Pre-sliding of the femoral neck system to prevent postoperative shortening of femoral neck fractures.

Objective: The purpose of this study is to evaluate the effect of pre-sliding of the femoral neck system (FNS) in the prevention of postoperative femoral neck shortening in femoral neck fractures. Method: This study was designed to retrospectively analyze data from 109 patients with femoral neck fractures who were admitted to a Level I trauma center between April 2020 and June 2022. Of these patients, 90 were followed up for more than 12 months. The study included 52 males and 38 females, with 35 cases of Garden I and II fractures and 55 cases of Garden III and IV fractures. The Harris Hip Score at 12 months postoperatively were recorded. The patients were divided into two groups based on their surgical records and postoperative radiography: the Pre-sliding group and the No-pre-sliding group. The purpose of this study is to analyze the role of pre-sliding in preventing femoral neck shortening, fracture healing time, degree of postoperative shortening, complications, and Harris Hip Score, and to make a comparison between the two groups. Results: All 90 patients were followed up for over one year after surgery. A statistically significant difference was observed in the preoperative Garden classification (P < 0.05). At 1 year after the operation, the shortening distance was 6.5 ± 6.4 mm in the No-pre-sliding group and 3.9 ± 3.4 mm in the Pre-sliding group. The Harris Hip Score were 88.7 (79.8, 93.5) in the No-pre-sliding group and 94.8 (87.7, 96.9) in the Pre-sliding group, with a statistically significant difference between the two groups (P < 0.05). Shortening was concentrated at 3 months postoperatively and reached a stable state within 6 months, with less persistent shortening occurring after 6 months. There was no statistically significant difference in the preoperative baseline data. Conclusion: Pre-sliding of the FNS prevents postoperative shortening of the femoral neck and improves hip function as measured by the Harris Hip Score.

Discovery of novel bis-evodiamine derivatives with potent antitumor activity.

Inspired by antitumor natural product evodiamine, a series of novel bis-evodiamine derivatives were designed and synthesized, which showed potent antitumor activity. In particular, compound 13b effectively inhibited the proliferation and migration of HCT116 cells. Further mechanism studies revealed that compound 13b acted by inducing HCT116 cell apoptosis and arresting the cell cycle at the G2/M phase. Thus, compound 13b represents a promising lead compound for the discovery of novel antitumor agents.

Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors.

On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.

Structural simplification of evodiamine: Discovery of novel tetrahydro-ß-carboline derivatives as potent antitumor agents.

Natural products (NPs) have played a crucial role in the discovery and development of antitumor drugs. However, the high structural complexity of NPs generally results in unfavorable physicochemical profiles and poor drug-likeness. A powerful strategy to tackle this obstacle is the structural simplification of NPs by truncating nonessential structures. Herein, a series of tetrahydro-ß-carboline derivatives were designed by elimination of the D ring of NP evodiamine. Structure-activity relationship studies led to the discovery of compound 45, which displayed highly potent antitumor activity against all the tested cancer cell lines and excellent in vivo antitumor activity in the HCT116 xenograft model with low toxicity. Further mechanistic research indicated that compound 45 acted by dual Top1/2 inhibition and induced caspase-dependent cell apoptosis coupled with G2/M cell cycle arrest. This proof-of-concept study validated the effectiveness of structural simplification in NP-based drug development, discovered compound 45 as a potent antitumor lead compound and enriched the structure-activity relationships of evodiamine.

The Use of Autologous Iliotibial Band With Gerdy's Tubercle for Irreparable Rotator Cuff Tears.

OBJECTIVE: To determine the radiographic and functional outcomes after autologous iliotibial band with Gerdy's tubercle (ITB-GT) interposition in patients with irreparable rotator cuff tears (IRCTs). METHODS: From December 2015 to March 2017, a total of 16 patients who underwent autologous ITB-GT interposition for IRCTs were identified, including 4 males and 12 females. The mean age was 56.1 ± 10.3 years (range, 44-67 years). Functional assessment consisted of active range of motion (ROM), Visual Analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley score, and patient satisfaction rate. The tendon integrity and acromiohumeral interval (AHI) were assessed by postoperative magnetic resonance imaging (MRI). RESULTS: The mean duration of follow-up was 25.3 ± 3.5 months. At final follow-up, the patients exhibited significantly improved forward elevation, external rotation, and internal rotation (75.00° ± 13.16° to 159.37° ± 8.51°, t = 26.71, P = 0.001; 17.81° ± 11.54° to 35.31° ± 8.26°, t = 6.57, P = 0.001; 2 to 11, t = 13.10, P = 0.001). Other functional outcomes as measured by VAS score, ASES score, and Constant-Murley score also improved significantly (6.50 ± 1.41 to 1.06 ± 0.93, t = 11.68, P = 0.001; 38.50 ± 8.68 to 81.75 ± 6.80, t = 15.42, P = 0.001; 32.50 ± 8.53 to 77.12 ± 6.72, t = 17.28, P = 0.001). The overall satisfaction rate was 87.5%. The postoperative MRI showed that the tendon integrity was fully intact in 14 patients and partially intact in two patients. The AHI improved significantly from 3.63 ± 1.25 mm preoperatively to 8.37 ± 1.02 mm postoperatively (t = 11.78, P = 0.001). CONCLUSION: Autologous ITB-GT interposition was a useful treatment option for patients with IRCTs, which resulted in significant improvements in active ROM, subjective functional outcomes, and AHI with excellent tendon integrity at a minimum 2-year follow-up.

A CEP Peptide Receptor-Like Kinase Regulates Auxin Biosynthesis and Ethylene Signaling to Coordinate Root Growth and Symbiotic Nodulation in Medicago truncatula.

Because of the large amount of energy consumed during symbiotic nitrogen fixation, legumes must balance growth and symbiotic nodulation. Both lateral roots and nodules form on the root system, and the developmental coordination of these organs under conditions of reduced nitrogen (N) availability remains elusive. We show that the Medicago truncatula COMPACT ROOT ARCHITECTURE2 (MtCRA2) receptor-like kinase is essential to promote the initiation of early symbiotic nodulation and to inhibit root growth in response to low N. C-TERMINALLY ENCODED PEPTIDE (MtCEP1) peptides can activate MtCRA2 under N-starvation conditions, leading to a repression of YUCCA2 (MtYUC2) auxin biosynthesis gene expression, and therefore of auxin root responses. Accordingly, the compact root architecture phenotype of cra2 can be mimicked by an auxin treatment or by overexpressing MtYUC2, and conversely, a treatment with YUC inhibitors or an MtYUC2 knockout rescues the cra2 root phenotype. The MtCEP1-activated CRA2 can additionally interact with and phosphorylate the MtEIN2 ethylene signaling component at Ser643 and Ser924, preventing its cleavage and thereby repressing ethylene responses, thus locally promoting the root susceptibility to rhizobia. In agreement with this interaction, the cra2 low nodulation phenotype is rescued by an ein2 mutation. Overall, by reducing auxin biosynthesis and inhibiting ethylene signaling, the MtCEP1/MtCRA2 pathway balances root and nodule development under low-N conditions.

A CEP Peptide Receptor-like Kinase Regulates Auxin Biosynthesis and Ethylene Signaling to Coordinate Root Growth and Symbiotic Nodulation in Medicago truncatula.

Because of the high energy consumed during symbiotic nitrogen fixation, legumes must balance growth and symbiotic nodulation. Both lateral roots and nodules form on the root system and the developmental coordination of these organs according to reduced nitrogen (N) availability remains elusive. We show that the Compact Root Architecture 2 (MtCRA2) receptor-like kinase is essential to promote the initiation of early symbiotic nodulation and to inhibit root growth in response to low-N. MtCEP1 peptides can activate MtCRA2 under N-starvation conditions, leading to a repression of MtYUC2 auxin biosynthesis gene expression, and therefore of auxin root responses. Accordingly, the compact root architecture phenotype of cra2 can be mimicked by an auxin treatment or by over-expressing MtYUC2, and conversely, a treatment with YUC inhibitors or a MtYUC2 knock-out rescues the cra2 root phenotype. The MtCEP1-activated CRA2 can additionally interact with and phosphorylate the MtEIN2 ethylene signaling component at Ser643 and Ser924, preventing its cleavage and therefore repressing ethylene responses, thus locally promoting the root susceptibility to rhizobia. In agreement, the cra2 low nodulation phenotype is rescued by an ein2 mutation. Overall, by reducing auxin biosynthesis and inhibiting ethylene signaling, the MtCEP1/MtCRA2 pathway balances root and nodule development under low-N conditions.

Arthroscopic side-to-side repair for complete radial posterior lateral meniscus root tears.

BACKGROUND: The aim of this study was to determine the radiographic, second-look, and functional outcomes after arthroscopic side-to-side repair for complete radial posterior lateral meniscus root tears (PLMRTs). METHODS: Patients who underwent arthroscopic side-to-side repair for complete radial PLMRTs were identified. Clinical assessment consisted of symptoms (locking, catching, giving way and effusion), examinations of joint-line tenderness and McMurray test, and subjective scores of International Knee Documentation Committee (IKDC), Lysholm, and Tegner. In addition, postoperative MRI scan and second-look arthroscopy were performed to assess the healing status of the repaired meniscus. RESULTS: Twenty-nine patients met the inclusion criteria. The mean age was 25.41 years. The mean follow-up period was 26.68 months. During the follow-up, none of the patients had symptoms of meniscal retear, lateral joint-line tenderness or a positive McMurray test. The postoperative subjective scores of IKDC, Lysholm, and Tegner improved significantly compared to the preoperative values (P = 0.01). Postoperative MRI scan showed that 28/29 (96.6%) patients achieved meniscus healing. Twenty-two patients underwent second-look arthroscopy, among whom 19 (86.4%) patients showed complete meniscus healing and 3 (13.6%) patients showed partial healing. CONCLUSION: Arthroscopic side-to-side repair was a valuable surgical repair technique for complete radial PLMRTs, which leaded to significant improvements in both objective and subjective functional outcomes with a high rate of meniscus healing. LEVEL OF EVIDENCE: Level IV, case series.

Osteochondral allograft transplantation for large Hill-Sachs lesions: a retrospective case series with a minimum 2-year follow-up.

PURPOSE: To investigate the clinical outcomes after osteochondral allograft transplantation for large Hill-Sachs lesions. METHODS: Patients who underwent osteochondral allograft transplantation for large Hill-Sachs lesions were identified. Clinical assessment consisted of active range of motion (ROM), American Shoulder and Elbow Surgeons score (ASES), Constant-Murley score, Rowe score, and patient satisfaction rate. Radiographic assessment was performed with CT scan. RESULTS: Nineteen patients met the inclusion criteria. The mean age was 21.7 years. The mean preoperative size of the Hill-Sachs lesion was 35.70 ± 3.02%. The mean follow-up was 27.8 months. All grafts achieved union at an average of 3.47 months after surgery. At the final follow-up, graft resorption was observed in 43.1% of patients. The average size of residual humeral head articular arc loss was 12.31 ± 2.79%. Significant improvements (P < .001) were observed for the active ROM, ASES score, Constant-Murley score, and Rowe score. The overall satisfaction rate was 94.7%. No significant difference was found between the resorption group and the nonresorption group in postoperative clinical outcomes. CONCLUSION: Osteochondral allograft transplantation is a useful treatment option for patients with large Hill-Sachs lesions. Although the incidence of graft resorption may be relatively high, the clinical outcomes at a minimum 2-year follow-up are favorable. LEVEL OF EVIDENCE: Level IV, case series.

Transcription Factor bHLH2 Represses CYSTEINE PROTEASE77 to Negatively Regulate Nodule Senescence.

Legume-rhizobia symbiosis is a time-limited process due to the onset of senescence, which results in the degradation of host plant cells and symbiosomes. A number of transcription factors, proteases, and functional genes have been associated with nodule senescence; however, whether other proteases or transcription factors are involved in nodule senescence remains poorly understood. In this study, we identified an early nodule senescence mutant in Medicago truncatula, denoted basic helix-loop-helix transcription factor2 (bhlh2), that exhibits decreased nitrogenase activity, acceleration of plant programmed cell death (PCD), and accumulation of reactive oxygen species (ROS). The results suggest that MtbHLH2 plays a negative role in nodule senescence. Nodules of wild-type and bhlh2-TALEN mutant plants at 28 d postinoculation were used for transcriptome sequencing. The transcriptome data analysis identified a papain-like Cys protease gene, denoted MtCP77, that could serve as a potential target of MtbHLH2. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis demonstrated that MtbHLH2 directly binds to the promoter of MtCP77 to inhibit its expression. MtCP77 positively regulates nodule senescence by accelerating plant PCD and ROS accumulation. In addition, the expression of MtbHLH2 in the nodules gradually decreased from the meristematic zone to the nitrogen fixation zone, whereas the expression of MtCP77 showed enhancement. These results indicate that MtbHLH2 and MtCP77 have opposite functions in the regulation of nodule senescence. These results reveal significant roles for MtbHLH2 and MtCP77 in plant PCD, ROS accumulation, and nodule senescence, and improve our understanding of the regulation of the nodule senescence process.

Collaborative ISL1/GATA3 interaction in controlling neuroblastoma oncogenic pathways overlapping with but distinct from MYCN.

Background: Transcription factor ISL1 plays a critical role in sympathetic neurogenesis. Expression of ISL1 has been associated with neuroblastoma, a pediatric tumor derived from sympatho-adrenal progenitors, however the role of ISL1 in neuroblastoma remains unexplored. Method: Here, we knocked down ISL1 (KD) in SH-SY5Y neuroblastoma cells and performed RNA-seq and ISL1 ChIP-seq analyses. Results: Analyses of these data revealed that ISL1 acts upstream of multiple oncogenic genes and pathways essential for neuroblastoma proliferation and differentiation, including LMO1 and LIN28B. ISL1 promotes expression of a number of cell cycle associated genes, but represses differentiation associated genes including RA receptors and the downstream target genes EPAS1 and CDKN1A. Consequently, Knockdown of ISL1 inhibits neuroblastoma cell proliferation and migration in vitro and impedes tumor growth in vivo, and enhances neuronal differentiation by RA treatment. Furthermore, genome-wide mapping revealed a substantial co-occupancy of binding regions by ISL1 and GATA3, and ISL1 physically interacts with GATA3, and together they synergistically regulate the aforementioned oncogenic pathways. In addition, analyses of the roles of ISL1 and MYCN in MYCN-amplified and MYCN non-amplified neuroblastoma cells revealed an epistatic relationship between ISL1 and MYCN. ISL1 and MYCN function in parallel to regulate common yet distinct oncogenic pathways in neuroblastoma. Conclusion: Our study has demonstrated that ISL1 plays an essential role in neuroblastoma regulatory networks and may serve as a potential therapeutic target in neuroblastoma.

Sin3a-Tet1 interaction activates gene transcription and is required for embryonic stem cell pluripotency.

Sin3a is a core component of histone-deacetylation-activity-associated transcriptional repressor complex, playing important roles in early embryo development. Here, we reported that down-regulation of Sin3a led to the loss of embryonic stem cell (ESC) self-renewal and skewed differentiation into mesendoderm lineage. We found that Sin3a functioned as a transcriptional coactivator of the critical Nodal antagonist Lefty1 through interacting with Tet1 to de-methylate the Lefty1 promoter. Further studies showed that two amino acid residues (Phe147, Phe182) in the PAH1 domain of Sin3a are essential for Sin3a-Tet1 interaction and its activity in regulating pluripotency. Furthermore, genome-wide analyses of Sin3a, Tet1 and Pol II ChIP-seq and of 5mC MeDIP-seq revealed that Sin3a acted with Tet1 to facilitate the transcription of a set of their co-target genes. These results link Sin3a to epigenetic DNA modifications in transcriptional activation and have implications for understanding mechanisms underlying versatile functions of Sin3a in mouse ESCs.

Temporal requirements for ISL1 in sympathetic neuron proliferation, differentiation, and diversification.

Malformations of the sympathetic nervous system have been associated with cardiovascular instability, gastrointestinal dysfunction, and neuroblastoma. A better understanding of the factors regulating sympathetic nervous system development is critical to the development of potential therapies. Here, we have uncovered a temporal requirement for the LIM homeodomain transcription factor ISL1 during sympathetic nervous system development by the analysis of two mutant mouse lines: an Isl1 hypomorphic line and mice with Isl1 ablated in neural crest lineages. During early development, ISL1 is required for sympathetic neuronal fate determination, differentiation, and repression of glial differentiation, although it is dispensable for initial noradrenergic differentiation. ISL1 also plays an essential role in sympathetic neuron proliferation by controlling cell cycle gene expression. During later development, ISL1 is required for axon growth and sympathetic neuron diversification by maintaining noradrenergic differentiation, but repressing cholinergic differentiation. RNA-seq analyses of sympathetic ganglia from Isl1 mutant and control embryos, together with ISL1 ChIP-seq analysis on sympathetic ganglia, demonstrated that ISL1 regulates directly or indirectly several distinct signaling pathways that orchestrate sympathetic neurogenesis. A number of genes implicated in neuroblastoma pathogenesis are direct downstream targets of ISL1. Our study revealed a temporal requirement for ISL1 in multiple aspects of sympathetic neuron development, and suggested Isl1 as a candidate gene for neuroblastoma.

A Lipid-Anchored NAC Transcription Factor Is Translocated into the Nucleus and Activates Glyoxalase I Expression during Drought Stress.

The plant-specific NAC (NAM, ATAF1/2, and CUC2) transcription factors (TFs) play a vital role in the response to drought stress. Here, we report a lipid-anchored NACsa TF in Medicago falcata MfNACsa is an essential regulator of plant tolerance to drought stress, resulting in the differential expression of genes involved in oxidation reduction and lipid transport and localization. MfNACsa is associated with membranes under unstressed conditions and, more specifically, is targeted to the plasma membrane through S-palmitoylation. However, a Cys26-to-Ser mutation or inhibition of S-palmitoylation results in MfNACsa retention in the endoplasmic reticulum/Golgi. Under drought stress, MfNACsa translocates to the nucleus through de-S-palmitoylation mediated by the thioesterase MtAPT1, as coexpression of APT1 results in the nuclear translocation of MfNACsa, whereas mutation of the catalytic site of APT1 results in colocalization with MfNACsa and membrane retention of MfNACsa. Specifically, the nuclear MfNACsa binds the glyoxalase I (MtGlyl) promoter under drought stress, resulting in drought tolerance by maintaining the glutathione pool in a reduced state, and the process is dependent on the APT1-NACsa regulatory module. Our findings reveal a novel mechanism for the nuclear translocation of an S-palmitoylated NAC in response to stress.