Effect of ultrasound-guided injection of botulinum toxin type A into shoulder joint cavity on shoulder pain in poststroke patients: study protocol for a randomized controlled trial.

BACKGROUND: Hemiplegic shoulder pain (HSP) is a common complication after stroke. It severely affects the recovery of upper limb motor function. Early shoulder pain in hemiplegic patients is mainly neuropathic caused by central nerve injury or neuroplasticity. Commonly used corticosteroid injections in the shoulder joint can reduce shoulder pain; however, the side effects also include soft tissue degeneration or increased tendon fragility, and the long-term effects remain controversial. Botulinum toxin injections are relatively new and are thought to block the transmission of pain receptors in the shoulder joint cavity and inhibit the production of neuropathogenic substances to reduce neurogenic inflammation. Some studies suggest that the shoulder pain of hemiplegia after stroke is caused by changes in the central system related to shoulder joint pain, and persistent pain may induce the reorganization of the cortical sensory center or motor center. However, there is no conclusive evidence as to whether or not the amelioration of pain by botulinum toxin affects brain function. In previous studies of botulinum toxin versus glucocorticoids (triamcinolone acetonide injection) in the treatment of shoulder pain, there is a lack of observation of differences in changes in brain function. As the content of previous assessments of pain improvement was predominantly subjective, objective quantitative assessment indicators were lacking. Functional near-infrared imaging (fNIRS) can remedy this problem. METHODS: This study protocol is designed for a double-blind, randomized controlled clinical trial of patients with post-stroke HSP without biceps longus tenosynovitis or acromion bursitis. Seventy-eight patients will be randomly assigned to either the botulinum toxin type A or glucocorticoid group. At baseline, patients in each group will receive shoulder cavity injections of either botulinum toxin or glucocorticoids and will be followed for 1 and 4 weeks. The primary outcome is change in shoulder pain on the visual analog scale (VAS). The secondary outcome is the assessment of changes in oxyhemoglobin levels in the corresponding brain regions by fNIRS imaging, shoulder flexion, external rotation range of motion, upper extremity Fugl-Meyer, and modified Ashworth score. DISCUSSION: Ultrasound-guided botulinum toxin type A shoulder joint cavity injections may provide evidence of pain improvement in patients with HSP. The results of this trial are also help to analyze the correlation between changes in shoulder pain and changes in cerebral hemodynamics and shoulder joint motor function. TRIAL REGISTRATION: Chinese clinical Trial Registry, ChiCTR2300070132. Registered 03 April 2023, https://www.chictr.org.cn/showproj.html?proj=193722 .

[Prognostic Value of Prothrombin Time and Activated Partial Thromboplastin Time in Newly Diagnosed Patients with Multiple Myeloma].

OBJECTIVE: To evaluate the clinical and prognostic value of prothrombin time (PT) and activated partial thromboplastin time (APTT) in newly diagnosed patients with multiple myeloma (MM). METHODS: The clinical data of 116 newly diagnosed MM patients in the Second Hospital and Third Hospital of Shanxi Medical University from October 2014 to March 2022 were analyzed retrospectively, and the patients were divided into two groups: normal PT and APTT group and prolonged PT or APTT group. The differences in sex, age, classification, staging, bleeding events, laboratory indicators [including hemoglobin (Hb), platelet count (PLT), serum calcium, serum albumin (ALB), lactate dehydrogenase (LDH), serum creatinine and ß2-microglobulin], and cytogenetic characteristics between the two groups of patients were compared. The effect of prolonged PT or APTT on survival of patients with MM was analyzed. RESULTS: Compared with patients in normal PT and APTT group, patients in prolonged PT or APTT group were more likely to experience bleeding events (χ2=5.087, P =0.024), with lower ALB levels (χ2=4.962, P =0.026) and PLT levels (χ2=4.309, P =0.038), and higher serum calcium levels (χ2=5.056, P =0.025). The positive rates of del17p, del13q and 1q21+ in prolonged PT or APTT group were higher than those in normal PT and APTT group, but the difference was not statistically significant (P >0.05). K-M survival analysis showed that the prolonged PT or APTT group had a shorter median progression-free survival (PFS) (P =0.032) and overall survival (OS) (P =0.032). Multivariate Cox analysis showed that prolonged PT or APTT (HR=2.116, 95%CI :1.025-4.372, P =0.043) and age ≥65 years (HR=2.403, 95%CI : 1.195-4.836, P =0.014) were independent risk factor for OS in newly diagnosed MM patients. However, prolonged PT or APTT had no significant effect on PFS of newly diagnosed MM patients (HR=1.162, 95%CI : 0.666-2.026, P =0.597). CONCLUSION: Newly diagnosed MM patients with prolonged PT or APTT have worse clinical indicators, shorter PFS and OS. Prolonged PT or APTT is an independent risk factor for OS in MM patients.

A longitudinal study of self-injurious thoughts and behaviors transitions and help-seeking intentions among young adults.

PURPOSE: Engagement in self-injurious thoughts and behaviors (SITBs) is associated with low help-seeking intentions. Nevertheless, prior research has primarily relied on cross-sectional data, leaving uncertainties about the longitudinal dynamics between SITBs and help-seeking intentions. This study aims to investigate the longitudinal relationship between SITBs and help-seeking intentions for them. METHOD: A one-year interval follow-up investigation was conducted among 1788 Chinese students (71.5% girls, Mage = 19.5). Changes in help-seeking intentions were initially analyzed among four SITBs transition groups. Subsequently, a cross-lagged model was employed to explore the possible bidirectional associations. RESULTS: 232 participants (12.90%) experienced changes in SITBs, while 65 participants (3.60%) exhibited sustained SITBs between two measurement time points. Changes in help-seeking intentions varied across SITBs transition groups. Participants whose SITBs faded 1 year later showed a significant increase in help-seeking intentions, whereas those who experienced newly developed SITBs across two measurement time points demonstrated a significant decline. The cross-lagged analysis revealed that help-seeking intentions negatively predicted the subsequent risk of experiencing SITBs. CONCLUSIONS: Greater help-seeking intentions predicted decreased SITBs 1 year later. Changes in help-seeking intentions serve as a valuable indicator for distinguishing between different types of SITBs transition. These findings underscore the importance of implementing prevention and intervention strategies targeted at enhancing help-seeking intentions to reduce SITBs.

The impact of various antiplatelet strategies on the incidence of gouty arthritis in hospitalized patients with acute cerebral infarction.

OBJECTIVES: 1.To explore the incidence of concurrent gouty arthritis (GA) during hospitalization in patients with different subtypes of acute stroke. 2.To investigate disparities in acute cerebral infarction patients with coexisting GA undergoing various antiplatelet strategies. MATERIALS AND METHODS: Data from acute stroke patients admitted to the Affiliated Panyu Central Hospital of Guangzhou Medical University, from January 2019 to December 2021, underwent screening. The incidence of GA in acute stroke patients of various subtypes were analyzed. Subsequently, we divided cerebral infarction cases into three cohorts based on distinct antiplatelet therapies: the aspirin group, the dual antiplatelet therapy group (DAPT，aspirin plus clopidogrel), and the clopidogrel group. Investigate disparities in acute cerebral infarction patients with coexisting GA undergoing various antiplatelet strategies. RESULTS: A total of 12,381 patients with acute stroke were screened in this study. The incidence of GA in various subtypes of acute stroke was as follows: cerebral infarction (3.56 %, n = 9890), TIA (1.81 %, n = 443), cerebral hemorrhag (0.64 %, n = 1713), and SAH (0.30 %, n = 335). The incidence of GA in patients with ischemic stroke is higher than that of hemorrhagic stroke (χ2 = 49.258, p<0.001). No significant differences were observed in the incidence of GA among three different antiplatelet therapy groups. But there was marginal statistical difference in the incidence of GA between the aspirin group and the DAPT group (P = 0.051), as well as between the clopidogrel group and the DAPT group (P = 0.059). CONCLUSIONS: The incidence of GA in patients with ischemic stroke is higher than that of hemorrhagic stroke. No significant differences were observed in the incidence of GA in acute cerebral infarction across various antiplatelet Strategies. The marginal statistical difference in the incidence of GA between the single antiplatelet group and the DAPT group requires further investigation.

Public Restroom Access and Mental Health Among Gender-Minoritized Individuals in China.

This cross-sectional study assesses the adequacy of gender-neutral public restrooms and examines the association of public restroom­related stress with mental health among gender-diverse individuals in China.

Tumor-repopulating cells evade ferroptosis via PCK2-dependent phospholipid remodeling.

Whether stem-cell-like cancer cells avert ferroptosis to mediate therapy resistance remains unclear. In this study, using a soft fibrin gel culture system, we found that tumor-repopulating cells (TRCs) with stem-cell-like cancer cell characteristics resist chemotherapy and radiotherapy by decreasing ferroptosis sensitivity. Mechanistically, through quantitative mass spectrometry and lipidomic analysis, we determined that mitochondria metabolic kinase PCK2 phosphorylates and activates ACSL4 to drive ferroptosis-associated phospholipid remodeling. TRCs downregulate the PCK2 expression to confer themselves on a structural ferroptosis-resistant state. Notably, in addition to confirming the role of PCK2-pACSL4(T679) in multiple preclinical models, we discovered that higher PCK2 and pACSL4(T679) levels are correlated with better response to chemotherapy and radiotherapy as well as lower distant metastasis in nasopharyngeal carcinoma cohorts.

Particle size effect on surface/interfacial tension and Tolman length of nanomaterials: A simple experimental method combining with theoretical.

Surface tension and interfacial tension are crucial to the study of nanomaterials. Herein, we report a solubility method using magnesium oxide nanoparticles of different radii (1.8-105.0 nm, MgO NPs) dissolved in pure water as a targeted model; the surface tension and interfacial tension (and their temperature coefficients) were determined by measuring electrical conductivity and combined with the principle of the electrochemical equilibrium method, and the problem of particle size dependence is discussed. Encouragingly, this method can also be used to determine the ionic (atomic or molecular) radius and Tolman length of nanomaterials. This research results disclose that surface/interfacial tension and their temperature coefficients have a significant relationship with particle size. Surface/interfacial tension decreases rapidly with a radius <10 nm (while the temperature coefficients are opposite), while for a radius >10 nm, the effect is minimal. Especially, it is proven that the value of Tolman length is positive, the effect of particle size on Tolman length is consistent with the surface/interfacial tension, and the Tolman length of the bulk does not change much in the temperature range. This work initiates a new era for reliable determination of surface/interfacial tension, their temperature coefficients, ionic radius, and Tolman length of nanomaterials and provides an important theoretical basis for the development and application of various nanomaterials.

Proteomic Identification of Small Extracellular Vesicle Proteins LAMB1 and Histone H4 for Prostate Cancer Diagnosis and Risk Stratification.

Diagnosis and stratification of prostate cancer (PCa) patients using the prostate-specific antigen (PSA) test is challenging. Extracellular vesicles (EVs), as a new star of liquid biopsy, has attracted interest to complement inaccurate PSA screening and invasiveness of tissue biopsy. In this study, a panel of potential small EV (sEV) protein biomarkers is identified from PCa cell lines using label-free LC-MS/MS proteomics. These biomarkers underwent further validation with plasma and urine samples from different PCa stages through parallel reaction monitoring-based targeted proteomics, western blotting, and ELISA. Additionally, a tissue microarray containing cancerous and noncancerous tissues is screened to provide additional evidence of selected sEV proteins associated with cancer origin. Results indicate that sEV protein LAMB1 is highly expressed in human plasma of metastatic PCa patients compared with localised PCa patients and control subjects, while sEV protein Histone H4 is highly expressed in human urine of high-risk PCa patients compared to low-risk PCa patients and control subjects. These two sEV proteins demonstrate higher specificity and sensitivity than the PSA test and show promise for metastatic PCa diagnosis, progression monitoring, and risk stratification.

Early prediction of sudden cardiac death risk with Nested LSTM based on electrocardiogram sequential features.

Electrocardiogram (ECG) signals are very important for heart disease diagnosis. In this paper, a novel early prediction method based on Nested Long Short-Term Memory (Nested LSTM) is developed for sudden cardiac death risk detection. First, wavelet denoising and normalization techniques are utilized for reliable reconstruction of ECG signals from extreme noise conditions. Then, a nested LSTM structure is adopted, which can guide the memory forgetting and memory selection of ECG signals, so as to improve the data processing ability and prediction accuracy of ECG signals. To demonstrate the effectiveness of the proposed method, four different models with different signal prediction techniques are used for comparison. The extensive experimental results show that this method can realize an accurate prediction of the cardiac beat's starting point and track the trend of ECG signals effectively. This study holds significant value for timely intervention for patients at risk of sudden cardiac death.

NUP85 alleviates lipid metabolism and inflammation by regulating PI3K/AKT signaling pathway in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the common causes of chronic liver disease in the world. The problem of NAFLD had become increasingly prominent. However, its pathogenesis is still indistinct. As we all know, NAFLD begins with the accumulation of triglyceride (TG), leading to fatty degeneration, inflammation and other liver tissues damage. Notably, structure of nucleoporin 85 (NUP85) is related to lipid metabolism and inflammation of liver diseases. In this study, the results of researches indicated that NUP85 played a critical role in NAFLD. Firstly, the expression level of NUP85 in methionine-choline-deficient (MCD)-induced mice increased distinctly, as well as the levels of fat disorder and inflammation. On the contrary, knockdown of NUP85 had the opposite effects. In vitro, AML-12 cells were stimulated with 2 mm free fatty acids (FFA) for 24 h. Results also proved that NUP85 significantly increased in model group, and increased lipid accumulation and inflammation level. Besides, NUP85 protein could interact with C-C motif chemokine receptor 2 (CCR2). Furthermore, when NUP85 protein expressed at an extremely low level, the expression level of CCR2 protein also decreased, accompanied with an inhibition of phosphorylation of phosphoinositol-3 kinase (PI3K)-protein kinase B (AKT) signaling pathway. What is more, trans isomer (ISRIB), a targeted inhibitor of NUP85, could alleviate NAFLD. In summary, our findings suggested that NUP85 functions as an important regulator in NAFLD through modulation of CCR2.

[Total polyphenols of Cydonia oblonga inhibited proliferation and migration of renal cancer cells by PI3K/Akt/mTOR pathway].

The mechanism of total polyphenols of Cydonia oblonga Miller(TPCOM) against kidney cancer was elucidated through a combination of network pharmacology, bioinformatics, and experimental verification. The active polyphenolic compounds from C. oblonga were screened by network pharmacological techniques and kidney cancer-related targets were collected through the database. The differential gene expression analysis was performed on RNA sequencing data from tumor tissue and normal tissue of kidney cancer patients obtained from the Gene Expression Omnibus(GEO) database. The results of network pharmacology predictions and differential gene expression analysis were used to identify the core genes targeted by TPCOM in kidney cancer. Survival analysis was conducted to identify key targets that could impact patient survival, followed by Kyoto Encyclopedia of Genes and Genomes(KEGG) and Gene Ontology(GO) enrichment analyses. Cell proliferation and activity experiments(cell counting kit-8) were conducted using TPCOM at concentrations ranging from 20 to 640 µg·mL~(-1) on 786-O and Renca cells. Additionally, TPCOM at concentrations of 40, 80, and 160 µg·mL~(-1) was applied to kidney cancer cells to assess its effect on cell migration and its regulation of protein expression levels related to the protein kinase B(Akt), mammalian target of rapamycin(mTOR), and phosphoinositide 3-kinase(PI3K) signaling pathways. Network pharmacology predicted eight active polyphenolic compounds from C. oblonga. Survival analysis revealed 15 significantly differentially expressed genes in kidney cancer that were affected by TPCOM and had a significant impact on patient survival. KEGG and GO analysis results indicated that these 15 targets were primarily associated with the PI3K/Akt signaling pathway, cell migration, and proliferation. The results showed that TPCOM could inhibit the proliferation of 786-O and Renca cells, with IC_(50) values of 121.4 and 137.9 µg·mL~(-1), respectively. TPCOM was also found to inhibit the migration of these cells and suppress the PI3K/Akt/mTOR signaling pathway. TPCOM may exert its anti-kidney cancer effects by inhibiting the activation of the PI3K/Akt/mTOR signaling pathway, thereby restraining the proliferation and migration of kidney cancer cells. This study provides a foundation for the research on the anti-tumor effects of natural product C. oblonga, particularly in Xinjiang, and holds significance for further promoting its development and utilization.

[Characteristics of VOCs Emissions and Ozone Formation Potential for Typical Chemicals Industry Sources in China].

This study selected five typical types of chemical industry volatile organic compounds (VOCs) emission characteristics in China for analysis. The results from 70 source samples showed that alkanes were the dominant VOCs category from synthetic material industry sources, petrochemical industry sources, and coating industry sources (accounting for 43%, 63%, and 68%, respectively); olefins were the main VOCs category from the daily supplies chemical industry (46%); and halogenated hydrocarbons were the dominate VOCs category from specialty chemicals industry account source emissions (43%). Additionally, the machine learning method was applied in this study to analyze the marker components of the above industries. The results showed that decane and tetrahydrofuran were the source markers of the synthetic material industry; n-butanol and toluene were the markers of the daily supplies industry source; 1,2,3-trimethylbenzene and 1,3,5-trimethylbenzene were the markers of the petrochemical industry source; propylene and 3-methyl pentane were the source markers of the coating industry; and P-Xylene and cumene were the markers of the specialty chemicals industry source. The maximum incremental reactivity method (MIR) was used to estimate the ozone formation potential (OFP) of different VOCs-sources. The calculation results showed that when considering per unit TVOCs concentration emissions, the contribution to the ozone generation potential was in the order of the daily supplies chemical industry, specialty chemical industry, petrochemical industry, synthetic material industry, and coating industry. Therefore, we suggest that more attention should be paid to the key active species emitted by various industry sources rather than only the total amount of VOCs emissions in future ozone prevention and control efforts.

[The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy].

OBJECTIVE: To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. METHODS: The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. RESULTS: After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. CONCLUSION: VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

SORBS1 inhibits epithelial to mesenchymal transition (EMT) of breast cancer cells by regulating PI3K/AKT signaling and macrophage phenotypic polarization.

This study aimed to explore the regulatory role of SORBS1 in macrophage polarization and the PI3K/AKT signaling pathway, as well as analyze its mechanism in epithelial-mesenchymal transition (EMT) of breast cancer cells. We established SORBS1-overexpressing and knockout cell lines and verified the effects of SORBS1 on cell viability, invasion, and migration by phenotyping experiments and assaying the expression of associated proteins. Furthermore, we established a breast cancer cell and macrophage co-culture system to validate the effect of SORBS1 expression on macrophage polarization and killing of breast cancer cells. Bioinformatics analysis showed that SORBS1 was lowly expressed in breast cancer (BRCA) samples and highly expressed in healthy tissues. Decreased SORBS1 expression was associated with poor prognosis, and the PI3K/AKT signaling pathway was the most significantly enriched pathway. In vitro experiments showed that high expression of SORBS1 inhibited the migration of breast cancer cells, as well as the PI3K/AKT signaling pathway, and blocked EMT of these cells. In addition, SORBS1 induced macrophage polarization to the M1-type and enhanced the killing effect on breast cancer cells in the co-culture system. In conclusion, we successfully verified that SORBS1 inhibits the invasion and migration of breast cancer cells, induces macrophage M1-type polarization, and blocks EMT of breast cancer cells, and it may act by regulating the PI3K/AKT signaling pathway.

Perfusable adipose decellularized extracellular matrix biological scaffold co-recellularized with adipose-derived stem cells and L6 promotes functional skeletal muscle regeneration following volumetric muscle loss.

Muscle tissue engineering is a promising therapeutic strategy for volumetric muscle loss (VML). Among them, decellularized extracellular matrix (dECM) biological scaffolds have shown certain effects in restoring muscle function. However, researchers have inconsistent or even contradictory results on whether dECM biological scaffolds can efficiently regenerate muscle fibers and restore muscle function. This suggests that therapeutic strategies based on dECM biological scaffolds need to be further optimized and developed. In this study, we used a recellularization method of perfusing adipose-derived stem cells (ASCs) and L6 into adipose dECM (adECM) through vascular pedicles. On one hand, this strategy ensures sufficient quantity and uniform distribution of seeded cells inside scaffold. On the other hand, auxiliary L6 cells addresses the issue of low myogenic differentiation efficiency of ASCs. Subsequently, the treatment of VML animal experiments showed that the combined recellularization strategy can improve muscle regeneration and angiogenesis than the single ASCs recellularization strategy, and the TA of former had greater muscle contraction strength. Further single-nucleus RNA sequencing (snRNA-seq) analysis found that L6 cells induced ASCs transform into a new subpopulation of cells highly expressing Mki67, CD34 and CDK1 genes, which had stronger ability of oriented myogenic differentiation. This study demonstrates that co-seeding ASCs and L6 cells through vascular pedicles is a promising recellularization strategy for adECM biological scaffolds, and the engineered muscle tissue constructed based on this has significant therapeutic effects on VML. Overall, this study provides a new paradigm for optimizing and developing dECM-based therapeutic strategies.

Time-Resolved Multielectron Coincidence Spectroscopy of Double Auger-Meitner Decay Following Xe 4d Ionization.

We introduce time-resolved multielectron coincidence spectroscopy and apply it to the double Auger-Meitner (AM) emission process following xenon 4d photoionization. The photoelectron and AM electron(s) are measured in coincidence by using a magnetic-bottle time-of-flight spectrometer, enabling an unambiguous assignment of the complete cascade pathways involving two AM electron emissions. In the presence of a near-infrared (NIR) laser pulse, the intermediate Xe^{2+*} state embedded in the Xe^{3+} continuum is probed through single NIR photon absorption and the lifetime of this intermediate Xe^{2+*} state is directly obtained as (109±22) fs.

A photoelectrochemical aptasensor based on double Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for sensitive detection of circulating tumor cells.

A novel photoelectrochemical (PEC) aptasensor based on a dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction for the ultrasensitive detection of circulating tumor cells (CTCs) was developed. The α-Fe2O3/MoS2/Bi2S3 nanocomposite was prepared via a step-by-step route, and the photoproduced electron/hole transfer path was speculated by conducting trapping experiments of reactive species. α-Fe2O3/MoS2/Bi2S3-modified electrodes exhibited greatly enhanced photocurrent under visible light due to the double Z-scheme charge transfer process, which met the requirement of the PEC sensor for detecting larger targets. After the aptamer was conjugated on the photoelectrode through chitosan (CS) and glutaraldehyde (GA), when MCF-7 cells were presented and captured, the photocurrent of the PEC biosensing system decreased due to steric hindrance. The current intensity had a linear relationship with the logarithm of MCF-7 cell concentration ranging from 10 to 1×105 cells mL-1, with a low detection limit of 3 cell mL-1 (S/N = 3). The dual Z-scheme α-Fe2O3/MoS2/Bi2S3 ternary heterojunction-modified PEC aptasensor exhibited high sensitivity and excellent specificity and stability. Additionally, MCF-7 cells in human serum were determined by this PEC aptasensor, exhibiting great potential as a promising tool for clinical detection.

Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability.

Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.

The correlation between self-Hounsfield units and adjacent vertebral fracture after percutaneous vertebral augmentation: a retrospective cohort study.

Background: Adjacent vertebral fracture (AVF) represents a prevalent and challenging complication after percutaneous vertebral augmentation (PVA) treatment for osteoporosis vertebral compressive fracture (OVCF). Lower bone mineral density (BMD) and intervertebral leakage are reportedly independent risk factors for AVF. Vertebral Hounsfield units (HU) measured from computed tomography (CT) scans can evaluate bone quality. This study sought to explore the risk factors associated with AVF and analyze the relationship between AVF and the Hounsfield units of adjacent vertebrae (self-HU) following PVA. Methods: In this retrospective cohort study, we included consecutive OVCF patients who presented to Xuzhou Central Hospital in Jiangsu Province, China from 1 January 2016, to 31 December 2019 for PVA treatment. Clinical and imaging data were collected, and baseline data were recorded. Patients were divided into the AVF group and the no-AVF group based on the presence of AVF during follow-up. Patients in the AVF group were further subdivided into the leakage group and the no-leakage group according to the presence of intervertebral leakage. Age, body mass index (BMI), fracture location, prior fracture, self-HU, and intervertebral leakage were included in univariate logistic regression analysis. Variables with a P value of less than 0.1 were then included in multivariate logistic regression analysis to determine the risk factors for AVF. Kaplan-Meier curves were plotted to assess the effect of intervertebral leakage on AVF using a log-rank test. Results: A total of 460 patients were included in this study and followed up for an average of 50.9 months (range, 37-83 months). Among them, 82 cases (17.83%) developed AVF and were included in the AVF group. Multivariate logistic regression analysis showed that lower self-HU [odds ratio (OR) =0.972, 95% confidence interval (CI): 0.959-0.985, P<0.001] and intervertebral leakage (OR =2.618, 95% CI: 1.415-4.844, P=0.002) were risk factors for AVF following PVA. In the AVF group, 29 patients (35.37%) with intervertebral leakage were included in the leakage group. Patients in the leakage group had a shorter time to AVF (22.07±13.83 vs. 31.42±18.73, P=0.021) and higher self-HU (78.05±16.41 vs. 64.23±20.49, P=0.002) than those in the no-leakage group. Kaplan-Meier curves showed that the fracture-free time was shorter in the leakage group compared to the no-leakage group (log-rank test, P=0.014). Conclusions: Lower self-HU and intervertebral leakage are risk factors for AVF, and higher self-HU may lead to AVF when intervertebral leakage is present.