Further delineation of neuropsychiatric findings in Tatton-Brown-Rahman syndrome due to disease-causing variants in DNMT3A: seven new patients.

Tatton-Brown-Rahman (TBRS) syndrome is a recently described overgrowth syndrome caused by loss of function variants in the DNMT3A gene. This gene encodes for a DNA methyltransferase 3 alpha, which is involved in epigenetic regulation, especially during embryonic development. Somatic variants in DNMT3A have been widely studied in different types of tumors, including acute myeloid leukemia, hematopoietic, and lymphoid cancers.

Exonic variants of genes related to the vitamin D signaling pathway in the families of familial multiple sclerosis using whole-exome next generation sequencing.

Introduction: Vitamin D (VD) deficiency has been associated with multiple sclerosis (MS) and other autoimmune diseases (AIDs). However, the effect of the genetics of VD on the risk of MS is subject to debate. This study focuses on genes linked to the VD signaling pathway in families with MS.

Mitochondria and lipid raft-located FOF1-ATP synthase as major therapeutic targets in the antileishmanial and anticancer activities of ether lipid edelfosine.

Background: Leishmaniasis is the world's second deadliest parasitic disease after malaria, and current treatment of the different forms of this disease is far from satisfactory. Alkylphospholipid analogs (APLs) are a family of anticancer drugs that show antileishmanial activity, including the first oral drug (miltefosine) for leishmaniasis and drugs in preclinical/clinical oncology trials, but their precise mechanism of action remains to be elucidated.

Methodology/principal Findings: Here we show that the tumor cell apoptosis-inducer edelfosine was the most effective APL, as compared to miltefosine, perifosine and erucylphosphocholine, in killing Leishmania spp.

Genomic profiling of fungal cell wall-interfering compounds: identification of a common gene signature.

Background: The fungal cell wall forms a compact network whose integrity is essential for cell morphology and viability. Thus, fungal cells have evolved mechanisms to elicit adequate adaptive responses when cell wall integrity (CWI) is compromised. Functional genomic approaches provide a unique opportunity to globally characterize these adaptive mechanisms.

Chromosome segregation and organization are targets of 5'-Fluorouracil in eukaryotic cells.

The antimetabolite 5'-Fluorouracil (5FU) is an analog of uracil commonly employed as a chemotherapeutic agent in the treatment of a range of cancers including colorectal tumors. To assess the cellular effects of 5FU, we performed a genome-wide screening of the haploid deletion library of the eukaryotic model Schizosaccharomyces pombe. Our analysis validated previously characterized drug targets including RNA metabolism, but it also revealed unexpected mechanisms of action associated with chromosome segregation and organization (post-translational histone modification, histone exchange, heterochromatin).

New insights into the RNA-based mechanism of action of the anticancer drug 5'-fluorouracil in eukaryotic cells.

5-Fluorouracil (5FU) is a chemotherapeutic drug widely used in treating a range of advanced, solid tumours and, in particular, colorectal cancer. Here, we used high-density tiling DNA microarray technology to obtain the specific transcriptome-wide response induced by 5FU in the eukaryotic model Schizosaccharomyces pombe. This approach combined with real-time quantitative PCR analysis allowed us to detect splicing defects of a significant number of intron-containing mRNA, in addition to identify some rRNA and tRNA processing defects after 5FU treatment.

Drug uptake, lipid rafts, and vesicle trafficking modulate resistance to an anticancer lysophosphatidylcholine analogue in yeast.

The ether-phospholipid edelfosine, a prototype antitumor lipid (ATL), kills yeast cells and selectively kills several cancer cell types. To gain insight into its mechanism of action, we performed chemogenomic screens in the Saccharomyces cerevisiae gene-deletion strain collection, identifying edelfosine-resistant mutants. LEM3, AGP2, and DOC1 genes were required for drug uptake.

Genome-wide analysis of factors affecting transcription elongation and DNA repair: a new role for PAF and Ccr4-not in transcription-coupled repair.

RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide.

A chemical genomic screen in Saccharomyces cerevisiae reveals a role for diphthamidation of translation elongation factor 2 in inhibition of protein synthesis by sordarin.

Sordarin and its derivatives are antifungal compounds of potential clinical interest. Despite the highly conserved nature of the fungal and mammalian protein synthesis machineries, sordarin is a selective inhibitor of protein synthesis in fungal organisms. In cells sensitive to sordarin, its mode of action is through preventing the release of translation elongation factor 2 (eEF2) during the translocation step, thus blocking protein synthesis.

A chemogenomic screening of sulfanilamide-hypersensitive Saccharomyces cerevisiae mutants uncovers ABZ2, the gene encoding a fungal aminodeoxychorismate lyase.

Large-scale phenotypic analyses have proved to be useful strategies in providing functional clues about the uncharacterized yeast genes. We used here a chemogenomic profiling of yeast deletion collections to identify the core of cellular processes challenged by treatment with the p-aminobenzoate/folate antimetabolite sulfanilamide. In addition to sulfanilamide-hypersensitive mutants whose deleted genes can be categorized into a number of groups, including one-carbon related metabolism, vacuole biogenesis and vesicular transport, DNA metabolic and cell cycle processes, and lipid and amino acid metabolism, two uncharacterized open reading frames (YHI9 and YMR289w) were also identified.

Increased efficacy of internal carotid artery stenting using a low-profile stent with a tapered tip.

Angioplasty and stent placement is becoming a widely accepted method of carotid artery revascularization. Two cases are presented where 1 standard low-profile stent failed to cross the lesion, but a different low-profile stent with a tapered tip delivery system was successfully deployed. The technical advantages of the tapered delivery system in certain anatomic situations are described.

Clinical observation: congenital absence of the left portal vein in a patient undergoing hepatic resection.

Congenital absence of the left portal vein is a rare vascular anomaly with a reported prevalence varying from one in 62 to one in 507 cases. A patient admitted for recurrent cholangitis secondary to extensive dilation of the left biliary ductal system associated with Caroli's Disease was determined by preoperative dynamic CT to have an excessively large right portal vein and no left portal vein. The surgeon must be aware of any variations in portal vascular anatomy in patients undergoing hepatic resection in order to prevent potentially fatal postoperative complications.

Neoadjuvant therapy of high-risk gastric cancer: a phase II trial of preoperative FAMTX and postoperative intraperitoneal fluorouracil-cisplatin plus intravenous fluorouracil.

Purpose And Methods: We identified patients with gastric cancer at high risk for recurrence before therapy using endoscopic ultrasonography (EUS). Neoadjuvant therapy using the fluorouracil, doxorubicin, and metrotrexate (FAMTX) regimen was given for three courses before planned laparotomy with the intention to perform curative resection. Postoperatively, intraperitoneal (IP) cisplatin and fluorouracil (FU) and intravenous (i.

Malignant hepatic hilar tumors: can ultrasonography be used as an alternative to angiography with CT arterial portography for determination of resectability?

Nineteen consecutive patients with malignant hilar obstruction were imaged with angiography, CT portography, and ultrasonography with color and spectral Doppler technique; all had surgical pathologic correlation. At surgery, 12 of 19 patients (63%) were found to have portal vein involvement; 15 of 19 (79%) had parenchymal invasion; and 11 of 19 (58%) had lobar atrophy. Level of biliary obstruction was determined in seven of 19 patients (37%) without drainage catheters.

Correlation of the findings of thallium-201 chloride scans with those of other imaging modalities and histology following therapy in patients with bone and soft tissue sarcomas.

We performed a retrospective [corrected] study to evaluate the imaging potential of thallium-201 as compared with other imaging modalities in differentiating residual/recurrent tumors from post-therapy changes in patients with musculoskeletal sarcomas. 201Tl scans, magnetic resonance imaging (17), X-ray computed tomography (6) or contrast angiography (6) studies in 29 patients previously treated for musculoskeletal sarcomas were correlated with either histopathologic findings (26 patients) or 2-year clinical follow-up (three patients). All imaging studies were acquired within 2 weeks.

Endoscopic ultrasonography of the gastrointestinal tract.

Endoscopic ultrasonography (EUS) combines the advantages of conventional endoscopy with the capabilities of ultrasonography. EUS allows clinicians to see through the wall of the gastrointestinal tract. The close proximity allows the use of relatively high frequencies with the resulting increase in tissue contrast and resolution.

Clinical trial of the Bard CT guide system.

Purpose: The Bard computed tomography (CT) guide holds a Monopty gun within the CT gantry and mechanically aids insertion of the needle tip. The clinical efficacy and accuracy of this device, its effect on procedure time, and the limitations of the device were studied.

Patient And Methods: In a prospective study, the outcome of 107 consecutive biopsies performed with 18-gauge needles was evaluated.

Identification of blood meals of Phlebotomus perniciosus (Diptera: Psychodidae) in Spain by a competitive enzyme-linked immunosorbent assay biotin/avidin method.

Blood meals from Phlebotomus perniciosus Newstead, collected in four different places in Spain, were identified to determine host-selection patterns. Blood meals were tested using a competitive enzyme-linked immunosorbent assay (ELISA) biotin-avidin method. Results indicate that this species is an opportunist that feeds on those animals to which it has easiest access.

Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma.

Purpose: To determine the toxicity, response rate, and survival of a regimen of hepatic arterial floxuridine (FUDR) with leucovorin (LV) and dexamethasone (Dec) for the treatment of unresectable hepatic metastases from colorectal carcinoma.

Patients And Methods: Sixty-two patients with hepatic metastases (33 previously untreated with chemotherapy) were treated with FUDR (0.30 mg/kg/d) and LV (15 mg/m2/d) and Dec (20 mg total dose) as a 14-day hepatic arterial infusion via an implantable pump alternating with 2 weeks of saline.

Large gastric folds: a diagnostic approach using endoscopic ultrasonography.

The evaluation of large gastric folds poses a difficult diagnostic problem. Exploratory laparotomy with full-thickness gastric biopsy is frequently required in order to rule out malignancy. To examine the utility of endoscopic ultrasonography in the diagnostic evaluation of large gastric folds, 28 consecutive patients with endoscopically or radiographically diagnosed large gastric folds were studied; in most of these patients endoscopic biopsies had been inconclusive for malignancy.

Hepatic arterial floxuridine and leucovorin for unresectable liver metastases from colorectal carcinoma. New dose schedules and survival update.

Background: We studied three new dose schedules of hepatic arterial infusion of floxuridine (FUDR) and leucovorin and update survival analysis of a previously reported trial using these drugs by hepatic arterial infusion for patients with hepatic metastases from colorectal carcinoma.

Methods: Untreated patients with hepatic metastases from colorectal cancer were treated with three dose schedules: Group D, FUDR (0.3 mg/kg/day) and leucovorin (30 mg/m2/day) as a 14-day continuous infusion through an implantable hepatic arterial pump alternating with a 4-week rest period; Group E, a lower dose of FUDR (0.