The efficacy and feasibility of neoadjuvant immunotherapy plus chemotherapy followed by McKeown minimally invasive oesophagectomy for locally advanced oesophageal squamous cell carcinoma.

Introduction: In immunotherapy, antibodies are activated to block immune checkpoints, resist tumour immunosuppression, shrink tumours and prevent a recurrence. As the science behind tumour immunotherapy continuously develops and improves, neoadjuvant immunotherapy bears more prominent advantages: antigen exposure not only enhances the degree of tumour-specific T-cell response but also prolongs the duration of actions. In this study, we evaluated the efficacy and safety of McKeown minimally invasive oesophagectomy (McKeown MIO) following neoadjuvant immunotherapy combined with chemotherapy (NICT) in patients with locally advanced oesophageal cancer (OC). Patients and Methods: In this retrospective study, 94 patients underwent either NICT or neoadjuvant chemotherapy (NCT) followed by MIO at our institution from January 2020 to October 2022. We assessed the therapy-related adverse events and perioperative outcomes and compared them between the two groups. Results: After completing at least two cycles of neoadjuvant therapy, all patients underwent McKeown MIO with negative margins within 4-7 weeks. Demographic data of the two cohorts were similar. Regarding perioperative characteristics, the median intraoperative blood loss was 50 ml in the NICT group, lower than that of the NCT group (100 ml, P < 0.05). In addition, the NICT group had significantly more harvested lymph nodes than the NCT group (P < 0.05). No significant differences were found in post-operative complications. The rate of objective response rate in the NICT group was higher than that in the NCT group (88.3% vs. 58.8%). Regarding tumour regression, the number of patients with TRG Grades 1-3 in the NICT group was more than that in the NCT. Adverse events experienced by the two groups included anaemia and elevated transaminase. We found no difference in the adverse events between the two groups. Conclusions: This study showed the efficacy and feasibility of NICT followed by McKeown MIO in treating locally advanced OC.

Integrative Analysis of Transcriptomic and Metabolomic Data for Identification of Pathways Related to Matrine-Induced Hepatotoxicity.

Matrine (MT) is a major bioactive compound extracted from Sophorae tonkinensis. However, the clinical application of MT is relatively restricted due to its potentially toxic effects, especially hepatotoxicity. Although MT-induced liver injury has been reported, little is known about the underlying molecular mechanisms. In this study, transcriptomics and metabolomics were applied to investigate the hepatotoxicity of MT in mice. The results indicated that liver injury occurred when the administration of MT (30 or 60 mg/kg, i.g) lasted for 2 weeks, including dramatically increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), etc. The metabolomic results revealed that steroid biosynthesis, purine metabolism, glutathione metabolism, and pyruvate metabolism were involved in the occurrence and development of MT-induced hepatotoxicity. Further, the transcriptomic data indicated that the downregulation of NSDHL with CYP51, FDFT1, and DHCR7, involved in steroid biosynthesis, resulted in a lower level of cholic acid. Besides, Gstps and Nat8f1 were related to the disorder of glutathione metabolism, and HMGCS1 could be treated as the marker gene of the development of MT-induced hepatotoxicity. In addition, other metabolites, such as taurine, flavin mononucleotide (FMN), and inosine monophosphate (IMP), also made a contribution to the boosting of MT-induced hepatotoxicity. In this work, our results provide clues for the mechanism investigation of MT-induced hepatotoxicity, and several biomarkers (metabolites and genes) closely related to the liver injury caused by MT are also provided. Meanwhile, new insights into the understanding of the development of MT-induced hepatotoxicity or other monomer-induced hepatotoxicity were also provided.

Learning Curve for Lymph Node Dissection Around the Recurrent Laryngeal Nerve in McKeown Minimally Invasive Esophagectomy.

BACKGROUND: Compared to open esophagectomy (OE), minimally invasive esophagectomy (MIE) is associated with lower morbidity and mortality. However, lymph node (LN) dissection around the recurrent laryngeal nerve (RLN) is still an important factor that affects the length of the learning curve of MIE. This study aims to evaluate the surgical outcomes of the first nearly 5-year period and explore the learning curve for LN dissection around the RLN in McKeown MIE by a new single surgical team. METHODS: A total of 285 consecutive patients who underwent McKeown MIE between March 2016 and September 2020 were included at our institution. According to the cumulative sum (CUSUM) analysis of LN dissection around the RLN, the patients were divided into three groups: exploration period, adjustment period, and stable period. We assessed the impact of surgical proficiency on postoperative outcomes and explored the learning curve for LN dissection around the RLN in McKeown MIE. RESULTS: The CUSUM graph showed that a point of upward inflection for LN dissection around the RLN was observed in 151 cases. After 151 cases, LNs around the right and left RLNs were dissected thoroughly compared to the exploration and adjustment period (P = 0.010 and P = 0.012, respectively), and the postoperative incidence of hoarseness significantly decreased from 11.1 to 1.5% (P<0.001). CONCLUSIONS: Our study results revealed that not only are the LN, around the RLN, sufficiently dissected but also the incidence of hoarseness significantly decreased in the stable phase. Consequently, the learning curve length was approximately 151 cases for LN dissection around the RLN in McKeown MIE.

Alisol B 23-Acetate Ameliorates Azoxymethane/Dextran Sodium Sulfate-Induced Male Murine Colitis-Associated Colorectal Cancer via Modulating the Composition of Gut Microbiota and Improving Intestinal Barrier.

Hunting for natural compounds that can modulate the structure of the intestinal flora is a new hotspot for colitis-associated cancer (CAC) prevention or treatment. Alisol B 23-acetate (AB23A) is a natural tetracyclic triterpenoid found in Alismatis rhizoma which is well known for dietary herb. Alismatis rhizoma is often used clinically to treat gastrointestinal diseases in China. In this study, we investigated the potential prevention of AB23A in male mouse models of azoxymethane (AOM) and dextran sulfate sodium (DSS)-induced CAC. AB23A intervention alleviated the body weight loss, disease activity index, colon tumor load, tissue injury, and inflammatory cytokine changes in CAC mice. AB23A intervention leads to remarkable reductions in the activation of TLR, NF-κB and MAPK. AB23A significantly decreased the phosphorylation of p38, ERK, and JNK and up-regulated mucin-2 and the expression of tight junction proteins. The gut microbiota of AB23A-interfered mice was characterized with high microbial diversity, the reduced expansion of pathogenic bacteria, such as Klebsiella, Citrobacter, and Akkermansia, and the increased growth of bacteria including Bacteroides, Lactobacillus, and Alloprevotella. These data reveal that AB23A has the potential to be used to treat CAC in the future.

lncRNA LINC00473 promotes proliferation, migration, invasion and inhibition of apoptosis of non-small cell lung cancer cells by acting as a sponge of miR-497-5p.

Lung cancer is the leading cause of cancer-associated death worldwide and exhibits a poor prognosis. The present study aimed to determine the effect of long non-coding (lnc)RNA-LINC00473 on the development of non-small cell lung cancer (NSCLC) cells by regulating the expression of microRNA (miR)-497-5p. Reverse transcription-quantitative PCR was conducted to detect the level of LINC00473 and miR-497-5p. An MTT assay, flow cytometry and Transwell tests were performed to evaluate the proliferation, apoptosis, migration and invasion of NSCLC cells. Western blotting was performed to detect the expression of apoptosis- and migration-related proteins. RNA immunoprecipitation and a luciferase reporter assay were performed to verify the regulatory relationship between lncRNA-LINC00473 and miR-497-5p. LINC00473 expression was upregulated in lung cancer tissues and NSCLC cells (A549 and H1299) when compared with adjacent tissues or human bronchial epithelial cell lines and the 5-year survival rate was lower in patients with high LINC00473 expression compared with in patients with low LINC00473 expression. A negative correlation between LINC00473 and miR-497-5p was observed in lung cancer tissues. Proliferation, migration and invasion as well as the related protein levels were increased in A549 and H1299 transfected with pcDNA3.1-LINC00473, while the opposite results were obtained in A549 and H1299 transfected with small interfering (si)-LINC00473. Notably, it was demonstrated that LINC00473 could bind directly with miR-497-5p and inhibit its expression. miR-497-5p inhibitors reversed the effect of si-LINC00473. Furthermore, the present study demonstrated that LINC00473 promoted the malignant behaviour of NSCLC cells via regulating the ERK/p38 and MAPK signalling pathways and the expression of miR-497-5p.

New 30-norlupane derivatives through chemical-microbial semi-synthesis of betulinic acid and their neuroprotective effect.

In this study, seven 30-norlupane derivatives (2-8) wasobtained from the chemical oxidation ofbetulinic acidfollowed bybiotransformationviaBacillus megateriumCGMCC 1.1741. And metabolites 2-4 and 6-8 were newly identified products. In the first step, betulinic acid was chemically oxidizedto platanic acid (1). Following the chemical oxidation, B. megaterium catalyzed the hydroxylation at C-7, C-11, C-15 and C-23 of platanic acid (1) as well as the oxidation of C-3 hydroxyl group. Compared to the labor-intensive isolation from natural plants, this chemical-microbial semi-synthesis is more capable to provide increased structural diversity of oxygenated 30-norlupane. Finally, the potential neuroprotective effect of the derivatives was assessed on neuron-like PC12 cells induced by cobalt chloride (CoCl2). Metabolite 6 showed a potent neuroprotective activity.

Application of tandem biotransformation for biosynthesis of new pentacyclic triterpenoid derivatives with neuroprotective effect.

Tandem whole-cell biotransformation was applied successfully to deliver novel pentacyclic triterpenoid derivatives for the first time. In this process, the starting substrate oleanolic acid (1) was biotransformed into a hydroxylated metabolite 1a by Rhizopus chinensis CICC 40335 and then was further glycosylated to 1b by Bacillus subtilis ATCC 6633. Moreover, metabolite 1a was furtherly oxidized by Streptomyces griseus ATCC 13273 and generated two new derivatives as 1c and 1d. To validate the feasibility, tandem biotransformation of 18ß-glycyrrhetinic acid (2) by R. chinensis and B. subtilis was also conducted and offered a glycosylated derivative (2c). Finally, the neuroprotective effects of the derivatives were assessed on neural injury PC12 cell model induced by cobalt chloride.

TRPM7 overexpression enhances the cancer stem cell-like and metastatic phenotypes of lung cancer through modulation of the Hsp90α/uPA/MMP2 signaling pathway.

BACKGROUND: Waixenicin A, a bioactive extract of soft coral Sarcothelia edmondsoni, has been shown to be anti-neoplastic. However, its mechanisms of action remain unclear. Cancer stem cells (CSCs) and associated stemness factors are implicated in lung cancer. Here, we investigated the role of Waixenicin A on CSCs-like and metastatic lung cancer cells. METHODS: We demonstrated and compared TRPM7 expression in the non-tumor lung tissues or bronchial epithelial 16-HBE cell line. TRPM7 was aberrantly expressed in the cancer tissues and SPCA-1, NCI-H520, SK-MES-1, A549 and 95D cell lines. RESULTS: Increased TRPM7 expression was associated with enhanced SOX2, KLF4, and CD133, Hsp90α, uPA, and MMP2 expression in lung cancer cells. TRPM7-silencing inhibited epithelial-to-mesenchymal transition (EMT), suppressed stemness markers and phenotypes, concomitantly suppressed Hsp90α/uPA/MMP2 axis. Coincidently, Waixenicin A treatment downregulated TRPM7 and oncogenic markers; Waixenicin A also attenuated the ability of lung cancer cells to form tumorspheres, in vitro. In validation, our clinicopathological analyses showed that a higher TRPM7 expression was positively correlated with the larger tumor size (p = 0.007), positive lymph node metastasis (p = 0.005) and disease grade (p = 0.003). CONCLUSIONS: Through its ability to inhibit Hsp90α/uPA/MMP2 signaling and suppress TRPM7 expression, we showed that Waixenicin A is a potential anticancer therapeutic agent for treating malignant lung cancer.

Voltage adjustment improves rigidity and tremor in Parkinson's disease patients receiving deep brain stimulation.

Deep brain stimulation of the subthalamic nucleus is recognized as the most effective treatment for moderate and advanced Parkinson's disease. Programming of the stimulation parameters is important for maintaining the efficacy of deep brain stimulation. Voltage is considered to be the most effective programming parameter. The present study is a retrospective analysis of six patients with Parkinson's disease (four men and two women, aged 37-65 years), who underwent bilateral deep brain stimulation of the subthalamic nucleus at the First Affiliated Hospital of Sun Yat-sen University, China, and who subsequently adjusted only the stimulation voltage. We evaluated motor symptom severity using the Unified Parkinson's Disease Rating Scale Part III, symptom progression using the Hoehn and Yahr scale, and the levodopa equivalent daily dose, before surgery and 1 and 2 years after surgery. The 2-year follow-up results show that rigidity and tremor improved, and clinical symptoms were reduced, while pulse width was maintained at 60 µs and frequency at 130 Hz. Voltage adjustment alone is particularly suitable for patients who cannot tolerate multiparameter program adjustment. Levodopa equivalent daily dose was markedly reduced 1 and 2 years after surgery compared with baseline. Our results confirm that rigidity, tremor and bradykinesia can be best alleviated by voltage adjustment. The trial was registered at ClinicalTrials.gov (identifier: NCT01934881).

Synthesis of tigogenin MeON-Neoglycosides and their antitumor activity.

To discover new potent cytotoxic steroidal saponins, a series of tigogenin neoglycosides were synthesized via oxyamine neoglycosylation for the first time. The preliminary bioassays for their in vitro antitumor activities against five human cancer cell lines (A375, A-549, HCT-116, HepG2 and MCF-7) were conducted. The results revealed a sugar-dependent activity profile of their cytotoxicity, the glycoconjugation converted the non-active tigogenin to the most potential product Tg29 ((3R)-N-methoxyamino-tigogenin-ß-2-deoxy-d-galactoside) with IC50 value of 2.7µM and 4.6µM against HepG2 and MCF-7 cells respectively. And the 3R-tigogenin neoglycosides exhibited enhanced antitumor activity while the 3S-tigogenin almost showed no activity. Among the five cell lines, HepG2 and MCF-7 cells showed more sensitive cytotoxic responses to the products. Therefore, the neoglycosylation could be a promising strategy for the synthesis of antitumor steroidal saponins and it also proved the essential role of carbohydrate moiety of steroidal saponins in the biological activity.

New derivatives of ursolic acid through the biotransformation by Bacillus megaterium CGMCC 1.1741 as inhibitors on nitric oxide production.

Microbial transformation of ursolic acid (1) by Bacillus megaterium CGMCC 1.1741 was investigated and yielded five metabolites identified as 3-oxo-urs-12-en-28-oic acid (2); 1ß,11α-dihydroxy-3-oxo-urs-12-en-28-oic acid (3); 1ß-hydroxy-3-oxo-urs-12-en-28, 13-lactoe (4); 1ß,3ß, 11α-trihydroxyurs-12-en-28-oic acid (5) and 1ß,11α-dihydroxy-3-oxo-urs-12-en-28-O-ß-d-glucopyranoside (6). Metabolites 3, 4, 5 and 6 were new natural products. Their nitric oxide (NO) production inhibitory activity was assessed in lipopolysaccharide (LPS) - stimulated RAW 264.7 cells. Compounds 3 and 4 exhibited significant activities with the IC50 values of 1.243 and 1.711µM, respectively. A primary structure-activity relationship was also discussed.

Microbial hydroxylation and glycosylation of pentacyclic triterpenes as inhibitors on tissue factor procoagulant activity.

To discover new inhibitors on tissue factor procoagulant activity, 20 pentacyclic triterpenes were semi-synthetized through microbial transformation and assayed on the model of human THP-1 cells stimulated by lipopolysaccharide. In the biotransformation two types of reactions were observed, regio-selective hydroxylation and glycosylation. The bioassay results showed that most of tested compounds were significant effective on this model and two of the biotransformation products 23-hydroxy-28-O-ß-d-glucopyranosyl betulinic acid (3d) and 28-O-ß-d-glucopyranosyl oleanic acid (1a) exhibited most potential activities with the IC50 values of 0.028, 0.035nM respectively. The preliminary structure and activity relationship analysis revealed that the aglycones with single free hydroxyl group on the skeleton (1, 1j) were less effective than that with more free hydroxyl groups (1d, 1f, 2), mono-glycosylation can significantly enhance their inhibitory effects. Our findings also provide some potential leading compounds for tissue factor-related diseases, such as cancer and cardiovascular diseases.

[Effect of Combination Therapy of Tetramethylpyrazine with Methotrexate on Inflammatory Reac- tions and Hemorheology in Collagen-induced Arthritis Rats].

OBJECTIVE: To explore the effect of combination therapy of tetramethylpyrazine (TMP) with methotrexate (MTX) on collagen induced arthritis (CIA) rats. METHODS: Totally 55 male SD rats were stratified by body weight. Nine of them were randomly recruited as the normal control group. The rest 46 were immunized with type II bovine collagen (C II) for establishing rheumatoid arthritis (RA) model. Forty successfully modeled rats were randomly divided into 4 groups according to swollen toe degree, i.e., the CIA group, the TMP group, the MTX group, and the TMP plus MTX group, 10 in each group. Rats in the MTX group were administered with MTX (1. 2 mg/kg) , once per week for 4 continuous weeks. Those in the TMP group were administered with 40 mg/kg TMP, once per day for 10 continuous days, and then discontinued for 7 successive days, and continued for another 10 successive days. Rats in the TMP plus MTX group were administered with a mixture of equal dose MTX and TMP, and when MTX was discontinue, TMP was administered according to the way in the TMP group. Equal volume of saline solution was given to rats in the normal control group and the CIA group. Clinical parameters including ankle width (mediolateral diameter) and hindpaw swelling were measured at day 0, 4, 11, 18, and 26 after treatment. Rats were sacrificed 28 days after treatment, their knee joints and ankle joints were collected for pathological analyses. Serum levels of IL-1ß, IL-6, and IL-17A were detected by ELISA. Changes of fibrinogen (FIB) and platelet aggregation rate (PAg) were detected. RESULTS: Compared with the normal control group, the ankle width and hindpaw swelling increased significantly (P < 0.01), contents of FIB and PAg increased obviously (P < 0.05, P < 0.01), serum levels of IL-1ß, IL-6, and IL-17 increased remarkably (P <0. 01) in the CIA group. Obvious cell proliferation, inflammatory cell infiltration, hyperemia and edema of synovial tissues could be seen. Pannus formed and immerged in cartilages, resulting in necrosis. Compared with the model group, changes of ankle width and hindpaw swelling were all alleviated in each medicated group (P <0. 05, P <0. 01). Of them, the effect was superior in the MTX group to that of the TMP group and the MTX plus TMP group (P < 0.05, P < 0.01). Contents of FIB, serum levels of IL-1ß and IL-6 decreased significantly in the MTX group (P < 0.05). Contents of FIB, serum levels of IL-1ß and IL-6 decreased significantly in the TMP group and the MTX plus TMP group (P < 0.05). Besides, serum levels of FIB and IL-6 were obviously lower in the MTX plus TMP group than in the TMP group and the MTX group (P < 0.01). Levels of PAg and IL-17A were more significantly lowered in the TMP group than in the MTX plus TMP group and the MTX group. Pathological changes could be alleviated in each medicated group, with the optimal effect obtained in the MTX plus TMP group. CONCLUSION: Combination of TMP with MTX could significantly ameliorate inflammatory reactions and FIB contents of CIA rats.

Silencing of MICAL-L2 suppresses malignancy of ovarian cancer by inducing mesenchymal-epithelial transition.

Ovarian cancer remains the disease with the highest associated mortality rate of gynecologic malignancy due to cancer metastasis. Rearrangement of actin cytoskeleton by cytoskeleton protein plays a critical role in tumor cell metastasis. MICAL-L2, a member of MICAL family, can interact with actin-binding proteins, regulate actin cross-linking and coordinate the assembly of adherens junctions and tight junctions. However, the roles of MICAL-L2 in tumors and diseases have not been explored. In this study, we found that MICAL-L2 protein is significantly up-regulated in ovarian cancer tissues along with FIGO stage and associated with histologic subgroups of ovarian cancer. Silencing of MICAL-L2 suppressed ovarian cancer cell proliferation, migration and invasion ability. Moreover, silencing of MICAL-L2 prevented nuclear translocation of ß-catenin, inhibited canonical wnt/ß-catenin signaling and induced the mesenchymal-epithelial transition (MET). Taken together, our data indicated that MICAL-L2 may be an important regulator of epithelial-mesenchymal transition (EMT) in ovarian cancer cells and a new therapeutic target for interventions against ovarian cancer invasion and metastasis.

[Significance of CD37 expression in malignant B cells].

The aim of this study was to clarify the clinical significance of CD37 expression in B cells from B acute lymphoblastic leukemia (B-ALL) and B cell non-Hodgkin's lymphoma (B-NHL). The expression level of CD37 on B cells from bone marrow samples of normal controls (n = 19), B-ALL patients [including untreated cases (n = 5) and cases with minimal residual disease (MRD, n = 15)] and B-NHL patients (n = 25) whose bone marrow was involved by lymphoma cells, was detected by multiple parameter flow cytometry. The results indicated that the B cells from both untreated cases and cases with MRD lowly expressed CD37 (1.04 ± 0.24 and 1.50 ± 0.89), the normal precursor B cells (control cases) also lowly expressed CD37 (1.64 ± 0.52). There was no difference of CD37 expression level between 3 groups of cases(P > 0.05). Meanwhile the normal mature B cells and B-NHL cells highly expressed CD37 (14.23 ± 7.84 and 14.53 ± 10.93), but there was no difference of CD37 expression between them (P > 0.05). The comparison of CD37 expression level in normal B cells of development stages showed that the progenitor B cells lowly expressed CD37 (0.88 ± 0.17), the CD37 expression of precursor B cells was enhanced (2.44 ± 0.69), while the CD37 expression level of mature B cells was highest. It is concluded that the low expression of CD37 is not the characteristic of B- ALL cells. The expression level of CD37 increases gradually during the mature process of B cells, i.e, the expression level of CD37 does not associate with benignity or malignancy of B cells.

[IL15 DNA adjuvant enhances cellular and humoral immune responses induced by DNA and adenoviral vectors encoding HIV-1 subtype B gp160 gene].

To enhance the immunogenicity of DNA and adenoviral vector vaccines expressing HIV-1 subtype B gp160, human interleukin 15 (hIL15) DNA adjuvant (pVR-hIL15) was constructed. BALB/c mice received DNA prime/protein boost immunization with pVR-HIVgp160/Ad5-HIVgp160 alone or combined with pVR-hIL15. Cellular and humoral immune responses were evaluated by IFN-gamma enzyme-linked immunosorbent spot assay and enzyme-linked immunosorbent assay, respectively. Compared with those immunized with vaccines alone, the mice immunized with vaccines combined with pVR-hIL15 had significantly increased specific cellular response and antibody titer (P < 0.05). It suggests that the IL15 DNA adjuvant can enhance the immune responses induced by prime-boost regimen using DNA and adenoviral vector encoding HIV-1 subtype B gp160.

[Cyclosporine A based therapy for myelodysplastic syndrome].

To determine the efficacy and tolerance to cyclosporine A (CsA) based therapy in patients with myelodysplastic syndrome (MDS), 16 patients with MDS consisting of 10 refractory anemia (RA) and 6 refractory anemia with accessory blasts less than 10% (RAEB-1) were analyzed. Five patients had hypocellular bone marrows and 11 patients had normocellular or hypercellular marrows. The dose of CsA was 2.5-5.5 mg/(kg.d) for 2 weeks to 2 years (mean 8 months). Two out of 16 patients were treated with CsA alone, 14 patients were treated with CsA, recombinant human erythropoietin, androgens, 1, 25 dihydroxy vitamin D(3) or two or three of them combination with CsA. Treatment responses were classified according to the International Working Group (IWG) criteria as complete remission (CR), partial remission (PR), hematological improvement (HI) and no response (NR). Patients who obtained CR, PR or HI were defined as responders. The results showed that HI was observed in 12 patients, PR in 2 patients and NR in 2 patients. Total response rate was 87.5%. Response rates shown in neutrophil lineage, platelet and erythroid lineage were 83.3%, 66.7% and 60%, respectively; their shortest time required to obtain some hematologic improvement after initiation of CsA therapy was 2 weeks, 1 month and 1 month, respectively. Of 13 patients being transfusion-dependent before treatment, 3 patients did not need transfusion any more and 5 showed the reduced transfusion requirements after CsA therapy. In 10 patients with RA, 9 responded to CsA. Of 6 patients with RAEB, 1 patient had no response and died of RAEB-t and 5 patients had transient responses. One of the latter transformed to CMML and two relapsed. The total response rate decreased to 50% in the patients with CsA therapy lasting more than 3 months at the end of following-up. The adverse effects included hirsutism, hyperplastic gingiva, reversible hepatic and renal dysfunction. In conclusion, the usefulness of CsA based therapy for MDS-RA and RAEB-1 with any marrow cellularity is useful, the CsA dose of 3-5 mg/(kg.d) is safe and efficacious.