Antibody-drug conjugates in urothelial carcinoma: scientometric analysis and clinical trials analysis.

In 2020, bladder cancer, which commonly presents as urothelial carcinoma, became the 10th most common malignancy. For patients with metastatic urothelial carcinoma, the standard first-line treatment remains platinum-based chemotherapy, with immunotherapy serving as an alternative in cases of programmed death ligand 1 expression. However, treatment options become limited upon resistance to platinum and programmed death 1 or programmed death ligand 1 agents. Since the FDA's approval of Enfortumab Vedotin and Sacituzumab Govitecan, the therapeutic landscape has expanded, heralding a shift towards antibody-drug conjugates as potential first-line therapies. Our review employed a robust scientometric approach to assess 475 publications on antibody-drug conjugates in urothelial carcinoma, revealing a surge in related studies since 2018, predominantly led by U.S. institutions. Moreover, 89 clinical trials were examined, with 36 in Phase II and 13 in Phase III, exploring antibody-drug conjugates as both monotherapies and in combination with other agents. Promisingly, novel targets like HER-2 and EpCAM exhibit substantial therapeutic potential. These findings affirm the increasing significance of antibody-drug conjugates in urothelial carcinoma treatment, transitioning them from posterior-line to frontline therapies. Future research is poised to focus on new therapeutic targets, combination therapy optimization, treatment personalization, exploration of double antibody-coupled drugs, and strategies to overcome drug resistance.

Advances and key focus areas in gastric cancer immunotherapy: A comprehensive scientometric and clinical trial review (1999-2023).

BACKGROUND: Gastric cancer (GC) is the sixth most common cancer and third leading cause of cancer-related deaths worldwide. Current treatments mainly rely on surgery- and chemotherapy-based systemic; however, the prognosis remains poor for advanced disease. Recent studies have suggested that immunotherapy has significant potential in cancer therapy; thus, GC immunotherapy may improve quality of life and survival for patients with this disease. AIM: To provide a comprehensive overview of the knowledge structure and research hotspots of GC immunotherapy. METHODS: We conducted a bibliometric analysis of publications on immunotherapy related to GC in the Web of Science Core Collection database. We analyzed 2013 pub-lications from 1999 to February 1, 2023, using the VOSviewer and CiteSpace software. We assessed publication and citation distributions using the WoS platform and explored research countries, institutions, journals, authors, references, and keywords (co-occurrence, timeline view, and burst analysis). In addition, we examined 228 trials on immunotherapy, 137 on adoptive cell therapy, 274 on immune checkpoint inhibitors (ICIs), and 23 on vaccines from ClinicalTrials.gov and the International Clinical Trials Registry Platform. The Impact Index Per Article for the top ten high-cited papers collected from Reference Citation Analysis (RCA) are presented. RESULTS: Our bibliometric analysis revealed that the study of immunotherapy in GC has developed rapidly in recent years. China accounted for almost half the publications, followed by the United States. The number of publications in recent years has been growing continuously, and most institutions and authors with the most publications are from China. The main keywords or clusters identified were "tumor microenvironment", "adoptive immunotherapy", "dendritic therapy", and "microsatellite instability". CONCLUSION: Our analysis of 2013 publications indicated that immunotherapy for GC has led to several new developments in recent years. Considerable progress has been made in vaccinations, immune checkpoint therapy, and adoptive cellular therapy. In particular, ICIs and chimeric antigen receptor T-cells are novel options for the treatment of GC. We suggest that the combination of ICIs, chemotherapy, targeted therapy, and other immunotherapies should be the primary research direction in the future.

Impact of TP53 Mutations on EGFR-Tyrosine Kinase Inhibitor Efficacy and Potential Treatment Strategy.

BACKGROUND: We investigated the impact of factors that influence TP53 mutations on the efficacy of EGFR-tyrosine kinase inhibitors and potential treatment strategies. MATERIALS AND METHODS: Tumor samples were collected to screen gene mutations by next-generation sequencing, as well as the patients' baseline characteristics. The overall response to treatment with TKIs was evaluated based on interval computed tomography scans at each follow-up time point. A Fisher's exact test and log-rank test were used to determine the statistical differences in this study. RESULTS: A total of 1134 clinical samples were collected from NSCLC patients, and TP53mut was identified in 644 cases and EGFRmut in 622 cases. A low frequency of TP53mut or more than 50% EGFR co-mutation rate were related to the prognosis of TKI-treated patients. In addition, TP53mut in the region outside of the DB domain had the strongest correlation with TKI resistance, whereas various types of mutations in the DB domain only had an impact on PFS. A grouping study of EGFR-TKI-based treatment revealed that EGFR-TKIs with chemotherapy were associated with more significant survival benefits for patients with prognostic TP53mut, whereas EGFR-TKI therapy was favorable for TP53wt patients. Furthermore, TP53mut could shorten the time to the relapse of postoperative patients, who will also likely respond well to EGFR-TKIs with chemotherapy. CONCLUSION: Various characteristics of TP53mut affect the prognosis of TKI-treated patients to varying degrees. EGFR-TKIs with chemotherapy were benefit for patients' survival with prognostic TP53mut, which provides an important reference for treatment management of EGFRmut patients.

Dynamic changes of gut fungal community in horse at different health states.

Accumulating studies indicated that gut microbial changes played key roles in the progression of multiple diseases, which seriously threaten the host health. Gut microbial dysbiosis is closely associated with the development of diarrhea, but gut microbial composition and variability in diarrheic horses have not been well characterized. Here, we investigated gut fungal compositions and changes in healthy and diarrheic horses using amplicon sequencing. Results indicated that the alpha and beta diversities of gut fungal community in diarrheal horses changed significantly, accompanied by distinct changes in taxonomic compositions. The types of main fungal phyla (Neocallimastigomycota, Ascomycota, and Basidiomycota) in healthy and diarrheal horses were same but different in relative abundances. However, the species and abundances of dominant fungal genera in diarrheal horses changed significantly compared with healthy horses. Results of Metastats analysis indicated that all differential fungal phyla (Blastocladiomycota, Kickxellomycota, Rozellomycota, Ascomycota, Basidiomycota, Chytridiomycota, Mortierellomycota, Neocallimastigomycota, Glomeromycota, and Olpidiomycota) showed a decreasing trend during diarrhea. Moreover, a total of 175 differential fungal genera were identified for the gut fungal community between healthy and diarrheal horses, where 4 fungal genera increased significantly, 171 bacterial genera decreased dramatically during diarrhea. Among these decreased bacteria, 74 fungal genera even completely disappeared from the intestine. Moreover, this is the first comparative analysis of equine gut fungal community in different health states, which is beneficial to understand the important role of gut fungal community in equine health.

Comparative Analysis of Gut Microbiota Between Healthy and Diarrheic Horses.

Increasing evidence reveals the importance of gut microbiota in animals for regulating intestinal homeostasis, metabolism, and host health. The gut microbial community has been reported to be closely related to many diseases, but information regarding diarrheic influence on gut microbiota in horses remains scarce. This study investigated and compared gut microbial changes in horses during diarrhea. The results showed that the alpha diversity of gut microbiota in diarrheic horses decreased observably, accompanied by obvious shifts in taxonomic compositions. The dominant bacterial phyla (Firmicutes, Bacteroidetes, Spirochaetes, and Kiritimatiellaeota) and genera (uncultured_bacterium_f_Lachnospiraceae, uncultured_bacterium_f_p-251-o5, Lachnospiraceae_AC2044_group, and Treponema_2) in the healthy and diarrheic horses were same regardless of health status but different in abundances. Compared with the healthy horses, the relative abundances of Planctomycetes, Tenericutes, Firmicutes, Patescibacteria, and Proteobacteria in the diarrheic horses were observably decreased, whereas Bacteroidetes, Verrucomicrobia, and Fibrobacteres were dramatically increased. Moreover, diarrhea also resulted in a significant reduction in the proportions of 31 genera and a significant increase in the proportions of 14 genera. Taken together, this study demonstrated that the gut bacterial diversity and abundance of horses changed significantly during diarrhea. Additionally, these findings also demonstrated that the dysbiosis of gut microbiota may be an important driving factor of diarrhea in horses.

A special prognostic indicator: tumor mutation burden combined with immune infiltrates in lung adenocarcinoma with TP53 mutation.

BACKGROUND: TP53 mutation (TP53 mut) is significantly associated with immunotherapy response in lung adenocarcinoma (LUAD), but not an ideal independent prognostic predictor for it. Here, we investigated a novel potential biomarker and constructed a model for prognostic prediction in LUAD TP53 mut patients. METHODS: 469 LUAD samples retrieved from The Cancer Genome Atlas database were divided into TP53 wt (wild-type TP53) and TP53 mut groups. TMB values were calculated based on the number of variants/exon lengths, and high- and low-TMB groups were divided by the median value. Differentially expressed genes (DEGs) between the two TMB groups were identified using "limma" package, and functional analyses were performed by Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis. The infiltration ratio of 22 immune cells were calculated with the CIBERSORT algorithm. Survival analyses were estimated by Kaplan-Meier with the log-rank test. Finally a TMB prognostic index (TMBPI) with receiver operating characteristic (ROC) curve was constructed and calculated to evaluate the predictive value in TP53 mut LUAD. RESULTS: There were diverse mutation types in 100% of TP53 mutants, while mutations were present in 86.5% of cases with TP53 wt. TP53 mut patients had higher TMB levels than TP53 wt patients. Overall survival in TP53 mut patients with low-TMB levels was significantly shorter than that in high-TMB TP53 mut patients. High-TMB patients had higher levels of CD8 T cell and effector B cell, while lower levels of resting memory CD4 T cells, monocytes, activated dendritic cells, etc. than low-TMB patients. Poor survival outcome in TP53 mut patients was correlated with lower effector B cell infiltration and higher activated dendritic cell. Survival risk analyses of 121 DEGs showed that good survival outcomes correlated positively with FBXO36 and KLHL35 expression levels, but correlated negatively with that of LINC0054. TMBPI analysis of the TP53 mut patients showed that high-TMBPI patients had worse survival outcomes than low-TMBPI patients. CONCLUSIONS: Our findings suggest that the TMB value with immune infiltrates is a novel potential biomarker for prognostic prediction of TP53 mut patients. The TMBPI combined with detection of TP53 mutation can be used as a better predictor of prognosis in LUAD.

Risk factors for necrosis of skin flap-like wounds after ED debridement and suture.

BACKGROUND: Skin flap-like wounds are common. These wound flaps are prone to avascular necrosis with simple debrided and sutured, and postoperative hyperplastic scarring and contracture of wound surfaces can adversely affect the patient's appearance. Here, we evaluate the data of cases with flap-like wounds to identify the causes of flap necrosis. METHODS: Six hundred patients with skin flap-like wounds between January 1, 2013 and December 31, 2016 were retrospectively reviewed. Their age, sex, injury reason, size of flap, length-width ratio of wound, thickness of pedicle, operation time, injury site, direction of blood perfusion in the flap and operating methods were recorded. The risks for flap necrosis were analyzed with one-factor analysis. RESULTS: A total success rate of 92.5% (555/600) for flap-like wound reconstruction was obtained. Among 67 flaps with vascular crisis, 22 were salvaged by subcutaneous injection of anisodamine, selective suture removal, and pressure dressing with elastic bandages. For the 45 patients with flap necrosis, there was no significant difference from patients without necrosis in terms of sex, age, and size of flap (P > 0.05). The incidence of flap necrosis was significantly different in terms of injury reason, length-width ratio of wound, thickness of pedicle, operation time, injury site, direction of blood perfusion in the flap and operating methods (P < 0.05). CONCLUSION: Injury reason, length-width ratio of wound, thickness of pedicle, operation time, injury site, direction of blood perfusion in the flap and operating methods, rather than age, sex and size of flap, were significant risk factors for necrosis of flap-like wounds.

Exogenous peripheral blood mononuclear cells affect the healing process of deep­degree burns.

The regenerative repair of deep­degree (second degree) burned skin remains a notable challenge in the treatment of burn injury, despite improvements being made with regards to treatment modality and the emergence of novel therapies. Fetal skin constitutes an attractive target for investigating scarless healing of burned skin. To investigate the inflammatory response during scarless healing of burned fetal skin, the present study developed a nude mouse model, which was implanted with normal human fetal skin and burned fetal skin. Subsequently, human peripheral blood mononuclear cells (PBMCs) were used to treat the nude mouse model carrying the burned fetal skin. The expression levels of matrix metalloproteinase (MMP)­9 and tissue inhibitor of metalloproteinases (TIMP)­1 were investigated during this process. In the present study, fetal skin was subcutaneously implanted into the nude mice to establish the murine model. Hematoxylin and eosin staining was used to detect alterations in the skin during the development of fetal skin and during the healing process of deep­degree burned fetal skin. The expression levels of MMP­9 and TIMP­1 were determined using immunochemical staining, and their staining intensity was evaluated by mean optical density. The results demonstrated that fetal skin subcutaneously implanted into the dorsal skin flap of nude mice developed similarly to the normal growth process in the womb. In addition, the scarless healing process was clearly observed in the mice carrying the burned fetal skin. A total of 2 weeks was required to complete scarless healing. Following treatment with PBMCs, the burned fetal skin generated inflammatory factors and enhanced the inflammatory response, which consequently resulted in a reduction in the speed of healing and in the formation of scars. Therefore, exogenous PBMCs may alter the lowered immune response environment, which is required for scarless healing, resulting in scar formation. In conclusion, the present study indicated that the involvement of inflammatory cells is important during the healing process of deep­degree burned skin, and MMP­9 and TIMP­1 may serve important roles in the process of scar formation.

A novel dermal matrix generated from burned skin as a promising substitute for deep-degree burns therapy.

The extensive skin defects induced by severe burns are dangerous and can be fatal. Currently, the most common therapy is tangential excision to remove the necrotic or denatured areas of skin, followed by skin grafting. Xenogeneic dermal substitutes, such as porcine acellular dermal matrix (ADM), are typically used to cover the burn wounds, and may accelerate wound healing. It is assumed that burned skin that still maintains partial biological activity may be recycled to construct an autologous acellular dermal matrix, termed 'deep­degree burned dermal matrix (DDBDM)'. In theory, DDBDM may avoid the histoincompatibility issues associated with foreign or xenogeneic dermal matrices, and reduce therapy costs by making full use of discarded skin. In the present study, the collagens within prepared DDBDM were thickened, disorganized and partially fractured, however, they still maintained their reticular structure and tensile strength (P<0.01). Through microarray analysis of the cytokines present in ADM and DDBDM, it was determined that the DDBDM did not produce excessive levels of harmful burn toxins. Following 4 weeks of subcutaneous implantation, ADM and DDBDM were incompletely degraded and maintained good integrity. No significant inflammatory reaction or rejection were observed, which indicated that ADM and DDBDM have good histocompatibility. Therefore, DDBDM may be a useful material for the treatment of deep­degree burns.

[Scarless fetal wound healing and its mechanism].

Scarless healing is considered as the most ideal mode of wound repair. This ability generally exists in the early period of mammalian embryos, however it gradually turns to scar healing with the development of the embryos. This phenomenon is the result of the interaction of multiple biological functions, and the mechanism is still uncertain. This article deals with a systematical review of literature concerning the mechanism of scarless healing based on the recent experimental studies, hoping to provide evidence for the treatment of wounds to realize scarless healing in adult.

Conditioning and sampling issues of EMG signals in motion recognition of multifunctional myoelectric prostheses.

Historically, the investigations of electromyography (EMG) pattern recognition-based classification of intentional movements for control of multifunctional prostheses have adopted the filter cut-off frequency and sampling rate that are commonly used in EMG research fields. In practical implementation of a multifunctional prosthesis control, it is desired to have a higher high-pass cut-off frequency to reduce more motion artifacts and to use a lower sampling rate to save the data processing time and memory of the prosthesis controller. However, it remains unclear whether a high high-pass cut-off frequency and a low-sampling rate still preserve sufficient neural control information for accurate classification of movements. In this study, we investigated the effects of high-pass cut-off frequency and sampling rate on accuracy in identifying 11 classes of arm and hand movements in both able-bodied subjects and arm amputees. Compared to a 5-Hz high-pass cut-off frequency, excluding the EMG components below 60 Hz decreased the average accuracy of 0.1% in classifying the 11 movements across able-bodied subjects and increased the average accuracy of 0.1 and 0.4% among the transradial (TR) and shoulder disarticulation (SD) amputees, respectively. Using a 500 Hz instead of a 1-kHz sampling rate, the average classification accuracy only dropped about 2.0% in arm amputees. The combination of sampling rate and high-pass cut-off frequency of 500 and 60 Hz only resulted in about 2.3% decrease in average accuracy for TR amputees and 0.4% decrease for SD amputees in comparison to the generally used values of 1 kHz and 5 Hz. These results suggest that the combination of sampling rate of 500 Hz and high-pass cut-off frequency of 60 Hz should be an optimal selection in EMG recordings for recognition of different arm movements without sacrificing too much of classification accuracy which can also remove most of motion artifacts and power-line interferences for improving the performance of myoelectric prosthesis control.

Selection of sampling rate for EMG pattern recognition based prosthesis control.

Most previous studies of electromyography (EMG) pattern recognition control of multifunctional myoelectric prostheses adopted a conventional sampling rate that is commonly used in EMG research fields. However, it is unknown whether using a lower sampling rate in EMG acquisition still preserves sufficient neural control information for accurate classification of user movement intents. This study investigated the effects of EMG sampling rate on the performance of EMG pattern recognition in identifying 11 classes of arm and hand movements. Our results showed that decreasing the sampling rate from 1 kHz to 500 Hz only caused 0.8% reduction of the average classification accuracy over five able-bodied subjects and 2.2% decrease over two transradial amputees. When using a 400 Hz sampling rate, the average classification accuracy decreased 1.3% and 2.8% in able-bodied subjects and amputees, respectively. These results suggest that a sampling rate between 400-500 Hz would be optimal for EMG acquisition in EMG pattern recognition based control of a multifunctional prosthesis.