Research Spotlight

Posted February 15th 2019

Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.

Teodoro Bottiglieri Ph.D.

Teodoro Bottiglieri Ph.D.

Arora, K., J. M. Sequeira, J. M. Alarcon, B. Wasek, E. Arning, T. Bottiglieri and E. V. Quadros (2019). “Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.” FASEB J 33(2): 2563-2573.

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In humans, vitamin B12 deficiency causes peripheral and CNS manifestations. Loss of myelin in the peripheral nerves and the spinal cord (SC) contributes to peripheral neuropathy and motor deficits. The metabolic basis for the demyelination and brain disorder is unknown. The transcobalamin receptor-knockout mouse ( Cd320(-/-)) develops cobalamin (Cbl) deficiency in the nervous system, with mild anemia. A decreased S-adenosylmethionine: S-adenosylhomocysteine ratio and increased methionine were seen in the brain with no significant changes in neurotransmitter metabolites. The structural pathology in the SC presented as loss of myelin in the axonal tracts with inflammation. The sciatic nerve (SN) showed increased nonuniform, internodal segments suggesting demyelination, and remyelination in progress. Consistent with these changes, the Cd320(-/-) mouse showed an increased latency to thermal nociception. Further, lower amplitude of compound action potential in the SN suggested that the functional capacity of the heavily myelinated axons were preferentially compromised, leading to loss of peripheral sensation. Although the metabolic basis for the demyelination and the structural and functional alterations of the nervous system in Cbl deficiency remain unresolved, the Cd320(-/-) mouse provides a unique model to investigate the pathologic consequences of vitamin B12 deficiency. -Arora, K., Sequeira, J. M., Alarcon, J. M., Wasek, B., Arning, E., Bottiglieri, T., Quadros, E. V. Neuropathology of vitamin B12 deficiency in the Cd320(-/-) mouse.


Posted February 15th 2019

Lynch-like syndrome is as frequent as Lynch syndrome in early-onset non-familial non-polyposis colorectal cancer.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Antelo, M., M. Golubicki, E. Roca, G. Mendez, M. Carballido, S. Iseas, M. Cuatrecasas, L. Moreira, A. Sanchez, S. Carballal, A. Castells, C. R. Boland, A. Goel and F. Balaguer (2019). “Lynch-like syndrome is as frequent as Lynch syndrome in early-onset non-familial non-polyposis colorectal cancer.” Int J Cancer Jan 29. [Epub ahead of print].

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Early-onset (<50 years-old) non-polyposis non-familial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC<50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.


Posted February 15th 2019

The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.

Binu Tharakan, Ph.D.

Binu Tharakan, Ph.D.

Anasooya Shaji, C., B. D. Robinson, A. Yeager, M. R. Beeram, M. L. Davis, C. L. Isbell, J. H. Huang and B. Tharakan (2019). “The Tri-phasic Role of Hydrogen Peroxide in Blood-Brain Barrier Endothelial cells.” Sci Rep 9(1): 133.

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Hydrogen peroxide (H2O2) plays an important role physiologically as the second messenger and pathologically as an inducer of oxidative stress in injury, ischemia and other conditions. However, it is unclear how H2O2 influences various cellular functions in health and disease differentially, particularly in the blood-brain barrier (BBB). We hypothesized that the change in cellular concentrations of H2O2 is a major contributor in regulation of angiogenesis, barrier integrity/permeability and cell death/apoptosis in BBB endothelial cells. Rat brain microvascular endothelial cells were exposed to various concentrations of H2O2 (1 nM to 25 mM). BBB tight junction protein (zonula ocludens-1; ZO-1) localization and expression, cytoskeletal organization, monolayer permeability, angiogenesis, cell viability and apoptosis were evaluated. H2O2 at low concentrations (0.001 muM to 1 muM) increased endothelial cell tube formation indicating enhanced angiogenesis. H2O2 at 100 muM and above induced monolayer hyperpermeability significantly (p < 0.05). H2O2 at 10 mM and above decreased cell viability and induced apoptosis (p < 0.05). There was a decrease of ZO-1 tight junction localization with 100 mum H2O2, but had no effect on protein expression. Cytoskeletal disorganizations were observed starting at 1 mum. In conclusion H2O2 influences angiogenesis, permeability, and cell death/apoptosis in a tri-phasic and concentration-dependent manner in microvascular endothelial cells of the blood-brain barrier.


Posted February 15th 2019

A Rare Case of Cutaneous Metastases Secondary to Hepatocellular Carcinoma.

Ranjeeta Bahirwani M.D.

Ranjeeta Bahirwani M.D.

Alsahhar, J. S., R. Idriss and R. Bahirwani (2019). “A Rare Case of Cutaneous Metastases Secondary to Hepatocellular Carcinoma.” Clin Gastroenterol Hepatol 17(3): e17.

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A 54-year-old man presented with a 2-month history of an abdominal rash, initially small papules over the epigastrium that spread medially and subsequently becoming painful. His past medical history included decompensated hepatitis C cirrhosis with hepatocellular carcinoma (HCC) BCLC stage B diagnosed 1 year before presentation (3 lesions, largest measuring 5 cm). He underwent chemoembolization followed by cyberknife radiation 6 months before the current presentation. Physical examination revealed a Sister Mary Joseph nodule surrounded by erythematous tender subcutaneous nodules. His serum α-fetoprotein was 1000 ng/mL. Given the high suspicion for metastases, punch biopsy of a nodule was performed revealing anastomosing cords of highly atypical cells with enlarged hyperchromatic pleomorphic nuclei and atypical mitoses, consistent with high-grade adenocarcinoma of hepatobiliary origin. The patient died of liver failure 2 weeks after presentation. Extrahepatic metastases occur in up to a third of HCC cases, lung being the most common metastatic site. Metastases to skin are rare , primarily occurring because of direct seeding of the tumor at sites of biopsies or biliary drains. Our case highlights an atypical presentation of HCC cutaneous metastases and the importance of biopsy to differentiate HCC from other malignancies with similar presentations. (Text of this image study, p. e17.)


Posted February 15th 2019

An Atypical Biliary Fistula In A Liver Transplant Recipient.

Robert S. Rahimi M.D.

Robert S. Rahimi M.D.

Alsahhar, J. S., D. Hansen, J. Page, U. Sandkovsky, S. Burdick, J. Trotter and R. S. Rahimi (2019). “An Atypical Biliary Fistula In A Liver Transplant Recipient.” Liver Transpl Jan 28. [Epub ahead of print].

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A 55-years-old Caucasian male presented with chest pain, dyspnea and hypotension four-months after simultaneous liver and kidney transplantation. His post-transplant course was complicated with only one episode of acute cellular rejection one month prior to presentation, successfully treated with steroids. His immunosuppression consisted of tacrolimus and mycophenolic acid. Transthoracic echocardiogram (TTE) in the emergency room showed a large pericardial effusion and tamponade physiology. Emergent pericardiocentesis removed 560 mL of bloody fluid (red blood cell count of 6.74 million) and a pericardial drain was placed. Fluid studies including bacterial, fungal, and acid-fast bacilli cultures, viral PCR (herpes simplex, adenovirus, human herpesvirus 6, cytomegalovirus), histoplasma, coccidioides antigens, and cytology were negative.