[Research Status and Trend of Devices for Treating Advanced Heart Failure].

Heart failure (HF),a chronic progressive disease,is a global health problem and the leading cause of deaths in the global population.The pathophysiological abnormalities of HF mainly include abnormal cardiac structure (myocardium and valves),disturbance of electrophysiological activities,and weakened myocardial contractility.In addition to drug therapy and heart transplantation,interventional therapies can be employed for advanced-stage HF,including transcatheter interventions and mechanical circulatory assist devices.This article introduces the devices used for advanced HF that have been marketed or certified as innovative or breakthrough devices around the world and summarizes the research status and prospects the trend in this field.As diversified combinations of HF devices are used for the treatment of advanced HF,considerations regarding individualized HF therapy,risk-benefit evaluation on device design,medical insurance payment,post-market supervision system,and protection of intellectual property rights of high-end technology are needed,which will boost the development of the technology and industry and benefit the patients.

Association of cardiac disease with the risk of post-lung transplantation mortality in Chinese recipients aged over 65 years.

The current organ allocation rules prioritize elderly and urgent patients on the lung transplantation (LT) waiting list. A steady increase in the threshold at which age is taken into consideration for LT has been observed. This retrospective cohort study recruited 166 lung transplant recipients aged ≽ 65 years between January 2016 and October 2020 in the largest LT center in China. In the cohort, subgroups of patients aged 65-70 years (111 recipients, group 65-70) and ≽ 70 years (55 recipients, group ≽ 70) were included. Group D restrictive lung disease was the main indication of a lung transplant in recipients over 65 years. A significantly higher percentage of coronary artery stenosis was observed in the group ≽ 70 (30.9% vs. 14.4% in group 65-70, P = 0.014). ECMO bridging to LT was performed in 5.4% (group 65-70) and 7.3% (group ≽ 70) of patients. Kaplan-Meier estimates showed that recipients with cardiac abnormalities had a significantly increased risk of mortality. After adjusting for potential confounders, cardiac abnormality was shown to be independently associated with the increased risk of post-LT mortality (HR 6.37, P = 0.0060). Our result showed that LT can be performed in candidates with an advanced age and can provide life-extending benefits.

[Recent Advance of Stainless Steel Used In Non-active Surgical Implantable Medical Device and Regulatory Perspective].

Stainless steel has been widely used in non-active surgical implantable medical device of cardiovascular, orthopedics, dental and ophthalmology. In this paper, we mainly focused on development of stainless steel, as well as the material-related standard evolution. We further summarized the recent advancement of stainless steel use in surgical implantable medical device. Insight and regulatory perspective has been further demonstrated.

Association of Pulmonary Artery Pressure Change With Post-Lung Transplantation Survival: Retrospective Analysis of China Registry.

Background: Extracorporeal membrane oxygenation (ECMO) has been used as intraoperative hemodynamic support in patients with end-stage lung diseases and pulmonary hypertension undergoing lung transplantation (LT). Objectives: The aim of this study was to identify the association of pulmonary artery pressure change during ECMO and post-LT survival. Methods: The study investigators collected and analyzed the data from Chinese Lung Transplantation Registry. Patients who have severe pulmonary hypertension with intraoperative ECMO support were enrolled. Post-LT mortality and morbidity were further collected and compared. Results: A total of 208 recipients were included in the study, during which 53 deaths occurred post-LT. All the patients had severe pulmonary hypertension and were supported by intraoperative ECMO. Using eXtreme Gradient Boosting, or XGboost, model method, 20 variables were selected and ranked. Changes of mean pulmonary artery pressure at the time of ECMO support and ECMO wean-off (ΔmPAP) were related to post-LT survival, after adjusting for potential confounders (recipient age, New York Heart Association functional class status before LT, body mass index, pre-LT hypertension, pre-LT steroids, and pre-LT ECMO bridging). A nonlinear relationship was detected between ΔmPAP and post-LT survival, which had an inflection point of 35 mm Hg. Recipients with ΔmPAP ≦35 mm Hg had higher mortality rate calculated through the Kaplan-Meier estimator (P = 0.041). Interaction analysis showed that recipients admitted in LT center with high case volume (≥50 cases/year) and ΔmPAP >35 mm Hg had better long-term survival. The trend was reversed in recipients who were admitted in LT center with low case volume (<50 cases/year). Conclusions: The relationship between ΔmPAP and post-LT survival was nonlinear. Optimal perioperative ECMO management strategy with experienced team is further warranted.

Lung transplantation during the outbreak of Coronavirus Disease 2019 in China.

OBJECTIVES: The study objectives were to illustrate our workflow for lung donation and transplantation during the Coronavirus Disease 2019 crisis and to report our preliminary experience with perioperative care. METHODS: We retrospectively analyzed data in the China Lung Transplantation Registration from January 23, 2020, to March 23, 2020 (2020 cohort), compared with the same period in 2019 (2019 cohort). Pre- and post-lung transplantation management strategies, including measures aiming to prevent severe acute respiratory syndrome coronavirus 2 infection, were applied to all recipients, including 5 post-Coronavirus Disease 2019 transplants during the Coronavirus Disease 2019 pandemic period in China. RESULTS: Twenty-eight lung transplant procedures were performed, including lung transplant for 5 patients with acute respiratory distress syndrome due to Coronavirus Disease 2019-related pulmonary fibrosis. Compared with the 2019 cohort, more patients with urgent conditions received transplantation in 2020, with a shorter pre-lung transplant admission time and early mobilization post-lung transplant. A large proportion (60%) of lung donations were transported on high-speed trains and commercial flights or highways and commercial flights. Grafts in the preservation containers were handed over to the receiving staff at the airport for 40% (10/25) of donations, which reduced the unnecessary quarantine of transporting staff entering the city. Listed candidates were urgently transferred to other qualified centers in 17.9% of cases (5/28), which reduced the risk of severe acute respiratory syndrome coronavirus 2 exposure in Coronavirus Disease 2019-designated hospitals. The 90-day survival of the transplant recipients in 2020 was 85.7%, including 3 of 5 recipients (60%) who had critically severe Coronavirus Disease 2019. CONCLUSIONS: Lung transplant and donation amid Coronavirus Disease 2019 can be performed safely with coordinated efforts on medical resource sharing and medical staff protection based on stratification of the infection risk. Outcomes were not compromised during the Coronavirus Disease 2019 outbreak. Lung transplantion can be regarded as salvage therapy for critical patients with Coronavirus Disease 2019 with a confirmed positive turned negative virology status.

Case Report: Delayed Lung Transplantation With Intraoperative ECMO Support for Herbicide Intoxication-Related Irreversible Pulmonary Fibrosis: Strategy and Outcome.

Background: Lung transplantation is recognized as the only therapeutic option for patients who develop irreversible pulmonary fibrosis after herbicide intoxication. Methods: We have collected and presented clinical course and outcome of four patients who received lung transplantation due to paraquat and diquat intoxication from 2018 to 2021. Another patient who received initial lung transplantation due to paraquat intoxication and re-transplantation due to chronic lung allograft dysfunction in 2019, was further reported. Patients were admitted in lung transplantation centers, including the 1st affiliated hospital of Zhengzhou University and Wuxi Lung transplantation center. Previous reported cases from Europe, Canada and China were also summarized as benchmark. Results: During the period from the year of 2018 to 2021, there have been four patients in China, who received lung transplantation due to herbicide intoxication. Median age of the four patients was 37 (IQR 34.5, 39.75) years old. Median time from intoxication to lung transplantation was 27.5 (IQR 27, 30.5) days. Bilateral lung transplantation was performed in three patients, while one single lung transplantation was performed in an urgent listed patient. Extracorporeal Membrane Oxygenation (ECMO) and hemopurification support were used in all patients (100%). Details of the cases with follow-ups were further presented and analyzed. Conclusions: Late timing of bilateral lung transplantation can be performed successfully for pulmonary fibrosis after paraquat or diquat intoxication. The survival of patients with complex perioperative conditions can be achieved with a multidisciplinary team to manage the irreversible effects of intoxication.

Lung transplantation as therapeutic option in acute respiratory distress syndrome for coronavirus disease 2019-related pulmonary fibrosis.

BACKGROUND: Critical patients with the coronavirus disease 2019 (COVID-19), even those whose nucleic acid test results had turned negative and those receiving maximal medical support, have been noted to progress to irreversible fatal respiratory failure. Lung transplantation (LT) as the sole therapy for end-stage pulmonary fibrosis related to acute respiratory distress syndrome has been considered as the ultimate rescue therapy for these patients. METHODS: From February 10 to March 10, 2020, three male patients were urgently assessed and listed for transplantation. After conducting a full ethical review and after obtaining assent from the family of the patients, we performed three LT procedures for COVID-19 patients with illness durations of more than one month and extremely high sequential organ failure assessment scores. RESULTS: Two of the three recipients survived post-LT and started participating in a rehabilitation program. Pearls of the LT team collaboration and perioperative logistics were summarized and continually improved. The pathological results of the explanted lungs were concordant with the critical clinical manifestation, and provided insight towards better understanding of the disease. Government health affair systems, virology detection tools, and modern communication technology all play key roles towards the survival of the patients and their rehabilitation. CONCLUSIONS: LT can be performed in end-stage patients with respiratory failure due to COVID-19-related pulmonary fibrosis. If confirmed positive-turned-negative virology status without organ dysfunction that could contraindicate LT, LT provided the final option for these patients to avoid certain death, with proper protection of transplant surgeons and medical staffs. By ensuring instant seamless care for both patients and medical teams, the goal of reducing the mortality rate and salvaging the lives of patients with COVID-19 can be attained.

China lung transplantation developing: past, present and future.

Lung transplantation in China has been developing for almost 40 years (1979-2019). The pioneers of this procedure experienced struggles and obstacles upon accomplishment of the initial 20 cases of lung transplantation. Like the expanding process of transplant programs elsewhere in western countries and other regions in Asia, transplant teams in China have found their own way to step forward, with the establishment of the two largest centers in Beijing and Wuxi. Since 2015, which was a novel start and milestone for transplant affairs in China, the pace of transplant volume and comparable quality of care for lung transplant recipients have increased noticeably. We reviewed the advancement of lung transplantation programs and registry setup in China and indicated that more socioeconomic factors and human care aspects needed to be considered to benefit Chinese recipients, which may further inspire the modification of criteria of listing and organ utilization based on East Asian cultural and traditional origins.

Splenectomy Promotes Macrophage Polarization in a Mouse Model of Concanavalin A- (ConA-) Induced Liver Fibrosis.

BACKGROUND: Splenectomy can improve liver function and survival in patients with autoimmune hepatitis (AIH) and liver cirrhosis. We investigated the underlying mechanism in a mouse model of concanavalin A- (ConA-) induced liver fibrosis. METHODS: We used ConA to induce immune liver fibrosis in BALB/c mice. Splenectomy was performed alone or with the administration of dexamethasone (DEX). Changes in blood and liver tissues were evaluated. RESULTS: Mice treated with ConA for 7 weeks developed advanced liver fibrosis, while splenectomy suppressed liver fibrosis. Although the populations of macrophages/monocytes and M1 macrophages decreased after splenectomy, the inflammatory factors associated with M2 macrophages increased after splenectomy. Furthermore, the population of circulating CD11b+Ly6Chigh myeloid-derived suppressor cells (MDSCs) increased after splenectomy. After ConA treatment, elevated levels of activated and total NF-kBp65/p50 combined with DNA were observed in hepatic tissues. In contrast, the levels of NF-κB p65/p50 decreased after splenectomy. CONCLUSIONS: Splenectomy may promote the polarization of CD11b+Ly6Chigh MDSCs and the differentiation of M2 macrophages while restricting the level of NF-κB p65-p50 heterodimers. These factors may suppress the progression of liver fibrosis.

NK Cell Subtypes as Regulators of Autoimmune Liver Disease.

As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity to destroy tumors or infected cells, but also act to regulate the functions of other cells in the immune system by secreting cytokines and chemokines. Thus, NK cells provide surveillance in the early defense against viruses, intracellular bacteria, and cancer cells. However, the effecter function of NK cells must be exquisitely controlled to prevent inadvertent attack against normal "self" cells. In an organ such as the liver, where the distinction between immunotolerance and immune defense against routinely processed pathogens is critical, the plethora of NK cells has a unique role in the maintenance of homeostasis. Once self-tolerance is broken, autoimmune liver disease resulted. NK cells act as a "two-edged weapon" and even play opposite roles with both regulatory and inducer activities in the hepatic environment. That is, NK cells act not only to produce inflammatory cytokines and chemokines, but also to alter the proliferation and activation of associated lymphocytes. However, the precise regulatory mechanisms at work in autoimmune liver diseases remain to be identified. In this review, we focus on recent research with NK cells and their potential role in the development of autoimmune liver disease.

Ligation-Assisted Endoscopic Enucleation for the Resection of Gastrointestinal Tumors Originating from the Muscularis Propria: Analysis of Efficacy and Facility.

BACKGROUND: Gastrointestinal tumors originating from the muscularis propria are believed to have the potential to progress to malignant tumors. The efficacy of 'pre-management' with elastic band or endoloop assistant ligation after initial submucosal dissection in endoscopic enucleation procedure of these tumors was investigated and evaluated. METHODS: The study included 21 patients with small gastric stromal tumors arising in the gastric muscularis propria as determined by endoscopy (endoscopic ultrasonography). A standard endoscope with a transparent cap attached to the tip was used. The cap was placed over the lesion, after incision of the surrounding tissue, maximum sustained suction was applied. Then the elastic band or endoloop was released around the base. Circumference resection was performed with clips strengthening the defect closure. RESULTS: The 22 gastrointestinal stromal tumors sloughed completely. The mean time required for the full-thickness resection was 48 min. Minor perforation occurred with metal clips closing the defect of the gastric wall. Follow-up ranged from 13 to 42 months, during which time no recurrence was observed postoperatively. CONCLUSIONS: The band or endoloop assistant endoscopic ligation technique is effective for the enucleation of deep gastric tumors. It may help avoiding disturbance the abdominal cavity hemostasis in traditional full-thickness enucleation procedure.

IL-37b gene transfer enhances the therapeutic efficacy of mesenchumal stromal cells in DSS-induced colitis mice.

AIM: To investigate whether the transfer of the IL-37b gene, a newly identified inhibitor of both innate and adaptive immunity, could improve the therapeutic efficacy of mesenchumal stromal cells (MSCs) in inflammatory bowel disease (IBD). METHODS: The expression of IL-37 in biopsied specimens of the patients with active ulcerative colitis (UC) was detected using RT-PCR and immunohistochemistry. Mice were treated with 3% dextran sulfate sodium (DSS) for 8 days to induce colitis. Before DSS treatment, the mice were injected with MSCs, MSC-eGFP or MSC-IL37b. Their body weight was measured each day, and the colons and spleens were harvested on d 10 for pathological and biochemical analyses. RESULTS: In biopsied specimens of the patients with active UC, the expression of IL-37 was dramatically elevated in inflamed mucosa, mainly in epithelial cells and infiltrating immune cells. Compared to MSC-eGFP or MSCs, MSC-IL37b administration significantly attenuated the body weight and colon length reduction, and decreased the histological score in DSS-induced colitis mice. Furthermore, MSC-IL37b administration increased the percentage of myeloid-derived suppressor cells (MDSCs) among total splenic mononuclear cells as well as the percentage of regulatory T cells (Tregs) among splenic CD4+ T cells in the mice. Moreover, MSC-IL37b administration increased the IL-2+ cells and decreased the IFN-γ+ cells among splenic CD4+ T cells. CONCLUSION: IL-37 is involved in the pathophysiology of UC. IL-37b gene transfer enhances the therapeutic efficacy of MSCs in DSS-induced colitis mice by inducing Tregs and MDSCs and regulating cytokine production.

Enteropathy-associated T-cell lymphoma presenting with gastrointestinal tract symptoms: A report of two cases and review of diagnostic challenges and clinicopathological correlation.

The gastrointestinal tract is the most common location for primary extranodal non-Hodgkin lymphoma (NHL) with cases less commonly found in the intestine. The majority of primary intestinal B-cell lymphomas are exophytic, whereas enteropathy-associated T-cell lymphomas present predominantly as thickened plaques, ulcers or strictures. Crohn's disease (CD) is a chronic inflammatory disease of the intestines with fissures and ulcers, which is difficult for clinicians to diagnose based on endoscopic observations alone. Malignant lymphoma must be considered when clinically diagnosed CD is refractory to medication or when its clinical course becomes aggressive. The current study presents a rare case of primary colon T-cell lymphoma in a 16-year-old male with poor prognosis, as well as a case of gastrointestinal lymphoma occurring in the duodenum and colon in a 62-year-old male with a 10-year history of NHL. It was difficult to determine the diagnosis by a single endoscopic biopsy as the majority of biopsy specimens revealed mixed inflammation within which the lymphoma cells were difficult to identify. The present study indicated that it is important to recognize ulcerative or stenotic lymphoma and to differentiate it from CD as it exhibits a much more aggressive clinical behavior. The correct diagnosis may be confirmed by careful histopathological study and ancillary examination.

Antigen presentation by dendritic cells in tumors is disrupted by altered metabolism that involves pyruvate kinase M2 and its interaction with SOCS3.

Dendritic cell (DC) function is negatively affected by tumors and tumor-derived factors, but little is known about the underlying mechanisms. Here, we show that intracellular SOCS3 in DCs binds to pyruvate kinase type M2 (M2-PK), which plays a critical role in ATP production through glycolysis. The interaction of SOCS3 with M2-PK reduced ATP production and impaired DC-based immunotherapy against tumors. Thus, SOCS3, which has been shown to be upregulated by tumor-derived factors, interacts with M2-PK to decrease ATP production, causing DC dysfunction. These dysfunctional DCs have a reduced ability to present antigens. Alteration of DC metabolism mediated by SOCS3 represents a novel mechanism for DC dysfunction in the tumor microenvironment.

AA28-67 domain within MyD88 suppresses c-myc activity and expression to regulate differentiation and function of dendritic cells.

The mechanism by which c-myc expression in undifferentiated cells rapidly declines following induction of differentiation is poorly characterized. We demonstrate here that MyD88, which can activate NF-kappaB and MAPK, also suppresses c-myc activity and expression. The aa 28-67 domain, a highly conserved region within MyD88, plays a critical role in the MyD88-mediated inhibition. Indeed, deletion of the aa 28-67 domain (MyD88 Delta 28-67) or mutation of the highly conserved amino acid residue phenylalanine (aa 36) to aspartic acid (MyD88 Delta F36D) significantly promoted c-myc activity and expression. Additionally, we found that MyD88 Delta 28-67-mediated c-myc activity and expression could be abrogated using PI3K inhibitor, suggesting that the PI3K/Akt signaling pathway may be involved in MyD88-mediated suppression of c-myc. Compared to MyD88-transduced DCs, MyD88 Delta 28-67- and MyD88 Delta F36D-transduced DCs derived from MyD88-/- bone marrow cells had lower antigen-presenting ability. Thus, MyD88 induces the differentiation and maturation of DCs not only by activating NF-kappaB and MAPK but also via suppressing c-myc activity and expression.

Suppressor of cytokine signaling 3 promotes bone marrow cells to differentiate into CD8+ T lymphocytes in lung tissue via up-regulating Notch1 expression.

Suppressor of cytokine signaling 3 (SOCS3) expression in bone marrow cells (BMC) was up-regulated upon exposure to interleukin 6, lipopolysaccharide, or tumor-associated factors. But, how the up-regulated SOCS3 affects differentiation of BMCs is incompletely characterized. Here, we showed that SOCS3 promoted BMCs to intently differentiate into CD8 T cells. Importantly, lung can be as one athymus tissue for the BMCs to differentiate into CD8(+) T cells. Notch1 plays a critical role in the differentiation from SOCS3-transfected BMCs to CD8(+) T cells. We conclude that the up-regulated SOCS3 in some pathologic conditions, such as tumor and inflammation, might promote BMCs to differentiate into CD8(+) T lymphocytes in lung tissue via up-regulating Notch1 expression. This may represent a new mechanism against diseases such as tumor.

Regulation of arginase I activity and expression by both PD-1 and CTLA-4 on the myeloid-derived suppressor cells.

An elevated number of Gr-1(+)CD11b(+) myeloid-derived suppression cells (MDSCs) has been described in mice and human bearing tumor and associated with immune suppression. Arginase I production by MDSCs in the tumor environment may be a central mechanism for immunosuppression and tumor evasion. In this study and before, we found that Gr-1(+)CD11b(+) MDSCs from ascites and spleen of mice bearing ovarian 18D carcinoma express a high level of PD-1, CTLA-4, B7-H1 and CD80 while other co-stimulatory molecules, namely CD40, B7-DC and CD86 are not detected. Further studies showed that PD-1 and CTLA-4 on the Gr-1(+)CD11b(+) MDSCs regulated the activity and expression of arginase I. The blockage and silencing of PD-1, CTLA-4 or both PD-1 and CTLA4 molecules could significantly reduce arginase I activity and expression induced with tumor-associated factor. Similar results were also observed while their ligands B7-H1 and/or CD80 were blocked or silenced. Furthermore, CD80 deficiency also decreased the arginase I expression and activity. Antibody blockade or silencing of PD-1, CTLA-4 or both reduced the suppressive potential of PD-1+CTLA-4+MDSCs. Blockade of PD-1, CTLA-4 or both also slowed tumor growth and improved the survival rate of tumor-bearing mice. Thus, there may exist a coinhibitory and costimulatory molecules-based immuno-regulating net among MDSCs.

[RGS1 is involved in the regulation of co-stimulatory molecules and cytokines in RAW264.7 cells].

AIM: To investigate the effect of regulator of G protein 1 (RGS1) on the expression of costimulatory molecules and the production of cytokines in RAW264.7 cells. METHODS: RGS1 was cloned and then used to transfect RAW264.7 cells to set up stably tranfected cell line. The function of RGS1 was detected by flow cytometry (FACS) and global microarray. RESULTS: RGS1 inhibited the activation of NF-kappaB, significantly promoted the expression of surface molecular CD86, and down-regulated the expression of CD80. Upon the exposure to different kinds of Toll like receptor ligands (TLRL), RGS1 remarkably inhibited the expression of surface molecules CD40, CD80 and PD1. Meanwhile, RGS1 significantly up-regulated the expression of IL-6 and IL-15, down-regulated the expression of IL-10 and IL-1. CONCLUSION: RGS1 can modulate the expression of costimulatory molecules and cytokine secretion, and interrupt Toll like receptor signal pathways, which suggest that RGS1 may play a role in regulating immune responses.