OBJECTIVE: To investigate the efficacy and safety of combination regimen containing daratumumab in multiple myeloma (MM) patients. METHODS: The clinical data of 14 newly diagnosed MM patients and 58 relapsed refractory MM patients treated with combination regimen containing daratumumab from November 2020 to March 2023 in the First Affiliated Hospital of Nanchang University were retrospectively analyzed. The efficacy and safety of combination regimen were analyzed. RESULTS: The median age of the 72 patients was 62 (38-78) years, including 35 males and 37 females. The overall response rate (ORR) of patients receiving first-line, second-line, and third-line or above treatment was 92.9% (13/14), 68.2% (30/44), and 42.9% (6/14), respectively. The median progression-free survival (PFS) was not reached, 15.4 months, and 9.7 months in three groups, respectively (all P <0.05), while the median overall survival (OS) was all not reached. Among relapsed refractory patients, the ORR of those treated with DVd, DPd and DRd regimen was 50.0% (12/24), 40.0% (4/10) and 100% (10/10), the median PFS was 2.8 months, 10.3 months and not reached, and the median OS was 15.4 months, not reached and not reached, respectively. Furthermore, the PFS and OS in the DRd group were superior to those in the other two groups (all P <0.05). Cox univariate and multivariate analysis showed that lactate dehydrogenase (LDH) ≥250 U/L and extramedullary disease were independent adverse prognostic factors for PFS, and LDH ≥250 U/L was also an independent adverse prognostic factor for OS. Hematologic adverse reactions were mainly lymphopenia (87.5%) and thrombocytopenia (52.8%), while non-hematologic adverse reactions were mainly infusion-related reactions (19.4%) and infections (11.1%). CONCLUSIONS The combination regimens containing daratumumab can be used as first-line treatment for patients with newly diagnosed MM. In patients with relapsed refractory MM, early use of regimens containing daratumumab may improve treatment response rate and prolong PFS. The DRd regimen has better therapeutic response and survival advantages. LDH is an independent prognostic factor affecting PFS and OS in MM patients.
Humans ; Multiple Myeloma/drug therapy* ; Middle Aged ; Aged ; Male ; Female ; Antibodies, Monoclonal/administration & dosage* ; Adult ; Retrospective Studies ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Treatment Outcome

Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

Glutamine provides carbon and nitrogen to support the proliferation of cancer cells. However, the precise reason why cancer cells are particularly dependent on glutamine remains unclear. In this study, we report that glutamine modulates the tumor suppressor F-box and WD repeat domain-containing 7 (FBW7) to promote cancer cell proliferation and survival. Specifically, lysine 604 (K604) in the sixth of the 7 substrate-recruiting WD repeats of FBW7 undergoes glutaminylation (Gln-K604) by glutaminyl tRNA synthetase. Gln-K604 inhibits SCFFBW7-mediated degradation of c-Myc and Mcl-1, enhances glutamine utilization, and stimulates nucleotide and DNA biosynthesis through the activation of c-Myc. Additionally, Gln-K604 promotes resistance to apoptosis by activating Mcl-1. In contrast, SIRT1 deglutaminylates Gln-K604, thereby reversing its effects. Cancer cells lacking Gln-K604 exhibit overexpression of c-Myc and Mcl-1 and display resistance to chemotherapy-induced apoptosis. Silencing both c-MYC and MCL-1 in these cells sensitizes them to chemotherapy. These findings indicate that the glutamine-mediated signal via Gln-K604 is a key driver of cancer progression and suggest potential strategies for targeted cancer therapies based on varying Gln-K604 status.
Glutamine/metabolism* ; Myeloid Cell Leukemia Sequence 1 Protein/genetics* ; Humans ; Proto-Oncogene Proteins c-myc/genetics* ; Cell Proliferation ; Signal Transduction ; Neoplasms/pathology* ; F-Box-WD Repeat-Containing Protein 7/genetics* ; Cell Survival ; Cell Line, Tumor ; Apoptosis

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Objective To observe the effects of Yitangkang on brown fat thermogenesis and mitochondrial biogenesis of PGC1α-NRF1/2-TFAM pathway in db/db mice;To explore its mechanism of regulating glucose and lipid metabolism.Methods Totally 27 six-week-old db/db mice were randomly divided into model group,Yitangkang group(30 g/kg)and liraglutide group(200 μg/kg),another 9 db/m mice of the same age were set as normal group.All groups received intervention with drugs or saline for 6 weeks.The body mass and FBG were measured weekly.After intervention,oral glucose tolerance test(OGTT)was carried out,the contents of serum TC,TG,LDL-C and HDL-C were detected by biochemical analyzer,HE staining was used to observe the morphology of brown adipose tissue(BAT)in scapular region,RT-qPCR and Western blot were used to detect the expressions of UCP1,PRDM16,PGC1α related to BAT thermogenesis and NRF1,Nrf2,TFAM related to mitochondrial biogenesis.Results Compared with the normal group,the body mass,FBG,area under the curve of OGTT and serum TG,TC,LDL-C content of model group significantly increased(P<0.01),the content of HDL-C significantly decreased(P<0.01);the diameter of BAT cells in scapular region was larger,white vacuoles appeared,lipid droplets increased,and the mRNA and protein expressions of UCP1,PRDM16,PGC-1α,NRF1,NRF2 and TFAM in BAT decreased significantly(P<0.01).Compared with the model group,the body mass,FBG,area under the curve of OGTT and serum TG,TC,LDL-C contents of Yitangkang group and liraglutide group significantly decreased(P<0.01),the content of HDL-C increased(P<0.01);BAT cells were smaller in diameter,more closely arranged,more regular in shape,and more abundant in capillary,the mRNA and protein expressions of UCP1,PRDM16,PGC-1α,NRF1,NRF2 and TFAM in BAT increased significantly(P<0.01).Conclusion Yitangkang can regulate mitochondrial biogenesis through PGC1α-NRF1/2-TFAM pathway to activate brown fat in db/db mice and improve glucose and lipid metabolism in db/db mice.

Objective To observe the effects of Yitangkang on brown fat thermogenesis and mitochondrial biogenesis of PGC1α-NRF1/2-TFAM pathway in db/db mice;To explore its mechanism of regulating glucose and lipid metabolism.Methods Totally 27 six-week-old db/db mice were randomly divided into model group,Yitangkang group(30 g/kg)and liraglutide group(200 μg/kg),another 9 db/m mice of the same age were set as normal group.All groups received intervention with drugs or saline for 6 weeks.The body mass and FBG were measured weekly.After intervention,oral glucose tolerance test(OGTT)was carried out,the contents of serum TC,TG,LDL-C and HDL-C were detected by biochemical analyzer,HE staining was used to observe the morphology of brown adipose tissue(BAT)in scapular region,RT-qPCR and Western blot were used to detect the expressions of UCP1,PRDM16,PGC1α related to BAT thermogenesis and NRF1,Nrf2,TFAM related to mitochondrial biogenesis.Results Compared with the normal group,the body mass,FBG,area under the curve of OGTT and serum TG,TC,LDL-C content of model group significantly increased(P<0.01),the content of HDL-C significantly decreased(P<0.01);the diameter of BAT cells in scapular region was larger,white vacuoles appeared,lipid droplets increased,and the mRNA and protein expressions of UCP1,PRDM16,PGC-1α,NRF1,NRF2 and TFAM in BAT decreased significantly(P<0.01).Compared with the model group,the body mass,FBG,area under the curve of OGTT and serum TG,TC,LDL-C contents of Yitangkang group and liraglutide group significantly decreased(P<0.01),the content of HDL-C increased(P<0.01);BAT cells were smaller in diameter,more closely arranged,more regular in shape,and more abundant in capillary,the mRNA and protein expressions of UCP1,PRDM16,PGC-1α,NRF1,NRF2 and TFAM in BAT increased significantly(P<0.01).Conclusion Yitangkang can regulate mitochondrial biogenesis through PGC1α-NRF1/2-TFAM pathway to activate brown fat in db/db mice and improve glucose and lipid metabolism in db/db mice.

Objective:To explore the clinical characteristics and prognostic factors of patients with extranasal NK/T-cell lymphoma(NKTCL).Methods:The clinical data of 138 patients with NKTCL diagnosed in 10 medical centers of Huaihai Lymphoma Working Group from June 2015 to April 2021 were collected and analyzed retrospectively.The differences in clinicopathological characteristics of patients with different involvement and efficacy of pegaspargase regimen were compared,as well as perform survival analysis.Results:A total of 138 extranasal NKTCL patients were included,with a median age of 46 years,and the ratio of males to females was approximately 2∶1.There were 39 patients with gastrointestinal involvement,32 patients with oropharyngeal involvement,17 patients with skin involvement,11 patients with lymph node involvement,11 patients with orbital involvement,and 28 patients with other parts involvement.Patients with skin involvement had a higher proportion of advanced disease and a lower proportion of CD56 positive rate compared to those with oropharyngeal involvement.Among the patients with gastrointestinal involvement,the survival rate of patients who received pegaspargase regimen was significantly higher than those who were treated without pegaspargase(P＜0.01).Multivariate analysis showed that serum creatinine was an independent prognostic factor for patients with skin involvement(HR=1.027,95％CI:1.001-1.054,P=0.040),ECOG PS and EBV DNA were independent prognostic factors for patients with gastrointestinal involvement(HR=2.635,95％CI:1.096-6.338,P=0.030;HR=4.772,95％CI:1.092-20.854,P=0.038),and ECOG PS and CA stage were independent prognostic factors for patients with oropharyngeal involvement(HR=13.875,95％CI:2.517-76.496,P=0.002;HR=20.261,95％CI:2.466-166.470,P=0.005).Conclusion:The clinicopathological characteristics of extranasal NKTCL patients with different sites of involvement are vary,and effective individualized treatment need to be further explored.

Objective Spotted fever group rickettsiae(SFGR)are globally prevalent obligate intracellular bacteria that have the potential to cause severe and fatal human diseases. A study to investigate the species and genetic characteristics of SFGR was conducted in 2023 in the Ningxia region of northwestern China. Methods Tick samples were collected from Ningxia, identified, and used to isolate SFGR. The isolated strain was identified as Rickettsia raoultii through morphological observation, multi-locus sequence typing(MLST), and phylogenetic analysis. Then, it was subjected to whole-genome sequencing using next-generation technology, which revealed it to be a TIGMIC strain. Results The TIGMIC strain was demonstrated to exhibit a capacity for growth in mammalian cell lines. The complete genome sequence of the TIGMIC strain was assembled into a circular chromosome, which exhibited a length of 1 312 176 bp and comprised 1 488 genes. Functional annotation revealed that the main key genes of the TIGMIC strain were primarily associated with biosynthesis, nutrient metabolism, and cell membrane biogenesis. Apart from the rickA gene, most typical rickettsial virulence genes of the TIGMIC strain were relatively conserved. Conclusions These findings will help identify SFGR, provide etiological evidence for spotted fever in Ningxia, and emphasize the need for enhanced surveillance to prevent the spread of SFGR.

Objective To assess the status of rodent infestation in commercial kitchens using data from the‘Bright Kitchen, Clean Stove' initiative. The potential use of artificial-intelligence(AI)-based surveillance systems to monitor rodent density was explored, thereby providing a scientific basis for rodent control strategies. Methods As a component of the ‘Bright Kitchen, Clean Stove' initiative, the Minhang District Market Supervision Administration in Shanghai has installed cameras in 297 kitchens. These systems incorporate an AIpowered rodent image recognition method that automatically captures and stores the first image captured in each kitchen each day when a rodent is detected. In 2023, the system collected and stored 736 screenshots of rodents. Following manual verification,720 of the images were confirmed to contain rodents. The images were analyzed by noting the time, location, and kitchen area, and the species were manually identified to assess the population density. Results Rodent activity was detected in 34 of the 297 monitored kitchens, with an overall infestation rate of 11.45%. Of the 720 confirmed images of rodents, Rattus norvegicus(brown rat)was the predominant species, present in 409(56.81 %)images. Rodents were primarily concentrated in hot food preparation spaces. The density fluctuation curve had a multimodal pattern peaking in spring and autumn. The peak of daily activity was between 22: 00 and 2: 00. There was a significant difference in the rodent detection frequency between weekends and weekdays during peak hours and during non-peak hours(χ2=7.18, P＜ 0.01). Conclusions The ‘Bright Kitchen, Clear Stove' smart monitoring system has been proven to be applicable to rodent density monitoring. To control rodents in commercial kitchens, greater efforts are required to address and identify the specific infesting conditions and the key points in the control process.

Acute liver injury (ALI) is one of the common severe diseases in clinic, which is characterized by redox imbalance and inflammatory storm. Untimely treatment can easily lead to liver failure and even death. Rosmarinic acid (RA) has been proved to have anti-inflammatory and antioxidant activity, but it is not clear how to protect ALI through antioxidation and inhibition of inflammation. Therefore, this study explored the therapeutic effect and molecular mechanism of RA on ALI through in vitro and in vivo experiments. In the mouse ALI model, the effects of RA on liver function and inflammatory indexes were studied, the pathological changes of liver were observed by HE, the effect of RA on reactive oxygen species in liver was detected by fluorescence method, and the level of F4/80 in liver tissue was detected by immunohistochemical method. The levels of thioredoxin interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3) and cysteinyl aspartate specific proteinase-1 (CASPASE-1) in liver tissue were measured by Western blot. All animal welfare and experimental procedures follow the rules of the Animal Ethics Committee of Southwest Minzu University. In vitro, human hepatoma cell line HepG2 was used to establish the model of oxidative damage induced by H₂O₂. The cell viability was detected by CCK-8 method. The level of interleukin-1β (IL-1β) in the supernatant was detected by enzyme linked immunosorbent assay (ELISA), the activity of lactatede hydrogenase (LDH) was detected by LDH kit, and the level of ROS was detected by fluorescence probe DCFH-DA labeling. The mRNA expression of Txnip, Nlrp3, Caspase 1, Il1β was detected by real-time fluorescence quantitative PCR (qPCR), and the protein levels of nuclear factor erythroid-2 related factor 2 (NRF2), TXNIP, NLRP3 and CASPASE-1 were measured by Western blot. The results showed that compared with the model group, the degree of liver swelling, tissue injury, liver function index in RA group were significantly lower than those in model group. And RA significantly attenuated the increases of ROS in liver tissue. The expression levels of TXNIP, NLRP3 and CASPASE-1 in liver tissue were significantly lower than those in model group. Additionally, RA inhibited the expressions of F4/80 and IL-1β. In vitro experiment, compared with model group, RA effectively inhibited the secretion of IL-1β and LDH. The level of ROS also decreased significantly. RA inhibited the mRNA expressions of Txnip, Caspase 1, Il1β. Furthermore, RA significantly increased the expression level of NRF2 protein in nucleus, and decreased the expression level of TXNIP and NLRP3 protein. Specifically, with the addition of ML385, the effect of RA on NRF2, TXNIP, NLRP3, CASPASE-1 protein expression was reversed. Collectively, these findings suggested that RA may inhibit the production of ROS by promoting NRF2 nuclear transfer, and then reduce the activation of NLRP3 inflammatory bodies by TXNIP, reduce cell death and inflammatory response to prevent the liver injury.