Sound-localization-related activation and functional connectivity of dorsal auditory pathway in relation to demographic, cognitive, and behavioral characteristics in age-related hearing loss.

Background: Patients with age-related hearing loss (ARHL) often struggle with tracking and locating sound sources, but the neural signature associated with these impairments remains unclear. Materials and methods: Using a passive listening task with stimuli from five different horizontal directions in functional magnetic resonance imaging, we defined functional regions of interest (ROIs) of the auditory "where" pathway based on the data of previous literatures and young normal hearing listeners (n = 20). Then, we investigated associations of the demographic, cognitive, and behavioral features of sound localization with task-based activation and connectivity of the ROIs in ARHL patients (n = 22). Results: We found that the increased high-level region activation, such as the premotor cortex and inferior parietal lobule, was associated with increased localization accuracy and cognitive function. Moreover, increased connectivity between the left planum temporale and left superior frontal gyrus was associated with increased localization accuracy in ARHL. Increased connectivity between right primary auditory cortex and right middle temporal gyrus, right premotor cortex and left anterior cingulate cortex, and right planum temporale and left lingual gyrus in ARHL was associated with decreased localization accuracy. Among the ARHL patients, the task-dependent brain activation and connectivity of certain ROIs were associated with education, hearing loss duration, and cognitive function. Conclusion: Consistent with the sensory deprivation hypothesis, in ARHL, sound source identification, which requires advanced processing in the high-level cortex, is impaired, whereas the right-left discrimination, which relies on the primary sensory cortex, is compensated with a tendency to recruit more resources concerning cognition and attention to the auditory sensory cortex. Overall, this study expanded our understanding of the neural mechanisms contributing to sound localization deficits associated with ARHL and may serve as a potential imaging biomarker for investigating and predicting anomalous sound localization.

Site-specific Antibody-Nitric Oxide Conjugate HN02 Possesses Improved Antineoplastic and Safety Properties.

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

Relationship between syncopal symptoms and head-up tilt test modes.

OBJECTIVE: Head-up tilt test (HUTT) is an important tool in the diagnosis of pediatric vasovagal syncope. This research will explore the relationship between syncopal symptoms and HUTT modes in pediatric vasovagal syncope. METHODS: A retrospective analysis was performed on the clinical data of 2513 children aged 3-18 years, who were diagnosed with vasovagal syncope, from Jan. 2001 to Dec. 2021 due to unexplained syncope or pre-syncope. The average age was 11.76 ± 2.83 years, including 1124 males and 1389 females. The patients were divided into the basic head-up tilt test (BHUT) group (596 patients) and the sublingual nitroglycerine head-up tilt test (SNHUT) group (1917 patients) according to the mode of positive HUTT at the time of confirmed pediatric vasovagal syncope. RESULTS: (1) Baseline characteristics: Age, height, weight, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and composition ratio of syncope at baseline status were higher in the BHUT group than in the SNHUT group (all P < 0.05). (2) Univariate analysis: Age, height, weight, HR, SBP, DBP, and syncope were potential risk factors for BHUT positive (all P < 0.05). (3) Multivariate analysis: syncope was an independent risk factor for BHUT positive, with a probability increase of 121% compared to pre-syncope (P<0.001). CONCLUSION: The probability of BHUT positivity was significantly higher than SNHUT in pediatric vasovagal syncope with previous syncopal episodes.

Prostate cancer burden in major BRICS countries, 1990-2019: findings from the 2019 global burden of disease study.

BACKGROUND: This study assessed prostate cancer burden and trends in major BRICS countries (Brazil, Russia, India, China, and South Africa) from 1990 to 2019. METHODS: Utilizing Global Burden of Disease Study 2019 data, we calculated age-standardized rates for prostate cancer incidence, prevalence, mortality, and disability-adjusted life years (DALYs) with 95% uncertainty intervals (UIs). Joinpoint regression analysis determined the average annual percentage change (AAPC) for trend characterization. RESULTS: Prostate cancer ranked highest in China for incidence, prevalence, mortality, and DALYs. In 2019, Brazil had the highest age-standardized incidence rate (ASIR) [55.029 (95% UI: 47.744-81.831)] and age-standardized prevalence rate (ASPR) [372.511 (95% UI: 327.549-549.128)], while South Africa recorded the highest age-standardized mortality rate (ASMR) [42.241 (95% UI: 32.146-47.933)], and age-standardized DALY rate (ASDR) [666.085 (95% UI: 522.626-764.612)]. ASIR and ASPR increased significantly over three decades (AAPC > 0), with varying ASMR and ASDR trends. CONCLUSION: Prostate cancer poses a significant public health challenge. While incidence and prevalence rise, mortality declines in China, India, and Brazil. Tailored health policies are crucial to address diverse disease burden characteristics.

Case Report: Antibiotic Irrigation and Drainage Tube for Managing Chronic Suppurative Otitis Media After Cochlear Implantation.

Cochlear implantation (CI) is the most effective solution for patients with severe-to-profound sensorineural hearing loss, especially in children. However, a major postoperative complication, known as chronic suppurative otitis media (CSOM), poses challenges for both doctors and families of the patients, which can affect post-CI hearing outcomes. We present the case of post-CI CSOM in a 15-year-old girl. She had been utilizing a unilateral cochlear implant for 7 years and had been experiencing intermittent earache and discharge in her only audible ear for the past 15 months. After antibiotic treatment failed to resolve her symptoms, we opted for a tympanomastoidectomy, and removed the receiver-stimulator package while keeping the electrode inside her cochlea. Simultaneously, we inserted an irrigation and drainage tube into the mastoid and middle ear space to discharge the exudate and control infection by applying topical antibiotics. The patient's ear discharge had resolved within 1 month, and her tympanic membrane healed naturally. Our successful experience shows that antibiotic irrigation and draining have effectively controlled infection and accelerated wound healing in this patient with post-CI CSOM, and it further prompted the patient to undergo bilateral CI 9 months later.

Endoscopic lithotripsy combined with drug lithotripsy vs. drug lithotripsy for the treatment of phytobezoars: analysis of 165 cases.

AIM: To analyze efficacy of endoscopic lithotripsy combined with drug lithotripsy as compared with drug lithotripsy for the treatment of phytobezoars. METHODS: We collected and evaluated case records of 165 patients with phytobezoars from 2014 to 2023. And we analyzed demographic and clinical characteristics, imaging features, endoscopic features, complications of phytobezoars, and compared efficacy between endoscopic lithotripsy combined with drug lithotripsy (Group A) and drug lithotripsy (sodium bicarbonate combined with proton pump inhibitor) (Group B). RESULTS: The median age of patients with phytobezoars was 67.84 ± 4.286 years old. Abdominal pain was the most common symptom and peptic ulcers (67.5%) were the most common complication. Bezoar-induced ulcers were more frequent in the gastric angle. The success rate of phytobezoars vanishing in Group A and Group B were similar (92.3% vs. 85.1% within 48 h, 98.7% vs. 97.7% within a week), while the average hospitalization period, average hospitalization cost, second endoscopy rate, and average endoscopic operation time were significantly lower in patients in Group B than in Group A. CONCLUSION: Drug lithotripsy is the preferred effective and safe treatment option for phytobezoars. We advise that an endoscopy should be completed after 48 h for drug lithotripsy.

Electron-Rich Ru Supported on N-Doped Coffee Biochar for Selective Reductive Amination of Furfural to Furfurylamine.

Highly selective synthesis of primary amines from renewable biomass has attracted increasing attention, but it still faces great challenges in chemical industry applications. In this study, an electron-rich Ru catalyst was constructed by doping N into coffee biochar using a one-pot carbonization method (Ru/NCB-600). Ru/NCB-600 showed high catalytic activity and yield for the reductive amination of furfural with green and cheap NH3 and H2. The excellent catalytic performance of Ru/NCB-600 was closely correlated to the formation of electron-rich Ruδ- species (Ruδ--Nxδ+), which endowed Ru/NCB-600 with an enhanced H2 adsorption and activation ability. Ru/NCB-600 showed a high formation rate of 95.6 gfurfurylamine·gRu-1·h-1 and a high yield of furfurylamine (98.6%) at 50 °C. Ru/NCB-600 can also be used for the reductive amination of various carbonyl compounds in good to excellent yield (95.4-99%). This study thus provides a potential pathway for the highly selective reductive amination of carbonyl compounds by regulating the electron density of Ru.

Mining key circRNA-associated-ceRNA networks for milk fat metabolism in cows with varying milk fat percentages.

BACKGROUND: Cow milk fat is an essential indicator for evaluating and measuring milk quality and cow performance. Growing research has identified the molecular functions of circular RNAs (circRNAs) necessary for mammary gland development and lactation in mammals. METHOD: The present study analyzed circRNA expression profiling data in mammary epithelial cells (MECs) from cows with highly variable milk fat percentage (MFP) using differential expression analysis and weighted gene co-expression network analysis (WGCNA). RESULTS: A total of 309 differentially expressed circRNAs (DE-circRNAs) were identified in the high and low MFP groups. WGCNA analysis revealed that the pink module was significantly associated with MFP (r = - 0.85, P = 0.007). Parental genes of circRNAs in this module were enriched mainly in lipid metabolism-related signaling pathways, such as focal adhesion, ECM-receptor interaction, adherens junction and AMPK. Finally, six DE-circRNAs were screened from the pink module: circ_0010571, circ_0007797, circ_0002746, circ_0003052, circ_0004319, and circ_0012840. Among them, circ_0002746, circ_0003052, circ_0004319, and circ_0012840 had circular structures and were highly expressed in mammary tissues. Subcellular localization revealed that these four DE-circRNAs may play a regulatory role in the mammary glands of dairy cows, mainly as competitive endogenous RNAs (ceRNAs). Seven hub target genes (GNB1, GNG2, PLCB1, PLCG1, ATP6V0C, NDUFS4, and PIGH) were obtained by constructing the regulatory network of their ceRNAs and then analyzed by CytoHubba and MCODE plugins in Cytoscape. Functional enrichment analysis revealed that these genes are crucial and most probable ceRNA regulators in milk fat metabolism. CONCLUSIONS: Our study identified several vital circRNAs and ceRNAs affecting milk fat synthesis, providing new research ideas and a theoretical basis for cow lactation, milk quality, and breed improvement.

Application of flipped classroom teaching method based on ADDIE concept in clinical teaching for neurology residents.

BACKGROUND: As an important medical personnel training system in China, standardized residency training plays an important role in enriching residents' clinical experience, improving their ability to communicate with patients and their clinical expertise. The difficulty of teaching neurology lies in the fact that there are many types of diseases, complicated conditions, and strong specialisation, which puts higher requirements on residents' independent learning ability, the cultivation of critical thinking, and the learning effect. Based on the concept of ADDIE (Analysis-Design-Development-Implementation-Evaluation), this study combines the theory and clinical practice of flipped classroom teaching method to evaluate the teaching effect, so as to provide a basis and reference for the implementation of flipped classroom in the future of neurology residency training teaching. METHODS: The participants of the study were 90 neurology residents in standardised training in our hospital in the classes of 2019 and 2020. A total of 90 residents were divided into a control group and an observation group of 45 cases each using the random number table method. The control group used traditional teaching methods, including problem based learning (PBL), case-based learning (CBL), and lecture-based learning (LBL). The observation group adopted the flipped classroom teaching method based on the ADDIE teaching concept. A unified assessment of the learning outcomes of the residents was conducted before they left the department in the fourth week, including the assessment of theoretical and skill knowledge, the assessment of independent learning ability, the assessment of critical thinking ability, and the assessment of clinical practice ability. Finally, the overall quality of teaching was assessed. RESULTS: The theoretical and clinical skills assessment scores achieved by the observation group were significantly higher than those of the control group, and the results were statistically significant (P < 0.001). The scores of independent learning ability and critical thinking ability of the observation group were better than those of the control group, showing statistically significant differences (P < 0.001). The observation group was better than the control group in all indicators in terms of Mini-Cex score (P < 0.05). In addition, the observation group had better teaching quality compared to the control group (P < 0.001). CONCLUSION: Based on the concept of ADDIE combined with flipped classroom teaching method can effectively improve the teaching effect of standardized training of neurology residents, and had a positive effect on the improvement of residents' autonomous learning ability, critical thinking ability, theoretical knowledge and clinical comprehensive ability.

Soft interface confined DNA walker for sensitive and specific detection of SARS-CoV-2 variants.

Nucleic acid detection is conducive to preventing the spread of COVID-19 pandemic. In this work, we successfully designed a soft interface confined DNA walker by anchoring hairpin reporter probes on cell membranes for the detection of SARS-CoV-2 variants. In the presence of target RNA, the cyclic self-assembly reaction occurred between hairpin probes H1 and H2, and the continuous walking of target RNA on cell membranes led to the gradual amplification of fluorescence signal. The enrichment of H1 on membranes and the unique fluidity of membranes promoted the collision efficiency between DNA strands in the reaction process, endowing this method with high sensitivity. In addition, the double-blind test of synthetic RNA in 5% normal human serum demonstrated the good stability and anti-interference in complex environment of this method, which exhibited great potential in clinical diagnostics.

Identification of Panax notoginseng origin using terahertz precision spectroscopy and neural network algorithm.

Panax notoginseng (P. notoginseng), a Chinese herb containing various saponins, benefits immune system in medicines development, which from Wenshan (authentic cultivation) is often counterfeited by others for large demand and limited supply. Here, we proposed a method for identifying P. notoginseng origin combining terahertz (THz) precision spectroscopy and neural network. Based on the comparative analysis of four qualitative identification methods, we chose high-performance liquid chromatography (HPLC) and THz spectroscopy to detect 252 samples from five origins. After classifications using Convolutional Neural Networks (CNNs) model, we found that the performance of THz spectra was superior to that of HPLC. The underlying mechanism is that there are clear nonlinear relations among the THz spectra and the origins due to the wide spectra and multi-parameter characteristics, which makes the accuracy of five-classification origin identification up to 97.62%. This study realizes the rapid, non-destructive and accurate identification of P. notoginseng origin, providing a practical reference for herbal medicine.

Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis.

With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors' binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors' attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors.

Assessing the impact of different contact patterns on disease transmission: Taking COVID-19 as a case.

Human-to-human contact plays a leading role in the transmission of infectious diseases, and the contact pattern between individuals has an important influence on the intensity and trend of disease transmission. In this paper, we define regular contacts and random contacts. Then, taking the COVID-19 outbreak in Yangzhou City, China as an example, we consider age heterogeneity, household structure and two contact patterns to establish discrete dynamic models with switching between daytime and nighttime to depict the transmission mechanism of COVID-19 in population. We studied the changes in the reproduction number with different age groups and household sizes at different stages. The effects of the proportion of two contacts patterns on reproduction number were also studied. Furthermore, taking the final size, the peak value of infected individuals in community and the peak value of quarantine infected individuals and nucleic acid test positive individuals as indicators, we evaluate the impact of the number of random contacts, the duration of the free transmission stage and summer vacation on the spread of the disease. The results show that a series of prevention and control measures taken by the Chinese government in response to the epidemic situation are reasonable and effective, and the young and middle-aged adults (aged 18-59) with household size of 6 have the strongest transmission ability. In addition, the results also indicate that increasing the proportion of random contact is beneficial to the control of the infectious disease in the phase with interventions. This work enriches the content of infectious disease modeling and provides theoretical guidance for the prevention and control of follow-up major infectious diseases.

Thermogravimetric experiments based prediction of biomass pyrolysis behavior: A comparison of typical machine learning regression models in Scikit-learn.

A variety of machine learning (ML) models have been extensively utilized in predicting biomass pyrolysis owing to their prowess in deciphering complex non-linear relationships between inputs and outputs, but there is still a lack of consensus on the optimal methods. This study elaborates on the development, optimization, and evaluation of three ML methodologies, namely, artificial neural networks, random forest (RF), and support vector machines, aimed to determine the optimal model for accurate prediction of biomass pyrolysis behavior using thermogravimetric data. This work assesses the utility of thermal data derived from these models in the computation of kinetic and thermodynamic parameters, alongside an analysis of their statistical performance. Eventually, the RF model exhibits superior physical interpretability and the least discrepancy in predicting kinetic and thermodynamic parameters. Furthermore, a feature importance analysis conducted within the RF model framework quantitatively reveals that temperature and heating rate account for 98.5 % and 1.5 %, respectively.

A progress update on the biological effects of biodegradable microplastics on soil and ocean environment: a perfect substitute or new threat?

Conventional plastics are inherently difficult to degrade, causing serious plastic pollution. With the development of society, biodegradable plastics (BPs) are considered as an alternative to traditional plastics. However, current research indicated that BPs do not undergo complete degradation in natural environments. Instead, they may convert into biodegradable microplastics (BMPs) at an accelerated rate, thereby posing a significant threat to environment. In this paper, the definition, application, distribution, degradation behaviors, bioaccumulation and biomagnification of BPs were reviewed. And the impacts of BMPs on soil and marine ecosystems, in terms of physicochemical property, nutrient cycling, microorganisms, plants and animals were comprehensively summarized. The effects of combined exposure of BMPs with other pollutants, and the mechanism of ecotoxicity induced by BMPs were also addressed. It was found that BMPs reduced pH, increased DOC content, and disrupted the nitrification of nitrogen cycle in soil ecosystem. The shoot dry weight, pod number and root growth of soil plants, and reproduction and body length of soil animals were inhibited by BMPs. Furthermore, the growth of marine plant, and locomotion, body length and survival of marine animals were suppressed by BMPs. Additionally, the ecotoxicity of combined exposure of BMPs with other pollutants has not been uniformly concluded. Exposure to BMPs induced several types of toxicity, including neurotoxicity, gastrointestinal toxicity, reproductive toxicity, immunotoxicity and genotoxicity. The future calls for heightened attention towards the regulation of the degradation of BPs in the environment, and pursuit of interventions aimed at mitigating their ecotoxicity and potential health risks to human.

The FGFR2 Variant rs13387042 is Associated With Breast Cancer Risk: A Meta-Analysis and Systematic Review.

OBJECTIVE: The association of FGFR2-rs13387042 polymorphism with breast cancer (BC) susceptibility in women remains inconclusive due to varying reports. In this study, we conducted a meta-analysis to explore the relationship between FGFR2-rs13387042 polymorphism and susceptibility to BC. METHODS: Relevant literature were acquired through searches across multiple databases. Odds ratio (OR) values were pooled to assess the risk of BC for different alleles and genotypes. The heterogeneity among the included literature was evaluated. Sensitivity analysis was used to verify the stability of the results. Egger's linear regression test was used to assess the significance of publication bias of the included literature. RESULTS: A total of 17 publications were included, encompassing 122,607 cases and 175,966 controls. There was significantly increased risk of BC for allele A compared with G (OR = 1.15, 95% CI = 1.14-1.67, P < .001), genotype AA compared with GG (OR = 1.34, 95% CI = 1.29-1.38, P < .001), and genotype GA compared with GG (OR = 1.19, 95% CI = 1.12-1.26, P < .001). Both Egger's test and funnel plot indicated the presence of publication bias. After adjusting potential publication bias by the trim-and-fill method, the comparison of allele A versus G (OR = 1.15, 95% CI = 1.13-1.17, P < .001), genotype AA versus GG (OR = 1.32, 95% CI = 1.28-1.37, P < .001), and genotype GA versus GG (OR = 1.15, 95% CI = 1.09-1.22, P < .001) remained statistically significant. In various subgroups, the allele A showed significantly higher risk of BC upon allele G in estrogen receptor (ER) positive BC, ER negative BC, progesterone receptor (PR) positive BC, PR negative BC, triple-negative BC, pathological grade I BC, grade II BC, and grade III breast cancer. The subsequent sensitivity analysis suggested the above findings stable and reliable. CONCLUSION: In this study, we found that the allele A of the FGFR2-rs13387042 polymorphism is associated with increased risk of developing breast cancer. This study underscores its potential as a genetic marker for personalized risk assessment and targeted interventions.

Three-dimensional bioprinting of tissue-engineered skin: Biomaterials, fabrication techniques, challenging difficulties, and future directions: A review.

As an emerging new manufacturing technology, Three-dimensional (3D) bioprinting provides the potential for the biomimetic construction of multifaceted and intricate architectures of functional integument, particularly functional biomimetic dermal structures inclusive of cutaneous appendages. Although the tissue-engineered skin with complete biological activity and physiological functions is still cannot be manufactured, it is believed that with the advances in matrix materials, molding process, and biotechnology, a new generation of physiologically active skin will be born in the future. In pursuit of furnishing readers and researchers involved in relevant research to have a systematic and comprehensive understanding of 3D printed tissue-engineered skin, this paper furnishes an exegesis on the prevailing research landscape, formidable obstacles, and forthcoming trajectories within the sphere of tissue-engineered skin, including: (1) the prevalent biomaterials (collagen, chitosan, agarose, alginate, etc.) routinely employed in tissue-engineered skin, and a discerning analysis and comparison of their respective merits, demerits, and inherent characteristics; (2) the underlying principles and distinguishing attributes of various current printing methodologies utilized in tissue-engineered skin fabrication; (3) the present research status and progression in the realm of tissue-engineered biomimetic skin; (4) meticulous scrutiny and summation of the extant research underpinning tissue-engineered skin inform the identification of prevailing challenges and issues.

Design, synthesis, and evaluation of formylpiperazine analogs of Ferrostatin-1 as novel improved ferroptosis inhibitors.

In this study, a series of new formylpiperazine-derived ferroptosis inhibitors were designed and synthesized based on the structure of a known ferroptosis inhibitor, ferrostatin-1 (Fer-1). The anti-ferroptosis activity of these synthetic compounds in human umbilical vein endothelial cells (HUVECs) induced by Erastin was evaluated. It was found that some of the new compounds, especially compound 26, showed potent anti-ferroptosis activity, as evidenced by its ability to restore cell viability, reduce iron accumulation, scavenge reactive oxygen species, maintain mitochondrial membrane potential, increase GSH levels, decrease LPO and MDA content, and upregulate GPX4 expression. Moreover, compound 26 exhibited superior microsomal stability than Fer-1. The present results suggest that compound 26 is a promising lead compound for the development of new ferroptosis inhibitors for the treatment of vascular diseases.

Anti-VEGFR2-Interferon α Promotes the Infiltration of CD8+ T Cells in Colorectal Cancer by Upregulating the Expression of CCL5.

SUMMARY: Immunocytokines are a promising immunotherapeutic approach in cancer therapy. Anti-VEGFR2-interferon α (IFNα) suppressed colorectal cancer (CRC) growth and enhanced CD8+ T-cell infiltration in the tumor microenvironment, exhibiting great clinical translational potential. However, the mechanism of how the anti-VEGFR2-IFNα recruits T cells has not been elucidated. Here, we demonstrated that anti-VEGFR2-IFNα suppressed CRC metastasis and enhanced CD8+ T-cell infiltration. RNA sequencing revealed a transcriptional activation of CCL5 in metastatic CRC cells, which was correlated with T-cell infiltration. IFNα but not anti-VEGFR2 could further upregulate CCL5 in tumors. In immunocompetent mice, both IFNα and anti-VEGFR2-IFNα increased the subset of tumor-infiltrating CD8+ T cells through upregulation of CCL5. Knocking down CCL5 in tumor cells attenuated the infiltration of CD8+ T cells and dampened the antitumor efficacy of anti-VEGFR2-IFNα treatment. We, therefore, propose upregulation of CCL5 is a key to enhance infiltration of CD8+ T cells in metastatic CRC with IFNα and IFNα-based immunocytokine treatments. These findings may help the development of IFNα related immune cytokines for the treatment of less infiltrated tumors.

Carborane-FAPI conjugate: A potential FAP-targeted boron agent with improved boron content.

Boron neutron capture therapy (BNCT) has received extensive attention as an advanced binary radiotherapy method. However, BNCT still faces poor selectivity of boron agent and is insufficient boron content in tumor tissues. To improve the tumor-targeted ability and boron content, this research aims to design, synthesize and preliminary evaluate a new borane agent Carborane-FAPI, which coupling the o-carborane to the compound skeleton of a mature fibroblast activating protein (FAP) inhibitor (FAPI). FAP is a tumor-associated antigen. FAP expressed lowly in normal organs and highly expressed in tumors, so it is a potential target for diagnosis and treatment. Boronophenylalanine (BPA) is the most widely investigated BNCT drug in present. Compared with BPA, the boron content of a single molecule is increased and drug targeting is enhanced. The results show that Carboaren-FAPI has low toxicity to normal cells, and selective enrichment in tumor tissues. It is a promising boron drug that has the potential to be used in BNCT.