[The 488th case: chronic diarrhea and abnormal liver function].

A 56-year-old female was admitted to Department of Gastroenterology at Peking Union Medical College Hospital with diarrhea for seven months, and abnormal liver function for six months. She had a history of type 1 diabetes. The main clinical manifestations were recurrent fatty diarrhea and abnormal liver function, accompanied by abdominal and retroperitoneal lymphadenopathy, elevated CA19-9 and CEA. Progressive impairment of hepatic synthetic function and shrinkage of liver developed in a short period of time. The pathology of liver biopsy suggested that nodular regeneration of hepatocytes was followed by hyperplasia of thin bile ducts after submassive necrosis. Intestinal mucosa biopsies were performed twice. The pathology showed that the intestinal villi were completely blunt, accompanied with crypt hyperplasia. Goblet cells disappeared with reduced mucin. Paneth cells were barely seen without intraepithelial infiltration of lymphocytes. Rifaximin was not effective, while glucocorticoids improved clinical situation. The diagnosis of autoimmune enteropathy was finally confirmed by multidisciplinary team including departments of gastroenterology, pathology, endocrinology, hematology, infectious diseases, and rheumatology. With the administration of glucocorticoid and sirolimus, diarrhea relieved and liver function returned to normal.

[Prognostic significance of early assessment of minimal residual disease in acute myeloid leukemia with mutated NPM1 patients].

Objective: To explore prognostic significance of early assessment of minimal residual leukemia (MRD) in adult patients with de novo acute myeloid leukemia (AML) with mutated NPM1. Methods: The response, NPM1 mutated transcript level after induction chemotherapy and the first 2 cycles of consolidation chemotherapy, disease-free survival (DFS) and overall survival (OS) in 137 patients with AML with NPM1 mutations of A, B and D were retrospectively analyzed. Results: Data of 137 patients were collected, 67 were male, the median age was 49 years (16-67 years) , 107 (78.1%) had normal karyotype, 57 (41.6%) had positive FLT3-ITD mutation, the median NPM1 mutated transcript level at diagnosis was 84.1%. Among the 134 evaluable patients, 115 (85.8%) achieved a complete remission (CR) . Multivariate analyses revealed that WBC<100×10(9)/L (OR=0.3, 95% CI 0.1-0.9, P=0.027) and first induction therapy with "IA10" protocol (OR=0.3, 95% CI 0.1-0.8, P=0.015) were factors associated with achieving a CR. With a median follow-up period of 24 months (range, 2 to 91 months) in 77 survived CR patients, the probabilities of DFS and OS at 3 years were 48.0% and 63.9%, respectively. Multivariate analyses showed that positive FLT3-ITD (HR=3.2, 95% CI 1.6-6.7, P=0.002) , high MRD level after 2 cycles of consolidation chemotherapy (NPM1 mutation transcript level <3-log reduction from the individual baseline, HR=23.2, 95% CI 7.0-76.6, P<0.001) and chemotherapy or autologous hematopoietic stem cell transplantation (auto-HSCT) rather than allogeneic HSCT (allo-HSCT) (HR=2.6, 95% CI 1.0-6.6, P=0.045) were the unfavorable factors affecting DFS, high MRD level at the time of achieving the first CR (NPM1 mutation transcript level <2-log reduction from the individual baseline, OR=2.5, 95% CI 1.0-6.1, P=0.040) and after 2 cycles of consolidation chemotherapy (HR=4.5, 95% CI 2.0-10.3, P<0.001) were the unfavorable factors affecting OS. Furthermore, DFS and OS rates at 3 years in those receiving chemotherapy or auto-HSCT were 39.7% and 59.1%, respectively; positive FLT3-ITD and high MRD level after 2 cycles of consolidation chemotherapy were independent factors associated with both shorter DFS (HR=3.5, 95% CI 1.6-7.6, P=0.002 and HR=8.9, 95% CI 3.8-20.7, P<0.001) and OS (HR=2.7, 95% CI 1.1-6.9, P=0.036 and HR=3.1, 95% CI 1.2-8.0, P=0.021) ; meanwhile, high MRD level at the time of achieving the first CR associated with shorter OS (HR=3.1, 95% CI 1.2-8.0, P=0.022) . Conclusion: Positive FLT3-ITD mutation and high MRD level after induction or consolidation chemotherapy associated with poor outcomes in AML patients with mutated NPM1.

Genome-wide association study identifies QTLs for EBV of backfat thickness and average daily gain in Duroc pigs.

Backfat thickness (BFT) and average daily gain (ADG) are two important economic traits in commercial swine production. Identifying QTLs and uncovering the molecular mechanism for BFT and ADG would greatly help to speed up the breeding progress. In current breeding program, EBV for these two traits are calculated and formulated a comprehensive breeding index, which then be used to improve pig performance. Using Illumina PorcineSNP60 BeadChip, a pilot genomewide association studies (GWAS) for BFT and ADG in 83 Duroc pigs were performed. A total of 31 genome-wise significant SN Ps were detected to be associated with BFT on SSC 4, 9, 11, 12 and 14, ten of which were coincident with previously reported QTL regions. There are two genome-wise loci prominently associated with ADG on SSC2 and SSC13, respectively. The two loci on SSC2 are well overlapped with the QTL regions previously reported. All the 31 significant SNPs associated with BFT are verified on 219 outbreed pigs, six SN Ps reach an extreme significant level and seven SNP reaches a significant level, CACNA1E and ACBD6 are chosen as positional candidate genes. Our findings not only confirmed previously findings, but also revealed a number of novel SNPs associated with BFT and ADG. Two positional candidate genes CACNA1E and ACBD6 were identified for further study. These results would facilitate the identification of causative genes for BFT and ADG.

SUSCEPTIBILITY LOCI FOR UMBILICAL HERNIA IN SWINE DETECTED BY GENOME-WIDE ASSOCIATION.

Umbilical hernia (UH) is a complex disorder caused by both genetic and environmental factors. UH brings animal welfare problems and severe economic loss to the pig industry. Until now, the genetic basis of UH is poorly understood. The high-density 60K porcine SNP array enables the rapid application of genome-wide association study (GWAS) to identify genetic loci for phenotypic traits at genome wide scale in pigs. The objective of this research was to identify susceptibility loci for swine umbilical hernia using the GWAS approach. We genotyped 478 piglets from 142 families representing three Western commercial breeds with the Illumina PorcineSNP60 BeadChip. Then significant SNPs were detected by GWAS using ROADTRIPS (Robust Association-Detection Test for Related Individuals with Population Substructure) software base on a Bonferroni corrected threshold (P = 1.67E-06) or suggestive threshold (P = 3.34E-05) and false discovery rate (FDR = 0.05). After quality control, 29,924 qualified SNPs and 472 piglets were used for GWAS. Two suggestive loci predisposing to pig UH were identified at 44.25MB on SSC2 (rs81358018, P = 3.34E-06, FDR = 0.049933) and at 45.90MB on SSC17 (rs81479278, P = 3.30E-06, FDR = 0.049933) in Duroc population, respectively. And no SNP was detected to be associated with pig UH at significant level in neither Landrace nor Large White population. Furthermore, we carried out a meta-analysis in the combined pure-breed population containing all the 472 piglets. rs81479278 (P = 1.16E-06, FDR = 0.022475) was identified to associate with pig UH at genome-wide significant level. SRC was characterized as plausible candidate gene for susceptibility to pig UH according to its genomic position and biological functions. To our knowledge, this study gives the first description of GWAS identifying susceptibility loci for umbilical hernia in pigs. Our findings provide deeper insights to the genetic architecture of umbilical hernia in pigs.

Different kinetic patterns of BCR-ABL transcript levels in imatinib-treated chronic myeloid leukemia patients after achieving complete cytogenetic response.

Bone marrow BCR-ABL transcript levels were monitored serially by real-time quantitative PCR in 46 imatinib-treated chronic myeloid leukemia patients after achieving complete cytogenetic response (CCyR) for a median of 42 months (range: 9-53). Of 41 patients in continuous CCyR, 32 and nine could achieve a >/=3-log (MMoR group) or 2- to 3-log reduction (non-MMoR group), respectively. The MMoR group had a significantly lower recurrence rate of Ph+ metaphase than the non-MMoR group (6/32 vs. 7/9, P = 0.002), which was not significantly different between patients first achieving CCyR within or after 12 months of imatinib treatment (7/27 vs. 6/14, P = 0.086). Five patients suffered cytogenetic or hematological relapse. For all 46 patients, a >2-log reduction but not time when CCyR was first achieved was related to a lower relapse rate (1/42 vs. 4/4, P < 0.001). We concluded that the depth of BCR-ABL reduction after CCyR is more critical than when CCyR is first achieved. The kinetic pattern of BCR-ABL transcript is a good predictor of disease stability.

Effect of stealthy liposomal topotecan plus amlodipine on the multidrug-resistant leukaemia cells in vitro and xenograft in mice.

BACKGROUND: Multidrug resistance (MDR) is a major obstacle to successful cancer chemotherapy as the over-expressed MDR protein acts as an efflux pump, which leads to a reduction in the uptake of the anticancer agent by tumour cells. We combined topotecan and amlodipine together into the stealthy liposomes, in which amlodipine was applied as a MDR reversing agent to overcome the resistance. MATERIALS AND METHODS: Cytotoxicity, apoptosis and the signalling pathway assays were performed on human chronic myelogenous leukaemia K562, promyelocytic leukaemia HL-60 and MDR HL-60 cells, respectively. Pharmacokinetics and antitumour activity studies were performed on normal Kunming mice and female BALB/c nude mice with MDR HL-60 xenografts, respectively. RESULTS: Topotecan alone was effective in inhibiting the growth of non-resistant leukaemia cells, K562 and HL-60 cells but not the growth of MDR HL-60 cells. The resistance of topotecan in MDR HL-60 cells was potently reversed by the addition of amlodipine. Moreover, amlodipine enhanced the apoptosis-inducing effect of topotecan synergistically. Apoptosis was through activating caspases in a cascade: first, the initiator caspase 8 and then effectors caspase 3/7 (total activity of caspases 3 and 7) were activated. Being encapsulated into the stealthy liposomes with an acidic internal medium, topotecan existed dominantly in an active lactone species, which was reversibly changed from an inactive carboxylate form via a pH-dependent reaction. After administration of stealthy liposomes to mice, the blood exposure of the lactone form was evidently increased and extended. The antitumour effects in the MDR HL-60 xenografted tumour were stealthy liposomal topotecan (SLT) plus amlodipine > SLT > un-encapsulated topotecan > blank control. CONCLUSIONS: The enhanced antitumour activity in the MDR HL-60 cells by the SLT plus amlodipine could be owing to multiple reasons: (a) synergistic apoptosis inducing effect, (b) reversing MDR by amlodipine and (c) increasing the availability of active lactone of topotecan by the stealthy liposomes. The apoptosis induced by amlodipine is through caspase 8 and then the 3/7 signalling pathway.