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Mec1 is one of multiple kinases that prime the Mcm2-7 helicase for phosphorylation by Cdc7

Randell, John C W; Fan, Andy; Chan, Clara; Francis, Laura I; Heller, Ryan C; Galani, Kyriaki; Bell, Stephen P
Activation of the eukaryotic replicative DNA helicase, the Mcm2-7 complex, requires phosphorylation by Cdc7/Dbf4 (Dbf4-dependent kinase or DDK), which, in turn, depends on prior phosphorylation of Mcm2-7 by an unknown kinase (or kinases). We identified DDK phosphorylation sites on Mcm4 and Mcm6 and found that phosphorylation of either subunit suffices for cell proliferation. Importantly, prior phosphorylation of either S/T-P or S/T-Q motifs on these subunits is required for DDK phosphorylation of Mcm2-7 and for normal S phase passage. Phosphomimetic mutations of DDK target sites bypass both DDK function and mutation of the priming phosphorylation sites. Mrc1 facilitates Mec1 phosphorylation of the S/T-Q motifs of chromatin-bound Mcm2-7 during S phase to activate replication. Genetic interactions between priming site mutations and MRC1 or TOF1 deletion support a role for these modifications in replication fork stability. These findings identify regulatory mechanisms that modulate origin firing and replication fork assembly during cell cycle progression.
PMCID:3021128
PMID: 21070963
ISSN: 1097-4164
CID: 2393412

Silent celiac disease activated by pancreaticoduodenectomy

Maple, John T; Pearson, Randall K; Murray, Joseph A; Kelly, Darlene G; Lara, Luis F; Fan, Andy C
Diarrhea and weight loss are common after pancreaticoduodenectomy, and arise from varying etiologies. An uncommon but important cause for these symptoms is the postoperative activation of silent celiac disease. We sought to describe the clinical presentation, diagnosis, treatment, and follow-up of a series of patients with silent celiac disease unmasked after pancreaticoduodenectomy, and to summarize the existing case reports on this association. A search of the electronic medical record at our institution was performed cross-referencing terms associated with celiac disease and pancreaticoduodenectomy for the years 1976-2004. Cases were then reviewed to ensure that no signs or symptoms attributable to celiac disease were present preoperatively. Seven patients were identified; five were male, and the median age was 56. All patients underwent surgery for a presumed pancreatic or ampullary malignancy. Six patients developed symptoms ultimately attributable to celiac disease immediately after pancreaticoduodenectomy, most commonly diarrhea and weight loss. A single patient had silent celiac disease incidentally diagnosed at pancreaticoduodenectomy that remained silent postoperatively on an unrestricted diet. Symptoms completely resolved in 4 of 6 patients after initiation of a gluten-free diet, with partial improvement in the remaining 2 patients. The median delay from pancreaticoduodenectomy to diagnosis of celiac disease in the 6 symptomatic patients was 6 months. Clinicians should consider celiac disease as a potential diagnosis in patients with failure to thrive and diarrhea after pancreaticoduodenectomy. This entity is uncommon, but may be under-recognized. The underlying mechanism may relate to an increased antigenic load secondary to postsurgical changes in intestinal physiology.
PMID: 17373587
ISSN: 0163-2116
CID: 160574

Comparison of direct percutaneous endoscopic jejunostomy and PEG with jejunal extension

Fan, Andy C; Baron, Todd H; Rumalla, Ashwin; Harewood, Gavin C
BACKGROUND: Jejunostomy tubes can be placed endoscopically by means of percutaneous gastrostomy with jejunal extension (PEG-J) or by direct percutaneous jejunostomy. These 2 techniques were retrospectively compared in patients requiring long-term jejunal feeding. METHOD: An endoscopy database was used to identify all patients who underwent endoscopic jejunal feeding tube placement from January 1996 to May 2001. Patients with a history of upper GI surgery were excluded. There were 56 patients with a direct percutaneous jejunostomy and 49 with a percutaneous gastrostomy with jejunal extension. Patients in the direct percutaneous jejunostomy group received a 20F direct jejunostomy tube; a 20F PEG tube with a 9F jejunal extension was used in the percutaneous gastrostomy with jejunal extension group. Medical records for the period of 6 months after establishment of jejunal access were reviewed. Complications and need for further endoscopic intervention within this time frame were recorded. The duration of feeding tube patency (number of days from established jejunal access to first endoscopic reintervention) was compared for both groups. RESULTS: Feeding tube patency was significantly longer in patients who had a direct percutaneous jejunostomy compared with those with a percutaneous gastrostomy with jejunal extension. Within the 6-month period, 5 patients with a direct percutaneous jejunostomy required endoscopic reintervention for tube dysfunction compared with 19 patients who had a percutaneous gastrostomy with jejunal extension (p < 0.0001). CONCLUSIONS: For patients who require long-term jejunal feeding, a direct percutaneous jejunostomy with a 20F tube provides more stable jejunal access compared with a percutaneous gastrostomy with jejunal extension with a 9F extension and has a lower associated rate of endoscopic reintervention.
PMID: 12447304
ISSN: 0016-5107
CID: 160575

Combined tracheal and esophageal stenting for palliation of tracheoesophageal symptoms from mediastinal lymphoma [Case Report]

Fan, Andy C; Baron, Todd H; Utz, James P
Mediastinal lymphoma as a cause of tracheobronchial obstruction is uncommon, and a malignant tracheoesophageal fistula in the setting of mediastinal lymphoma is rare. Malignant tracheoesophageal fistulas are associated with pronounced morbidity and mortality. We describe a patient with mediastinal lymphomatous infiltration resulting in tracheal obstruction, esophageal obstruction, and tracheoesophageal fistula that were successfully palliated with combined airway and esophageal stent placement.
PMID: 12479523
ISSN: 0025-6196
CID: 160576