising, yet it remains incurable and represents a significant disease burden. Clinical registries can provide important information on management and outcomes, and are vital platforms for clinical trials and other research. The Asia-Pacific Myeloma and Related Diseases Registry (APAC MRDR) was developed to monitor and explore variation in epidemiology, treatment regimens and their impact on clinical outcomes across this region. Here we describe the registry's design and development, initial data, progress and future plans. METHODS: The APAC MRDR was established in 2018 as a multicentre collaboration across the Asia-Pacific, collecting prospective data on patients newly diagnosed with MM, MGUS, PCL and plasmacytoma in Korea, Singapore, Malaysia and Taiwan, with China recently joining. Development of the registry required a multidisciplinary team of clinicians, researchers, legal and information technology support, and financial resources, as well as local clinical context from key opinion leaders in the APAC region. Written informed consent is obtained and data are routinely collected throughout treatment by hospital staff. Data are stored securely, meeting all local privacy and ethics requirements. Data were collected from October 2018 to March 2024. RESULTS: Over 1700 patients from 24 hospitals have been enrolled onto the APAC MRDR to date, with the majority (86%) being newly diagnosed with MM. Bortezomib with an immunomodulatory drug was most frequently used in first-line MM therapy, and lenalidomide-based therapy was most common in second-line. Establishment and implementation challenges include regulatory and a range of operational issues. CONCLUSION: The APAC MRDR is providing 'real-world' data to participating sites, clinicians and policy-makers to explore factors influencing outcomes and survival, and to support high quality studies. It is already a valuable resource that will continue to grow and support research and clinical collaboration in MM and related diseases across the APAC region.

Health economics study of paliperidone palmitate in the treatment of schizophrenia: a 12-month cohort study.

BACKGROUND: To analyze the economic benefits of paliperidone palmitate in the treatment of schizophrenia. METHODS: We collected 546 patients who met the diagnostic criteria for schizophrenia according to the 《International Statistical Classification of Diseases and Related Health Problems,10th》(ICD-10). We gathered general population data such as gender, age, marital status, and education level, then initiated treatment with paliperidone palmitate. Then Follow-up evaluations were conducted at 1, 3, 6, 9, and 12 months after the start of treatment to assess clinical efficacy, adverse reactions, and injection doses. We also collected information on the economic burden before and after 12 months of treatment, as well as the number of outpatient visits and hospitalizations in the past year to analyze economic benefits. RESULTS: The baseline patients totaled 546, with 239 still receiving treatment with paliperidone palmitate 12 months later. After 12 months of treatment, the number of outpatient visits per year increased compared to before (4 (2,10) vs. 12 (4,12), Z=-5.949, P < 0.001), while the number of hospitalizations decreased (1 (1,3) vs. 1 (1,2), Z = 5.625, P < 0.001). The inpatient costs in the direct medical expenses of patients after 12 months of treatment decreased compared to before (5000(2000,12000) vs. 3000 (1000,8050), P < 0.05), while there was no significant change in outpatient expenses and direct non-medical expenses (transportation, accommodation, meal, and family accompanying expenses, etc.) (P > 0.05); the indirect costs of patients after 12 months of treatment (lost productivity costs for patients and families, economic costs due to destructive behavior, costs of seeking non-medical assistance) decreased compared to before (300(150,600) vs. 150(100,200), P < 0.05). CONCLUSION: Palmatine palmitate reduces the number of hospitalizations for patients, as well as their direct and indirect economic burdens, and has good economic benefits.

Factors determining contamination and time trends in cyclic and linear siloxanes in sediments from an industrialized lake in Korea.

Siloxanes, widely used in various consumer and industrial products, are emerging concerns of contaminants. Despite this, limited studies have been conducted on contamination and time trends on siloxanes in coastal environments. In the present study, four cyclic and 15 linear siloxanes were measured in sediments collected from an artificial saltwater lake in Korea during 2001-2016 to investigate contamination, time trends, and ecotoxicological concerns. Cyclic siloxanes were detected in all sediment samples, whereas linear siloxanes were not frequently detected. The highest siloxane concentrations were observed in creeks passing through various industrial complexes, indicating that industrial activities predominantly contributed to siloxane contamination in coastal environments. Decamethylcyclopentasiloxane (D5) and dodecylcyclohexasiloxane (D6) were predominant siloxanes in sediments over the last two decades. Siloxane concentrations significantly increased in creek sediments from 2008 to 2016, whereas those in inshore and offshore regions significantly decreased due to a strong dilution effect by the operation of tidal power plant. This suggests that consumption patterns and coastal development activities are crucial factors determining the contamination and time trends in the sedimentary siloxanes. The sedimentary concentrations of octamethylcyclotetrasiloxane (D4) and D5 exceeded several thresholds, raising the potentials for ecological risks to aquatic organisms.

Triphenyltin induced darker body coloration by disrupting melanocortin system and pteridine metabolic pathway in a reef fish, Amphiprion ocellaris.

Triphenyltin (TPT) is a typical persistent organic pollutant whose occurrence in coral reef ecosystems may threaten the survival of reef fishes. In this study, a brightly colored representative reef fish, Amphiprion ocellaris was used to explore the effects of TPT at environmental levels (1, 10, and 100 ng/L) on skin pigment synthesis. After the fish were exposed to TPT for 60 days, the skin became darker, owing to an increase in the relative area of black stripes, a decrease in orange color values while an increase in brown color values, and an increase in the number of melanocytes in the orange part of the skin tissues. To explore the mechanisms by which TPT induces darker body coloration, the enzymatic activity and gene expression levels of the members of melanocortin system that affect melanin synthesis were evaluated. Leptin levels and lepr expression were found to be increased after TPT exposure, which likely contributed to the increase found in pomc expression and α-melanocyte-stimulating hormone (α-MSH) levels. Then Tyr activity and mc1r, tyr, tyrp1, mitf, and dct were upregulated, ultimately increasing melanin levels. Importantly, RT-qPCR results were consistent with the transcriptome analysis of trends in lepr and pomc expression. Because the orange color values decreased, pterin levels and the pteridine metabolic pathway were also evaluated. The results showed that TPT induced BH4 levels and spr, xdh, and gch1 expression associated with pteridine synthesis decreased, ultimately decreasing the colored pterin content (sepiapterin). We conclude that TPT exposure interferes with the melanocortin system and pteridine metabolic pathway to increase melanin and decrease colored pterin levels, leading to darker body coloration in A. ocellaris. Given the importance of body coloration for the survival and reproduction of reef fishes, studies on the effects of pollutants (others alongside TPT) on body coloration are of high priority.

Chryseobacterium oryctis sp. nov., isolated from the gut of the beetle Oryctes rhinoceros, and Chryseobacterium kimseyorum sp. nov., isolated from a stick insect rearing cage.

Two strains of Chryseobacterium identified from different experiments are proposed to represent new species. Strain WLa1L2M3T was isolated from the digestive tract of an Oryctes rhinoceros beetle larva. Strain 09-1422T was isolated from a cage housing the stick insect Eurycantha calcarata. Sequence analysis of the 16S rRNA and rpoB genes found both strains to be similar but not identical to other Chryseobacterium species. Whole-genome sequencing suggested the isolates represent new species, with average nucleotide identity values ranging from 74.6 to 80.5 %. Genome-to-genome distance calculations produced values below 25.3 %, and digital DNA-DNA hybridization values were 13.7-29.9 %, all suggesting they are distinct species. The genomic DNA G+C content of WLa1L2M3T is approximately 32.53 %, and of 09-1422T is approximately 35.89 %. The predominant cellular fatty acids of strain WLa1L2M3T are C15 : 0 iso, summed feature 9 (C16 : 0 10OH or C17 : 1 iso ω6c), C17 : 0 iso 3OH, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C15 : 0 iso 3OH, C15 : 0 anteiso and C13 : 0 iso, and those of strain 09-1422T are C15 : 0 iso, summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c), C17 : 0 iso 3OH, C15 : 0 anteiso, C15 : 0 iso 3OH, C16 : 1 ω7c, C17 : 0 2OH and C18 : 0. In addition, physiological and biochemical tests revealed phenotypic differences from related Chryseobacterium type strains. These cumulative data indicate that the two strains represent novel species of the genus Chryseobacterium for which the names Chryseobacterium oryctis sp. nov. and Chryseobacterium kimseyorum sp. nov. are proposed with WLa1L2M3T (=BCRC 81350T=JCM 35215T=CIP 112035T) and 09-1422T (=UCDFST 09-1422T=BCRC 81359T=CIP 112165T), as type strains, respectively.

Development and validation of a new risk assessment model for immunomodulatory drug-associated venous thrombosis among Chinese patients with multiple myeloma.

BACKGROUND: Individuals with multiple myeloma (MM) receiving immunomodulatory drugs (IMiDs) are at risk of developing venous thromboembolism (VTE), a serious complication. There is no established clinical model for predicting VTE in the Chinese population. We develop a new risk assessment model (RAM) for IMiD-associated VTE in Chinese MM patients. METHODS: We retrospectively selected 1334 consecutive MM patients receiving IMiDs from 16 medical centers in China and classified them randomly into the derivation and validation cohorts. A multivariate Cox regression model was used for analysis. RESULTS: The overall incidence of IMiD-related VTE in Chinese MM patients was 6.1%. Independent predictive factors of VTE (diabetes, ECOG performance status, erythropoietin-stimulating agent use, dexamethasone use, and VTE history or family history of thrombosis) were identified and merged to develop the RAM. The model identified approximately 30% of the patients in each cohort at high risk for VTE. The hazard ratios (HRs) were 6.08 (P < 0.001) and 6.23 (P < 0.001) for the high-risk subcohort and the low-risk subcohort, respectively, within both the derivation and validation cohorts. The RAM achieved satisfactory discrimination with a C statistic of 0.64. The stratification approach of the IMWG guidelines yielded respective HRs of 1.77 (P = 0.053) and 1.81 (P = 0.063). The stratification approach of the SAVED score resulted in HRs of 3.23 (P = 0.248) and 1.65 (P = 0.622), respectively. The IMWG guideline and the SAVED score-based method yielded C statistics of 0.58 and 0.51, respectively. CONCLUSIONS: The new RAM outperformed the IMWG guidelines and the SAVED score and could potentially guide the VTE prophylaxis strategy for Chinese MM patients.

A neuromusculoskeletal modelling approach to bilateral hip mechanics due to unexpected lateral perturbations during overground walking.

BACKGROUND: Current studies on how external perturbations impact gait dynamics have primarily focused on the changes in the body's center of mass (CoM) during treadmill walking. The biomechanical responses, in particular to the multi-planar hip joint coordination, following perturbations in overground walking conditions are not completely known. METHODS: In this study, a customized gait-perturbing device was designed to impose controlled lateral forces onto the subject's pelvis during overground walking. The biomechanical responses of bilateral hips were simulated by subject-specific neuromusculoskeletal models (NMS) driven by in-vivo motion data, which were further evaluated by statistical parameter mapping (SPM) and muscle coactivation index (CI) analysis. The validity of the subject-specific NMS was confirmed through comparison with measured surface electromyographic signals. RESULTS: Following perturbations, the sagittal-plane hip motions were reduced for the leading leg by 18.39° and for the trailing leg by 8.23°, while motions in the frontal and transverse plane were increased, with increased hip abduction for the leading leg by 10.71° and external rotation by 9.06°, respectively. For the hip kinetics, both the bilateral hip joints showed increased abductor moments during midstance (20%-30% gait cycle) and decreased values during terminal stance (38%-48%). Muscle CI in both sagittal and frontal planes was significantly decreased for perturbed walking (p < 0.05), except for the leading leg in the sagittal plane. CONCLUSION: The distinctive phase-dependent biomechanical response of the hip demonstrated its coordinated control strategy for balance recovery due to gait perturbations. And the changes in muscle CI suggested a potential mechanism for rapid and precise control of foot placement through modulation of joint stiffness properties. These findings obtained during actual overground perturbation conditions could have implications for the improved design of wearable robotic devices for balance assistance.

Occurrence, time trends, and human exposure of siloxanes and synthetic musk compounds in indoor dust from Korean homes.

Siloxanes and synthetic musk compounds (SMCs) have been widely used as additives in household and personal care products. Humans are easily exposed to siloxanes and SMCs originating from these products through ingestion and dermal absorption of indoor dust. In the present study, indoor dust samples were analyzed for 19 siloxanes (cyclic and linear) and 12 SMCs (polycyclic, macrocyclic, and nitro musks) to assess their occurrence, time trends over time, source, and health risks. A total of 18 siloxanes and 10 SMCs were detected in all indoor dust samples obtained from 2011⎯2021, indicating widespread and long-term contamination. Higher detection frequencies and concentrations were associated with siloxanes and SMCs with higher use and strong resistance against degradation processes. Indoor dust samples were dominated by linear siloxanes (L11-L13), 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-(g)-2-benzopyran (HHCB), musk ketone (MK), and 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN). The frequent use of household and personal care products is likely an important source of siloxane and SMC contamination in indoor environments. The concentrations of siloxanes and SMCs in indoor dust increased from 2011 to 2021, particularly, those of linear siloxanes, reflecting the impact of regulatory actions addressing cyclic siloxanes. The profiles of siloxanes remained stable throughout the study period, whereas those of SMCs shifted from nitro to polycyclic musks. The estimated daily intakes (EDIs) of siloxanes and SMCs arising from ingestion were greater than from dermal absorption of indoor dust. The EDIs of siloxanes and SMCs associated with indoor dust indicated that children are exposed to these pollutants.

Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor (MARCH): a phase II, single-arm study.

BACKGROUND: Selinexor 80 mg combined with low-dose dexamethasone (Sd) demonstrated significant clinical benefit in patients with relapsed/refractory multiple myeloma (RRMM) who had disease refractory to a proteasome inhibitor (PI), an immunomodulator (IMiD), and an anti-CD38 monoclonal antibody based on a global phase II STORM study. The present study, MARCH, addresses China regulatory needs to further validate the data from STORM in Chinese patients with RRMM. METHODS: The MARCH study was conducted at 17 sites in China, where eligible Chinese RRMM patients who had disease refractory to PI and IMiD were enrolled. Selinexor 80 mg combined with dexamethasone 20 mg was administered orally on day 1 and day 3 of each week in 4-week cycles. The primary endpoint was the overall response rate (ORR) per an independent review committee, with the null hypothesis of ≤15%. Patients who received at least 1 dose of study treatment were included in the safety population. The pharmacokinetic (PK) profile was characterized by parameter and ethnicity sensitivity analyses. RESULTS: A total of 82 patients with RRMM were enrolled in the study, with a median age of 60 years. Of the 82 patients, 55 patients (67.1%) had high-risk cytogenetic abnormalities, defined as one or more of del 17p13, t(4;14), t(14;16), or 1q amplification identified by fluorescence in situ hybridization (FISH); 18 patients (22.0%) had abnormal renal function. Enrolled patients were heavily pre-treated with a median prior regimen number of 5. All 82 patients (100%) were refractory to both PI and IMiD, including 20 patients (24.4%) categorized as triple-class refractory population (refractory to PI, IMiD, and daratumumab). Ten patients (12.2%) had undergone CAR-T therapy. ORR was 29.3% (95% CI 19.7, 40.4) with a median DOR of 4.7 months. The median PFS and OS were 3.7 and 13.2 months, respectively. ORR was 25.0% (95% CI 8.7, 49.1) in the triple-class refractory population. Efficacy was consistent across various subgroups. The most frequent grade 3/4 adverse events (AEs) included anemia (57.3%), thrombocytopenia (51.2%), lymphopenia (42.7%), neutropenia (40.2%), hyponatremia (29.3%), and lung infection (26.8%). Serious AEs were reported in 54.9% of patients. No significant drug accumulation was shown following multiple administrations. No human PK ethnicity difference was identified between Chinese and western patients. CONCLUSIONS: With an encouraging ORR, the MARCH study has demonstrated that selinexor combined with low-dose dexamethasone (Sd) delivers meaningful clinical benefit to Chinese patients with RRMM, including triple-class refractory patients. AEs were expected and manageable with supportive care and dose modification. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03944057 (May 09, 2019); Chinadrugtrials.org.cn , CTR20190858 (June 05, 2019).

Newly diagnosed multiple myeloma patients with CD56 expression benefit more from autologous stem cell transplantation.

BACKGROUND: Several studies showed that lack of CD56 expression was a poor prognostic factor for patients with newly diagnosed multiple myeloma (NDMM). However, other studies were not able to confirm the prognostic value of CD56 in NDMM. This study aimed to evaluate the prognostic value of CD56 expression for patients with NDMM who received autologous stem cell transplantation (ASCT). METHODS: We retrospectively analyzed 370 patients with NDMM under 66 years old and the propensity score matching technique was used to reduce the bias between two groups. RESULTS: CD56 expression was observed in 250 (67.6%) patients, and only half of transplant-eligible patients received ASCT for financial and adverse effects concerns after induction therapy. 54.8% (137/250) CD56 positive patients received ASCT; and 47.5% (57/120) CD56 negative patients received ASCT. Univariate and multivariate analyses showed that ASCT was correlated with longer overall survival (OS) (p < 0.001) and progression-free survival (PFS) (p < 0.001) for CD56 positive patients. However, ASCT had no impact on OS and PFS in univariate and multivariate analysis (p > 0.05). In the propensity score matching analysis, 186 CD56 positive patients were identified, 93 patients had received ASCT and 93 patients had no ASCT. Among 120 CD56 negative patients, 80 patients, 40 in each group, were identified. Among 186 matched CD56 positive patients, patients with ASCT had longer OS (87.6 vs.56.1 months, p = 0.049) and PFS (36.7 vs.30.9 months, p = 0.040). However, ASCT had no impact on OS and PFS for matched CD56 negative patients (p > 0.05). CONCLUSIONS: These results demonstrated that ASCT may improve OS and PFS of CD56 positive patients and had no impact on survival of CD56 negative patients.

Mechanisms underlying synergism between circularized tumor necrosis factor-related apoptosis inducing ligand and bortezomib in bortezomib-sensitive or -resistant myeloma cells.

Mechanisms underlying interactions between a novel, clinically relevant circularized tumor necrosis factor-related apoptosis inducing ligand (TRAIL) agonist, circularly permuted TRAIL (CPT) have been examined in multiple myeloma (MM) cells sensitive or resistant to bortezomib (BTZ). Various MM cell lines for example, U266, including those resistant to bortezomib-resistant U266 cells were exposed to low nanomolar concentrations of bortezomib ± CPT and apoptosis monitored. Circularly permuted TRAIL and bortezomib synergistically induced apoptosis in both BTZ-naïve and -resistant cells. The regimen up-regulated DR4 receptor internalization in MM cells, known to modulate both NF-κB and extrinsic apoptotic pathways. CPT/BTZ disrupted the non-canonical NF-κB pathway, reflected by tumor necrosis factor (TNF) receptor associated factors 3 (TRAF3) up-regulation, NF-κB inducing kinase down-regulation, diminished p52 and p50 processing, and B-cell lymphoma-extra large (BCL-XL) down-regulation, but failed to inactivate the canonical NF-κB pathway, reflected by unchanged or increased expression of phospho-p65. The regimen also sharply increased extrinsic apoptotic pathway activation. Cells exhibiting TRAF3 knock-down, dominant-negative Fas-associated protein with death domain, knock-down of caspase-8, BCL-2/BCL-XL, or exposure to a caspase-9 inhibitor displayed markedly reduced CPT/BTZ sensitivity. Concordant results were observed in bortezomib-resistant cells. The regimen was also active in the presence of stromal cells and was relatively sparing toward normal CD34+ hematopoietic cells. Finally, ex vivo results revealed synergism in primary MM primary cells, including those BTZ, and the CPT/BTZ regimen significantly decreased tumor growth in a patient-derived MM xenograft model. These results indicate that the CPT/BTZ regimen acts via the non-canonical NF-κB as well as intrinsic/extrinsic apoptotic pathways to induce cell death in MM cells, and may represent an effective strategy in the setting of bortezomib resistance.

Hymenobacter piscis sp. nov., isolated from a fish pond.

Bacterial strain NST-14T, isolated from a freshwater fish pond in Taiwan, was characterized using a polyphasic taxonomy approach. The strain was Gram-stain-negative, strictly aerobic, non-motile, rod-shaped and formed pink colonies. Optimal growth occurred at 30 °C, pH 7 and in the absence of NaCl. Phylogenetic analyses based on 16S rRNA gene sequences and coding sequences of 92 protein clusters indicated that strain NST-14T formed a phylogenetic lineage in the genus Hymenobacter. Analysis of 16S rRNA gene sequences showed that strain NST-14T had the highest similarity to Hymenobacter actinosclerus CCUG 39621T (97.7%), Hymenobacter amundsenii P5136T (97.3%) and Hymenobacter humicola P6312T (96.9%). Strain NST-14T showed 75.1-85.3 % average nucleotide identity, 73.7-89.8 % average amino acid identity and 14.5-26.0 % digital DNA-DNA hybridization with the type strains of other closely related Hymenobacter species. Strain NST-14T contained iso-C15 : 0, C16 : 1 ω5c and summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) as the predominant fatty acids. The major hydroxyl fatty acids were iso-C17 : 0 3-OH and iso-C15 : 0 3-OH. The polar lipids were phosphatidylethanolamine, one unidentified glycolipid, four unidentified aminophospholipids, one unidentified aminolipid, two unidentified phospholipids and three unidentified lipids. The major polyamine was homospermidine. The major isoprenoid quinone was MK-7. The DNA G+C content of the genomic DNA was 62.4 mol%. Differential phenotypic properties, together with the phylogenetic inference, demonstrate that strain NST-14T should be classified as a novel species of the genus Hymenobacter, for which the name Hymenobacter piscis sp. nov. is proposed. The type strain is NST-14T (=BCRC 81249T=LMG 31686T).

Design and synthesis of epigallocatechin (EGC) analogs selective to inhibit α-amylase over α-glucosidases via the incorporation of caffeine acid and its derivatives.

Natural products are a promising and underappreciated reservoir for the preferred chemical scaffolds in the search of antidiabetic drugs. In this study twenty-one EGC-based derivatives selective to inhibit human pancreatic α-amylase (HPA), the enzyme at the top of the starch digestion pyramid, have been designed and synthesized in terms of the lead myricetin-caffeic acid conjugate 1 reported ever. We focus on methylation of caffeic acid, length of a liker, a double bond contained in the linker on the inhibition activity and selectivity of EGC-based conjugates. As a result, methylation of caffeic acid and the length of a linker affect significantly the activity and selectivity of EGC-based conjugates, but the effect of a double in caffeic acid is limited. Conjugate 2a-1 having a six-carbon-atom linker fused to EGC and caffeic acid demonstrates the most ponent inhibitory activity to HPA and its selectivity towards HPA over α-glucosidase by far superior to that construct 1. Molecular docking studies reveal that conjugate 2a-1 accommodates well to the active site of HPA with four hydrogen bonds in the form of the preorganization of two moieties EGC and caffeic acid via π-stacking interaction. Collectively, conjugating caffeic acid and EGC with an appropriate linker possibly provides a new strategy for finding the specific HPA inhibitors in the discovery of anti-diabetes mellitus drugs.

The influence of local pain on balance control in patients with chronic ankle instability.

BACKGROUND: Local pain around the ankle joint is a common symptom in patients with chronic ankle instability (CAI). However, whether the local pain would impose any influence on the balance control performance of CAI patients is still unknown. METHODS: A total of twenty-six subjects were recruited and divided into the following two groups: pain-free CAI (group A) and pain-present CAI (group B). Subjects in both groups received two independent tests: the star excursion balance test and the single-leg stance test, in order to reflect their balance control ability more accurately. RESULTS: Compared with group A, the group B showed significantly more episodes of the history of sprains, decreased ankle maximum plantarflexion angle, and lower Cumberland scores (all p < 0.05). In the star excursion balance test, group B demonstrated a significantly reduced anterior reach distance than group A (p < 0.05). During the single leg stance test, group B showed a significant increase in the magnitude of electromyographic signals both in peroneus longus and soleus muscles than group A (each p < 0.05). Additionally, group B had a significantly more anterolaterally positioned plantar center of pressure than group A (p < 0.05). CONCLUSION: CAI patients with local pain around the ankle joint had more episodes of sprains and lower functional scores when compared to those without pain. The balance control performance was also worse in the pain-present CAI patients than those without pain.

Finite element stress analysis of the bearing component and bone resected surfaces for total ankle replacement with different implant material combinations.

BACKGROUND: A proper combination of implant materials for Total Ankle Replacement (TAR) may reduce stress at the bearing component and the resected surfaces of the tibia and talus, thus avoiding implant failure of the bearing component or aseptic loosening at the bone-implant interface. METHODS: A comprehensive finite element foot model implanted with the INBONE II implant system was created and the loading at the second peak of ground reaction force was simulated. Twelve material combinations including four materials for tibial and talar components (Ceramic, CoCrMo, Ti6Al4V, CFR-PEEK) and three materials for bearing components (CFR-PEEK, PEEK, and UHMWPE) were analyzed. Von Mises stress at the top and articular surfaces of the bearing component and the resected surfaces of the tibia and talus were recorded. RESULTS: The stress at both the top and articular surfaces of the bearing component could be greatly reduced with more compliant bearing materials (44.76 to 72.77% difference of peak stress value), and to a lesser extent with more compliant materials for the tibial and talar components (0.94 to 28.09% difference of peak stress value). Peak stresses at both the tibial and talar bone-implant interface could be reduced more strongly by using tibial and talar component materials with smaller material stiffness (7.31 to 66.95% difference of peak stress value) compared with bearing materials with smaller material stiffness (1.11 to 24.77% difference of peak stress value). CONCLUSIONS: Implant components with smaller material stiffness provided a stress reduction at the bearing component and resected surfaces of the tibia and talus. The selection of CFR-PEEK as the material of tibial and talar components and UHMWPE as the material of the bearing component seemed to be a promising material combination for TAR implants. Wear testing and long-term failure analysis of TAR implants with these materials should be included in future studies.

Effect of loading history on material properties of human heel pad: an in-vivo pilot investigation during gait.

BACKGROUND: This study was aimed to develop a novel dynamic measurement technique for testing the material properties and investigating the effect of continuous compression load on the structural and mechanical properties of human heel pad during actual gait. METHODS: The dual fluoroscopic imaging system (DFIS) and dynamic foot-ground contact pressure-test plate were used for measuring the material properties, including primary thickness, peak strain, peak stress, elastic modulus, viscous modulus and energy dissipation rate (EDR), both at time zero and following continuous loading. Ten healthy pilot subjects, aged from 23 to 72 (average: 46.5 ± 17.6), were enrolled. A "three-step gait cycle" is performed for all subjects, with the second step striking at a marked position on the force plate with the heel to maintain the location of the tested foot to be in the view of fluoroscopes. The subjects were measured at both relaxed (time-zero group) and fatigue (continuous-loading group) statuses, and the left and right heels were measured using the identical procedures. RESULTS: The peak strain, peak stress, elastic modulus, and EDR are similar before and after continuous load, while the viscous modulus was significantly decreased (median: 43.9 vs. 20.37 kPa•s; p < 0.001) as well as primary thicknesses (median: 15.99 vs. 15.72 mm; p < 0.001). Age is demonstrated to be moderately correlated with the primary thicknesses both at time zero (R = -0.507) and following continuous load (R = -0.607). The peak stress was significantly correlated with the elastic modulus before (R = 0.741) and after continuous load (R = 0.802). The peak strain was correlated with the elastic modulus before (R = -0.765) and after continuous load (R = -0.801). The correlations between the viscous modulus and peak stress/ peak strain are similar to above(R = 0.643, 0.577, - 0.586 and - 0.717 respectively). The viscous modulus is positively correlated with the elastic modulus before (R = 0.821) and after continuous load (R = 0.784). CONCLUSIONS: By using dynamic fluoroscopy combined with the plantar pressure plate, the in vivo viscoelastic properties and other data of the heel pad in the actual gait can be obtained. Age was negatively correlated with the primary thickness of heel pad and peak strain, and was positively correlated with viscous modulus. Repetitive loading could decrease the primary thickness of heel pad and viscous modulus.

Application of a lateral intertubercular sulcus plate in the treatment of proximal humeral fractures: a finite element analysis.

BACKGROUND: Inversion deformities caused by insufficient medial support are especially common when the PHILOS locking plate is used to treat proximal humeral fractures. Using finite element analysis, we aimed to compare the biomechanical properties of a PHILOS locking plate (PLP) and a PLP combined with a lateral intertubercular sulcus plate (PLP-LSP) in the fixation of proximal humeral fractures with loss of the medial column. METHODS: After creating a three-dimensional finite element model of a proximal humeral fracture with loss of the medial column, three implant models were established. A full-screw PLP was used in Group A, a PHILOS plate lacking medial screw support and an additional steel plate (MPLP-LSP) were used in Group B, and a full-screw PLP-LSP was used in Group C. The three fixation models were applied to the proximal humeral fracture model, following which horizontal, compressive, and rotational loads were applied to the humerus model. We evaluated structural stiffness and stress distribution in the implant and compared displacement and angle changes among the three models. RESULTS: Displacement and angle changes were smallest in Group C (PLP-LSP). The implant model used in Group C also exhibited greater structural rigidity, endured less von Mises stress, and was more stable than the models used in Group A and Group B. CONCLUSION: An LSP placed at the intertubercular sulcus provides effective lateral and medial support, thereby reducing stress on the PLP and providing better stability with proximal humeral fractures.