[Clinicopathological characteristics and prognosis of patients with sporadic multiple primary gastrointestinal stromal tumors].

Objective: To investigate the clinicopathological characteristics and prognosis of sporadic multiple primary gastrointestinal stromal tumor (GIST). Methods: A retrospective cohort study was conducted. Case inclusion criteria: (1) postoperative pathological diagnosis of GIST; (2) primary GIST with single lesion or sporadic multiple primary GIST (sporadic GIST was defined as primary GIST other than familial and syndrome-related GIST, and multiple primary GIST was defined as the number of primary GISTs in the same patient ≥ 2); (3) patients with complete clinicopathological data. Those with tumor recurrence or distant metastasis, and with other malignancies were excluded. Medical records of patients with primary GIST who underwent surgical resection in the Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2010 to December 2020 were collected. Patients were divided into sporadic multiple primary GIST group and single primary GIST group according to the number of primary GIST lesions. The clinicopathological data and prognosis of the two groups were observed and compared. Results: A total of 1200 patients with primary GIST were enrolled in this study, including 628 males (52.3%) and 572 females (47.7%), with a median onset age of 58 (19-93) years. Among them, 1165 cases (97.1%) were sporadic primary GIST with single lesion; 35 cases (2.9%) were sporadic multiple primary GIST. Among 35 cases of sporadic multiple primary GIST, 3 cases (8.6%) had acid reflux as the first symptom, which was higher than the single primary GIST group (22/1165, 1.9%) (χ(2)=7.437, P=0.006). There were no significant differences in other clinical characteristics between the two groups (all P>0.05). Patients in the sporadic multiple primary GIST group contained a total of 80 primary tumors. Compared with the single primary GIST group, the sporadic multiple primary GIST group had a higher proportion of tumors originating in the stomach [87.5% (70/80) vs. 59.1% (689/1165)], lower proportion of spindle cell in histology [85.0% (68/80) vs. 93.7% (1092/1165)], higher proportion of positive CD34 [97.5% (78/80) vs. 87.6% (1021/1165)], smaller maximum diameter [maximum diameter ≤2.0 cm: 61.2% (49/80) vs. 28.8% (335/1165)], lower mitotic rate [≤5/50 high-power fields (HPF): 93.8% (75/80) vs. 74.5% (868/1165)], lower risk of recurrence [60.0% (48/80) vs. 23.3% (271/1165)], and the differences were all statistically significant (all P<0.05). The 3-year recurrence-free survival rate in the sporadic multiple primary group and the single primary GIST group was 96.6% and 89.3% respectively (P=0.160), and the 3-year overall survival rate was 100.0% and 92.8%, respectively (P=0.088). Conclusions: The most common type of sporadic multiple primary GIST is multiple tumors originating in the stomach at the same time. Compared with primary GIST with single lesion, sporadic multiple primary GIST presents smaller maximum diameter and lower mitotic rate. The prognosis of patients between two groups is not significantly different.

[Adherence to adjuvant with therapy imatinib in patients with gastrointestinal stromal tumor: a national multi-center cross-sectional study].

Objective: To analyze the current adherence to imatinib in patients with gastrointestinal stromal tumors (GIST) in China and its influencing factors. Methods: A cross-sectional survey was conducted. Study period: from October 1, 2020 to November 31, 2020. Study subjects: GIST patients taking imatinib who were diagnosed and treated in public tertiary level A general hospitals or oncology hospitals; those who had not been pathologically diagnosed, those who never received imatinib, or those who had taken imatinib in the past but stopped afterwards were excluded. The Questionnaire Star online surgery platform was used to design a questionnaire about the adherence to adjuvant imatinib therapy of Chinese GIST patients. The link of questionnaire was sent through WeChat. The questionnaire contained basic information of patients, medication status and Morisky Medication Adherence Scale. Results: A total of 2162 questionnaires from 31 provinces, autonomous regions, and municipalities were collected, of which 2005 were valid questionnaires, with an effective rate of 92.7%. The survey subjects included 1104 males and 901 females, with a median age of 56 (22-91) years old. Working status: 609 cases (30.4%) in the work unit, 729 cases (36.4%) of retirement, 667 cases of flexible employment or unemployment (33.3%). Education level: 477 cases (23.8%) with bachelor degree or above, 658 cases (32.8%) of high school, 782 cases (39.0%) of elementary or junior high school, 88 cases (4.4%) without education. Marital status: 1789 cases (89.2%) were married, 179 cases (8.9%) divorced or widowed, 37 cases (1.8%) unmarried. Two hundred and ninety-four patients (14.7%) had metastasis when they were first diagnosed, including 203 liver metastases, 52 peritoneal metastases, and 39 other metastases. One thousand eight hundred and sixty-nine patients underwent surgical treatment, of whom 1642 (81.9%) achieved complete resection. The median time of taking imatinib was 25 (1-200) months. Common adverse reactions of imatinib included 1701 cases (84.8%) of periorbital edema, 1031 cases (51.4%) of leukopenia, 948 cases (47.3%) of fatigue, 781 cases (39.0%) of nausea and vomiting, 709 cases (35.4%) of rash, and 670 cases (33.4%) of lower extremity edema. The score of the Morisky Medication Adherence Scale showed that 392 cases (19.6%) had poor adherence, 1023 cases (51.0%) had moderate adherence, and 590 cases (29.4%) had good adherence. Univariate analysis showed that gender, age, work status, economic income, residence, education level, marriage, the duration of taking medication and adverse reactions were associated with adherence to adjuvant imatinib therapy (all P<0.05). Multivariate analysis showed that female (OR=1.264, P=0.009), non-retirement (OR=1.454, P=0.001), monthly income ≤4000 yuan (OR=1.280, P=0.036), township residents (OR=1.332, P=0.005), unmarried or divorced or widowed (OR=1.362, P=0.026), the duration of imatinib medication >36 months (OR=1.478, P<0.001) and adverse reactions (OR=1.719, P=0.048) were independent risk factors for poor adherence to adjuvant imatinib. Among patients undergoing complete resection, 324 (19.7%) had poor adherence, 836 (50.9%) had moderate adherence, and 482 (29.4%) had good adherence. Meanwhile, 55 patients with good adherence (11.4%) developed recurrence after surgery, 121 patients with moderate adherence (14.5%) developed recurrence, 61 patients with poor adherence (18.8%) developed recurrence, and the difference was statistically significant (P=0.017). Conclusions: The adherence to adjuvant therapy with imatinib in Chinese GIST patients is relatively poor. Females, non-retirement, monthly income ≤4000 yuan, township residents, unmarried or divorced or widowed, the duration of imatinib medication >36 months, and adverse reactions are independently associated with poor adherence of GIST patients. Those with poor adherence have a higher risk of recurrence after surgery. Positive interventions based on the above risk factors are advocated to improve the prognosis of patients with GIST.

[A model to predict the recurrence of middle-high risk gastrointestinal stromal tumors based on preoperative fibrinogen and peripheral blood inflammatory indexes].

Objective: At present, the modified NIH classification commonly used in clinical practice is still insufficient for assessing the risk of postoperative recurrence in some patients with intermediate-high risk gastrointestinal stromal tumors (GIST). Through exploring risk factors for recurrence of intermediate-high risk GIST, this study establishes a predictive model for recurrence with more convenience and more precision in order to guide adjuvant therapy for intermediate-high risk GIST patients. Methods: A retrospective case-control study was carried out. Clinical and pathological data of 432 GIST patients who did not receive preoperative targeted treatment, underwent complete resection in the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2005 to June 2018, and were diagnosed as intermediate- or high-risk based on modified NIH classification by postopertive pathology, were retrospectively analyzed. Cox regression model was used to idenitify independent risk factors of recurrence, and a recurrence risk scoring model was established. The receiver operating characteristic curve (ROC curve), consistency index (C-index) and calibration curve were used to evaluate the accuracy of the scoring model in predicting the recurrence of moderate-risk and high-risk GIST patients. Results: Among 432 GIST patients, 332 were diagnosed as high-risk and 100 as moderate-risk; 237 were males and 195 females with average age of (57.4±12.4) years. Of 432 patients, 211 cases (48.8%) had fibrinogen (FIB) >3.5 g/L; 85 cases (19.7%) had platelet to lymphocyte ratio (PLR)>272.5; 122 cases (28.2%) had neutrophil to lymphocyte ratio (NLR) > 4.2; 102 cases (23.6%) had systemic inflammatory reaction index (SIRI)> 2.7; 198 cases (45.8%) had tumor long diameter >8 cm and 108 cases (25.0%) had mitotic counts > 8/50 HPF. Cox multivariable analysis showed that FIB (HR=1.789, 95% CI: 1.058-3.027, P=0.030), PLR (HR=1.862, 95% CI: 1.067-3.249, P=0.029), SIRI (HR=1.790, 95% CI: 1.039-3.084, P=0.036), tumor long diameter (HR=1.970, 95% CI: 1.105-2.925, P=0.017) and mitotic counts (HR=2.187, 95% CI:1.211-3.950, P=0.009) were independent risk factors for recurrence in patients with middle-risk and high-risk GIST. These 5 factors were included in the risk scoring model, which was given a weight score of 58 points, 62 points, 58 points, 63 points, and 78 points, respectively. Patients with a total score of ≤ 78 points were classified as moderate-risk recurrence (group I), those of 78 to 136 points as high-risk recurrence (group II) and those of >136 points as very high-risk recurrence (group III). ROC curve showed that the area under the curve (AUC) of the scoring model was 0.730 and the C-index was 0.724 (95% CI:0.687-0.787). The calibration curves and the Kaplan-Meier curves of patients in the three groups revealed that this model had a good predictive accuracy. Conclusions: For intermediate-risk and high-risk GIST patients, the preoperative FIB >3.5 g/L, PLR > 272.5 and SIRI > 2.7 are independent risk factors of recurrence after surgery. The recurrence risk scoring model established by combining tumor long diameter, mitotic counts, FIB, PLR and SIRI can effectively predict the risk of postoperative recurrence and metastasis in moderate-risk and high-risk GIST patients.

[Laparoscopic versus open surgery for gastric gastrointestinal stromal tumors in unfavorable location: a propensity score-matching analysis].

Objective: To investigate the efficacy and feasibility of laparoscopic resection for gastric gastrointestinal stromal tumor (GIST) in unfavorable location by comparing with open surgery. Methods: Clinicopathological and follow-up data of 176 patients with gastric GIST in unfavorable location admitted at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2005 to December 2017 were analyzed retrospectively. There were 94 males and 82 females, aging of (57.4±12.7) years (range: 20-90 years). Of the 176 patients, 64 underwent laparoscopic surgery (laparoscopic group) and 112 underwent open surgery (open group). One-to-one propensity score matching (PSM) was performed to balance the covariance between laparoscopic group and open surgery group. Before PSM, the differences between the two group in tumor size and modified National Institutes of Health risk classification were significant. After PSM, there were 63 pairs (63 cases in laparoscopic group and 63 cases in open group) and the baseline characteristics were comparable between the two groups(P>0.05). The difference of short-term outcome between the two groups were compared using t test, χ(2) test or Wilcoxon rank-sum test. The survival curve was established by Kaplan-Meier method and the Log-rank test was used to compare the survival of the two groups. Results: The operation time of laparoscopic group was shorter ((141.6±100.6) minutes vs. (100.4±67.7) minutes, t=2.681, P=0.008), the hospitalization cost was higher ((5.2±0.7) ten thousand yuan vs. (4.2±0.8) ten thousand yuan, t=7.357, P=0.000) than open group. The time to first flatus ((49.1±8.2) hours vs. (71.0±4.6) hours, t=-18.482, P=0.000) and preoperative hospital stay ((10.3±6.0) days vs. (14.8±7.6) days, t=-3.717, P=0.000) was shorter in laparoscopic group. With a median follow-up time of 44 months (range: 10 to 154 months), the 1-, 3-, 5-year relapse-free survival rates in the laparoscopic group and open group were 98.3%, 92.1%, 92.1% and 100%, 86.3%, 83.2%, respectively (χ(2)=0.696, P=0.404). The 1-, 3-, 5-year overall survival rates in the laparoscopic group and open group were 96.6%, 94.7%, 94.7% and 100%, 91.1%, 81.4%, respectively (χ(2)=0.366, P=0.545). Conclusions: In experienced medical centers, laparoscopic resection is safe and feasible for GIST in unfavorable location. Compared to open surgery, laparoscopic resection achieves a faster postoperative recovery and a similar long-term prognosis.

Bta-miR-130a regulates the biosynthesis of bovine milk fat by targeting peroxisome proliferator-activated receptor gamma.

Milk fat determines the quality of milk and is also a main targeted trait in dairy cow breeding. Recent studies have revealed important regulatory roles of microRNAs (miRNA) in milk fat synthesis in the mammary gland. However, the role of miRNA in bovine mammary epithelial cells (BMEC) remains largely unknown. In this study, we found that the overexpression of miR-130a significantly decreased cellular triacylglycerol (TAG) levels and suppressed lipid droplet formation, whereas the inhibition of miR-130a resulted in greater lipid droplet formation and TAG accumulation in BMEC. MiR-130a also significantly affected mRNA expression related to milk fat metabolism. Specifically, the overexpression of miR-130a reduced the mRNA expression of , , , and , whereas the downregulation of miR-130a increased the mRNA expression of , , , , , and . Furthermore, western blot analysis revealed the protein level of PPARG in miR-130a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Finally, luciferase reporter assays verified that PPARG was the direct target of miR-130a. This study provides the first experimental evidence that miR-130a directly affects TAG synthesis in BMEC by targeting PPARG, suggesting that miR-130a potentially could be used to improve beneficial milk components in dairy cows.

Protein disulfide isomerase a4 acts as a novel regulator of cancer growth through the procaspase pathway.

Protein disulfide isomerase a4 (PDIA4) is implicated in the growth and death of tumor cells; however, its molecular mechanism and therapeutic potential in cancer are unclear. Here, we found that PDIA4 expression was upregulated in a variety of tumor cell lines and human lung adenocarcinoma tissues. Knockdown and overexpression of PDIA4 in tumor cells showed that PDIA4 facilitated cell growth via the reduction of caspases 3 and 7 activity. Consistently, Lewis lung carcinoma cells overexpressing PDIA4 grew faster than did parental cells in tumor-bearing mice, as shown by a reduced survival rate, increased tumor size and metastasis, and decreased cell death and caspases 3 and 7 activity. PDIA4 knockdown resulted in opposite outcomes. Moreover, results obtained in mice with spontaneous hepatoma indicated that PDIA4 deficiency significantly reduced hepatic tumorigenesis and cyst formation and increased mouse survival, tumor death, and caspases 3 and 7 activity. Mechanistic studies illustrated that PDIA4 negatively regulated tumor cell death by inhibiting degradation and activation of procaspases 3 and 7 via their mutual interaction in a CGHC-dependent manner. Finally, we found that 1,2-dihydroxytrideca-5,7,9,11-tetrayne, a PDIA4 inhibitor, reduced tumor development via enhancement of caspase-mediated cell death in TSA tumor-bearing mice. These findings characterize PDIA4 as a negative regulator of cancer cell apoptosis and suggest that PDIA4 is a potential therapeutic target for cancer.

miR-27a controls triacylglycerol synthesis in bovine mammary epithelial cells by targeting peroxisome proliferator-activated receptor gamma.

Growing evidence has revealed that microRNA are central elements in milk fat synthesis in mammary epithelial cells. A negative regulator of adipocyte fat synthesis, miR-27a has been reported to be involved in the regulation of milk fat synthesis in goat mammary epithelial cells; however, the regulatory role of miR-27a in bovine milk fat synthesis remains unclear. In the present study, primary bovine mammary epithelial cells (BMEC) were harvested from mid-lactation cows and cultured in Dulbecco's modified Eagle's medium/F-12 medium with 10% fetal bovine serum, 5 µg/mL of insulin, 1 µg/mL of hydrocortisone, 2 µg/mL of prolactin, 1 µg/mL of progesterone, 100 U/mL of penicillin, and 100 µg/mL of streptomycin. We found that the overexpression of miR-27a significantly suppressed lipid droplet formation and decreased the cellular triacylglycerol (TAG) levels, whereas inhibition of miR-27a resulted in a greater lipid droplet formation and TAG accumulation in BMEC. Meanwhile, overexpression of miR-27a inhibited mRNA expression of peroxisome proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein beta (C/EBPß), perilipin 2 (PLIN2), and fatty acid binding protein 3 (FABP3), whereas miR-27a downregulation increased PPARG, C/EBPß, FABP3, and CCAAT enhancer binding protein alpha (C/EBPα) mRNA expression. Furthermore, Western blot analysis revealed the protein level of PPARG in miR-27a mimic and inhibitor transfection groups to be consistent with the mRNA expression response. Moreover, luciferase reporter assays verified that PPARG was the direct target of miR-27a. In summary, these results indicate that miR-27a has the ability to control TAG synthesis in BMEC via targeting PPARG, suggesting that miR-27a could potentially be used to improve beneficial milk components in dairy cows.

How to Improve the Positive Predictive Value of Urinary Decoy Cell Surveillance for Polyomavirus BK-Associated Nephropathy in Kidney Transplant Patients.

BACKGROUND: Polyomavirus BK-associated nephropathy (BKVN) has been a serious problem after kidney transplantation. Detection of urinary decoy cells (UDCs) and assessment of polyomavirus BK nucleic acids by polymerase chain reactions (PCRs) are currently used, noninvasive tests. PCRs have better positive predictive value (PPV) but higher cost and lower accessibility. This study investigated ways to improve the PPV of UDCs for BKVN prediction. METHODS: From 2000 to 2013, kidney transplant recipients with sustained UDCs for more than half a month and who had received allograft biopsies were enrolled. We analyzed the PPV of UDCs for BKVN with 2 variables: (i) the percentage changes in serum creatinine (SCr) levels and (ii) the duration of sustained UDCs by receiver operating characteristic (ROC) curve analysis; we predicted the percentage changes in SCr levels with the corresponding PPV using a linear regression model. RESULTS: BKVN was diagnosed in 26 of 68 enrolled patients. The percentage changes in SCr levels significantly deteriorated in the BKVN group during 1-2 months of UDC positivity. According to ROC curve analysis, percentage changes in SCr levels had a significant discriminating power for BKVN during 1-1.5 month, and if the percentage changes in SCr levels were >19%, the PPV of UDCs for BKVN was 50%. CONCLUSIONS: An UDC surveillance program is a judicious strategy to predict BKVN in kidney transplant patients, particularly when graft renal function shows deterioration after 1 month of UDC positivity.

FSHR genotype affects estrogen levels but not pregnancy rates in Luxi cattle subjected to embryo transfer.

Follicle-stimulating hormone receptor (FSHR), which mediates the functioning of FSH, plays a central role in reproduction. We investigated bovine FSHR gene polymorphisms and analyzed their relationships with pregnancy rates after embryo transfer and with hormone concentrations on the day of embryo transfer. One reported SNP of FSHR, G-278A, located in the 5'-upstream region, was analyzed and three genotypes (GG, GA and AA) were detected in 132 Luxi cattle recipients. Statistical analysis revealed that recipients with the GG genotype had significantly higher estrogen levels on the day of embryo transfer than did GA and AA genotypes. There were no significant differences in pregnancy rates among genotypes, after embryo transfer. We conclude that variation at these loci of the FSHR gene has no significant effect on pregnancy rates in Luxi cattle.

Polymorphism of the inhibin ßA gene and its relationship with superovulation traits in Chinese Holstein cows.

Inhibin is a major regulator of secretion of follicle-stimulating hormone, which is involved in follicular development and regulation of steroidogenesis in females. The objectives of this study were to detect polymorphisms of the bovine inhibin beta-A subunit (INHßA) gene and to evaluate its associations with superovulatory responses in 171 Chinese Holstein cows treated for superovulation. Polymerase chain reaction-restricted fragment length polymorphism revealed a C>T transition determining the StyI polymorphism at position 7639 in intron I of the bovine INHßA gene, and three genotypes (CC, CT, and TT) were detected. The frequencies of the three genotypes showed a tendency for CT > TT > CC, and this polymorphism was in Hardy-Weinberg equilibrium. Statistical analysis revealed no significant differences of least square means for superovulation traits among the three genotypes (P > 0.05). These results demonstrate, for the first time, that the detected loci of the INHßA gene have no significant effects on superovulation performance in Chinese Holstein cows.

Prognostic implication of molecular aberrations in cytogenetically normal acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation.

Different molecular aberrations can be discriminated into certain prognostic subgroups in cytogenetically normal acute myeloid leukemia (CN-AML) patients but their impact on allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains controversial and studies from Asian populations are lacking. Forty-two adult non-M3 AML patients receiving allo-HSCT from 2002 to 2009 in southern Taiwan were retrospectively reviewed for survey, 23 (54.7%) of whom were CN-AML. NPM1, FLT3-ITD, and CEBPA were analyzed. After a median follow-up of 104 weeks (range, 8 to 384), patients in the good risk group (harboring either NPM1 or CEBPA mutation without concurrent FLT3-ITD) showed a borderline worse overall survival (OS) compared with the intermediate/poor risk group (P = 0.08). Interestingly, a poorer OS was found in patients with the CEBPA mutation (P = 0.003) but not the NPM1 mutation (P = 0.96). No OS difference was found between patients with or without FLT3-ITD (P = 0.15). In patients receiving allo-HSCT at first remission, there was no significant OS benefit in the good risk group (P = 0.33). In patients receiving allo-HSCT beyond first remission, disease status played a major role (P = 0.006), irrespective of molecular aberrations. Allo-HSCT in good risk patients should be carefully evaluated in Taiwanese, especially in patients with the CEBPA mutation. Conversely, allo-HSCT should be considered in first remission in patients with an intermediate/poor risk, where it may overcome the adverse impact of FLT3-ITD. Disease status remained a main issue in patients receiving allo-HSCT beyond first remission.

The deubiquitinating enzyme USP37 regulates the oncogenic fusion protein PLZF/RARA stability.

Acute promyelocytic leukemia (APL) is predominantly characterized by chromosomal translocations between the retinoic acid receptor, alpha (RARA) gene and the promyelocytic leukemia (PML) or promyelocytic leukemia zinc finger (PLZF) gene. In APL cells with PML/RARA fusions, arsenic trioxide and all-trans retinoic acid treatments specifically target the fusion protein for proteasome-dependent degradation, thereby promoting cellular differentiation and clinical remission of disease. In contrast, APL cells expressing PLZF/RARA fusion proteins are largely resistant to similar treatments and prognosis for patients with this translocation is poor. Understanding the molecular mechanisms regulating PLZF/RARA protein stability would provide novel therapeutic targets for PLZF/RARA-associated APL. Toward this end, we have performed an RNAi-based screen to identify factors affecting PLZF/RARA stability. Among the factors identified was the ubiquitin-specific peptidase 37 (USP37). We showed that USP37 interacted with PLZF/RARA through the PLZF moiety and sustained PLZF/RARA steady state levels. Domain mapping study revealed that N-terminal domain of USP37 is required for the PLZF/RARA interaction and protein regulation. Furthermore, overexpression or depletion of USP37 caused an increase or decrease of PLZF/RARA protein half-life, correlating with down- or upregulation of PLZF/RARA poly-ubiquitination, respectively. By PLZF/RARA-transduced primary mouse hematopoietic progenitor cells, we demonstrated that Usp37 knockdown alleviated PLZF/RARA-mediated target gene suppression and cell transformation potential. Altogether, our findings of USP37-modulating PLZF/RARA stability and cell transformation suggest that USP37 is a potential therapeutic target for PLZF/RARA-associated APL.

Tubulointerstitial nephritis and uveitis syndrome (TINU) with Fanconi's syndrome.

We report a 57-year-old woman with concurrent tubulointerstitial nephritis and uveitis syndrome (TINU) and Fanconi's syndrome. She presented with sudden onset of bilateral ocular pain, blurred vision, acute renal failure, glucosuria and proteinuria. Slit lamp examination revealed acute bilateral anterior uveitis. Tubulointerstitial nephritis was confirmed by kidney biopsy. Laboratory examination revealed normoglycemic glucosuria, proteinuria, normal anion-gap metabolic acidosis, phosphaturia, urinary uric acid wasting and kaliuresis leading to hypokalemia. Her vision and renal function improved gradually after systemic steroid therapy. There have been rare reports of TINU syndrome which had features of Fanconi's syndrome. The prevalence of TINU syndrome may be underestimated, and its association with Fanconi's syndrome requires further investigation.

Results of kidney transplantation from high-terminal creatinine donors and the role of time-zero biopsy.

BACKGROUND: Deceased-donor kidney transplantation (DDKT) from high-terminal creatinine donors is associated with lower graft survival. These kidneys may be considered for discarding, worsening the organ shortage crisis. Using time-zero biopsy for histologic evaluation of these kidneys, we identified those organs eligible for transplantation, seeking to achieve better graft utility with comparable outcomes. METHODS: From April 2004 to April 2008, 55 patients underwent DDKT. A time-zero biopsy was used to examine glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arteriolar narrowing. A scoring system was used to determine a discard. RESULTS: Twenty-five patients received DDKT from donors whose terminal creatinine levels were >2.0 mg/dL (high terminal creatinine, HTC group) and 30 from donors whose terminal creatinine levels were <2.0 mg/dL (low terminal creatinine, LTC group). Patients who accepted kidneys from HTC donors had shorter waiting times (P = .011) but a higher incidence of delayed graft function after transplantation (P < .001). Nonetheless, 5-year graft survival rates were similar between the two groups. CONCLUSIONS: With a time-zero biopsy for histologic evaluation, kidneys recovered from high-terminal creatinine donors can be transplanted to overcome the organ shortage while achieving reasonable graft survival.

Suppression of cell-cycle progression by Jun dimerization protein-2 (JDP2) involves downregulation of cyclin-A2.

We report here a novel role for Jun dimerization protein-2 (JDP2) as a regulator of the progression of normal cells through the cell cycle. To determine the role of JDP2 in vivo, we generated Jdp2-knockout (Jdp2KO) mice by targeting exon-1 to disrupt the site of initiation of transcription. The epidermal thickening of skin from the Jdp2KO mice after treatment with 12-O-tetradecanoylphorbol 13-acetate (TPA) proceeded more rapidly than that of control mice, and more proliferating cells were found at the epidermis. Fibroblasts derived from embryos of Jdp2KO mice proliferated faster and formed more colonies than fibroblasts from wild-type mice. JDP2 was recruited to the promoter of the gene for cyclin-A2 (ccna2) at the AP-1 site. Cells lacking Jdp2 had elevated levels of cyclin-A2 mRNA. Furthermore, reintroduction of JDP2 resulted in the repression of transcription of ccna2 and of cell-cycle progression. Thus, transcription of the gene for cyclin-A2 appears to be a direct target of JDP2 in the suppression of cell proliferation.

Sequential pituitary MR imaging in Sheehan syndrome: report of 2 cases.

We present the evolution of pituitary changes in the cases of 2 patients with Sheehan syndrome as assessed by MR imaging. Both patients had severe postpartum hemorrhage, symptoms of pituitary gland apoplexy, and hypopituitarism. Sequential MR imaging demonstrated evidence of ischemic infarct in the pituitary gland with enlargement followed by gradual shrinkage during several months, to pituitary atrophy.

Association evidence of schizophrenia with distal genomic region of NOTCH4 in Taiwanese families.

Evidence for association with schizophrenia has been reported for NOTCH4, although results have been inconsistent. Previous studies have focused on polymorphisms in the 5' promoter region and first exon of NOTCH4. Our aim was to test the association of the entire genomic region of NOTCH4 in 218 families with at least two siblings affected by schizophrenia in Taiwan. We genotyped seven single nucleotide polymorphisms (SNPs) of this gene, with average intermarker distances of 5.3 kb. Intermarker linkage disequilibrium (LD) was calculated using gold software, and single-locus and haplotype association analyses were performed using transmit software. We found that the T allele of SNP rs2071285 (P= 0.035) and the G allele of SNP rs204993 (P= 0.0097) were significantly preferentially transmitted to the affected individuals in the single-locus association analysis. The two SNPs were in high LD (D' > 0.8). Trend for overtransmission was shown for the T-G haplotype of the two SNPs to affected individuals (P= 0.053), with the A-A haplotype significantly undertransmitted (P= 0.034). The associated region distributed across the distal portion of the NOTCH4 gene and overlapped with the genomic region of the G-protein signaling modulator 3 and pre-B-cell leukemia transcription factor 2. In summary, we found modest association evidence between schizophrenia and the distal genomic region of NOTCH4 in this Taiwanese family sample. Further replication for association with the distal genomic region of NOTCH4 is warranted.