Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus.

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis.

Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-γ/STAT-1, IL-6/STAT-3, and NF-κB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n = 38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-γ, T-bet, IRF-1, Nox2, IL-33, and eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis.

Repetitive percutaneous epididymal sperm aspirations (PESA's) resulted in asthenospermia and significant inflammation.

INTRODUCTION: In obstructive azoospermia, choosing a sperm retrieval method for intracytoplasmic sperm injection (ICSI) depends on the preference and expertise of both the urologist and the reproductive endocrinologist. Generally, a percutaneous epididymal sperm aspiration (PESA) is attempted first. Not uncommonly, multiple PESA's are necessary. This study utilizes a rat model to provide an understanding of sperm parameter and histological changes resulting from repetitive PESA procedures. MATERIALS AND METHODS: A cohort of 30 male Wistar rats of reproductive age (68-73 days) was divided into three groups of 10 (G1-G3). All three groups underwent a left epididymal head PESA using a 253/8 gauge needle. The untouched right epididymis acted as the control. At 14 day intervals, G2 and G3 underwent a second and third PESA respectively. Fourteen days after the final PESA, both epididymides and a 1 cm segment of both vas deferentia were harvested for sperm and histological evaluations. RESULTS: The percentage of vas specimens with a sperm count ≥ 5 x104/cc was 100%, 22%, and 20% for the G1, G2, G3 PESA samples respectively. Moreover, the percentage of the vas specimens with sperm motility ≥ 10% was 90%, 22%, and 20%, respectively. Epididymal granulomas were not seen in the control side, but formed in 70%, 100%, and 80% of G1, G2, G3 PESA specimens, respectively. CONCLUSIONS: In a rat model, PESA resulted in significant epididymal inflammation and a reduction in both sperm concentration and motility.

Systemic calciphylaxis.

An 11-year-old male developed systemic calciphylaxis during induction therapy for acute lymphoblastic leukemia. His predisposing conditions were hypercalcemia, supplements for pamidronate-induced hypocalcemia and hypophosphatemia and renal insufficiency. He died of cardiorespiratory arrest on the 20th day of induction treatment. Autopsy revealed extensive calcium deposits in the heart, lungs and kidneys. He had diffused alveolar damage, acute tubular necrosis, chronic pancreatitis and marked hepatic steatosis. Systemic calcium deposition may progress rapidly in children with hypercalcemia of malignancy. Since pamidronate reduces mineral resorption from tissues, calcium and phosphate replacements increase systemic mineral deposits. Thus, mineral supplements should be considered only to combat symptoms.

CHTM1, a novel metabolic marker deregulated in human malignancies.

A better understanding of the link between cellular metabolism and tumorigenesis is needed. Here, we report characterization of a novel protein named coiled-coil helix tumor and metabolism 1 (CHTM1). We have found that CHTM1 is associated with cancer and cellular metabolism. CHTM1 localizes to mitochondria and cytosol, and its deficiency in cancer cells results in decreased mitochondrial oxygen consumption and ATP levels as well as oxidative stress indicating mitochondrial dysfunction. CHTM1-deficient cancer cells display poor growth under glucose/glutamine-deprived conditions, whereas cells expressing increased levels of exogenous CHTM1 exhibit enhanced proliferation and survival under similar conditions. CHTM1 deficiency also leads to defects in lipid metabolism resulting in fatty acid accumulation, which explains poor growth of CHTM1-deficient cells under glucose/glutamine deprivation since nutrient deprivation increases dependency on lipids for energy generation. We also demonstrate that CHTM1 mediates its effect via the PKC, CREB, and PGC-1alpha signaling axis, and cytosolic accumulation of CHTM1 during nutrient deprivation appears to be important for its effect on cellular signaling events. Furthermore, analyses of tissue specimens from 71 breast and 97 colon cancer patients show CHTM1 expression to be upregulated in the majority of tumor specimens representing these malignancies. Collectively, our findings are highly significant because CHTM1 is a novel metabolic marker that is important for the growth of tumorigenic cells under limiting nutrient supplies and thus, links cellular metabolism and tumorigenesis.

1500 gram suprarenal mass: a case report.

Adrenocortical carcinoma can have a clinical presentation that mimics a primary renal tumor. We describe a case of a 47-year-old male who presented with flank pain, weight loss, and a 14 cm mass arising from the upper pole of the right kidney on imaging. Upon surgical resection he was found to have a 1500 gram stage II adrenocortical carcinoma. The clinical features, pathologic findings, grading criteria, and differential diagnosis of adrenocortical carcinoma are reviewed.

Dynamic alveolar mechanics in four models of lung injury.

OBJECTIVE: To determine whether pathological alterations in alveolar mechanics (i.e., the dynamic change in alveolar size and shape with ventilation) at a similar level of lung injury vary depending on the cause of injury. DESIGN AND SETTING: Prospective controlled animal study in a university laboratory. SUBJECTS: 30 male Sprague-Dawley rats (300-550 g). INTERVENTIONS: Rats were separated into one of four lung injury models or control (n=6): (a) 2% Tween-20 (Tween, n=6), (b) oleic acid (OA, n=6), (c) ventilator-induced lung injury (VILI, PIP 40/ZEEP, n=6), (d) endotoxin (LPS, n=6). Alveolar mechanics were assessed at baseline and after injury (PaO2/FIO2 <300 mmHg) by in vivo microscopy. MEASUREMENTS: Alveolar instability (proportional change in alveolar size during ventilation) was used as a measurement of alveolar mechanics. RESULTS: Alveoli were unstable in Tween, OA, and VILI as hypoxemia developed (baseline vs. injury: Tween, 7+/-2% vs. 67+/-5%; OA: 3+/-2% vs. 82+/-9%; VILI, 4+/-2% vs. 72+/-5%). Hypoxemia after LPS was not associated with significant alveolar instability (baseline vs. injury: LPS, 3+/-2 vs. 8+/-5%). CONCLUSIONS: These data demonstrate that multiple pathological changes occur in dynamic alveolar mechanics. The nature of these changes depends upon the mechanism of lung injury.

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.

OBJECTIVE: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. METHODS: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-ß2 -glycoprotein I (anti-ß2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control. RESULTS: Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-ß2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-ß2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice. CONCLUSION: In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.

Periampullary and Pancreatic Metastases of Renal Cell Carcinoma: An Underdiagnosed Event.

The National Cancer Institute reports high incidence of renal cell carcinoma (RCC) in the US compared to other regions. However, pancreatic and periampullary metastasis are uncommon when only 17% of the RCC cases metastasize overall. We herein present a case series of four patients with periampullary or pancreatic metastatic disease following complete resection of RCC, evaluating their occurrences and outcomes. We reviewed the cases of four male patients retrospectively, mean age 75 years (range 65 - 87) who had a previous history of nephrectomy for RCC. They experienced recurrence with periampullary (two patients) or pancreatic (two patients) metastatic disease between 0 and 108 months (mean time 41.5 months) following primary tumor resection. In patients with periampullary metastasis, one had asymptomatic presentation with progressive dilatation of the pancreatic duct noted on surveillance CT scans. The other patient had iron deficiency anemia and melena with esophagogastroduodenoscopy (EGD) findings of large fungating infiltrative ulcerating mass in the area of the duodenal papilla (the only patient with metastasis to other sites: lungs and colon). As for those with pancreatic metastasis, one patient presented with hematuria and abdominal pain and was found to have pancreatic metastasis at the time of RCC diagnosis. The other patient was admitted for further workup of a mass in the pancreatic tail upon surveillance. Pathologic findings included high grade RCC in the metastatic foci. Management of such patients included: distal pancreatectomy in two patients without chemoradiation, one was awaiting Whipple procedure and received four cycles of sunitinib, while the last was a poor surgical candidate and received aminocaproic acid. Three patients are still alive to date. Optimal management is challenging given the very high risk of delayed relapse following tumor resection of the localized disease, leaving such cases with a very poor prognosis. Therefore to enhance survival, it is imperative to have careful stage-dependent surveillance in patients who have undergone a prior resection of RCC. We emphasize the importance of raising awareness for this unusual presentation. Disease recurrence as a pancreatic mass or hepatobiliary ductal dilatation might be more frequent than previously reported.

Preoperative cross-sectional imaging allows for avoidance of unnecessary adrenalectomy during RCC surgery.

OBJECTIVES: To assess the frequency of adrenal involvement and the reliability of preoperative imaging to predict adrenal involvement in patients treated for cortical renal masses at a single institution. METHODS: Using a retrospective pathology database, we identified 117 consecutive patients who underwent radical nephrectomy and concomitant ipsilateral adrenalectomy at our institution over the course of 2 decades. Patient demographics, tumor characteristics, and radiographic results were obtained for analysis. RESULTS: Of 117 patients, only 6 (5.1%) were identified as having adrenal involvement. The average age of the patient was 58.3 years, and the average tumor size was 7.13 cm. The mean tumor size in patients without adrenal involvement was 6.79 cm, whereas in those with adrenal involvement, it was 9.62 cm (P = 0.057). Of 6 patients with adrenal involvement, 5 had imaging studies available for review, and all 5 demonstrated suspicion for adrenal involvement preoperatively. Among 111 patients without adrenal involvement, 53 (47.7%) had imaging available for review, with only 3 (5.7%) demonstrating suspicion for adrenal involvement. The negative predictive value was 100%, whereas the sensitivity and specificity were 100% and 94.3%, respectively. CONCLUSIONS: Ipsilateral adrenal involvement in renal cell carcinoma is uncommon and reliably predicted by preoperative cross-sectional imaging. Among all adrenalectomies in this series, nearly 95% were performed unnecessarily. With careful review, preoperative imaging can help avoid unnecessary adrenalectomy during radical nephrectomy in patients with renal cortical tumors.

c-Abl Mediated Tyrosine Phosphorylation of Aha1 Activates Its Co-chaperone Function in Cancer Cells.

The ability of Heat Shock Protein 90 (Hsp90) to hydrolyze ATP is essential for its chaperone function. The co-chaperone Aha1 stimulates Hsp90 ATPase activity, tailoring the chaperone function to specific "client" proteins. The intracellular signaling mechanisms directly regulating Aha1 association with Hsp90 remain unknown. Here, we show that c-Abl kinase phosphorylates Y223 in human Aha1 (hAha1), promoting its interaction with Hsp90. This, consequently, results in an increased Hsp90 ATPase activity, enhances Hsp90 interaction with kinase clients, and compromises the chaperoning of non-kinase clients such as glucocorticoid receptor and CFTR. Suggesting a regulatory paradigm, we also find that Y223 phosphorylation leads to ubiquitination and degradation of hAha1 in the proteasome. Finally, pharmacologic inhibition of c-Abl prevents hAha1 interaction with Hsp90, thereby hypersensitizing cancer cells to Hsp90 inhibitors both in vitro and ex vivo.

Characterization of prostate cancer missed by sextant biopsy.

There is a trend to increase the number of prostate biopsies taken to increase the detection rate of prostate cancer. We examined radical prostatectomy specimens and correlated the findings to those of preoperative sextant biopsy in an effort to identify the characteristics of tumors that went undetected by our biopsy regimen. Seventy-one patients diagnosed with prostate cancer based on sextant biopsy who underwent radical prostatectomy at our institution from June 1995 to November 2001 had prostatectomy specimens and biopsy slides reviewed. These specimens were step-sectioned and whole-mounted. The location, size, and grade of individual cancer foci in the prostatectomy specimens were correlated with results of the original sextant biopsies. Clinically significant tumors were defined as those with volume > 0.5 mL or Gleason score > or= 7 and extracapsular extension. In 33 patients (46%), there was concordance of biopsy and prostatectomy findings. In 38 patients (54%), additional lesions were demonstrated in the prostatectomy specimens that were not detected by our sextant biopsies. These included 13 cases (34%) with tumors > 0.5 mL and 25 cases in which the lesions were < 0.5 mL in size. However, 7 of these cases contained tumors with Gleason score > or =7. Tumors were located in the transition zone in 8 of these 38 cases (21%), and the remaining tumors were located in the peripheral zone (79%). No tumors with extracapsular extension were missed. Thus, 20 of the 71 cases (28%) had clinically significant cancers that went undetected by the traditional sextant biopsy method. Greater than 50% of patients who underwent sextant biopsy of the prostate had additional tumors that were missed when compared to the pathologic specimen. As many as 28% of these patients had clinically significant cancer based on size and grade criteria. A strategy of increased numbers of biopsies would improve the detection rate of these clinically important tumors. However, the ideal strategy for optimizing cancer detection requires further investigation because increased numbers of biopsies would also increase detection of clinically insignificant tumors.

Diagnosis of calcium pyrophosphate dihydrate deposition disease by fine needle aspiration biopsy: a case report.

BACKGROUND: Calcium pyrophosphate dihydrate deposition disease is a relatively rare disease with variable clinical presentations. CASE: A 73-year-old man presented with worsening lower back pain and fever. Fine needle aspiration biopsy of the lumbar vertebral bodies (L3-L4) revealed abundant neutrophils admixed with small, birefringent, rhomboid crystals in Diff-Quik-stained smears. These crystals were confirmed as calcium pyrophosphate dihydrate on cell block sections. A diagnosis of osteomyelitis and calcium pyrophosphate dihydrate deposition disease was rendered. The patient was treated with antibiotics and responded well. CONCLUSION: Calcium pyrophosphate dihydrate deposition disease can be diagnosed by fine needle aspiration biopsy, and an accurate diagnosis can be greatly facilitated by cell block sections. However, such a diagnosis may be neglected if the specimen is not carefully inspected.

Polymorphism in the SCN9A voltage-gated sodium channel gene associated with interstitial cystitis/bladder pain syndrome.

OBJECTIVE: To determine whether an association exists between interstitial cystitis/bladder pain syndrome (IC/BPS) and a nonsynonymous single nucleotide polymorphism in the SCN9A voltage-gated sodium channel gene previously associated with other chronic pain syndromes. MATERIALS AND METHODS: Germline deoxyribonucleic acid was sampled from archived bladder biopsy specimens from patients with a documented diagnosis of IC/BPS. Deoxyribonucleic acid from hysterectomy specimens was obtained as a control population. The genotype of single nucleotide polymorphism rs6746030 was determined by deoxyribonucleic acid sequencing after polymerase chain reaction amplification. Contingency analysis of genotypes was performed using Pearson's chi-square test and Fisher's exact test. RESULTS: Polymerase chain reaction product was obtained from 26 of 31 control specimens and from 53 of 57 IC/BPS biopsy specimens. Of the 26 control subjects, 3 (11.5%) were genotype AG and 23 were GG. In contrast, AA or AG genotypes were present in 21 of 53 (39.6%) patients with IC/BPS, a statistically significant difference compared with the controls (Pearson's chi-square, P=.036). Similarly, the A allele was at a greater frequency in the IC/BPS group using Fisher's exact test (P=.009). CONCLUSION: These data strongly suggest that pain perception in at least a subset of patients with IC/BPS is influenced by this polymorphism in the SCN9A voltage-gated sodium channel.

Immune markers and differential signaling networks in ulcerative colitis and Crohn's disease.

BACKGROUND: Cytokine signaling pathways play a central role in the pathogenesis of inflammatory bowel disease (IBD). Ulcerative colitis (UC) and Crohn's disease (CD) have unique as well as overlapping phenotypes, susceptibility genes, and gene expression profiles. This study aimed to delineate patterns within cytokine signaling pathways in colonic mucosa of UC and CD patients, explore molecular diagnostic markers, and identify novel immune mediators in IBD pathogenesis. METHODS: We quantified 70 selected immune genes that are important in IBD signaling from formalin-fixed, paraffin-embedded (FFPE) colon biopsy samples from normal control subjects and UC and CD patients having either severe colitis or quiescent disease (n = 98 subjects). We utilized and validated a new modified real-time reverse-transcription polymerase chain reaction (RT-PCR) technique for gene quantification. RESULTS: Expression levels of signaling molecules including IL-6/10/12/13/17/23/33, STAT1/3/6, T-bet, GATA3, Foxp3, SOCS1/3, and downstream inflammatory mediators such as chemokines CCL-2/11/17/20, oxidative stress inducers, proteases, and mucosal genes were differentially regulated between UC and CD and between active and quiescent disease. We also document the possible role of novel genes in IBD, including SHP-1, IRF-1,TARC, Eotaxin, NOX2, arginase I, and ADAM 8. CONCLUSIONS: This comprehensive approach to quantifying gene expression provides insights into the pathogenesis of IBD by elucidating distinct immune signaling networks in CD and UC. Furthermore, this is the first study demonstrating that gene expression profiling in FFPE colon biopsies might be a practical and effective tool in the diagnosis and prognosis of IBD and may help identify molecular markers that can predict and monitor response to individualized therapeutic treatments.

Intracranial aneurysms in klippel-trenaunay/weber syndromes: case report.

OBJECTIVE: We present a comprehensive review of intracranial aneurysms in Klippel-Trenaunay and Klippel-Trenaunay-Weber syndromes (KTS/KTWS), and examine factors influencing the risks of surgery vs conservative management. CLINICAL PRESENTATION: A 58-year-old physician with KTS affecting the right extremities presented with left hemispheric cerebellar stroke and was discovered to harbor four intracranial aneurysms of the posterior circulation: fusiform mid and distal BA (2.6 x 2 x 2 cm), fusiform right proximal P1 (2 x 1.3 x 1.3 cm), fusiform right distal P1 (2.8 x 2.7 x 2 cm), and saccular left distal posterior inferior cerebellar artery (2.5 x 2.5 x 2.5 cm). Ten years later he had an infarct in the paramedian distribution of the basilar artery and a right internal capsule stroke. Two months later, he developed hydrocephalus, ultimately presenting in status epilepticus 4 months later secondary to ongoing aneurysm expansion and mass effect. INTERVENTION: Systemic anticoagulation for acute thrombosis with possible distal arterioarterial embolization from giant P1 aneurysms. Ventriculoperitoneal shunting for hydrocephalus. The patient died within 9 days after admission and 10 years after the initial discovery of aneurysms. CONCLUSION: Strict control of modifiable risk factors compromising vascular integrity and periodic neuroimaging are warranted in KTS/KTWS patients. KTS/KTWS patients are hypercoagulable, and may be predisposed to aneurysm thrombosis with increased risk for distal arterial microembolization. Stroke-related morbidity secondary to distal arterioarterial aneurysm thrombus embolization and acute aneurysm thrombosis may be decreased with systemic anticoagulation in this patient population. KTS/KTWS patients have significantly higher rates of DVT and PE than the general population, and should be classified in the high-risk category for venous thromboembolism prophylaxis. Both endovascular and open cerebrovascular techniques have been used successfully in KTS/KTWS patients with intracranial aneurysms.

The spectrum of eosinophilic cystitis in males: case series and literature review.

CONTEXT: Eosinophilic cystitis (EC) is an inflammatory condition of the bladder that has been linked to food allergens, infectious agents, drugs, and other genitourinary conditions. Like interstitial cystitis, EC has a strong female predominance. It is characterized by an intense eosinophilic infiltrate in the acute phase and fibrosis in the chronic phase. OBJECTIVES: To document and focus on specific features of EC in males and highlight the relationship between clinical and histopathologic findings. DESIGN: The bladder biopsies of male patients were reviewed. Eight cases of EC were selected. RESULTS: Several known associations were noted as well as unreported features and associations such as Charcot-Leyden crystals, celiac disease, lupus anticoagulant, and additional viral and bacterial agents. CONCLUSIONS: Eosinophilic cystitis represents a response to a variety of agents and may often be overlooked. The temporally biphasic morphologic features are the hallmark of this condition. Because clinical and imaging studies are not specific, a high index of clinical suspicion is often crucial to the correct diagnosis and proper management of EC.

Prevention of hepatocarcinogenesis and increased susceptibility to acetaminophen-induced liver failure in transaldolase-deficient mice by N-acetylcysteine.

Although oxidative stress has been implicated in acute acetaminophen-induced liver failure and in chronic liver cirrhosis and hepatocellular carcinoma (HCC), no common underlying metabolic pathway has been identified. Recent case reports suggest a link between the pentose phosphate pathway (PPP) enzyme transaldolase (TAL; encoded by TALDO1) and liver failure in children. Here, we show that Taldo1-/- and Taldo1+/- mice spontaneously developed HCC, and Taldo1-/- mice had increased susceptibility to acetaminophen-induced liver failure. Oxidative stress in Taldo1-/- livers was characterized by the accumulation of sedoheptulose 7-phosphate, failure to recycle ribose 5-phosphate for the oxidative PPP, depleted NADPH and glutathione levels, and increased production of lipid hydroperoxides. Furthermore, we found evidence of hepatic mitochondrial dysfunction, as indicated by loss of transmembrane potential, diminished mitochondrial mass, and reduced ATP/ADP ratio. Reduced beta-catenin phosphorylation and enhanced c-Jun expression in Taldo1-/- livers reflected adaptation to oxidative stress. Taldo1-/- hepatocytes were resistant to CD95/Fas-mediated apoptosis in vitro and in vivo. Remarkably, lifelong administration of the potent antioxidant N-acetylcysteine (NAC) prevented acetaminophen-induced liver failure, restored Fas-dependent hepatocyte apoptosis, and blocked hepatocarcinogenesis in Taldo1-/- mice. These data reveal a protective role for the TAL-mediated branch of the PPP against hepatocarcinogenesis and identify NAC as a promising treatment for liver disease in TAL deficiency.

Putative precursors of gallbladder dysplasia: a review of 400 routinely resected specimens.

CONTEXT: Dysplasia is thought to be a precursor of invasive gallbladder carcinoma, but it is unsettled whether dysplasia arises from other precursor lesions. OBJECTIVE: To ascertain the presence and nature of precursors of dysplasia in the gallbladder. DESIGN: Four hundred consecutive cholecystectomy specimens were processed and stained routinely for diagnosis. We retrospectively reviewed these cases to look for the presence of epithelial changes, including antral-type metaplasia, intestinal metaplasia, and dysplasia. RESULTS: Antral-type metaplasia, intestinal metaplasia, and dysplasia were found in 238 (59.5%), 39 (9.8%), and 20 (5.0%) cases, respectively. The mean patient age was 47.7 years (range, 15-93 years). The mean ages for patients with antral-type metaplasia, intestinal metaplasia, and dysplasia were 49.4, 50.9, and 52.6 years, respectively. Statistically significant associations were found between antral-type metaplasia and intestinal metaplasia (P = .007, chi2 test) and between intestinal metaplasia and dysplasia (P < .001, chi2 test). CONCLUSION: These associations, along with the age gradient from antral-type metaplasia to dysplasia, suggest a progression from antral-type metaplasia to dysplasia via intestinal metaplasia.