Effects of Staphylococcus aureus on stem cells and potential targeted treatment of inflammatory disorders.

Due to the advanced studies on stem cells in developmental biology, the roles of stem cells in the body and their phenotypes in related diseases have not been covered clearly. Meanwhile, with the intensive research on the mechanisms of stem cells in regulating various diseases, stem cell therapy is increasingly being attention because of its effectiveness and safety. As one of the most widely used stem cell in stem cell therapies, hematopoietic stem cell transplantation shows huge advantage in treatment of leukemia and other blood-malignant diseases. Besides, due to the effect of anti-inflammatory and immunomodulatory, mesenchymal stem cells could be a potential therapeutic strategy for variety infectious diseases. In this review, we summarized the effects of Staphylococcus aureus (S. aureus) and its components on different types of adult stem cells and their downstream signaling pathways. Also, we reviewed the roles of different kinds of stem cells in various disease models caused by S. aureus, providing new insights for applying stem cell therapy to treat infectious diseases.

Hydrolytic endonucleolytic ribozyme (HYER) is programmable for sequence-specific DNA cleavage.

Ribozymes are catalytic RNAs with diverse functions including self-splicing and polymerization. This work aims to discover natural ribozymes that behave as hydrolytic and sequence-specific DNA endonucleases, which could be repurposed as DNA manipulation tools. Focused on bacterial group II-C introns, we found that many systems without intron-encoded protein propagate multiple copies in their resident genomes. These introns, named HYdrolytic Endonucleolytic Ribozymes (HYERs), cleaved RNA, single-stranded DNA, bubbled double-stranded DNA (dsDNA), and plasmids in vitro. HYER1 generated dsDNA breaks in the mammalian genome. Cryo-electron microscopy analysis revealed a homodimer structure for HYER1, where each monomer contains a Mg2+-dependent hydrolysis pocket and captures DNA complementary to the target recognition site (TRS). Rational designs including TRS extension, recruiting sequence insertion, and heterodimerization yielded engineered HYERs showing improved specificity and flexibility for DNA manipulation.

Effects of Dopamine on stem cells and its potential roles in the treatment of inflammatory disorders: a narrative review.

Inflammation is the host's protective response against harmful external stimulation that helps tissue repair and remodeling. However, excessive inflammation seriously threatens the patient's life. Due to anti-inflammatory effects, corticosteroids, immunosuppressants, and monoclonal antibodies are used to treat various inflammatory diseases, but drug resistance, non-responsiveness, and severe side effect limit their development and application. Therefore, developing other alternative therapies has become essential in anti-inflammatory therapy. In recent years, the in-depth study of stem cells has made them a promising alternative drug for the treatment of inflammatory diseases, and the function of stem cells is regulated by a variety of signals, of which dopamine signaling is one of the main influencing factors. In this review, we review the effects of dopamine on various adult stem cells (neural stem cells, mesenchymal stromal cells, hematopoietic stem cells, and cancer stem cells) and their signaling pathways, as well as the application of some critical dopamine receptor agonists/antagonists. Besides, we also review the role of various adult stem cells in inflammatory diseases and discuss the potential anti-inflammation function of dopamine receptors, which provides a new therapeutic target for regenerative medicine in inflammatory diseases.

[Hematopoietic Stem Cells Differentiate into the Megakaryocyte Lineage--Review].

Abstract　　Hematopoietic stem cells are able to self-renewal and differentiate to all blood lineages. With the development of new technologies, recent studies have proposed the revised versions of hematopoiesis. In the classical model of hematopoietic differentiation, HSCs were located at the apex of hematopoietic hierarchy. During differentiation process, HSCs progressively lose self-renewal potential to be commited to progenitors with restricted differentiation potential. For instance, HSCs first give rise to multipotent progenitor cells, then produce bipotent and unipotent progenitors, and finally differentiate to mature blood cells. For the differentiation of megakaryocytes, common myeloid progenitors derived from HSCs give rise to megakaryocyte-erythrocyte progenitors and then develop to megakaryocytes. However, recent results show that megakaryocytes can be directly generated from HSCs without multipotent or bipotent phases. Alternatively, platelet-biased HSCs produce megakaryocyte progenitors. In this article, recent advances in the hematopoiesis and megakaryocyte differentiation pathway are reviewed.

Conditioning Regimen of 5-Day Decitabine Administration for Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome and Myeloproliferative Neoplasms.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, post-HSCT relapse remains a major cause of treatment failure. Here we assessed the efficacy of a new conditioning regimen comprising decitabine (Dec), busulfan (Bu), cyclophosphamide (Cy), fludarabine (Flu), and cytarabine (Ara-c) for allo-HSCT in patients with MDS and MDS/MPN. A total of 48 patients were enrolled, including 44 with MDS and 4 with chronic myelomonocytic leukemia (CMML). Patients received Dec 20 mg/m2/day on days -9 to -5, combined with a Bu/Cy/Flu/Ara-c-modified preparative regimen. At a median follow-up of 522 days (range, 15 to 1313 days), the overall survival (OS) was 86%, relapse incidence was 12%, and nonrelapse mortality was 12%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 23% and that of chronic GVHD was 15%. At 2 years, OS was 74% and 86%, respectively for high-risk and very-high-risk patients with MDS. Survival was promising in patients with poor-risk gene mutations, such as TP53 and ASXL1 (88%), and in those with ≥3 gene mutations (79%). Results of immunomonitoring studies revealed that proper natural killer cells made essential contributions to these favorable clinical outcomes. Overall, this new regimen was associated with a low relapse rate, low incidence and severity of GVHD, and satisfactory survival in allo-HSCT recipients with MDS and MDS/MPN.

[Emerging role of Mitochondria in Maintenance of Hematopoietic Stem Cells--Review].

Mitochondria are double-membrane organelles existing only in eukaryotic cells. Mitochondria perform various important functions，such as producing energy，regulating signal transduction，and contributing to stress response. Recent studies have highlighted an important role of mitochondria in the determination of hematopoietic stem cells （HSC） fate. Limited biogenesis or timely clearance of mitochondria is an important way against oxidative stress，which favors the quiescence of HSC. Accumulation of mitochondria may lead to proliferation of HSC，even the aging of HSC. Mitochondrial signaling regulates Ca2+ concentration，which is essential for HSC differentiation. This review summarizes the current findings of the mitochondrial roles in HSC quiescence，self-renewal，lineage differentiation and aging.

Two novel compound heterozygous mutations associated with types I and II protein C deficiency with unusual phenotypes.

INTRODUCTION: We diagnosed two Chinese hereditary PC deficiency families and identified two novel compound heterozygous mutations (p.Arg194Cys/Gly324Ser and p.Glu274X/Asp297His) in the protein C (PROC) gene. The probands were classified as types I and II PC deficiency. The aim of this article is to access the influence of the mutations on PC activity, antigen and protein structure, and to evaluate whether there is abnormal PC localization. MATERIALS AND METHODS: Genomic DNA of all family members was extracted, PCR amplified, and sequenced. The mutant PC expression plasmids were constructed. Expression assays, intracellular localization, and molecular modeling were performed. RESULTS: Proband 1, a type II PC defect, harbored a compound heterozygous mutation, p.Arg194Cys/Gly324Ser in the PROC gene, underwent two thromboembolic events. Expression assays indicated that the p.Arg194Cys mutant lead to decreased PC activity and normal PC Ag levels. Intracellular localization showed that both p.Arg194Cys and p.Gly324Ser co-localized with the endoplasmic reticuli and the Golgi apparatus. Molecular modeling suggested that the p.Gly324Ser mutation disturbed the interaction between the heavy and light chains of the PC protein. Proband 2, a type I PC defect, harbored a compound heterozygous PROC gene mutation, p.Glu274X/Asp297His, presented with recurrent spontaneous abortion and right popliteal vein thrombosis. Expression results were in accordance with the PC changes of the patient, and existed in defective PC transport. Structural model suggested p.Glu274X lead to disulfide bond between heavy and light chain cannot form. CONCLUSIONS: Our results confirm that two novel compound heterozygous PROC gene mutations are causative on the two PC deficiency families.

Surgical treatment of patients with intermediate-terminal pancreatic cancer.

AIM: To investigate the surgical treatment of patients with intermediate-terminal pancreatic cancer. METHODS: A retrospective analysis was made of the clinical data of 163 patients with intermediate-terminal pancreatic cancer who were surgically treated between August 1994 and August 2003. RESULTS: A total of 149 patients underwent palliative surgery. The mortality rate of those who underwent cholecystojejunostomy alone was 14.2%, the icterus or cholangitis recurrence rate was 61.9% with an average survival period of 7.1 mo. The mortality rate for those who received hepatic duct-jejunostomy (HDJS) was 5.7%, the icterus or cholangitis recurrence rate was 6.8% with an average survival period of 7.1 mo. But 31.8% of the patients developed duodenum obstruction within 6 mo after the surgery, six of seven patients with severe pain were given peri-abdominal aorta injection with absolute alcohol and their pain was alleviated. The other patients underwent percutaneous transhepatic cholangial drainage (PTCD) and their icterus index returned to normal level within 40 d with an average survival period of 7.5 mo. CONCLUSION: Roux-en-Y HDJS combined with prophylactic gastrojejunostomy is recommended for patients with intermediate-terminal pancreatic cancer, and biliary prosthesis can partly relieve biliary obstruction in a short term.

[Treatment and surgery of primary hepatic cancer with portal vengus tumor thrombosis].

OBJECTIVE: To study the methods of surgery for hepatocellular carcinoma (HCC) with tumor thrombi in portal vein (TTPV). METHODS: To Analyze and summarize the clinical information from 138 HCC patients with tumor thrombi in portal vein collected during January 1990 and January 2003. RESULTS: Thirty-seven patients receiving palliative therapy died from 1 to 8 months, and average survival time is 3.9 months. 101 patients had operation treatment, 23 of them underwent hepatoma resection, and average survival time was 10.9 months; 78 patients underwent hepatoma resection and removal of tumor thrombi, and average survival time was 26.8 months. 52 of whom underwent hepatic artery and portal vein chemoembolization, the 1-, 3-, 5-year survival rates was 96.2%, 51.9%, 11.5%, the 1-, 3-, 5-year survival rates of the 26 patients who didn't undergo chemoembolization were 76.9%, 23.1%, 0%. CONCLUSIONS: Operation treatment can comparatively extend the survival time of hepatocellular carcinoma with tumor thrombi in portal vein patients, and the best choice is hepatoma resection and removal of tumor thrombi, hepatic artery and portal vein chemoembolization after operation can enhance the effect.

[Surgical treatments for hilar cholangiocarcinoma].

OBJECTIVE: To explore the diagnosis and surgical treatment of hilar cholangiocarcinoma. METHODS AND RESULTS: Of 102 patients with hilar cholangiocarcinoma, 21 (20.6%) underwent surgical exploration and biopsy with an average survival time of 72 d, 18 (17.6%) received drainage with that of 8.3 months, and 63 (61.8%) were subjected to surgical resection and anastomosis with that of 25.7 months. The surgical approaches included resections of the perihepatic cholangiocarcinoma, of the quadrate lobe and outer bile ductule carcinoma, of the left half of the liver, of the caudal lobe and outer bile ductule carcinoma, and Roux-en-Y ligation of the intraheptic bile ductule-jeajunum. CONCLUSIONS: Resection is a the primary choice for treatment of hilar cholangiocarcinoma, and radical resection may prolong the patients' survival time and achieve better effect than simple drainage. In cases where resection is impossible, jaundice management should be carried out.