Integrin α _v β ₃ is overexpressed in various tumor cells and angiogenesis. To date, no drug has been proven to target it for therapy. A first-in-human study was designed to investigate the safety, pharmacokinetics, and dosimetry of ¹⁷⁷Lu-AB-3PRGD2, a novel integrin α _v β ₃-targeting radionuclide drug with an albumin-binding motif to optimize the pharmacokinetics. Ten patients (3 men, 7 women; aged 45 ± 16 years) with integrin α _v β ₃-avid tumors were recruited to accept ¹⁷⁷Lu-AB-3PRGD2 injection in a dosage of 1.57 ± 0.08 GBq (42.32 ± 2.11 mCi), followed by serial scans to obtain its dynamic distribution in the body. Safety tests were performed before and every 2 weeks after the treatment for 6-8 weeks. No adverse event over grade 3 was observed. ¹⁷⁷Lu-AB-3PRGD2 was excreted mainly through the urinary system, with intense radioactivity in the kidneys and bladder. Moderate distribution was found in the liver, spleen, and intestines. The estimated blood half-life was 2.85 ± 2.17 h. The whole-body effective dose was 0.251 ± 0.047 mSv/MBq. The absorbed doses were 0.157 ± 0.032 mGy/MBq in red bone marrow and 0.684 ± 0.132 mGy/MBq in kidneys. This first-in-human study of ¹⁷⁷Lu-AB-3PRGD2 treatment indicates its promising potential for targeted radionuclide therapy of integrin α _v β ₃-avid tumors. It merits further studies in more patients with escalating doses and multiple treatment courses.

Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

Objective:To evaluate cerebrospinal fluid (CSF) flow dynamics and volume changes of pulsatile tinnitus (PT) patients induced by sigmoid sinus wall dehiscence (SSWD) using MRI.Methods:This was a cross-sectional study. Totally 55 SSWD-PT patients, and 35 age- and sex-matched healthy controls were prospectively enrolled at Beijing Tongren Hospital, Capital Medical University from October 2019 to September 2023. The CSF at the midbrain aqueduct level was analyzed based on phase-contrast MRI to obtain the flow dynamics information. Based on T 1-weighted turbo field echo sequence, the CSF was segmented and the volume of CSF was calculated using ITK-SNAP software. The Mann-Whitney U test was used to compare the differences of each parameter between the two groups. Binary logistic regression was used to analyze the parameters with statistically significant differences to obtain the independent influencing factors of SSWD-PT and establish the combined parameters. Receiver operating characteristic curve analysis was used to evaluate the efficacy of diagnosing SSWD-PT. Results:Compared with controls, the SSWD-PT group showed significantly decreased mean flux (MF), mean velocity, peak velocity( P<0.05), and significantly increased regurgitant fraction (RF), CSF volume ( P<0.05). No significant differences were observed in forward flow volume, backward flow volume, and stroke volume ( P>0.05). The logistic regression results showed that MF ( OR=0.497, 95% CI 0.305-0.808, P=0.005) and RF ( OR=1.809, 95% CI 1.040-3.147, P=0.036) were independent influencing factors of SSWD-PT. The area under the curve (AUC) of MF and RF for diagnosing SSWD-PT were 0.641 (95% CI 0.517-0.766) and 0.675 (95% CI 0.564-0.786), respectively. The AUC of the combination of MF and RF was 0.724 (95% CI 0.614-0.833). Conclusions:SSWD-PT patients have abnormal changes in CSF flow dynamics and volume. The MF and RF demonstrate moderate diagnostic value for diagnosing SSWD-PT.

Objective:To investigate the clinical features of patients with congenital atresia of the oval window (CAOW).Methods:A retrospective analysis was conducted on 7 cases (8 ears) of surgically confirmed CAOW treated at our department from July 2018 to July 2024. Among the cases, 1 patient had bilateral CAOW, and 4 patients had unilateral CAOW combined with other types of ossicular chain malformations in the contralateral ear. We collected and analyzed the clinical data, audiological features, and temporal bone HRCT results of all patients.Results:The 7 patients were diagnosed at ages ranging from 8 to 19 years, with a mean age of (13.2±6.9) years. None of the patients exhibited significant auricular deformities. All presented with conductive hearing loss or mixed hearing loss predominantly of the conductive type, with an intact tympanic membrane. The diagnosis of CAOW was confirmed via endoscopic tympanotomy, revealing a concave oval window area on the medial wall of the tympanic cavity, sealed by a bony plate. All 8 ears exhibited additional ossicular chain deformities. Stapes absence was present in all 8 ears. Partial absence of the incus long process was observed in 3 ears, while, abnormal bony connections between the incus long process and the promontory were seen in 4 ears, 1 ear had a short malleolar handle, 1 ear had a smaller than normal malleus volume. In addition, facial nerve deformities were found in 6 ears, with 4 ears showing bifurcation of the facial nerve and 2 ears showing facial nerve obscuration of the oval window. Pure-tone audiometry revealed that 62.5% (5/8 ears) of patients had air conduction (AC) thresholds≥60 dB preoperatively, with a mean pure-tone average (PTA) of (69.0±11.8) dB HL and a mean air-bone gap (ABG) of (52.0±7.0) dB. The mean AC threshold and ABG were higher in the low-frequency (125-1 000 Hz) range compared to the high-frequency (2 000-8 000 Hz) range (both P<0.05). Preoperative HRCT showed abnormalities in all patients, with 7 ears being diagnosable as CAOW. Although the remaining 1 ear could not be diagnosed as CAOW, stapes and incus long process absence were detected. Conclusion:CAOW is rare in clinical, as the patients with non-progressive conductive hearing loss (AC≥60 dB, ABG≥50 dB) since childhood, intact tympanic membrane without malformations of auricle and external auditory canal, and thick bony plate covered the oval window of the HRCT imaging, CAOW should be highly suspected, which could be confirmed by the exploratory tympanotomy.

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OBJECTIVE To study the anatomic characteristics of the anterior ethmoidal canal(AEC)based on 0.1 mm ultra-high resolution CT.METHODS Nine cadavers(18 side orbits)fixed in 10%buffered formalin were enrolled and underwent U-HRCT and MSCT.Divided AEC into horizontal,superior oblique,and inferior oblique segments and observed the displaying rate of each section.Subjective evaluation of display situation was performed by two experienced radiologists independently.The diameter of each AEC segment was measured.RESULTS No significant difference was found in the display rate of the horizontal and superior oblique segments between U-HRCT and MSCT groups(P>0.05),the display rate of inferior oblique segment of U-HRCT group was significantly higher than MSCT group(P<0.05).There was no significant difference in the objective evaluation results between two evaluators and consistency was strong.Subjective scores of each segment of AEC in U-HRCT group were 10.00 points(9.75 points,10.00 points),2.00 points(2.00 points,3.00 points)and 8.00 points(6.00 points,10.00 points),in MSCT group were7.00 points(5.75 points,8.00 points),2.00 points(2.00 points,2.00 points)and 2.00 points(2.00 points,4.00 points).Subjective scores of horizontal and inferior oblique segments of AEC in U-HRCT were higher than MSCT(P<0.05).The anteroposterior diameter of the horizontal section of AEC is(0.92±0.12)mm,the axial diameter is(1.04±0.22)mm.The anteroposterior diameter of the inferior oblique segment is(0.47±0.08)mm,and the transverse diameter is(0.50±0.06)mm.The anteroposterior diameter of the superior oblique segments is(0.66±0.11)mm,and the transverse diameter is(0.72±0.20)mm.CONCLUSION U-HRCT is better to evaluate AEC than MSCT.It could be used to help to study the anatomic characteristics of AEC before surgery to avoid complications.

OBJECTIVE To evaluate cerebrospinal fluid(CSF)flow dynamics and volume changes of pulsatile tinnitus(PT)patients caused by sigmoid sinus wall dehiscence(SSWD)with different intracranial pressure via MRI.METHODS Prospective enrolled 35 SSWD-PT patients with intracranial hypertension,25 SSWD-PT patients with normal intracranial pressure and 35 age-,sex-matched healthy controls.Demographic characteristics were recorded.Intracranial pressure was assessed by the index of transverse sinus stenosis(ITSS)and morphology changes.CSF flow dynamics were evaluated via phase-contrast magnetic resonance imaging(PC-MRI)and CSF volume were evaluated via three-dimensional T1-weighted turbo field echo(3D T1-TFE)sequence and ITK-SNAP software.Compared the differences of each index between three groups.RESULTS The mean flux and regurgitant fraction were significantly different among the three groups(P<0.05).The intracranial hypertension group presented significantly decreased mean flux(MF)and significantly increased regurgitant fraction(RF)compared to controls(P<0.017).There were no significant differences in MF and RF of normal intracranial pressure group compared with intracranial hypertension group and control group(P>0.017).There were no statistical differences in age,sex,body mass index,forward flow volume,backward flow volume,mean velocity,peak velocity,stroke volume and CSF volume(P>0.05).CONCLUSION SSW D-PT patients have abnormal changes in CSF,and those with increased intracranial pressure are more obvious.These changes may be associated with abnormal hemodynamics in the sigmoid sinus and the occurrence of PT.

The sound generation and conduction of pulsatile tinnitus(PT)caused by sigmoid sinus wall dehiscence(SSWD)are closely related to abnormal blood flow and intracranial pressure,sigmoid plate and temporal bone air cells.Clarifying the mechanism of tinnitus is the premise of targeted treatment.This article reviews the research progress on the mechanism of SSWD-PT.

Objective To explore the clinical value of serum stromal cell-derived factor-1(SDF-1)and macro-phage inflammatory protein-1α(MIP-1α)in predicting biliary tract infection after endoscopic retrograde cholangiopancreatography(ERCP)stone removal in patients with common bile duct stones.Methods From January 2022 to January 2024,100 patients with common bile duct stones who underwent ERCP stone removal surgery in Pingdingshan First People's Hospital were collected.They were grouped into an infection group(12 cases)and a non-infection group(88 cases)based on whether biliary tract infection occurred after surgery.The general information of patients in the two groups was compared.ELISA method was used to measure the levels of serum SDF-1 and MIP-1α.Spearman method was applied to analyze the correlation between the severity of infec-tion and serum level of SDF-1 and MIP-1α.ROC curve was applied to analyze the value of serum SDF-1 and MIP-1α to predict biliary tract infection after ERCP stone removal in patients with common bile duct stones.Results A total of 36 strains of pathogenic bacteria were detected in the biliary drainage fluid samples of the infection group,among which Gram-negative bacteria accounted for 55.56%and Gram-positive bacteria accounted for 44.44%.The infection group showed significantly higher serum levels of SDF-1 and MIP-1α(P＜0.05).As the infection wors-ened,SDF-1 and MIP-1α levels progressively increased(P＜0.05).The severity of biliary tract infection was sig-nificantly positively correlated with both serum SDF-1 and MIP-1α levels(P＜0.05).For predicting biliary tract in-fection,SDF-1 and MIP-1α exhibited AUC values of 0.761 and 0.825,sensitivities of 63.33%and 66.67%,and specificities of 83.33%and 83.33%,respectively.When combined,the predictive AUC reached 0.977,with a sensitivity of 83.33%and a specificity of 98.33%.Conclusions Serum level of SDF-1 and MIP-1α are significant-ly elevated in patients with common bile duct stones and biliary tract infections after ERCP stone removal surgery,showing a positive correlation with the severity of the infection.The combination of these two biomarkers demon-strates excellent predictive efficacy for postoperative infection.