Interpretable feature extraction and dimensionality reduction in ESM2 for protein localization prediction.

As the application of large language models (LLMs) has broadened into the realm of biological predictions, leveraging their capacity for self-supervised learning to create feature representations of amino acid sequences, these models have set a new benchmark in tackling downstream challenges, such as subcellular localization. However, previous studies have primarily focused on either the structural design of models or differing strategies for fine-tuning, largely overlooking investigations into the nature of the features derived from LLMs. In this research, we propose different ESM2 representation extraction strategies, considering both the character type and position within the ESM2 input sequence. Using model dimensionality reduction, predictive analysis and interpretability techniques, we have illuminated potential associations between diverse feature types and specific subcellular localizations. Particularly, the prediction of Mitochondrion and Golgi apparatus prefer segments feature closer to the N-terminal, and phosphorylation site-based features could mirror phosphorylation properties. We also evaluate the prediction performance and interpretability robustness of Random Forest and Deep Neural Networks with varied feature inputs. This work offers novel insights into maximizing LLMs' utility, understanding their mechanisms, and extracting biological domain knowledge. Furthermore, we have made the code, feature extraction API, and all relevant materials available at https://github.com/yujuan-zhang/feature-representation-for-LLMs.

Liquid-embedded (bio)printing of alginate-free, standalone, ultrafine, and ultrathin-walled cannular structures.

While there has been considerable success in the three-dimensional bioprinting of relatively large standalone filamentous tissues, the fabrication of solid fibers with ultrafine diameters or those cannular featuring ultrathin walls remains a particular challenge. Here, an enabling strategy for (bio)printing of solid and hollow fibers whose size ranges could be facilely adjusted across a broad spectrum, is reported, using an aqueous two-phase embedded (bio)printing approach combined with specially designed cross-linking and extrusion methods. The generation of standalone, alginate-free aqueous architectures using this aqueous two-phase strategy allowed freeform patterning of aqueous bioinks, such as those composed of gelatin methacryloyl, within the immiscible aqueous support bath of poly(ethylene oxide). Our (bio)printing strategy revealed the fabrication of standalone solid or cannular structures with diameters as small as approximately 3 or 40 µm, respectively, and wall thicknesses of hollow conduits down to as thin as <5 µm. With cellular functions also demonstrated, we anticipate the methodology to serve as a platform that may satisfy the needs for the different types of potential biomedical and other applications in the future, especially those pertaining to cannular tissues of ultrasmall diameters and ultrathin walls used toward regenerative medicine and tissue model engineering.

Decoding the "Fingerprint" of Implant Materials: Insights into the Foreign Body Reaction.

Foreign body reaction (FBR) is a prevalent yet often overlooked pathological phenomenon, particularly within the field of biomedical implantation. The presence of FBR poses a heavy burden on both the medical and socioeconomic systems. This review seeks to elucidate the protein "fingerprint" of implant materials, which is generated by the physiochemical properties of the implant materials themselves. In this review, the activity of macrophages, the formation of foreign body giant cells (FBGCs), and the development of fibrosis capsules in the context of FBR are introduced. Additionally, the relationship between various implant materials and FBR is elucidated in detail, as is an overview of the existing approaches and technologies employed to alleviate FBR. Finally, the significance of implant components (metallic materials and non-metallic materials), surface CHEMISTRY (charge and wettability), and physical characteristics (topography, roughness, and stiffness) in establishing the protein "fingerprint" of implant materials is also well documented. In conclusion, this review aims to emphasize the importance of FBR on implant materials and provides the current perspectives and approaches in developing implant materials with anti-FBR properties.

Genome-wide analysis of R2R3-MYB transcription factors in poplar and functional validation of PagMYB147 in defense against Melampsora magnusiana.

MAIN CONCLUSION: Transcription of PagMYB147 was induced in poplar infected by Melampsora magnusiana, and a decline in its expression levels increases the host's susceptibility, whereas its overexpression promotes resistance to rust disease. Poplars are valuable tree species with diverse industrial and silvicultural applications. The R2R3-MYB subfamily of transcription factors plays a crucial role in response to biotic stresses. However, the functional studies on poplar R2R3-MYB genes in resistance to leaf rust disease are still insufficient. We identified 191 putative R2R3-MYB genes in the Populus trichocarpa genome. A phylogenetic analysis grouped poplar R2R3-MYBs and Arabidopsis R2R3-MYBs into 33 subgroups. We detected 12 tandem duplication events and 148 segmental duplication events, with the latter likely being the main contributor to the expansion of poplar R2R3-MYB genes. The promoter regions of these genes contained numerous cis-acting regulatory elements associated with response to stress and phytohormones. Analyses of RNA-Seq data identified a multiple R2R3-MYB genes response to Melampsora magnusiana (Mmag). Among them, PagMYB147 was significantly up-regulated under Mmag inoculation, salicylic acid (SA) and methyl jasmonate (MeJA) treatment, and its encoded product was primarily localized to the cell nucleus. Silencing of PagMYB147 exacerbated the severity of Mmag infection, likely because of decreased reactive oxygen species (ROS) production and phenylalanine ammonia-lyase (PAL) enzyme activity, and up-regulation of genes related to ROS scavenging and down-regulation of genes related to PAL, SA and JA signaling pathway. In contrast, plants overexpressing PagMYB147 showed the opposite ROS accumulation, PAL enzyme activity, SA and JA-related gene expressions, and improved Mmag resistance. Our findings suggest that PagMYB147 acts as a positive regulatory factor, affecting resistance in poplar to Mmag by its involvement in the regulation of ROS homeostasis, SA and JA signaling pathway.

DLP Fabrication of Multiple Hierarchical Biomimetic GelMA/SilMA/HAp Scaffolds for Enhancing Bone Regeneration.

Severe bone defects resulting from trauma and diseases remain a persistent clinical challenge. In this study, a hierarchical biomimetic microporous hydrogel composite scaffold was constructed by mimicking the hierarchical structure of bone. Initially, gelatin methacrylamide (GelMA) and methacrylic anhydride silk fibroin (SilMA) were synthesized, and GelMA/SilMA inks with suitable rheological and mechanical properties were prepared. Biomimetic micropores were then generated by using an aqueous two-phase emulsification method. Subsequently, biomimetic microporous GelMA/SilMA was mixed with hydroxyapatite (HAp) to prepare biomimetic microporous GelMA/SilMA/HAp ink. Hierarchical biomimetic microporous GelMA/SilMA/HAp (M-GSH) scaffolds were then fabricated through digital light processing (DLP) 3D printing. Finally, in vitro experiments were conducted to investigate cell adhesion, proliferation, and inward migration as well as osteogenic differentiation and vascular regeneration effects. In vivo experiments indicated that the biomimetic microporous scaffold significantly promoted tissue integration and bone regeneration after 12 weeks of implantation, achieving 42.39% bone volume fraction regeneration. In summary, this hierarchical biomimetic microporous scaffold provides a promising strategy for the repair and treatment of bone defects.

Prevalence of childhood hypertension and associated factors in Zhejiang Province: a cross-sectional analysis based on random forest model and logistic regression.

With childhood hypertension emerging as a global public health concern, understanding its associated factors is crucial. This study investigated the prevalence and associated factors of hypertension among Chinese children. This cross-sectional investigation was conducted in Pinghu, Zhejiang province, involving 2,373 children aged 8-14 years from 12 schools. Anthropometric measurements were taken by trained staff. Blood pressure (BP) was measured in three separate occasions, with an interval of at least two weeks. Childhood hypertension was defined as systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) ≥ age-, sex-, and height-specific 95th percentile, across all three visits. A self-administered questionnaire was utilized to collect demographic, socioeconomic, health behavioral, and parental information at the first visit of BP measurement. Random forest (RF) and multivariable logistic regression model were used collectively to identify associated factors. Additionally, population attributable fractions (PAFs) were calculated. The prevalence of childhood hypertension was 5.0% (95% confidence interval [CI]: 4.1-5.9%). Children with body mass index (BMI) ≥ 85th percentile were grouped into abnormal weight, and those with waist circumference (WC) > 90th percentile were sorted into central obesity. Normal weight with central obesity (NWCO, adjusted odds ratio [aOR] = 5.04, 95% CI: 1.96-12.98), abnormal weight with no central obesity (AWNCO, aOR = 4.60, 95% CI: 2.57-8.21), and abnormal weight with central obesity (AWCO, aOR = 9.94, 95% CI: 6.06-16.32) were associated with an increased risk of childhood hypertension. Childhood hypertension was attributable to AWCO mostly (PAF: 0.64, 95% CI: 0.50-0.75), followed by AWNCO (PAF: 0.34, 95% CI: 0.19-0.51), and NWCO (PAF: 0.13, 95% CI: 0.03-0.30). Our results indicated that obesity phenotype is associated with childhood hypertension, and the role of weight management could serve as potential target for intervention.

The learning curve of a novel seven-axis robot-assisted total hip arthroplasty system: a randomized controlled trial.

BACGROUND: The aim of this study was to assess the learning curve of a novel seven-axis robot-assisted total hip arthroplasty (RaTHA) system. METHODS: A total of 59 patients who underwent unilateral total hip arthroplasty at our institution from June 2022 to September 2022 were prospectively included in the study. In this randomized controlled clinical trial, robot-assisted THA (RaTHA) and Conventional THA (CoTHA) were performed using cumulative sum (CUSUM) analysis to evaluate the learning curve of the RaTHA system. The demographic data, preopera1tive clinical data, duration of operation, postoperative Harris Hip Score (HHS), postoperative Western Ontario and McMaster Universities Arthritis Index (WOMAC) score, and duration of operation between the learning stage and the proficiency stage of the RaTHA group were compared between the two groups. RESULTS: The average duration of operation of the RaTHA group was increased by 34.73 min compared with the CoTHA group (104.26 ± 19.33 vs. 69.53 ± 18.38 min, p < 0.01). The learning curve of the RaTHA system can be divided into learning stage and proficiency stage, and the former consists of the first 13 cases by CUSUM analysis. In the RaTHA group, the duration of operation decreased by 29.75 min in the proficiency stage compared to the learning stage (121.12 ± 12.84 vs.91.37 ± 12.92, p < 0.01). CONCLUSIONS: This study demonstrated that the surgical team required a learning curve of 13 cases to become proficient using the RaTHA system. The duration of operation, total blood loss, and drainage gradually shortened (decreased) with the learning curve stage, and the differences were statistically significant. TRIAL REGISTRATION: Number: ChiCTR2200061630, Date: 29/06/2022.

Nanofiber Aerogels with Precision Macrochannels and LL-37-Mimic Peptides Synergistically Promote Diabetic Wound Healing.

Fast healing of diabetic wounds remains a major clinical challenge. Herein, this work reports a strategy to combine nanofiber aerogels containing precision macrochannels and the LL-37-mimic peptide W379 for rapid diabetic wound healing. Nanofiber aerogels consisting of poly(glycolide-co-lactide) (PGLA 90:10)/gelatin and poly-p-dioxanone (PDO)/gelatin short electrospun fiber segments were prepared by partially anisotropic freeze-drying, crosslinking, and sacrificial templating with three-dimensional (3D)-printed meshes, exhibiting nanofibrous architecture and precision micro-/macrochannels. Like human cathelicidin LL-37, W379 peptide at a concentration of 3 µg/mL enhanced the migration and proliferation of keratinocytes and dermal fibroblasts in a cell scratch assay and a proliferation assay. In vivo studies show that nanofiber aerogels with precision macrochannels can greatly promote cell penetration compared to aerogels without macrochannels. Relative to control and aerogels with and without macrochannels, adding W379 peptides to aerogels with precision macrochannels shows the best efficacy in healing diabetic wounds in mice in terms of cell infiltration, neovascularization, and re-epithelialization. The fast re-epithelization could be due to upregulation of phospho-extracellular signal-regulated kinase (p38 MAPK) after treatment with W379. Together, the approach developed in this work could be promising for the treatment of diabetic wounds and other chronic wounds.

Micropore-Forming Gelatin Methacryloyl (GelMA) Bioink Toolbox 2.0: Designable Tunability and Adaptability for 3D Bioprinting Applications.

It is well-known that tissue engineering scaffolds that feature highly interconnected and size-adjustable micropores are oftentimes desired to promote cellular viability, motility, and functions. Unfortunately, the ability of precise control over the microporous structures within bioinks in a cytocompatible manner for applications in 3D bioprinting is generally lacking, until a method of micropore-forming bioink based on gelatin methacryloyl (GelMA) was reported recently. This bioink took advantage of the unique aqueous two-phase emulsion (ATPE) system, where poly(ethylene oxide) (PEO) droplets are utilized as the porogen. Considering the limitations associated with this very initial demonstration, this article has furthered the understanding of the micropore-forming GelMA bioinks by conducting a systematic investigation into the additional GelMA types (porcine and fish, different methacryloyl-modification degrees) and porogen types (PEO, poly(vinyl alcohol), and dextran), as well as the effects of the porogen concentrations and molecular weights on the properties of the GelMA-based ATPE bioink system. This article exemplifies not only the significantly wider range of micropore sizes achievable and better emulsion stability, but also the improved suitability for both extrusion and digital light processing bioprinting with favorable cellular responses.

Lobaplatin hyperthermic intraperitoneal chemotherapy plus cytoreduction and rechallenge using cetuximab for wild-type RAS peritoneal metastatic colon cancer: a case report and literature review.

BACKGROUND: Synchronous peritoneal metastasis of colorectal cancer usually predicts a bleak prognosis. Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) have brought a glimmer of hope to the treatment of peritoneal cancer. Few cases treated with lobaplatin have been reported in the literature and the regimen is controversial. In this case, the comprehensive treatment scheme of lobaplatin-based HIPEC plus CRS and rechallenge using cetuximab plus systemic chemotherapy is effective, especially for the patients with left colon cancer (wild-type RAS). CASE PRESENTATION: A 49 year-old man with signet ring cell carcinoma of sigmoid colon with extensive abdominal metastasis (wild-type RAS) was hospitalized with prolonged abdominal pain, distention and abdominal mass. After receiving HIPEC with lobaplatin and XELOX regimen combined with cetuximab for eight cycles, the patient had been treated with the FOLFIRI regimen and cetuximab for 24 cycles, which discontinued due to myelosuppression. Because the disease recurred unfortunately 4 months later, the FOLFIRI + cetuximab regimen was initiated again and stopped after two cycles. Intestinal obstruction occurred 1 month later, so open total colectomy, CRS + HIPEC and ileorectal anastomosis were performed. Capecitabine adjuvant chemotherapy was administered, followed by the maintenance therapy with FOLFIRI + cetuximab regimen. After that, the patient has been in relatively stable condition. By August 2021, the overall survival is more than 45 months, which displays significant curative effect. CONCLUSION: For peritoneal metastasis from left colon cancer, the management with CRS + lobaplatin HIPEC and rechallenge of systemic chemotherapy plus targeted medicine based on gene detection can dramatically improve prognosis and extend the overall survival.

Comparison of the outcomes of cytoreductive surgery versus surgery plus hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis: a propensity score matching analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective treatment options for selected patients with peritoneal carcinomatosis (PC). We compared the short-term outcomes of surgery plus HIPEC and CRS alone for PC. METHODS: We retrospectively examined patients who underwent CRS-HIPEC for PC at a single center from 2014 to 2019 using the Chinese CRS-HIPEC patient database at our institution. Patients were divided into two groups: surgery plus HIPEC (450) and surgery alone (200). A 1:1 propensity score matching (PSM) analysis was performed. The postoperative outcomes, mortality, and length of hospital stay were compared between the surgery plus HIPEC and CRS alone groups. RESULTS: Propensity scoring generated 162 pairs. There was no statistically significant difference in the 30-day mortality rate between the groups (0% vs 0%, P = 1.000), and the morbidity rates were similar in both groups (7.4% vs 8.0%, P = 0.835). The surgery plus HIPEC group had a longer operative time (247.81 ± 64.70 vs 184.55 ± 29.56, P ≤ 0.001) and a slightly longer postoperative hospital stay (14.64 ± 5.24 vs 12.59 ± 3.76, P ≤ 0.001). No other baseline characteristics were significantly different. CONCLUSIONS: Surgery plus HIPEC is feasible for select patients and is associated with prolonged surgery times and prolonged hospital stays, and there is no significant difference in mortality rates or postoperative outcomes.

First Report of Leaf Rust of Acer mono Caused by Pucciniastrum hikosanense in China.

Acer mono Maxim, mainly distributed in China, Japan, Korea and eastern Russia (Shang et al. 2012), is a widely planted ornamental and pharmaceutical tree (Zhang et al. 2015). In September 2020, leaf samples of A. mono infected by uredinia were collected in Shaanxi Province (34°15'40.06'' N, 108°3'54.54'' E, alt. 432.35m), China. Telia development was observed in late autumn. Voucher specimens were deposited in the Herbarium Mycologicum Academiae Sinicae (no. HMAS249354), China. This led to premature defoliation and in the 90% planting wide incidence. Geospatial investigations revealed that this rust was widely distributed in local urban parks, but was nonpathogenic to A. buergerianum, A. negundo, A. oblongum, A. palmatum and A. rubrum. This fungus was morphologically characterized and most closely matched descriptions of Pucciniastrum. Uredinia were hypophyllous, subepidermal, scattered to gregarious, oval or round, 0.10-0.30 × 0.08-0.15 mm, golden yellow to orange, somewhat pulverulent. Peridia were hemispherical, erumpent with apical pores; peridial cells minute, irregularly polygonal, hyaline to pale yellow; ostiolar cells ellipsoid or roundish. Urediniospores were subglobose, ovate or ellipsoid, 20-33 × 15-21 µm, yellow to pale orange; wall 1-2 µm thick, hyaline to pale yellow, echinulate, somewhere smooth. Pedicels were deciduous, hyaline, minute, fragile. Telia were hypophyllous, subepidermal, intermixed with uredinia, irregularly polygonal, restricted by veins, 0.34-0.91 × 0.21-0.54 mm, and orange to amber brown. Teliospores were produced parallelly single-layered, and were subglobose, oblong, sometimes angular, 23-47 × 16-34 µm, colorless to pale yellow, 1-5 mediastinal, 2-6-celled; lateral wall 1-1.6 µm thick, apical wall 1-3 µm thick, smooth, hyaline. The internal transcribed spacer (ITS) and rDNA-28S regions were amplified using ITS1F/ITS4 and NL1/NL4 (Ji et al. 2019) to confirm the identification. The aligned sequences were deposited in GenBank (accession no. MW391829, MW543709, MW541916, MW541917). Phylogenetic trees were constructed based on neighbor-joining (NJ), maximum-likelihood (ML) and Bayesian methods. ML and NJ bootstrap values were calculated by bootstrap analyses of 1,000 replicates with GTR+G+I model using MEGA-X (Kumar et al. 2018), while Bayesian Markov chain Monte Carlo analyses were performed using MrBayes ver. 3.1.2 (Huelsenbeck & Ronquist 2001; Ji et al. 2019). Phylogenetic analysis revealed that HMAS249354 and Pucciniastrum hikosanense were grouped into one clade highly supported by bootstrap values of NJ, ML, and Bayesian posterior probability (Bpp) of 97%/93%/1, respectively. Koch's postulates were fulfilled with 1-year-old healthy plants of A. mono. Fresh urediniospores were collected and suspended in a 0.05% water solution of Tween 20, and 100 µl of urediniospores suspension (106 urediniospores/ml) per leaf (n=10) were sprayed, with another ten healthy leaves sprayed with sterile water as the control. The plants were placed in dark for 48 h and then moved into greenhouse at 22°C with 12 h light per day. Disease symptoms after 10-12 days' inoculation on the inoculated leaves which were identical to the original observations, while the control leaves remained healthy. Previously, P. hikosanense was reported to infect Acer rufinerve Sieb. et Zucc. in Japan (Hiratsuka 1940) and A. rubescens Hayata in Taiwan, China (Dai 1979). This is the first report of leaf rust of Acer mono caused by Pucciniastrum hikosanense Hirats. f. in China.

First report of alternate hosts of willow rust disease caused by Melampsora ferrinii in China.

Corydalis acuminata Franch., C. edulis Maxim. and C. racemosa (Thunb.) Pers. of family Papaveraceae are rich in multiple alkaloids and widely used as Chinese medicinal herbs, for treating cough, pruritus, sores tinea and snake venom (Zhang et al. 2008, Iranshahy et al. 2014). In April 2021, orange rust pustules were observed on C. acuminata, C. edulis and C. racemosa in Shaanxi Province (34°4'56'' N, 108°2'9'' E, alt. 770 m), China. Samples were collected and voucher specimens were preserved in the Herbarium Mycologicum Academiae Sinicae (nos. HMAS249947-HMAS249949), China. Consequent geospatial investigations revealed that diseased plants can be observed at an altitude of 400-1000 m, and show an incidence from 40% to 80% varied by altitude. Spermogonia epiphyllous, subcuticular, densely grouped, oval or round, 0.14-0.36 × 0.09-0.30 mm, pale orange-yellow, and type 3 of Cummins and Hiratsuka (1963). Aecia mostly hypophyllous, subepidermal without peridia, Caeoma-type, erumpent, densely grouped, oval or round, 0.27-0.85 × 0.15-0.43 mm, and orange-yellow; hyaline peridial cells produced in a periphery of the sorus under the ruptured epidermis of host plants. Aeciospores globoid or broadly ellipsoid, catenulate with intercalary cells, 15.7-20.1 × 10.8-15.7 µm, yellow to pale orange; walls hyaline, verrucose, 1.7-3.1 µm thick. This fungus was morphologically identified as Melampsora (Melampsoraceae). The rDNA-28S and the internal transcribed spacer (ITS) regions were amplified using primers NL1/NL4 and ITS1/ITS4 (Ji et al. 2020; Wang et al. 2020). Bi-directional sequences were assembled and deposited in GenBank (accession nos. MW990091-MW990093 and MW996576-MW996578). Phylogenetic trees were constructed with the ITS+rDNA-28S dataset based on maximum-likelihood (ML), maximum-parsimony (MP) and Bayesian Inference (BI). ML and MP bootstrap values were calculated by bootstrap analyses of 1,000 replicates using MEGA-X (Kumar et al. 2018), while BI posterior probabilities (Bpps) were calculated using MrBayes ver. 3.1.2 (Ji et al. 2020; Wang et al. 2020). Phylogenetic analyses grouped our specimens and Melampsora ferrinii Toome & Aime into one clade, highly supported by bootstrap values of ML, MP, and Bpps of 100%/100%/1. Inoculations were conducted with 1-year-old plants of original host, Salix babylonica L. (Toome & Aime 2015). Aeciospores suspension with a concentration of 106 spores/ml were sprayed on 20 healthy leaves, with another 20 healthy leaves sprayed with sterile water as the control. The inoculated plants were kept in darkness at 20-25 °C for 2 days and then transferred into greenhouse at 23°C with 16 h light per day. After 8-10 days of inoculation, yellow pustules of uredinia appeared on abaxial surfaces of the inoculated leaves, which were identical to Toome & Aime (2015) reported, while the control leaves remained healthy. Inoculations with the same method were conducted by spraying urediniospores, and the same rust symptoms developed after 8 days. Genus Corydalis was verified as the alternate host of M. chelidonii-pierotii Tak. Matsumoto, M. coleosporioides Dietel, M. idesiae Miyabe and M. yezoensis Miyabe & T. Matsumoto (Shinyama & Yamaoka 2012; Okane et al. 2014; Yamaoka & Okane 2019), and C. incisa (Thunb.) Pers. was speculated as the potential alternate host of M. ferrinii (Toome & Aime 2015). Based on morphology, phylogeny and pathogenicity, we firstly report M. ferrinii in mainland China and verify C. acuminata, C. edulis and C. racemosa instead of C. incisa as its alternate hosts.

Downregulation of microRNA let-7f mediated the Adriamycin resistance in leukemia cell line.

Multidrug resistance (MDR) has become the major cause of failure chemotherapy for leukemia and high mortality of leukemia. The study aimed to investigate whether the let-7f mediate the Adriamycin (ADR) resistance of leukemia, and to explore the potential molecular mechanism. Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and the soft agar clone formation assay. Flow cytometry was performed to detected cell cycle and apoptosis. The targeted regulationship was analyzed by dual-luciferase assay. Real-time polymerase chain reaction and Western blot were used to measure the expressions of let-7f, ABCC5, ABCC10, cell cycle-related proteins, and apoptosis-related proteins. The xenograft mouse model was used to conduct the tumor formation assay in vivo. The results demonstrated that the expression of let-7f was lower in multidrug-resistant K562/A02 cell lines compared to that in K562, while ABCC5 and ABCC10 were upregulated. Overexpression of let-7f in K562/A02 cell lines downregulated the ABCC5 and ABCC10 expression, enhanced cell sensitivity to ADR, promoted cell apoptosis, and inhibited cell proliferation. let-7f was proved to negatively regulate ABCC5 and ABCC10. Tumor formation assay further determined that let-7f overexpression increased sensitivity to ADR. Taken together, the let-7f downregulation induced the ADR resistance of leukemia by upregulating ABCC5 and ABCC10 expression. Our study provided a novel perspective to study the mechanism of MDR and a new target for the reversal of MDR.

Intravenous and subsequent long-term oral tranexamic acid in enhanced-recovery primary total knee arthroplasty without the application of a tourniquet: a randomized placebo-controlled trial.

BACKGROUND: To assess the efficacy and safety of intravenous and subsequent long-term oral tranexamic acid (TXA) following total knee arthroplasty (TKA) without a tourniquet. METHODS: In this double-blinded trial, 118 patients undergoing primary TKA were randomized into two groups: the patients in group A received intravenous TXA at 20-mg/kg 10 min before the surgery and 3 h postoperatively, and then oral 1 g TXA from postoperative day (POD) 1 to POD 14, and the patients in group B received intravenous TXA at 20-mg/kg 10 min before surgery and 3 h postoperatively, and then oral 1 g placebo from postoperative day (POD) 1 to POD 14. The primary outcome was total blood loss. Secondary outcomes included ecchymosis area and morbidity, postoperative transfusion, postoperative laboratory values, postoperative knee function and length of hospital stay. Complications, and patient satisfaction were also recorded. RESULTS: The mean total blood loss was lower in Group A than in Group B (671.7 ml vs 915.8 ml, P = 0.001). There was no significant difference in the transfusion rate between the two groups. Group A had a higher hemoglobin than Group B on POD 3 (106.0 g/L vs 99.7 g/L, P = 0.001). However, no significant difference was found for Hb or hematocrit on POD 1 or POD 14 between the two groups. Patients in Group A had less ecchymosis morbidity (7 vs 38, P = 0.001), smaller ecchymosis area (1.6 vs 3.0, P = 0.001) than Group B. The blood coagulation level as measured by fibrinolysis (D-Dimer) was lower in Group A than in Group B on POD 1 and POD 3 (4.6 mg/L vs. 8.4 mg/L, respectively, P = 0.001; 1.5 mg/L vs. 3.3 mg/L, respectively, P = 0.001). However, there was no significant difference on POD 14, and the fibrin degradation products showed the same trend. Patients in Group A had less swelling than those in Group B on POD 3 and POD 14. The circumference of the knee was 43.1 cm vs. 46.1 cm (POD 3, P = 0.001) and 41.4 cm vs. 44.9 cm (POD 14, P = 0.001) in Group A vs Group B, respectively. Nevertheless, the circumference of the knee in the two groups was similar on POD 1 and POD 3 M. No significant differences were identified in knee function, pain score, or hospital stay. No significant differences were identified in thromboembolic complications, infection, hematoma, wound healing and patients satisfaction between the two groups. CONCLUSION: Intravenous and subsequent long-term oral TXA produced less blood loss and less swelling and ecchymosis compared with short-term TXA without increasing the risk of complications. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR-IPR-17012264 ).

Supercapsular percutaneously-assisted total hip (SuperPath) versus posterolateral total hip arthroplasty in bilateral osteonecrosis of the femoral head: a pilot clinical trial.

BACKGROUND: The supercapsular percutaneously-assisted total hip arthroplasty (SuperPath) was proposed to be minimally invasive and tissue sparing with possible superior postoperative outcomes to traditional approaches of total hip arthroplasty (THA). Here, we compared the short-term outcomes of staged THA with the SuperPath or through posterolateral approach (PLA) for bilateral osteonecrosis of the femoral head (ONFH). METHODS: Patients with bilateral late-stage ONFH were prospectively recruited from our department from March 2017 to March 2018. Staged bilateral THAs with one side SuperPath and the other side PLA were performed consecutively in the same patients with right and left hips alternating within approaches. The average time interval between the staged THAs was 3 months. Perioperative status (operation time, incision length, intraoperative blood loss, soft tissue damage, and length of hospital stay) and postoperative function (range of motion, pain, and hip function) were recorded and compared between the SuperPath and PLA approaches within 12-month postoperatively. RESULTS: Four male patients (age, 51.00 ± 4.54; BMI, 21.49 ± 1.73) with bilateral alcohol-induced ONFH (Ficat III/IV) were followed up over 12 months postoperatively. Compared with the PLA, the SuperPath yielded shorter incision length (7.62 vs. 11.12 cm), longer operation time (103.25 vs. 66.50 min), more blood loss (1108.50 vs. 843.50 ml), deficient abduction angle of the acetabular cup (38.75° vs. 44.50°), and inferior early-term hip function (Harris hip score, 72.50 vs. 83.25) at 12-month postoperatively. Soft tissue damage, length of hospital stay, postoperative pain, postoperative range of motion, and 12-month patient satisfaction were comparable between both approaches. CONCLUSION: The SuperPath may be a minimally invasive technique but the present study shows less favorable short-term outcomes than PLA for total hip arthroplasty in osteonecrosis of the femoral head. More investigations are required to provide convincing favorable evidences of the SuperPath over other traditional THA approaches. TRIAL REGISTRATION INFORMATION: The trial was retrospectively registered in https://www.researchregistry.com (No. Researchregistry4993) on July 04, 2019. The first participant was enrolled on March 13, 2017.

The efficacy and safety of multiple-dose oral tranexamic acid on blood loss following total hip arthroplasty: a randomized controlled trial.

PURPOSES: To explore the efficacy and safety of multiple-dose oral tranexamic acid (TXA) on blood loss following primary total hip arthroplasty (THA). METHODS: A total of 152 patients were randomized into three groups to receive 2 g of oral TXA two hours  pre-operatively (group A), or another bolus of 2 g of oral TXA four hours post-operatively (group B), or another three boluses of 2 g of oral TXA four, ten, and 16 hours post-operatively (group C). The primary outcomes were total blood loss (TBL), hidden blood loss (HBL), and transfusion rate. The secondary outcomes were haemoglobin (Hb) and haematocrit (Hct) drop, the level of fibrinolysis parameters (fibrin degradation products, D-dimer), and complications (thrombotic diseases, stroke, cardiac infarction, and infection). RESULTS: The mean TBL and HBL in group C were lower than those in group A (p < 0.001 and p < 0.001) and group B (p = 0.012 and p = 0.029). The Hb drop on post-operative day one (POD1) and POD3 in group C was lower than those in group A (p < 0.001 and p = 0.029) and group B (p < 0.001 and p = 0.004). The difference was similar regarding Hct drop on POD3 (p < 0.001 and p = 0.014). Moreover, fibrin degradation products and D-dimer in group C were lower than in groups A and B on POD1 and POD3 (p < 0.001 and p < 0.001). The incidence of complications such as venous thromboembolism did not differ significantly among the three groups (p > 0.05). CONCLUSIONS: Multiple boluses of oral TXA could further reduce blood loss, Hb and Hct drop, and restrain post-operative fibrinolysis in primary THA without increasing the risk of complications. LEVEL OF EVIDENCE I: Therapeutic study.

LncRNA MALAT1 promotes cell proliferation and imatinib resistance by sponging miR-328 in chronic myelogenous leukemia.

BACKGROUND: Chronic myeloid leukemia (CML) is a type of cancer that starts in certain blood-forming cells of the bone marrow. LncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), a well known protooncogene, has be shown to be upregulated in various tumor types, including multiple myeloma. However, the biological function of MALAT1 in CML remains has yet to be explored. This study was designed to investigate the effects of MALAT1 on the physiological processes in CML and its underlying mechanisms, which will be helpful for us to have a better understanding of CML development and progression as well as improved therapeutic method. METHODS: Recombinant virus construction and infection was performed to overexpress or knockdown the expression of MALAT1. Dual luciferase reporter assay was applied to vetify the interaction between MALAT1 and miR-328. The cell viability and cell cycle were analyzed by CCK-8 assay and flow cytometry, respectively. Quantitative real time PCR and western blotting assays were used to measure the expression of genes and proteins. RESULTS: The expression of MALAT1 was significantly increased in CML cells compared with peripheral blood cells from health donors. Silencing of MALAT1 significantly inhibited the proliferation and arrested cell cycle of CML cells by targeting miR-328. Moreover, MALAT1 knockdown enhanced imatinib sensitivity of K562 cells, while silencing of miR-328 abolished this effect. CONCLUSIONS: These findings indicate that lncRNA MALAT1/miR-328 axis promotes the proliferation and imatinib resistance of CML cells, providing new perspectives for the future study of MALAT1 as a therapeutic target for CML.

The Expression of Actin-Related Protein 2/3 Complex Subunit 5 (ARPC5) Expression in Multiple Myeloma and its Prognostic Significance.

BACKGROUND The aim of this study was to analyze the prognostic value of ARPC5 in patients with multiple myeloma (MM). MATERIAL AND METHODS MM gene expression studies GSE6477, GSE31162, GSE24080, and GSE19784 were obtained and analyzed. The expression of ARPC5 was assessed in normal plasma cells, baseline MM cells, and relapsed MM cells. Univariate and multivariable analyses were used to determine the relationship between ARPC5 expression and clinical characteristics and survivals of MM patients. Quantitative PCR was used to detect the expression ARPC5 in bone marrow mononuclear cells of MM patients and normal controls. GSEA was conducted to identify associated mechanisms. RESULTS ARPC5 expression was significantly increased in baseline MM cells compared to normal plasma cells (P=0.0414). Meanwhile, ARPC5 was significantly increased in relapsed MM cells compared to baseline MM cells (P<0.0001). ARPC5 expression was significantly associated with ß2-microglobin (P=0.047), serum lactate dehydrogenase (P=0.007), and rates of aspirate plasma cells (P=0.007). Meanwhile, patients in the ARPC5 high expression group were associated with poor overall survival (P=0.0027) and event-free survival (P=0.0102) compared to those in the ARPC5 low expression group. Multivariable analysis indicated that ARPC5 was an independent prognostic factor for MM patients. Quantitative PCR demonstrated that ARPC5 was significantly increased in MM patients. GSEA results indicated that ARPC5 might affect cellular growth of myeloma cells through mammalian target of rapamycin (mTOR)C1 signaling pathway. CONCLUSIONS ARPC5 could be treated as an independent biomarker for patients with MM.

Comparison of oral versus intra-articular tranexamic acid in enhanced-recovery primary total knee arthroplasty without tourniquet application: a randomized controlled trial.

BACKGROUND: Although randomized controlled trials have confirmed oral tranexamic acid (TXA) can provide similar blood-sparing efficacy compared with intravenous (IV) TXA in total knee arthroplasty (TKA), some concerns do remain about thromboembolic events after such systemic administration. Many studies have confirmed that intra-articular (IA) application of TXA can show similar blood-saving efficacy with minimal levels of systemic absorption compared with IV TXA. However, it remains unclear whether the efficacy and safety of oral TXA administration is equal to or less than that of IA administration in TKA without the use of a tourniquet and drain. Thus, this study was to verify non-inferior efficacy and safety of oral TXA compared with IA TXA in primary TKA. METHODS: A double-blind, randomized, controlled trial was performed to compare three oral doses of TXA (2 g of TXA 2 h before incision, and 1 g of TXA 6 and 12 h after surgery, respectively) with IA TXA (3 g of TXA in 100 mL of saline solution). One hundred forty-seven patients scheduled for TKA were randomized to one of the two interventions. The primary outcome was total blood loss. The secondary outcomes included reduction of hemoglobin concentration, clinical outcomes, blood coagulation values, thromboembolic complications, and transfusion rates. RESULTS: The mean total blood loss was 788.8 mL in the oral TXA group compared with 872.4 mL in the IA TXA group, with no statistical significance (p > 0.05). There were no significant differences in reduction of hemoglobin level, blood coagulation level, and clinical outcomes. The transfusion rates were 4% in oral group and 5% IA group, respectively. Also, no significant differences were identified in thromboembolic complications. CONCLUSION: Oral TXA according to the described protocol demonstrated non-inferiority for primary TKA, with no safety concerns and a greatly reduced cost, compared with the IA TXA. This randomized controlled trial supports the oral administration of TXA in TKA. TRIAL REGISTRATION: The trial was registered in the Chinese Clinical Trial Registry ( ChiCTR-INR-17010968 ) dated 23rd March 2017.