Unraveling the future: Innovative design strategies and emerging challenges in HER2-targeted tyrosine kinase inhibitors for cancer therapy.

Human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor-like protein with tyrosine kinase activity that plays a vital role in processes such as cell proliferation, differentiation, and angiogenesis. The degree of malignancy of different cancers, notably breast cancer, is strongly associated with HER2 amplification, overexpression, and mutation. Currently, widely used clinical HER2 tyrosine kinase inhibitors (TKIs), such as lapatinib and neratinib, have several drawbacks, including susceptibility to drug resistance caused by HER2 mutations and adverse effects from insufficient HER2 selectivity. To address these issues, it is essential to create innovative HER2 TKIs with enhanced safety, effectiveness against mutations, and high selectivity. Typically, SPH5030 has advanced to phase I clinical trials for its strong suppression of four HER2 mutations. This review discusses the latest research progress in HER2 TKIs, with a focus on the structural optimization process and structure-activity relationship analysis. In particular, this study highlights promising design strategies to address these challenges, providing insightful information and inspiration for future development in this field.

Discovery and mechanistic insights into thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines inhibitors targeting tubulin for cancer therapy.

Guided by the X-ray cocrystal structure of the lead compound 4a, we developed a series of thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines demonstrating potent antiproliferative activity against four tumor cell lines. Two analogs, 13 and 25d, exhibited IC50 values around 1 nM and overcame P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). At low concentrations, 13 and 25d inhibited both the colony formation of SKOV3 cells in vitro and tubulin polymerization. Furthermore, mechanistic studies showed that 13 and 25d induced G2/M phase arrest and apoptosis in SKOV3 cells, as well as dose-dependent inhibition of tumor cell migration and invasion at low concentrations. Most notably, the X-ray cocrystal structures of compounds 4a, 25a, and the optimal molecule 13 in complex with tubulin were elucidated. This study identifies thieno[3,2-d]pyrimidine and heterocyclic fused pyrimidines as representatives of colchicine-binding site inhibitors (CBSIs) with potent antiproliferative activity.

Analysis of Factors Associated with Lumbar Degenerative Disease Complicated by Baastrup's Disease.

OBJECTIVE: To investigate the factors associated with the occurrence of Baastrup's disease (BA) in patients with lumbar degenerative diseases (LDDs). METHODS: A retrospective analysis was conducted on 168 patients with LDDs (including lumbar disc herniation, lumbar spinal stenosis, and lumbar spondylolisthesis) who were treated at our hospital from January 2020 to January 2023, comprising 95 males and 73 females, aged 48-84 years.Patients were divided into two groups based on the presence of Baastrup's disease: those with BA (Group A) and those without BA (Group B).Relevant patient factors were extracted, including age, gender, occupation, smoking history, alcohol consumption history, body mass index, bone density, presence of internal diseases (diabetes, hypertension), lumbar lordosis angle, endplate Modic changes, degree of intervertebral disc degeneration, and facet joint degeneration (Weishaupt grading).Statistical analysis was performed using, Statistical Package for the Social Sciences 26.0 software to compare the differences in these factors between the two groups, and statistically significant results were included in a multivariate logistic regression analysis. RESULTS: Univariate analysis indicated that there were no statistically significant differences between the two groups in terms of gender, smoking history, alcohol consumption history, bone density, presence of internal diseases (diabetes, hypertension), lumbar lordosis angle, and endplate Modic changes (P>0.05),whereas age, occupation, body mass index, degree of intervertebral disc degeneration, and degree of facet joint degeneration showed statistically significant differences (P < 0.05).Multivariate logistic regression analysis revealed that age, degree of intervertebral disc degeneration, and degree of facet joint degeneration were independent risk factors for the occurrence of BA in patients with LDDs (P < 0.05). CONCLUSIONS: BA is relatively common in patients with LDDs, and advanced age, severe intervertebral disc degeneration, and facet joint degeneration are its independent risk factors.

Levels of 91 circulating inflammatory proteins and risk of lumbar spine and pelvic fractures and peripheral ligament injuries: a two-sample mendelian randomization study.

OBJECTIVE: Lumbar spine and pelvic fractures(LPF) are combined with peripheral ligament injuries(PLI), frequently. It has been reported that the site of fracture injury is usually paralleled by the secretion of inflammatory proteins. This study aimed to investigate the causal relationship between 91 circulating inflammatory proteins and LPF and PLI by using a Two-sample Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) associated with 91 circulating inflammatory proteins, as exposures were selected from a large genome-wide association study (GWAS). The genetic variant data for LPF and PLI as outcomes from the FinnGen consortium. The inverse-variance-weighted (IVW) method was utilized as the main analysis for exposures and outcomes. In addition, the final results were reinforced by the methods of MR Egger, weighted median, simple mode, and weighted mode. The sensitivity analyses were used to validate the robustness of results and ensure the absence of heterogeneity and horizontal pleiotropy. MR-Steiger was used to assess whether the causal direction was correct to avoid reverse causality. RESULTS: This study has shown that Beta-nerve growth factor(Beta-NGF) and Interferon gamma(IFN-gamma) are both involved in the occurrence of LPF and PLI, and they are reducing the risk of occurrence(OR:0.800, 95%CI: 0.650-0.983; OR:0.723, 95%CI:0.568-0.920 and OR:0.812, 95%CI:0.703-0.937; OR:0.828, 95%CI:0.700-0.980). Similarly, Axin-1 and Sulfotransferase 1A1 (SULT-1A1) were causally associated with LPF(OR:0.687, 95%CI:0.501-0.942 and OR:1.178,95%CI:1.010-1.373). Furthermore, Interleukin-4(IL-4), Macrophage inflammatory protein 1a(MIP-1a), and STAM binding protein(STAM-BP) were causally associated with PLI(OR:1.236, 95% CI: 1.058-1.443; OR:1.107, 95% CI: 1.008-1.214 and OR:0.759, 95% CI: 0.617-0.933). The influence of heterogeneity and horizontal pleiotropy were further excluded by sensitivity analysis. CONCLUSION: This study provides new insights into the relationship between circulating inflammatory proteins and LPF and PLI, and may provide new clues for predicting this risk.

Adjuvant chemotherapy for pT1-3N0-1 breast cancer patients with HR+, HER2- subtype: a propensity-score matched study with competing risk analysis.

OBJECTIVE: To wholly evaluate the prognostic value of CHT for pT1-3N0-1 breast cancer patients with HR+, HER2- subtype using the Surveillance, Epidemiology, and End Results (SEER) database. METHOD: A total of 126,102 eligible cases diagnosed between January 2010 and December 2018 were included in the SEER database. A propensity-score matched (PSM) study with competing risk analysis was conducted. The Kaplan-Meier method was used to visualize the survival disparities between chemotherapy (CHT) and no CHT groups. The cumulative incidences of different subgroups were compared by Fine-Gray's test. RESULTS: Before PSM, patients in the CHT group had worse OS and CSS (both P < 0.001). After PSM, we were surprised that patients in the CHT group had a better OS than those in the no CHT group (HR 0.74, 95% CI 0.68-0.80, P < 0.001), while no significant survival disparities were observed for CSS (HR 1.00, 95% CI 0.89-1.12, P = 0.952). In the competing risk analysis, the OS disparities between the CHT and no CHT groups were mainly attributed to deaths of other causes (subdistribution HR [95% CI] 0.50 [0.44-0.57]). After adjusting for other competitive risk events, there was no significant difference in cumulative death risk of breast cancer between the CHT and no CHT groups (subdistribution HR [95% CI] 1.01 [0.90-0.1.13]). CONCLUSION: The present study is the first, to our knowledge, to wholly evaluate the prognostic value of CHT for pT1-3N0-1 breast cancer patients with HR+, HER2- subtype using a propensity-score matched study with competing risk analysis. All pT1-3N0-1 breast cancer patients with HR+, HER2- subtype do not benefit from CHT. Genetic testing may be the only effective tool to determine the need for CHT at the present.

Thoracolumbar Osteoporotic Vertebral Compression Fracture Treatment by Unilateral Percutaneous Vertebroplasty Using Curved Diffusion Needle.

Objective: To investigate the clinical effect of unilateral puncture vertebroplasty with curved diffusion needle (CDN) in the treatment of thoracolumbar osteoporotic vertebral compression fracture (OVCFs). Methods: We used the method of a retrospective study. The clinical data of 38 patients with OVCFs treated by unilateral puncture vertebroplasty with curved diffusion needle from January 2021 to January 2022 were analyzed. The operation time and the amount of bone cement injected were recorded to observe the leakage and dispersion of bone cement during the operation and the incidence of vertebral re-fracture at the last follow-up. Visual analog scale (VAS) and Oswestry disability index (ODI) were used to evaluate the pain and functional improvement before and after surgery. Results: All patients successfully completed the operation. The operation time was 31.2 ± 5.1 min, and the bone cement injection volume was 4.8 ± 1.1 ml. During the operation, three patients had bone cement leakage, and the leakage rate was 7.8%. The bone cement dispersion was excellent in 31 cases, among which seven cases were good; the postoperative follow-up time was 3-10 months, with an average of 6.3 months; no vertebral body re-fracture occurred. VAS score and ODI at 1d after the operation and at the last follow-up were significantly improved compared with those before the operation, and the difference was statistically significant (P < 0.05). Also there was a significant difference between the postoperative 1d and the last follow-up (P < 0.05). Conclusions: Unilateral puncture vertebroplasty for the treatment of thoracolumbar OVCFs can obtain good bone cement distribution, safety and does not increase complications, and the clinical effect is satisfactory.

Targeting glutaminase 1 (GLS1) by small molecules for anticancer therapeutics.

Glutaminase-1 (GLS1) is a critical enzyme involved in several cellular processes, and its overexpression has been linked to the development and progression of cancer. Based on existing research, GLS1 plays a crucial role in the metabolic activities of cancer cells, promoting rapid proliferation, cell survival, and immune evasion. Therefore, targeting GLS1 has been proposed as a promising cancer therapy strategy, with several GLS1 inhibitors currently under development. To date, several GLS1 inhibitors have been identified, which can be broadly classified into two types: active site and allosteric inhibitors. Despite their pre-clinical effectiveness, only a few number of these inhibitors have advanced to initial clinical trials. Hence, the present medical research emphasizes the need for developing small molecule inhibitors of GLS1 possessing significantly high potency and selectivity. In this manuscript, we aim to summarize the regulatory role of GLS1 in physiological and pathophysiological processes. We also provide a comprehensive overview of the development of GLS1 inhibitors, focusing on multiple aspects such as target selectivity, in vitro and in vivo potency and structure-activity relationships.

Design, Synthesis, and Biological Evaluation of Heterocyclic-Fused Pyrimidine Chemotypes Guided by X-ray Crystal Structure with Potential Antitumor and Anti-multidrug Resistance Efficacy Targeting the Colchicine Binding Site.

Herein, a series of quinazoline and heterocyclic fused pyrimidine analogues were designed and synthesized based on the X-ray co-crystal structure of lead compound 3a, showing efficacious antitumor activities. Two analogues, 15 and 27a, exhibited favorable antiproliferative activities, which were more potent than lead compound 3a by 10-fold in MCF-7 cells. In addition, 15 and 27a exhibited potent antitumor efficacy and tubulin polymerization inhibition in vitro. 15 reduced the average tumor volume by 80.30% (2 mg/kg) in the MCF-7 xenograft model and 75.36% (4 mg/kg) in the A2780/T xenograft model, respectively. Most importantly, supported by structural optimization and Mulliken charge calculation, X-ray co-crystal structures of compounds 15, 27a, and 27b in complex with tubulin were resolved. In summary, our research provided the rational design strategy of colchicine binding site inhibitors (CBSIs) based on X-ray crystallography with antiproliferation, antiangiogenesis, and anti-multidrug resistance properties.

Discovery and biological evaluation of 4,6-pyrimidine analogues with potential anticancer agents as novel colchicine binding site inhibitors.

Novel 4,6-pyrimidine analogues were designed and synthesized as colchicine binding site inhibitors (CBSIs) with potent antiproliferative activities. Among them, compound 17j has the most potent activities against 6 human cancer cell lines with IC50 values from 1.1 nM to 4.4 nM, which was 76 times higher than the lead compound 3 in A549 cells. The co-crystal structure of 17j in complex with tubulin confirms the key binding mode at the colchicine binding site. Moreover, 17j inhibited the tubulin polymerization in biochemical assays, depolymerized cellular microtubules, induced the G2/M arrest, inhibited the cell migration, and promoted the initiation of apoptosis. In vivo, 17j effectively inhibits primary tumor growth with tumor growth inhibition rates of 42.51% (5 mg/kg) and 65.42% (10 mg/kg) in A549 xenograft model. Taken together, 17j represents a promising new generation of CBSIs.

Synthesis and biological evaluation of a novel c-Myc inhibitor against colorectal cancer via blocking c-Myc/Max heterodimerization and disturbing its DNA binding.

c-Myc is a transcription factor that is aberrantly expressed in the majority of human cancers. Recent studies unveiled that abnormal expression of c-Myc protein is involved in the development of colorectal cancer (CRC). Previously, we reported a novel phenoxy-N-phenylaniline derivative A-42 that can inhibit c-Myc protein and the growth of different CRC cancer cells potently. To look for a better candidate, the structure-activity relationship (SAR) of A ring, D ring and the linker between A and B rings of A-42 was investigated, and a series of compounds were synthesized. Among them, compound B13 was identified as the most active c-Myc inhibitor with cytotoxicity activity against HT29 and HCT116 cells at IC50 0.29 µM and IC50 0.64 µM, respectively, which is superior to that of A-42. According to the bioassays, compound B13 not only can suppress CRC cells proliferation and migration, but also inhibit the binding of c-Myc/Max dimer to DNA, which further interfere with the expression of the relevant proteins of apoptosis pathway. Furthermore, B13 could inhibit HT29 tumor growth in xenograft mouse models potently with tumor growth inhibitions (TGIs) up to 65.49% at dose of 40 mg/kg, which is superior to A-42 (55.82%, 40 mg/kg). Overall, B13 may potentially serve as an effective CRC therapy via blocking c-Myc/Max binding with DNA.

[The effect of axis pedicle and intra-axial vertebral artery on C 2 pedicle screw placement].

Objective: To investigate the influence of axis pedicle and intra-axial vertebral artery (IAVA) alignment on C 2 pedicle screw placement by measuring the data of head and neck CT angiography. Methods: The axis pedicle diameter (D), isthmus height (H), isthmus thickness (T), and IAVA alignment types were measured in 116 patients (232 sides) who underwent head and neck CT angiography examinations between January 2020 and June 2020. Defined the IAVA offset direction by referencing the vertical line through the center of C 3 transverse foramen on the coronal scan, it was divided into lateral (L), neutral (N), and medial (M). Defined the IAVA high-riding degree by referencing the horizontal line through the outlet of the C 2 transverse foramen, it was divided into below (B), within (W), and above (A). The rate of pedicle stenosis, high-riding vertebral artery, and different IAVA types were calculated, and their relationships were analysed. Simulative C 2 pedicle screws were implanted by Mimics 19.0 software, and the interrelation among the rates of pedicle stenosis, high-riding vertebral artery, IAVA types, and vertebral artery injury were analyzed. Results: The rate of C 2 pedicle stenosis was 33.6% (78/232), and the rate of high-riding vertebral artery was 35.3% (82/232). According to the offset direction and the degree of riding, IAVA was divided into 9 types, among which the N-W type (29.3%) was the most, followed by the L-W type (19.0%) and the L-B type (12.9%), accounting for 60.9%. The vertebral artery injury rate of simulative implanted C 2 pedicle screws was 35.3% (82/232). The vertebral artery injury rate in patients with pedicle stenosis and high-riding vertebral artery was significantly higher than that who were not ( P<0.001). The rate of pedicle stenosis, high-riding vertebral artery, and vertebral artery injury were significantly different among IAVA types ( P<0.001), and M-A type was the most common. Conclusion: Vertebral artery injury is more common in pedicle stenosis and/or high-riding vertebral artery and/or IAVA M-A type. Preoperative head and neck CT angiography examination has clinical guiding significance.

Percutaneous endoscopic interlaminar discectomy via inner border of inferior pedicle approach for downmigrated disc herniation: a retrospective study.

OBJECTIVE: To evaluate the efficacy and feasibility of percutaneous endoscopic interlaminar discectomy (PEID) via the inner border of the inferior pedicle approach for downmigrated disc herniation. METHODS: Seventeen patients who had downmigrated disc herniation were included in this study from May 2020 to February 2021. After PEID via the inner border of the inferior pedicle approach, a retrospective study was conducted on all patients. Radiologic findings were investigated, and based on the level of migration seen on preoperative magnetic resonance imaging (MRI), participants were divided into two types (high-grade and low-grade migrations). Preoperative, 1st post-operative day, 3rd post-operative month, and the final follow-up visual analogue scale (VAS) assessments for back and leg pain and preoperative, 3rd post-operative month, and the final follow-up Oswestry disability index (ODI) evaluations were performed. The clinical effects at the final follow-up were assessed by the modified MacNab criterion. RESULTS: All patients successfully completed surgery. There were 10 males and 7 females in the group. These patients were 42 years old on average (range, 25-68 years). Four and 13 patients had downmigrated disc herniation with high-grade and low-grade, respectively, on MRI. The mean follow-up duration was 10.47 ± 1.84 months (range, 8-14 months). The mean VAS score for back and leg improved from 5.18 ± 0.81 preoperatively to 1.35 ± 0.49 at the final follow-up (P < 0.05) and 6.94 ± 0.66 preoperatively to 1.47 ± 0.51 at the final follow-up (P < 0.05), respectively. The mean ODI score improved from 48.00 ± 3.64 preoperatively to 18.71 ± 1.31 at the final follow-up (P < 0.05). According to the modified MacNab criterion, 15 patients (88.2%) obtained excellent, while the rest 2 patients (11.8%) reported good outcomes. CONCLUSION: PEID via the inner border of the inferior pedicle approach could be a good alternative option for the treatment of downmigrated disc herniation.

Development of Dual Inhibitors Targeting Epidermal Growth Factor Receptor in Cancer Therapy.

Epidermal growth factor receptor (EGFR) is of great significance in mediating cell signaling transduction and tumor behaviors. Currently, third-generation inhibitors of EGFR, especially osimertinib, are at the clinical frontier for the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC). Regrettably, the rapidly developing drug resistance caused by EGFR mutations and the compensatory mechanism have largely limited their clinical efficacy. Given the synergistic effect between EGFR and other compensatory targets during tumorigenesis and tumor development, EGFR dual-target inhibitors are promising for their reduced risk of drug resistance, higher efficacy, lower dosage, and fewer adverse events than those of single-target inhibitors. Hence, we present the synergistic mechanism underlying the role of EGFR dual-target inhibitors against drug resistance, their structure-activity relationships, and their therapeutic potential. Most importantly, we emphasize the optimal target combinations and design strategies for EGFR dual-target inhibitors and provide some perspectives on new challenges and future directions in this field.

Custom design and biomechanical clinical trials of 3D-printed polyether ether ketone femoral shaft prosthesis.

During the surgical resection and reconstruction of a pathological femoral fracture, the removal of the femoral tumor leaves a large bone defect. Thus, it is necessary to reconstruct the defect and perform internal fixation. Polyether ether ketone (PEEK) has been widely used in spinal fusion and cranioplasty given its excellent biomechanical properties, biocompatibility, and stability. The typical design method of femoral prosthesis is based on the contralateral mirror image model (M-model), and we propose a novel method for designing femoral prosthesis, which is based on the cross section and centerline of the mirrored femur (C-model). In this study, the femoral shaft prostheses based on two models were manufactured using fused deposition modeling technology, and we use mechanical test and finite element analysis (FEA) to reveal the differences in mechanical properties of the two models. The mechanical results showed that the maximum loading force and yield strength were increased by 3% and 6% in the C-model prosthesis compared with the M-model prosthesis, respectively. In FEA, the results indicate that the C-model prosthesis could reduce the stress concentration by 5.4%-10.9% compared to the M-model prosthesis. Finally, the 3D-printed PEEK femoral shaft prosthesis based on C-model was implanted, no early complications occurred. Postoperative radiological examination indicated that the prosthesis and the femoral osteotomy end were closely matched and fixed well.

[Application of Curved Diffusion Needle in unilateral percutaneous vertebroplasty].

OBJECTIVE: To evaluate the effectiveness of Curved Diffusion Needle in unilateral percutaneous vertebroplasty (PVP) by compared with bilateral PVP. METHODS: A clinical data of 93 patients with osteoporotic vertebral compression fracture (OVCF) treated with PVP between January 2020 and January 2021 was retrospectively analyzed, including 47 patients underwent unilateral PVP assisted with Curved Diffusion Needle (unilateral group) and 46 patients underwent bilateral PVP (bilateral group). There was no significant difference in gender, age, cause of injury, time from injury to operation, T value of bone mineral density, AO classification, distribution of injured vertebrae, and preoperative visual analogue scale (VAS) score, Oswestry disability index (ODI), relative height of injured vertebrae, and Cobb angle between the two groups ( P>0.05). The operation time, the amount of bone cement injection, the incidence of bone cement leakage, the bone cement diffusion distribution, VAS score, ODI, the relative height of injured vertebrae, and Cobb angle were recorded and compared between the two groups. RESULTS: All operations successfully completed. The operation time was significantly shorter in unilateral group than in bilateral group ( t=-13.936, P=0.000), and the amount of bone cement injection was significantly less in unilateral group than in bilateral group ( t=-13.237, P=0.000). The incidence of bone cement leakage in unilateral group was 19.14%, which was significantly lower than that in bilateral group (39.13%) ( χ 2=4.505, P=0.034). The score of bone cement distribution in unilateral group was 7.0±1.3, of which 41 cases were excellent and 6 cases were well. The score of bilateral group was 7.4±0.8, of which 43 cases were excellent and 3 cases were well. There was no significant difference in score and grading of bone cement distribution between the two groups ( t=-1.630, P=0.107; Z=-1.013, P=0.311). All patients were followed up and the follow-up time was 3-10 months (mean, 6.5 months) in unilateral group and 3-10 months (mean, 6.1 months) in bilateral group. The VAS score, ODI, the relative height of injured vertebrae, and Cobb angle at 24 hours after operation and last follow-up were significantly better than those before operation in the two groups ( P<0.05). There were significant differences in all indicators between 24 hours after operation and last follow-up ( P<0.05). There was no significant difference in all indexes between the two groups ( P>0.05) at the same time point after operation. During follow-up, there was no complication such as contralateral vertebral collapse, refracture, adjacent vertebral fracture, or local kyphosis in the two groups. CONCLUSION: Unilateral PVP assisted with Curved Diffusion Needle for OVCF is beneficial to the distribution of bone cement, which can not only achieve similar effectiveness to bilateral PVP, but also achieve shorter operation time, less bone cement injection, and lower risk of bone cement leakage.

The diagnostic performance of dynamic contrast-enhanced MRI and its correlation with subtypes of breast cancer.

ABSTRACT: To evaluate diagnostic performance of perfusion-weighted imaging in differentiating benign from malignant breast lesions, and the correlation between the prognostic factors/subtypes of breast cancers and the perfusion parameters.A total of 76 patients (59 cases with breast cancer) were included in our study. The Wilcoxon rank-sum test or the Kruskal-Wallis test were adopted for comparisons according to the dichotomous histopathologic prognostic factors or immunohistochemical subtypes. Receiver operating characteristic curves were used to determine the area under the curve (AUC) values for perfusion parameters to assess discrimination ability.Confirming by pathology after operation, the percentage of benign lesions is 22.37% (17/76), malignant lesions (breast cancer) is 77.63% (59/76). According to puncture and pathological findings after operation, the standard of the molecular subtypes of breast cancer, triple negative account for 13.6% (8/59), non-triple negative account for 86.4% (51/59). The value of mean Ktrans and Kep were lower in benign than malignant lesions (P ≤ .001). The AUC of the 3 indicators are significantly improved after adjusting for age (AUC = 0.858 for Ktrans, AUC = 0.926 for Kep, and AUC = 0.827 for Ve). Moreover, the Ve index showed better discrimination performance than other indicators in identifying patients with triple-negative subtypes. Similarly, the identification ability came to the highest when combing Kep and Ve.Perfusion parameters on dynamic enhanced magnetic resonance imaging are statistically significant in distinguishing benign from malignant breast lesion, and may potentially be used as biomarkers in discriminating patients with triple-negative molecular subtypes of breast cancer.

[Comparative study on the effectiveness of improved and traditional Kirschner wire tension band fixation in treatment of type C patellar fractures].

OBJECTIVE: To compare the effectiveness of improved and traditional Kirschner wire tension band fixation in treatment of type C patellar fractures. METHODS: Between January 2017 and January 2019, 26 patients with type C patellar fractures were treated with improved Kirschner wire tension band fixation (group A), and 24 patients were treated with traditional Kirschner wire tension band fixation (group B). There was no significant difference in gender, age, injury cause, disease duration, and side and type of fracture between 2 groups ( P>0.05). The operation time, intraoperative blood loss, the visual analogue scale (VAS) scores at 1 and 3 days after operation, the fracture healing time, and the occurrence of complications (skin irritation of Kirschner wires, failure of internal fixation, fracture reduction loss) were recorded, and the knee function was evaluated by Lysholm scoring standard in 2 groups. RESULTS: The operation time in group A was significantly less than that in group B ( t=-4.742, P=0.000). There was no significant difference in the intraoperative blood loss and VAS scores at 1 and 3 days after operation between 2 groups ( P>0.05). All incisions healed by first intention. All patients were followed up 8-15 months, with an average of 11 months. The fracture healing time was (3.3±0.6) months in group A and (3.2±0.6) months in group B, showing no significant difference ( t=0.589, P=0.559). At last follow-up, the knee joint function was evaluated according to Lysholm scoring standard. And there were 15 cases of excellent, 8 cases of good, and 3 cases of fair, with an excellent and good rate of 88.5% in group A; there were 8 cases of excellent, 7 cases of good, 7 cases of fair, and 2 cases of poor, with an excellent and good rate was 62.5%. The difference between 2 groups was significant ( Z=2.828, P=0.005). The internal fixators were removed after the fracture healed in 2 groups. At last follow-up, no skin irritation of Kirschner wires occurred in group A, but 3 cases in group B. X-ray films reexamination showed that 5 cases of internal fixation failure and no fracture reduction loss were found in group A, while 9 cases of internal fixation failure and 1 case of fracture reduction loss in group B. The incidence of complications in group A was 19.2% (5/26), which was significantly lower than that in group B (54.2%, 13/24) ( χ 2=6.611, P=0.010). CONCLUSION: Compared with the traditional Kirschner wire tension band fixation, the improved Kirschner wire tension band fixation in treatment of type C patellar fracture can shorten the operation time, reduce the incidence of complications, and benefit the functional recovery of knee joint.

The X-ray structure of tubulysin analogue TGL in complex with tubulin and three possible routes for the development of next-generation tubulysin analogues.

Microtubule-targeting agents (MTAs) are the most commonly used anti-cancer drugs. At least fourteen microtubule inhibitors and ten antibody drug conjugates (ADCs) linking MTAs are approved by FDA for clinical use in cancer therapy. In current research, we determined the crystal structure of tubulysin analogue TGL in complex with tubulin at a high resolution (2.65 Å). In addition, we summarized all of the previously published high-resolution crystal structures of ligands in the vinca site to provide structural insights for the rational design of the new vinca-site ligands. Moreover, based on the aligned results of the vinca site ligands, we provided three possible routes for designing new tubulysin analogues, namely macrocyclization between the N-14 side chain and the N-9 side chain, the hybird of tubulysin M and phomopsin A, and growing new aryl group at C-21. These designed structures will inspire the development of new MTAs or payloads in cancer therapy.

C3 ester side chain plays a pivotal role in the antitumor activity of Maytansinoids.

Maytansinoids, the chemical derivatives of Maytansine, are commonly used as potent cytotoxic payloads in antibody-drug conjugates (ADC). Structure-activity-relationship studies had identified the C3 ester side chain as a critical element for antitumor activity of maytansinoids. The maytansinoids bearing the methyl group at C3 position with D configuration were about 100 to 400-fold less cytotoxic than their corresponding L-epimers toward various cell lines. The detailed mechanism of how chirality affects the anticancer activity remains elusive. In this study, we determined the high-resolution crystal structure of tubulin in complex with maytansinol, L-DM1-SMe and D-DM1-SMe. And we found the carbonyl oxygen atom of the ester moiety and the tail thiomethyl group at C3 side chain of L-DM1-SMe form strong intramolecular interaction with the hydroxyl at position 9 and the benzene ring, respectively, fixing the bioactive conformation and enhancing the binding affinity. Additionally, ligand-based and structure-based virtually screening methods were used to screen the commercially macrocyclic compounds library, and 15 macrocyclic structures were picketed out as putatively new maytansine-site inhibitors. Our study provides a possible strategy for the rational discovery of next-generation maytansine site inhibitors.

Downregulation of SUV39H1 and CITED2 Exerts Additive Effect on Promoting Adipogenic Commitment of Human Mesenchymal Stem Cells.

Human adipogenesis is the process through which uncommitted human mesenchymal stem cells (hMSCs) differentiate into adipocytes. Through a siRNA-based high-throughput screen that identifies adipogenic regulators whose expression knockdown leads to enhanced adipogenic differentiation of hMSCs, two new regulators, SUV39H1, a histone methyltransferase that catalyzes H3K9Me3, and CITED2, a CBP/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 were uncovered. Both SUV39H1 and CITED2 are normally downregulated during adipogenic differentiation of hMSCs. Further expression knockdown induced by siSUV39H1 or siCITED2 at the adipogenic initiation stage significantly enhanced adipogenic differentiation of hMSCs as compared with siControl treatment, with siSUV39H1 acting by both accelerating fat accumulation in individual adipocytes and increasing the total number of committed adipocytes, whereas siCITED2 acting predominantly by increasing the total number of committed adipocytes. In addition, both siSUV39H1 and siCITED2 were able to redirect hMSCs to undergo adipogenic differentiation in the presence of osteogenic inducing media, which normally only induces osteogenic differentiation of hMSCs in the absence of siSUV39H1 or siCITED2. Interestingly, simultaneous knockdown of both SUV39H1 and CITED2 resulted in even greater levels of adipogenic differentiation of hMSCs and expression of CEBPα and PPARγ, two master regulators of adipogenesis, as compared with those elicited by single gene knockdown. Furthermore, the effects of co-knockdown were equivalent to the additive effect of individual gene knockdown. Taken together, this study demonstrates that SUV39H1 and CITED2 are both negative regulators of human adipogenesis, and downregulation of both genes exerts an additive effect on promoting adipogenic differentiation of hMSCs through augmented commitment.