Postmortem Diffusion of Aconitum Alkaloids and Their Metabolites in Rabbits.

OBJECTIVES: To explore the postmortem diffusion rule of Aconitum alkaloids and their metabolites in poisoned rabbits, and to provide a reference for identifying the antemortem poisoning or postmortem poisoning of Aconitum alkaloids. METHODS: Twenty-four rabbits were sacrificed by tracheal clamps. After 1 hour, the rabbits were administered with aconitine LD50 in decocting aconite root powder by intragastric administration. Then, they were placed supine and stored at 25 ℃. The biological samples from 3 randomly selected rabbits were collected including heart blood, peripheral blood, urine, heart, liver, spleen, lung and kidney tissues at 0 h, 4 h, 8 h, 12 h, 24 h, 48 h, 72 h and 96 h after intragastric administration, respectively. Aconitum alkaloids and their metabolites in the biological samples were analyzed by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: At 4 h after intragastric administration, Aconitum alkaloids and their metabolites could be detected in heart blood, peripheral blood and major organs, and the contents of them changed dynamically with the preservation time. The contents of Aconitum alkaloids and their metabolites were higher in the spleen, liver and lung, especially in the spleen which was closer to the stomach. The average mass fraction of benzoylmesaconine metabolized in rabbit spleen was the highest at 48 h after intragastric administration. In contrast, the contents of Aconitum alkaloids and their metabolites in kidney were all lower. Aconitum alkaloids and their metabolites were not detected in urine. CONCLUSIONS: Aconitum alkaloids and their metabolites have postmortem diffusion in poisoned rabbits, diffusing from high-content organs (stomach) to other major organs and tissues as well as the heart blood. The main mechanism is the dispersion along the concentration gradient, while urine is not affected by postmortem diffusion, which can be used as the basis for the identification of antemortem and postmortem Aconitum alkaloids poisoning.

Antitumor immunity and prognosis value elicited by FAT3 and LRP1B co-mutation in endometrial cancer.

OBJECTIVE: FAT3 and LRP1B are two tumor suppressor genes with high mutation frequency in multiple cancer types, we sought to investigate the prognostic and immunological significance of these two genes in EC. METHODS: Based on a cohort of 502 EC samples, we conducted a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information, the potential impact of FAT3 and LRP1B co-mutation on antitumor immune response and prognosis were systematically discussed. RESULTS: We observed that FAT3 and LRP1B co-mutation was not only defined a dataset with prominently increased TMB, decreased tumor aneuploidy, and specially enriched in MSI-H subtype, but also manifested increased expression of immune-related markers, especially exclusive upregulation of PD-L1 levels and higher PD-L1+/CD8A+ proportion. Further analysis focused on lymphocyte infiltration and pathway enrichment explored the immune cell composition of the microenvironment and underlying molecular mechanisms affecting tumor development. Furthermore, EC patients with FAT3 and LRP1B co-mutation possessed significantly prolonged PFS and OS, and the co-mutation status was proved to be an independent prognostic factor. And a nomogram with high predictive performance was constructed by incorporating co-mutation with clinical features. More strikingly, the prognosis of MSI-H patients in EC with co-mutation was significantly improved, and their survival reached a level consistent with the POLE subtype. CONCLUSIONS: In endometrial cancer, co-mutation of FAT3 and LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.

Stress Granule Core Protein-Derived Peptides Inhibit Assembly of Stress Granules and Improve Sorafenib Sensitivity in Cancer Cells.

Upon a variety of environmental stresses, eukaryotic cells usually recruit translational stalled mRNAs and RNA-binding proteins to form cytoplasmic condensates known as stress granules (SGs), which minimize stress-induced damage and promote stress adaptation and cell survival. SGs are hijacked by cancer cells to promote cell survival and are consequently involved in the development of anticancer drug resistance. However, the design and application of chemical compounds targeting SGs to improve anticancer drug efficacy have rarely been studied. Here, we developed two types of SG inhibitory peptides (SIPs) derived from SG core proteins Caprin1 and USP10 and fused with cell-penetrating peptides to generate TAT-SIP-C1/2 and SIP-U1-Antp, respectively. We obtained 11 SG-inducing anticancer compounds from cell-based screens and explored the potential application of SIPs in overcoming resistance to the SG-inducing anticancer drug sorafenib. We found that SIPs increased the sensitivity of HeLa cells to sorafenib via the disruption of SGs. Therefore, anticancer drugs which are competent to induce SGs could be combined with SIPs to sensitize cancer cells, which might provide a novel therapeutic strategy to alleviate anticancer drug resistance.

Cervicovaginal metabolome and tumor characteristics for endometrial cancer detection and risk stratification.

PURPOSE: Endometrial cancer is highly prevalent and lacking non-invasive diagnostic techniques. Diagnosis depends on histological investigation of biopsy samples. Serum biomarkers for endometrial cancer have lacked sensitivity and specificity. The objective of this study was to investigate the cervicovaginal environment to improve understanding of metabolic reprogramming related to endometrial cancer and identify potential biomarker candidates for non-invasive diagnostic and prognostic tests. EXPERIMENTAL DESIGN: Cervicovaginal lavages were collected from 192 participants with endometrial cancer (n=66) and non-malignant conditions (n=108), and global untargeted metabolomics was performed. Using the metabolite data (n=920), we completed a multivariate biomarker discovery analysis. RESULTS: We analyzed grade 1/2 endometrioid carcinoma (n=53) and other endometrial cancer subtypes (n=13) to identify shared and unique metabolic signatures between the subtypes. When compared to non-malignant conditions, downregulation of proline (p<0.0001), tryptophan (p<0.0001), and glutamate (p<0.0001) was found among both endometrial cancer groups, relating to key hallmarks of cancer including immune suppression and redox balance. Upregulation (q<0.05) of sphingolipids, fatty acids, and glycerophospholipids was observed in endometrial cancer in a type-specific manner. Furthermore, cervicovaginal metabolites related to tumor characteristics, including tumor size and myometrial invasion. CONCLUSIONS: Our findings provide insights into understanding the endometrial cancer metabolic landscape and improvement into diagnosis. The metabolic dysregulation described in this paper linked specific metabolites and pathophysiological mechanisms including cellular proliferation, energy supply, and invasion of neighbouring tissues. Furthermore, cervicovaginal metabolite levels related to tumor characteristics, which are used for risk stratification. Overall, development of non-invasive diagnostic can improve both the acceptability and accessibility of diagnosis.

Combination Administration of Heparin and Nitroglycerin for the Treatment of Polycaprolactone-Induced Intravascular Embolism: A Preclinical Investigation.

BACKGROUND: As a new-generation collagen stimulator, polycaprolactone (PCL) containing filler has been extensively applied in facial dermal fillers and other medical aesthetic fields. However, inadvertent intravascular injection of PCL may result in complications such as tissue edema, flap necrosis, and even blindness. To date, there is no effective treatment for PCL-induced intravascular embolism. OBJECTIVES: The aim of this study was to identify a viable resolution for the embolism resulting from intravascular administration of PCL-containing fillers. METHODS: Two different animal experiments were performed: (1) PCL-induced rat inferior epigastric arteries embolism, followed by gross observation, histological evaluation, and cytokines analysis from serum; and (2) PCL-induced rabbit auricular artery embolism, immediately treated with heparin and nitroglycerin. The ears were then evaluated by gross observation, Laser speckle imaging, in vivo imaging system (IVIS) imaging, and histological evaluation. Saline and hyaluronic acids (HA) were used as controls, hyaluronidase was used as a positive drug. RESULTS: In a rat model of inferior epigastric arteries embolism, both intravascular injection of HA and PCL resulted in flap necrosis, indicating that the filler-induced intravascular embolism can lead to serious complications. In a rabbit model of auricular artery embolism, the combination treatment of heparin and nitroglycerin resulted in a relative blood reperfusion recovery of 80% in the ischemic area of the PCL group on day 7 post-operation, which was comparable to that of the HA group treated with hyaluronidase. Histological analysis revealed that the administration of heparin and nitroglycerin significantly attenuated intravascular thrombosis formation and inflammatory cell aggregation. CONCLUSIONS: The combination of heparin and nitroglycerin effectively restores blood flow reperfusion in the intravascular embolization caused by PCL filler injection, alleviates local tissue edema and flap necrosis. These findings offer a novel approach for future clinical management of intravascular embolization with PCL-containing filler injection. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Rapid Screening of 34 Emerging Contaminants in Surface Water by UHPLC-Q-TOF-MS.

OBJECTIVES: To establish a rapid screening method for 34 emerging contaminants in surface water by ultra-high performance liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC-Q-TOF-MS). METHODS: The pretreatment conditions of solid phase extraction (SPE) were optimized by orthogonal experimental design and the surface water samples were concentrated and extracted by Oasis® HLB and Oasis® MCX SPE columns in series. The extracts were separated by Kinetex® EVO C18 column, with gradient elution of 0.1% formic acid aqueous solution and 0.1% formic acid methanol solution. Q-TOF-MS 'fullscan' and 'targeted MS/MS' modes were used to detect 34 emerging contaminants and to establish a database with 34 emerging contaminants precursor ion, product ion and retention times. RESULTS: The 34 emerging contaminants exhibited good linearity in the concentration range respectively and the correlation coefficients (r) were higher than 0.97. The limit of detection was 0.2-10 ng/L and the recoveries were 81.2%-119.2%. The intra-day precision was 0.78%-18.70%. The method was applied to analyze multiple surface water samples and 6 emerging contaminants were detected, with a concentration range of 1.93-157.71 ng/L. CONCLUSIONS: The method is simple and rapid for screening various emerging contaminants at the trace level in surface water.

Metal-Free Catalytic Formation of a Donor-Acceptor-Donor Molecule and Its Lewis Acid-Adduct Singlet Diradical with High-Efficient NIR-II Photothermal Conversion.

We have synthesized a quinone-incorporated bistriarylamine donor-acceptor-donor (D-A-D) semiconductor 1 by B(C6F5)3 (BCF) catalyzed C-H/C-H cross coupling via radical ion pair intermediates. Coordination of Lewis acids BCF and Al(ORF)3 (RF=C(CF3)3) to the semiconductor 1 afforded diradical zwitterions 2 and 3 by integer electron transfer. Upon binding to Lewis acids, the LUMO energy of 1 is significantly lowered and the band gap of the semiconductor is significantly narrowed from 1.93 eV (1) to 1.01 eV (2) and 1.06 eV (3). 2 and 3 are rare near-infrared (NIR) diradical dyes with broad absorption both centered around 1500 nm. By introducing a photo BCF generator, 2 can be generated by light-dependent control. Furthermore, the integer electron transfer process can also be reversibly regulated via the addition of CH3CN. In addition, the temperature of 2 sharply increased and reached as high as 110 °C in 10 s upon the irradiation of near-infrared-II (NIR-II) laser (1064 nm, 0.7 W cm-2), exhibiting a fast response to laser. It displays excellent photothermal stability with a photothermal (PT) conversion efficiency of 62.26 % and high-quality PT imaging.

Diverse ALS mutations and cross-and multiple-resistance to ALS and EPSPS inhibitors in flucarbazone­sodium-resistant Bromus japonicus populations from Hebei province, China.

Japanese brome (Bromus japonicus) has become one of the main weeds in wheat fields in Hebei province of China and causes a large decrease of wheat production. A total of 44 putative resistant and 2 susceptible Japanese brome populations were collected in the 2021/2022 crop season from Hebei province of China to determine resistance levels to flucarbazone­sodium and to investigate the diversity of acetolactate synthase (ALS) mutations, as well as to confirm the cross-and multiple-resistance levels to ALS and EPSPS (5-enolpyruvate shikimate-3-phosphate synthetase) inhibitors. Whole plant bioassay results showed that 15 out of 44 populations tested or 34% were resistant to flucarbazone­sodium. The resistance indices of Japanese brome to flucarbazone­sodium ranged from 43 to 1977. The resistant populations were mainly distributed in Baoding and Shijiazhuang districts, and there was only one resistant population in Langfang district. Resistant Japanese brome had diverse ALS mutations, including Pro-197-Ser, -Thr, -Arg and Asp-376-Glu. The incidence of Pro-197-Ser mutation was the highest at 68%. Application of the CYP450 inhibitor malathion suggested that CYP450 was involved in metabolic resistance in a population without an ALS mutation. The population with Pro-197-Thr mutation evolved weak cross-resistance to mesosulfuron-methyl and pyroxsulam, and it is in the process of evolving multiple-resistance to glyphosate.

Proximity labeling-assisted click conjugation for electrochemical analysis of specific subpopulations in circulating extracellular vesicles.

Sensitive and accurate analysis of specific subpopulations in circulating extracellular vesicles (EVs) can provide a wealth of information for cancer diagnosis and management. Thus, we propose herein a new electrochemical biosensing method based on a proximity labeling-assisted click conjugation strategy. The method's core design is use of antibody-guided proximity labeling to equip target EVs with a large amount of alkyne groups, so that azide-tagged silver nanoparticles can be accurately loaded onto target EV surfaces, via click conjugation, to generate significant electrochemical responses. Adopting CD44-positive EVs as the model, the electrochemical method was demonstrated by analyzing target EVs across a wide linear range (103-109 particles/mL) with acceptable sensitivity and specificity. Satisfactory utility in clinical blood samples, and versatility with human epidermal growth factor receptor-2-positive EVs as alternative targets, were also shown. This method may thus provide a novel approach to specific subgroup analyses of circulating EVs, and is expected to offer reliable guidance for cancer diagnoses and management strategies.

A Cross-Sectional Survey on Pain Management in Dermal Filler Injections from Physicians' and Patients' Perspectives.

BACKGROUND: Hyaluronic acid (HA) dermal fillers injection is a common procedure in patients with cosmetic needs. Concomitant pain is a major complaint among patients undergoing HA filler injections. Relevant research is limited and there is no consensus on pain management of dermal filler injection. OBJECTIVES: To assist physicians in determining a more appropriate treatment approach, and to better provide treatment suggestions. METHODS: A nationwide (China) cross-sectional survey was conducted using questionnaires designed for physicians and patients, respectively. A total of 62 semi-structured questionnaires were administered to aesthetic physicians via face-to-face interview, whereas 123 online-based questionnaires were collected from patients who have ever undergone HA treatment. The collected questionnaire information was analyzed using descriptive statistics and content analysis. RESULTS: 42 (67.74%) physicians observed that over 50% of their patients were concerned about pain during injection. 101 (82.11%) of patients were concerned about impending pain ≥5 points (a total score is 10) before injection. For preferred pain relief modalities, 48 (77.42%) physicians would choose a hyaluronic acid dermal filler with lidocaine, and 82 (66.67%) patients would choose anesthetic-containing products. 59 (95.16%) physicians who injected lidocaine-containing hyaluronic acid found patients had a comfortable treatment experience. CONCLUSIONS: Pain management during hyaluronic acid dermal fillers injection is important from both perspectives of physicians and patients. This survey showed that compared with other analgesic methods, lidocaine-containing hyaluronic acid has offered a more satisfying experience. It also provides insights to physicians and patients in pain management. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Trp-574-Leu mutation and metabolic resistance by cytochrome P450 gene conferred high resistance to ALS-inhibiting herbicides in Descurainia sophia.

Descurainia sophia (flixweed) is a troublesome weed in winter wheat fields in North China. Resistant D. sophia populations with different acetolactate synthetase (ALS) mutations have been reported in recent years. In addition, metabolic resistance to ALS-inhibiting herbicides has also been identified. In this study, we collected and purified two resistant D. sophia populations (R1 and R2), which were collected from winter wheat fields where tribenuron-methyl provided no control of D. sophia at 30 g a.i. ha-1. Whole plant bioassay and ALS activity assay results showed the R1 and R2 populations had evolved high-level resistance to tribenuron-methyl and florasulam and cross-resistance to imazethapyr and pyrithiobac­sodium. The two ALS genes were cloned from the leaves of R1 and R2 populations, ALS1 (2004 bp) and ALS2 (1998 bp). A mutation of Trp 574 to Leu in ALS1 was present in both R1 and R2. ALS1 and ALS2 were cloned from R1 and R2 populations respectively and transferred into Arabidopsis thaliana. Homozygous T3 transgenic seedlings with ALS1 of R1 or R2 were resistant to ALS-inhibiting herbicides and the resistant levels were the same. Transgenic seedlings with ALS2 from R1 or R2 were susceptible to ALS-inhibiting herbicides. Treatment with cytochrome P450 inhibitor malathion decreased the resistant levels to tribenuron-methyl in R1 and R2. RNA-Seq was used to identify target cytochrome P450 genes possibly involved in resistance to ALS-inhibiting herbicides. There were five up-regulated differentially expressed cytochrome P450 genes: CYP72A15, CYP83B1, CYP81D8, CYP72A13 and CYP71A12. Among of them, CYP72A15 had the highest expression level in R1 and R2 populations. The R1 and R2 populations of D. sophia have evolved resistance to ALS-inhibiting herbicides due to Trp 574 Leu mutation in ALS1 and possibly other mechanisms. The resistant function of CYP72A15 needs further research.

Comparison of effectiveness and cost of different HCV testing strategies in high-risk populations in China.

High-risk populations are the predominant populations affected by hepatitis C virus (HCV) infection, and there is an urgent need for efficient and cost-effective HCV testing strategies for high-risk populations to identify potential undiagnosed HCV-infected individuals. This study compared several commonly used testing strategies and conducted effectiveness and cost analysis to select the appropriate testing strategy for diagnosing HCV infection in high-risk populations. Among the 2093 samples from high-risk populations in this study, 1716 were HCV negative, 237 were current HCV infection, 137 were past HCV infection, and three were acute early HCV infection. It was found that out of 237 patients with HCV current infection, Strategy A could detect 225 cases, with a missed detection rate of 5.06%, and the total cost was 33 299 RMB. In addition, Strategy B could detect 237 cases of current HCV infection, and the HCV missed detection rate was 0.00%, and the total cost was 147 221 RMB. While 137 cases of past HCV infection could be distinguished by strategy C, but 14 cases with current HCV infection were missed, with an HCV-positive missed detection rate of 5.91%, and the total cost for Strategy C was 43 059 RMB. In conclusion, in high-risk populations, the HCV positivity rate is typically higher. If feasible, the preferred approach is to directly conduct HCV RNA testing, which effectively minimizes the risk of missing cases. However, in situations with limited resources, it is advisable to initially choose a highly sensitive method for anti-HCV screening, followed by HCV RNA testing on reactive samples.

Pluronic F127-Lipoic Acid Adhesive Nanohydrogel Combining with Ce3+/Tannic Acid/Ulinastatin Nanoparticles for Promoting Wound Healing.

Developing strong anti-inflammatory wound dressings is of great significance for protecting inflammatory cutaneous wounds and promoting wound healing. The present study develops a nanocomposite Pluronic F127 (F127)-based hydrogel dressing with injectable, tissue adhesive, and anti-inflammatory performance. Briefly, Ce3+/tannic acid/ulinastatin nanoparticles (Ce3+/TA/UTI NPs) are fabricated. Meanwhile, α-lipoic acid is bonded to the ends of F127 to prepare F127-lipoic acid (F127LA) and its nanomicelles. Due to the gradual viscosity change instead of mutation during phase transition, the mixed Ce3+/TA/UTI NPs and F127LA nanomicelles show well-performed injectability at 37 °C and can form a semisolid composite nanohydrogel that can tightly attach to the skin at 37 °C. Furthermore, ultraviolet (UV) irradiation without a photoinitiator transforms the semisolid hydrogel into a solid hydrogel with well-performed elasticity and toughness. The UV-cured composite nanohydrogel acts as a bioadhesive that can firmly adhere to tissues. Due to the limited swelling property, the hydrogel can firmly adhere to tissues in a wet environment, which can seal wounds and provide a reliable physical barrier for the wounds. Ce3+/TA/UTI NPs in the hydrogel exhibit lipopolysaccharide (LPS)-scavenging ability and reactive oxygen species (ROS)-scavenging ability and significantly reduce the expression of inflammatory factors in wounds at the early stage, accelerating LPS-induced wound healing.

Preoperative quality of life at time of gynecologic surgery: considerations for postoperative management.

BACKGROUND: Patients presenting for gynecologic surgery are a heterogeneous group. Preoperative quality of life may be a useful tool to guide postoperative management. OBJECTIVE: This study aimed to examine the key drivers of preoperative quality of life to improve counseling and postoperative management. STUDY DESIGN: This study analyzed preoperative survey results from 154 participants using the following surveys: National Institutes of Health Toolbox Global Health v1.2, Gastrointestinal: Gas and Bloating v1.1 13a, Gastrointestinal: Diarrhea v1.0 6a, and Sexual Function and Satisfaction Brief Profile (Female) v2.0, Perceived Stress Scale, the Vaginal Assessment Scale, and the Vulvar Assessment Scale. Survey results in the form of T-scores were compared in patients with endometrial cancer and patients with benign gynecologic conditions using the Kruskal-Wallis test. The multivariate analysis was performed using linear regression to adjust the comparisons for age, body mass index, and comorbidity. RESULTS: Of the 154 patients, preoperative diagnosis was benign in 66% (n=102) and endometrial cancer in 34% (n=52). Patients with endometrial cancer were more likely to be older, non-White, in lower income brackets, have higher body mass index, and be postmenopausal (P<.05). Although preoperative global health scores were similar between benign and malignant cases (P>.05), when adjusted for age, the differences in global health quality of life between patients with benign gynecologic conditions and those with endometrial cancer became significant, because the endometrial cancer group was older than the benign group (P<.05). However, when adjusting for age, body mass index, and comorbidities (hypertension and diabetes), the differences were no longer significant (P>.05). Sexual interest was decreased in the patients with endometrial cancer both in the unadjusted and adjusted model; and vulvar complaints became significantly different between the groups when controlling for body mass index, age, and comorbidities (P<.05). CONCLUSION: Despite substantial differences in preoperative diagnosis, preoperative quality of life is highly influenced by age, body mass index, and comorbidities. Therefore, these factors should be explored in surgical outcomes and postoperative management trials.

Interfacial reactivity-modulated fluorescent metal-organic frameworks for sensitive detection of interferon-γ towards tuberculosis diagnosis.

A new aptamer-based method has been developed for interferon-γ (IFN-γ) detection by utilizing interface reactivity-modulated fluorescent metal-organic frameworks (MOFs). Specifically, the binding of IFN-γ to its aptamer decreases the interface reactivity between the biotin-labeled aptamer and the streptavidin-functionalized magnetic beads by generating significant steric effects. As a result, several biotin-labeled aptamers escape from the enrichment of magnetic beads and remain in the supernatant, which subsequently undergo the terminal deoxynucleotidyl transferase-catalyzed polymerization elongation. Along with the elongation, pyrophosphate is continuously produced as the by-product, triggering the decomposition of fluorescent MOFs to generate a remarkable fluorescent response with the excitation/emission wavelength of 610 nm/685 nm. Experimental results show that the method enables the detection of IFN-γ in the range 0.06 fM to 6 pM with a detection limit of 0.057 fM. The method also displays high specificity and repeatability with an average relative standard deviation of 2.04%. Moreover, the method demonstrates satisfactory recoveries from 96.3 to 105.5% in serum samples and excellent utility in clinical blood samples. Therefore, this work may provide a valuable tool for IFN-γ detection and is expected to be of high potential in tuberculosis diagnosis in the future.

ErbB4 affects Th1/Th17 cell differentiation and promotes psoriasis progression.

Psoriasis seriously harms people's physical and mental health. More and more people pay attention to improving the psoriasis process by immune cells. Our study alters the course of psoriasis by discovering the effect of ErbB4 on the ratio of Th1/Th17 cells. We detected the expression of ErbB4 in CD4-positive T cells in peripheral blood of clinical patients and clinical samples by qPCR and detected the expression of ErbB4 in mouse samples of the model group. ErbB4 siRNA was designed and transfected into cells. The effect of ErbB4 siRNA on Th1/Th17 cell ratio was observed by flow cytometry. ErbB4 siRNA was transfected into mice by lentivirus infection to observe its effect on psoriasis. Finally, the mechanism of ErbB4 affecting psoriasis was observed by Western Blot. According to the results, ErbB4 is highly expressed in clinical samples of psoriasis and CD4-positive T cells of patients with psoriasis. Inhibition of ErbB4 expression can reduce the proportion of Th1/Th17 cells, improve the pathogenesis of psoriasis and have therapeutic effect on psoriasis. Western Blot results showed that ErbB4 affected psoriasis through the IL23/IL17A signal axis. Our study demonstrates that ErbB4 could be a potential immune target for the treatment of psoriasis.

ODAD1 variants resulting from splice-site mutations retain partial function and cause primary ciliary dyskinesia with outer dynein arm defects.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defects in motile ciliary function and/or structure. Outer dynein arm docking complex subunit 1 (ODAD1) is an important component of the outer dynein arm docking complex (ODA-DC). To date, 13 likely pathogenic mutations of ODAD1 have been reported. However, the pathogenesis of ODAD1 mutations remains elusive. To investigate the pathogenesis of splice-site mutations in ODAD1 discovered in this study and those reported previously, molecular and functional analyses were performed. Whole-exome sequencing revealed a compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) in a patient with PCD, with c.598-2A>C being a novel mutation that resulted in two mutant transcripts. The compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) led to aberrant splicing that resulted in the absence of the wild-type ODAD1 and defects of the outer dynein arm in ciliary axonemes, causing a decrease in ciliary beat frequency. Furthermore, we demonstrated that the truncated proteins resulting from splice-site mutations in ODAD1 could retain partial function and inhibit the interaction between wild-type ODAD1 and ODAD3. The results of this study expand the mutational and clinical spectrum of PCD, provide more evidence for genetic counseling, and offer new insights into gene-based therapeutic strategies for PCD.

The diagnosis interval influences risk factors of mortality in patients with co-existent active tuberculosis and lung cancer: a retrospective study.

BACKGROUND: Previous studies reported that tuberculosis (TB) is associated with an increased risk of lung cancer or the survival and mortality of lung cancer. However, the impact of coexisting TB on the survival of lung cancer patients was controversial. We aimed to identify risk factors on the survival rate of patients with co-existent active TB and lung cancer. METHODS: One hundred seventy-three patients diagnosed with active TB and lung cancer from January 2016 to August 2021 in Shanghai pulmonary hospital were selected and divided into two groups (≤ 6 months, > 6 months) according to the diagnosis interval between active TB and lung cancer (the order of diagnosis is not considered). The clinical characteristics and survival were analyzed. Univariate and multivariate logistic regression analyses were used to identify the risk factors for overall survival (OS). RESULTS: One hundred seventy-three patients were diagnosed with lung cancer and active TB. The study population exhibited a median age of 64 years, with a majority of 81.5% being male, 58.0% of patients had a history of smoking. Among those involved, 93.6% had pulmonary TB, 91.9% were diagnosed with non-small cell lung cancer (NSCLC), 76.9% were Eastern Cooperative Oncology Group (ECOG) 0-2 and 12.7% were ECOG 3-4. We observed better survival in the > 6 months group compared with the ≤ 6 months group (hazard ratio [HR] 0.456, 95% confidence interval [CI]:0.234-0.889, P = 0.017). The 1-, 3-, and 5- year OS rates were 94.2%, 80.3%, and 77.6%, respectively, in the > 6 months group and 88.3%, 63.8%, and 58.5%, respectively, in the ≤ 6 months group. Surgery (HR 0.193, [95% CI, 0.038-0.097]; P = 0.046) and ECOG Performance Status (HR 12.866, [95% CI, 2.730-60.638]; P = 0.001) were independent prognostic factors in the > 6 months group. CONCLUSIONS: Patients diagnosed with lung cancer and active TB for more than half a year have a significantly better prognosis than those diagnosed within half a year. ECOG Performance Status and surgery might possibly affect the outcomes of patients with co-existent active TB and lung cancer.