4027 Background: Concurrent chemoradiotherapy is the standard treatment method for inoperable and locally advanced esophageal cancer. Nevertheless, due to decreased physical function and the presence of multiple complications, older patients often have reduced tolerance to radiotherapy and chemotherapy. Methods: We conducted this prospective, single-center, phase II study to evaluate the efficacy and safety of nimotuzumab (an epidermal growth factor receptor antibody) plus concurrent radiotherapy and S-1 in 75 years and older patients with stage II-IVB esophageal squamous cell carcinoma (ESCC). The primary endpoint was progression-free survival (PFS). The secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, nutritional indicators, and quality of life (QOL). Most nutritional indicators remained stable after treatment. Results: As of June 2024, a total of 56 patients were enrolled in this study. The median follow-up was 24.1 months (95% CI: 8.8, 34.1). 11 patients had complete response, 39 patients had partial response, 5 patients had stable disease, and 1 patient had progressive disease. The ORR was 89.2%, and the DCR was 98.1%. The 1- and 3-year PFS rates were 67.8% (95% CI: 55.5%, 80.1%) and 35.8% (95% CI: 17.6%, 54.0%), with the median PFS was 25.3 months (95% CI: 16.5, 34.1). The 1- and 3-year OS rates were 79.6% (95% CI: 68.8%, 90.4%) and 40.1% (95% CI: 21.1%, 59.1%), with the median OS was 28.2 months (95% CI: 24.1, 32.3). Most adverse events were grade 1-2 (85.7%). Among survivors, 45.5% patients reported high satisfaction with their QOL, and 84.8% patients did not experience weight loss. Conclusions: Our treatment combination of nimotuzumab plus S-1 and concurrent radiotherapy indicated favorable efficacy and safety profile. This might be an underlying treatment choice for older patients with ESCC. Clinical trial information: NCT06048913 .

BACKGROUND:This phase II trial prospectively assessed the efficacy and safety of induction chemoimmunotherapy followed by sequential concurrent chemoradiotherapy plus immunotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who were ineligible for surgery. METHODS:Forty-four patients received 2 cycles of induction therapy (paclitaxel plus carboplatin/nedaplatin combined with a PD-1 inhibitor), followed by concurrent radiotherapy with two additional cycles of chemoimmunotherapy and subsequent immune maintenance therapy for up to 1 year. The primary endpoint was progression-free survival (PFS); the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), safety, and quality of life (QoL). RESULTS:At the data cut-off point (median follow-up: 25.5 months), both the ORR and DCR were 95.5%. The median PFS was 26 months (95% CI, 14.8-37.2), and the median OS was 29 months (95% CI, 23.0-35.0). The 1-, 2-, and 3-year PFS rates were 75.0%, 51.9%, and 40.4%, respectively, and the OS rates were 81.8%, 63.1%, and 42.0%, respectively. Distant metastasis represented the main failure mode (64.0%). Treatment-related adverse events were generally mild; moreover, 17 patients (38.6%) experienced grade ≥3 events, primarily involving hematologic toxicity (14/17). Severe immune-related adverse events were rarely observed. QoL assessment in surviving patients (n = 21) indicated favorable overall function and well-being. CONCLUSIONS:This regimen of induction chemoimmunotherapy followed by concurrent chemoradiotherapy and maintenance immunotherapy demonstrated promising survival outcomes, a manageable safety profile, and a preserved QoL, thereby offering a viable nonsurgical alternative for patients with locally advanced ESCC.

This study aims to evaluate the clinical effectiveness of trilaciclib in preventing myelosuppression in patients with esophageal cancer undergoing chemotherapy. Based on the use of trilaciclib, 81 patients were divided into a primary prevention group (PP group, n = 49) and a secondary prevention group (SP group, n = 32). The incidence of myelosuppression, antibiotic usage rate, survival outcomes, and other treatment-related toxicities were analyzed using chi-square tests and Kaplan–Meier survival curves. The incidence of chemotherapy-induced myelosuppression in the SP group was significantly higher than that in the PP group (96.9% vs. 79.6%), with a significantly higher proportion of grade III and above events (37.6% vs. 8.2%, p < 0.05). For chemotherapy-induced neutropenia, the incidence of grade III/IV events in the SP group was significantly higher than in the PP group (28.1% vs. 8.2%, p = 0.017). Additionally, the SP group experienced higher rates and severity of chemotherapy-induced anemia and thrombocytopenia. The PP group provided better protection against grade III/IV leukopenia and neutropenia (p < 0.05). Non-hematological toxicities and efficacy outcomes were similar between groups (p > 0.05). The study is the first to demonstrate that trilaciclib is a safe and effective option for the prevention of myelosuppression in esophageal cancer patients.

Primary osteoporosis, manifesting as decreased bone mass and increased bone fragility, is a “silent disease” that is often ignored until a bone breaks. Accordingly, it is urgent to develop reliable biomarkers and novel therapeutic strategies for osteoporosis treatment. Here, we identified REGγ as a potential biomarker of osteoporotic populations through proteomics analysis. Next, we demonstrated that REGγ deficiency increased osteoclast activity and triggered bone mass loss in REGγ knockout (KO) and bone marrow-derive macrophage (BMM)-conditional REGγ KO mice. However, the osteoclast activity decreased in BMM-conditional REGγ overexpression mice. Mechanistically, we defined that REGγ-20S proteasome directly degraded TRAF6 to inhibit bone absorption in a ubiquitin-independent pathway. More importantly, BMM-conditional Traf6 KO with REGγ KO mice could “rescue” the osteoporosis phenotypes. Based on NIP30 (a REGγ “inhibitor”) dephosphorylation by CKII inhibition activated the ubiquitin-independent degradation of TRAF6, we selected TTP22, an inhibitor of CKII, and defined that TTP22 could alleviate osteoporosis in vitro and in vivo. Overall, our study reveals a unique function of NIP30/REGγ/TRAF6 axis in osteoporosis and provides a potential therapeutic drug TTP22 for osteoporosis.

Background: Pancreatic cancer (PC) is a malignant gastrointestinal tumor with a terrible prognosis. Cuproptosis is a recently discovered form of cell death. This study is intended to explore the relationship between cuproptosis-related lncRNAs (CRLncs) signature with the prognosis and the tumor microenvironment (TME) of PC.Methods: Transcript sequencing data of PC samples with clinical information were obtained from the Cancer Genome Atlas (TCGA). Univariate Cox regression analysis and LASSO regression analysis were employed to construct the prognostic signature based on CRLncs associated with PC survival. A nomogram was created according to this signature, and the signaling pathway enrichment was analyzed. Subsequently, we explored the link between this prognostic signature with the mutational landscape and TME. Eventually, drug sensitivity was predicted based on this signature.Results: Forty-six of 159 CRLncs were most significantly relevant to the prognosis of PC, and a 6-lncRNA prognostic signature was established. The expression level of signature lncRNAs were detected in PC cell lines. The AUC value of the ROC curve for this risk score predicting 5-year survival in PC was .944, which was an independent prognostic factor for PC. The risk score was tightly related to the mutational pattern of PC, especially the driver genes of PC. Single-sample gene set enrichment analysis (ssGSEA) demonstrated a significant correlation between signature with the TME of PC. Ultimately, compounds were measured for therapy in high-risk and low-risk PC patients, respectively.Conclusion: A prognostic signature of CRLncs for PC was established in the current study, which may serve as a promising marker for the outcomes of PC patients and has important forecasting roles for gene mutations, immune cell infiltration, and drug sensitivity in PC.

1 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Texas Children’s Hospital, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA 3 Center for Cancer and Immunology Research, Children’s National Research Institute, Children’s National Hospital, Washington, DC, USA 4 Department of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 5 Advanced Technology Cores, Baylor College of Medicine, Houston, USA 6 Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA 7 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA *Correspondence to: H Zhang, Department of Pathology and Laboratory Medicine, Memorial

OBJECTIVE:To scrutinize the impact of overexpression and interference of NFE2L3 on radiosensitivity of esophageal squamous cell carcinoma cells (ESCC) and its downstream mechanism and to assess whether NFE2L3 expression alters in vivo radiosensitivity of ESCC by developing a subcutaneous tumor model in mice.METHODS:Through RNA-Seq, we compared the differentially expressed genes between the ECA-109R cell line and its parent ECA-109 cell line. The differentially expressed genes were selected and verified by qRT-PCR. Transfection of ESCC cell lines with NFE2L3 inhibitor or mimic lentivirus constructs was done to study the activity of NFE2L3. To assess the effect of NFE2L3 on cellular growth and proliferation, clonogenic survival assay, EdU incorporation assay, and CCK-8 assay were done after irradiation. To probe how many irradiated DNA double-strand breaks were produced, the corresponding intensity of γ-H2AX foci were detected by immunofluorescence. Apoptotic cells were assayed by flow cytometry assay after irradiation; To investigate the downstream genes of NFE2L3, we knocked NFE2L3, and RNA-Seq was used to find out the downstream genes. qRT-PCR and western blot ensued to score associated protein profiles. The in vivo ESCC cell radiosensitivity was scrutinized by nude mouse xenograft models.RESULTS:The differential genes between ECA-109R cells and its parent ECA-109 cells were compared by qRT-PCR to unveil a significant increase in NFE2L3 expression. Functional analysis indicated that NFE2L3 increased radioresistance in ESCC cells. Then, through high-throughput sequencing and bioinformatics analysis, IL-6 was found to be a hub gene that played a role downstream of NFE2L3 and was verified by qRT-PCR, western blot, and double luciferase reporter gene experiment. NFE2L3 could regulate ESCC cell radiosensitivity via the IL-6-STAT3 signaling pathway, and downregulation of IL-6 expression could reverse the effects of highly expressed NFE2L3. In vivo tumor xenograft experiments confirmed that NFE2L3 affects the sensitivity to radiation therapy.CONCLUSION:NFE2L3 can affect the radiosensitivity of ESCC cells through IL-6 transcription and IL-6/STAT3 signaling pathway. This makes NFE2L3 a putative target to regulate ESCC cell radiosensitivity.

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

The radioresistance of oesophageal squamous cell carcinoma (OSCC) is a critical factor leading to a poor prognosis among patients. The expression of PBX1 is abnormally high in a broad range of human tissues, and this gene plays a key role in tumour proliferation. This research intended to explore the radiosensitization of OSCC by silencing PBX1. The OSCC cell lines KYSE450 and KYSE150 were subjected to PBX1 silencing and/or irradiation (IR). Cell proliferation, colony formation, and apoptosis were tested to evaluate the radiosensitization ability of PBX1 silencing. The levels of STAT3 and p-STAT3 in the OSCC cells were tested by Western blotting. Furthermore, KYSE150 cells with or without PBX1 silencing were xenografted into nude mice with or without radiation exposure. Concomitant PBX1 silencing and IR can obviously suppress growth and enhance radiosensitivity in OSCC cells and xenografts. Moreover, the downregulation of PBX1 inhibits the expression of STAT3 and p-STAT3. The downregulation of PBX1 may increase radiosensitivity in OSCC cells and xenografts via the PBX1/STAT3 pathway. Our findings demonstrate that PBX1 may be a potential target for promoting the effect of radiation therapy in OSCC patients.

Radioresistance reduces the success of therapy for patients with ESCC. Enhancing our understanding of the cardinal principles of radioresistance may improve the response of patients to irradiation. MicroRNAs perform a key role in posttranscriptional regulation, which is linked with the response of tumors to irradiation. Here, we successfully constructed a radioresistant cell line model, ECA109R, from parental esophageal cancer cell line ECA109. We used RNA-Seq analysis and qRT-PCR to compare the miRNA expression profiles of the ECA109 and ECA109R cell lines. The results revealed that miR-450a-5p was downregulated in the radioresistant cells. Functional analysis indicated that miR-450a-5p increases cellular radiosensitivity and suppresses autophagy in ESCC cells. We utilized a luciferase reporter assay to identify the target gene, DUSP10, as an indispensable regulator of the p38 and SAPK/JNK signaling pathways. Upregulation or downregulation of DUSP10 expression could reverse the effects of miR-450a-5p overexpression or inhibition. Tumor xenograft experiments verified that miR-450a-5p overexpression could increase sensitivity to radiation therapy in vivo. In general, our findings indicate that miR-450a-5p is a latent radiosensitizer and may represent a potential novel therapeutic target for radioresistance in ESCC.

膝骨性关节炎(knee osteoarthritis,KOA)是膝关节的慢性退变性疾病.KOA的主要病理改变是关节软骨的进行性破坏,软骨下骨质丢失.目前临床上对于早中期KOA的治疗方法十分有限.富血小板血浆(platelet-rich plasma,PRP)是外周血多次离心后的血小板浓缩物,在医学专业应用近三十年,近十年逐渐应用于骨科修复软骨、肌腱和韧带等,成为治疗KOA的热点.PRP治疗KOA的可能机制主要包括通过释放多种生长因子、促进蛋白多糖和胶原蛋白的合成以及刺激骨髓间充质干细胞和内源性透明质酸(hyaluronic acid,HA)的生成,达到修复软骨、延缓KOA进展的目的.多数研究表明,相对于传统的关节腔内注射药物和口服非甾体抗炎药(Non-steroidal anti-inflammatory drugs,NASIDs),关节内注射PRP可有效改善KOA病人的临床症状,但是关于PRP的作用时间、使用剂量和注射次数尚无统一标准.本文通过回顾目前关于PRP治疗KOA的基础、动物及临床研究,对PRP的生物学特性、作用机制、临床疗效及存在的问题进行综述.

Although human dermal fibroblast heterogeneity has been acknowledged for several decades and a large body of in vitro studies has been performed with zonal dermal fibroblast, current autologous dermal fibroblast therapies do not reflect human dermal fibroblast heterogeneity. To determine if the utilization of human dermal fibroblast heterogeneity in autologous dermal fibroblast therapy is more of a translational perspective that may thus be more likely to make it to the clinic, this article critically reviews the previous studies on dermal fibroblast heterogeneity performed to date. We found that in vitro studies of human dermal fibroblast heterogeneity have run nearly parallel to the in vivo study of autologous dermal fibroblast therapy. Although several human to nude mice xenotransplantation experiments have been performed in different layers of human dermal fibroblast, their clinical significance remains to be considered. We conclude that there is still a great gap between basic experiments and the clinical employment of human dermal fibroblast heterogeneity. To overcome this, it is necessary to conduct clinical trials, which might be restricted by ethical issues. Alternatively, it might be easier to conduct in vivo studies in animal models. Based on our previous study of dermal fibroblast heterogeneity in pigs, we propose the use of pigs as a good animal model for dermal fibroblast heterogeneity. Time will show whether the utilization of human dermal fibroblast heterogeneity in autologous dermal fibroblast therapy is an overcomplicated strategy or a promising approach. Anat Rec, 302:2126-2131, 2019. © 2019 American Association for Anatomy.

Aim:Radiation therapy has been proven “safe and effective” in the management of colorectal cancer liver metastases, especially for oligometastases. However, to date, there is no consensus on optimal prescribed doses or dose fraction schemes. The current study was conducted to investigate the effectiveness and safety of 2 different radiation therapy methods, conventional conformal radiation therapy and stereotactic body radiation therapy, in the treatment of limited colorectal cancer liver metastases. Methods:From December 2011 to December 2016, twenty-six patients with colorectal cancer having postoperative liver metastases (≤3) who were being treated with radiation therapy, either conventional conformal radiation therapy (50 Gy in 25 fractions) or stereotactic body radiation therapy (50 Gy in 10 fractions), were selected for this study. Overall survival and local control survival were analyzed by log-rank and Cox regression methods. Results:Radiation therapy delivered to each of the 26 patients with a total of 50 liver lesions. Conformal radiation therapy was delivered to 32 lesions in a total of 15 patients. Stereotactic body radiation therapy was delivered to 18 lesions in a total of 11 patients. Median follow-up was 13 months. Three-year overall survival and local control survival were 0% and 38.5%, 20.5%, and 53.0%, respectively, for the conformal radiation therapy and stereotactic body radiation therapy groups. The slightly better overall survival and local control survival in the stereotactic body radiation therapy group in comparison to the conformal radiation therapy group (P = .323 and .297) is insignificant. There were no differences in grade 3 hepatic toxicity between the 2 groups. Eastern Cooperative Oncology Group performance status and the number of liver lesions were significant prognostic factors in both univariate and multivariate analyses. Conclusions:Noninvasive radiation therapy provides satisfactory survival benefit for limited colorectal cancer liver metastases without intolerable toxicity and is therefore especially suitable for those elderly patients with poor performance status. Furthermore, stereotactic body radiation therapy with a higher biological equivalent dose and an abbreviated course of treatment has been shown to provide a better outcome than conventional conformal radiation therapy.

S100 calcium-binding protein B (S100B) is expressed and released by adipocytes, and is positively correlated with body mass index, however, the direct effects of S100B on adipocytes remain unclear. Bone marrow-derived mesenchymal stem cells have the capacity to differentiate into osteoblasts and adipocytes, which is important for bone metabolism. The current study aimed to determine the effect of S100B on adipogenesis and osteogenesis. The mouse embryo cell line C3H/10T1/2 was used to build cell models with varying levels of S100B protein expression. Western blot analysis was performed to assess the expression of various marker proteins. Oil red O staining and alizarin red S staining were used to detect adipogenesis and osteogenesis, respectively. S100B overexpression was associated with a significant increase in oil red O staining and a significant reduction in alizarin red S staining. Runt-related transcription factor-2 and bone morphogenetic protein 2 expression levels were significantly increased in the S100B underexpression group, however not in the S100B overexpression group. By contrast, the expression levels of the adipogenesis markers peroxisome proliferator-activated receptor and CCAAT-enhancer-binding protein was significantly increased in the S100B overexpression group, however not in the S100B underexpression group. Osteogenesis stimulation increased extracellular signal-regulated kinase (ERK) phosphorylation, and adipogenesis stimulation increased c-Jun N-terminal kinase (JNK) phosphorylation. The results suggest that S100B inhibits osteogenesis, however stimulates adipogenesis. The ERK pathway is involved in the regulation of osteogenesis, whereas the JNK pathway is involved in the regulation of adipogenesis.

The goal of this study was to determine if neurofibromin is expressed in cultured human osteoblasts and chondrocytes that were isolated from ilia and ilial growth plate. Purity of the osteoblast and chondrocyte cultures was confirmed by alkaline phosphatase and toluidine blue staining, respectively. The reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect neurofibromin mRNA. Indirect immunofluorescence and Western blot studies were done to delineate the cellular distribution and expression levels of neurofibromin. These experiments show that neurofibromin is expressed at low levels in human osteoblasts and chondrocytes and is located mainly in the cytoplasm. Only the type II isoform of neurofibromin is detected in these cells. These findings suggest that the type II isoform of neurofibromin plays a physiological role in human osteoblasts and chondrocytes. Whether functional deficiency of neurofibromin is responsible for skeletal abnormalities remains to be established.