BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans

Objective To investigate the mechanism of matrix metalloproteinase(MMP)-9 involved in epithelial mesenchymal transformation(EMT)in chronic sinusitis(CRS).Methods The expression of MMP-9 from polypoid middle turbinate tissue was detected by immunohistochemical staining qPCR and Western blot assay in 42 patients with CRS and 8 patients underwent septoplasty.Primary human nasal epithelial cells HNEpc were cultured in vitro and divided into the control group,the TGF-β1 group(5 μg/L TGF-β1 intervention)and the TGF-β1+si-MMP-9 group(transfected with si-MMP-9 and 5 μg/L TGF-β1 intervention).The expression of MMP-9 was detected by cell immunofluorescence staining.Expression levels of TGF-β1,MMP-9 and EMT-related proteins E-cadherin,vimentin and α-SMA were detected by Western blot assay.Results(1)The positive expression rate of MMP-9 was significantly higher in the nasal mucosa of CRS with nasal polyps(CRSwNP)group(54.5%,12/22)than that of the CRS without polyps(25.0%,5/20)group and the control group(12.8%,1/8).The relative expression levels of MMP-9 mRNA and protein in nasal mucosa were higher in the CRSwNP group than those in the CRSsNP group and the control group(P＜0.05).(2)Compared with the control group,the expressions levels of TGF-β1,MMP-9,vimentin and α-SMA were increased in the TGF-β1 group,while the expression of E-cadherin was decreased(P＜0.05).Compared with the TGF-β1 group,expression levels of TGF-β1,MMP-9,vimentin and α-SMA were decreased in the TGF-β1+si-MMP-9 group,and the expression of E-cadherin was increased(P＜0.05).Conclusion The expression of MMP-9 is increased in CRS patients,which may be involved in the development of CRS through the regulation of EMT.

Objective:To evaluate the impact of preemptive analgesia with ibuprofen on postoperative pain following the extraction of impacted mandibular third molars in a Chinese population, aiming to provide a clinical reference for its application.Methods:This multicenter, randomized, double-blind, placebo-controlled parallel-group trial was conducted from April 2022 to October 2023 at the Capital Medical University School of Stomatology (40 cases), Beijing TianTan Hospital, Capital Medical University (22 cases), and Beijing Chao-Yang Hospital, Capital Medical University (20 cases). It included 82 patients with impacted mandibular third molars, with 41 in the ibuprofen group and 41 in the control group. Participants in the ibuprofen group received 300 mg of sustained-release ibuprofen capsules orally 15 min before surgery, while the control group received a placebo. Both groups were instructed to take sustained-release ibuprofen capsules as planned for 3 days post-surgery. Pain intensity was measured using the numerical rating scale at 30 min, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h after surgery, and the use of additional analgesic medication was recorded during days 4 to 6 postoperatively.Results:All 82 patients completed the study according to the protocol. No adverse events such as nausea, vomiting, or allergies were reported in either group during the trial. The ibuprofen group exhibited significantly lower pain scores at 4 h [2.0 (1.0, 4.0) vs. 4.0 (3.0, 5.0)] ( Z=-3.73, P<0.001), 6 h [2.0 (1.0, 4.0) vs. 5.0(2.5, 6.0)] ( Z=-3.38, P<0.001), and 8 h [2.0 (1.0, 4.0) vs. 5.0 (2.0, 6.0)] ( Z=-2.11, P=0.035) postoperatively compared to the control group. There were no statistically significant differences in pain scores between the groups at 30 min, 24 h, 48 h, and 72 h postoperatively ( P>0.05). Additionally, 11 out of 41 patients (26.8%) in the ibuprofen group and 23 out of 41 patients (56.1%) in the control group required extra analgesic medication between days 4 and 6 post-surgery, with the ibuprofen group taking significantly fewer additional pills [0.0 (0.0, 1.0) vs. 1.0 (0.0, 3.0)] ( Z=-2.81, P=0.005). Conclusions:A pain management regimen involving 300 mg of oral sustained-release ibuprofen capsules administered 15 minutes before surgery and continued for 3 d postoperatively effectively reduces pain levels and the total amount of analgesic medication used after the extraction of impacted mandibular third molars. Considering its efficacy, safety, and cost-effectiveness, ibuprofen is recommended as a first-line drug for perioperative pain management, enhancing patient comfort during diagnosis and treatment in a feasible manner.

Objective:To evaluate the effect of preemptive analgesia with ibuprofen on postoperative pain following single posterior tooth implantation, aiming to provide a clinical reference for its application.Methods:A multicenter, randomized, double-blind, placebo-controlled parallel-group trial was conducted. A total of 82 participants were included in the trial, meeting the eligibility criteria from April 2022 to April 2024 at the Capital Medical University School of Stomatology (40 cases), Beijing TianTan Hospital, Capital Medical University (22 cases), Beijing Chao-Yang Hospital, Capital Medical University (20 cases). Participants were randomly assigned in a 1∶1 ratio to either the ibuprofen group or the control group, with each group comprising 41 individuals. Participants in the ibuprofen group received 300 mg of sustained-release ibuprofen capsules orally 15 min before surgery, while the control group received a placebo. Both groups received the same postoperative analgesic regimen for 3 days. Pain scores were assessed using the numerical rating scale at 30 min, 4 h, 6 h, 8 h, 24 h, 48 h, and 72 h postoperatively, and the additional use of analgesic medication was recorded from days 4 to 6 postoperatively.Results:A total of 82 participants were initially enrolled in the study, with 7 dropouts (4 from the control group and 3 from the ibuprofen group), resulting in 75 participants (37 in the control group and 38 in the ibuprofen group) completing the trial. There were no reports of adverse events such as nausea or vomiting among the participants. The ibuprofen group exhibited significantly lower pain scores at 4 h, 6 h and 8 h [1.0 (0.0, 2.0), 1.0 (0.0, 2.0), 1.5 (0.0, 3.0) ] postoperatively compared to the control group 4 h, 6 h and 8 h [2.0 (1.0, 3.0), 3.0 (1.5, 4.0), 2.0 (1.0, 4.0)] ( Z=-1.99, P=0.047; Z=-3.01, P=0.003; Z=-2.10, P=0.036). The proportions of patients requiring additional analgesic medication between days 4 and 6 post-surgery were 18.4% (7/38) in the ibuprofen group and 27.0% (10/37) in the control group, with no significant difference (χ 2=0.79, P=0.373). The median additional medication usage postoperatively was [0.0 (0.0, 0.0) pills] in the ibuprofen group and [0.0 (0.0, 1.0) pills] in the control group, with no significant difference ( Z=-0.78, P=0.439). Conclusions:Preemptive analgesia with ibuprofen effectively reduces postoperative pain following tooth implantation, representing a safe and effective perioperative pain management strategy.

Objective:To explore the association between postoperative radiotherapy for bladder cancer and the risk of second primary rectal cancer.Methods:Eligible 75 120 patients with bladder cancer from the Surveillance, Epidemiology, and End Result database (SEER) of the National Cancer Institute (NCI) (1975-2017) were enrolled in this study. The second primary cancers referred to rectal cancers patients suffered after more than five years post-treatment for bladder cancer, and the cumulative incidence was estimated using Fine-Gray competing risk regression. The relative risk (RR) of rectal cancer in patients treated with or without radiotherapy (the RT group or the NRT group) was evaluated using Poisson regression.Results:Among the 75 120 patients, 70 045 (92.4%) were Caucasian, with a median age of 65.8 years (54-74 years). A total of 2 236 (3%) received postoperative radiotherapy, while 72 884 (97%) received surgery alone. The 30-year follow-up revealed a cumulative incidence of rectal cancer of 0.93% in the RT group and 0.43% in the NRT group ( P = 0.004). The competing risk regression analysis identified a significant association between radiotherapy and rectal cancer ( HR: 1.86; 95% CI 1.26-2.74, P < 0.009). Furthermore, the RR of radiotherapy-associated rectal cancer significantly increased as the diagnosis occurred earlier (1975-1985 vs. 1985-1994: RR 2.59; 95% CI 1.20-4.86, P < 0.001), and a lower age at the time of radiotherapy was associated with a higher probability of second primary tumors (≤50-year old vs. > 50 year old : RR 7.89, 95% CI 2.97-21.30, P < 0.001). As calculated using the Poisson distribution, the RR of second rectal tumors was higher in the RT group ( RR: 2.20, 95% CI 1.45-3.18, P < 0.001), even after adjusting the date of diagnosis ( RR: 1.77, 95% CI 1.17-2.57, P = 0.009). Conclusions:An increased risk of rectal cancer following bladder cancer radiotherapy necessitates aggressive follow-ups for the purpose of early detecting second primary rectal cancer associated with bladder cancer radiotherapy.

Objective·To study the alterations in vestibular hair cell morphology and function of ATPase plasma membrane Ca2+transporting 2 oblivion(Atp2b2 Oblivion)heterozygous mice at different ages.Methods·Atp2b2 Oblivion heterozygous male mice aged 2 months and 8 months were selected with ten in each kind and C57BL/6J wild-type mice with the same gender,age and number were selected as the control group.Expression patterns of ATP2B2 in vestibular hair cells and numbers of hair cells in the striola zone and the extra striola zone in the two groups of mice at different ages were observed and calculated respectively through immunofluorescence assay.Hair bundle structures were detected by scanning electron microscopy(SEM),and mitochondria and ribbon synapse structures were observed by transmission electron microscopy(TEM).Vestibular evoked potential(VsEP),vestibular evoked myogenic potential(VEMP),rotarod rod test,and balance beam test were adopted for the evaluation of vestibular functions.Results·ATP2B2 was mainly expressed in the hair bundle of vestibular hair cells in the two groups of mice.Hair cell numbers in the striola zone and the extra-striola zone did not exhibit any differences between Atp2b2 Oblivion heterozygous mutant mice and wild-type mice of 2-month-old and 8-month-old.No visible structural abnormality in the hair bundle could be seen through SEM.TEM results implied no morphological abnormality in mitochondria or ribbon synapses in the 2-month-old heterozygous mutant mice,while vacuolar degeneration was discovered in the mitochondria under the cuticular plate in the 8-month-old heterozygous mutant mice with the normal ribbon synapses and the normal mitochondria near the innervation site.VsEP and VEMP thresholds of 2-month-old and 8-month-old Atp2b2 Oblivion heterozygous mutant mice were significantly elevated compared with the wild-type mice.Analysis of VsEP waveform manifested prolonged P1 latency and declined P1N1 amplitude in heterozygous mutant mice(P＜0.05).Results of rotarod rod test and balance beam test acquired from 2-month-old Atp2b2 Oblivion heterozygous mutant mice were not significantly different from the wild-type mice,while the ability of the mutant mice to accomplish the tests descended significantly at 8 months of age compared with the wild-type mice(P＜0.05).Conclusion·Atp2b2 Oblivion heterozygous mutant mice showed defective vestibular electrophysiological function at 2 months old,and abnormalities in vestibule-related behaviors can be detected at 8 months old.The vestibular function ofAtp2b2 Oblivion heterozygous mutant mice deteriorate progressively.

Objective:To investigate the effect of free thenar perforator flap on repair of finger pulp defect.Methods:From September 2019 to November 2021, 79 cases of finger injuries complicated with defects in the pulp of fingers received free thenar perforator flap transfer surgery for reconstruction of finger pulps in the Department of Hand and Foot Surgery, Taizhou Hospital, Zhejiang Province. The patients were 51 males and 28 females, aged from 17 to 52(37.5±5.2) years old. There were 34 finger-pulp defects of index fingers, 15 of middle fingers, 26 of ring fingers and 4 of little fingers. All patients were treated with free thenar perforator flaps sized 2.0 cm×2.5 cm-3.0 cm×3.5 cm. All thenar perforator flaps were pedicled with the perforator artery and subcutaneous superficial vein in the thenar region, and the vessels were anastomosed with the proper palmar digital artery and dorsal digital vein, respectively. At the same time, subcutaneous nerve and proper palmar digital nerve were sutured to reconstruct the sensation of flaps. During the operation, the dominant perforating branch of thenar was found being originated from the superficial palmar branch of radial artery in 27 cases, from the superficial palmar arch in 21 cases, from the perforating branch of metacarpophalangeal proper artery of thumb in 11 cases, from the radial artery in 10 cases and from the main artery of thumb in 10 cases. The origins of nerves within the flaps were found from the superficial branch of radial nerve(24 cases), the terminal branch of lateral cutaneous nerve of forearm(22 cases) and the palmar branch of median nerve(33 cases). The operation time was (96.7±10.7) minutes. The donor site for the flap was closed directly without skin grafting. Most of the follow-up were conducted through the visit of outpatient clinic and the patients from other regions were reviewed via telephone or WeChat.Results:All perforator flaps survived completely and the flap donor sites healed smoothly. Follow-up lasted for (20.5±3.8) months. The reconstructed finger pulp was not bulky and the texture was satisfactory. TPD of the flaps was (5.6±0.9) mm. Only a linear scar left in the flap donor sites without significant affect on thenar function.Conclusion:The vascular anatomy of thenar perforator flap is constant, which helps to regain sensations of the flap. The texture and thickness of the flap are similar to those of the finger. It is ideal for reconstruction of defect of finger pulp.

Objective:To observe the peripapillary atrophy (PPA) and peripapillary choroidal vascularity index (CVI) in patients with different degrees of myopia and to analyze their correlations.Methods:A cross-sectional clinical study. From September 2021 to December 2021, 281 mypoic patients of 281 eyes treated in Eye Hospital of Wenzhou Medical University at Hangzhou were included in this study, and the right eye was used as the treated eye. There were 135 eyes in 135 males and 146 eyes in 146 females. The age was 28.18±5.78 years. The spherical equivalent refraction (SE) was -5.13±2.33 D. The patients were divided into three groups: low myopia group (group A, -3.00 D

Objective:To investigate the infrequent gene mutations of KRAS, NRAS and BRAF in colorectal cancer and their clinical significance.Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 1 513 patients with colorectal cancer who were admitted to the Peking University Cancer Hospital from December 2013 to November 2018 were collected. There were 921 males and 592 females, aged from 15 to 97 years, with an average age of 59 years. The genomic DNA of tumor tissue was extracted, and the mutation status of KRAS (exon 2, 3), NRAS (exon 2, 3) and BRAF (exon 15) was detected by the Sanger sequencing. Observation indicators: (1) mutation status of KRAS, NRAS and BRAF; (2) relationship of different mutation status of KRAS, NRAS and BRAF with clinicopathological characteristics; (3) infrequent mutation status of single gene and its clinicopathological characteristics; (4) simultaneous mutations of two genes and their clinicopathological characteristics. Count data were expressed by absolute numbers or percentages, and comparison between groups was analyzed by the chi-square test.Results:(1) Mutation status of KRAS, NRAS and BRAF: the mutation rates of KRAS, NRAS and BRAF were 37.806%(572/1 513), 3.173%(48/1 513) and 5.486%(83/1 513) of the 1 513 patients with colorectal cancer, respectively. The mutation rates of exon 2 and exon 3 in KRAS were 35.889%(543/1 513) and 1.917%(29/1 513), respectively. The mutation rates of exon 2 and exon 3 in NRAS were 1.322%(20/1 513) and 1.851%(28/1 513), respectively. The mutation rate of exon 15 in BRAF was 5.486%(83/1 513). The mutation of KRAS mainly occurred in codon 12, 13 of exon 2 and codon 61 of exon 3, with a mutation rate of 27.759%(420/1 513), 7.733%(117/1 513), and 1.586%(24/1 513), respectively. Infrequent mutation in codon 14, 59, 60 of KRAS were found in 7 patients with colorectal cancer [0.463%(7/1 513)], including V14I mutation in 2 cases [0.132%(2/1 513)], A59T mutation in 2 cases [0.132%(2/1 513)], A59E mutation in 2 cases [0.132%(2/1 513)] and G60D mutation in 1 case [0.066%(1/1 513)]. The mutation of NRAS mainly occurred in codon 12, 13 of exon 2 and codon 61 of exon 3, including Q61K with a mutation rate of 0.925%(14/1 513), followed by G12D with a mutation rate of 0.727%(11/1 513). The mutation rates of Q61R, Q61H, Q61L, G13R, G12C, G12V, G12S, G13D, and G13C were relatively low. The mutation of BRAF mainly occurred in codon 600 of exon 15 as V600E mutation, with a mutation rate of 4.957%(75/1 513). Infrequent mutation in BRAF were found in 8 patients with colorectal cancer, with a mutation rate of 0.529%(8/1 513), including D594G mutation in 5 cases [0.330%(5/1 513)], D594H mutation in 1 case [0.066%(1/1 513)], S607T mutation in 1 case [0.066%(1/1 513)], and 599-600 codon insertion AGA in 1 case [0.066%(1/1 513)]. Of the 1 513 patients, 4 [0.264%(4/1 513)] had simultaneous mutations at codon 12 and 13 of KRAS, including 2 [0.132%(2/1 513)] with simultaneous mutations at G12V and G13D, 1 [0.066%(1/1 513)] with simultaneous mutations at G12D and G13A, and 1 [0.066%(1/1 513)] with simultaneous mutations at G12V and G13F. In addition, 1 patient [0.066%(1/1 513)] had simultaneous mutations at G13D of KRAS and G12S of NRAS, and 1 patient [0.066%(1/1 513)] had simultaneous mutations at G12C of KRAS and Q61H of NRAS. (2) Relationship of different mutation status of KRAS, NRAS and BRAF with clinicopathological characteristics: patients with different tumor location and tumor differentiation degree had significantly different KRAS mutation status ( χ2=25.317, 4.166, P<0.05); patients with different gender, tumor location, tumor differentiation degree, and lymph node metastasis had significantly different BRAF mutation status ( χ2= 11.290, 22.317, 38.035, 12.611, P<0.05). The proportion of Q61K mutation and Q61R mutation of NRAS in the patients with age of < 65 and ≥ 65 years was 12/18, 2/10 and 1/18, 5/10, respectively, showing significant differences between the two groups ( χ2=5.600, 7.542, P<0.05). (3) Infrequent mutation status of single gene and its clinicopathological characteristics: 15 of the 1 513 patients had single gene mutation. Of the 7 patients with infrequent mutations in codon 14, 59 and 60 of KRAS, 6 were males and 1 was female; 6 were < 65 years old and 1 was ≥ 65 years old; 3 had tumors located in the left colon, 3 in the right colon and 1 in the rectum; 6 had highly or moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 6 were in stage Ⅳ and 1 was in stage Ⅱ of TNM staging; 6 had distant metastasis and 1 had no distant metastasis; 3 had lymph node metastasis and 4 had no lymph node metastasis; there was no postoperative recurrence. Of the 8 patients with infrequent gene mutation of BRAF, 4 were males and 4 were females; 4 were < 65 years old and 4 were ≥ 65 years old; 5 had tumors located in the left colon, 1 in the right colon and 2 in the rectum; 7 had moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 5 were in stage Ⅳ, 2 in stage Ⅲ, and 1 in stage Ⅱ of TNM staging; 6 had distant metastasis and 2 had no distant metastasis; 3 had lymph node metastasis and 5 had no lymph node metastasis; 1 had postoperative recurrence. (4) Simultaneous mutations of two genes and their clinicopathological characteristics: 6 of the 1 513 patients had simultaneous mutations of two genes. Of 6 patients with simultaneous mutations of two genes, 5 were males and 1 was female; 2 were < 65 years old and 4 were ≥ 65 years old; 1 had tumor located in the left colon, 4 in the right colon and 1 in the rectum; 5 had highly or moderately differentiated adenocarcinoma and 1 had poorly differentiated adenocarcinoma; 5 were in stage Ⅳ and 1 was in stage Ⅱ of TNM staging; 4 had distant metastasis and 2 had no distant metastasis; 3 had lymph node metastasis and 3 had no lymph node metastasis; 1 had postoperative recurrence. Conclusions:The infrequent mutations of KRAS and BRAF in colorectal cancer often occur in the rare codon region and mainly are point mutations. Different mutations of KRAS, NRAS and BRAF are related to clinicopathological features, which provide an important basis for treatment of colorectal cancer.