Enhanced Detection of Early Pulmonary Fibrosis Disease Using 68Ga-FAPI-LM3 PET.

Early detection of pulmonary fibrosis is a critical yet insufficiently met clinical necessity. This study evaluated the effectiveness of FAPI-LM3, a 68Ga-radiolabeled heterobivalent molecular probe that targets fibroblast activating protein (FAP) and somatostatin receptor 2 (SSTR2), in the early detection of pulmonary fibrosis, leveraging its potential for early disease identification. A bleomycin-induced early pulmonary fibrosis model was established in C57BL/6 mice for 7 days. FAP and SSTR2 expression levels were quantitatively assessed in human idiopathic pulmonary fibrosis lung tissue samples and bleomycin-treated mouse lung tissues by using western blotting, real-time quantitative PCR (RT-qPCR), and immunofluorescence techniques. The diagnostic performance of FAPI-LM3 was investigated by synthesizing monomeric radiotracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3 alongside the heterobivalent probe 68Ga-FAPI-LM3. These imaging radiopharmaceuticals were used in small-animal PET to compare their uptake in fibrotic and normal lung tissues. Results indicated significant upregulation of FAP and SSTR2 at both RNA and protein levels in fibrotic lung tissues compared with that in normal controls. PET imaging demonstrated significantly enhanced uptake of the 68Ga-FAPI-LM3 probe in fibrotic lung tissues, with superior visual effects compared to monomeric tracers. At 60 min postinjection, early stage fibrotic tissues (day 7) demonstrated low-to-medium uptake of monomeric probes, including 68Ga-DOTA-LM3 (0.45 ± 0.04% ID/g) and 68Ga-FAPI-46 (0.78 ± 0.09% ID/g), whereas the uptake of the heterobivalent probe 68Ga-FAPI-LM3 (1.90 ± 0.10% ID/g) was significantly higher in fibrotic lesions than in normal lung tissue. Blockade experiments confirmed the specificity of 68Ga-FAPI-LM3 uptake, which was attributed to synergistic targeting of FAP and SSTR2. This study demonstrates the potential of 68Ga-FAPI-LM3 for early pulmonary fibrosis detection via molecular imaging, offering significant benefits over monomeric tracers 68Ga-FAPI-46 and 68Ga-DOTA-LM3. This strategy offers new possibilities for noninvasive and precise early detection of pulmonary fibrosis.

Highly Sensitive Detection of PIK3CA Mutations by Looping-Out Probes-Based Melting Curve Analysis.

PIK3CA mutations have important therapeutic and prognostic implications in various cancer types. However, highly sensitive detection of PIK3CA hotspot mutations in heterogeneous tumor samples remains a challenge in clinical settings. To establish a rapid PCR assay for highly sensitive detection of multiple PIK3CA hotspot mutations. We described a novel melting curve analysis-based assay using looping-out probes that can enrich target mutations in the background of excess wild-type and concurrently reveal the presence of mutations. The analytical and clinical performance of the assay were evaluated. The developed assay could detect 10 PIK3CA hotspot mutations at a mutant allele fraction of 0.05-0.5% within 2 h in a single step. Analysis of 82 breast cancer tissue samples revealed 43 samples with PIK3CA mutations, 28 of which were confirmed by Sanger sequencing. Further testing of 175 colorectal cancer tissue samples showed that 24 samples contained PIK3CA mutations and 19 samples were confirmed by Sanger sequencing. Droplet digital PCR supported that all mutation-containing samples undetected by sequencing contained mutations with a low allele fraction. The rapidity, ease of use, high sensitivity and accuracy make the new assay a potential screening tool for PIK3CA mutations in clinical laboratories.

DPY30 promotes colorectal carcinoma metastasis by upregulating ZEB1 transcriptional expression.

DPY30 belongs to the core subunit of components of the histone lysine methyltransferase complex, which is implicated in tumorigenesis, cell senescence, and other biological events. However, its contribution to colorectal carcinoma (CRC) progression and metastasis has yet to be elucidated. Therefore, this study aimed to investigate the biological function of DPY30 in CRC metastasis both in vitro and in vivo. Herein, our results revealed that DPY30 overexpression is significantly positively correlated with positive lymph nodes, epithelial-mesenchymal transition (EMT), and CRC metastasis. Moreover, DPY30 knockdown in HT29 and SW480 cells markedly decreased EMT progression, as well as the migratory and invasive abilities of CRC cells in vitro and lung tumor metastasis in vivo. Mechanistically, DPY30 increased histone H3K4me3 level and promoted EMT and CRC metastasis by upregulating the transcriptional expression of ZEB1. Taken together, our findings indicate that DPY30 may serve as a therapeutic target and prognostic marker for CRC.

DPY30 Promotes Proliferation and Cell Cycle Progression of Colorectal Cancer Cells via Mediating H3K4 Trimethylation.

DPY30, a core subunit of the SET1/MLL histone H3K4 methyltransferase complexes, plays an important role in diverse biological functions through the epigenetic regulation of gene transcription, especially in cancer development. However, its involvement in human colorectal carcinoma (CRC) has not been elucidated yet. Here we demonstrated that DPY30 was overexpressed in CRC tissues, and significantly associated with pathological grading, tumor size, TNM stage, and tumor location. Furthermore, DPY30 knockdown remarkably suppressed the CRC cell proliferation through downregulation of PCNA and Ki67 in vitro and in vivo, simultaneously induced cell cycle arrest at S phase by downregulating Cyclin A2. In the mechanistic study, RNA-Seq analysis revealed that enriched gene ontology of cell proliferation and cell growth was significantly affected. And ChIP result indicated that DPY30 knockdown inhibited H3 lysine 4 trimethylation (H3K4me3) and attenuated interactions between H3K4me3 with PCNA, Ki67 and cyclin A2 respectively, which led to the decrease of H3K4me3 establishment on their promoter regions. Taken together, our results demonstrate overexpression of DPY30 promotes CRC cell proliferation and cell cycle progression by facilitating the transcription of PCNA, Ki67 and cyclin A2 via mediating H3K4me3. It suggests that DPY30 may serve as a potential therapeutic molecular target for CRC.

Development of Fibroblast Activation Protein Inhibitor-Based Dimeric Radiotracers with Improved Tumor Retention and Antitumor Efficacy.

Fibroblast activation protein (FAP), a fundamental component of the tumor stroma, is overexpressed in cancer-associated fibroblasts (CAFs). As a promising theranostic probe, we evaluated whether the FAP inhibitor (FAPI) dimer (DOTA-2P[FAPI]2) is more effective than its monomeric analogs for FAP-targeted radionuclide therapy. [68Ga]Ga/[177Lu]Lu-DOTA-2P(FAPI)2 were assayed in a stability study, small-animal positron emission tomography (PET) and single-photon emission computed tomography (SPECT), biodistribution, and radionuclide therapy to comprehensively evaluate their preclinical pharmacokinetics. The pharmacokinetics of [68Ga]Ga-DOTA-2P(FAPI)2 and [177Lu]Lu-DOTA-2P(FAPI)2 were determined in FAP-positive hepatocellular carcinoma patient-derived xenografts (PDXs) and HT-1080-FAP cell-derived xenografts (CDXs). [68Ga]Ga-DOTA-2P(FAPI)2 and [177Lu]Lu-DOTA-2P(FAPI)2 were stable in phosphate-buffered saline for 4 h. The tumor retention of [68Ga]Ga-DOTA-2P(FAPI)2 was better than that of [68Ga]Ga-FAPI-46 in HT-1080-FAP CDXs, while healthy organs showed low tracer uptake and fast body clearance. In single-photon emission computed tomography, [177Lu]Lu-DOTA-2P(FAPI)2 showed a higher uptake and longer retention for tumors in both PDXs and CDXs from 1-48 h. [177Lu]Lu-DOTA-2P(FAPI)2 showed the best inhibition of tumor growth in PDXs and CDXs. DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared to FAPI-46, which significantly improves the use of FAPI-based vectors for PET imaging and radionuclide therapy. [177Lu]Lu-DOTA-2P(FAPI)2 may be safe and effective for the treatment of FAP-positive malignant tumors.

Effect of Denonvilliers' Fascia Preservation Versus Resection During Laparoscopic Total Mesorectal Excision on Postoperative Urogenital Function of Male Rectal Cancer Patients: Initial Results of Chinese PUF-01 Randomized Clinical Trial.

OBJECTIVE: To compare the outcomes of laparoscopic total mesorectal excision (L-TME) with Denonvilliers' fascia (DVF) preservation versus resection on urogenital function of male patients with rectal cancer. BACKGROUND: The protective effect of DVF during L-TME on pelvic autonomic nerves and postoperative urogenital function remains controversial. METHODS: Between August 26, 2015 and July 18, 2019, 253 male patients with cT1-4 (T1-2 for anterior wall) N0-2M0 rectal cancer from 11 institutions were enrolled, and randomly assigned to L-TME with DVF preservation (Exp-group, n = 123) or resection procedures (Con-group, n = 130). Urinary function was assessed by residual urine volume, maximal flow rate, and International Prostate Symptom Score; sexual function was assessed by 5-item version of the International Index of Erectile Function (IIEF-5) and ejaculation grading. RESULTS: The Exp-group patients showed a lower urinary dysfunction rate (6.8% vs 25.4%, P = 0.003), higher maximal flow rate (16.25 ±â€Š8.02 vs 12.40 ±â€Š7.05 mL/s, P = 0.007), and lower International Prostate Symptom Score (6.55 ±â€Š5.86 vs 8.57 ±â€Š5.85, P = 0.026) than the Con-group patients at 2 weeks after surgery. The incidence of erectile dysfunction (IIEF-5 ≤ 11) at 12 months after surgery was lower in the Exp-group than in the Con-group (12.5% vs 34.2%, P = 0.023); Exp-group manifested superior IIEF-5 (16.63 ±â€Š6.28 vs 12.26 ±â€Š6.83, P = 0.018). The incidence of ejaculation dysfunction was lower in the Exp-group than in the Con-group at 12 months after surgery (10.0% vs 29.4%, P = 0.034). CONCLUSIONS: DVF preservation during L-TME revealed protective effects on postoperative urogenital function, and could be a better choice for male rectal cancer patients with specific staging and location. TRIAL REGISTRATION NUMBER: NCT02435758.

Conditional survival and recurrence of remnant gastric cancer after surgical resection: A multi-institutional study.

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow-up strategies. A total of 298 patients were analyzed for their 3-year conditional overall survival (COS3), 3-year conditional disease-specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5-year overall survival (OS) and the 5-year disease-specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%-83.0%, Δ36.6% vs ≤T2: 82.4%-85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time-dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time-dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow-up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow-up model for RGC patients of different stages, which may affect the design of future clinical trials.

Dexmedetomidine alleviates smoke-induced bronchial and alveolar epithelial cell injury.

Dexmedetomidine (Dex) is a selective α2-adrenoceptor agonist and has ability to prevent inflammation and apoptosis in tissues injury. However, whether Dex could alleviate smoke-induced lung injury remains unknown. This study aimed to explore the protective effects of Dex against smoke-induced lung injury. Bronchial and alveolar epithelial cells were treated with cigarette smoke extract (CSE) for 24 h to simulate cigarette smoke-induced lung injury. Results showed that CSE reduced cell viability and increased levels of pro-inflammatory cytokines TNFα, IL-1ß and IL-6, thus activating NF-κB and COX2 expression. CSE also increased ROS generation, whereas lessened MnSOD and catalase generation. Besides, the ratio of apoptotic cells was enhanced upon CSE stimuli, together with disturbance of apoptotic-related proteins including Bcl-2, Bax and caspase-3. However, Dex reduced the damage of CSE to cell viability. The increased activities of TNFα, IL-1ß and IL-6 induced by CSE were partially attenuated by Dex. Dex also recovered the levels of NF-κB and COX2, as well as mnSOD, catalase and ROS. Furthermore, the increase of cell apoptosis together with imbalance of apoptotic proteins induced by CSE was rescued by Dex. Our results demonstrated that Dex alleviated CSE-induced lung injury through inhibition of inflammation, oxidative stress and apoptosis.

Histone demethylase JMJD1A promotes colorectal cancer growth and metastasis by enhancing Wnt/ß-catenin signaling.

The histone demethylase Jumonji domain containing 1A (JMJD1A) is overexpressed in multiple tumors and promotes cancer progression. JMJD1A has been shown to promote colorectal cancer (CRC) progression, but its molecular role in CRC is unclear. Here, we report that JMJD1A is overexpressed in CRC specimens and that its expression is positively correlated with that of proliferating cell nuclear antigen (PCNA). JMJD1A knockdown decreased the expression of proliferative genes such as c-Myc, cyclin D1, and PCNA, suppressed CRC cell proliferation, arrested cell cycle progression, and reduced xenograft tumorigenesis. Furthermore, JMJD1A knockdown inhibited CRC cell migration, invasion, and lung metastasis by decreasing matrix metallopeptidase 9 (MMP9) expression and enzymatic activity. Moreover, bioinformatics analysis of GEO profile datasets revealed that JMJD1A expression in human CRC specimens is positively correlated with the expression of Wnt/ß-catenin target genes, including c-Myc, cyclin D1, and MMP9. Mechanistically, JMJD1A enhanced Wnt/ß-catenin signaling by promoting ß-catenin expression and interacting with ß-catenin to enhance its transactivation. JMJD1A removed the methyl groups of H3K9me2 at the promoters of c-Myc and MMP9 genes. In contrast, the JMJD1AH1120Y variant, which lacked demethylase activity, did not demethylate H3K9me2 at these promoters, failed to assist ß-catenin to induce the expression of Wnt/ß-catenin target genes, and failed to promote CRC progression. These findings suggest that JMJD1A's demethylase activity is required for Wnt/ß-catenin activation. Of note, high JMJD1A levels in CRC specimens predicted poor cancer outcomes. In summary, JMJD1A promotes CRC progression by enhancing Wnt/ß-catenin signaling, implicating JMJD1A as a potential molecular target for CRC management.

Steroid Receptor Coactivator 3 Contributes to Host Defense against Enteric Bacteria by Recruiting Neutrophils via Upregulation of CXCL2 Expression.

Steroid receptor coactivator 3 (SRC-3) is a transcriptional coactivator that interacts with nuclear receptors and some other transcription factors to enhance their effects on target gene transcription. We reported previously that SRC-3-deficient (SRC-3-/-) mice are extremely susceptible to Escherichia coli-induced septic peritonitis as a result of uncontrolled inflammation and a defect in bacterial clearance. In this study, we observed significant upregulation of SRC-3 in colonic epithelial cells in response to Citrobacter rodentium infection. Based on these findings, we hypothesized that SRC-3 is involved in host defense against attaching and effacing bacterial infection. We compared the responses of SRC-3-/- and wild-type mice to intestinal C. rodentium infection. We found that SRC-3-/- mice exhibited delayed clearance of C. rodentium and more severe tissue pathology after oral infection with C. rodentium compared with wild-type mice. SRC-3-/- mice expressed normal antimicrobial peptides in the colons but exhibited delayed recruitment of neutrophils into the colonic mucosa. Accordingly, SRC-3-/- mice showed a delayed induction of CXCL2 and CXCL5 in colonic epithelial cells, which are responsible for neutrophil recruitment. At the molecular level, we found that SRC-3 can activate the NF-κB signaling pathway to promote CXCL2 expression at the transcriptional level. Collectively, we show that SRC-3 contributes to host defense against enteric bacteria, at least in part via upregulating CXCL2 expression to recruit neutrophils.

Risk factors for neck hematoma requiring surgical re-intervention after thyroidectomy: a systematic review and meta-analysis.

BACKGROUND: In this systematic review and meta-analysis, we aimed to determine the risk factors associated with neck hematoma requiring surgical re-intervention after thyroidectomy. METHODS: We systematically searched all articles available in the literature published in PubMed and CNKI databases through May 30, 2017. The quality of these articles was assessed using the Newcastle-Ottawa Quality Assessment Scale, and data were extracted for classification and analysis by focusing on articles related with neck hematoma requiring surgical re-intervention after thyroidectomy. Our meta-analysis was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. RESULTS: Of the 1028 screened articles, 26 met the inclusion criteria and were finally analyzed. The factors associated with a high risk of neck hematoma requiring surgical re-intervention after thyroidectomy included male gender (odds ratio [OR]: 1.86, 95% confidence interval [CI]: 1.60-2.17, P < 0.00001), age (MD: 4.92, 95% CI: 4.28-5.56, P < 0.00001), Graves disease (OR: 1.81, 95% CI: 1.60-2.05, P < 0.00001), hypertension (OR: 2.27, 95% CI: 1.43-3.60, P = 0.0005), antithrombotic drug use (OR: 1.92, 95% CI: 1.51-2.44, P < 0.00001), thyroid procedure in low-volume hospitals (OR: 1.32, 95% CI: 1.12-1.57, P = 0.001), prior thyroid surgery (OR: 1.93, 95% CI: 1.11-3.37, P = 0.02), bilateral thyroidectomy (OR: 1.19, 95% CI: 1.09-1.30, P < 0.0001), and neck dissection (OR: 1.55, 95% CI: 1.23-1.94, P = 0.0002). Smoking status (OR: 1.19, 95% CI: 0.99-1.42, P = 0.06), malignant tumors (OR: 1.00, 95% CI: 0.83-1.20, P = 0.97), and drainage used (OR: 2.02, 95% CI: 0.69-5.89, P = 0.20) were not significantly associated with postoperative neck hematoma. CONCLUSION: We identified certain risk factors for neck hematoma requiring surgical re-intervention after thyroidectomy, including male gender, age, Graves disease, hypertension, antithrombotic agent use, history of thyroid procedures in low-volume hospitals, previous thyroid surgery, bilateral thyroidectomy, and neck dissection. Appropriate intervention measures based on these risk factors may reduce the incidence of postoperative hematoma and yield greater benefits for the patients.

High ligation of the inferior mesenteric artery during sigmoid colon and rectal cancer surgery increases the risk of anastomotic leakage: a meta-analysis.

BACKGROUND: The ideal level of ligation of the inferior mesenteric artery (IMA) during curative resection of sigmoid colon and rectal cancer is still controversial. The aim of this meta-analysis was to examine the impact of high ligation and low ligation of the IMA on anastomotic leakage, overall morbidity, postoperative mortality, and oncological outcomes in patients undergoing surgery for sigmoid colon and rectal cancer. METHODS: PubMed, EMBASE, Web of Science, and BioMed Central databases were searched to identify relevant articles published from May 1953 to March 2018. A total of 18 articles (14 non-randomized studies and 4 randomized clinical trials) were identified. Review Manager 5.3 software was used for analysis of data. The pooled odds ratio (OR) and weighted mean difference (WMD), with 95% CI, were calculated using either the fixed effects model or random effects model. RESULTS: Of the 5917 patients included in this meta-analysis, 3652 patients underwent low ligation of the IMA and 2265 patients underwent high ligation of the IMA. Anastomotic leakage rate was 9.8% in high ligation patients vs. 7.0% in low ligation patients; the risk of anastomotic leakage was significantly higher in high ligation patients (OR = 1.33; 95% CI 1.10-1.62; P = 0.004). What is more, overall morbidity was also significantly higher in high ligation patients (OR = 1.39; 95% CI, 1.05-1.68; P = 0.05). Postoperative mortality, number of harvested lymph nodes, overall recurrence rate, and 5-year survival rate did not differ significantly between the two groups. CONCLUSION: Low ligation of the IMA during curative resection of sigmoid colon and rectal cancer appears to be associated with lower risk of anastomotic leakage and overall morbidity. However, there was no significant advantage of low ligation over high ligation of IMA in terms of postoperative mortality, the number of harvested lymph nodes, overall recurrence rate, or 5-year survival rate.

Correlation Between Interleukin-1ß-511 C/T Polymorphism and Gastric Cancer in Chinese Populations: A Meta-Analysis.

BACKGROUND Several studies have indicated that interleukin (IL)-1ß-511 C/T polymorphism may contribute to individual susceptibility to gastric cancer, but the results vary among regions and races. No relevant meta-analysis has been conducted in a Chinese population. Therefore, we performed the current meta-analysis to investigate the possible correlation between IL-1ß-511 C/T polymorphism and gastric cancer susceptibility in Chinese subjects. MATERIAL AND METHODS PubMed, EmBase, Cochrane Library, Chinese Biology Medicine (CBM), Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases were searched for case-control studies published before 21 January 2015 and investigating a correlation between IL-1ß-511 C/T polymorphism and gastric cancer susceptibility. Two investigators independently screened the studies, extracted data, and evaluated the quality of included studies with the Newcastle-Ottawa scale. Meta-analysis was conducted with STATA 12.0. RESULTS A total of 27 articles from 28 case-control studies were collected. Meta-analysis showed that IL-1ß-511C/T polymorphism was related to increased susceptibility to gastric cancer in Chinese subjects [T vs. C: OR=1.21, 95%CI (1.07-1.37), P<0.01; TT vs. CC: OR=1.41, 95%CI (1.11-1.80), P<0.01; CT vs. CC: OR=1.26, 95% CI (1.05-1.50), P<0.01; TT+CT vs. CC: OR=1.31, 95%CI (1.08-1.58), P<0.01; and TT vs. CT+CC: OR=1.24, 95%CI (1.05-1.47), P<0.01]. Subgroup analysis showed a significant correlation between IL-1ß-511C/T polymorphism and susceptibility to gastric cancer in residents of southern China and in patients with intestinal-type gastric cancer, but not in residents of northern China or in patients with diffuse gastric cancer. Moreover, H. pylori-infected subjects carrying T (CT+TT) exhibited a relatively higher risk of GC [OR=2.4, 95% CI (1.2-5.1), P=0.02]. CONCLUSIONS IL-1ß-511C/T polymorphism is significantly associated with increased susceptibility to gastric cancer in residents of southern China and in intestinal-type gastric cancer. We also found a synergistic interaction between IL-1ß-511C/T polymorphism and H. pylori infection in the development of GC.

Design, synthesis and evaluation of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives as antithrombotic agents.

A series of isoxazolo[5,4-d]pyrimidin-4(5H)-one derivatives have been designed and synthesized as novel antithrombotic agents. The 4-acetoxyl substituted derivative (6g) displays very strong FXa inhibitory activity (IC50=0.013µM), excellent anticoagulant effect in human plasma (2×PT=2.12µM) and high selectivity to thrombin and trypsin. Docking investigation of 6g with FXa protein revealed that the pyrimidone ring of 6g formed a π-π interaction with the phenyl ring of Tyr99, and the carbonyl group in the P1 moiety formed multiple hydrogen bonds to Ser214 and Trp215. These results showed that isoxazolo[5,4-d]pyrimidin-4(5H)-one is an attractive scaffold for designing novel factor Xa inhibitors and 4-carbonyl substituted phenyl ring could be used as novel S1 binding element.

[Clinicopathological features and prognosis of renal cell carcinoma with sarcomatoid differentiation].

OBJECTIVE: To study the clinicopathological features and prognosis of renal cell carcinoma with sarcomatoid differentiation (RCCS). METHODS: The clinical data and pathological materials of 18 RCCS cases were retrospectively reviewed.The follow up data were available in 13 RCCS cases, and were compared with the follow up data of 20 cases of clear cell renal cell carcinoma (RCC). RESULTS: The 18 RCCS patients included 14 males and 4 females, and were 49-79 years old (mean age: 62 years old). On gross examination, the tumor size was 3-19 cm in diameter (mean diameter: 9.8 cm). Histologically, all tumors were composed of a mixture of typical RCC with sarcomatoid component, including 9 clear cell RCC, 3 chromophobe RCC and one papillary RCC. The sarcomatoid components included 9 cases of fibrosarcoma, 3 cases of leiomyosarcoma, 5 cases of malignant fibrous histocytoma and one case of undifferentiated sarcoma. Immunohistochemistry showed that the sarcomatoid components were strongly vimentin-positive in 18 cases, and one or more epithelial markers (EMA, AE1/AE3, CK7, CK18) were expressed to varying degrees in 14 cases, but the high-molecular weight keratin 34ßE12 was scarcely expressed. The sarcomatoid components presented positive expressions of CAIX in 88.9% (16/18) and CD10 in 72.2% (13/18) cases. Among the 18 RCCS patients, 13 patients were followed-up: 9 patients died in 1-25 months after the surgery, of which 5 cases died of lung or bone metastasis, and 4 patients died of systemic failure. The twenty RCC cases without sarcomatoid differentiation were followed up for 3-65 months after the surgery, and the majority of them was alive uneventfully except for 2 cases who died of lung or bone metastasis of the tumor. The Kaplan-Meier survival analysis showed that the median survival time of the 18 RCCS patients was 8 months, while that of the 20 RCC cases without sarcomatoid differentiation was 62 months (P<0.001). CONCLUSIONS: The presence of sarcomatoid differentiation in renal cell carcinoma indicates highly aggressive behavior and poor prognosis. The positive expressions of the immune markers CAIX and CD10 may play important roles in the transformation from renal cell carcinoma to sarcomatoid component.

The relationship between physical activity, self-efficacy and quality of life in colorectal cancer survivors: a multicenter cross-sectional study.

PURPOSE: This study aimed to investigate the current situation and factors influencing physical activity, self-efficacy, and quality of life in Chinese colorectal cancer survivors. Additionally, this study explored the associations between physical activity, self-efficacy, and quality of life. METHODS: A multicenter, cross-sectional study was conducted, involving 173 colorectal cancer survivors with a mean age of 59 years. Self-reported data on basic demographic characteristics, physical activity, self-efficacy, and quality of life were collected. RESULTS: Among 173 colorectal cancer survivors, 90 (52.0%) were engaged in manual work. The self-efficacy score was found to be 25.99 ± 7.10, while the global health status score was 54.96 ± 21.56. Global health status was associated with sex, residence, chemoradiotherapy, and monthly income (p < 0.01). The self-efficacy score exhibited a significant positive correlation with quality of life, while demonstrating a negative correlation with symptom scores (p < 0.01). Recreational PA scores were positively associated with global health status (P < 0.05). Self-efficacy, recreational physical activity during winter, and whether the participants underwent chemoradiotherapy explained 29.3% of the variance in quality of life among colorectal cancer survivors. CONCLUSIONS: Colorectal cancer survivors exhibited low levels of physical activity, self-efficacy, and quality of life. Their health is influenced by self-efficacy, recreational physical activity, and chemoradiotherapy. When developing intervention plans for colorectal cancer survivorship, it is crucial to consider survivors' self-efficacy and the type of physical activity in which they engage.

DPY30 knockdown suppresses colorectal carcinoma progression via inducing Raf1/MST2-mediated apoptosis.

Colorectal Carcinoma (CRC) is one of the most common malignant tumors of the digestive tract, with a high mortality rate. DPY30 is one of the core subunits of the histone methyltransferase complex, which was involved in many cancer processes. However, the role of DPY30 in the occurrence and progression of CRC remains unclear. In this study, we sought to evaluate the role and mechanism of DPY30 in CRC cells apoptosis. Here, we identified that knockdown of DPY30 significantly inhibited the HT29 and HCT116 cells proliferation in vitro. Moreover, the knockdown of DPY30 significantly increased the apoptosis rate and promoted the expression of apoptosis-related proteins in CRC cells. Meanwhile, DPY30 knockdown promoted CRC cells apoptosis through endogenous programmed death and in a caspase activation-dependent manner. Furthermore, RNA-seq analysis revealed that the action of DPY30 is closely related to the apoptosis biological processes, and screened its potential effectors Raf1. Mechanistically, DPY30 downregulation promotes MST2-induced apoptosis by inhibiting Raf1 transcriptional activity through histone H3 lysine 4 trimethylation (H3K4me3). In vivo experiments showed that DPY30 was correlated with Raf1 in nude mouse subcutaneous xenografts tissues significantly. Clinical colorectal specimens further confirmed that overexpression of DPY30 in malignant tissues was significantly correlated with Raf1 level. The vital role of the DPY30/Raf1/MST2 signaling axis in the cell death and survival rate of CRC cells was disclosed, which provides potential new targets for early diagnosis and clinical treatment of CRC.

Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

A 5-hydroxymethylcytosine-based non-invasive model for early detection of colorectal carcinomas and advanced adenomas: the METHOD-2 study.

PURPOSE: Detection of colorectal carcinomas (CRC) at a time when there are more treatment options is associated with better outcomes. This prospective case-control study assessed the 5-hydroxymethylcytosine (5hmC) biomarkers in circulating cell-free DNA (cfDNA) for early detection of CRC and advanced adenomas (AA) Experimental Design: Plasma cfDNA samples from 2,576 study participants from the multi-center METHOD-2 study (NCT03676075) were collected, comprising patients with newly diagnosed CRC (n=1,074), AA (n=356), other solid tumors (n=80), and non-CRC/AA controls (n=1,066), followed by genome-wide 5hmC profiling using the 5hmC-Seal technique and the next-generation sequencing (NGS). A weighted diagnostic model for CRC (stage I-III) and AA was developed using the elastic net regularization in a discovery set and validated in independent samples. RESULTS: Distribution of 5hmC in cfDNA reflected gene regulatory relevance and tissue of origin. Besides being confirmed in internal validation, a 96-gene model achieved an area under the curve (AUC) of 90.7% for distinguishing stage I-III CRC from controls in 321 samples from multiple centers for external validation, regardless of primary location or mutation status. This model also showed cancer-type specificity as well as high capacity for distinguishing AA from controls with an AUC of 78.6%. Functionally, differential 5hmC features associated with CRC and AA demonstrated relevance to CRC biology, including pathways such as calcium and MAPK signaling. CONCLUSIONS: Genome-wide mapping of 5hmC in cfDNA shows the promise as a highly sensitive and specific non-invasive blood test to be integrated in screening programs for improving early detection of CRC and high-risk AA.

The safety, feasibility, and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0 vs. 35.0%, P =0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9 vs. 32.8%, P =0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P =0.173; OS: log-rank P =0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P >0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was noninferior to OCTG in both short-term and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.