Rats were randomly divided into six groups (n = 8) and were subje

Rats were randomly divided into six groups (n = 8) and were subjected to the following treatments: Group 1 (Control):

Rats were treated with distilled water (5 mL/kg body weight) throughout the experimental period and injected with single dose of saline. Group 2 (Saffron): Rats were administered orally 300 mg/kg saffron alone throughout the experimental period. Group 3 (HCC): Rats were induced with DEN and DAPT concentration 2-AAF as described before. Whereas animals of the protective groups (groups 4-6) were orally fed 300 mg/kg (+Saffron HD [high dose]), 150 mg/kg (+Saffron MD [medium dose]), and 75 mg/kg (+Saffron LD [low dose]), saffron suspension, respectively, 2 weeks prior to HCC initiation and continued for 22 weeks. Doses of saffron were selected based on previously reported pharmacological studies of this plant. Saffron at doses varying from 100-200 mg/kg has been reported to suppress chemically-induced skin cancer.4, 6 No adverse effect has been reported for saffron treatment up to 2000 mg/kg.8 Hepatocarcinogenesis was then induced as detailed in the

previous section. Group 1 was treated with equal volume of vehicle. After 22 weeks of DEN administration, all animals were anesthetized 24 hours after the last treatment. Following anesthesia, blood was collected from the retro-orbital plexus. Collected blood samples were centrifuged at 1500×g for 20 minutes at 4°C to obtain serum. For biochemical determination, frozen liver samples were homogenized Proteasome inhibitor Methamphetamine in ice-cold Tris-HCL buffer (150 mM, pH 7.4). The wt/vol ratio of the tissue to the homogenization buffer was (1:10 wt/vol). Aliquots were prepared and used for determination of different biochemical markers. Activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transpeptidase (GGT) were measured spectrophotometrically using Shimadzu recording spectrophotometer (UV-160).

The assay was performed using BioMerieux reagent kit, according to the protocol supplied with the kit. Alpha-fetoprotein (AFP) is produced by the fetal liver and is used as marker for hepatic carcinoma.9 AFP was determined in serum by enzyme-immunoassay method using a commercial kit (Calbiotech) and following their protocol. Determination of MDA in liver homogenate was carried out based on its reaction with thiobarbituric acid to form a pink complex with absorption maximum at 535 nm.10 Protein carbonyl (P.carbonyl) contents were determined according to the method of Reznick and Packer.11 This method is based on spectrophotometric detection of the end product of reaction of 2,4-dinitophenylhydrazine with P.carbonyl to form protein hydrazones at 370 nm. The results were expressed as nanomoles of carbonyl group per milligram of protein with molar extinction coefficient of 22,000 M/cm. Myeloperoxidase (MPO) activity in homogenate was determined as described in Hillegass et al.12 One unit of MPO was defined as the amount of MPO present that degrades 1 μM peroxide per minute.

Kidney biopsy was performed to determine the exact cause

Kidney biopsy was performed to determine the exact cause

of nephrotic syndrome, and histopathological results were suggestive of Ig M nephropathy. He was treated with diuretics and supportive care alone. Interestingly two weeks after the ESD was performed, the patient edema improved along with a reduction in the proteinuria. At 30 months follow-up after ESD, all the laboratory tests showed normal results and no peripheral edema was noted. Conclusion: Physicians should be alerted to a case of early gastric cancer with nephrotic syndrome that improved after resection of the primary gastric lesion by endoscopic submucosal dissection (ESD). Key Word(s): 1. Early gastric cancer; 2. ESD; 3. Nephrotic syndrome; Presenting Author: PING-HONG ZHOU Additional Authors: QUAN-LIN LI, LI-QING YAO, MEI-DONG XU, WEI-FENG CHEN, YI-QUN ZHANG,

JIAN-WEI HU, MING-YAN CAI Corresponding Author: PING-HONG ZHOU JNK inhibitors Affiliations: Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University Objective: A circular muscle myotomy preserving the longitudinal outer esophageal muscular layer is often recommended during peroral endoscopic myotomy (POEM) for achalasia. However, because the longitudinal muscle fibers of the esophagus are extremely thin and fragile, and completeness of myotomy is the basis for the excellent result of conventional surgical myotomy, this modification needs to www.selleckchem.com/products/icg-001.html be OSBPL9 further debated. Here, we retrospectively analyzed our prospectively maintained

POEM database to compare the outcomes of endoscopic full-thickness and circular muscle myotomy. Methods: According to the myotomy depth, 103 patients with full-thickness myotomy were assigned to group A, while 131 patients with circular muscle myotomy were assigned to group B. Symptom relief, procedure-related parameters and adverse events, manometry outcomes, and reflux complications were compared between groups.Results: The mean operation times were significantly shorter in group A compared with group B (P = 0.02). There was no increase in any procedure-related adverse event after full-thickness myotomy (all P < 0.05). During follow-up, treatment success (Eckardt score ≤3) persisted for 96.0% (95/99) of cases in group A and for 95.0% (115/121) of cases in group B (P = 0.75). There were no statistical significant differences of pre/post-treatment D-value of symptom scores and LES pressures between groups (both P > 0.05). The overall clinical reflux complication rates were also similar (21.2% vs. 16.5%, P = 0.38). Conclusion: Short-term symptom relief and manometry outcomes of each method were comparable. Full-thickness myotomy significantly reduced the procedure time but did not increase the procedure-related adverse events or clinical reflux complications. Key Word(s): 1. POEM; 2. Full-thickness; 3.

A significant trabecular bone

loss was observed in infect

A significant trabecular bone

loss was observed in infected IL-10-deficient male mice but not in females [65]. Moreover, H. hepaticus infection suppressed osteoblast markers only in male mice. The latter suffered from more severe colitis and presented higher levels of H. hepaticus colonization than females. IL-10 receptor-blocking antibody treatment Sirolimus chemical structure during chronic H. hepaticus infection of mice lacking inducible expression of major histocompatibility complex class II (MHCII) molecules led to colitis associated with increased innate effector cell infiltration and expression of proinflammatory cytokines [66]. Moreover, exacerbated colitis correlated with the inability of intestinal epithelial cells to upregulate MHCII expression. The Wiskott–Aldrich

syndrome protein (WASP) is a hematopoietic cell-specific intracellular signaling molecule that regulates the actin cytoskeleton. WASP deficiency is associated with IBD. Helicobacter species see more were detected in feces of WASP-deficient mice [67]. After Helicobacter eradication, these mice did not develop spontaneous colitis, and reinfection with H. bilis led to typhlitis and colitis which, in several cases, evolved toward dysplasia with 10% demonstrating colon carcinoma. In addition, a T-cell transfer model of colitis dependent on WAPS-deficient innate immune cells also required Helicobacter colonization. H. hepaticus-infected Rag2-deficient mice emulate many aspects of human IBD, and infected mice develop severe colitis progressing into colon carcinoma. A translational comparison of protein expression and protein damage products in tissues of H. hepaticus-infected Rag2-deficient mice and patients with

human IBD assessed the validity of this animal model for human IBD [68]. The study determined some systemic inflammatory markers in serum that were most closely associated with disease activity and were common to human IBD and H. hepaticus-associated colitis in Rag2-deficient mice. Necrotizing enterocolitis (NEC) is the second most common cause of morbidity in premature infants, and dysbiosis crotamiton is thought to play an important role in disease onset. H. hepaticus infection of premature formula-fed rats (model of NEC) induced inflammation, increased levels of TLR4 receptor, altered activation of autophagy, and increased the incidence and severity of NEC in rats exposed to asphyxia and cold stress [69]. These results are consistent with observations in neonates of blooms of proinflammatory microbes just before the onset of NEC and support dysbiosis in the incidence of NEC. H. hepaticus infection is sufficient to enhance prostate intra-epithelial neoplasia and microinvasive carcinoma in mice with a genetic predilection for dysregulation of wnt signaling (ApcMin/+ mutant), in an inflammation-dependent manner [70]. Intraperitoneal injection of mesenteric lymph node cells from H.

The intramucosal or SM1 invasive undifferentiated cancer (signet

The intramucosal or SM1 invasive undifferentiated cancer (signet ring cell carcinoma and poorly differentiated adenocarcinoma) ≤ 3 cm were also included for endoscopic treatment group. Cases with differentiated mucosal cancer without ulcer ≤ 2 cm were defined as standard criteria. The outcome measures were respectability and incidence of procedure-related complications such as bleeding and perforation. PD0325901 supplier The difference in disease free survival rate and local recurrence rate between three groups were estimated. Results: Total 116 patients (71 patients in expanded criteria; 33 patients in standard criteria; 12 patients in undifferentiated cancer) underwent ESD and then received periodic endoscopic survey for 17–601

days (mean, 91 days). There was no significant difference in en bloc resection rates, curative resection rates and incidence of procedure-related complications between three groups. The local

recurrence rates in three groups were 1.9% and 3.4%, 14.3%, respectively.(p = 0.232). The disease free survival rates in three groups were 97.4% and 91.7%, 80% respectively.(p = 0.648). There was no case with metastasis to lymph node or distant organs during the study period in three groups. Data were analysed the chi-square test. ★ One way ANOVA test ★★the Kaplan-Meier method and Log-rank. Conclusion: Standard criteria and expanded criteria of ESD and undifferentiated cancer have similar clinical outcomes CT99021 mouse in en bloc resection rates, local recurrence and disease free survival rates. It is suggested that EGC that categorized into expanded criteria and undifferentiated cancer will be indication of endoscopic treatment. Key Word(s): 1. ESD; 2. EGC; 3. Expanded Criteria;   Expanded criteria Standard ALOX15 criteria Undifferentiated P value En bloc resection 87.3% 97.0% 83.3% 0.242 Curative resection 88.7% 97.0% 75.0% 0.093 Perforation 2.9% 6.1% 0% 0.564 Bleeding (decreased 2point

Hgb) 11.3% 0% 0% 0.066 Local recurrence 1.9% 3.4% 14.3% 0.232 Median Follow-up period (range); 85 days (17–601) 73 days (34–373) 245 days (68–405) 0.394* Disease free survival 97.4% 91.7% 80% 0.648** Presenting Author: LIU JUAN Additional Authors: JIANGHAI XING Corresponding Author: JIANGHAI XING Affiliations: guangxi medical university Objective: To evaluate the effectiveness and safety of endoscopic submucosal dissection (ESD) in diagnosis and therapy of gastrointestinal mucosal and submucosal lesions. Methods: We collected 58 cases were treated by ESD in the First Affiliated Hospital of Guangxi Medical University between September 2009 and January 2012. The gastrointestinal mucosal protrusive lesions were were detected by endoscopy. A total of 45 cases were proved to originate from the mucosa layer, muscularis mucosa layer, submucosal and muscularis propria layer. The patients without contraindications were treated with ESD. The specimens were sent to histological examinations. We made recommendations to all the patients on regular endoscopic follow-up.

This study showed that bottom sea-ice algae from the east Antarct

This study showed that bottom sea-ice algae from the east Antarctic possess a high level of plasticity in their light-acclimation capabilities and identified the xanthophyll cycle as a critical mechanism in photoprotection and the preferred means by which sea-ice diatoms regulate

energy flow to PSII. “
“This article describes a new diatom genus Moreneis from the Yellow Sea sand flats on the west coast of Korea. The new genus SB431542 molecular weight is characterized by a unique combination of morphological characteristics, including the shape of the plastids, which have not been previously observed in diatoms. The valve morphology resembles other genera belonging to Lyrellaceae, within which we place this genus. In terms of areolae structure, Moreneis resembles Petroneis and Placoneis; however, Staurosporine research buy it differs from both genera with respect to the raphe system and plastid shape. Cells of Moreneis spp. have a single large plastid appressed to the girdle of the secondary side of the valve, with two lobes extended toward the primary side of the valve. Furthermore, the unique feature of Moreneis frustules is the raphe, which has both external central and apical endings bent in opposite directions. We differentiated four taxa, which we describe as new for

science. However, based on our findings, several established species from Navicula should also be formally transferred to Moreneis, including N. alpha Cleve, N. besarensis Giffen, N. epsilon

Cleve, N. menaiana Hendey, N. polae Heiden, and N. quadri-undulata F. Meister. Analysis of published data revealed that species belonging to Moreneis are numerous in tropical marine littoral waters, and in moderate climate zones, especially in the western Pacific, with only a few species occurring in the Mediterranean and Atlantic. “
“Algae have important functional roles in estuarine wetlands. We quantified differences in macroalgal abundance, composition and diversity, and sediment chl a and pheophytin a (pheo a) among three National Wetlands Benzatropine Inventory (NWI) emergent marsh classes in four Oregon estuaries spanning a range of riverine to marine dominance. We also assessed the strength of macroalgal-vascular plant associations and the degree to which environmental variables correlated with algal community metrics in marsh and woody wetlands. The frequency of occurrence of most macroalgal genera, total benthic macroalgal cover, macroalgal diversity, and sediment chl a content were several times higher in low emergent marsh than in high marsh or palustrine tidal marsh. Conversely, pheo a: chl a ratios were highest in high and palustrine marsh.

5-13 Hz) and beta (13 5-25 5 Hz) EEGs were classified as normal/

5-13 Hz) and beta (13.5-25.5 Hz). EEGs were classified as normal/abnormal based on the spectral criteria proposed by Van der Rijt et al.14 and subsequently modified by Amodio et al.15 Patients were qualified as having minimal HE if psychometric and/or neurophysiological Fulvestrant manufacturer abnormalities were present. Venous blood was obtained for routine full blood count, renal

function and electrolytes, protein profile, glucose, aminotransferases, bilirubin, clotting screen and C-reactive protein (CRP); ammonia was measured in the emergency laboratory immediately after blood had been drawn in an iced tube. Serum was frozen at −20°C for subsequent measurement of interleukin-6 (IL-6), TNFα, indole, and oxindole. IL-6 and TNFα were measured using a solid-phase immunological method with two antibodies: a monoclonal immobilizing murine antibody and a polyclonal enzyme-labeled (bovine alkaline phosphatase) antibody. The system was coupled in a chemoluminescent selleck sequential immunometric assay, and the method was automated in a DPC Immulyte One analyzer (Medical Systems, Genova, Italy).16 The results are not confounded by hemolysis or by bilirubin and lipids in clinical sample concentrations. Interference by heterophilic antibodies was ruled out by standard laboratory procedures. The intra-assay coefficient of variation (CV) was 3.5-4% for IL-6 and 2.6-3.5% for TNFα; the inter-assay CV was 5.1%-5.3%

for IL-6 and 5.3%-6.5% for TNFα; the limit of detection was 2 μg/L for IL-6 and 1.7 μg/L for TNFα. Indole plasma concentrations were measured using a procedure based on high-performance liquid chromatography separation and fluorescence spectrophotometer detection as previously described.17 Briefly, 2 mL of pure methanol was added to 1 mL of Amobarbital plasma. The mixture was centrifuged (18,000g for 20 minutes), and an aliquot of the supernatant was injected into the high-performance liquid chromatography apparatus. The column was an 18 SpheriSorb octadecyl silane 10-μm column (Alltech, Deerfield, IL) and the mobile phase was water/methanol (40%/60%) at a flow rate of 1.2 mL/minute. Detection was obtained at wavelengths of 285-nm excitation and 340-nm emission.

Oxindole plasma levels were evaluated as previously described18: 2 mL HClO4 0.4 N was added to 1 mL plasma to precipitate proteins. After centrifugation (18,000g for 20 minutes), the supernatant was collected. The procedure was repeated to improve plasma extraction. The supernatants were then mixed with 8 mL of chloroform for at least 5 minutes. The organic layer was collected and evaporated under a stream of N2. Residues were dissolved in HClO4 0.4 N (200 μL), and a portion was injected into a high-performance liquid chromatography apparatus equipped with an ultraviolet spectrophotometer detector. A 25-cm reverse-phase 18 SpheriSorb octadecyl silane 10-μm column and a mobile phase of 0.5 M acetic acid/acetonitrile at a ratio of 90%/10 % wt/wt at a flow rate of 1.5 mL/minute were used.

g Van Gossum & Sherratt, 2008), there are several plausible alte

g. Van Gossum & Sherratt, 2008), there are several plausible alternative hypotheses that do not involve frequency dependence at all. One of these proposes that andromorphs will

have an advantage at high population densities by mimicking males, and this advantage will be offset by the risk of not mating at all at low densities (Hinnekint, 1987). Very few studies have considered this hypothesis, and no supportive Ibrutinib evidence has been found (Cordero-Rivera & Egido-Pérez, 1998). An alternative hypothesis suggests that andromorphs will benefit from avoiding interspecific matings, while paying the cost of higher vulnerability to predation (Johnson, 1975). However, it is not clear how andromorphs would be more efficient than heteromorphs at avoiding interspecific matings, data supporting this hypothesis are lacking, and the trade-off would have to be perfectly balanced for polymorphism to persist at equilibrium. Abiotic factors could also play a role in the maintenance Rucaparib mouse of the polymorphism. Morph

frequencies have been observed to vary across geographical ranges where climatic conditions differ (Van Gossum et al., 2007; Hammers & Van Gossum, 2008; Gosden, Stoks & Svensson, 2011), and it has been found that ambient temperature affects mass and protein content of female morphs differently (Bots et al., 2009). It has also been observed that spatiotemporal patterns of morph frequencies do not always correlate with estimates of male harassment (Van Gossum et al., 2007; Hammers & Van Gossum, 2008; Iserbyt et al., 2010). It is thus plausible that different morphs

are at a selective advantage in different populations, and that gene flow among those populations maintains diversity Protirelin in each. Additionally, recent studies suggest the effects of multiple mechanisms, selective and stochastic, acting simultaneously, and varying in time and space (Iserbyt et al., 2010; Sánchez-Guillén et al., 2011; Iserbyt, Van Gossum & Stoks, 2012). However, these hypotheses have not been well explored in damselflies, or other species in which there are sex-limited polymorphisms, and much of what we know about the potential for climatic selection and the interplay of multiple mechanisms to maintain diversity comes from a rather different example of an invertebrate colour polymorphism: that seen in the land snails of the genus Cepaea (Cook, 1998; Cameron & Pokryszko, 2008), which is discussed later in this review. Mate choice could lead to NFDS, and consequently, to the maintenance of balanced polymorphisms, when either females or males prefer to mate with a rare morph of the opposite sex.

We performed six major orthopaedic procedures, one emergency orch

We performed six major orthopaedic procedures, one emergency orchidectomy and one open appendectomy. The dosing schedules were at the higher end of those described in the literature but within the recommendations of the summary of product characteristics. Despite this, we encountered non-surgical bleeding in four of eight episodes. Three of these occurred in one individual suggesting a patient factor. The overall outcome was good for all episodes. The hybrid regimen combines

flexibility of dose and dosing frequency of rFVIIa in the immediate postoperative setting with the advantage of a reduced dosing frequency with FEIBA® in the subsequent days. This study also emphasizes that surgical procedures in this patient group remain a challenge. “
“Joint pain related to haemophilia affects large ABT-888 mouse numbers of people and has a significant impact on their quality of life. This article reviews evidence about behavioural and psychological aspects of joint pain in haemophilia, learn more and considers that evidence in the context of research on other chronic pain conditions. The aim is to inform initiatives to improve pain self-management among people with haemophilia (PWH). Reduced pain intensity predicts better physical quality of life, so better pain management should lead to improved physical quality

of life. Increased pain acceptance predicts better mental quality of life, so acceptance-based approaches to self-management could potentially be adapted for PWH. Pain self-management interventions could include elements designed to: improve assessment of pain; increase understanding of the difference between acute and chronic pain; improve adherence to clotting factor treatment; improve knowledge and understanding about the

benefits and costs of using pain medications; improve judgements about what is excessive use of pain medication; increase motivation to self-manage pain; reduce negative emotional thinking about pain; and Bupivacaine increase pain acceptance. The influence of behavioural and psychological factors related to pain are similar in haemophilia and other chronic pain conditions, so there should be scope for self-management approaches and interventions developed for other chronic pain conditions to be adapted for haemophilia, provided that careful account is taken of the need to respond promptly to acute bleeding pain by administering clotting factor. “
“The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL−1). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression.

The parasites detected included: Entamoeba histolytica (15; 3%),

The parasites detected included: Entamoeba histolytica (15; 3%), Giardia lamblia (106; 18%), helminths (24; learn more 4%), Cryptosporidium species (82; 14%), Isospora belli (70; 12%), Cyclospora cayetanensis (20; 3%), and microsporidia (2; 0.3%). Intestinal coccidia and microsporidia were

more common among immunocompromised than immunocompetent patients (138/300 vs 36/300; p < 0.001). 5% (28/600) patients had co-infections with one or more pathogenic parasite. No coccidia or microsporidia was detected in controls. Multilocus genotyping of Cryptosporidium spp. identified 70% as C. hominis (54/77) as compared to 30% C. parvum (23/77) [14 monkey, 9 bovine genotype]. To delineate transmission pattern of cryptosporidiosis, no association could be established with relation to habitat (rural or urban) and to environmental exposure. Only 2 cases of C. parvum bovine genotype had history of exposure to contact with cattle. All the Giardia isolates were Assemblage B. Conclusion: In

a tropical setting, 50% of the patients with diarrhea harbored some kind of intestinal parasites. Incidence of C. hominis and C. parvum was high in HIV-infected individuals as compared to non-HIV. Transmission of both Cryptosporidium and Giardia appeared largely anthroponotic. Key Word(s): 1. Transmission; 2. Cryptosporidium; Bortezomib 3. genotype; 4. diarrhea; Presenting Author: BIJAN SHAHBAZKHANI Additional Authors: NAJMEH ALETAHA, MOHAMMAD GHONCHEH, RAMIN SHAKERI, REZA MALEKZADEH Corresponding Author: BIJAN SHAHBAZKHANI Affiliations: Digestive Diseases Research Center, Tehran University of Medical Sciences Objective: Osteopenia and osteoporosis are well-known and prevalent complication of celiac disease. However, the relative prevalence of celiac disease among osteoporotic populations is not known, and the benefit of screening for celiac disease among the osteoporotic population remains controversial. Methods: We evaluated 560 individuals, 460 with osteoporosis

and 100 healthy subjects, Phosphoprotein phosphatase from the rheumatology clinic in Imam Khomeini and Shariati Hospital by IgA anti tissue transglutaminase for celiac disease. Then individuals with positive serologic test underwent upper GI Endoscopy & 2nd part duodenum biopsies. The clinical findings were evaluated in the both groups and were compared together. Results: 5 (≈1%) of 460 patients with osteoporosis and 1 (1%) of 100 subjects without osteoporosis had celiac disease by positive serologic & pathology result. 3 patients with serology & pathology positive test were female. All patients in osteoporotic group had at least one other symptoms of celiac disease. Two of them had anemia and others had chronic abdominal pain, recurrent oral aphtous lesion & chronic bloating.

Diminished levels of Cdk1, elevated levels of pCdk1 (Thr14), and

Diminished levels of Cdk1, elevated levels of pCdk1 (Thr14), and delayed expression of p-histone suggest impairment in the entry of mutant hepatocytes into mitosis. In particular, p53 has been well described as acting as a hub for incoming stress signals, which are then transduced to growth arrest,

DNA repair, or apoptosis.26 Our results demonstrate a significant induction of p53 in mutant mice beginning at 24 hours post-PHx, correlating with initial expression of PCNA and elevated levels of pRb (Ser249/Thr252) and cyclin D1, suggesting evidence of cellular or genomic stress during DNA synthesis. This is further supported by increased expression of pChk2 (Thr68) and elevated levels of phospho-p53 (ser15 and 20). In response to DNA damage, ATM/ATR-kinases activate Chk2 (an evolutionarily conserved and well-described kinase) by phosphorylating Thr68.27 This in turn mediates Osimertinib in vitro a chain of phosphorylation events, including phosphorylation of p53 on ser20 and disruption of p53-MDM2 binding, stabilized p53,26 and recruitment of the transcription factors Midostaurin cost p300, CBP, and P/CAF, which

stimulate transcription from p53-responsive promoters.28 In response to DNA damage, p53 is also modified by ATM-mediated ser15 phosphorylation, resulting in increased stability and biochemical activation.29 Elevated p53 levels remained through 48 hours post-PHx in mutant mice, correlating with persistent expression of pChk2 and increased expression of phosphorylated histone protein H2AX (ser139) or γH2AX, a marker representative of double-strand DNA breaks. Elevated p53 in mutant mice also correlates with regulation of several downstream target genes like p21, GADD45, U0126 and MDM2.30 We found a similar induction of p21 in correlation with elevated p53 and hepatocyte DNA synthesis in mutant mice. Previous studies demonstrated the key role of p21 in G1/S phase arrest6 and prolongation of G2/M-phase arrest by way of phosphorylation of Cdk1 at the

Thr14 and Tyr15 inhibitory sites.31 Mitosis occurred by 72 hours after PHx in the mutant mice, correlating with elevated p21 expression, increased Cdk1, and diminished phosphorylation of Cdk1. p53-p21-mediated growth arrest in β2SP mutant mice is also demonstrated with diminished expression and phosphorylation of STAT3, a key mitogen necessary for liver regeneration.32 Further microarray analysis demonstrated significant induction of several p53 high-affinity DNA repair genes, including GADD45 and Cdc6. Interestingly, previous work has also demonstrated that the p53-p21 checkpoint pathway induces accumulation of the growth suppressive, hypophosphorylated, form of pRb (Ser249/Thr252).33 Induction of p53 is not the only factor mediating aberrant cell cycle progression in regenerating β2SP+/− hepatocytes.