The lethal K18-hACE2 knock-in mouse model mimicking the severe pneumonia of COVID-19 is practicable for antiviral development.

Animal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR - Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development.

Development of an aptamer capable of multidrug resistance reversal for tumor combination chemotherapy.

Multidrug resistance (MDR) is a major factor in the failure of many forms of tumor chemotherapy. Development of a specific ligand for MDR-reversal would enhance the intracellular accumulation of therapeutic agents and effectively improve the tumor treatments. Here, an aptamer was screened against a doxorubicin (DOX)-resistant human hepatocellular carcinoma cell line (HepG2/DOX) via cell-based systematic evolution of ligands by exponential enrichment. A 50 nt truncated sequence termed d3 was obtained with high affinity and specificity for HepG2/DOX cells. Multidrug resistance protein 1 (MDR1) is determined to be a possible recognition target of the selected aptamer. Aptamer d3 binding was revealed to block the MDR of the tumor cells and increase the accumulation of intracellular anticancer drugs, including DOX, vincristine, and paclitaxel, which led to a boost to the cell killing of the anticancer drugs and lowering their survival of the tumor cells. The aptamer d3-mediated MDR-reversal for effective chemotherapy was further verified in an in vivo animal model, and combination of aptamer d3 with DOX significantly improved the suppression of tumor growth by treating a xenograft HepG2/DOX tumor in vivo. This work demonstrates the feasibility of a therapeutic DNA aptamer as a tumor MDR-reversal agent, and combination of the selected aptamer with chemotherapeutic drugs shows great potential for liver cancer treatments.

Clinical characteristics and risk factors associated with bone erosion in patients with tophi.

INTRODUCTION: If a large amount of urate crystals is deposited in a joint cavity for an extended period of time, bone erosion will occur and gradually cause skeletal muscle necrosis and joint deformity. The aim of this study was to describe the clinical characteristics and factors associated with bone erosion in gout patients with tophi. METHODS: A total of 210 gout patients with tophi were enrolled and divided into a bone erosion group (n = 135) and a non-bone erosion group (n = 75). Digital radiography (DR) was performed to detect bone erosion in the elbow, wrist, knee, ankle joints, interphalangeal and metatarsophalangeal joints. The clinical characteristics were recorded and compared between the two groups. Multivariate logistic regression analysis was conducted to explore the factors associated with bone erosion. RESULTS: Compared with the non-bone erosion group, the bone erosion group had an older age, longer disease duration of gout and tophi, higher level of serum creatinine (sCr), higher proportion of drinking history and ulceration, and a lower glomerular filtration rate (GFR). Univariate logistic regression analysis results showed that sex, age, body mass index (BMI), gout duration, tophi duration, GFR, white blood cell (WBC) count, sCr level, smoking history, drinking history, and presence of ulceration were associated with bone destruction. Multivariable logistic regression analysis results indicated that tophi duration, drinking history, ulceration and sCr were positively and independently related to bone erosion. CONCLUSIONS: Tophi patients with bone erosion presented different clinical characteristics. Tophi duration, drinking history, ulceration and sCr were associated with bone erosion in gout patients with tophi.

ILK inhibition reduces osteophyte formation through suppression of osteogenesis in BMSCs via Akt/GSK-3ß/ß-catenin pathway.

BACKGROUND: Osteophyte development is a common characteristic of inflammatory skeletal diseases. Elevated osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) participates in pathological osteogenesis. Integrin-linked kinase (ILK) positively regulates the osteoblastic differentiation of osteoprogenitors, but whether the ILK blockage prevents osteophytes and its potential mechanism is still unknown. Furthermore, the low-dose tumor necrosis factor-α (TNF-α) promotes osteogenic differentiation, but a lack of study reports on the relationship between this cytokine and ILK. OSU-T315 is a small ILK inhibitor, which was used to determine the effect of ILK inhibition on osteogenesis and osteophyte formation. METHODS AND RESULTS: The osteogenesis of BMSCs was evaluated using Alizarin red S staining, alkaline phosphatase, collagen type I alpha 2 chain, and bone gamma-carboxyglutamate protein. The expression and phosphorylation of protein were assessed through western blot. Immunofluorescence was employed to display the distribution of ß-catenin. microCT, hematoxylin-eosin, and safranin O/fast green staining were utilized to observe the osteophyte formation in collagen antibody-induced arthritis mice. We found that ILK blockage significantly declined calcium deposition and osteoblastic markers in a dose- and time-dependent manner. Furthermore, it lowered osteogenesis in the TNF-α-induced inflammatory microenvironment by diminishing the effect of ILK and inactivating the Akt/ GSK-3ß/ ß-catenin pathway. Nuclear ß-catenin was descended by OSU-T315 as well. Finally, the ILK suppression restrained osteophyte formation but not inflammation in vivo. CONCLUSIONS: ILK inhibition lowered osteogenesis in TNF-α-related inflammatory conditions by deactivating the Akt/ GSK-3ß/ ß-catenin pathway. This may be a potential strategy to alleviate osteophyte development in addition to anti-inflammatory treatment.

Comparison of open, laparoscopic, and robotic left colectomy for radical treatment of colon cancer: a retrospective analysis in a consecutive series of 211 patients.

BACKGROUND: Robotic surgery has been widely used in the radical treatment of colonic cancer. However, it is unclear what advantages the robotic approach offers over other approaches in left colectomy. This study aims to explore the advantage of robotic surgery in left colectomy by comparing open, laparoscopic, and robotic surgery. METHODS: A retrospective analysis was performed on the clinical data of patients with radical left colectomy for colon cancer who were admitted to the Department of General Surgery, The First Affiliated Hospital of Nanchang University, from November 2012 to November 2017. Two hundred eleven patients included were divided into the open surgery group (OS, n=49), laparoscopic surgery group (LS, n=92), and robotic surgery group (RS, n=70) according to surgical techniques. The clinicopathologic data were collected for clinical outcome assessment. Finally, the clinical value of RS in radical left colectomy was further evaluated by propensity score matching (PSM) analysis. RESULTS: Three groups were similar in demographics and clinical characteristics. Compared with OS, LS and RS groups had better intraoperative and perioperative clinical outcomes. Moreover, the RS group exhibited the minimum operative times, length of stay (LOS), and evaluated blood loss. LS and RS also exhibited less perioperative and postoperative long-term complications. Three groups showed similar postoperative pathological outcomes. The overall survival and disease-free survival were also similar among the three groups (all P > 0.05). Cox regression analysis showed surgical approach was not a prognostic factor for overall survival (P = 0.671) and disease-free survival (P = 0.776). PSM analysis of RS and LS by clinical characteristics showed RS showed shorter operation time (P < 0.001) and LOS for patients without complications (P = 0.005). However, no significant differences were found in perioperative and long-term postoperative complications, pathological outcomes, overall survival, and disease-free survival. CONCLUSIONS: Among three techniques for radical left colectomy, LS and RS had significant advantages over OS in short-term clinical outcomes, and no significant differences were found in overall, disease-free survival, local recurrence, and distant metastasis incidence. Moreover, RS shows better perioperative clinical outcomes but without compromising survival compared with LS.

Case Report: Baricitinib as an Alternative in the Maintenance Therapy for Macrophage Activation Syndrome Secondary to Nodular Panniculitis.

Background: Macrophage activation syndrome (MAS) is a severe complication of autoimmune diseases with high mortality. We report the effectiveness of baricitinib as an option for the maintenance therapy in MAS secondary to nodular panniculitis. Case summary: A 24-year-old female came to our hospital with repeated fever and a skin nodule on right tibial tuberosity. Results were notable for raised serum ferritin (SF), triglycerides (TG), elevated liver function enzymes, interleukin-6 (IL-6), interferon-γ (IFN-γ), soluble interleukin-2 receptor (sIL-2R) and decreased activity of NK cells. The pathological biopsy of the subcutaneous nodules indicated nodular panniculitis. Hemophagocytic cells were found in bone marrow aspiration. She was diagnosed as MAS secondary to nodular panniculitis. With the treatment of methylprednisolone (MP) and immunoglobulin, her symptoms and laboratory data gradually improved. Nevertheless, her disease relapsed when the MP dose was tapered. Regarding the usage of JAK inhibitors in MAS, we used baricitinib (JAK1/2 inhibitor) to treat MAS and her symptom and abnormal laboratory findings returned to normal. During follow-up, though the MP dose was tapered, she was stable without a MAS recurrence. Conclusion: The case report suggested baricitinib is an option for MAS in the maintenance therapy phase and is potentially beneficial to prevent recurrence.

Role of minimally invasive techniques in gastrointestinal surgery: Current status and future perspectives.

In recent years, the incidence of gastrointestinal cancer has remained high. Currently, surgical resection is still the most effective method for treating gastrointestinal cancer. Traditionally, radical surgery depends on open surgery. However, traditional open surgery inflicts great trauma and is associated with a slow recovery. Minimally invasive surgery, which aims to reduce postoperative complications and accelerate postoperative recovery, has been rapidly developed in the last two decades; it is increasingly used in the field of gastrointestinal surgery and widely used in early-stage gastrointestinal cancer. Nevertheless, many operations for gastrointestinal cancer treatment are still performed by open surgery. One reason for this may be the challenges of minimally invasive technology, especially when operating in narrow spaces, such as within the pelvis or near the upper edge of the pancreas. Moreover, some of the current literature has questioned oncologic outcomes after minimally invasive surgery for gastrointestinal cancer. Overall, the current evidence suggests that minimally invasive techniques are safe and feasible in gastrointestinal cancer surgery, but most of the studies published in this field are retrospective studies and case-matched studies. Large-scale randomized prospective studies are needed to further support the application of minimally invasive surgery. In this review, we summarize several common minimally invasive methods used to treat gastrointestinal cancer and discuss the advances in the minimally invasive treatment of gastrointestinal cancer in detail.

No beneficial effect on survival but a decrease in postoperative complications in patients with rectal cancer undergoing robotic surgery: a retrospective cohort study.

BACKGROUND: Robotic surgery has been taken as a new modality to surpass the technical limitations of conventional surgery. Here we aim to compare the oncologic outcomes of patients with rectal cancer receiving robotic vs. laparoscopic surgery. METHODS: Data from patients diagnosed with rectal cancer between March 2011 and December 2018 were obtained for outcome assessment at the First Affiliated Hospital of Nanchang University. All patients were separated into two groups: a robot group (patients receiving robotic surgery, n = 314) and a laparoscopy group (patients receiving laparoscopic surgery, n = 220). The primary endpoint was survival outcomes. The secondary endpoints were the general conditions of the operation, postoperative complications and pathological characteristics. RESULTS: The 5-year overall survival (OS) and disease-free survival (DFS) at years 1, 3 and 5 were 96.6%, 88.7%, and 87.7% vs. 96.7%, 88.1%, and 78.4%, and 98.6%, 80.2-, and 73.5% vs. 96.2-, 87.2-, and 81.1% in the robot and laparoscopy groups, respectively (P > 0.05). In the multivariable-adjusted analysis, robotic surgery was not an independent prognostic factor for OS and DFS (P = 0.925 and 0.451, respectively). With respect to the general conditions of the operation, patients in the robot group had significantly shorter operation times (163.5 ± 40.9 vs. 190.5 ± 51.9 min), shorter times to 1st gas passing [2(1) vs. 3(1)d] and shorter hospital stay days [7(2) vs. 8(3)d] compared to those in the laparoscopy group (P < 0.01, respectively). After the operation, the incidence of short- and long-term complications in the robot group was significantly lower than that in the laparoscopy group (15.9% vs. 32.3%; P < 0.001), especially for urinary retention (1.9% vs. 7.3%; 0.6% vs. 4.1%, P < 0.05, respectively). With regard to pathological characteristics, TNM stages II and III were more frequently observed in the robot group than in the laparoscopy group (94.3% vs. 83.2%, P < 0.001). No significant difference were observed in lymph nodes retrieved, lymphovascular invasion and circumferential resection margin involvement between the two groups (P > 0.05, respectively). CONCLUSIONS: This monocentre retrospective comparative cohort study revealed short-term advantages of robot-assisted rectal cancer resection but similar survival compared to conventional laparoscopy.

Cavernous haemangioma of the duodenum with acute massive bleeding in the ascending portion: a case report.

Duodenal cavernous haemangiomas are rare, benign disorders, and massive gastrointestinal (GI) bleeding is a rare clinical condition. The present case report describes a 50-year-old male patient who presented with severe, ongoing haematochezia. A peripheral blood smear at the time of admission showed significant anaemia, and haemoglobin level was 52 g/l (normal range, 120-175 g/l). Albumin level was also low at 28 g/l (normal range, 40-55 g/l). Standard computed tomography (CT) showed mural thickening and relative lumen stenosis in the ascending (fourth) portion of the duodenum. Contrast-enhanced CT using hypotonic solution revealed the lesions to be hypervascular haemangiomas. Laparotomy and segmental duodenum resection were performed, and the first jejunal limb was anastomosed using a side-to-end technique. Histopathological examination confirmed the diagnosis of cavernous haemangioma. The patient showed marked improvement during follow-up. The present case findings emphasize that duodenal haemangioma is possible without a history of chronic anaemia, and should remain a consideration in differential diagnosis for patients presenting with massive GI bleeding. CT is useful for preoperative diagnosis of massive bleeding, and surgery with segmental resection is usually curative.

miR-144-3p inhibited the growth, metastasis and epithelial-mesenchymal transition of colorectal adenocarcinoma by targeting ZEB1/2.

miR-144-3p is aberrantly expressed in several types of human cancer and functions as a tumor suppressor by inhibiting metastasis. However, the clinical significance and biological function of miR-144-3p in colorectal adenocarcinoma (CRA) have yet to be elucidated. Here we reported that miR-144-3p expression level was significantly down-regulated in CRA tissues compared with matched noncancerous colorectal mucosae tissues. Low miR-144-3p expression was correlated with adverse clinicopathologic characteristics and poor prognosis of CRA patients. Cox regression analysis showed that low miR-144-3p expression was an independent risk factor for DFS and OS in CRA. In vitro and in vivo assays showed that miR-144-3p significantly inhibited proliferation, migration and invasion of CRA cells. In particular, miR-144-3p could suppress EMT process of CRA cells by regulating the cytoskeleton and EMT markers. Bioinformatics analysis indicated that EMT associated transcription factors ZEB1 and ZEB2 were potential targets of miR-144-3p, and miR-144-3p inhibited ZEB1 and ZEB2 expression and was negatively correlated with their expression in CRA. Finally, we confirmed that ZEB1 and ZEB2 down-regulation collaboratively mediated the inhibitory effect of miR-144-3p on proliferation, invasion and EMT of CRA cells. In conclusion, our study provided evidence that miR-144-3p could inhibit CRA cell proliferation, invasion and EMT by targeting ZEB1/2.

Molecular evidence suggesting the persistence of residual SARS-CoV-2 and immune responses in the placentas of pregnant patients recovered from COVID-19.

OBJECTIVES: Recent studies have shown the presence of SARS-CoV-2 in the tissues of clinically recovered patients and persistent immune symptoms in discharged patients for up to several months. Pregnant patients were shown to be a high-risk group for COVID-19. Based on these findings, we assessed SARS-CoV-2 nucleic acid and protein retention in the placentas of pregnant women who had fully recovered from COVID-19 and cytokine fluctuations in maternal and foetal tissues. MATERIALS AND METHODS: Remnant SARS-CoV-2 in the term placenta was detected using nucleic acid amplification and immunohistochemical staining of the SARS-CoV-2 protein. The infiltration of CD14+ macrophages into the placental villi was detected by immunostaining. The cytokines in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens at delivery were profiled using the Luminex assay. RESULTS: Residual SARS-CoV-2 nucleic acid and protein were detected in the term placentas of recovered pregnant women. The infiltration of CD14+ macrophages into the placental villi of the recovered pregnant women was higher than that in the controls. Furthermore, the cytokine levels in the placenta, maternal plasma, neonatal umbilical cord, cord blood and amniotic fluid specimens fluctuated significantly. CONCLUSIONS: Our study showed that SARS-CoV-2 nucleic acid (in one patient) and protein (in five patients) were present in the placentas of clinically recovered pregnant patients for more than 3 months after diagnosis. The immune responses induced by the virus may lead to prolonged and persistent symptoms in the maternal plasma, placenta, umbilical cord, cord blood and amniotic fluid.

CD4+ T cell depletion does not affect the level of viremia in chronically SHIVSF162P3N-infected Chinese cynomolgus monkeys.

Chronically SHIVSF162P3N-infected cynomolgus monkeys were used to determine the effects of the antibody-mediated acute CD4+ T cell depletion on viral load as well as on the immunological factors associated with disease progression. Compared with the control animals, CD4+ T cell-depleted animals with SHIV infection showed (i) little alteration in plasma viral load over the period of 22 weeks after the depletion; (ii) increased CD4+ T cell proliferation and turnover of macrophages at the early phase of the depletion, but subsequent decline to the basal levels; and (iii) little impact on the expression of the inflammatory cytokines and CC chemokines associated with disease progression. These findings indicate that the antibody-mediated acute CD4+ T cell depletion had minimal impact on plasma viral load and disease progression in chronically SHIVSF162P3N-infected cynomolgus monkeys. Future investigations are necessary to identify the key factor(s) related to the immune activation and macrophage infection during the CD4 deletion in chronic viral infection.

Comparison of robotic and laparoscopic rectal cancer surgery: a meta-analysis of randomized controlled trials.

OBJECTIVE: Robotic and laparoscopic surgery for rectal cancer has been applied in the clinic for decades; nevertheless, which surgical approach has a lower rate of postoperative complications is still inconclusive. Therefore, the aim of this meta-analysis was to compare the postoperative complications within 30 days between robotic and laparoscopic rectal cancer surgery based on randomized controlled trials. METHODS: Randomized controlled trials (until May 2020) that compared robotic and laparoscopic rectal cancer surgery were searched through PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, and China Biology Medicine disc (CBMdisc). Data regarding sample size, clinical and demographic characteristics, and postoperative complications within 30 days, including overall postoperative complications, severe postoperative complications (Clavien-Dindo score ≥ III), anastomotic leakage, surgical site infection, bleeding, ileus, urinary complications, respiratory complications, conversion to open surgery, unscheduled reoperation, perioperative mortality, and pathological outcomes, were extracted. The results were analyzed using RevMan v5.3. RESULTS: Seven randomized controlled trials that included 507 robotic and 516 laparoscopic rectal cancer surgery cases were included. Meta-analysis showed that the overall postoperative complications within 30 days [Z = 1.1, OR = 1.18, 95% CI (0.88-1.57), P = 0.27], severe postoperative complications [Z = 0.22, OR = 1.12, 95% CI (0.41-3.07), P = 0.83], anastomotic leakage [Z = 0.96, OR = 1.27, 95% CI (0.78-2.08), P = 0.34], surgical site infection [Z = 0.18, OR = 1.05, 95% CI (0.61-1.79), P = 0.86], bleeding [Z = 0.19, OR = 0.89, 95% CI (0.27-2.97), P = 0.85], ileus [Z = 1.47, OR = 0.66, 95% CI (0.38-1.15), P = 0.14], urinary complications [Z = 0.66, OR = 1.22, 95% CI (0.67-2.22), P = 0.51], respiratory complications [Z = 0.84, OR = 0.64, 95% CI (0.22-1.82), P = 0.40], conversion to open surgery [Z = 1.73, OR = 0.61, 95% CI (0.35-1.07), P = 0.08], unscheduled reoperation [Z = 0.14, OR = 0.91, 95% CI (0.26-3.20), P = 0.89], perioperative mortality [Z = 0.28, OR = 0.79, 95% CI (0.15-4.12), P = 0.78], and pathological outcomes were similar between robotic and laparoscopic rectal surgery. CONCLUSION: Robotic surgery for rectal cancer was comparable to laparoscopic surgery with respect to postoperative complications within 30 days.

Postoperative complications after robotic resection of colorectal cancer: An analysis based on 5-year experience at a large-scale center.

BACKGROUND: As a common gastrointestinal malignancy, colorectal cancer (CRC) poses a serious health threat globally. Robotic surgery is one of the future trends in surgical treatment of CRC. Robotic surgery has several technical advantages over laparoscopic surgery, including 3D visualization, elimination of the fulcrum effect, and better ergonomic positioning, which together lead to better surgical outcomes and faster recovery. However, analysis of independent factors of postoperative complications after robotic surgery is still insufficient. AIM: To analyze the incidence and risk factors for postoperative complications after robotic surgery in patients with CRC. METHODS: In total, 1040 patients who had undergone robotic surgical resection for CRC between May 2015 and May 2020 were analyzed retrospectively. Postoperative complications were categorized according to the Clavien-Dindo (C-D) classification, and possible risk factors were evaluated. RESULTS: Among 1040 patients who had undergone robotic surgery for CRC, the overall, severe, local, and systemic complication rates were 12.2%, 2.4%, 8.8%, and 3.5%, respectively. Multivariate analysis revealed that multiple organ resection (P < 0.001) and level III American Society of Anesthesiologists (ASA) score (P = 0.006) were independent risk factors for overall complications. Multivariate analysis identified multiple organ resection (P < 0.001) and comorbidities (P = 0.029) as independent risk factors for severe complications (C-D grade III or higher). Regarding local complications, multiple organ resection (P = 0.002) and multiple bowel resection (P = 0.027) were independent risk factors. Multiple organ resection (P < 0.001) and level III ASA score (P = 0.007) were independent risk factors for systemic complications. Additionally, sigmoid colectomy had a lower incidence of overall complications (6.4%; P = 0.006) and local complications (4.7%; P = 0.028) than other types of colorectal surgery. CONCLUSION: Multiple organ resection, level III ASA score, comorbidities, and multiple bowel resection were risk factors for postoperative complications, with multiple organ resection being the most likely.

The cellular and molecular components involved in pre-metastatic niche formation in colorectal cancer liver metastasis.

Introduction: Liver metastasis is the main cause of death in colorectal cancer (CRC). Premetastatic niche (PMN), a favorable microenvironment for cancer cells colonization at the distant organ, plays a pivotal role in CRC liver metastasis (CRCLM). Our understanding of the mechanisms mediating the formation of liver PMN in CRC has been significantly advanced in recent years, there are still many challenges and questions that remain.Areas covered: This review covers cellular and molecular components, and the interaction of theprimary cancer with the resident microenvironment of the distant organ that leads to PMN formation in CRCLM based on the latest literature.Expert Opinion: Various cellular and molecular events are involved in the liver PMN formation in CRC such as bone marrow-derived cells (BMDCs), hepatic stellate cells, Kupffer cells, extracellular matrix, and CRC-derived factors. The formation of the liver PMN depends on a complex interaction of CRC with the liver microenvironment including BMDCs recruitment, vascularization, immunosuppression, inflammatory response, and extracellular matrix remodeling. This review firstly discusses on the cellular and molecular components contributing to the formation of the liver PMN in CRC, so as to provide new ideas for designing effective therapeutic strategies and prognostic markers for CRCLM.

Peritumoral activated hepatic stellate cells are associated with hepatic recurrence for resectable colorectal adenocarcinoma liver metastasis following resection.

The formation of the pre-metastatic niche (PMN), which precedes the establishment of tumor lesions, plays a critical role in cancer recurrence and metastasis. Hepatic stellate cells (HSCs), a critical liver stromal cell component, can be induced to facilitate metastasis by modeling liver PMN formation. In the present study, activated HSCs were observed in the peritumor non-cancerous liver tissues (PNLT) colorectal adenocarcinoma liver metastasis (CRALM), and the density of activated HSCs was higher in PNLT compared with that in normal liver tissues (NLT). High density of activated HSC in the PNLT was positively associated with the number of tumor liver metastases (P=0.036), maximum diameter of liver metastases (P=0.002), and recurrence following synchronous radical resection (P=0.003). High density of activated HSCs in the PNLT was identified as a significant and independent prognostic factor for disease-free survival (HR, 2.083; 95% CI, 1.504-2.885; P=0.016) and overall survival (HR, 2.039; 95% CI, 1.312-3.169; P=0.019). Functionally, in vitro assays revealed that activated HSCs facilitated colorectal adenocarcinoma (CRA) cells to colonize the liver. Molecularly, it was demonstrated that the pro-recurrence of activated HSCs depended on paracrine hepatic growth factor. Taken together, the present results showed that high density of activated HSCs in the PNLT was an independent predictor for CRALM recurrence following resection, and they exerted their roles via their effect on CRA cell recruitment and proliferation by paracrine HGF.

MiR-26a-5p enhances cells proliferation, invasion, and apoptosis resistance of fibroblast-like synoviocytes in rheumatoid arthritis by regulating PTEN/PI3K/AKT pathway.

Behavior alterations in fibroblast-like synoviocytes (FLS) contribute to a pivotal role in pathogenesis of rheumatoid arthritis (RA). MiRNAs are closely involved in a variety of pathologic conditions. In the present study, we aimed to screen for the aberrant expression of miRNAs in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) to further identify the altered expression of miR-26a-5p in RA-FLS and to investigate the role of miR-26a-5p in RA. The altered expression of miR-26a-5p in RA-FLS was screened by microarray analysis and confirmed by quantitative real time PCR. The effect of miR-26a-5p on proliferation, cell cycle, apoptosis, and invasion in RA-FLS were studied. The verification of miR-26a-5p target mRNA and downstream signaling pathway was elucidated by bioinformatics analysis, dual luciferase reporter assay, and western blot. Expression of miR-26a-5p was higher in RA-FLS than in fibroblast-like synoviocytes from osteoarthritis patients and trauma patients. Overexpression of miR-26a-5p RA-FLS promoted cells proliferation, G1/S transition, cells invasion, and resisted apoptosis in RA-FLS, whereas it led to contrary effects when inhibiting the expression of miR-26a-5p. The 3'UTR of tensin homolog (PTEN) was directly targetted by miR-26a-5p and activation of phosphoinositide 3-kinase (PI3K)/AKT pathway was observed when overexpression of miR-26a-5p. Our study suggested that miR-26a-5p has a complementary role in cells proliferation, invasion, and apoptosis of RA-FLS, which may be attributed to its activation effect on PI3K/AKT signaling pathway via targetting PTEN. MiR-26a-5p is likely to be a clinically helpful target for novel therapeutic strategies in RA.

Clinical and MRI response to dose reduction of an etanercept-biosimilar for hip arthritis in patients with ankylosing spondylitis: an observational, retrospective cohort study.

OBJECTIVES: Hip arthritis plays a critical role in the prognosis of ankylosing spondylitis (AS). Dose reduction of tumor necrosis factor inhibitors preserves general improvement of AS, so this study attempted to examine the equivalence between Yisaipu® tapering and conventional therapy for hip arthritis in AS patients, using clinical parameters and magnetic resonance image (MRI). METHODS: AS patients received this etanercept-biosimilar injections (50 mg/week) in the first 12 weeks. Participants in the tapering group were treated with this reagent 50 mg every other week from week 13 to week 24, while the control group kept undergoing full-dose therapy. Clinical and laboratory parameters were assessed at baseline, week 12 and week 24. MRI examination of hip was performed at baseline and week 24. RESULTS: One hundred and thirty-six patients were enrolled, and 80 of them were in the tapering group. Linear mixed model revealed that main effects of tapering group with control group as reference in disease activity parameters were insignificant (p > 0.05). Main effects of baseline with week 24 as reference were significant (p < 0.05), but main effects of week 12 with week 24 as reference were not (p > 0.05). Prevalence of acute inflammatory change in MRI significantly decreased in the tapering group (76.88% vs 20.00%, p < 0.05) and control group (76.79% vs 19.64%, p < 0.05). Influence of both treatments on acute inflammatory change was equivalent (p > 0.05). CONCLUSION: Efficacy of Yisaipu® tapering treatment is comparable to the full-dose therapy for hip arthritis in AS patients. Both treatments maintain remission of hip arthritis after patients achieved low disease activity.

Mycobacterium tuberculosis Erdman infection of cynomolgus macaques of Chinese origin.

BACKGROUND: Nearly one-third of the population worldwide is estimated to have latent tuberculosis infection (LTBI), which represents a vast reservoir for a constant source of tuberculosis (TB) transmission. It has been suggested that cynomolgus macaques are less susceptible to Mycobacterium tuberculosis (M.tb) infection than rhesus macaques, we examined M.tb infection of Chinese cynomolgus macaques. METHODS: Eight Chinese cynomolgus macaques were infected with M.tb Erdman strain with a small [25 colony forming unit (CFU)] or large dose (500 CFU) via bronchoscopy. The infected animals were monitored for symptoms and examined by chest X-ray, computed tomography (CT), tuberculin skin test (TST), and enzyme-linked immunospot (ELISPOT). RESULTS: Based on TST conversion and the specific immune responses to M.tb antigens, all animals were successfully infected. Half of the animals developed active infection and died within 15 months postinfection. The other four animals were grouped with latent M.tb infection because of positive TST but few clinical signs and pathological changes of TB during the course of this study. Interestingly, a challenge with a large dose of M.tb also induced latent infection. Similar to the changes that occur with human TB patients, the animals with active infection exhibited weight loss, cough and typical TB pathological changes, including caseous granulomas, cavities, consolidation, lipid pneumonia, pleural effusion, lymphadenopathy and bacterial burden in lungs and other organs. CONCLUSIONS: The low dose of M.tb was sufficient to cause both active and latent M.tb infection in cynomolgus macaques of Chinese origin.