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.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.
Animals ; tau Proteins/metabolism* ; Alzheimer Disease/metabolism* ; Fibrinogen/metabolism* ; Mice, Transgenic ; Mice ; Disease Models, Animal ; Memory Disorders/metabolism* ; Male ; Mice, Inbred C57BL ; Brain/metabolism* ; Hippocampus/metabolism* ; Protein Aggregation, Pathological/metabolism* ; Apoptosis ; Phosphorylation

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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.

Megestrol acetate is widely used in clinical practice and offers benefits to patients. However, it carries potential adverse effects, such as hypoadrenocorticism, which is often overlooked due to its atypical clinical manifestations. This report describes two cases of megestrol acetate-induced hypoadrenocorticism. Through a review of relevant literature, the mechanisms, clinical characteristics, and treatment strategies are summarized to enhance clinicians′ awareness of this potential complication.

The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.