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关键词： Tumors  

摘要： Purpose Nectin-4 is highly expressed in pancreatic cancer. Accurate and quantitative measurements of Nectin-4 is useful for tumor diagnosis, treatment selection, and prognostic assessment. This study aimed to evaluate the diagnostic efficacy of a Nectin-4-targeted radioligand [Ga-68]Ga-FZNR-1 for pancreatic ductal adenocarcinoma. Methods Thirty-three patients with PDAC were recruited and underwent head-to-head [Ga-68]Ga-FZNR-1 and [F-18]-FDG PET/CT for initial staging or to detect recurrence and metastases. PET/CT findings were confirmed by histopathology or follow-up imaging. Thirteen primary and metastatic lesions from the 33 patients were evaluated for Nectin-4 immunohistochemical expression. Results [F-18]-FDG and [Ga-68]Ga-FZNR-1 PET/CT were comparable in detecting primary tumors, lymph node metastases, and distant metastases (96.00% [24/25] vs. 92.00% [23/25], 88.24% [15/17] vs. 82.35% [14/17], 95.24% [20/21] vs. 95.24% [20/21]). [Ga-68]Ga-FZNR-1 PET/CT demonstrated slightly higher specificity and accuracy than [F-18]-FDG PET/CT for distant metastases (100.00% vs. 93.75%, 100.00% vs. 96.97%). The receiver operating characteristic (ROC) curve revealed that [Ga-68]Ga-FZNR-1 had high sensitivity and specificity in detecting Nectin-4-expressing lesions. Both SUVmax and TBR on [Ga-68]Ga-FZNR-1 PET/CT were significantly and positively correlated with the expression of Nectin-4 (both r = 0.89, both p < 0.001). Conclusion [Ga-68]Ga-FZNR-1 is excellent in diagnosing primary, metastatic, and recurrent lesions of PDAC. In particular, it may be a useful complement in patients with distant metastases that cannot be detected by [F-18]-FDG PET/CT. [Ga-68]Ga-FZNR-1 PET/CT could quantify the Nectin-4 expression. Moreover, [Ga-68]Ga-FZNR-1 PET/CT may have potential predictive value in the prognostic assessment of patients with PDAC.

关键词： delta-like 1 homolog (DLK1)   Notch1   STAT3   stemness   ovarian cancer   CD44   CD133   drug resistance  

摘要： Ovarian cancer is a heterogeneous gynecologic malignancy, with most cases diagnosed at an advanced stage. Despite the availability of effective treatments such as surgery and platinum/taxane-based chemotherapy, advanced ovarian cancer frequently recurs, highlighting the need to investigate mechanisms of chemotherapy resistance. Delta-like non-canonical Notch ligand 1 (DLK1), a transmembrane protein of the EGF-like family, is aberrantly expressed in several cancers. Our previous study demonstrated that DLK1 promotes oncogenic behaviors and epithelial-mesenchymal transition in ovarian high-grade serous carcinoma. In this study, we observed a positive correlation between DLK1 and stemness markers CD44 and CD133 in human epithelial ovarian cancer using tissue microarray analysis. Overexpression of DLK1 by an adenovirus vector accelerated sphere-forming capability and upregulated CD44, CD133, and ABCG2 expression in human ovarian cancer cell lines. Conversely, DLK1 silencing by siRNA abolished the stimulatory effects on the stem cell-like properties and reduced CD44 and CD133 expression in ovarian cancer cells. Furthermore, DLK overexpression by an adenovirus vector enhanced colony formation and suppressed the cisplatin- and taxol-induced death in human ovarian cancer cells. Conversely, DLK1 siRNA reversed cell death and colony formation induced by these chemotherapeutic agents. Finally, we demonstrated that DLK1 regulates CD44, CD133, and ABCG2 expression through the Notch1/AKT/STAT3 signaling pathway, involving the phosphorylation and translocation of STAT3. Collectively, these results suggest that targeting DLK1 may represent a potential therapeutic strategy to improve outcomes in recurrent ovarian cancer following chemotherapy.

摘要： Objectives Mutations in the 3 '-polypurine tract (3 ' PPT) of HIV-1 have been observed under pressure with two integrase strand transfer inhibitors, dolutegravir and cabotegravir. In the DOMONO randomized clinical trial, 3 ' PPT mutations emerged in a participant who experienced treatment failure under dolutegravir monotherapy. To understand the basis for this rare mutational pathway, we examined baseline viral sequences and identified the K156N natural polymorphism. Given the role of K156 in viral DNA binding, the potential relationship between K156N and 3 ' PPT mutations was further *** We assessed the impact of K156N on integrase using in silico modelling and biochemical assays with recombinant proteins. Infectivity, replicative capacity, and drug susceptibility of viruses carrying K156N, 3 ' PPT mutations, or both were measured. Viral evolution was assessed in cell *** Structural models indicated that K156N altered viral DNA binding. K156N reduced strand transfer activity through decreased affinity for the LTR but increased 3 '-processing. The K156N virus had normal infectivity, whereas the 3 ' PPT mutations decreased infectiousness sixfold and lowered maximal infectivity. K156N partially compensated for this defect, but maximal infectivity remained diminished. K156N also partially compensated for defects in replicative capacity imposed by 3 ' PPT mutations. K156N alone did not confer resistance against dolutegravir, nor did it increase the modest (2.5-fold) resistance conferred by the 3 ' PPT mutations. K156N alone promoted the spontaneous emergence of 3 ' PPT mutations distinct from those seen in *** These findings establish a direct functional relationship between natural variation in HIV-1 integrase and the emergence of 3 ' PPT mutations. People harbouring a virus with the K156N natural polymorphism may be predisposed to developing 3 ' PPT mutations upon failure with DTG. However, the clinical relevance of this ass

摘要： Purpose: Narrowband (NB) chirps have recently been of great interest in audiology for the electrophysiological assessment of hearing in infants, but clinicians have little information about these new stimuli and how they compare to more standard stimuli, such as 2-1-2-cycle tones. The current study examined the frequency specificity of NB chirps by comparing the spectral characteristics of 500-, 1000-, 2000-, and 4000-Hz NB CE-Chirp LS ("level-specific" version) stimuli with those of the 2-1-2 tones. Method: Spectral characteristics, including center frequency (CF), bandwidth, and stimulus energy changes after stopband filtering, were compared. Bandwidth was computed as the difference between the upper and lower frequencies at the -20 and -3 dB cutoff points of the main lobe;CF was determined as the geometric mean of the upper and lower frequencies at the -20 and -3 dB cutoff points. Results: At 100 dB peSPL, the bandwidths of the 500-, 1000-, and 2000-Hz NB CE-Chirp LS acoustic spectra were 1.8-1.9 times wider than those of the acoustic spectra for the 2-1-2 tones;the 4000-Hz NB CE-Chirp LS bandwidths were 1.4-1.5 times wider than those of the 2-1-2 tones. The energy of the NB CE-Chirp LS stimuli was concentrated within +/- 0.75 octave of the CF, compared to +/- 0.5 octave for 2-1-2 tones. These spectral characteristics did not change with stimulus intensity. Conclusions: The NB CE-Chirp LS stimuli demonstrated poorer frequency specificity compared with that of the 2-1-2 tones. NB-chirp thresholds may therefore underestimate true thresholds, especially in steeply sloping hearing loss. Further studies are needed to investigate the cochlear place specificity of auditory brainstem responses to the NB CE-Chirp LS stimuli before recommending them for clinical use.

关键词： Lymphoma associated with immunodeficiency or dysregulation (IDD lymphoma)   JAK inhibitor   Upadacitinib   Mantle cell lymphoma   Psoriasis/psoriatic arthritis  

摘要： Mantle cell lymphoma (MCL) associated with immunodeficiency or dysregulation (IDD) has not been linked to the use of JAK inhibitors (JAKi). While the development of lymphoma in patients receiving JAKi for rheumatoid arthritis and psoriatic arthritis (PsA) has been reported, no MCL patients have been reported. A 73-year-old man receiving methotrexate (MTX) for at least a 17-year history of PsA developed cervical lymphadenopathy. Biopsy revealed MCL, and lymphadenopathy resolved following cessation of MTX. Upadacitinib (UPA), a JAK-1 inhibitor, was initiated as an alternative treatment for PsA. While it was very effective, it also led to recurrent lymphadenopathy. Upon discontinuation of UPA, lymphadenopathy regressed. This pattern occurred a third time, ultimately leading to significant exacerbation. A second biopsy revealed histology associated with the pleomorphic variant of MCL. In situ hybridization for Epstein-Barr virus-encoded small RNA and immunohistochemistry for human herpesvirus 8 were negative. A FISH analysis detected the IGH::CCND1 fusion, confirming the diagnosis. The clinical staging was Ann Arbor stage II, and the MCL International Prognostic Index indicated intermediate risk. Partial response was achieved with radiotherapy. Although JAKi and MCL are uncommon in the established IDD setting, their potential relationship warrants consideration.

关键词： FT-IR   NMR   TOF-MS   BGG protein   VMH reaction   DFT  

摘要： A novel compound, 2-(1-methyl-3-(o-tolyl)ureido)-N-(o-tolyl)acetamide (compound 4), was successfully synthesized and comprehensively characterized using FT-IR, H-1-NMR, C-13-NMR, 2D-NMR, HRMS, and UV-Vis spectroscopy, confirming its structural integrity. DFT calculations performed at the B3LYP level of theory further elucidated its electronic configuration, revealing a HOMO-LUMO energy gap of 4.47 eV, indicative of high kinetic stability and low chemical reactivity. Molecular electrostatic potential (MESP) mapping identified the C = O group as the primary electrophilic site, while C-H regions exhibited nucleophilic tendencies, highlighting potential interaction hotspots. Fukui function analysis pinpointed the most reactive atomic centers, with N26 (0.096) as the preferred nucleophilic site, C8 (1.611) as the primary electrophilic center, and C8 (0.801) as the most susceptible position for radical attack. Additionally, protein-ligand interaction studies with bovine gamma globulin (BGG) demonstrated a favorable and spontaneous binding event, supported by a calculated Gibbs free energy (Delta G) of -32.69 kJ mol(-1). These findings collectively provide critical insights into the compound's structural stability, reactive potential, and biomolecular affinity.

关键词： allergic asthma   cell adhesion   Dermatophagoides microceras   house dust mite   protease  

摘要： House dust mites (HDMs) allergens are major contributors to allergic asthma, with their protease activity playing a critical role in airway inflammation. Der m 1, a Group 1 HDMs allergen from Dermatophagoides microceras, is a cysteine protease known for its ability to degrade host proteins. In this study, we identified novel fibrinogen cleavage sites targeted by Der m 1, which are distinct from those cleaved by thrombin or plasmin. By employing biochemical and bioinformatic approaches, we identified the fibrinogen alpha C domain as a key component of Der m 1-derived fibrinogen cleavage products (FCPs). To assess their functional effects, we treated human bronchial epithelial cells with Der m 1-derived FCPs and the fibrinogen alpha C domain. Both treatments significantly enhanced cell adhesion, with effects peaking at 2-4 h post-treatment before gradually declining. Transcriptomic analysis, including RNA sequencing and gene set enrichment analysis (GSEA), revealed that both Der m 1-derived FCPs and the alpha C domain induced similar transcriptional responses, particularly in adhesion-related pathways involving integrin signaling. Functional validation using Cilengitide, a cyclic RGD peptide that antagonizes alpha V beta 3 and alpha V beta 5 integrins, confirmed that the pro-adhesive effects were integrin alpha V-dependent. These findings reveal that Der m 1 not only cleaves fibrinogen but also produces bioactive fragments that influence epithelial adhesion and signaling, offering new insight into airway remodeling in allergic asthma.

关键词： Metabolic acidosis   Drug treatment   Respiratory acidosis  

摘要： Virtually every protein in our bodies binds protons, resulting in a specific electrical charge. If the surrounding proton concentration changes, such as in acidosis or alkalosis, the charge of the protein can change, as well, which in turn can affect protein folding and thus function. Therefore, disturbances of acid-base homeostasis can have serious clinical consequences, and for this reason, the blood pH is usually strictly controlled with the kidneys playing a major part in the long-term maintenance of acid-base homeostasis. Here we review alterations in blood pH that can occur as a side effect of medical treatments, with this first part discussing those resulting in *** abstractA higher resolution version of the Graphical abstract is available as Supplementary information