New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells

The specific alpha subunit of the interleukin-3 receptor (IL-3Ralpha, CD123) is strongly expressed in various leukemic blasts and leukemic stem cells and seems to be an excellent target for the therapy of leukemias. In this study, immunotoxins were developed to target CD123 only, which bypasses the dependence on other subunits to form intact IL-3R. Three anti-CD123 hybridomas (26292, 32701, and 32716) were selected on the basis of their affinity for CD123. Total RNAs were extracted from the 3 anti-CD123 hybridomas and used to clone the fragment of variable region (Fvs). The Fvs were assembled into single chain Fvs and fused to a 38-kd fragment of Pseudomonas exotoxin A to make recombinant immunotoxins. 26292(Fv)-PE38 was found to have the highest cytotoxic activity on the CD123 expressing leukemia cell line TF-1. It bound the cells with a kd of 3.5 nM. Another immunotoxin, 32716(Fv)-PE38, belonging to a different epitope group, had a similar binding ability but was less active, demonstrating the role of epitope selection in immunotoxin action. The cytotoxic activity of 26292(Fv)-PE38 was increased from 200 to about 40 ng/mL by mutating the REDLK sequence at the C terminus to KDEL. 26292(Fv)-PE38-KDEL was specifically cytotoxic to several CD123 expressing cell lines (TF-1, Molm-13, and Molm-14) with good CD123 expression but not to ML-1 or U937 with low or absent expression. In conclusion, 26292(Fv)-PE38-KDEL shows good cytotoxic activity against CD123 expressing cell lines, and merits further development for the possible treatment of acute myeloid leukemia and other CD123 expressing malignancies.     

Presentation of cauda equina syndrome due to an intradural extramedullary abscess: a case report

Background contextCauda equina syndrome is caused by compression or injury to the nerve roots distal to the level of the spinal cord. This syndrome presents as low back pain, motor and sensory deficits in the lower extremities, and bladder as well as bowel dysfunction. Although various etiologies of cauda equina syndrome have been reported, a less common cause is infection.PurposeTo report a case of cauda equina syndrome caused by infection of an intradural extramedullary abscess with Staphylococcus aureus.Study design/settingCase report and review of the literature.MethodsThe literature regarding the infectious causes of cauda equina syndrome was reviewed and a case of cauda equina syndrome caused by infection of an intradural extramedullary abscess with Staphylococcus aureus was reported.ResultsA 37-year-old woman, with history of intravenous drug abuse, hepatitis C, and hepatitis B, presented with low back pain lasting 2 months, lower extremity pain, left greater than right with increasing weakness and difficulty ambulating, and urinary and fecal incontinence. Her presentation was consistent with cauda equina syndrome. The patient underwent a T12–L2 laminectomy, and intradural exploration revealed an abscess. Methicillin-resistant Staphylococcus aureus was found on wound culture.ConclusionsCauda equina syndrome, presenting as a result of spinal infection, such as the case reported here, is extremely rare but clinically important. Surgical intervention is generally the recommended therapeutic modality.     

Species of <Emphasis Type="Italic">Lasiodiplodia</Emphasis> associated with papaya stem-end rot in Brazil

The last decade has revealed an unexpected fungal diversity associated with natural rocks, often collected in environments influenced by harsh climatic conditions. Yet the phylogenetic affiliations and the taxonomy of many of these extreme fungi, mainly within Dothideomycetes, the largest class of Ascomycota, have only partially been described. In the present study we confirm that most rock inhabiting-fungi (RIF) are highly polyphyletic among Dothideomycetidae, mainly within the order Capnodiales, an order otherwise incorporating several families of major plant pathological importance. Novel taxa were identified within the two major and distinct clades of Teratosphaeriaceae, both comprising meristematic black fungi. Thirty one novel species and 13 new genera are proposed, based on ITS and partial nucLSU, RPB2 and BT2 sequences.     

Neoadjuvant Therapy for Rectal Cancer: Histologic Response of the Primary Tumor Predicts Nodal Status

PURPOSE: This study was designed to compare histologic T and N stages in patients with rectal adenocarcinoma undergoing various neoadjuvant radiotherapy regimens and proctectomy, in an attempt to determine if final histologic stage of the mural tumor predicts nodal status.METHODS: Data were collected from computerized databases at two institutions on 649 consecutive patients who underwent neoadjuvant radiotherapy or chemoradiotherapy and proctectomy for primary adenocarcinoma of the rectum from 1990 to 2002.RESULTS: Five patients were excluded because of incomplete pathology data sets, leaving a study population of 644. Patients underwent neoadjuvant radiotherapy alone (2,000 cGy in 5 fractions, n = 191; or 4,500 cGy in 25 fractions, n = 259) or chemoradiation (4,500 cGy in 25 fractions with concurrent 5-fluorouracil, n = 194). Histologic stage of the remaining mural tumor (ypT) correlated with nodal status (ypN). Lymph nodes harboring metastatic tumor were found in 1 of 42 (2 percent) ypT0 patients, 2 of 45 (4 percent) ypT1 patients, 43 of 186 (23 percent) ypT2 patients, 158 of 338 (47 percent) ypT3 patients, and 16 of 33 (48 percent) ypT4 patients (P < 0.001, chi-squared test). The probability of finding ypN+ disease was 3 of 87 (3 percent) in patients with ypT0-1 residual primary tumors vs. 220 of 557 (39 percent) in patients with ypT2-4 residual primary tumors (P < 0.0001; Fishers exact test).CONCLUSIONS: Nodal metastases are rare in patients whose mural tumor burden shrinks to ypT0-1 after neoadjuvant radiotherapy. If transanal excision is offered to select patients with distal rectal cancer, it is reasonable to select those who have an excellent clinical response to neoadjuvant therapy for transanal excision, and then reserve proctectomy for patients proven to have residual ypT2-4 disease.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

No Association Between NRG1 and ErbB4 Genes and Psychopathological Symptoms of Schizophrenia

Neuregulin 1 (NRG1) and v-erb-a erythroblastic leukemia viral oncogene homolog 4 (ErbB4) have been extensively studied in schizophrenia susceptibility because of their pivotal role in key neurodevelopmental processes. One of the reasons for the inconsistencies in results could be the fact that the phenotype investigated has mostly the diagnosis of schizophrenia per se, which is widely heterogeneous, both clinically and biologically. In the present study we tested, in a large cohort of 461 schizophrenia patients recruited in Scotland, whether several SNPs in NRG1 and/or ErbB4 are associated with schizophrenia symptom dimensions as evaluated by the Positive and Negative Syndrome Scale (PANSS). We then followed up nominally significant results in a second cohort of 439 schizophrenia subjects recruited in Germany. Using linear regression, we observed two different groups of polymorphisms in NRG1 gene: one showing a nominal association with higher scores of the PANSS positive dimension and the other one with higher scores of the PANSS negative dimension. Regarding ErbB4, a small cluster located in the 5′ end of the gene was detected, showing nominal association mainly with negative, general and total dimensions of the PANSS. These findings suggest that some regions of NRG1 and ErbB4 are functionally involved in biological processes that underlie some of the phenotypic manifestations of schizophrenia. Because of the lack of significant association after correction for multiple testing, our analyses should be considered as exploratory and hypothesis generating for future studies.     

Transesophageal Echocardiography of Intracardiac Thrombus in Congenital Heart Disease and Atrial Flutter: The Importance of Thorough Examination of the Fontan

Transesophageal echocardiography (TEE) is used in atrial flutter or fibrillation (AFF) before electric cardioversion to detect intracardiac thrombi. Previous studies have described the use of TEE to diagnose intracardiac thrombi in the left atrium and left atrial appendage, which has an incidence of 8 % among patients without congenital heart disease (CHD). In their practice the authors have noted a significant incidence of intracardiac thrombi in other structures of patients with CHD and AFF. This study aimed to determine the incidence and location of intracardiac thrombi using TEE in patients with CHD requiring electric cardioversion of AFF and to compare the use of TEE and transthoracic echo (TTE) to detect intracardiac thrombus in this population. A retrospective chart review of TEE and TTE findings for all patients with CHD who had electric cardioversion of AFF at our institution from 2005 to 2013 was conducted. The diagnosis, presence, and location of intracardiac thrombus were determined. The TEE and TTE results were compared. The study identified 27 patients with CHD who met the study entry criteria at our institution between 2005 and 2013. Seven of these patients had a single ventricle with Fontan palliation. All the patients presented with AFF and had TEE before electric cardioversion. No patients were excluded from the study. The patients ranged in age from 2 to 72 years (median, 21 years) and weighed 17–100 kg (median, 65 kg). The duration of AFF before TEE and attempted cardioversion ranged from 1 day to 3 weeks (median, 3.5 days). Intracardiac thrombus was present in 18 % (5/27) of the patients and in 57 % (4/7) of the Fontan patients with AFF. No embolic events were reported acutely or during a 6-month follow-up period. Among patients with CHD who present with AFF, a particularly high incidence of intracardiac thrombi is present in the Fontan patients that may be difficult to detect by TTE. Thorough TEE examination of the Fontan and related structures is indicated before electric cardioversion of AFF. The incidence of intracardiac thrombus in CHD patients is more than double that reported in non-CHD patients.