Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity.

BACKGROUND: The human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch. METHODS: First, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous ß-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed. RESULTS: We found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo. CONCLUSION: The HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.

Association of CDKN2A/2B deletion with relapse after hematopoietic stem cell transplantation for acute lymphoblastic leukemia.

The most important prognostic factor for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is minimal residual disease (MRD). Previous studies have reported copy number variants of genes such as IKZF1, CDKN2A/2B, and PAX5. These gene mutations can be analyzed using multiplex ligation-dependent probe amplification (MLPA), which is less costly and easier to perform than large-scale gene mutation analyses. In this study, we performed copy number variant analysis of leukemia cells at the first onset of Ph+ALL in a case series of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using the MLPA method. We analyzed how it influenced allo-HSCT prognosis together with MRD information. CDKN2A/2B copy number variations significantly increased the rate of post-transplant recurrence (P=0.025) and significantly reduced disease-free survival (P=0.015). Additionally, patients with IKZF1 deletions had a significantly higher post-transplant recurrence rate (P=0.042). Although they were positive for pre-transplant MRD, no relapse was observed in patients with wild-type copy number variations in IKZF1 or CDKN2A/2B. CDKN2A/2B copy number variation is a crucial factor that can be confirmed at initial onset as a post-transplant prognostic factor of Ph+ALL.

Donor cord blood aging accelerates in recipients after transplantation.

Cord blood stem cell transplantation is an important alternative for patients needing hematopoietic stem cell transplantation. However, it is unclear how cord blood cells, which are 0 years old, age in the recipient's body after allogeneic transplantation. We performed DNA methylation (DNAm) age analysis to measure the age of cells using post-transplant peripheral blood in 50 cases of cord blood transplantation. The median chronological age (the time elapsed from the date of the cord blood transplant to the day the sample was taken for DNAm analysis) of donor cells was 4.0 years (0.2-15.0 years), while the median DNAm age was 10.0 years (1.3-30.3 years), and the ratio of DNAm age to chronological age (AgeAccel) was 2.7 (1.2-8.2). When comparing the mean values of AgeAccel in cord blood transplant cases and controls, the values were significantly higher in cord blood transplant cases. The characteristics of patients and transplant procedures were not associated with AgeAccel in this analysis, nor were they associated with the development of graft-versus-host disease. However, this analysis revealed that transplanting 0-year-old cord blood into a recipient resulted in cells aging more than twice as quickly as the elapsed time. The results shed light on the importance of the mismatch between cord blood stem cells and donor environmental factors in stem cell aging.

Fetal hemoglobin level predicts lower-risk myelodysplastic syndrome.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5 years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS (n = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

Mitochondrial Electron Transport Chain Complex II Dysfunction Causes Premature Aging of Hematopoietic Stem Cells.

Mitochondria are indispensable in maintaining hematopoietic stem cells (HSCs), and mitochondrial complex II (MCII) has been recognized as a key component of HSCs. However, the physiological role of MCII on long-term hematopoiesis and hematopoietic reconstitution capacity remains unknown. Hence, this study evaluated the impact of MCII dysfunctions on long-term HSC maintenance and hematopoietic homeostasis among conditional transgenic mice with a missense mutation in the succinate dehydrogenase complex subunit C gene (SdhcV69E). HSCs collected from SdhcV69E mice had a higher reactive oxygen species (ROS) accumulation and DNA damage in response to mitochondrial activation. Via the aging stress response, MCII dysfunctions caused decreased white blood cell count with myeloid-skewing property, macrocytic anemia, and thrombocytosis. Moreover, the HSCs of aged SdhcV69E mice exhibited greater ROS accumulation and lower membrane potential. Transplantation-induced replicative stress also caused premature senescent hematopoiesis. Furthermore, accelerated ROS accumulation and profound DNA damage in HSCs were observed in the SdhcV69E-derived cell recipients. The long-term hematopoietic reconstitution capacity was remarkably impaired in HSCs from the SdhcV69E-derived cell recipients. Taken together, MCII plays an essential role in long-term hematopoiesis, and MCII dysfunctions with aging or replicative stresses caused excessive ROS accumulation and DNA damage in HSCs, leading to premature senescence.

Correction to: Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

[This corrects the article DOI: 10.1007/s13340-021-00551-0.].

Correction to: Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

[This corrects the article DOI: 10.1007/s13340-021-00551-0.].

Metabolic surgery in treatment of obese Japanese patients with type 2 diabetes: a joint consensus statement from the Japanese Society for Treatment of Obesity, the Japan Diabetes Society, and the Japan Society for the Study of Obesity.

Bariatric surgery has been shown to have a variety of metabolically beneficial effects for patients with type 2 diabetes (T2D), and is now also called metabolic surgery. At the 2nd Diabetes Surgery Summit held in 2015 in London, the indication for bariatric and metabolic surgery was included in the "algorithm for patients with type T2D". With this background, the Japanese Society for Treatment of Obesity (JSTO), the Japan Diabetes Society (JDS) and the Japan Society for the Study of Obesity (JASSO) have formed a joint committee to develop a consensus statement regarding bariatric and metabolic surgery for the treatment of Japanese patients with T2D. Eventually, the consensus statement was announced at the joint meeting of the 38th Annual Meeting of JSTO and the 41st Annual Meeting of JASSO convened in Toyama on March 21, 2021. In preparing the consensus statement, we used Japanese data as much as possible as scientific evidence to consider the indication criteria, and set two types of recommendation grades, "recommendation" and "consideration", for items for which recommendations are possible. We hope that this statement will be helpful in providing evidence-based high-quality care through bariatric and metabolic surgery for the treatment of obese Japanese patients with T2D. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13340-021-00551-0.

Association between measurable residual disease kinetics and outcomes of Philadelphia chromosome-positive acute lymphoblastic leukemia.

The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) has improved dramatically. Although measurable residual disease (MRD) kinetics during pretransplant treatment has been recently reported to correlate with patient outcomes, it is unclear whether prognosis is better if the MRD falls below the detection sensitivity soon after induction therapy. We retrospectively analyzed data of 37 Ph + ALL patients who were treated with autologous or allogeneic stem cell transplantation (auto-SCT, allo-SCT) at our institute from 2003 to 2019. Based on MRD kinetics, patients were divided into three groups: early responders (MRD became negative after induction therapy [n = 10, 27.0%]); late responders (MRD remained positive after induction therapy and became negative just before SCT [n = 12, 32.4%]); and poor responders (MRD was positive until just before SCT [n = 15, 40.5%]). The 5-year disease-free survival (DFS) rates for the three groups were 80.0%, 60.0%, and 29.9%, respectively (P = 0.037). The 5-year overall survival rates were not significantly different. The 5-year relapse rates were 0.0%, 31.7%, and 49.5%, respectively (P = 0.045). Non-relapse mortality (NRM) rates were similar among the three groups. Subgroup analysis for the cases that received posttransplantation tyrosine kinase inhibitor maintenance therapy revealed that DFS was similarly dependent on MRD kinetics (P = 0.022). This study clarified that MRD kinetics was a significant prognosticator for DFS and relapse rate in Ph + ALL.

Plasminogen activator inhibitor type-1 is a negative regulator of hematopoietic regeneration in the adipocyte-rich bone marrow microenvironment.

Bone marrow adipocytes (BMAs) have recently been recognized as a niche component with a suppressive function. Obese individuals with abundant BMAs exhibit impaired hematopoietic regeneration after hematopoietic stem cell transplantation (HSCT). We hypothesized that plasminogen activator inhibitor type-1 (PAI-1), an adipokine that regulates the fibrinolytic system, contributes to impaired hematopoiesis in bone marrow (BM) microenvironment with abundant BMAs. We demonstrated that BMAs differentiated in vitro could secrete PAI-1 and were positive for PAI-1 in vivo. In addition, the abundance of BMAs was associated with high levels of PAI-1 expression. The BMA-rich microenvironment exhibited impaired hematopoietic regeneration after HSCT when compared with a BMA-less microenvironment. The impaired hematopoietic regeneration in BMA-rich microenvironment was significantly alleviated by PAI-1 knockout or PAI-1 inhibitor treatment. Obese mice with abundant BMAs, compared with normal-weight mice, exhibited higher bone marrow PAI-1 concentrations, increased fibrinolytic system suppression, and lower stem cell factor (SCF) concentrations after HSCT. PAI-1 inhibitor administration significantly activated the fibrinolytic system in obese mice, contributing to the higher SCF concentration. Moreover, PAI-1 inhibitor treatment significantly alleviated the impaired hematopoietic regeneration in obese mice both after 5-fluorouracil injection and HSCT. These results indicate that PAI-1 hinders hematopoietic regeneration in BMA-rich microenvironments. The blockade of PAI-1 activity could be a novel therapeutic means of facilitating hematopoietic reconstitution in BMA-rich patients.

A case of JAK2V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor.

The Janus kinase/signal transducers and activators of transcription signaling pathway induces programmed death ligand-1 (PD-L1) expression. JAK2 mutation at position 617 (JAK2V617) is a frequent driver of myeloproliferative neoplasms (MPN) through PD-L1 expression. Although PD-1 inhibitors should be effective against MPN with JAK2V617F mutation, this has not yet been reported in humans. Thus, we assessed the efficacy of a PD-1 inhibitor in a lung cancer patient with JAK2V617F-positive essential thrombocythemia (ET). A 71-year-old man was diagnosed with ET, and with lung carcinoma 3 years later. After right lobectomy and postoperative chemotherapy, pembrolizumab [a PD-1 inhibitor (200 mg, every 3 weeks)] was initiated for refractory lung carcinoma. Lung cancer progression did not occur for 1.5 years under treatment. Most megakaryocytes were PD-L1-positive, and after pembrolizumab initiation, platelet count remained below 45 × 104/µL without the need for other cytoreductive therapies for ET. The JAK2V617F allele burden gradually decreased from 11.5% at diagnosis to 2.9% after 17 months of pembrolizumab treatment. Other peripheral blood lineages did not decrease, and pembrolizumab treatment was continued without any adverse events. This is the first report demonstrating the effectiveness of pembrolizumab in an MPN patient with JAK2V617F mutation.

Multisite studies for validation and improvement of a highly efficient culture assay for detection of undifferentiated human pluripotent stem cells intermingled in cell therapy products.

BACKGROUND AIMS: The Multisite Evaluation Study on Analytical Methods for Non-Clinical Safety Assessment of Human-Derived Regenerative Medical Products (MEASURE) is a Japanese experimental public-private partnership initiative, which aims to standardize methodology for tumorigenicity evaluation of human pluripotent stem cell (hPSC)-derived cell therapy products (CTPs). Undifferentiated hPSCs possess tumorigenic potential, and thus residual undifferentiated hPSCs are one of the major hazards for the risk of tumor formation from hPSC-derived CTPs. Among currently available assays, a highly efficient culture (HEC) assay is reported to be one of the most sensitive for the detection of residual undifferentiated hPSCs. METHODS: MEASURE first validated the detection sensitivity of HEC assay and then investigated the feasibility of magnetic-activated cell sorting (MACS) to improve sensitivity. RESULTS: The multisite experiments confirmed that the lower limit of detection under various conditions to which the human induced pluripotent stem cell lines and culture medium/substrate were subjected was 0.001%. In addition, MACS concentrated cells expressing undifferentiated cell markers and consequently achieved a detection sensitivity of 0.00002%. CONCLUSIONS: These results indicate that HEC assay is highly sensitive and robust and that the application of MACS on this assay is a promising tool for further mitigation of the potential tumorigenicity risk of hPSC-derived CTPs.

An analysis of oral microbial flora by T-RFLP in patients undergoing hematopoietic stem cell transplantation.

Even though the hematopoietic stem cell transplantation (HSCT) procedure has been improved, oral mucositis (OM) is still a severe complication of the conditioning regimen. We investigated the association between OM severity and the alteration of oral bacterial flora using 16S rRNA gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis in 19 consecutive patients undergoing HSCT. Oral samples were collected at pre-transplantation, at the peak of mucositis and post-engraftment. T-RFLP profiles for each timepoint were constructed into an X-Y matrix, and the distances between timepoints were calculated. Patients with severe and moderate OM had larger changes in their oral bacterial flora from before HSCT to peak of mucositis than controls (p = 0.031 and 0.016, respectively). Moreover, severe mucositis was significantly associated with an extended period of fever until engraftment, high maximum C-reactive protein levels, and prolonged periods of opioid treatment and intravenous hyper-alimentation. These findings suggest that mucositis severity is associated with the magnitude of change in the oral bacterial flora. This novel finding may help advance strategies for the prevention or treatment of OM after HSCT.

Five-Year Outcomes of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Class I Obesity.

BACKGROUND: Bariatric surgery is being recognized increasingly as an effective treatment for obesity and related comorbidities. In Japan, the cost of laparoscopic sleeve gastrectomy (LSG) is covered by the national health insurance for adults with a body mass index (BMI) ≥ 35 kg/m2 and specific comorbidities (type 2 diabetes mellitus (T2DM), hypertension (HT), dyslipidemia (DL), and obstructive sleep apnea syndrome (OSAS)). However, only 0.6% of the adult population have a BMI ≥ 35 kg/m2. In contrast, 4.3% have class I obesity (a BMI of 30-34.9 kg/m2). The BMI of Asians with central obesity-induced diabetes and other metabolic disorders is much lower than that of Westerners. OBJECTIVES: To evaluate the medium-term (up to 5 years) outcomes of LSG performed in Japanese patients with class I obesity. METHODS: One hundred eighteen consecutive patients with class I obesity treated by LSG at our center between August 2007 and December 2018 were included in a retrospective study. Mean preoperative body weight (BW) and BMI were 88.6 ± 10.3 kg and 32.8 ± 1.6 kg/m2, respectively. Weight loss, comorbidity status, and adverse events were assessed. RESULTS: Mean BW/BMI at 1, 3, and 5 years after LSG decreased significantly to 66.6 ± 11.2 kg/24.6 ± 2.8 kg/m2, 68.0 ± 14.0 kg/25.4 ± 4.0 kg/m2, and 69.1 ± 12.9 kg/26.5 ± 3.0 kg/m2, respectively. Mean total weight loss at 1, 3, and 5 years was 24.7 ± 8.2%, 21.8 ± 12.1%, and 18.5 ± 9.7%, respectively. Metabolic disorders such as T2DM, HT, and DL improved significantly. There was no mortality. CONCLUSION: LSG is safe, yields excellent weight loss, and improves obesity-related comorbidities in Japanese patients with class I obesity.

Detection of 6pLOH in an aplastic anemia patient by in phase HLA genotyping.

Recent studies have reported loss of heterozygosity in the chromosome 6p arms (6pLOH) of acquired aplastic anemia (AA) patients, and in tumor cells trying to escape the autoimmune system. We thus sought to establish detection methods for LOH to investigate the mechanisms underlying AA and tumor immunity. Herein, we report our evaluation of 6pLOH in a patient with severe AA patient using super-high resolution, single-molecule, sequence-based typing (SS-SBT). The highest ratios of 6pLOH detection were observed during the patient's treatment with granulocyte colony stimulating factor (G-CSF). This result suggested that most of the neutrophil precursor cells stimulated by G-CSF already had LOH in the HLA lesion. The SS-SBT method is a simple NGS method that provides complete HLA allele coverage.

Maternal impacts and perinatal outcomes after three types of bariatric surgery at a single institution.

PURPOSE: Bariatric surgery is widely known to improve pregnancy outcomes and to increase the risk of having small for gestational age neonates. However, the specific causes of neonatal growth restriction are still unclear. This study aimed to investigate the impacts of bariatric surgery on pregnancy and perinatal status at a single institution. METHODS: 24 women delivered singleton births among the 193 reproductive-aged women who underwent bariatric surgery. We classified the surgery into three types: laparoscopic adjustable gastric banding (LAGB; n = 6), laparoscopic sleeve gastrectomy (LSG; n = 5), and malabsorptive surgery (MS; n = 13), and investigated the pregnancy complications and perinatal impacts. RESULTS: The median maternal weight gain after LAGB was 12.5 kg (LSG 6.9 kg, MS 9.0 kg). Gestational hypertension was observed in half of the women who underwent LAGB, but in none of those who underwent MS. No significant difference in neonatal birth weight was observed between the LAGB (median 3272 g) and LSG (median 3005 g) groups. The maternal impact after MS was a remarkable decrease in hemoglobin during prepregnancy (median 1.9 g/dl). About 69% of women developed gestational anemia after MS, and their neonatal birth weight was the lowest (median 2660 g). However, the birth weight of neonates delivered by mothers without anemia after undergoing MS was similar to that of those delivered by mothers after undergoing other types of bariatric surgery (median 3037 g). CONCLUSIONS: Maternal anemia after MS may lead to low neonatal birth weight, which could be attributed to the large-scale reduction in maternal micronutrient levels.

Impact of metabolic surgery on health-related quality of life and quality of alimentation.

BACKGROUND: Bariatric surgery for morbidly obese patients has been shown to ameliorate their quality of life (QOL). Little data are available in mildly obese patients undergoing metabolic surgery. OBJECTIVES: To investigate the impact of metabolic surgery for diabetic patients with body mass index <35 kg/m2 on health-related QOL (HR-QOL), food tolerance, and food satisfaction in a single institution. SETTING: Private practice, Japan. METHODS: Fifty-one consecutive mildly obese, diabetic patients underwent laparoscopic sleeve gastrectomy with duodenojejunal bypass were initially enrolled. Only 46 returned for follow-up and were eventually included in the final population. Preoperatively, the mean weight and body mass index were 89.1 ± 11.9 kg and 31.7 ± 2.2 kg/m2, respectively. The mean fasting plasma glucose and glycated hemoglobin were 196 ± 69 mg/dL and 9.0 ± 1.5%, respectively. The mean duration of diabetes was 9.0 ± 6.1 years. Before surgery, 40 patients (78.4%) were treated with oral hypoglycemic agents and 28 patients (54.9%) were treated with subcutaneous insulin. The 36-item Short Form Survey was used to gauge HR-QOL at the preoperative phase and at 1 year after surgery. Questionnaires regarding food tolerance, food satisfaction, and dietary intake were also distributed to the enrolled patients. RESULTS: The follow-up rate at 1 year was 90.2%. At this point, there was a decrease in mean weight and body mass index were 67.5 ± 11.6 kg and 23.9 ± 2.8 kg/m2, respectively (P < .001). This accounted for the mean percent total weight loss of 24.4 ± 8.3%. The mean fasting plasma glucose and glycated hemoglobin were 114 ± 35 mg/dL and 6.5 ± 1.1%, respectively (P < .001). Remission of diabetes was seen in 52.2% of the patients. With regard to the HR-QOL, significant improvements were observed in the aspects of physical functioning, bodily pain, general health, vitality, and mental health. Dietary intake significantly decreased from 2679 ± 952 kcal/d at baseline to 1346 ± 483 kcal/d at 1 year (P < .001). Food tolerance score significantly decreased from 21.6 ± .6 to 18.7 ± 3.9 (P < .001). By contrast, food satisfaction score significantly increased from 3.0 ± 1.1 to 3.5 ± 1.1 (P = .015). CONCLUSIONS: In mildly obese patients associated with severe diabetes who underwent laparoscopic sleeve gastrectomy with duodenojejunal bypass, marked amelioration in glycemic control was observed and, although the amount of food intake and food tolerance were affected, the overall HR-QOL as well as food satisfaction improved significantly.

Correction to: Preoperative Weight Loss and Operative Outcome After Laparoscopic Sleeve Gastrectomy.

In Table 2 on p. 2517 the heading for Group 3 should read as follows.

The Impact of Laparoscopic Sleeve Gastrectomy with Duodenojejunal Bypass on Intestinal Microbiota Differs from that of Laparoscopic Sleeve Gastrectomy in Japanese Patients with Obesity.

BACKGROUND AND OBJECTIVES: Bariatric surgery improves metabolic diseases and alters the intestinal microbiota in animals and humans, but different procedures reportedly have different impacts on the intestinal microbiota. We developed laparoscopic sleeve gastrectomy with duodenojejunal bypass (LSG-DJB) as an alternative to laparoscopic Roux-en-Y gastric bypass (LRYGB) in addition to laparoscopic sleeve gastrectomy (LSG) for Japanese patients with obesity. We investigated the precise change in the intestinal microbiota induced by these procedures in the present study. METHODS: A prospective observational study of 44 Japanese patients with obesity was conducted [22 patients underwent LSG, 18 underwent LSG-DJB, and 4 underwent laparoscopic adjustable gastric banding (LAGB)]. The patients' clinical parameters and intestinal microbiota were investigated before and for 6 months after surgery. The microbiota was analyzed by a 16S rDNA method. RESULTS: LSG and LSG-DJB significantly improved the metabolic disorders in the patients with obesity. The proportion of the phylum Bacteroidetes and order Lactobacillales increased significantly in the LSG group, and that of the order Enterobacteriales increased significantly in the LSG-DJB group. CONCLUSIONS: LSG and LSG-DJB improved obesity and type 2 diabetes in Japanese patients with obesity, but the impact of LSG-DJB on the intestinal microbiota differed from that of LSG. This difference in the impact on the intestinal environment could explain the different efficacies of LSG and LSG-DJB in terms of their ability to resolve metabolic disorders in the clinical setting.

NKG2D gene polymorphisms are associated with disease control of chronic myeloid leukemia by dasatinib.

A recent study reported that treatment-free remission (TFR) of chronic myeloid leukemia (CML) after dasatinib (Das) treatment was significantly associated with natural killer (NK) cell proliferation in the peripheral blood. However, biomarkers to predict lymphocytosis or successful TFR are not well characterized. In order to clarify individual differences in NK cell responses among patients treated with Das, we retrospectively analyzed the association between polymorphisms in the natural killer group 2D receptor [NKG2D; also known as killer cell lectin like receptor K1 (KLRK1)] gene and clinical outcomes in 31 patients treated with Das as first-line treatment for CML. Patients with the NKG2D HNK1/HNK1 (high-cytotoxic activity-related allele on NKG2D hb-1) haplotype achieved MR4.5 more quickly than those with other haplotypes [hazard ratio (HR) 4.39; 95% confidence interval (CI) 2.75-118.6; P = 0.004]. In addition, NK cells with the NKG2D HNK1 allele exhibited enhanced phosphorylation of vav guanine nucleotide exchange factor 1 (VAV1) at Tyr174. These data suggest that NKG2D gene polymorphisms may represent candidate biomarkers for the prediction of TFR following Das treatment.