Lymphoma and cerebral vasculitis in association with X-linked lymphoproliferative disease

Lymphoma is seen in up to 30%of patients with X-linked lymphoproliferative disease(XLP),but cerebral vasculitis related with XLP after cure of Burkitt lymphoma is rarely reported.We describe a case of a 5-year-old boy with XLP who developed cerebral vasculitis two years after cure of Burkitt lymphoma.He had Burkitt lymphoma at the age of 3 years and received chemotherapy(non-Hodgkin’s lymphomaBerlin-Frankfurt-Milan-90 protocol plus rituximab),which induced complete remission over the following two years.At the age of 5 years,the patient first developed headache,vomiting,and then intellectual and motorial retrogression.His condition was not improved after anti-infection,dehydration,or dexamethasone therapy.No tumor cells were found in his cerebrospinal fluid.Magnetic resonance imaging showed multiple non-homogeneous,hypodense masses along the bilateral cortex.Pathology after biopsy revealed hyperplasia of neurogliocytes and vessels,accompanied by lymphocyte infiltration but no tumor cell infiltration.Despite aggressive treatment,his cognition and motor functions deteriorated in response to progressive cerebral changes.The patient is presently in a vegetative state.We present this case to inform clinicians of association between lymphoma and immunodeficiency and explore an optimal treatment for lymphoma patients with compromised immune system.

Pulmonary alveolar proteinosis induced by X-linked agammaglobulinemia:A case report

BACKGROUND Pulmonary alveolar proteinosis(PAP)and X-linked agammaglobulinemia(XLA)are rare diseases in children.Many theories infer that immunodeficiency can induce PAP,but these reports are almost all review articles,and there is little clinical evidence.We report the case of a child with both PAP and XLA.CASE SUMMARY A 4-month-old boy sought medical treatment due to coughing and difficulty in breathing for>2 wk.He had been hospitalized multiple times due to respiratory infections and diarrhea.Chest computed tomography and alveolar lavage fluid showed typical PAP-related manifestations.Genetic testing confirmed that the boy also had XLA.Following total lung alveolar lavage and intravenous immunoglobulin replacement therapy,the boy recovered and was discharged.During the follow-up period,the number of respiratory infections was significantly reduced,and PAP did not recur.CONCLUSION XLA can induce PAP and improving immune function contributes to the prognosis of children with this type of PAP.

Epstein-Barr virus positive post-transplant lymphoproliferative disorder with significantly decreased T-cell chimerism early after transplantation:A case report

BACKGROUND Post-transplant lymphoproliferative disorder(PTLD)is a rare but highly fatal complication occurring after allogeneic hematopoietic cell transplantation(allo-HCT)or solid organ transplantation(SOT).Unlike SOT,PTLD after allo-HCT usually originates from the donor and is rarely accompanied by a loss of donor chimerism.CASE SUMMARY We report a case of Epstein-Barr virus positive PTLD manifesting as diffuse large B-cell lymphoma(DLBCL)with significantly decreased T-cell chimerism early after allo-HCT.A 30-year-old patient with acute myeloid leukemia underwent unrelated allo-HCT after first complete remission.Nearly 3 mo after transplantation,the patient developed cervical lymph node enlargement and gastric lesions,both of which were pathologically suggestive of DLBCL.Meanwhile,the patient experienced a significant and persistent decrease in T-cell chimerism.A partial remission was achieved after chemotherapy with single agent rituximab and subsequent R-CHOP combined chemotherapy.CONCLUSION The loss of T-cell chimerism and the concomitant T-cell insufficiency may be the cause of PTLD in this patient.

Impact of EBV infection and immune function assay for lymphoproliferative disorder in pediatric patients after liver transplantation: A single-center experience

Background:Post-transplant lymphoproliferative disorder(PTLD)is a lethal complication after pediatric liver transplantation,but information regarding risk factors for the development of PTLD remains unclear.This study was to identify characteristics and risk factors of PTLD.Methods:A total of 705 pediatric patients who underwent liver transplantation between January 2017 and October 2018 were studied.Impact of clinical characteristics and Epstein-Barr virus(EBV)infection on the development of PTLD was evaluated.In addition,ImmuKnow assay was adopted in partial patients to analyze the immune status.Results:Twenty-five(3.5%)patients suffered from PLTD with a median time of 6 months(3–14 months)after transplantation.Extremely high tacrolimus(TAC)level was found in 2 fatal cases at PTLD onset.EBV infection was found in 468(66.4%)patients.A higher peak EBV DNA loads(>9590 copies/mL)within 3 months was a significant indicator for the onset of PTLD.In addition,the ImmuKnow assay demonstrated that overall immune response was significantly lower in patients with EBV infection and PTLD(P<0.0001).The cumulative incidence of PTLD was also higher in patients with lower ATP value(≤187 ng/mL,P<0.05).Conclusions:A careful monitoring of EBV DNA loads and tacrolimus concentration might be supportive in prevention of PTLD in pediatric patients after liver transplantation.In addition,application of the ImmuKnow assay may provide guidance in reducing immunosuppressive agents in treatment of PTLD.

Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level

To investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form.RESULTSThere were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035).CONCLUSIONIncidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point.

Role of IgG4 serology in identifying common orbital lymphoproliferative disorders

AIM： To explore the role of IgG4 serology in identifying common orbital lymphoproliferative disorders, METHODS： Eighty -one patients with orbital lymphoproliferative diseases were treated in the Department of Ocular Oncology, Beijing Tongren Hospital, Capital Medical University between September 2010 and December 2012. Serum IgG4 levels were measured in 46 cases of idiopathic orbital inflammatory pseudotumor （IOIP）, 17 benign lymphoepithelial lesion （BLEL）, 12 cases of orbital mucosa-associated lymphoid tissue （MALT）, and 6 cases of diffuse large B-cell lymphoma （DLBL） using immuno-scatter turbidmetry （ISTM）.RESULTS： The frequency of elevated IgG4 levels in patients with IOIP, BLEL, MALT, and DLBL was 30.43% （14/46）, 76.47% （13/17）, 8.33% （1/12）, and 0.00 （0/6）, respectively. Among the patients with elevated serum IgG4 levels, all IgG-IOIP patients were male, and 92.31% of the IgG4-BLEL patients were female （12/13）. The mean serum IgG4 level of IgG4-1OIP patients was lower than that of individuals with IgG4-BLEL, but the variation in serum IgG4 levels was larger in IgG4-1OIP than IgG4- BLEL patients. Only one case of IgG4-MALT with elevated serum IgG4 levels had a medical history 〉10y, which was significantly longer than the MALT patients with normal serum IgG4 levels. There was no significant elevation of serum IgG4 levels in patients with DLBL. CONCLUSION： Detecting serum IgG4 levels plays an important role in the differential diagnosis of orbital lymphoproliferative diseases.

Recent insights in the pathogenesis of post-transplantation lymphoproliferative disorders

Post-transplant lymphoproliferative disorder(PTLD) is an aggressive complication of solid organ and hematopoietic stem cell transplantation that arises in up to 20% of transplant recipients. Infection or reactivation of the Epstein-Barr virus(EBV), a ubiquitous human herpesvirus, in combination with chronic immunosuppression are considered as the main predisposing factors, however insight in PTLD biology is fragmentary. The study of PTLD is complicated by its morphological heterogeneity and the lack of prospective trials, which also impede treatment optimization. Furthermore, the broad spectrum of underlying disorders and the graft type represent important confounding factors. PTLD encompasses different malignant subtypes that resemble histologically similar lymphomas in the general population. Post-transplant diffuse large B-cell lymphoma(PT-DLBCL), Burkitt lymphoma(PTBL) and plasmablastic lymphoma(PT-PBL) occur most frequently. However, in many studies various EBV+ and EBV- PTLD subtypes are pooled, complicating the interpretation of the results. In this review, studies of the gene expression pattern, the microenvironment and the genetic profile of PT-DLBCL, PT-BL and PT-PBL are summarized to better understand the mechanisms underlying post-transplantation lymphomagenesis. Based on the available findings we propose stratification of PTLD according to the histological subtype and the EBV status to facilitate the interpretation of future studies and the establishment of clinical trials.

Persistent Epstein-Barr viral load in Epstein-Barr viral na?ve pediatric heart transplant recipients:Risk of late-onset post-transplant lymphoproliferative disease

AIM To examine the risk of late-onset post-transplant lymphoproliferative disorder(PTLD) in the presence of persisting high Epstein-Barr virus(EBV) in EBV na?ve pediatric heart transplant(HT) recipients. METHODS A retrospective review of the medical records of the 145 pediatric HT recipients who had serial EBV viral load monitoring at our center was performed. We defined EBV naive patients whose EBV serology either IgM or IgG in the blood were negative at the time of HT and excluded passive transmission from mother to child in subjects less than 6 mo of age. RESULTS PTLD was diagnosed in 8 out of 145 patients(5.5%); 6/91(6.5%) in those who were EBV seropositive and 2/54(3.7%) in the EBV na?ve group at the time of HT(P = 0.71). We found 32/145(22%) patients with persistently high EBV load during continuing follow-up; 20/91(22%) in EBV seropositive group vs 12/54(22%) in EBV na?ve group(P = 0.97). There was no significant association between pre-HT serostatus and EBV load after transplant(P > 0.05). In the EBV seropositive group, PTLD was diagnosed in 15%(3/20) of patients with high EBV vs 4.2%(3/71) of patients with low or undetectable EBV load(P = 0.14) whereas in EBV na?ve patients 8.3%(1/12) of those withhigh EBV load and 2.3%(1/42) with low or undetectable EBV load(P = 0.41). There was a highly significant association between occurrence of PTLD in those with high EBV load and duration of follow up(4.3 ± 3.9 years) after HT by Cochran-Armitage test for the entire cohort(P = 0.005). At least one episode of acute rejection occurred in 72%(23/32) of patients with high EBV vs 36%(41/113) patients with low or undetectable EBV after HT(P < 0.05). CONCLUSION There is an association between persistently high EBV load during post-HT follow up and the occurrence of late-onset PTLD in pediatric HT recipients irrespective of serostatus at the time of transplant. The occurrence of allograft rejection increased in patients with high EBV load presumably due to reduction in immunosuppression.

Hepatitis C virus-related lymphoproliferative disorders:An overview

Hepatitis C virus （HCV） is a global health problem affecting 3% of the world＇s population （about 180 million） and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproUferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV- related extrahepatic disorder. The association between extrahepatic （lymphoma） as well as hepatic malignancies （hepatocellular carcinoma） has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/ atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed.

Isolated peritoneal lymphomatosis defined as post-transplant lymphoproliferative disorder after a liver transplant: A case report

BACKGROUND Post-transplant lymphoproliferative disorder(PTLD) is a fatal complication of solid organ transplantation or allogenic hematopoietic stem cell transplantation that is associated with immunosuppressive therapy. Potential manifestations are diverse, ranging from reactive lymphoid hyperplasia to high-grade lymphoma.PTLD is usually of B-cell origin and associated with Epstein-Barr virus(EBV)infection. Herein, we describe a case of PTLD involving the peritoneal omentum.There has been only case of PTLD as a diffuse large B-cell lymphoma(DLBCL) in the peritoneum.CASE SUMMARY The patient was a 62-year-old man who had been receiving immunosuppressive therapy with tacrolimus since undergoing a liver transplant 15 years prior. He reported that he had experienced abdominal discomfort and anorexia 1 month prior to the current admission. Abdominal pelvic computed tomography(CT)revealed peritoneal and omental mass-like lesions without bowel obstruction.Ultrasonography-guided biopsy was performed, and he was histologically diagnosed with EBV-negative DLBCL. Positron emission tomography(PET)-CT depicted peritoneum and omentum involvement only, without any lymphadenopathy or organ masses, including in the gastrointestinal tract. Six cycles of chemotherapy with a "R-CHOP" regimen(rituximab-cyclophosphamide, doxorubicin, vincristine, prednisolone) were administered,and PET-CT performed thereafter indicated complete remission.CONCLUSION This is the first report of isolated peritoneal lymphomatosis defined as PTLD in a liver transplant recipient.

Clinical observations of vitreoretinal surgery for four different phenotypes of X-linked congenital retinoschisis

AIM： To evaluate the outcomes of vitreoretinal surgery for four different phenotypes of X-linked retinoschisis （XLRS）. METHODS： This study included thirty-one eyes of 25 patients who developed XLRS with severe complications. Among the 31 eyes, there were 7 eyes with vitreous hemorrhage, 8 eyes with retinal detachment and vitreous hemorrhage, and 16 eyes with rhegmatogenous retinal detachment. All of the patients underwent standard three-port pars plana vitrectomy. All of the eyes were divided into 4 groups before surgery according to a modified classification scheme, with the first three groups as follows： group A, with foveal cystic schisis; group B with macular lamellar schisis; and group C with foveolamellar changes. Peripheral schisis was not present in these 3 groups; however, group D was a complex group with both macular and peripheral changes. One year after surgery, we analyzed the best corrected visual acuity and postoperative anatomical and functional outcomes of these 4 groups. RESULTS： There were 7 eyes in group A （22.6%）, 1 eye in group B （3.2%）, 15 eyes in group C （48.4%） and 8 eyes in group D （25.8%）. Postoperative anatomical and functional outcomes were satisfactory at the last visit, while the mean visual acuity was increased to 0.27±0.11, with a significant difference （t=-1.049, P=0.000） compared with the results before surgery （0.1±0.08）. Visual acuity was improved in 23 eyes （74.2%）. Complications were found in three eyes： two eyes with proliferative vitreoretinopathy and traction retinal detachment 10 and 12mo after surgery, respectively; and one eye with vitreous hemorrhage 15mo after surgery. These eyes were in groups C and D. The retinas remained attached in these 3 eyes after reoperation. CONCLUSION： We should pay greater attention to XLRS with foveolamellar changes because it is the most changeable phenotype. Once complications occur, vitreoretinal surgery can significantly improve visual acuity and restore the anatomic structure of the retina.

X-linked juvenile retinoschisis： phenotypic and genetic characterization

Juvenile X-linked retinoschisis（XLRS, MIM#312700） belongs to a group of the vitreoretinal dystrophies. We aimed to describe the phenotype-genotype correlation of three XLRS cases in juveniles with different novel mutations from the Lithuanian population. The patients demonstrated macular retinoschisis and typical cyst-like cavities on spectral-domain optical coherence tomography（SD-OCT） images. The mean central foveal thickness was 569.7 μm. Two patients presented with peripheral retinoschisis. Flash electroretinogram demonstrated a reduced b/a ratio（〈1.0） in all patients. RS1（NM_000330.3） gene coding exons Sanger sequencing was performed. RS1 c.599 G〉T（p.R200 L） mutation was detected in one case, showing to be pathogenic in silico analysis. c.（92_97） ins C（p.W33 fs） mutation was identified for another patient, indicating the variant is possibly damaging in silico analysis. The third case was identified with a pathogenic mutation c.422 C〉G（p.R141 H）, HGMD CM981753. These are the first cases of XLRS in the Lithuanian population confirmed by molecular genotyping. Presented patients had a different genotype but similar phenotypic traits.

CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome:A case report and review of literature

The mutation in CNKSR2 leads to a broad spectrum of phenotypic variability and manifests as an X-linked intellectual disability. However, we reported that the male patient in this study not only had intellectual disability but also epileptic seizures. In addition, there were progressive language impairment, attention deficit hype-ractivity disorder and autism. Electroencephalograms showed continuous spike-and-wave during sleep. Genetic testing revealed a de novo mutation of the CNKSR2 gene(c.2185C >T, p.Arg729Ter) in the child that was not detected in the parents. Therefore, the child was diagnosed with X-linked epilepsy aphasia syndrome. Deletion of the CNKSR2 gene has been rarely reported in epilepsy aphasia syndrome, but no de novo mutation has been found in this gene. This report not only adds to the spectrum of epilepsy aphasia syndrome but also helps clinicians in diagnosis and genetic counseling.

Post-transplantation lymphoproliferative disorders:Current concepts and future therapeutic approaches

Transplant recipients are vulnerable to a higher risk of malignancy after solid organ transplantation and allogeneic hematopoietic stem-cell transplant.Posttransplant lymphoproliferative disorders(PTLD)include a wide spectrum of diseases ranging from benign proliferation of lymphoid tissues to frank malignancy with aggressive behavior.Two main risk factors of PTLD are:Firstly,the cumulative immunosuppressive burden,and secondly,the oncogenic impact of the Epstein-Barr virus.The latter is a key pathognomonic driver of PTLD evolution.Over the last two decades,a considerable progress has been made in diagnosis and therapy of PTLD.The treatment of PTLD includes reduction of immunosuppression,rituximab therapy,either isolated or in combination with other chemotherapeutic agents,adoptive therapy,surgical intervention,antiviral therapy and radiotherapy.In this review we shall discuss the prevalence,clinical clues,prophylactic measures as well as the current and future therapeutic strategies of this devastating disorder.

Inherited Genetic Susceptibility to Nonimmunosuppressed Epstein-Barr Virus-associated T/NK-cell Lymphoproliferative Diseases in Chinese Patients

Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.

Epstein-Barr virus-positive post-transplant lymphoproliferative disordepresenting as hematochezia and enterobrosis in renal transplant recipients in China: A report of two cases

BACKGROUND Post-transplant lymphoproliferative disorder(PTLD) is a rare severe complication after renal transplantation, with an incidence of approximately 0.3%-2.0% in patients undergoing renal transplantation. The clinical manifestations of PTLD are often nonspecific, leading to tremendous challenges in the clinical diagnosis and treatment of PTLD.CASE SUMMARY We report two Epstein-Barr virus(EBV)-positive PTLD cases whose main clinical manifestations were digestive tract symptoms. Both of them admitted to our hospital because of extranodal infiltration symptoms and we did not suspect of PTLD until the pathology confirmation. Luckily, they responded well to the treatment of rituximab. We also discuss the virological monitoring, clinical characteristics, diagnosis, and treatment of PTLD.CONCLUSION PTLD is a deceptive disease and difficult to diagnose. Once patients are confirmed with PTLD, immune suppressant dosage should be immediately reduced and rituximab should be used as first-line therapy.

Targeting X-linked inhibitor of apoptosis protein inhibits pancreatic cancer cell growth through p-Akt depletion

AIM: To determine whether lentivirus-mediated shRNA targeting the X-linked inhibitor of apoptosis protein (XIAP) gene could be exploited in the treatment of pancreatic cancer. METHODS: Human pancreatic cancer cells Panc-1, Mia-paca2, Bxpc-3 and SW1990, infected with lentivirus, were analyzed by real-time polymerase chain reaction (PCR). Western blotting was used to examine XIAP protein levels, survivin and p-Akt to confirm the result of real-time PCR and determine the possible mechanism. The 3-(4,5-cimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) assay was used to measure IC50 to determine chemosensitivity to the chemotherapeutic drugs 5-fluorouracil (5-FU) and gemcitabine. A colony assay, MTT assay and a tumorigenicity experiment were used to study cell proliferation in vitro and in vivo . Caspase-3/7 activity, 4',6-diamidino-2-phenylindole-staining and flow cytometric measurements were used to study apoptosis in SW1990 cells. RESULTS: XIAP proteins were found to be differen- tially expressed among pancreatic cancer cell lines Panc-1, Mia-paca2, Bxpc-3 and SW1990. Data of real-time PCR and Western blotting showed that XIAP was reduced persistently and markedly by lentivirus-mediated shRNA. Downregulation of XIAP by transfection with XIAP shRNA resulted in decreased p-Akt expression. XIAP shRNA also inhibited the growth of pancreatic cancer cells in vitro and in vivo , enhanced drug-induced apoptosis and increased chemosensitivity to 5-FU and gemcitabine. Results also suggest that inhibition of XIAP and subsequent p-Akt depletion may have an anti-tumor effect through attenuating the ability of cancer cells to survive. CONCLUSION: Lentivirus-mediated gene therapy is an attractive strategy in the treatment of pancreatic cancer and justifies the use of lentivirus in pancreatic cancer gene therapy studies.

Regulatory Effects of X-linked Inhibitor of Apoptosis Protein and Pro-apoptotic Protein Smac on Apoptosis Resistance to Chemotherapy in Pancreatic Cancer Cells~*

Objective： To investigate the relation of X-linked inhibitor of apoptosis （XIAP） and second mitochondria-derived activator of caspase （Smac） signaling pathway to chemoresistance in human pancreatic cancer Panc-1 and BXPC-3 cells. Methods： Apoptosis and the changes of XIAP expression in permeabilized cells induced by cisplatin and 5-fluorouracil （FU） were measured by flow cytometry. The cytosolic expression of XIAP, Smac and caspase-3 was detected by Western blot. A recombinant plasmid vector pEGFP-N1/Smac was constructed and transfected into of Pancol cells. The effect of cytosolic overexpression of Smac on apoptosis of Panc-1 cells was evaluated by flow cytometry. Results： Panc-1 was more resistant to cisplatin or 5-FU induced apoptosis than BXPC-3. Western blot revealed that chemoresistant Panc-1 highly expressed XIAP, and increased cytosolic expression of Smac might be responsible for the marked down-regulation of XIAP in chemo-sensitive BXPC-3 cells after exposure to cisplatin or 5-FU. Furthermore, cytosolic overexpression of Smac could significantly down-regulate the levels of XIAP and promote the activity of caspase-3, as well as sensitize Panc-1 cells to anticancer drug-induced apoptosis. Conclusion： Anticancer drug-induced apoptosis requires mitochondrial release of Smac and downregulation of XIAP, which may be an important determinant of chemo-sensitivity in pancreatic cancer cells. Up-regulation of cytosolic expression of Smac may act as an effective modifying signal to overcome apoptosis resistance to chemotherapy in pancreatic cancer cells.

Expression of second mitochondria-derived activator of caspases, X-linked inhibitor of apoptosis protein, and caspase-3 in pituitary adenomas

Studies concerning correlations between pituitary adenomas and cell apoptosis have mainly focused on upstream apoptosis signaling, but seldom on downstream mediators. In the present study, second mitochondria-derived activator of caspases （Smac）, X-linked inhibitor of apoptosis protein （XIAP）, and caspase-3 protein were qualitatively analyzed using immunohistochemistry, and quantified by western blot. Smac, XIAP, and caspase-3 mRNA expressions were detected by reverse transcription-PCR. Results showed that XIAP protein and mRNA expressions were greater in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. However, Smac and caspase-3 protein and mRNA expressions were lower in the invasive pituitary adenoma group compared with the noninvasive pituitary adenoma group. In the invasive pituitary adenomas, Smac expression was positively correlated with caspase-3 protein and mRNA expression （Protein： r = 0.55, P 0.01; mRNA： r = 0.50, P 0.01）. Smac and caspase-3 expressions were negatively correlated with XIAP protein and mRNA expression （Protein： r = -0.56, -0.64, P 0.01; mRNA： r = -0.69, -0.67, P 0.01）. However, no significant differences in correlation among Smac, XIAP, and caspase-3 were detectable in noninvasive pituitary adenomas. These data indicated that high expression of XIAP and low expression of Smac and caspase-3 suppressed cell apoptosis and led to enhanced invasiveness of pituitary adenomas. Thus, Smac, XIAP, and caspase-3 may be useful markers in determining the invasive behavior of pituitary adenomas.

A novel nonsense mutation of GPR143 gene in a Korean kindred with X-linked congenital nystagmus

Dear Editor,I am Dr.Ungsoo Samuel Kim.from Kim＇s Eye Hospital,Konyang University,Seoul,Korea.I write to present a novel mutation of GPR143 in Korean patients with X-linked congenital nystagmus by using exome sequencing.Congenital nystagmus is an inherited ocular disorder that can occur as an X-linked condition.