A five-year follow-up clinical study of the B cell maturation antigen chimeric antigen receptor-T cell therapy HDS269B in patients with relapsed or refractory multiple myeloma.

PURPOSE: This study aimed to report the five-year clinical outcomes of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell (HDS269B) therapy in relapsed/refractory multiple myeloma (RRMM) patients, including those with poor performance status (Eastern Cooperative Oncology Group [ECOG] 3-4), and to identify factors influencing long-term outcomes. METHODS: Forty-nine RRMM patients enrolled from 2016 to 2020 received HDS269B (9×106 cells/kg) after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS: With a median follow-up of 59.0 months, the overall response rate was 77.55%. The median progression-free survival (PFS) and overall survival (OS) were 9.5 months (95% confidence interval [CI], 5.01-13.99) and 20.0 months (95% CI, 11.26-28.74), respectively. The 5-year PFS and OS rates were 21.3% (95% CI, 12.3%-36.7%) and 34.1% (95% CI, 22.7%-51.3%), respectively. Patients with ECOG 0-2 had marked longer survival, with a median PFS of 11.0 months and median OS of 41.8 months. Early minimal residual disease negativity, and higher and persistent CAR-T cell expansion and absence of extramedullary disease were associated with better survival outcomes. No new CAR-T cell therapy associated toxicities were observed. Importantly, ECOG 0-2, prior therapy lines <4, and CAR-T cell persistence at ≥6 months were independently associated with longer OS. CONCLUSIONS: HDS269B is effective and safe, especially for patients with ECOG 0-2. Early CAR-T cell intervention may improve prognosis in patients with RRMM.

Identification of active compounds in Vernonia anthelmintica (L.) willd by targeted metabolome MRM and kaempferol promotes HaCaT cell proliferation and reduces oxidative stress.

Introduction: Vernonia anthelmintica (L.) Willd. is a traditional treatment for vitiligo in Xinjiang. However, its therapeutic mechanism remains unclear owing to its complex composition and limited research on its chemical profile. Methods: We employed a targeted metabolome approach, combining selective reaction monitoring/multiple response monitoring (SRM/MRM) with high-performance liquid chromatography and MRM mass spectrometry to quantitatively analyze the flavonoid constituents of Vernonia anthelmintica. We also used network pharmacology and molecular docking to identify potential vitiligo-linked compounds and targets of V. anthelmintica seeds. Additionally, we assessed HaCaT cell proliferation by AAPH-induced, alongside changes in SOD activity and MDA content, following treatment with V. anthelmintica components. Finally, flow cytometry was used to detect apoptosis and ROS levels. Results and Discussion: We identified 36 flavonoid compounds in V. anthelmintica seeds, with 14 compounds exhibiting druggability. AKT1, VEGFA, ESR1, PTGS2, and IL2 have been identified as key therapeutic target genes, with PI3K/AKT signaling being an important pathway. Notably, kaempferol, one of the identified compounds, exhibited high expression in network pharmacology analysis. Kaempferol exhibited a strong binding affinity to important targets. Further, kaempferol enhanced HaCaT cell viability, inhibited apoptosis, reduced MDA levels, suppressed ROS activity, and upregulated SOD activity, increase the expression of cellular antioxidant genes, including HO-1, GCLC, GCLM, Nrf2, NQO1 and Keap1, providing significant protection against oxidative stress damage in vitro. Here, we present the first comprehensive study integrating SRM/MRM approaches and network analysis to identify active flavonoid compounds within V. anthelmintica (L.) Willd. Moreover, we revealed that its active ingredient, kaempferol, offers protection against AAPH-induced damage in keratinocytes, highlighting its potential as a clinical resource.

Identification and validation of RNA-binding protein SLC3A2 regulates melanocyte ferroptosis in vitiligo by integrated analysis of single-cell and bulk RNA-sequencing.

BACKGROUND: The pathogenesis of vitiligo remains unclear. The genes encoding vitiligo-related RNA-binding proteins (RBPs) and their underlying pathogenic mechanism have not been determined. RESULTS: Single-cell transcriptome sequencing (scRNA-seq) data from the CNCB database was obtained to identify distinct cell types and subpopulations and the relative proportion changes in vitiligo and healthy samples. We identified 14 different cell types and 28 cell subpopulations. The proportion of each cell subpopulation significantly differed between the patients with vitiligo and healthy groups. Using RBP genes for unsupervised clustering, we obtained the specific RBP genes of different cell types in vitiligo and healthy groups. The RBP gene expression was highly heterogeneous; there were significant differences in some cell types, such as keratinocytes, Langerhans, and melanocytes, while there were no significant differences in other cells, such as T cells and fibroblasts, in the two groups. The melanocyte-specific RBP genes were enriched in the apoptosis and immune-related pathways in the patients with vitiligo. Combined with the bulk RNA-seq data of melanocytes, key RBP genes related to melanocytes were identified, including eight upregulated RBP genes (CDKN2A, HLA-A, RPL12, RPL29, RPL31, RPS19, RPS21, and RPS28) and one downregulated RBP gene (SLC3A2). Cell experiments were conducted to explore the role of the key RBP gene SLC3A2 in vitiligo. Cell experiments confirmed that melanocyte proliferation decreased, whereas apoptosis increased, after SLC3A2 knockdown. SLC3A2 knockdown in melanocytes also decreased the SOD activity and melanin content; increased the Fe2+, ROS, and MDA content; significantly increased the expression levels of TYR and COX2; and decreased the expression levels of glutathione and GPX4. CONCLUSION: We identified the RBP genes of different cell subsets in patients with vitiligo and confirmed that downregulating SLC3A2 can promote ferroptosis in melanocytes. These findings provide new insights into the pathogenesis of vitiligo.

Paired Electrolysis Enabled Trifluoromethylheteroaromatization of Alkenes and Alkyne with Trifluoromethyl Thianthrenium Triflate (TT-CF3+OTf-) as a Bifunctional Reagent.

We report a strategic exploitation of trifluoromethyl thianthrenium triflate (TT-CF3+OTf-) as both electromediator and CF3 radical precursors for paired electrolysis. Enabled by this strategy, the three-component trifluoromethylheteroaromatization of alkenes and alkynes was realized. The superiority of TT-CF3+OTf- to other electrophilic CF3 reagents is attributed to the cathodic generation of thianthrene (TT) as a mediator, which shifts the heterogeneous oxidation of interest to a homogeneous one.

The direct transfer approach for transcellular drug delivery.

A promising paradigm for drug administration that has garnered increasing attention in recent years is the direct transfer (DT) of nanoparticles for transcellular drug delivery. DT requires direct cell-cell contact and facilitates unidirectional and bidirectional matter exchange between neighboring cells. Consequently, DT enables fast and deep penetration of drugs into the targeted tissues. This comprehensive review discusses the direct transfer concept, which can be delineated into the following three distinct modalities: membrane contact-direct transfer, gap junction-mediated direct transfer (GJ-DT), and tunneling nanotubes-mediated direct transfer (TNTs-DT). Further, the intercellular structures for each modality of direct transfer and their respective merits and demerits are summarized. The review also discusses the recent progress on the drugs or drug delivery systems that could activate DT.

Efficacy of SBAR combined with CICAR Communication Mode in Enhancing CT Hydration Effect and Nursing Satisfaction in Elderly Patients with Low Education.

Objective: To explore the effect of nurse-patient communication using the SBAR and CICAR communication mode on CT hydration effectiveness and nursing satisfaction in elderly patients with low education. Methods: From December 2020 to April 2023, 120 elderly patients with low education who underwent chest examinations in our hospital's imaging department were selected. Divide into an observation group and a control group using clinical randomized controlled trial design principles. Both groups of patients received the same diagnosis and treatment plan and nursing measures during hospitalization. The control group received traditional nursing care, while the observation group used the SBAR combined with CICAR communication template for nurse patient communication. After completing all intervention measures, the patient's state anxiety level and satisfaction with nursing work were re evaluated, and the enhanced CT examination status, enhanced CT examination knowledge awareness, psychological status, and their impact relationship were compared between the two groups of patients. Results: The heart rate, preparation time, examination time, anxiety score, depression score, and satisfaction of the observation group were better than those of the control group during examination, with statistical significance (P < .05); The scores related to the understanding of enhanced CT examination, preparation and precautions before the examination, proper posture during the examination, and post-examination precautions in the observation group were significantly higher than those in the control group (P < .05). The understanding of CT examination knowledge has a negative impact on the CT examination status and psychological state (P < .05), and the hydration effect of enhanced CT in patients (P < .05). Conclusion: Nurse-patient communication using the SBAR and CICAR communication mode improved CT hydration effectiveness and nursing satisfaction in elderly patients with low education. This mode enhanced patient understanding, preparation, and adherence to CT examination protocols, leading to better outcomes and reduced anxiety and depression levels.

Immunomodulatory Effects of Microcin C7 in Cyclophosphamide-Induced Immunosuppressed Mice.

Microcin C7 (McC) as a viable immunomodulator peptide can be a potential solution for pathogenic microbial infection in the post-antibiotic era and has gained substantial attention. This study was designed to evaluate the immunomodulatory activity of Microcin C7 in a cyclophosphamide (CTX)-induced immunodeficient mouse model. We show that Microcin C7 treatment significantly alleviated the CTX-caused body weight loss, improved the feed and water consumption to improve the state of the mice, and elevated the absolute number and proportion of peripheral blood lymphocytes as well as the level of hemoglobulin. We further aim to characterize the phenotypes of the immune function and intestinal health profiles. The results demonstrate that Microcin C7 treatment increased serum levels of immunoglobulin A (IgA), IgG, interleukin 6, and hemolysin, promoted splenic lymphocyte proliferation induced by concanavalin A and LPS, and enhanced the phagocytosis of peritoneal macrophages immunized by sheep red blood cells. Additionally, Microcin C7 treatment decreased levels of diamine oxidase and d-lactate, ameliorated CTX-induced intestinal morphological damage, and increased the levels of zonula occluden 1, occludin, claudin-1, mucin 2, and secretary IgA in the jejunum and colon. Moreover, Microcin C7 administration is sufficient to reverse CTX-induced intestinal microbiota dysbiosis by increasing the number of Lactobacillus and Bifidobacterium, decreasing the number of Escherichia coli in colonic contents. Collectively, our results demonstrate that Microcin C7 may have protective and immunomodulatory functions and could be a potential candidate used in animal feed, functional foods, and immunological regimens..

Correlation analysis of the expression of mesenchymal circulating tumor cells and CD133 with the prognosis of colorectal cancer.

OBJECTIVE: To evaluate the expression of tumor stem cell marker CD133 in peripheral blood circulating tumor cells (CTC) and the value of CD133 in prognosis of patients with colorectal cancer (CRC). METHODS: Preoperative/pre-chemotherapy peripheral blood samples of 63 patients with CRC from January 2016 to January 2021 were selected to detect peripheral blood CTC by CanPatrol CTC enrichment technology. Expression of CD133 in different epithelial-mesenchymal transition (EMT) typing CTC was analyzed. Clinical data (including tumor size, tumor stage, pathological typing, molecular typing, lymph node metastasis, distant metastasis, carcinoembryonic antigen (CEA), and CA-199 expression), PFS time and OS time were followed up. The expression of CD133 in different CTCs was compared, and the correlation between CD133 and patient survival time was compared. RESULTS: The positive rate of E-CTC in patients with tumor diameter ≥5 cm was significantly higher than that of patients with tumor diameter <5 cm (P=0.035). The positive rate of M-CTC in patients with diabetes was significantly higher than that of patients without diabetes (P=0.006). The CD133-positive M-CTCs were significantly higher in DM and CEA>5 ng/mL patients than in non-DM and CEA≤5 ng/mL patients (P<0.001, P=0.0195). Fifty-five patients were followed up for a median of 14 months. During follow-up, 19 had disease progression and five died. According to the cutoff point obtained by ROC analysis, the PFS of M-CTC>2.5/5 ml patients (0%) was lower than that of ≤2.5/5 ml patients (76.5%), P<0.05. PFS in patients with CD133-positive M-CTC>0.5/5 mL (18.6%) was lower than in patients with ≤0.5/5 ml (76.5%), P<0.05. However, thedifference in the OS between patients with CD133-positive M-CTC>0.5/5 ml (71.7%) and those with ≤0.5/5 ml (93.8%), was not significant, P=0.054. CONCLUSION: CD133 positive M-CTC is closely related to distant metastasis in CRC. The expression of CD133 in CTC, especially in M-CTC, can be used as a prognostic indicator for colorectal cancer.

Cervical vertebrae for early bone loss evaluation in osteoporosis mouse models.

Background: Osteoporosis (OP), a systemic skeletal disease common in aged population, is an important public health problem worldwide. Animal models are important tools for understanding OP. In ovariectomy (OVX) or orchiectomy (ORX) OP models, lumbar vertebrae are often used for evaluating of the OP progression. However, unlike the bipeds, the lumbar vertebrae are not weight loading bones in quadruped animal, but the head-bearing cervical vertebrae take much higher stress. So, we compared the murine cervical vertebrae with lumbar vertebrae for OP assessment. Methods: OVX and ORX mouse models were established on C57BL/6J mice. Serum estradiol, testosterone and bone related biomarkers were verified. Bone quantity and quality were determined using micro computed tomography (micro-CT) analysis. Hard tissue sections were prepared, stained for histomorphological analyzing, and micro-indentation measured for bone mechanical property evaluation. Results: In OVX and ORX mice, serum estradiol or testosterone levels reduced, bone resorption level and related biomarkers elevated, indicated the successful generation of the OP models. In the early stage, the trabecular bone mineral density (BMD) of cervical vertebrae was already reduced 16.1% (OVX) and 21.7% (ORX) one-month post-gonadectomy, respectively; while this decline in the fifth lumbar vertebra were only 5% and 7.4%, respectively. Six months post-gonadectomy, the reduction of BMD in cervical vertebrae and the fifth lumbar vertebra were 31.2% & 36.1% and 28.5% & 30.7% respectively. In biomechanical aspects, cervical spines showed worse Vickers hardness (HV) and elastic modulus than lumbar spine in six-month OVX and ORX mice. Conclusions: We provide a new OP early-stage evaluation mouse model based on the cervical spine. Through the radiographic, biological and biomechanical assessments, the mouse cervical spine is more suitable for bone remodeling evaluation in OP models than the conventional lumbar vertebrae, especially for early-stage OP study.

Greater alteration of gut microbiota occurs in childhood obesity than in adulthood obesity.

The children's gut microbiota, associated with the development of obesity, is in maturation. The impact of obesity on the gut microbiota in childhood could have a more significant effect than on adulthood and eventually be lifelong lasting, but it has been rarely studied. Aimed to discover the difference in gut microbiota between children and adults with obesity, we collected published amplicon sequencing data from National Center for Biotechnology Information (NCBI) and re-analyzed them using a uniform bioinformatic pipeline, as well as predicted the obesity using gut microbiota based on the random forest model. Summarizing common points among these cohorts, we found that the gut microbiota had a significant difference between children with and without obesity, but this difference was not observed in adult cohorts. Based on the random forest model, it was more challenging to predict childhood obesity using gut microbiota than adulthood obesity. Our results suggest that gut microbiota in childhood is more easily affected than in adulthood. Early intervention for childhood obesity is essential to improve children's health and lifelong gut microbiota-related health.

A full-scale black soldier fly larvae (Hermetia illucens) bioconversion system for domestic biodegradable wastes to resource.

Domestic biodegradable wastes (DBW) pose a threat to environmental quality and human health. Bioconversion via black soldier fly larvae (BSFL; Hermitia illucens L.) is an expedient way for converting 'waste to resource' (insect protein and biofertilizer). Although researches abounded in laboratory-reared experiments and bioconversion mechanisms were pertinent, the void of data from actual and full-scale operation restricts the intensification of BSFL technology and its global adoption. Hence, a full-scale BSFL bioconversion system lasting 4 years in Hangzhou (China) was investigated, and the feasibility and efficiency of 15 tonnes of DBW per day were studied. Through continuous technical optimization, the average production of fresh larvae was increased from 8.5% in 2017 to 15.3% in 2020, along with bioconversion rate of final vermicompost decreased from 35.4% to 14.5%. The total biomass reduction rate in 2020 was 68.7 ± 17.4 kg/(m3 d), equivalent to 0.735 ± 0.215 kg/(kg d) in the form of fresh larvae. Crude fat in fresh larvae accounted for 13.4%, and crude protein accounted for 16.2% in which the determined amino acid profile bore a strong resemblance to fish meal only except histidine and tyrosine. Its economic benefits proved the feasibility of this technology, and the profit reached up to 35.9 US$ per tonne of DBW in 2019. In conclusion, BSFL bioconversion system under current 'insect-farm' operation was a promising solution for DBW treatment with value-added waste recycling.

Precise flap surgery for reconstruction of knee defects / 中华创伤骨科杂志

Objective:To introduce the concept and procedures of precise flap surgery in construction of knee defects and to report the preliminary clinical outcomes.Methods:The data of 16 patients with knee defects at 17 sides were retrospectively analyzed who had been treated under the guidance of the concept of precise flap surgery at Department of Orthopedic Surgery, The 920th Hospital of Joint Logistic Support Force of PLA from August 2014 to March 2022. There were 12 males and 4 females, aged 44(34, 54) years. The wounds were at the left side in 8 cases, at the right side in 7 ones and at bilateral sides in one, and their sizes ranged from 5 cm×3 cm to 15 cm×11 cm. The time from injury to surgery was 8.5(6.0, 13.0) days. Optimal repair protocols were chosen after the donor and recipient sites were evaluated according to the methods of precise flap surgery: a retrograde anterolateral thigh flap in 7 sides, a descending genicular artery perforator flap in 3 ones, a saphenous artery flap in 2 ones, and a superior genicular lateral artery perforator flap, a popliteal artery perforator flap, a medial sural perforator propeller flap, a peroneal artery perforator propeller flap, and a randomized flap in one, respectively. The flap sizes ranged from 10 cm×6 cm to 15 cm×15 cm. The outcomes and complications of skin flap repair, and functional recovery of the affected limb were recorded.Results:All the flaps at 17 sides survived after surgery; 3 cases developed distal edge necrosis which responded to dressing change. The follow-ups for the 16 patients were 14.5(10.0, 28.0) months. All the flaps presented with good color, texture and contour. Flap bulking, local osteomyelitis, and scar ulcer was found in one case respectively. According to the revascularization assessments in the digital replantation criteria by Hand Surgery Society, Chinese Medical Association, all the flaps at 17 sides were excellent. Accoding to the knee functional evaluation of Hospital for Special Surgery (HSS) at the last follow-up, the 17 affected limbs scored 86(80,91) points, yielding 9 excellent, 7 good and 1 fair sides.Conclusion:Although the defects and donor sites around the knee vary greatly, precise flap surgery may lead to effective control of the variations, choice of an optimal reconstruction protocol, and precise wound repair.

The application of antineutrophil cytoplasmic antibody renal risk score in children with antineutrophil cytoplasmic antibody-associated glomerulonephritis / 中华实用儿科临床杂志

Objective:To investigate the potential of the antineutrophil cytoplasmic antibody (ANCA) renal risk score (ARRS) in predicting the prognosis of children with ANCA-associated glomerulonephritis (AAGN).Methods:Laboratory testing, renal pathology results, treatment and prognosis of 61 children with AAGN diagnosed by renal biopsy from June 2007 to May 2022 in General Hospital of Eastern Theater Command were retrospectively analyzed.The Kaplan-Meier method was used to evaluate the overall and renal survival of children with AAGN, and risk factors of progression to end stage renal disease (ESRD) were analyzed by Cox regression analysis. Results:Among the 61 children with AAGN, there were 14 males and 47 females with the age of (15.65±3.74) years.According to ARRS, AAGN children were assigned into low-risk group (27 cases), medium-risk group (21 cases) and high-risk group (13 cases). During a median follow-up duration of 46.36 (14.58, 95.62) months, the number of ESRD cases in the high-risk group (9 cases) was significantly higher than that of low-risk group (2 cases) and medium-risk group (3 cases) ( χ2=13.079, P<0.001). Kaplan-Meier survival analysis showed that AAGN children in the high-risk group had the worst renal prognosis ( χ2=5.796, P=0.016), while no significant difference was detected in the overall survival among the 3 groups ( χ2=2.883, P=0.237). Multivariate Cox regression showed that estimate glomerular filtration rate(eGFR)≤15 mL/(min·1.73 m 2) ( HR=9.574, 95% CI: 4.205-25.187, P=0.015) and ARRS ( HR=2.115, 95% CI: 1.206-4.174, P=0.012) were independent risk factors for children with AAGN progress to ESRD.Receiver operating characteristic (ROC) curve analysis results showed that the area under the curve of ARRS for predicting the risk of progressing to ESRD in AAGN children was 0.880 (95% CI: 0.759-1.000), and the optimal cutoff value of ARRS was 5.50, with the sensitivity and specificity of 85.71% and 82.98%, respectively. Conclusions:ARRS was an independent risk factor for children with AAGN progress to ESRD, which had a predictive value for the progression of AAGN to ESRD.

Preparation of mesoporous silica nanoparticles with different sizes and study on the correlation between size and toxicity / 药学学报

To investigate the crucial role of particle size in the biological effects of nanoparticles, a series of mesoporous silica nanoparticles (MSNs) were prepared with particle size gradients (50, 100, 150, 200 nm) with the traditional Stober method and adjusting the type and ratio of the silica source. The correlation between toxicity and size-caused biological effects were then further examined both in vitro and in vivo. The results indicated that the prepared MSNs had a uniform size, good dispersal, and ordered mesoporous structure. Hemolytic toxicity was found to be independent of particle size. At the cellular level, MSNs with smaller particle sizes were more readily internalized by cells, which initiated to more intense oxidative stress, therefor inducing higher cytotoxicity, and apoptosis rate. In vivo studies demonstrated that MSNs primarily accumulated in the liver and kidneys of mice. Pharmacokinetic analysis revealed that larger MSNs were eliminated more efficiently by the urinary system than smaller MSNs. The mice's body weight monitoring, blood tests, and pathological sections of major organs indicated good biocompatibility for MSNs of different sizes. Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Zhejiang Chinese Medical University. Overall, this study prepared MSNs with a particle size gradient to investigate the correlation between toxicity and particle size using macrophages and endothelial cells. The study also examined the biosafety of MSNs with different particle sizes in vivo and in vitro, which could help to improve the safety design strategy of MSNs for drug delivery systems.

Evaluation of antibody responses against the whole virions of goatpox and sheeppox viruses after subcutaneous immunization of rabbits.

Antibody development is the integral process of generating and characterizing an antibody. It commences by inoculating the antigen of interest into laboratory animals, allowing the immune system develops large quantities of antibodies. This was aimed at developing antibodies against the virion of Goatpox and Sheeppox virus vaccines. The ability of Goatpox and Sheeppox vaccines was assessed. Regarding this study, the antibody titers against both Goatpox and Sheeppox viruses was increased in the same manner. The amount of IgG was determined to be 2.29 µg/µl and 2.18 µg/µl against virions of Goatpox virus and Sheeppox respectively. The purified IgG was analyzed by SDS-PAGE. Different bands of the purified antibodies were clearly visualized, and the molecular weight of IgG was estimated to be 67 kDa and 25 kDa. Additionally, antigen/antibody binding was confirmed by Western blot using GTPV A27 antigen. No significant differences in antibody titers were observed between the two groups (p < 0, 05).