To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

OBJECTIVE: To investigate the surgical technique and effectiveness of tension band-assisted plate fixation combined with external fixator for volar marginal fractures of the distal radius. METHODS: A retrospective analysis was performed on the clinical data of 12 patients with volar marginal fractures of the distal radius treated by Kirschner wire tension band-assisted anatomical plate fixation combined with external fixator between October 2018 and July 2023. The cohort included 9 males and 3 females, aged from 20 to 52 years (mean, 35.5 years). The injury causes included traffic accidents in 6 cases, falls from height in 3 cases, and fall in 3 cases. According to AO/Orthopaedic Trauma Association (AO/OTA), there were 1 case of type B2, 4 cases of type B3, 2 cases of type C1, 3 cases of type C2, and 2 cases of type C3. According to Fernandez classification, there were 2 cases of type Ⅲ, 5 cases of type Ⅳ, and 5 cases of type Ⅴ. Associated injuries included radiocarpal joint dislocation or subluxation in 7 cases and median nerve injury in 2 cases. The time from injury to operation was 2-7 days (mean, 3.2 days). Postoperatively, functional outcomes were evaluated using the modified Mayo wrist score and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Grip strength was measured as the ratio to the unaffected side, and wrist range of motion (ROM) including dorsiflexion, palmar flexion, ulnar deviation, and radial deviation was assessed. RESULTS: All procedures were successfully completed, with an operation time of 55-110 minutes (mean, 65 minutes). All patients were followed up 6-36 months (mean, 13.7 months). Surgical incisions healed by first intention, without complications such as vascular-nerve injury or infection. Bony union and articular congruency were attained in all patients, with a healing time of 3-5 months (mean, 3.8 months). During follow-up, 1 case of Kirschner wire migration occurred with no instances of infections, radiocarpal dislocations, internal fixation failures, or extensor pollicis longus tendon ruptures. At last follow-up, the modified Mayo wrist score ranged from 65 to 92 (mean, 80.8), the DASH score ranged from 7 to 15 (mean, 11.6), the grip strength was 65%-90% (mean, 78.2%) of the unaffected side; and wrist ROM was palmar flexion 60°-85° (mean, 77.4°), dorsiflexion 55°-80° (mean, 74.8°), radial deviation 10°-25° (mean, 18.8°), and ulnar deviation 15°-30° (mean, 24.5°). CONCLUSION Kirschner wire tension band-assisted anatomical plate fixation combined with external fixator for volar marginal fractures of the distal radius is a simple method with reliable fixation, which can achieve satisfactory effectiveness.
Humans ; Male ; Adult ; Female ; Radius Fractures/diagnostic imaging* ; Retrospective Studies ; Middle Aged ; Bone Plates ; Bone Wires ; External Fixators ; Young Adult ; Fracture Fixation, Internal/instrumentation* ; Treatment Outcome ; Range of Motion, Articular ; Hand Strength ; Wrist Injuries/surgery*

OBJECTIVE: To investigate the feasibility and effectiveness of precise-guided temporary fixation assistive devices in assisting the main nail guide pin placement and precise temporary fixation in proximal femoral nail antirotation (PFNA) internal fixation of femoral intertrochanteric fractures. METHODS: A prospective randomized controlled study was conducted to analyze the clinical data of 60 patients with femoral intertrochanteric fractures over 65 years old who met the selection criteria between January 2020 and June 2022 and were treated with PFNA internal fixation. The patients were randomly divided into the trial group (auxiliary device guided main nail guide pin placement and temporary fixation) and the control group (conventional treatment), with 30 cases in each group. There was no significant difference in baseline data such as gender, age, cause of injury, time from injury to operation, fracture side, AO/Orthopaedic Trauma Association (AO/OTA) classification, and combined medical diseases between the two groups ( P>0.05). The operation time, times of main nail guide pin placement, intraoperative fluoroscopy frequency, intraoperative blood loss, and perioperative blood transfusion were recorded and compared between the two groups. The quality of fracture reduction was evaluated by CHANG Shimin et al criteria. Harris score was used to evaluate the hip function at 1 year after operation. RESULTS: In the trial group, 2 temporary fixation needles were successfully placed 2-5 times, including 2 times in 13 cases (43.3%), 3 times in 8 cases (26.7%), 4 times in 7 cases (23.3%), and 5 times in 2 cases (6.7%). The operation time, times of main nail guide pin placement, intraoperative fluoroscopy frequency, and intraoperative blood loss in the trial group were significantly less than those in the control group, and the reduction quality score was significantly better than that in the control group ( P<0.05). There was no significant difference in perioperative blood transfusion between the two groups ( P>0.05). All patients were followed up 12-19 months (mean, 15 months). There was no complication such as incision infection, deep vein thrombosis, or internal fixation loosening. At 1 year after operation, the Harris score of the affected hip joint in the trial group was significantly higher than that in the control group ( P<0.05). CONCLUSION The technique of main nail guide pin placement and temporary fixation under the guidance of auxiliary devices in PFNA internal fixation can achieve faster insertion of the main nail guide pin, accurate temporary fixation to maintain reduction, and avoid the subsequent operation space, so as to improve the effectiveness.
Humans ; Bone Nails ; Male ; Female ; Hip Fractures/surgery* ; Fracture Fixation, Intramedullary/instrumentation* ; Aged ; Prospective Studies ; Operative Time ; Treatment Outcome ; Fracture Fixation, Internal/instrumentation* ; Aged, 80 and over

Objective To investigate the effects and mechanisms of silica dust on the apoptosis of alveolar epithelial cell (AEC) through in vitro and animal experiments. Methods i) In vitro experiment. A549 cells were stimulated with 100 mg/L silica suspension for 0, 12, 24 and 48 hours. The cell apoptosis rate was detected by flow cytometry. ii) Animal experiment. Specific pathogen-free male C57BL/6 mice were randomly divided into control, 14-day, 28-day, and 56-day groups, with five mice in each group. The mice in the control group were sacrificed at 56 days after being treated with 40.0 μL 0.9% sodium chloride solution, and the mice in the last three groups were sacrificed at 14, 28 and 56 days after being treated with 40.0 μL silica suspension with a mass concentration of 125 g/L via tracheal exposure method. The lung tissues of mice were collected to measure lung organ coefficients. Masson staining was used to detect the degree of pulmonary fibrosis, and Ashcroft scores were evaluated. The apoptosis of AEC in mice was observed by TUNEL immunofluorescence assay. iii) The mRNA relative expression of apoptosis-related genes in A549 cells and mouse lung tissue was detected using reverse transcription and real-time fluorescence quantitative polymerase chain reaction. Results i) In vitro experiment. The apoptosis rate of A549 cells increased with longer silica exposure (all P<0.05). The relative expression of B cell lymphoma-2 (BCL-2) mRNA in A549 cells in 24 h group and 48 h group decreased (both P<0.05), and the relative expression of BCL-2 associated X protein (BAX) mRNA increased (both P<0.05), compared with 0 h group. The mRNA relative expression of caspase (CASP) -3 and CASP-9 in A549 cells increased with longer silica exposure (all P<0.05). ii) Animal experiment. The lung organ coefficients and Ashcroft score in mice progressively increased (all P<0.05), the degree of pulmonary fibrosis was gradually aggravated, and TUNEL positive cells in lung tissue were gradually increased, while Bax, Casp-3 and Casp-9 mRNA relative expression increased with longer silica exposure (all P<0.05). Conclusion Silica dust may cause pulmonary fibrosis by inducing apoptosis of AEC, with a time-dependent effect. The mechanism may be related to the effect of silica dust on mitochondrial apoptosis through Bcl-2/Bax/Caspase-3 signaling pathway.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

To target the pivotal BCR/ABL oncoprotein in chronic myeloid leukemia (CML) cells, tyrosine kinase inhibitors (TKIs) are utilized as landmark achievements in CML therapy. However, TKI resistance and intolerance remain principal obstacles in the treatment of CML patients. In recent years, drug repositioning provided alternative and promising perspectives apart from the classical cancer therapies, and promoted anthelmintic mebendazole (MBZ) as an effective anti-cancer drug in various cancers. Here, we investigated the role of MBZ in CML treatment including imatinib-resistant CML cells. Our results proved that MBZ inhibited the proliferation and induced apoptosis in CML cells. We found that MBZ effectively suppressed BCR/ABL kinase activity and MEK/ERK signaling pathway by reducing p-BCR/ABL and p-ERK levels with ABL1 targeting ability. Meanwhile, MBZ directly targeted the colchicine-binding site of β-tubulin protein, hampered microtubule polymerization and induced mitosis arrest and mitotic catastrophe. In addition, MBZ increased DNA damage levels and hampered the accumulation of ataxia-telangiectasia mutated and DNA-dependent protein kinase into the nucleus. This work discovered that anthelmintic MBZ exerts remarkable anticancer effects in both imatinib-sensitive and imatinib-resistant CML cells in vitro and revealed mechanisms underlying. From the perspective of drug repositioning and multi‐target therapeutic strategy, this study provides a promising option for CML treatment, especially in TKI-resistant or intolerant individuals.

Objective To use direct dilution method to pretreat human urine, and to determine 19 elements in human urine using inductively coupled plasma mass spectrometry, and to evaluate the uncertainty of the entire experimental process. Methods The relevant mathematical models were established according to JJF 10591-2012 ^“Evaluation and Expression of Measurement Uncertainty^” and CNAS-GL006 ^“Guidance for Evaluation of Uncertainty in Chemical Analysis^”. Taking molybdenum as an example, the uncertainty sources in the determination of 19 elements in human urine by inductively coupled plasma method were analyzed and evaluated, including sample pretreatment, sample repeated measurement, standard solution preparation and standard curve fitting. Results The extended uncertainty of molybdenum in human urine is 2.12μg/L, and the measurement result of molybdenum is (44.8±2.12)μg/L. The measurement result of 19 elements in human urine ranges from less than the detection limit to 601μg/L, and the extended uncertainty range is 0.38~33.6μg/L.Conclusion It was found from the calculation that the uncertainty of the determination result was mainly affected by the uncertainty of the sample repeated measurement and the standard curve fitting. By adjusting the range of standard curve and increasing the number of parallel sample measurement, the uncertainty was reduced and the quality of detection was improved.

Background::The association and its population heterogeneities between low-density lipoprotein cholesterol (LDL-C) and all-cause and cardiovascular mortality remain unknown. We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease (CVD) mortality and heterogeneities in the associations among different population subgroups.Methods::A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork (ChinaHEART) (2014-2019) were included. Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories (<70.0, 70.0-99.9, 100.0-129.9 [reference group], 130.0-159.9, 160.0-189.9, and ≥190.0 mg/dL) and all-cause and cause-specific mortality.Results::During a median follow-up of 3.7 years, 57,391 and 23,241 deaths from all-cause and overall CVD were documented. We observed J-shaped associations between LDL-C and death from all-cause, overall CVD, coronary heart disease (CHD), and ischemic stroke, and an L-shaped association between LDL-C and hemorrhagic stroke (HS) mortality ( P for non-linearity <0.001). Compared with the reference group (100.0-129.9 mg/dL), very low LDL-C levels (<70.0 mg/dL) were significantly associated with increased risk of overall CVD (hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 1.06-1.14) and HS mortality (HR: 1.37, 95% CI: 1.29-1.45). Very high LDL-C levels (≥190.0 mg/dL) were associated with increased risk of overall CVD (HR: 1.51, 95% CI: 1.40-1.62) and CHD mortality (HR: 2.08, 95% CI: 1.92-2.24). The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age, low or normal body mass index, low or moderate 10-year atherosclerotic CVD risk, and those without diagnosed CVD or taking statins. Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people. Conclusions::People with very low LDL-C had a higher risk of all-cause, CVD, and HS mortality; those with very high LDL-C had a higher risk of all-cause, CVD, and CHD mortality. On the basis of our findings, comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.