CircHAS2 activates CCNE2 to promote cell proliferation and sensitizes the response of colorectal cancer to anlotinib.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. METHODS: The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). RESULTS: Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CONCLUSIONS: CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.

Efficacy of nab­paclitaxel vs. Gemcitabine in combination with S­1 for advanced pancreatic cancer: A multicenter phase II randomized trial.

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019.

VPS35 promotes gastric cancer progression through integrin/FAK/SRC signalling-mediated IL-6/STAT3 pathway activation in a YAP-dependent manner.

VPS35 is a key subunit of the retromer complex responsible for recognising cytosolic retrieval signals in cargo and is involved in neurodegenerative disease and tumour progression. However, the function and molecular mechanism of VPS35 in gastric cancer (GC) remains largely unknown. Here, we demonstrated that VPS35 was significantly upregulated in GC, which was associated with poor survival. VPS35 promoted GC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, VPS35 activated FAK-SRC kinases through integrin-mediated outside-in signalling, leading to the activation of YAP and subsequent IL-6 expression induction in tumour cells. What's more, combined mass spectrometry analysis of MGC-803 cell and bioinformatic analysis, we found that phosphorylation of VPS35 was enhanced in GC cells, and phosphorylated VPS35 has enhanced interaction with ITGB3. VPS35 interacted with ITGB3 and affected the recycling of ITGB3 in GC cells. Gain- and loss-of-function experiments revealed that VPS35 promoted tumour proliferation and metastasis via the IL-6/STAT3 pathway. Interestingly, we also found that STAT3 directly bound to the VPS35 promoter and increased VPS35 transcription, thereby establishing a positive regulatory feedback loop. In addition, we demonstrated that VPS35 knockdown sensitised GC cells to 5-FU and cisplatin. These findings provide evidence that VPS35 promotes tumour proliferation and metastasis, and highlight the potential of targeting VPS35- and IL-6/STAT3-mediated tumour interactions as promising therapeutic strategies for GC.

Paracrine activin B-NF-κB signaling shapes an inflammatory tumor microenvironment in gastric cancer via fibroblast reprogramming.

BACKGROUND: Important roles of INHBB in various malignancies are increasingly identified. The underlying mechanisms in gastric cancer (GC) microenvironment are still greatly unexplored. METHODS: The clinical significance of INHBB and the correlation between INHBB and p-p65 in GC were assessed through analyzing publicly available databases and human paraffin embedded GC tissues. The biological crosstalk of INHBB between GC cells and fibroblasts was explored both in vitro and in vivo. RNA-seq analyses were performed to determine the mechanisms which regulating fibroblasts reprogramming. Luciferase reporter assay and chromatin immunoprecipitation (CHIP) assay were used to verify the binding relationship of p65 and INHBB in GC cells. RESULTS: Our study showed that INHBB level was significantly higher in GC, and that increased INHBB was associated with poor survival. INHBB positively regulates the proliferation, migration, and invasion of GC cells in vitro. Also, activin B promotes the occurrence of GC by reprogramming fibroblasts into cancer-associated fibroblasts (CAFs). The high expression of INHBB in GC cells activates the NF-κB pathway of normal gastric fibroblasts by secreting activin B, and promotes fibroblasts proliferation, migration, and invasion. In addition, activin B activates NF-κB pathway by controlling TRAF6 autoubiquitination to induce TAK1 phosphorylation in fibroblasts. Fibroblasts activated by activin B can induce the activation of p65 phosphorylation of GC cells by releasing pro-inflammatory factors IL-1ß. p65 can directly bind to the INHBB promoter and increase the INHBB transcription of GC cells, thus establishing a positive regulatory feedback loop to promote the progression of GC. CONCLUSIONS: GC cells p65/INHBB/activin B and fibroblasts p65/IL-1ß signal loop led to the formation of a whole tumor-promoting inflammatory microenvironment, which might be a promising therapeutic target for GC.

Accumulation degree and risk assessment of metals in street dust from a developing city in Central Taiwan.

Due to the numerous industrial parks and high traffic density in Miaoli, Taiwan, large amounts of metals may be released into the atmosphere, accumulating in street dust. Therefore, this study aimed to collect street dust in Miaoli to quantify the metals and assess the accumulation degree, sources, and potential risks. The enrichment factor (EF), geological accumulation index (Igeo), ecological risk, and non-carcinogenic and lifetime carcinogenic risk were estimated to assess the accumulation degree and the potential environmental and health risks. Pearson correlation analysis, principal component analysis, and positive matrix factor model were used to clarify the relationship between levels of metals and identify possible sources. The levels of metals in street dust in order were Fe > Zn > Mn > Cu > Cr > Ni > Pb > Sr > Co > Sb. According to Igeo, the level of Ni indicated moderately polluted. The levels of Zn, Cu, and Pb showed moderate to strong pollution, strong pollution, and very strong pollution, respectively. Results of average ecological risk analysis pointed out that Pb and Cu represent a very high risk, while other metals posed low-to moderate-level ecological risks. Excluding the Steel Enterprise area, based on the EF value and source identification, it might be concluded that Co, Sr, Fe, Mn, and Sb were mainly from natural sources, while Cu, Pb, and Zn come from anthropogenic pollution sources. Based on the results of the risk assessments, most metals pose no serious adverse health risk to humans. But, in comparison to Miaoli townships, the health risks of residents living in the Steel Enterprise area were higher. However, given that children and adolescents exposure to Co, Cr, Pb, and Ni together constitute a relatively higher carcinogenic risk (CR > 10-6), more attention needs to be paid to the populations most susceptible.

Plasma Exosome Proteins ILK1 and CD14 Correlated with Organ-Specific Metastasis in Advanced Gastric Cancer Patients.

The exosome plays important roles in driving tumor metastasis, while the role of exosome proteins during organ-specific metastasis in gastric cancer has not been fully understood. To address this question, peripheral blood samples from 12 AGC patients with organ-specific metastasis, including distant lymphatic, hepatic and peritoneal metastasis, were collected to purify exosomes and to detect exosome proteins by Nano-HPLC-MS/MS. Gastric cancer cell lines were used for in vitro experiments. Peripheral blood sample and ascites sample from one patient were further analyzed by single-cell RNA sequencing. GO and KEGG enrichment analysis showed different expression proteins of hepatic metastasis were correlated with lipid metabolism. For peritoneal metastasis, actin cytoskeleton regulation and glycolysis/gluconeogenesis could be enriched. ILK1 and CD14 were correlated with hepatic and peritoneal metastasis, respectively. Overexpression of CD14 and ILK1 impacted the colony formation ability of gastric cancer and increased expression of Vimentin. CD14 derived from immune cells in malignant ascites correlated with high activation of chemokine- and cytokine-mediated signaling pathways. In summary, biological functions of plasma exosome proteins among AGC patients with different metastatic modes were distinct, in which ILK1 and CD14 were correlated with organ-specific metastasis.

ABT-263 exerts a protective effect on upper urinary tract damage by alleviating neurogenic bladder fibrosis.

This study investigated the mechanism of action of ABT-263 in the treatment of neurogenic bladder fibrosis (NBF)and its protective effects against upper urinary tract damage (UUTD). Sixty 12-week-old Sprague-Dawley (SD) rats were randomly divided into sham, sham + ABT-263 (50 mg/kg), NBF, NBF + ABT-263 (25 mg/kg, oral gavage), and NBF + ABT-263 (50 mg/kg, oral gavage) groups. After cystometry, bladder and kidney tissue samples were collected for hematoxylin and eosin (HE), Masson, and Sirius red staining, and Western Blotting (WB) and qPCR detection. Primary rat bladder fibroblasts were isolated, extracted, and cultured. After co-stimulation with TGF-ß1 (10 ng/mL) and ABT-263 (concentrations of 0, 0.1, 1, 10, and 100 µmol/L) for 24 h, cells were collected. Cell apoptosis was detected using CCK8, WB, immunofluorescence, and annexin/PI assays. Compared with the sham group, there was no significant difference in any physical parameters in the sham + ABT-263 (50 mg/kg) group. Compared with the NBF group, most of the markers involved in fibrosis were improved in the NBF + ABT-263 (25 mg/kg) and NBF + ABT-263 (50 mg/kg) groups, while the NBF + ABT-263 (50 mg/kg) group showed a significant improvement. When the concentration of ABT-263 was increased to 10 µmol/L, the apoptosis rate of primary bladder fibroblasts increased, and the expression of the anti-apoptotic protein BCL-xL began to decrease.ABT-263 plays an important role in relieving NBF and protecting against UUTD, which may be due to the promotion of myofibroblast apoptosis through the mitochondrial apoptosis pathway.

Robust Superhydrophobic PDMS@SiO2@UiO66-OSiR Sponge for Efficient Water-in-Oil Emulsion Separation.

A major challenge in oil/water separation is the processing of surfactant-stabilized emulsions from the water medium. One of the feasible schemes of emulsion separation is the porous melamine sponge coupled with functional particles. Here, we proposed a novel superhydrophobic metal-organic framework (MOF)-based sponge for water-in-oil emulsion separation. The porous melamine sponge was combined with poly(dimethylsiloxane) (PDMS)-coated hydrophobic SiO2 and UiO66-OSiR particles were prepared for demulsification via the one-step dipping method for the first time. The PDMS@SiO2@UiO66-OSiR sponge revealed excellent superhydrophobicity at a water contact angle of 160.7° and superlipophilicity at an oil contact angle of 0°. Compared with the pristine melamine sponge, the size-controllable PDMS@SiO2@UiO66-OSiR sponge could separate stabilized water-in-oil emulsions with ultrahigh separation efficiency (>98.64%) and high flux (e.g., 970 L·m-2·h-1). Meanwhile, the PDMS@SiO2@UiO66-OSiR sponge exhibited superior durability and mechanical reusability. Under harsh conditions such as strong acid and alkali, organic solvent corrosion, etc., all water contact angles of the PDMS@SiO2@UiO66-OSiR sponge were over 152°. Furthermore, the stress decreased by 5% when the sponge was subjected to 10 loading/unloading compression cycles at a constant strain of 60%. These results demonstrate that the PDMS@SiO2@UiO66-OSiR sponge can efficiently separate water-in-oil emulsions through its adjustable porous structure coupled with demulsification and hydrophobic particles. This study provides a step forward in developing a feasible strategy for the MOF-based sponge for emulsion separation.

Characteristics and in-hospital outcomes of elderly patients with cancer in a top-ranked hospital in China, 2016-2020: Real-world study.

BACKGROUND: Cancer is mostly a disease of aging, and older patients with cancer are generally frailer. This study aimed to describe the characteristics and in-hospital outcomes and explore factors associated with duration, cost, and mortality during first hospitalization, in older patients with cancer admitted to a top-ranked hospital in China. METHODS: Data on patients with solid cancer ≥65 years consecutively hospitalized in 2016-2020 were retrieved from the electronic medical records of Ruijin Hospital in Shanghai, China. Baseline characteristics, duration, cost, and mortality during hospitalization were described. Factors associated with duration, cost, and mortality during first hospitalization were explored using multivariable-adjusted logistic regression. RESULTS: 20,650 eligible patients with male proportion of 59% and median age of 70 years were analyzed. 45% of the patients underwent resection in our hospital. Upon first admission, 49% of patients had hypertension, 19% diabetes, 22% weight loss, and 28% risks of malnutrition. The median duration and cost of first hospitalization were 9 days and 32,000 RMB, respectively. 118 (0.6%) and 228 (1.1%) deaths occurred during first and any hospitalization, respectively. For first hospitalization, longer duration and higher cost were positively associated with older ages, male gender, emergency admission, certain tumor locations and histology, histories of diabetes, cirrhosis, and anticoagulant intake, higher body mass index, weight loss, reduced food intake, risk of falling, and worse self-care ability; in-hospital mortality was positively associated with age ≥85 years, emergency admission, certain cancer types, histories of hypertension and psychotropic intake, reduced food intake, and worse self-care ability. CONCLUSIONS: This study identified certain baseline patient and tumor characteristics, medical and medication histories, changes of weight and food intake, diet, and self-care ability which were independently associated with in-hospital outcomes among older patients with cancer admitted to our hospital and which should be paid special attention to. While the factors might not be easily modifiable, our study can help identify patients at higher risks of inferior in-hospital outcomes.

Clinical Observation of Fuzheng Xiaoji Granule in the Treatment of Stage IIIC Colorectal Cancer.

Objective: This study aimed to evaluate the effectiveness and safety of Fuzheng Xiaoji granule in patients with stage IIIC colorectal cancer. Methods: A total of 150 patients with stage IIIC colorectal cancer treated in Shanghai Ruijin Hospital from January 2019 to January 2022 were selected. They were divided into treatment and control groups according to a 2 : 1 random number table. There were 100 cases in the treatment group and 50 cases in the control group. The treatment group was administered Fuzheng Xiaoji (FZXJ) granule, and the control group was administered the placebo orally. The primary endpoint was disease-free survival (DFS). In addition, after 6 months, the changes in Traditional Chinese Medicine (TCM) symptom score (fatigue, emotional depression, chest tightness, insomnia, anorexia, abdominal distension, abdominal pain, soreness and weakness in the waist and legs, chills, and dysphoria in the chest, palm, and soles) were compared. Results: The DFS was 34.37 ± 2.91 months in the control group and 37.0 ± 1.08 months in the treatment group (p < 0.05). Compared with the control group, the treatment group showed less fatigue, abdominal distension, and soreness and weakness in the waist and legs (p < 0.05), significantly. The scores of emotional depression and anorexia decreased obviously, with a significant difference between the control and treatment groups (p < 0.01). There were no significant differences between the control and treatment groups in the incidence of chest tightness, insomnia, abdominal pain, chills, and dysphoria in the chest, palm, and soles (p > 0.05). Conclusion: Fuzheng Xiaoji granule can improve patients' symptoms and prolong the DFS.

Eight gene mutation-based polygenic hazard score as a potential predictor for immune checkpoint inhibitor therapy outcome in metastatic melanoma.

Background: Immune checkpoint inhibitor (ICI) therapies have revolutionized the treatment of metastatic cutaneous melanoma, but have only benefitted a subset of them. Gene mutations were reported to impact the ICI therapy outcomes in metastatic melanoma but have not been fully investigated. Hence, we systematically analyzed the impact of cancer-related gene mutations on the clinical outcome in metastatic melanoma patients who underwent ICI therapies. Methods: Publicly available discovery and validation cohorts (312 patients and 110 patients respectively, all the patients received ICI therapies) were included in this study. Cox proportional hazards regression analysis was used to assess the association of 468 cancer-related gene mutations with overall survival (OS) in the discovery cohort, and the polygenic hazard score (PHS) was constructed subsequently, and validated in the validation cohort. The Tumor Immune Estimation Resource (TIMER) online tools, which are based on The Cancer Genome Atlas database, were used to analyze the impact of gene mutations on tumor-infiltrated immune cells in melanoma samples. Results: We found eight gene mutations that were significantly associated with the overall survival (BAP1, CARD11, IGF1R, KMT2D, PTPRD, PTPRT, ROS1, and TERT, p < 0.05, mutation frequency >0.05). The PHS, which was based on these genes, was found to effectively discriminate the subset which benefited most from ICI therapies (HR = 1·54, 95%CI, 1.25-1.95; p < 0.001). After adjusting with age, sex, ICI regimes, and tumor mutation burden (TMB), we found that PHS was an independent predictor for the outcome of ICI therapies (adjusted HR = 1.84, 95%CI, 1.22-2.79; p = 0.004). The PHS was validated in the validation cohort (log-Rank p = 0.038). Further research found that CARD11 and PTPRD mutations were significantly associated with more tumor-infiltrated immune cells in melanoma samples. Conclusion: For the first time, we have shown that PHS can independently and effectively predict the ICI therapy outcome in metastatic melanoma, which once validated by larger research, may help the decision-making process in melanoma.

Nb2CTx MXene Cathode for High-Capacity Rechargeable Aluminum Batteries with Prolonged Cycle Lifetime.

Aluminum-ion batteries have garnered significant interest as a potentially safer and cheaper replacement for conventional lithium-ion batteries, offering a shorter charging time and denser storage capacity. Nonetheless, the progress in this field is considerably hampered by the limited availability of suitable cathode materials that can sustain the reversible intercalation of Al3+/[AlCl4]- ions, particularly after long cycles. Herein, we demonstrate that rechargeable Al batteries embedded with two-dimensional (2D) Nb2CTx MXene as a cathode material exhibit excellent capacity and exceptional long cyclic performance. We have successfully improved the initial electrochemical performance of Nb2CTx MXene after being properly delaminated to a single-layered microstructure and subjected to a post-synthesis calcining treatment. Compared to pristine Nb2CTx MXene, the Al battery embedded with the calcined Nb2CTx MXene cathode has, respectively, retained high capacities of 108 and 80 mAh g-1 after 500 cycles at current densities of 0.2 and 0.5 A g-1 in a wide voltage window (0.1-2.4 V). Noteworthily, the cyclic lifetime of Nb2CTx MXene was extended from ∼300 to >500 times after calcination. We reveal that attaining Nb2CTx nanosheets with a controllable d-spacing has promoted the migration of the [AlCl4]- and Al3+ ions in the MXene interlayers, leading to enhanced charge storage. Furthermore, we found out that the formation of niobium oxides and amorphous carbon after calcination probably benefits the electrochemical performance of Nb2CTx MXene electrode in Al batteries.

Molecular evolutionary process of advanced gastric cancer during sequential chemotherapy detected by circulating tumor DNA.

BACKGROUND: Efficacy of conventional sequential chemotherapy paradigm for advanced gastric cancer (AGC) patients has largely plateaued. Dynamic molecular changes during and after sequential chemotherapy have not been fully delineated. We aimed to profile the molecular evolutionary process of AGC patients during sequential chemotherapy by next generation sequencing (NGS) of plasma circulating tumor DNA (ctDNA). METHODS: A total of 30 chemo-naïve patients who were diagnosed with unresectable advanced or metastatic stomach adenocarcinoma were enrolled. All patients received sequential chemotherapy regimens following the clinical guideline. One hundred and eight serial peripheral blood samples were collected at baseline, radiographical assessment and disease progression. Plasma ctDNA was isolated and a customized NGS panel was used to detect the genomic features of ctDNA including single nucleotide variants (SNVs) and gene-level copy number variations (CNVs). KEGG pathway enrichment analysis was performed. RESULTS: Platinum-based combination chemotherapy was administrated as first-line regimen. Objective response rate was 50% (15/30). Patients with higher baseline values of copy number instability (CNI), CNVs and variant allel frequency (VAF) were more sensitive to platinum-based first-line regimens. Tumor mutation burden (TMB), CNI and CNV burden at partial response and stable disease were significantly lower than those at baseline, where at progressive disease they recovered to baseline levels. Dynamic change of TMB (ΔTMB) was correlated with progression-free survival of first-line treatment. Fluctuating changes of SNVs and gene-level CNVs could be observed during sequential chemotherapy. Under the pressure of conventional chemotherapy, the number of novel gene-level CNVs were found to be higher than that of novel SNVs. Such novel molecular alterations could be enriched into multiple common oncologic signaling pathways, including EGFR tyrosine kinase inhibitor resistance and platinum drug resistance pathways, where their distributions were found to be highly heterogenous among patients. The impact of subsequent regimens, including paclitaxel-based and irinotecan-based regimens, on the molecular changes driven by first-line therapy was subtle. CONCLUSION: Baseline and dynamic changes of genomic features of ctDNA could be biomarkers for predicting response of platinum-based first-line chemotherapy in AGC patients. After treatment with standard chemotherapy regimens, convergent oncologic pathway enrichment was identified, which is yet characterized by inter-patient heterogenous gene-level CNVs.

Bone marrow mesenchymal stem cell-derived extracellular vesicles facilitate endometrial injury repair by carrying the E3 ubiquitin ligase WWP1.

Bone marrow mesenchymal stem cells-derived extracellular vesicles (BMSC-EVs) relieve endometrial injury. This study aimed to elucidate the BMSC-EV mechanism in alleviating endometrial injury. Endometrial injury model in vivo was induced using 95% ethanol, and endometrial epithelial cells (EECs) treated with mifepristone were applied as an endometrial injury model in vitro. After BMSCs and BMSC-EVs were isolated and identified, the BMSC-EV function was evaluated by hematoxylin-eosin and Masson staining, immunohistochemistry, quantitative real-time PCR, Cell Counting Kit-8 assay, flow cytometry, enzyme-linked immunosorbent assay, and Transwell and tubule formation assays. The BMSC-EV mechanism was assessed using Western blot, ubiquitination, and cycloheximide-chase assays. After isolation and identification, BMSC-EVs were effective in endometrial injury repair in vivo and facilitated EEC proliferation and repressed cell apoptosis in vitro; the EEC supernatants accelerated human umbilical vein endothelial cell proliferation, migration, and invasion and facilitated angiogenesis after endometrial injury in vitro. For the BMSC-EV mechanism, E3 ubiquitin ligase WWP1 in BMSC-EVs mediated the ubiquitination of peroxisome proliferator-activated receptor gamma (PPARγ), thus relieving the PPARγ inhibition on vascular endothelial growth factor expression. Furthermore, the WWP1 in BMSC-EVs alleviated endometrial injury in vitro and in vivo. BMSC-EVs facilitated endometrial injury repair by carrying WWP1.

Efficacy and Safety of Conversion Therapy by Intraperitoneal and Intravenous Paclitaxel Plus Oral S-1 in Gastric Cancer Patients With Peritoneal Metastasis: A Prospective Phase II Study.

Background: Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients. Methods: Eligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST). Results: Sixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery. Conclusion: The NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS. Clinical Trial Registration: http://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ().

Camrelizumab and metronomic capecitabine for patients with treatment-refractory solid tumors (McCREST trial).

This is an open-label, single-center, multi-cohort phase Ib trial, which consists of three cohorts, including cohort 1 (HER2 negative gastric or gastric esophageal junction adenocarcinoma), cohort 2 (esophageal squamous cell carcinoma and head and neck squamous cell carcinoma) and cohort 3 (hepato-biliary-pancreatic and non-stomach non-esophagi gastrointestinal carcinoma). All eligible patients will be treated by camrelizumab (200 mg, every 2 weeks) and capecitabine (500 mg, twice a day, per os). The primary end point is the safety profiles of camrelizumab plus metronomic capecitabine according to CTCAE v5.0. The secondary end points are progression free survival, overall survival, objective response rate, disease control rate and duration of response. Planned enrollment is 20 subjects for each cohort. Total duration of this trial is expected to be 2 years.

Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have been used to treat gastrointestinal cancer patients in clinical practices. Combination with other drugs can improve the efficacy of ICIs. Metronomic chemotherapy using low dose and high frequency of cytotoxic drugs has multi-targeted anti-tumor effects and can be a potential partner of ICIs. In this study, the authors assess the safety and efficacy of a combination of a PD-1 inhibitor (camrelizumab) and an oral chemotherapy drug (capecitabine with metronomic dose) in patients with metastatic treatment-refractory solid tumors.

The Treatment of Subtrochanteric Fracture with Reversed Contralateral Distal Femoral Locking Compression Plate (DF-LCP) Using a Progressive and Intermittent Drilling Procedure in Three Osteopetrosis Patients.

OBJECTIVE: To describe the application of reversed contralateral distal femoral locking compression plate (DF-LCP) inserted through a progressive and intermittent drilling procedure in the treatment of osteopetrotic subtrochanteric fracture (OSF). METHODS: Three patients (one male and two females with an average age of 45.33 ± 11.09 years) with OSF hospitalized between September 2015 and September 2020, were included in this present study. Lateral approach was applied in all patients who accepted open reduction and internal fixation (ORIF) with a reversed contralateral DF-LCP inserted through a progressive and intermittent drilling procedure. The operation time and intraoperative blood loss were recorded to evaluate the efficiency of this surgical method. Physical examination and imaging examination of the fracture site were used to evaluate the fracture union status, the position and stability of the implant, and the alignment of the injured limb at 1, 3, 6, and 12 months after operation, then a subsequent visit was conducted at least once a year. Harris Hip Score (HHS) was used to evaluate the hip joint function at 6 and 12 months after operation. RESULTS: The average operation time was 140 ± 21.60 min (110, 160, and 150 min); The average intraoperative blood loss was about 333.33 ± 23.57 ml (300, 350, and 350 ml). The average follow-up time was 22.33 ± 7.41 months (29, 26, and 12 months). All patients achieved bone union with an average time of 6.67 ± 0.94 months (6, 8, and 6 months). At the time of 6 months after operation, case 1 and 3 were almost pain-free and could walk with full weight bearing while case 2 could walk only with partial weight bearing using a crutch. The HHS scores of cases 1, 2, and 3 were 84/100, 74/100, and 92/100, respectively. At the follow-up at 12 months after operation, the HHS score improved to 91/100, 81/100, and 96/100, respectively. The contralateral incomplete old subtrochanteric fracture was deteriorated in case 1 at 26 months after operation. After 3 months of limited weight bearing using a crutch, bone union was verified in radiograph imaging. Fresh contralateral subtrochanteric fracture occurred in case 2 at 26 months after operation, which was treated using a similar surgical approach, and its clinical outcome is under follow-up. Moreover, no perioperative complications including operation-related death, vascular/nerve injury, deep venous thrombosis, pulmonary embolism, and incision infection, and long-term complications involving malunion, nonunion, implant failure, ankylosis, heterotopic ossification, osteonecrosis, and osteomyelitis were identified. CONCLUSION: The application of reversed contralateral DF-LCP in OSF is practicable and reliable. Progressive and intermittent drilling is a safe and efficient method for implant insertion in this complicated situation.

Development and validation of risk and prognostic nomograms for bone metastases in Chinese advanced colorectal cancer patients.

BACKGROUND: Bone metastases (BM) from colorectal cancer (CRC) are often accompanied by extraosseous metastases, resulting in a dismal prognosis. The present study aimed to determine the risk factors for BM in metastatic CRC (mCRC) and the prognostic factors for CRC patients with BM. METHODS: The study was based on a training cohort of 214 mCRC patients (of which, 101 patients had BM) from our center, and a validation cohort of 511 mCRC patients (of which, 173 patients had BM) from another institute. Risk and prognostic nomograms for BM were developed using univariate and multivariate analyses. The goodness of fit, discrimination, and calibration performance of the nomograms were assessed by R2, concordance statistics (C-statistics), and the calibration curve. The results were internally validated using bootstrap resampling in the training cohort, and externally validated in the validation cohort. RESULTS: The novel BM risk nomogram comprised seven variables [degree of tumor differentiation, N-stage, serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), liver metastasis, and lung metastasis]. It showed good performance, with an R2 of 0.447 and a C-statistic of 0.846 [95% confidence interval (CI), 0.793 to 0.898] in the training cohort, and an R2 of 0.325 and a C-statistic of 0.792 (95% CI, 0.750 to 0.834) in the validation cohort. The optimal cutoff value to identify individuals at low or high risk was 56% probability, with a sensitivity of 71.3% and a specificity of 89.4%. The prognostic nomogram included five factors (tumor differentiation, number of extra-BM organs, number of BM lesions, ALP, and LDH), and had an R2 of 0.284 and a C-statistic of 0.723 (95% CI, 0.657 to 0.789) in the training set. This nomogram was externally validated in the validation cohort, with an R2 of 0.182 and a C-statistic of 0.682 (95% CI, 0.638 to 0.726). CONCLUSIONS: The developed and validated risk and prognostic nomograms showed good performance for predicting the occurrence of BM in mCRC as well as the prognosis of CRC patients with BM. The risk nomogram can be used as a cost-effective preliminary screening tool prior to bone scanning.

Characteristics of Pan-Cancer Patients With Ultrahigh Tumor Mutation Burden.

BACKGROUND: Tumor mutation burden has been proven to be a good predictor for the efficacy of immunotherapy, especially in patients with hypermutation. However, most research focused on the analysis of hypermutation in individual tumors, and there is a lack of integrated research on the hypermutation across different cancers. This study aimed to characterize hypermutated patients to distinguish between these patients and non-hypermutated patients. METHODS: A total of 5,980 tumor samples involving 23 types of solid tumors from the in-house database were included in the study. Based on the cutoff value of tumor mutation burden (TMB), all samples were divided into hypermutated or non-hypermutated groups. Microsatellite instability status, PD-L1 expression and other mutation-related indicators were analyzed. RESULTS: Among the 5,980 tumor samples, 1,164 were selected as samples with hypermutation. Compared with the non-hypermutated group, a significant increase in the mutation rates of DNA mismatch repair genes and polymerase genes was detected in the hypermutated group, and there was an overlap between high TMB and high microsatellite instability or high PD-L1. In addition, we found that EGFR, KRAS and PIK3CA had a high frequency of both single nucleotide variation and copy number variation mutations. These identified mutant genes were enriched in the oncogenic signaling pathway and the DNA damage repair pathway. At the same time, the somatic cell characteristics and distribution of the two groups were significantly different. CONCLUSIONS: This study identified genetic and phenotypic characteristics of hypermutated tumors and demonstrated that DNA damage repair is critically involved in hypermutation.

Effect of sidedness on survival among patients with early-stage colon cancer: a SEER-based propensity score matching analysis.

BACKGROUND: Most previous studies compared survival between left-sided and right-sided colon cancer without adjustment for clinicopathological parameters. We investigated the effect of sidedness on survival among patients with early-stage colon cancer, using a propensity score matching method. METHODS: The 18 registry custom data within the SEER database were used to identify patients who were diagnosed with colon cancer between 2010 and 2014. A propensity score matching analysis was performed using the nearest neighbor method. Survival was estimated using the Kaplan-Meier method. A Cox proportional hazards model was applied to determine the prognostic factors. RESULTS: In the unmatched cohort, 25,094 (35.72%) patients were diagnosed with left-sided colon cancer and 45,156 (64.28%) with right-sided colon cancer. After propensity score matching, each cohort included 5118 patients, and the clinicopathological characteristics were well balanced. In the unmatched cohort, left-sided colon cancer had superior all-cause (χ2=315, P<0.01) and cancer-specific (χ2=43, P<0.01) survival than right-sided tumors. However, in the matched cohort, no difference was observed for all-cause (χ2=0.7, P=0.4) and cancer-specific (χ2=0, P=0.96) survival between left and right colon cancer. The Cox model did not indicate sidedness as a prognostic factor. In the subgroup analysis, stage II right-sided colon cancer had a better survival outcome, while stage III left-sided tumors had a better survival outcome. CONCLUSIONS: After adjusting for clinicopathological characteristics in this study, sidedness showed no impact on survival in early-stage colon cancer. However, sidedness was associated with prognostic differences in stages II and III early-stage colon cancer.