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Abstract Background Renal cell carcinoma (RCC) is one of the most diagnosed urological malignancies with high mortality and increasing incidence. What’s more, the sunitinib resistance undoubtedly increased the difficulties in RCC therapy. Circular RNAs (circRNAs) are a newly found type of non-coding RNAs with a special circular structure, and are found to participate in the occurrence development, chemoresistance, and prognosis of cancers. Ferroptosis regulates disease progression mainly via polyunsaturated fatty acid metabolism and glutamine catabolic pathways. The mechanism of circRNAs contributed to sunitinib resistance through ferroptosis has not been elucidated clearly. Materials and methods In our research, we identified a novel circRNA Hsa_circ_0072732 from circRNA datasets (GSE108735 and GSE100186). RNase R and Actinomycin D assays were used to detect the loop structure and stability of circRNAs. qRT-PCR and western blot were used for the detection of RNA and protein levels. CCK8 assays were used to detect proliferation and cell viability. Lipid peroxidation (MDA), and reactive oxygen species (ROS) were detected by indicted kits. Dual-luciferase reporter and RNA pull-down assays were used to detect the RNA interactions. Results Our results showed that Hsa_circ_0072732 was highly expressed in RCC cells. Further investigations showed that the silence of Hsa_circ_0072732 could increase RCC sensitivity to sunitinib. Hsa_circ_0072732 contributed to sunitinib chemoresistance by impairing ferroptosis. Hsa_circ_0072732 exerts its function mainly by acting as sponges for miR-548b-3p and regulating the expression SLC7A11. Our research suggests that ferroptosis is involved in sunitinib resistance, and targeting ferroptosis is a promising way for RCC treatment. Conclusion Our research suggests Hsa_circ_0072732 enhanced renal cell carcinoma sunitinib resistance by inhibiting ferroptosis through miR-548b-3p/SLC7A11.

Abstract Cytokine storm (CS) emerges as an exacerbated inflammatory response triggered by various factors such as pathogens and excessive immunotherapy, posing a significant threat to life if left unchecked. Quercetin, a monomer found in traditional Chinese medicine, exhibits notable anti-inflammatory and antiviral properties. This study endeavors to explore whether quercetin intervention could mitigate CS through a combination of network pharmacology analysis and experimental validation. First, common target genes and potential mechanisms affected by quercetin and CS were identified through network pharmacology, and molecular docking experiments confirmed quercetin and core targets. Subsequently, in vitro experiments of Raw264.7 cells stimulated by lipopolysaccharide (LPS) showed that quercetin could effectively inhibit the overexpression of pro-inflammatory mediators and regulate the AKT1-FoxO1 signaling pathway. At the same time, quercetin can reduce ROS through the Keap1-Nrf2 signaling pathway. In addition, in vivo studies of C57BL/6 mice injected with LPS further confirmed quercetin's inhibitory effect on CS. In conclusion, this investigation elucidated novel target genes and signaling pathways implicated in the therapeutic effects of quercetin on CS. Moreover, it provided compelling evidence supporting the efficacy of quercetin in reversing LPS-induced CS, primarily through the regulation of the AKT1-FoxO1 and Keap1-Nrf2 signaling pathways.

In this paper, an improved self-coupled PI control dual-loop control strategy is proposed for the vector control of permanent magnet synchronous electric speed control system, to improve the poor motor control effect caused by the dead zone of the inverter, the presence of harmonics in the motor magnetic field distribution, and the error in the sampling process of the current. In order to reduce the tracking error of the signal, an acceleration feed-forward method is adopted, and the self-coupled PI controller with an additional Levant differentiator is introduced into the speed loop of the permanent magnet synchronous motor to ensure the accurate derivation of the input signal containing noise to improve the robustness of the system. In addition, this strategy combines the proportional term of the autotuned PI control structure with the standard resonator to form a proportional resonant autotuned PI in the current loop, so that the permanent magnet synchronous motor can better compensate the current in the current loop control to achieve the effect of current harmonic suppression. Finally, the control mechanism of the servo system analyzed, and based on the mathematical model of the controlled object PMSM, the design method of the improved self-coupling PI control structure is given. The experimental results show that the proposed control strategy can reduce the impact of the motor's own parameter changes on the system performance and has a good current harmonic suppression in the low-speed domain, which verifies the effectiveness of the designed improved self-coupled PI controller.

Objective To focus on the efficacy at variable frequency stimulation (VFS) after deep brain stimulation (DBS) for the treatment of axial symptoms in Parkinson's disease (PD). Methods Clinical data of 12 patients with PD who underwent bilateral DBS followed by VFS more than one year from January 2018 to June 2022 at Tianjin Huanhu Hospital, Tianjin University were retrospectively analyzed. Axial symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS)-gait posture, Timed Up and Go Test (TUGT) time and the occurrence of freezing of gait (FOG), The Freezing of Gait - Questionnaire (FOG - Q), and Berg Balance Scale (BBS). The above indicators were recorded one week before DBS surgery and in the drug "off" period (baseline), at the end of high frequency stimulation (the end of HFS), at one month follow-up of VFS (short-term VFS), and at one year or more follow-up of VFS (long-term VFS). Results Compared with baseline, BBS scores increased at the end of HFS (t = - 2.845, P = 0.008); UPDRS-gait posture (t = 12.703, P = 0.000; t = 11.737, P = 0.000), TUGT time (t = 8.923, P = 0.000; t = 8.025, P = 0.000) and the occurrence of FOG (t = 4.448, P = 0.000; t = 4.181, P = 0.000), and FOGQ scores (t = 9.186, P = 0.000; t = 8.186, P = 0.000) decreased, while the BBS scores increased (t = - 7.686, P = 0.000; t = - 6.106, P = 0.000) in both short-term VFS and long-term VFS. Compared with the end of HFS, UPDRS-gait posture (t = 11.583, P = 0.000; t = 10.618, P = 0.000), TUGT time (t = 6.922, P = 0.000; t = 6.022, P = 0.000) and the occurrence of FOG (t = 3.612, P = 0.001; t = 3.344, P = 0.002), and FOG-Q scores (t = 7.915, P = 0.000; t = 6.915, P = 0.000) decreased, while the BBS scores increased (t = - 4.842, P = 0.000; t = - 3.262, P = 0.003) in short-term VFS and long-term VFS. Conclusions For PD patients with HFS but poor axial symptoms efficacy after DBS, the use of VFS significantly improves multifaceted axial symptoms with reliable long-term efficacy.

Abstract Background Advanced cancer patients with good Eastern Cooperative Oncology Group (ECOG) performance status (score 0–1) are underrepresented in current qualitative reports compared with their dying counterparts. Aim To explore the experiences and care needs of advanced cancer patients with good ECOG. Design A qualitative phenomenological approach using semi-structured interview was employed. Data was analyzed using the Colaizzi’s method. Setting/Participants Purposive sample of terminal solid cancer patients on palliative care aged 18–70 years with a 0–1 ECOG score were recruited from a tertiary general hospital. Results Sixteen participants were interviewed. Seven themes were generated from the transcripts, including experiencing no or mild symptoms; independence in self-care, decision-making, and financial capacity; prioritization of cancer growth suppression over symptom management; financial concerns; hope for prognosis and life; reluctance to discuss death and after-death arrangements; and use of complementary and alternative medicine (CAM) and religious coping. Conclusions Advanced cancer patients with good ECOG have distinct experiences and care needs from their dying counterparts. They tend to experience no or mild symptoms, demonstrate a strong sense of independence, and prioritize cancer suppression over symptom management. Financial concerns were common and impact their care-related decision-making. Though being hopeful for their prognosis and life, many are reluctant to discuss death and after-death arrangements. Many Chinese patients use herbal medicine as a CAM modality but need improved awareness of and accessibility to treatment options. Healthcare professionals and policy-makers should recognize their unique experiences and needs when tailoring care strategies and policies.

Objective To explore the therapeutic effect of transcranial direct current stimulation (tDCS) with different current density on upper limb motor disorder in stroke patients. Methods A total of 45 stroke patients with upper limb motor disorder hospitalized in Xuanwu Hospital, Capital Medical University from March 2019 to June 2022 were selected and randomly divided into low current density stimulation group (low density group, 0.028 mA/cm2), medium current density stimulation group (medium density group, 0.057 mA/cm2), high current density stimulation group (high density group, 0.080 mA/cm2), 15 cases in each group. Upper limb motor function was evaluated by Fugl‑Meyer Assessment Scale for Upper Extremity (FMA‑UE) and Action Research Arm Test (ARAT) before and one week after treatment, and activity of daily living was evaluated by modified Barthel Index (mBI). Results After treatment of tDCS, FMA‑UE (F = 284.343, P = 0.000), ARAT (F = 180.427, P = 0.000) and mBI (F = 487.159, P = 0.000) scores in 3 groups were improved compared with those before treatment. FMA‑UE (F = 2.293, P = 0.000) and ARAT (F = 2.572, P = 0.000) scores were significantly different among 3 groups, FMA‑UE (t = 2.426, P = 0.029; t = 2.140, P = 0.035) and ARAT (t = 2.537, P = 0.024; t = 2.353, P = 0.028) scores in high density group and medium density group were higher than those in low density group. Conclusions tDCS is safe and effective in the treatment of upper limb motor disorder after stroke. Current densities of 0.057 and 0.080 mA/cm2 are more effective than those of 0.028 mA/cm2.

Lymphocyte activation gene 3 (LAG-3), also known as CD223, is an emerging immune checkpoint that follows PD-1 and CTLA-4. Several LAG-3 targeting inhibitors in clinical trials and the combination of relatlimab (anti-LAG-3) and nivolumab (anti-PD-1) have been approved for treating - unresectable or metastatic melanoma. Despite the encouraging clinical potential of LAG-3, the physiological function and mechanism of action in tumors are still not well understood. In this review, we systematically summarized the structure of LAG-3, ligands of LAG-3, cell-specific functions and signaling of LAG-3, and the current status of LAG-3 inhibitors under development.

Abstract Background Fruquintinib has demonstrated significant improvement in overall survival (OS) among previously treated metastatic colorectal cancer (mCRC) patients. However, the utilization of fruquintinib has been constrained by various toxicities, such as hand‐foot skin reaction (HFSR) and hypertension, particularly in elderly patients with reduced tolerance to the standard dosage. This study aims to investigate the efficacy and safety of fruquintinib dose‐escalation strategy for elderly refractory mCRC patients. Patients and Methods This open‐label, single‐arm, phase II trial included patients aged 65 years or over with mCRC who had progressed after two or more lines of chemotherapy. Fruquintinib was administered for 21 consecutive days of a 28‐day treatment cycle. The starting dose of fruquintinib was 3 mg/day and escalated to 4 mg/day in Week 2 and 5 mg/day in Week 3 if no significant drug‐related toxicity was observed. The highest tolerated dose from Cycle 1 would be administered in Cycle 2 and all subsequent cycles. Before commencing treatment, all enrolled patients underwent a G8 questionnaire and comprehensive geriatric assessments. The primary endpoint of the study was progression‐free survival (PFS). Results A total of 29 patients were enrolled and all started fruquintinib at 3 mg/day. Fifteen patients (51.7%) were subsequently escalated to 4 mg/day and 4 (13.8%) to 5 mg/day. Only four (13.8%) patients discontinued treatment due to adverse events (AEs). The median PFS was 3.8 months (95% CI, 2.7–4.9), and the median OS was 7.6 months (95% CI, 6.5–8.7). Treatment‐related adverse events (TRAEs) were observed in all 29 patients (100%). The most frequently occurring (>10%) TRAEs greater than Grade 3 were HFSR (20.7%), hypertension (20.7%), and diarrhea (10.3%). Conclusion Our study indicated that a dose of 4 mg/day was well tolerated by most elderly patients, suggesting that fruquintinib dose‐escalation strategy during the first cycle could serve as a viable alternative to the standard 5 mg/day dosing.

Rapid reduction of plasma triglycerides (TG) is believed to improve the outcome of pancreatitis in the context of hypertriglyceridaemia (HTG)-induced acute pancreatitis (HTG-AP). Previous studies have suggested that haemoperfusion (HP) with the Jafron cartridge series could be effective for reducing TG concentrations in patients with HTG-AP. However, the clearance capacity (CC) for TG removal has not been reported. This case series reports on data from three patients with HTG-AP who underwent HP with HA230 or HA330 cartridges. Blood samples were collected from both before and after the cartridge circuit every 30 min and the CC was calculated. Twelve pairs of blood samples were collected for each type of HP cartridge. The mean ± SD CC of the HA230 cartridge for TG removal in this case series was 0.009781 ± 1.117235 ml/min (95% confidence interval [CI], –0.7000762, 0.7196384 ml). The mean ± SD CC of the HA330 cartridge for TG removal in this case series was 0.344914 ± 1.412183 ml/min (95% CI, –0.5523448, 1.2421721 ml). Based on the findings of this small case series, special caution is advised when considering the use of the HA230 and HA330 cartridges for reducing blood TG concentration pending further conclusive evidence from larger studies.

Abstract Background Insulin pump therapy (IPT) improves glucose control in people with type 1 diabetes (T1D) compared with multiple daily injections (MDI). However, their size, the tethered insulin infusion set, intrusiveness when operating the device and the need to disconnect during showering limit their acceptance to many who may benefit. The Omnipod DASH® Insulin Management System is a small waterproof tubeless device which is wirelessly controlled by a handheld device which may be an acceptable alternative. However, there are no randomised controlled trials focusing on the impact on user perceptions of tubeless insulin pump therapy. This pilot study aims to assess study feasibility and acceptability of patch pump therapy compared with usual care in adults with T1D in Australia to inform power calculations and progression to a large-scale multi-site randomised controlled study. Methods A pilot multi-site parallel randomised controlled study will be conducted in sixty-four adults with T1D who are managed on MDI or IPT and self-monitoring with finger-stick blood glucose from four specialist diabetes centres in Victoria, Australia. Following carbohydrate counting education, participants will be randomised to use Omnipod DASH® System (Omnipod group) or continue usual care (usual care group) for 12 weeks, followed by a 12-week extension phase where all participants will use Omnipod DASH® System. The primary outcome measure is feasibility determined by study completion rates with a threshold of 0.80. Acceptability of the intervention (Omnipod DASH® System) will be assessed by the difference in Diabetes Technology Questionnaire ‘current’ (DTQ-current) score at 12 weeks post-randomisation compared to baseline. Secondary outcomes will include other measures of user acceptance, process outcomes, resource outcomes, participant-centred outcomes, healthcare professional perceptions and glycaemic outcomes. Discussion This pilot study will provide insights regarding the feasibility of the study design and the first data regarding user acceptance of insulin patch pump technology in Australian T1D adults. We anticipate that this study will provide information informing the design of a larger study evaluating the impact of patch pumps on subjective outcomes that are of significance to the person living with T1D. Trial registration Australian New Zealand Clinical Trials Registry ( https://anzctr.org.au/ ) ACTRN12621001195842 (8th September 2021). Please refer to Additional file 1: Appendix 1 for full details.

The dissimilar joining of Al/Cu and Al/Ni is required to reduce the weight of electronic and electrical devices. Ultrasonic spot welding (USW) is expected to be applied to dissimilar materials because of the low heat input during the joining process. However, to obtain high strength via USW, the relationship among the welding parameters, joining strength, and microstructure for different material combinations must be investigated. In this study, Al/Al, Al/Cu, and Al/Ni are joined via USW by systematically varying the welding parameters; subsequently, their tensile shear load and microstructure are investigated. Results show that the vibration amplitude and welding time impose greater effects on the joint strength than the welding pressure for all material combinations. High-strength joints that fractured at the Al upper plate are obtained by optimizing the welding parameters for each material combination. Al/Ni bonding had a narrower margin of welding time to obtain a higher tensile shear load compared with other material combinations. This is due to the high heating rate and maximum temperature of Al/Ni joints, which cause the excessive deformation of the Al upper plate during prolonged welding. Texture analysis showed that recrystallized grains with GOSS orientation was remained in the high-strength dissimilar joints.

This article examines two types of lexical effects in the voice system of Kanakanavu, an Austronesian language of Taiwan. The first concerns a well-attested phenomenon in the Austronesian literature: interactions between the semantic transitivity of verbs and their ability (or lack thereof) to undergo voice alternation. The second concerns a phenomenon that is typologically and areally rare in the western Austronesian context – differential agent marking. The pronominal agent in Kanakanavu’s patient-/undergoer-voice construction is differentially case-marked depending on the tense-aspect value of the clause. However, lexical effects are found in how the differentially marked agent is interpreted. When dynamic verbs are used, omitted agents in perfective clauses are interpreted as coreferential with a specific referent mentioned in prior discourse, but those in non-perfective clauses are interpreted as having generic reference, backgrounded, and/or not centrally involved in the situation expressed by the verb. When stative verbs are used, alternation between perfective and imperfective verb forms may have various effects on the interpretation of the agent. In some stative verbs, the agent is interpreted as a prototypical semantic agent in the perfective, but as a semantic experiencer in the imperfective. In other stative verbs, the perfective/non-perfective alternation has to do with whether a change of state is involved, without having any effects on agent interpretation. This study explores how lexical effects manifest across both elicited and natural discourse data. It also presents the phenomenon of differential agent marking in Kanakanavu as neither typical nor representative in the western Austronesian context.

Abstract Background There is a paucity of quantitative measurements of cardiac tumors and myocardium using parametric mapping techniques. This study aims to explore quantitative characteristics and diagnostic performance of native T1, T2, and extracellular volume (ECV) values of cardiac tumors and left ventricular (LV) myocardium. Methods Patients with suspected cardiac tumors who underwent cardiovascular magnetic resonance (CMR) between November 2013 and March 2021 were prospectively enrolled. The diagnoses of primary benign or malignant tumors were based on pathologic findings if available, comprehensive medical history evaluations, imaging, and long-term follow-up data. Patients with pseudo-tumors, cardiac metastasis, primary cardiac diseases, and prior radiotherapy or chemotherapy were excluded. Multiparametric mapping values were measured on both cardiac tumors and the LV myocardium. Statistical analyses were performed using independent-samples t-test, receiver operating characteristic, and Bland–Altman analyses. Results A total of 80 patients diagnosed with benign (n = 54), or primary malignant cardiac tumors (n = 26), and 50 age and sex-matched healthy volunteers were included. Intergroup differences in the T1 and T2 values of cardiac tumors were not significant, however, patients with primary malignant cardiac tumors showed significantly higher mean myocardial T1 values (1360 ± 61.4 ms) compared with patients with benign tumors (1259.7 ± 46.2 ms), and normal controls (1206 ± 44.0 ms, all P

ABSTRACT Porcine epidemic diarrhea virus (PEDV), a swine enteropathogenic coronavirus, causes severe diarrhea in neonatal piglets, which is associated with a high mortality rate. Thus, developing effective and safe vaccines remains a top priority for controlling PEDV infection. Here, we designed two lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) vaccines encoding either the full-length PEDV spike (S) protein or a multiepitope chimeric spike (Sm) protein. We found that the S mRNA-LNP vaccine was superior to the Sm mRNA-LNP vaccine at inducing antibody and cellular immune responses in mice. Evaluation of the immunogenicity and efficacy of the S mRNA vaccine in piglets confirmed that it induced robust PEDV-specific humoral and cellular immune responses in vivo. Importantly, the S mRNA-LNP vaccine not only protected actively immunized piglets against PEDV but also equipped neonatal piglets with effective passive anti-PEDV immunity in the form of colostrum-derived antibodies after the immunization of sows. Our findings suggest that the PEDV-S mRNA-LNP vaccine is a promising candidate for combating PEDV infection.IMPORTANCEPorcine epidemic diarrhea virus (PEDV) continues to harm the global swine industry. It is important to develop a highly effective vaccine to control PEDV infection. Here, we report a PEDV spike (S) mRNA vaccine that primes a potent antibody response and antigen-specific T-cell responses in immunized piglets. Active and passive immunization can protect piglets against PED following the virus challenge. This study highlights the efficiency of the PEDV-S mRNA vaccine and represents a viable approach for developing an efficient PEDV vaccine.

To address the problem of poor visual expression due to traditional methods’ poor image enhancement effect, this paper proposes an image processing model for visual communication of the human-computer interaction interface based on hierarchical analysis. The edge contour feature extraction method is used to extract the convenient information features of the HCI interface, and the cross-sectional information fusion technique is combined to realize the visual communication information enhancement processing of the HCI interface, extract the spatial multi-resolution feature amount of the visual communication image of the HCI interface, and realize the visual communication optimization design of the HCI interface. In the image processing model proposed in this paper, the traditional PCANet and computer vision methods are compared to test the effectiveness of the three image recognition methods. The recognition accuracy of the method proposed in this paper is 82.55%, 85.28%, 87.06%, and 85.87% for the four types of images, respectively; the recognition accuracy of PCANet is 75.53%, 76.48%, 81.26%, and 74.74%, respectively; and the recognition accuracy of computer vision method is 73.79%, 72.83%, 79.36%, and 73.71%. Comparing the data, it can be seen that the model in this paper can improve the fidelity of visual communication and the discriminative ability of interface output, which can greatly improve the performance of the graphical human-computer interaction interface.

Apoptosis Inhibitor 5 (API5) is a widely concerned nuclear protein with diverse functions in organisms, so far, study of API5 is still quite limited in lower animals, and its role in viral immune response has not been addressed. Here, we explored the function of API5 in mud crab (Scylla paramamosain) during White Spot Syndrome Virus (WSSV) infection. The interacting protein Hsp20 of API5 was screened by pull-down assay, and API5 and hsp20 were knocked down by RNAi interference. The results showed that API5 was upregulated along with virus infection, silencing of API5 led to increased WSSV copy numbers and apoptotic rate of hemocytes, highlighting its significance in the immune response. Moreover, we discovered a novel interaction between API5 and Heat Shock Protein 20 (Hsp20), and then revealed that Hsp20 could promote cell apoptosis of hemocytes and reduce viral copy numbers by suppressing API5. The current study therefore improves the knowledge of API5-Hsp20 axis and provides novel insights into intricate mechanisms governing the antiviral response in marine crustaceans.

Introduction: Aroma is a key inherent quality attributes of pepper fruit, yet the underlying mechanisms of aroma compound biosynthesis remain unclear.Methods: In this study, the volatile profile of the QH (cultivated Capsicum chinense) and WH (cultivated Capsicum annuum) pepper varieties were putatively identified during fruit development using gas chromatography-mass spectrometry (GC-MS).Results and discussion: The results identified 203 volatiles in pepper, and most of the esters, terpenes, aldehydes and alcohols were significantly down-regulated with fruit ripening. The comparison of volatile components between varieties revealed that aldehydes and alcohols were highly expressed in the WH fruit, while esters and terpenes with fruity or floral aroma were generally highly accumulated in the QH fruit, providing QH with a fruity odor. Transcriptome analysis demonstrated the close relationship between the synthesis of volatiles and the fatty acid and terpene metabolic pathways, and the high expression of the ADH, AAT and TPS genes was key in determining the accumulation of volatiles in pepper fruit. Furthermore, integrative metabolome and transcriptome analysis revealed that 208 differentially expressed genes were highly correlated with 114 volatiles, and the transcription factors of bHLH, MYB, ARF and IAA were identified as fundamental for the regulation of volatile synthesis in pepper fruit. Our results extend the understanding of the synthesis and accumulation of volatiles in pepper fruit.

基于准线性化隐式建模方法, 建立适用于大展弦比机翼的动力学模型, 研究分布式吊舱机翼的气动弹性特点。其中结构模型采用中等变形梁模型, 气动模型采用准定常理论, 利用小扰动和有限差分法, 建立求解机翼气弹稳定性的方法。在验证结构和气动模型准确性基础上, 研究吊舱的个数、质量、展向站位、弦向/法向偏置等参数对分布式吊舱机翼气动特性的影响。分析结果发现: 吊舱越靠近机翼中部、弦向和法向偏置越大机翼稳定性越高, 但质量分布不均时反而会降低稳定性; 机翼经历了振动收敛、单频简谐振动和倍频简谐振动, 其颤振形式为面内外弯曲和扭转耦合, 三维效应显著。文中的方法能够有效描述分布式吊舱机翼的气动弹性特性。

A statistical approach was carried out to identify the prevalent virulence factors responsible for post-weaning diarrhoea (PWD). Healthy piglets' faecal samples and diarrhoeic piglets' rectal swab specimens were secured. Twenty-six (26) and 100 independent enterotoxigenic Escherichia coli (ETEC) strains were subsequently isolated. These strains were assessed utilising polymerase chain reaction to identify the encoding genes of six virulence factors: heat-labile enterotoxin (LT; encoded by eltAB), heat-stable enterotoxin A (STa; encoded by estA), heat-stable enterotoxin B (STb; encoded by estB), enteroaggregative E. coli heat-stable enterotoxin 1 (EAST1; encoded by astA), Shiga toxin 2e (Stx2e; encoded by stx2e), and F18 fimbriae (encoded by fedA). The LT and ST secretions were investigated using enzyme-linked immunosorbent assays. From direct observation, no stx2e was evident in the 126 strains. Among the 26 strains retrieved from the healthy piglets, none harboured fedA or secreted LT; 23% (6/26) secreted ST, and 50% (13/26) carried astA. A statistical regression was applied on the 100 E. coli strains retrieved from the diarrhoeic piglets, where fedA was set as the dependent variable and the enterotoxin secretions were set as the independent variables. The results exhibit that the LT secretion was the only significant factor (P < 0.000 1) correlated to fedA in the diarrhoeic piglets; thus, it is concluded that the prevalent virulence factors for PWD were the ECET strain with F18 fimbriae adhesion and LT secretion, but not astA or stx2e.

Abstract Background Cell division cycle 6 (CDC6) has been proven to be associated with the initiation and progression of human multiple tumors. However, it’s role in glioma, which is ranked as one of the common primary malignant tumor in the central nervous system and is associated with high morbidity and mortality, is unclear. Methods In this study, we explored CDC6 gene expression level in pan-cancer. Furthermore, we focused on the relationships between CDC6 expression, its prognostic value, potential biological functions, and immune infiltrates in glioma patients. We also performed vitro experiments to assess the effect of CDC6 expression on proliferative, apoptotic, migrant and invasive abilities of glioma cells. Results As a result, CDC6 expression was upregulated in multiple types of cancer, including glioma. Moreover, high expression of CDC6 was significantly associated with age, IDH status, 1p/19q codeletion status, WHO grade and histological type in glioma (all p

AIM: To investigate the anxiety, depression and sleep status of patients with primary angle-closure glaucoma(PACG)and primary open angle glaucoma(POAG).METHODS: Retrospective clinical study. The Anxiety Self-Rating Scale(SAS), Depression Self-Rating Scale(SDS)and Pittsburgh Sleep Quality Index(PSQI)were used to evaluate 60 patients with primary glaucoma(30 PACG, 30 POAG)diagnosed in the department of ophthalmology in our hospital during the period from June 2019 to December 2020 and 30 healthy adults from the physical examination department of our hospital as a control group. The scores of anxiety, depression and sleep quality in the three groups were compared.RESULTS: The scores of SAS, SDS and PSQI in PACG and POAG groups(48.40±9.302, 53.40±8.625, 9.57±2.861; 42.57±9.684, 48.80±10.320, 7.23±2.223)were significantly higher than those in control group(37.03±6.805, 38.63±7.881, 4.87±2.688)(P7, the positive rates of anxiety, depression and insomnia in the PACG group(77%, 73%, 70%)were higher than those in the POAG group(43%, 40%, 37%)and the control group(13%, 10%, 20%)(P

BackgroundThe incidence and risk factors of acute kidney injury (AKI) in patients with malignancies receiving immune checkpoint inhibitors (ICIs) are being extensively reported with their widespread application.ObjectiveThis study aimed to quantify the incidence and identify risk factors of AKI in cancer patients treated with ICIs.MethodsWe searched the electronic databases of PubMed/Medline, Web of Science, Cochrane and Embase before 1 February 2023 on the incidence and risk factors of AKI in patients receiving ICIs and registered the protocol in PROSPERO (CRD42023391939). A random-effect meta-analysis was performed to quantify the pooled incidence estimate of AKI, identify risk factors with pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) and investigate the median latency period of ICI-AKI in patients treated with ICIs. Assessment of study quality, meta-regression, and sensitivity and publication bias analyses were conducted.ResultsIn total, 27 studies consisting of 24048 participants were included in this systematic review and meta-analysis. The overall pooled incidence of AKI secondary to ICIs was 5.7% (95% CI: 3.7%-8.2%). Significant risk factors were older age (OR: 1.01, 95% CI: 1.00–1.03), preexisting chronic kidney disease (CKD) (OR: 2.90, 95% CI: 1.65–5.11), ipilimumab (OR: 2.66, 95% CI: 1.42–4.98), combination of ICIs (OR: 2.45, 95% CI: 1.40–4.31), extrarenal immune-related adverse events (irAEs) (OR: 2.34, 95% CI: 1.53-3.59), and proton pump inhibitor (PPI) (OR: 2.23, 95% CI: 1.88–2.64), nonsteroidal anti-inflammatory drug (NSAID) (OR: 2.61, 95% CI: 1.90–3.57), fluindione (OR: 6.48, 95% CI: 2.72–15.46), diuretic (OR: 1.78, 95% CI: 1.32–2.40) and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs) (pooled OR: 1.76, 95% CI: 1.15–2.68) use. Median time from ICIs initiation to AKI was 108.07 days. Sensitivity and publication bias analyses indicated robust results for this study.ConclusionThe occurrence of AKI following ICIs was not uncommon, with an incidence of 5.7% and a median time interval of 108.07 days after ICIs initiation. Older age, preexisting chronic kidney disease (CKD), ipilimumab, combined use of ICIs, extrarenal irAEs, and PPI, NSAID, fluindione, diuretics and ACEI/ARB use are risk factors for AKI in patients receiving ICIs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023391939.

Bipolar androgen therapy (BAT) is a new endocrinologic treatment for castration-resistant prostate cancer (CRPC) that can restore some patients’ sensitivity to drugs such as abiraterone (Abi) and enzalutamide (Enz). We performed a meta-analysis using STATA16. Sensitivity analyses were performed by examining the effects of individual studies using different effect models and detecting any publication bias using the Harbord test. In a total of 108 unique records, ten studies were included in the final meta-analysis. Participants who underwent BAT achieved a PSA50 response rate of 27% (95%CI [0.22,0.31], I2=17.98%), ORR of 34% (95%CI [0.24,0.43], I2=0), and incidence of AEs (grade≥3) of 14% (95%CI [0.09,0.19], I2=0). Patients who completed BAT proceeded to AR-targeted therapy (Abi or Enz) and achieved a PSA50 response rate of 57% (95% CI [0.36,0.78], I2=0). Patients with prior Enz resistance had a stronger impact on the PSA50 of AR-target therapy rechallenge. The results of this meta-analysis indicate that BAT is a safe and effective treatment for patients who have progressed after Abi or Enz. BAT can trigger the resensitization of patients with CRPC to subsequent endocrine therapy and improve the overall survival of patients and their quality of life.

IntroductionImportant studies on the relationship of the intestinal microbial flora with obesity have uncovered profound changes in the composition of the gut microbiota in obese individuals. Animal studies successfully altered body phenotypes by fecal microbiota transplantation (FMT).MethodsIn this study, we analyzed the gut microbiome of Suncus murinus (S. murinus), a naturally obesity-resistant animal, and the changes of the gut flora of C57BL/6NCrSIc mice that received gut bacteria transplantation from S. murinus by 16S rRNA gene analysis method. And analyzed and discussed the possible impact of the use of antibiotics before transplantation on the outcome of transplantation.ResultsOur results showed no significant changes in body weight in the FMT group compared to the control (AB) group, but large fluctuations due to antibiotics. There was no change in blood lipid levels between groups before and after FMT. The gut microbiota of S. murinus were enriched in Firmicutes and Proteobacteria, while Bacteroidetes were not detected, and fewer OTUs were detected in the intestine gut in comparison to other mouse groups. Statistically significant differences in alpha diversity were observed between the FMT group and other groups. Furthermore, a beta diversity analysis indicated an apparent structural separation between the FMT group and other groups.ConclusionIt was suggested that the gut flora of S. murinus was not well established in the gut trace of mice through FMT, and the administration of antibiotics before transplantation was an important factor affecting the overall composition of the gut flora. Although FMT of S. murinus failed to completely colonize the intestinal tract of the mice, it still had a certain effect on the establishment of the intestinal flora of the mice. The unpredictable effects of pre-transplantation antibiotics on the results of transplantation cannot be ignored.

Abstract Breast cancer has become the most common and greatest threat to women's health in the world. As the most dangerous subtype of breast cancer, triple‐negative breast cancer (TNBC) can lead develop drug resistance, resulting in poor therapeutic effects. The synergistic effect of radiotherapy and immunotherapy can not only improve the therapeutic effect of in situ TNBC but also induce the strong abscopal effect of radiotherapy to remove the tumor cells from the metastatic tumor and prevent tumor recurrence. However, many preclinical studies have pointed out that the application of radioimmunotherapy still has such problems as large toxic and side effects of drugs and asynchronous administration scheme. With the increasing popularity of nanobiotechnology in tumor therapy, there are more and more research results related to nanoparticles, such as inorganic nanoparticles, organic nanoparticles, and nanoparticle–hydrogel complexes in radioimmunotherapy. In this review, we briefly summarize the related clinical treatment methods of TNBC and review the related nanobiotechnology used in the preclinical studies of TNBC radioimmunotherapy. It is mainly characterized by the controlled release of drugs locally, enhanced radiosensitization, and avoidance of systemic toxicity. However, further studies are needed to improve the convenience and effectiveness, so as to explore new options for the clinical treatment of TNBC.

Parkinson's disease (PD) is a complex, chronic and progressive neurodegenerative disease. When medication doesn't work well, surgical treatments should be considered to improve symptoms. Currently, surgical treatments to PD include not only neurosurgical ablation with different principles, such as radiofrequency ablation (RFA), magnetic resonance guided laser interstitial thermal therapy (MRgLITT), magnetic resonance guided focused ultrasound (MRgFUS) and stereotactic radiotherapy (SRT), but also neuromodulation techniques including deep brain stimulation (DBS). In addition, spinal cord stimulation (SCS), gene and transplantation therapy to PD are also being explored. This review focuses on advances of above treatments of PD, and analyzes their efficacy and safety in order to provide more theory and basis for clinical researchs.

Objective To investigate the therapeutic effect of deep brain stimulation (DBS) on non⁃motor symptoms of Parkinson's disease (PD). Methods A total of 41 patients with PD who underwent DBS in Tianjin Huanhu Hospital from January 2015 to January 2021 were selected as subjects. The cognitive function was assessed by Mini⁃Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3, 6 and 12 months after operation. Beck Depression Inventory Ⅱ (BDI⁃Ⅱ) and Hamilton Anxiety Rating Scale (HAMA) assessed depression and anxiety, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) assessed sleep disorders and sleepiness, and Unified Parkinson's Disease Rating Scale Ⅲ (UPDRSⅢ) assessed motor symptoms. Levodopa equivalent daily dose (LEDD) was used to assess postoperative dependence on anti⁃PD drugs. Results The BDI⁃Ⅱscore (P=0.000), HAMA total scores (P=0.000) and its somatic anxiety (P=0.000), mental anxiety (P=0.000), PSQI total scores (P=0.000) and its subjective sleep quality (P=0.000), time to fall asleep (P=0.000), sleep duration (P=0.000), sleep efficiency (P=0.000), sleep disorders (P=0.000), sleep drug use (P=0.015), daytime dysfunction (P=0.000), ESS score (P=0.000), UPDRSⅢ score (P=0.000) and LEDD (P=0.000) had statistically significant differences before and after surgery. The improvement rates of BDI⁃Ⅱ, HAMA, PSQI and ESS were 46.00%, 33.58%, 34.67% and 34.30%, 49.69%, 35.01%, 38.19% and 36.20%, 50.51%, 35.24%, 39.77% and 39.44% at 3, 6 and 12 months after surgery respectively. The scores at different postoperative observation points were significantly different from those before surgery (P＜0.01, for all). However, there were no significant differences in MMSE total scores and its score of orientation, memory, attention and computation, recall ability and language function, as well as MoCA total scores and its score of visual spatial and executive function, naming, attention, language, abstraction, delayed recall and orientation before and after surgery (P＞0.05, for all). Conclusions DBS can significantly improve the motor symptoms, mood and sleep disorder of non⁃motor symptoms (NMS) in PD patients, and reduce the dose of anti⁃PD drugs, but has no effect on cognitive function.

Based on current implantable devices, a battery’s rigidity and large size makes it prone to immune rejection and wound incisions. Additionally, it is limited by its finite lifespan, which hinders long-term usage. These limitations greatly restrict the development of implantable medical device systems towards miniaturization and minimally invasive approaches. Consequently, obtaining high-fidelity and stable biological signals from the target tissue area of the organism remains challenging. Therefore, there is a need to develop wireless power transmission technology. In this paper, we propose a wireless micro energy transfer method based on MEMS micro coils for charging implantable devices. Through simulation calculations, we first investigate the influence of coaxial distance, horizontal displacement, and rotation angle between the MEMS micro coil and the transmitting coil on power transmission. Subsequently, we utilize micro nanofabrication technology to create a MEMS micro spiral copper coil with a line width, thickness, and spacing of 50 µm and a total of five turns. Finally, we conduct wireless power transmission tests on the coil. The results show that, when the transmitting coil and the receiving coil are 10 mm apart and the operating frequency is 100 kHz, the power of the wireless power transmission system reaches 45 µW. This power level is sufficient to meet the power supply requirements of implantable pacemakers. Therefore, this technology holds great potential for applications in the field of wireless power transmission for implantable medical devices, including pacemakers and brain neurostimulators.

Perovskite solar cells (PSC) offer a promising solution for building integrated photovoltaics (BIPVs) due to its high photoelectric conversion efficiency (PCE). However, increasing the transparency of their functional layers dramatically decreases the PCE. Here, a computer controlled laser patterning method was proposed to directly turn PSC modules into semitransparent and with aesthetic artificial pattern, without additional complexities to the conventional PSCs fabrication process. A structured ST-PSC achieving a champion PCE of 17.5% with average visible transparency (AVT) of 18.2%, and a mini-module with 5 × 5 cm2 delivering a PCE of 9.1% with AVT of 37.7% were demonstrated. Rationally designed aesthetic patterns were imprinted on mini-modules, achieving a PCE of 14.4%. These results reveal a new route for low-cost facile fabricating high performance large-area aesthetic BIPV modules, and represent a big step forward toward the fabrication of solar cells with high efficiency and high transparency.

Patients after kidney transplantation have a much higher risk of developing malignant tumors than the general population. And the native kidney is an organ relatively susceptible to malignant tumors after renal transplantation. However, the simultaneous development of bilateral renal tumors is very rare; especially the bilateral native kidneys harbor different pathological types of renal cell carcinoma (RCC). We report a case of a patient who developed malignant tumors in both native kidneys nearly 19 years after renal transplantation. This patient underwent bilateral laparoscopic radical nephrectomy, and postoperative pathological examination showed clear cell RCC on the left native kidney and papillary RCC on the right one. And the early detection and surgical treatment resulted in a good prognosis. The literature related to the diagnosis and treatment of bilateral RCC after renal transplantation is also reviewed.

In recent years, zebrafish model has been widely concerned and recognized by scholars at home and abroad. As an animal model, zebrafish is of great research value because it is easy to feed, easy to operate, observe and analyze, and the model results can be highly combined with human body test data. Zebrafish model has been widely used in many fields, including basic medical science, clinical medicine, agricultural production, environmental toxicology and forensic science. This review introduces the biological characteristics of zebrafish, summarizes the research progress of zebrafish model in toxicology, and discusses the application prospect of zebrafish model in forensic science.

Atopic dermatitis (AD) is a chronic and pruritic skin inflammatory disease causing a significant burden to health care management and patient’s quality of life. Seemingly healthy skin or non-lesional sites on AD patients still presents skin barrier defects and immune response, which can develop to AD at a later stage. To investigate further the balance between the epidermal barrier impairment and intrinsic immune dysregulation in AD, we exploited multispectral Raster-Scanning Optoacoustic Mesoscopy (ms-RSOM) to image lesional and non-lesional skin areas on AD patients of different severities non-invasively to elucidate their structural features and functional information. Herein, we demonstrate the objective assessment of AD severity using relative changes in oxygen saturation (δsO2) levels in microvasculature along with other structural parameters such as relative changes in epidermis thickness (δET) and total blood volume (δTBV) between the lesional and non-lesional areas of the skin. We could observe an increasing trend for δsO2 and δTBV, which correlated well with the subjective clinical Scoring Atopic Dermatitis (SCORAD) for evaluating the severity. Notably, δET showed a decreasing trend with AD severity, indicating that the difference in epidermal thickness between lesional and non-lesional area of the skin decreases with AD severity. Our results also correlated well with conventional metrics such as trans-epidermal water loss (TEWL) and erythrosine sedimentation rate (ESR). We quantified the δsO2 and δET changes to objectively evaluate the treatment response before and four months after treatment using topical steroids and cyclosporine in one severe AD patient. We observed reduced δsO2 and δET post treatment. We envision that in future, functional and structural imaging metrics derived from ms-RSOM can be translated as objective markers to assess and stratify the severity of AD and understand the function of skin barrier dysfunctions and immune dysregulation. It could also be employed to monitor the treatment response of AD in regular clinical settings.

Abstarct Background Cytosine-phosphate-guanine (CpG) dinucleotides has been used as adjuvants for cancer immunotherapy. However, unmodified CpG are not very efficient in clinical trials. Glucose, ligand of C-type lectin receptors (CLRs), can promote DC maturation and antigen presentation, which is the first step of induction of adaptive immune responses. Therefore, conjugation of type B CpG DNA to glucose-containing glycopolymers may enhance the therapeutic effects against tumor by CpG-based vaccine. Methods gCpG was developed by chemical conjugation of type B CpG DNA to glucose-containing glycopolymers. The therapeutic effects of gCpG-based vaccine were tested in both murine primary melanoma model and its metastasis model. Results gCpG based tumor vaccine inhibited both primary and metastasis of melanoma in mice which was dependent on CD8 + T cells and IFNγ. In tumor microenvironment, gCpG treatment increased Th1 and CTL infiltration, increased M1 macrophages, decreased Tregs and MDSCs populations, and promoted inflammatory milieu with enhanced secretion of IFNγ and TNFα. The anti-tumor efficacy of gCpG was dramatically enhanced when combined with anti-PD1 immunotherapy. Conclusions We confirmed that gCpG was a promising adjuvant for vaccine formulation by activating both tumor-specific Th1 and Tc1 responses, and regulating tumor microenvironments. Graphical Abstract

Abstract Background As one of the leading threats for health among women worldwide, breast cancer has high morbidity and mortality. Surgical resection is the major clinical intervention for primary breast tumor, nevertheless high local recurrence risk and breast tissue defect remain two main clinical dilemmas, seriously affecting survival and quality of life of patients. Experimental We developed a thermoresponsive and injectable hybrid hydrogel platform (IR820/Mgel) by integration of co-loaded porous microspheres (MPs) and IR820 for preventing postoperative recurrence of breast cancer via photothermal therapy and promoting subsequent breast reconstruction. Results Our results suggested that IR820/Mgel could quickly heated to more than 50.0 ℃ under NIR irradiation, enabling killing effect on 4T1 cells in vitro and prevention effect on post-surgical tumor recurrence in vivo. In addition, the hydrogel platform was promising for its minimal invasion and capability of filling irregularly shaped defects after surgery, and the encapsulated MPs could help to increase the strength of gel to realize a long-term in situ function in vivo, and promoted the attachment and anchorage property of normal breast cells and adipose stem cells. Conclusions This photothermal hydrogel platform provides a practice paradigm for preventing locally recurrence of breast cancer and a potential option for reconstruction of breast defects. Graphic abstract

Background It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. Methods Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. Results A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). Conclusions Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

Immunotherapy has revolutionized colon cancer treatment. Immune checkpoint inhibitors (ICIs) have shown clinical benefits for colon cancer patients, especially those with high microsatellite instability (MSI-H). In 2020, the US Food and Drug Administration (FDA)-approved ICI pembrolizumab as the first-line treatment for metastatic MSI-H colon cancer patients. Additionally, neoadjuvant immunotherapy has presented efficacy in treating early-stage colon cancer patients. Although MSI has been thought of as an effective predictive biomarker for colon cancer immunotherapy, only a small proportion of colon cancer patients were MSI-H, and certain colon cancer patients with MSI-H presented intrinsic or acquired resistance to immunotherapy. Thus, further search for predictive biomarkers to stratify patients is meaningful in colon cancer immunotherapy. Except for MSI, other biomarkers, such as PD-L1 expression level, tumor mutation burden (TMB), tumor-infiltrating lymphocytes (TILs), certain gut microbiota, ctDNA, and circulating immune cells were also proposed to be correlated with patient survival and ICI efficacy in some colon cancer clinical studies. Moreover, developing new diagnostic techniques helps identify accurate predictive biomarkers for colon cancer immunotherapy. In this review, we outline the reported predictive biomarkers in colon cancer immunotherapy and further discuss the prospects of technological changes for biomarker development in colon cancer immunotherapy.

BackgroundThis umbrella review aims to consolidate evidence from systematic reviews and meta-analyses investigating the impact of the coronavirus disease−2019 (COVID-19) on kidney health, and the associations between kidney diseases and clinical outcomes in COVID-19 patients.MethodsFive databases, namely, EMBASE, PubMed, Web of Science, the Cochrane Database of Systematic Reviews and Ovid Medline, were searched for meta-analyses and systematic reviews from January 1, 2020 to June 2, 2022. Two reviewers independently selected reviews, identified reviews for inclusion and extracted data. Disagreements were resolved by group discussions. Two reviewers independently assessed the methodological quality of all included reviews using ROBIS tool. A narrative synthesis was conducted. The characteristics and major findings of the included reviews are presented using tables and forest plots. The included meta-analyses were updated when necessary. The review protocol was prospectively registered in PROSPERO (CRD42021266300).ResultsA total of 103 reviews were identified. Using ROBIS, 30 reviews were rated as low risk of bias. Data from these 30 reviews were included in the narrative synthesis. Ten meta-analyses were updated by incorporating 119 newly available cohort studies. Hospitalized COVID-19 patients had a notable acute kidney injury (AKI) incidence of 27.17%. AKI was significantly associated with mortality (pooled OR: 5.24) and severe conditions in COVID-19 patients (OR: 14.94). The pooled prevalence of CKD in COVID-19 patients was 5.7%. Pre-existing CKD was associated with a higher risk of death (pooled OR: 2.21) and disease severity (pooled OR: 1.87). Kidney transplant recipients were susceptible to SARS-CoV-2 infection (incidence: 23 per 10,000 person-weeks) with a pooled mortality of 18%.ConclusionKidney disease such as CKD or recipients of kidney transplants were at increased risk of contracting COVID-19. Persons with COVID-19 also had a notable AKI incidence. AKI, the need for RRT, pre-existing CKD and a history of kidney transplantation are associated with adverse outcomes in COVID-19.Systematic review registrationwww.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021266300, identifier: CRD42021266300.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. Methods The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan–Meier survival analyses were performed by the R version 3.6.1. Results The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). Conclusions In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of various types of cancer. However, even promising systemically administered ICB agents can cause immune-related adverse events (irAEs). The management of irAEs has been a significant concern. In addition to the risk of compromised immune function with corticosteroids and other immunomodulatory regimens used to treat irAEs, the complex mechanisms of irAEs make management of the “off-target” effects extremely challenging. Various materials with high biocompatibility, controllable degradability, and the ability for local and targeted delivery and controlled and sustained release of drugs have been explored to limit irAEs. Herein, we briefly review the fundamental mechanisms and clinical applications of immune checkpoint inhibitors and the potential mechanisms and clinical treatment of irAEs. We also highlight the application of emerging materials in the management of irAEs through “prevention” and “treatment”.

BackgroundBladder carcinoma (BLCA) is a common malignant tumor with high morbidity and mortality in the urinary system. Pyroptosis is a pattern of programmed cell death that is closely associated with progression of tumors. Therefore, it is significant to probe the expression of pyroptosis-related genes (PRGs) in BLCA.MethodsThe differentially expressed genes in normal and BLCA tissues were first obtained from the Cancer Genome Atlas (TCGA) database analysis, as well as PRGs from the National Center for Biotechnology Information (NCBI) database, intersecting to obtain differentially expressed pyroptosis-related genes (DEPRGs) in BLCA. With the construction of a prognostic model of pyroptosis by regression analysis, we derived and validated key genes, which were ascertained as a separate prognostic marker by individual prognostic and clinical relevance analysis. In addition, we gained six immune cells from the Tumor Immune Evaluation Resource (TIMER) website and analyzed the relationship between pyroptosis prognostic genes and immune infiltration.ResultOur results revealed that 31 DEPRGs were available by comparing normal and BLCA tissues with |log2 (fold change, FC)| > 0.5 and FDR

Objective To establish a method that can be used to analyze the distribution of DNA base damage sites at the genome-wide level, and use this method to analyze the distribution pattern of DNA base damage hotspots in non-small cell lung cancer cell line A549. Methods Chromatin immunoprecipitation sequencing(ChIP-seq)was used to perform immunoaffinity separation of specific binding DNA fragments with apurinic/apyrimidinic endonuclease 1(APE1)and 8-oxoguanine DNA glycosylase 1(OGG1)in A549 cells for sequence identification, and bioinformatics analysis was carried out to study the whole genome DNA base damage hotspots distribution. Results The binding peaks of APE1 and OGG1 were mainly distributed in the gene promoter region, with proportions of 41.70% and 49.26% respectively. The peaks of APE1 and OGG1 located in the 2 000 bp region upstream of TSS, accounting for 38.80% and 39.80%, respectively. The binding peaks of APE1 and OGG1 were significantly correlated(r=0.636 3, P < 0.01). The number of APE1 and OGG1 associated genes with the same binding peak was 25 038, among which 641 were directly associated with tumorigenesis. Conclusion A genome-wide analysis method is established to analyze the distribution of DNA base damage sites. DNA base damage is not randomly distributed in lung cancer cells, but mainly distributed in gene regulatory region. Hot spots related to base damage repair protein binding may be closely associated with tumor genesis and tumor inflammatory microenvironment.

Background: Angiosarcoma of the breast is a high-grade malignant soft tissue tumor, it can be divided into primary and radiation-associated angiosarcoma(secondary). However, the differences between primary and secondary angiosarcomas in terms of pathogenesis, clinical behavior, early diagnosis biomarkers, genetic abnormalities, and therapeutic targets remain to be fully elucidated. At the same time, due to its rarity, most of current information relating to angiosarcoma is provided by case reports. Therefore, exploring the mechanisms of primary and secondary breast angiosarcoma have important value for the discovery of new biomarkers and research into potential therapeutic targets. Methods: The differentially expressed genes (DEGs) between 36 cases of primary angiosarcoma and 54 cases of secondary angiosarcoma were screened. Then, the DEGs were used to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Then, a protein-protein interaction (PPI) network was constructed using the STRING database. Results: A total of 18 DEGs were identified, of which 13 were upregulated and 5 were downregulated in secondary breast angiosarcoma. The GO enrichment analysis showed that the DEGs were most enriched in metabolism, energy pathways, and protein metabolism in biological processes. The enriched signaling pathways of DEGs were the transforming growth factor-β (TGF-β), Wnt, Hippo and PI3K-Akt signaling pathways. Then, the PPI network was conducted and hub genes were identified and they were involved in thyroid hormone, Hippo and other signaling pathways. Conclusion: This study lay the foundation for the discovery of effective and reliable molecular biomarkers and essential therapeutic targets for these malignancies.

Background: Cytokine storm (CS) is a systemic inflammatory syndrome and a major cause of multi-organ failure and even death in COVID-19 patients. With the increasing number of COVID-19 patients, there is an urgent need to develop effective therapeutic strategies for CS. Baicalin is an anti-inflammatory and antiviral traditional Chinese medicine. In the present study, we aimed to evaluate the therapeutic mechanism of baicalin against CS through network analysis and experimental validation, and to detect key targets of CS that may bind closely to baicalin through molecular docking.Method: Access to potential targets of baicalin and CS in public databases. We constructed the protein-protein interaction (PPI) network of baicalin and CS by Cytoscape 9.0 software and performed network topology analysis of the potential targets. Then, the hub target was identified by molecular docking technique and validated in the CS model. Finally, GO and KEGG pathway functional enrichment analysis of common targets were confirmed using R language, and the location of overlapping targets in key pathways was queried via KEGG Mapper.Result: A total of 86 overlapping targets of baicalin and CS were identified, among which MAPK14, IL2, FGF2, CASP3, PTGS2, PIK3CA, EGFR, and TNF were the core targets. Moreover, it was found that baicalin bound most closely to TNF through molecular docking, and demonstrated that baicalin can effectively inhibit the elevation of TNF-α in vitro and in vivo. Furthermore, bioenrichment analysis revealed that the TNF signaling pathway and IL-17 signaling pathway may be potential key pathways for baicalin to treat CS.Conclusion: Based on this study, baicalin was identified as a potential drug for the alleviation of CS, and the possible key targets and pathways of baicalin for the treatment of CS were elucidated to reveal the main pharmacological mechanisms.

Gastric cancer (GC) is a typical inflammatory-related malignant tumor which is closely related to helicobacter pylori infection. Tumor inflammatory microenvironment plays a crucial role in tumor progression and affect the clinical benefit from immunotherapy. In recent years, immunotherapy for gastric cancer has achieved promising outcomes, but not all patients can benefit from immunotherapy due to tumor heterogeneity. In our study, we identified 29 differentially expressed and prognostic inflammation-related genes in GC and normal samples. Based on those genes, we constructed a prognostic model using a least absolute shrinkage and selection operator (LASSO) algorithm, which categorized patients with GC into two groups. The high-risk group have the characteristics of “cold tumor” and have a poorer prognosis. In contrast, low-risk group was “hot tumor” and had better prognosis. Targeting inflammatory-related genes and remodeling tumor microenvironment to turn “cold tumor” into “hot tumor” may be a promising solution to improve the efficacy of immunotherapy for patients with GC.