<p>PDF - 142K, Nude mice were subcutaneously injected with Panc-1 cells and therapy was started after 2 weeks. (A) Relative tumor growth is calculated by dividing the tumor volume at any time by the tumor volume at the start of treatment. (B) Net tumor growth was calculated by subtracting tumor volume on the first treatment day from that on the final day. Data are representative of mean values 9plus or minus) standard deviation from 6-8 mice per group.</p>
Background Common kinds of soft tissue sarcomas (STS) include well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS). In this case, we present a comprehensive clinical profile of a patient who underwent multiple recurrences during the progression from WDLPS to DDLPS. Case presentation A 62-year-old Asian female underwent retroperitoneal resection of a large tumor 11 years ago, the initial pathology revealed a fibrolipoma-like lesion. Over the next six years, the patient underwent three resections for recurrence of abdominal tumors. Postoperative histology shows mature adipose tissue with scattered “adipoblast”-like cells with moderate-to-severe heterogeneous spindle cells, pleomorphic cells, or tumor giant cells. Immunohistochemistry (IHC) demonstrated positive staining for MDM2 and CDK4, confirming that the abdominal tumor was WDLPS and gradually progressing to DDLPS. Post-operative targeted sequencing and IHC confirmed the POC1B::ROS1 fusion gene in DDLPS. Whole-exome sequencing (WES) revealed that WDLPS and DDLPS shared similar somatic mutations and copy number variations (CNVs), whereas DDLPS had more mutated genes and a higher and more concentrated amplification of the chromosome 12q region. Furthermore, somatic mutations in DDLPS were significantly reduced after treatment with CDK4 inhibitors, while CNVs remained elevated. Conclusion Due to the high likelihood of recurrence of liposarcoma, various effective treatments should be taken into consideration even if surgery is the primary treatment for recurrent liposarcoma. To effectively control the course of the disease following surgery, combination targeted therapy may be a viable alternative to chemotherapy and radiotherapy in the treatment of liposarcoma.
Although the medical potential of the hope for a cure has been fiercely debated within academia, few researchers have approached this topic from the perspective of terminally ill cancer patients themselves. As such, this article aims to help bridge the gap by exploring how terminally ill cancer patients in China construct the hope for a cure.Seventeen terminally ill cancer patients were recruited from the department of oncology at a tertiary hospital, where data were collected through individual interviews and participatory observation from April to December 2020 and analysed via thematic analysis.The respondents experienced a dynamic swing between construction and denial of the hope for a cure. Furthermore, the patients negotiated between three forms of hope, including the hope for a cure, the hope for prolonged life expectancy and the hope of living in the moment. Meanwhile, family-oriented hope was centred on intergenerational relationships, which further shaped the construction of the hope for a cure.Medical staff needs to be sensitive to terminally ill cancer patients' dynamic swing, negotiation and motivation during the process of constructing the hope for a cure.
Previous studies have shown conflicting results on the relation between clinicopathologic features and prognosis of patients with colorectal mucinous, signet-ring cell, or non-mucinous adenocarcinoma; only few such studies have been performed in China. This retrospective study analyzed data from our department to investigate clinicopathologic characteristics, prognosis and possible correlations of three histologic types - colorectal mucinous, signet-ring cell, and non-mucinous adenocarcinoma, to clarify the bases for observed differences which may lead to development of targeted therapies.Of 2079 patients diagnosed with colorectal cancer between 1994 and 2007, 144 had mucinous, 25 had signet-ring cell, and 1837 had non-mucinous adenocarcinoma. Their clinicopathologic parameters and survival were analyzed using established statistical methodologies.Mucinous and signet-ring cell adenocarcinomas were common in younger patients (P < 0.001). Location, size and disease stage differed significantly among the three types. Signet-ring cell tumors were more commonly found in the rectum than mucinous and non-mucinous adenocarcinoma (P < 0.001). Mucinous and signet-ring cell tumors presented in a later stage in life more often than non-mucinous adenocarcinoma, with lymph node involvement, serosal infiltration, peritoneal dissemination, and adjacent organ invasion (P < 0.01). The rate of radical resection, hepatic metastasis and local recurrence did not differ among types (P > 0.05). Compared with patients with non-mucinous adenocarcinoma, patients with mucinous and signet-ring cell tumors who underwent potentially curative resections or stage II/III disease had poorer long-term overall survival. Survival did not differ by type for patients with either stage I or IV disease (P > 0.05).Mucinous and signet-ring cell adenocarcinoma have unique carcinogenesis and similar biologic behavior. Our study confirms that both histologic types, especially signet-ring cell tumors, are independent, negative prognostic factors for patients with colorectal cancer. Type does not appear to have a significant effect on survival when disease is either stage I or IV at presentation.
Abstract BackgroundThe incidence of gastric stump cancer (GSC) following resection of gastric cancer has increase. However, the definition between GSC and recurrent gastric cancer (RGC) is still being debated. This study was conducted to compare the clinicopathological characteristics and outcome for this two groups.Patients and MethodsThe investigators retrospectively reviewed patients in the Surveillance Epidemiology and End Results (SEER) databases from 1975 to 2016 to identify patients who underwent resection of gastric cancer subsequently experienced metachronous gastric cancer. GSC was defined as cancer occurring in remnant stomach of ≥10 years after gastrectomy, while RGC was defined as <10 years after gastrectomy. T-test, Pearson χ2-test and Kaplan-Meier estimator method was used in the present study.ResultsAmong the 167,747 gastric cancer patients, 1,006 (0.6%) patients were diagnosed multiple gastric cancer, 93 patients met the GSC criterion, and 282 patients met the RGC criterion. The mean time interval between the initial cancer and second cancer for GSC was 13.34 years and 4.24 years for RGC. Male gender ( P= 0.003), younger age (60.1 years old vs. 65.9 years old, P< 0.001) developed more frequently in GSC group. The median OS in GSC group was 20.0 months compared with 16.0 months for RGC group ( p =0.302). Surgery treatment or not, the median OS have statistically significant (in RGC group, 64.0 months vs. 10.0 months, P ＜0.001; 33 months vs. 13 months, P =0.014 in GSC group).ConclusionIn our definition of GSC and RGC, the OS were not statistically significant and gastrectomy may be the appropriate treatment for this two groups. It may demand for a more suitable definition and TNM staging system for GSC.
Abstract Stress‐induced hair loss is a prevalent health concern, with mechanisms that remain unclear, and effective treatment options are not yet available. In this study, we investigated whether stress‐induced hair loss was related to an imbalanced immune microenvironment. Screening the skin‐infiltrated immune cells in a stressed mouse model, we discovered a significant increase in macrophages upon stress induction. Clearance of macrophages rescues mice from stress‐induced hair shedding and depletion of hair follicle stem cells (HFSCs) in the skin, demonstrating the role of macrophages in triggering hair loss in response to stress. Further flow cytometry analysis revealed a significant increase in M1 phenotype macrophages in mice under stressed conditions. In searching for humoral factors mediating stress‐induced macrophage polarization, we found that the hormone Norepinephrine (NE) was elevated in the blood of stressed mice. In addition, in‐vivo and in‐vitro studies confirm that NE can induce macrophage polarization toward M1 through the β‐adrenergic receptor, Adrb2. Transcriptome, enzyme‐linked immunosorbent assay (ELISA), and western blot analyses reveal that the NLRP3/caspase‐1 inflammasome signaling and its downstream effector interleukin 18 (IL‐18) and interleukin 1 beta (IL‐1β) were significantly upregulated in the NE‐treated macrophages. However, inhibition of the NE receptor Adrb2 with ICI118551 reversed the upregulation of NLRP3/caspase‐1, IL‐18, and IL‐1β. Indeed, IL‐18 and IL‐1β treatments lead to apoptosis of HFSCs. More importantly, blocking IL‐18 and IL‐1β signals reversed HFSCs depletion in skin organoid models and attenuated stress‐induced hair shedding in mice. Taken together, this study demonstrates the role of the neural (stress)‐endocrine (NE)‐immune (M1 macrophages) axis in stress‐induced hair shedding and suggestes that IL‐18 or IL‐1β may be promising therapeutic targets.
The complete genome of a novel virus from Arma chinensis was determined by RNA sequencing and rapid amplification of cDNA ends. This virus has a single-stranded RNA genome of 10,540 nucleotides (nt) excluding the poly(A) tail. Two non-overlapping open reading frames (ORFs) in the sense direction were predicted: one long ORF at the 5' end of the genome (6,219 nt) that encodes a polypeptide of 2,072 amino acids (aa), and one short ORF at the 3' end of the genome (3,033 nt) that encodes a polypeptide of 1,010 aa. Phylogenetic analysis indicated that the virus clusters within a large cluster of currently unidentified picorna-like viruses with a high bootstrap value. We named the virus isolate Arma chinensis picorna-like virus 1 (AcPV-1). The prevalence of AcPV-1 infection in samples of Arma chinensis from the wild was at a low level (5.48%, 8 positives in 146 samples). Keywords: Arma chinensis; genomic characterization; phylogenetic analysis; Arma chinensis picorna-like virus 1; prevalence.
170 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers and is characterized by early tissue invasion, metastasis and high resistance to systemic therapies. Gemcitabine, a standard cytotoxic therapy for pancreatic cancer, has shown limited clinical benefits. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel), an approved treatment for breast cancer, has shown efficacy as mono- and combination therapy in multiple tumor types including pancreatic, lung and ovarian cancer. We evaluated combination treatment benefits of nab-paclitaxel with gemcitabine in experimental pancreatic cancer. Methods: In vitro cell proliferation was evaluated by WST-1 assay in human PDAC cells. Animal survival studies were performed in murine xenografts. Results: Nab-paclitaxel inhibited in vitro proliferation of PDAC cell lines with IC50 levels of 7.6 mM, 208 nM, 519 nM and 526 nM for AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells. Nab-paclitaxel combination with gemcitabine had significant additive effect on inhibition of PDAC cell proliferation; 72-hour incubation demonstrated that nab-paclitaxel addition caused a 2.5, 2.5, 8.9 and 2.2-fold decrease in IC50 of gemcitabine in AsPC-1, BxPC-3, MIA PaCa-2 and Panc-1 cells, respectively. In an intraperitoneal murine xenograft model, 2-week therapy demonstrated that compared to controls (median survival: 23 days), animal survival increased after gemcitabine (27 days, p=0.05) and nab-paclitaxel monotherapy (35 days, p=0.0005). In a separate 3-week therapy experiment, animal survival was significantly longer in the nab-paclitaxel treated group (41 days, p<0.002 versus control and Gem) compared with gemcitabine (32 days, p=0.005 versus control), docetaxel (32 days, p=0.005) and controls (20 days). Animal survival in nab-paclitaxel / gemcitabine and docetaxel / gemcitabine sequential treatment group was 43 and 40 days, respectively. Conclusions: Nab-paclitaxel has significant antitumor activity as a single agent in experimental pancreatic cancer and can also enhance gemcitabine effects in combination. These findings provide a strong rationale for testing nab-paclitaxel in patients with pancreatic cancer.
Nicotinamide adenine dinucleotide (NAD+) is closely related to the pathogenesis of tumors. However, the effect of NAD+ metabolism of gastric cancer (GC) cells on immune cells remains unexplained. We targeted nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD+ synthesis salvage pathway, to observe its effect in the immune microenvironment.NAMPT of GC cell lines was inhibited by using the small molecule inhibitor (FK866) and short hairpin RNA (shRNA). CCK-8 test and flow cytometry were performed to detect cell viability and apoptosis. Immunofluorescence was used to observe changes in mitochondrial membrane potential (MMP).The transfected GC cells (AGS) and patient-derived organoids (PDOs) were cocultured with activated PBMCs, followed by flow cytometric analysis (FCA) for cytokines and inhibitory marker. The level of NAD and ATP of GC cells (AGS & MKN45) was tested combined with NMN and CD39 inhibitor.Targeting NAD+ by FK866 obviously reduced MMP, which ultimately inhibited proliferation and increased the apoptosis of GC cells. NAMPT silencing reduced intracellular NAD and ATP，further decreased extracellular adenosine. Meawhile, the cytokines of CD8+T cells were significantly increased after cocultured with transfected AGS, and the expression of PD-1 was distinctly decreased. NMN reversed the effect of shNAMPT and enhanced the immunosuppression. Consistent results were obtained by coculturing PBMCs with PDOs.Restraining the function of NAMPT resulted in the functional improvement of effector CD8+ T cells by decreasing extracellular adenosine levels and inducing apoptosis of GC cells simultaneously. Therefore, this study demonstrates that NAMPT can be an effective target for gastric cancer immunotherapy.
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