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ObjectiveTo assess the efficacy and safety of linear accelerator-based fractionated stereotactic radiotherapy (LINAC-FSRT) in patients with brain metastases (BM).MethodsWe retrospectively analyzed 214 patients treated with LINAC-FSRT, categorized based on biologically effective dose (BED10, α/β = 10) into two groups (≤55 Gy, >55 Gy). Stratified analyses were conducted based on targeted therapy to compare survival outcomes. To examine brain tissue dose-tolerance volume, patients were divided into two groups: the standard Hypofractionated Treatment Effects in the Clinic (HyTEC) protocol group and an adjusted HyTEC protocol group where dose-volume restrictions exclude the planning target volume (PTV).ResultsResults as of December 2023 showed median intracranial progression-free survival (iPFS) at 12.4 months, with median overall survival (OS) not reached and a one-year local control (LC) rate of 68.7%. Mild to moderate toxicity affected 17.3% of patients, while severe toxicity occurred in 2.8%. Multivariate Cox analysis indicated that uncontrolled extracranial disease significantly reduced iPFS (HR = 2.692, 95%CI:1.880–3.853, P < 0.001) and OS (HR = 3.063, 95%CI:1.987–4.722, P < 0.001). BED10 >55 Gy (HR = 0.656, 95%CI:0.431–0.998, P = 0.049) improved OS, showing statistical significance (P = 0.037) without affecting iPFS or CNS toxicity (P = 0.127, P = 0.091). Stratified analysis highlighted nearly significant OS improvements with high-dose FSRT and targeted therapy (P = 0.054), while concurrent therapy markedly enhanced iPFS (P = 0.027). No significant differences were observed in intracranial local failure (ILF—which represents progression in previously treated areas during follow-up), one-year LC rates, iPFS, or OS between dose-volume groups. Adjusting HyTEC volume restrictions did not significantly increase CNS adverse reactions (P = 0.889).ConclusionsLINAC-FSRT is safe and effective in BM. BED10>55 Gy notably enhances OS post-LINAC-FSRT and may benefit LC. High BED10 FSRT with targeted therapy likely boosts synergy, and concurrent targeted therapy significantly improves iPFS. Diminishing dose volume constraints at different fractions based on the HyTEC guidelines is feasible.

IntroductionThis study aimed to assess the diagnostic values of bronchoalveolar lavage fluid (BALF) real-time polymerase chain reaction (PCR) and BALF metagenomic next-generation sequencing (mNGS) for Pneumocystis jirovecii pneumonia (PJP) in patients infected with human immunodeficiency virus (HIV).MethodsA total of 99 HIV-infected PJP patients and 61 HIV-infected patients diagnosed with non-PJP pneumonia between March 2019 and December 2022 were enrolled. P. jirovecii and multiple other co-pathogens detected in BALF by mNGS were analyzed. The clinical final diagnosis was employed as a benchmark. We compared the diagnostic performance of mNGS in PJP with serum BDG and BALF real-time PCR. The mixed infections detected by mNGS and modifications of antimicrobial treatment were also analyzed.ResultsThe sensitivity of mNGS test of BALF samples reached 85.86%, which was significantly higher than serum BDG (39.39%, P < 0.001). The sensitivity of BALF P. jirovecii PCR (84.85%) was similar with mNGS (P > 0.05). The specificity of mNGS (100%) was also same as PCR (100.0%), and superior to serum BDG (88.52%, P < 0.001). Besides, mNGS performs remarkably well in identifying co-pathogens of PJP patients infected with HIV. In addition to P. jirovecii, 82 cases (82.83%) of other co-pathogens were identified based on mNGS. Moreover, thirty-four patients (34.34%) increased therapeutic dose of trimethoprim-sulfamethoxazole (TMP-SMZ) based on BALF P. jirovecii PCR. Based on the mNGS results, initial antimicrobial treatment was modified in 86.87% (86/99) of PJP patients.ConclusionBALF mNGS and real-time PCR are two powerful techniques for rapid diagnosis of PJP with high specificity and sensitivity. Moreover, the benefit of mNGS is that it may identify other organisms besides PJP and it may benefit proper and prompt treatment.

BackgroundAcanthamoeba castellanii infection is a rare condition primarily occurring in immunocompromised patients with extremely high mortality. Currently, there is no standard treatment for this condition, and successful treatment reports are scarce.Case presentationWe present a case of Acanthamoeba castellanii infection in a 63-year-old female patient with AIDS, who was admitted to our hospital with symptoms of fever, skin ulcers, subcutaneous nodules, and food regurgitation from the nose while eating. After initial empirical treatment failed, a biopsy of the subcutaneous nodule was performed, and metagenomic next-generation sequencing (mNGS) technology was used to detect pathogenic microorganisms in both the biopsy specimen and blood samples. The results revealed Acanthamoeba castellanii infection. Additionally, histopathological examination of the biopsy specimen and cytological examination of the secretions from the ulcer surface also confirmed this pathogenic infection. The patient’s symptoms significantly improved upon discharge after adjusting the treatment regimen to a combination of anti-amebic therapy.ConclusionImmunocompromised patients presenting with unexplained fever and skin or sinus lesions should be evaluated for Acanthamoeba castellanii infection. Multi-drug combination therapy is required for this organism infection, and a standard treatment protocol still needs further research. Metagenomic next-generation sequencing is a valuable tool for early diagnosis of unknown pathogen infections.

Purpose-Immunotherapy has revolutionized cancer therapy, becoming the standard of care for various malignancy treatments. Human immunodeficiency virus (HIV) patients, however, are an underserved group with limited access to clinical trials and cancer therapy. This study was to evaluate the safety and efficacy of programmed cell death 1 (PD - 1) inhibitors in patients with advanced cancer and HIV/acquired immunodeficiency syndrome (AIDS). Methods and Materials-We performed a prospective, open-label, nonrandomized, phase 1 single center study. Patients with advanced cancer and HIV/AIDS received the treatment of PD - 1 inhibitors (camrelizumab, 200 mg, administered intravenously every 3 weeks), along with combination antiretroviral therapy (cART) for HIV. Results-Sixteen participants (12 men and 4 women; median age, 46.5 (29 - 78) years) were enrolled; 1 had non - Hodgkin lymphoma (NHL), and 15 had non - AIDS - defining cancers. Safety was observed over 130 cycles of treatment with camrelizumab. Most treatment-emergent adverse events at least possibly attributed to camrelizumab were grade 1 or 2, including reactive cutaneous capillary endothelial proliferation (RCCEP) (9 participants), hearing loss (1 participant), hypophysitis (1 participant). 3 participants experienced hemorrhage due to poor performance status. HIV was controlled in all participants. Best tumor responses included 3 complete response, 5 partial response, 2 stable disease, and 6 progressive disease. The 2 years progression-free survival (PFS) was 67.0% (95% CI: -0.05, 0.00) and overall survival (OS) was 55.3% (95% CI: -0.05, 0.01) for the 16 patients who had received camrelizumab. Conclusions-This study demonstrates that camrelizumab treatment in patients with advanced cancers and HIV/AIDS was feasible and the clinical outcomes were acceptable.

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is an emerging zoonosis caused by a novel bunyavirus. Until recently, the SFTS related acute kidney injury (AKI) was largely unexplored. This study aimed to investigate the clinical characteristics and outcomes of AKI in patients with SFTS.MethodsThe non-AKI and AKI groups were compared in terms of general characteristics, clinical features, laboratory parameters and cumulative survival rate. The independent risk factors for in-hospital mortality in patients with SFTS were analyzed by multivariate logistic regression to identify the population with poor prognosis.ResultsA total of 208 consecutive patients diagnosed with SFTS were enrolled, including 153 (73.6%) patients in the non-AKI group and 55 (26.4%) patients in the AKI group. Compared with patients without AKI, patients with AKI were older and had a higher frequency of diabetes. Among these laboratory parameters, platelet count, albumin and fibrinogen levels of patients with AKI were identified to be significantly lower than those of patients without AKI, while ALT, AST, ALP, triglyceride, LDH, BUN, uric acid, creatine, Cys-C, β2-MG, potassium, AMY, lipase, CK-MB, TnI, BNP, APTT, thrombin time, D-dimer, CRP, IL-6, PCT and ESR levels were significantly higher in patients with AKI. A higher SFTS viral load was also detected in the AKI patients than in the non-AKI patients. The cumulative survival rates of patients at AKI stage 2 or 3 were significantly lower than those of patients without AKI or at AKI stage 1. However, there was no significant difference in the cumulative survival rates between patients without AKI and those with stage 1 AKI. Univariate and multivariate binary logistic regression analyses demonstrated that stage 2 or 3 AKI was an independent risk factor for in-hospital mortality in patients with SFTS.ConclusionAKI is associated with poor outcomes in patients with SFTS, especially patients at AKI stage 2 or 3, who generally have high mortality. Our findings support the importance of early identification and timely treatment of AKI in patients with SFTS.

IntroductionThis article aimed to compare the prevalence of dyslipidemia and determine risk factors associated with lipid levels in a cohort of HIV-infected patients receiving two different antiretroviral therapy (ART) regimens, nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor (NRTI/NNRTI) and nucleoside reverse transcriptase inhibitor/integrase strand transfer inhibitor (NRTI/INSTI).MethodsThis longitudinal study analyzed 633 HIV-infected patients with complete blood lipid profile records for at least 1 year at the ART clinic of Zhongnan Hospital of Wuhan University, China, from June 2018 to March 2021. Demographic and clinical data, including age, gender, body weight, height, current/former/non-smoker, current drinker, diabetes mellitus, hypertension, were extracted from electronic medical records. Laboratory tests included hematology, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Lipoprotein(a) and CD4 cell count. The observation duration of this study was a maximum of 33 months. Data comparisons were performed using the Chi-square test, Student’s t-test and Mann–Whitney U test. Generalized linear mixed-effects model (GLMM) and value of p

Numerous studies have demonstrated that soybean meal (SBM) contains high levels of anti-nutritional factors, which interrupt gastrointestinal homeostasis or metabolism normally of the weaned piglets. Here, the mixed probiotics, including Bacillus licheniformis (B. licheniformis, CGMCC 8147), Saccharomyces cerevisiae H11 (S. cerevisiae H11) and Lactobacillus casei (L. casei, CGMCC 8149) were applied to the three-stage fermentation of functional feed. Our research investigated the optimum ratio of inoculation, optimal time of inoculation, combination of substrates, and nutritional value of the fermented feed. The optimal microbial combination was B. licheniformis: S. cerevisiae: L. casei = 2:2:1, inoculating at 0, 12 and 24 h, respectively. The results revealed that crude protein and acid-soluble protein were remarkably improved and had lower pH. Trypsin inhibitor, glycinin and β-conglycinin were reduced by 79.86, 77.18, and 69.29%, respectively. Moreover, animal trials further evaluated the growth-promoting effects of the fermented feed. It was noted that the average daily gain of weaned piglets was significantly higher, and the ratio of feed with weight, diarrhea incidence and mortality were lower significantly. The concentrations of serum immunoglobulin G(IgG), IgA, IgM, Complement C3 and interferon-γ (IFN-γ), and lysozyme activity were all increased. The relative abundance of fecal microbiota improved, especially lactobacillus, which increased the abundance of fecal dominant probiotics. Overall, the fermented feed may be conducive to the growth and health of weaned piglets by improving nutritional value, immunity properties, relative abundance of fecal microflora, and decreasing anti-nutritional factors of feed, thereby making them viable and usable feedstuffs for potential use in livestock industries.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, driven by the BCR-ABL1 fusion oncoprotein. The discovery of orthosteric BCR-ABL1 tyrosine kinase inhibitors (TKIs) targeting its active ATP-binding pocket, such as first-generation Imatinib and second-generation Nilotinib (NIL), has profoundly revolutionized the therapeutic landscape of CML. However, currently targeted therapeutics still face considerable challenges with the inevitable emergence of drug-resistant mutations within BCR-ABL1. One of the most common resistant mutations in BCR-ABL1 is the T315I gatekeeper mutation, which confers resistance to most current TKIs in use. To resolve such conundrum, co-administration of orthosteric TKIs and allosteric drugs offers a novel paradigm to tackle drug resistance. Remarkably, previous studies have confirmed that the dual targeting BCR-ABL1 utilizing orthosteric TKI NIL and allosteric inhibitor ABL001 resulted in eradication of the CML xenograft tumors, exhibiting promising therapeutic potential. Previous studies have demonstrated the cooperated mechanism of two drugs. However, the conformational landscapes of synergistic effects remain unclear, hampering future efforts in optimizations and improvements. Hence, extensive large-scale molecular dynamics (MD) simulations of wide type (WT), WT-NIL, T315I, T315I-NIL, T315I-ABL001 and T315I-ABL001-NIL systems were carried out in an attempt to address such question. Simulation data revealed that the dynamic landscape of NIL-bound BCR-ABL1 was significantly reshaped upon ABL001 binding, as it shifted from an active conformation towards an inactive conformation. The community network of allosteric signaling was analyzed to elucidate the atomistic overview of allosteric regulation within BCR-ABL1. Moreover, binding free energy analysis unveiled that the affinity of NIL to BCR-ABL1 increased by the induction of ABL001, which led to its favorable binding and the release of drug resistance. The findings uncovered the in-depth structural mechanisms underpinning dual-targeting towards T315I BCR-ABL1 to overcome its drug resistance and will offer guidance for the rational design of next generations of BCR-ABL1 modulators and future combinatory therapeutic regimens.

PurposeLong non-coding RNAs (lncRNAs) play an important role in the occurrence and development of bladder cancer, but the underlying molecular mechanisms remain largely unknown. In this study, we found that LINC00467 was significantly highly expressed in bladder cancer through bioinformatic analysis. The present study aimed to explore the role of LINC00467 in bladder cancer and its possible underlying molecular mechanisms.MethodsThe expression of LINC00467 was obtained from GEO (GSE31189), the TCGA database, and qRT-PCR. The role of LINC00467 in bladder cancer was assessed both in vitro and in vivo. RIP, RNA pulldown, and CO-IP were used to demonstrate the potential mechanism by which LINC00467 regulates the progression of bladder cancer.ResultsThrough the analysis of GEO (GSE133624) and the TCGA database, it was found that LINC00467 was highly expressed in bladder cancer tissues and that the expression of LINC00467 was significantly negatively correlated with patient prognosis. Cell and animal experiments suggest that LINC00467 promotes the proliferation and invasion of bladder cancer cells. On the one hand, LINC00467 can directly bind to NF-kb-p65 mRNA to stabilize its expression. On the other hand, LINC00467 can directly bind to NF-kb-p65 to promote its translocation into the nucleus to activate the NF-κB signaling pathway, which promotes the progression of bladder cancer.ConclusionsLINC00467 is highly expressed in bladder cancer and can promote the progression of bladder cancer by regulating the NF-κB signaling pathway. Therefore, targeting LINC00467 is very likely to provide a new strategy for the treatment of bladder cancer and for improving patient prognosis.

Background: Increasing evidence indicates that long non-coding RNAs (lncRNAs) play crucial roles in cancer tumorigenesis and progression. TMPO antisense RNA 1 (TMPO-AS1) has been found to be involved in several cancers by acting as a competing endogenous RNA. However, the potential roles of TMPO-AS1 in bladder cancer (BC) and the potential interactions with proteins remain poorly understood.Methods: The expression of the lncRNA TMPO-AS1 was evaluated via bioinformatic analysis and further validated by quantitative real-time PCR (qRT-PCR). Loss- and gain-of-function assays were performed to determine the biological functions of TMPO-AS1 in BC cell proliferation, migration, and invasion. Moreover, chromatin immunoprecipitation, Western blotting, and fluorescence in situ hybridization, as well as RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays, were conducted to explore the upstream and downstream molecules interacting with TMPO-AS1.Results: TMPO-AS1 is upregulated in BC. Functional experiments demonstrated that TMPO-AS1 promotes cell proliferation, migration, and invasion in BC and inhibits cell apoptosis in vivo and in vitro. Mechanically, E2F1 is responsible for TMPO-AS1 upregulation. Additionally, TMPO-AS1 facilitates the interaction of E2F1 with OTU domain-containing ubiquitin aldehyde binding 1 (OTUB1), leading to E2F1 deubiquitination and stabilization; therefore, TMPO-AS1 promotes BC malignant phenotypes. Furthermore, rescue experiments showed that TMPO-AS1 promotes BC growth in an E2F1-dependent manner.Conclusions: Our study is the first to uncover the novel TMPO-AS1/E2F1 positive regulatory loop important for the promotion of BC malignant behaviors. The TMPO-AS1/E2F1 loop should be considered in the quest for new BC therapeutic options.

BackgroundAt present, the relationship between thyrotropin (TSH) and free thyroxine (FT4) in relation to postmenstrual age (PMA) in preterm infants is still unclear, and there is no reliable standard thyroid hormone reference ranges, resulting in different diagnostic criteria for congenital hypothyroidism been used by different newborn screening programs and different countries.ObjectivesTo investigate the relationship between TSH/FT4 and PMA in very preterm infants (VPIs) born with gestational age (GA)

Ubiquitin ligases have been shown to regulate drug sensitivity. This study aimed to explore the role of the ubiquitin ligase WD repeat and HMG-box DNA binding protein 1 (WDHD1) in regulating cisplatin sensitivity in lung adenocarcinoma (LUAD). A quantitative analysis of the global proteome identified differential protein expression between LUAD A549 cells and the cisplatin-resistant strain A549/DDP. Public databases revealed the relationship between ubiquitin ligase expression and the prognosis of patients with LUAD. Quantitative real-time polymerase chain reaction and Western blotting were used to estimate the WDHD1 expression levels. Analysis of public databases predicted the substrate of WDHD1. Western blotting detected the effect of WDHD1 on microtubule-associated protein RP/EB family member 2 (MAPRE2) and DSTN. Functional analysis of MAPRE2 verified the interaction between WDHD1 and MAPRE2, as well as the interacting sites by methyl-thiazolyl-tetrazolium assay and flow cytometry, immunoprecipitation, protein stability, and immunofluorescence. Cell and animal experiments confirmed the effect of WDHD1 and MAPRE2 on cisplatin sensitivity in LUAD. Clinical data evaluated the impact of WDHD1 expression level on cisplatin sensitivity. Quantitative analysis of the global proteome revealed ubiquitin-dependent protein catabolism to be more active in A549/DDP cells than in A549 cells. WDHD1 expression was higher in A549/DDP cells than in A549 cells, and knocking out WDHD1 increased the sensitivity of A549/DDP cells to cisplatin. WDHD1 overexpression negatively correlated with the overall survival of LUAD patients. We observed that MAPRE2 was upregulated when WDHD1 was knocked out. A MAPRE2 knockout in A549 cells resulted in increased cell viability while decreasing apoptosis when the A549 cells exposed to cisplatin. WDHD1 and MAPRE2 were found to interact in the nucleus, and WDHD1 promoted the ubiquitination of MAPRE2. Following cisplatin exposure, the WDHD1 and MAPRE2 knockout groups facilitated cell proliferation and migration, inhibited apoptosis in A549/DDP cells, decreased apoptosis, and increased tumor size and growth rate in animal experiments. Immunohistochemistry showed that Ki67 levels increased, and levels of apoptotic indicators significantly decreased in the WDHD1 and MAPRE2 knockout groups. Clinical data confirmed that WDHD1 overexpression negatively correlated with cisplatin sensitivity. Thus, the ubiquitin ligase WDHD1 induces cisplatin resistance in LUAD by promoting MAPRE2 ubiquitination.