Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers

Park SW, Chung NG, Hur SY, Kim HS, Yoo NJ, Lee SH. Mutational analysis of hypoxia‐related genes HIF1α and CUL2 in common human cancers. APMIS 2009; 117: 880–5. Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia‐inducible factor 1α (HIF1α) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1α is upregulated not only by hypoxia but also by genetic alterations in HIF1α‐related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL‐elongin B‐elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1α. The aim of this study was to explore whether HIF1α and CUL2 genes are somatically mutated, and contribute to HIF1α activation in common human cancers. For this, we have analyzed the coding region of oxygen‐dependent degradation domain of HIF1α in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single‐strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1α mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1α is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1α nor CUL2 mutation may play a central role in HIF1α activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias.     

Reversible,Complete Atrioventricular Block Caused by Primary Cardiac Lymphoma in a Nonimmunocompromised Patient

PCL in a Nonimmunocompromised Patient Primary cardiac lymphoma (PCL) is a rare entity that commonly presents as a heart rhythm disorder. We describe a previously healthy, immunocompetent patient presenting with complete atrioventricular block (AVB). The patient was found to have a cardiac mass on magnetic resonance imaging and underwent percutaneous biopsy eventually diagnosing PCL. After pacemaker implantation, the patient's tumor responded rapidly to chemotherapy and the AVB completely resolved. In otherwise healthy patients presenting with AV block, cardiac tumor should be considered. Additionally, if PCL is diagnosed and the patient is clinically stable with AVB, it may be reasonable to delay pacemaker implantation until the clinical response to chemotherapy is evaluated. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1386‐1389, December 2012)     

Rosmarinic Acid Induces Apoptosis of Activated T Cells from Rheumatoid Arthritis Patients via Mitochondrial Pathway

T cells play an important role in the initiation and the progression of rheumatoid arthritis (RA) and depletion of potentially pathogenic T cells was suggested as an important therapeutic protocol. We determined if rosmarinic acid (RosA), known as a secondary metabolite from herbal plants, had apoptotic activity toward T cells from RA patients and further verified target T-cell subsets. CD3(+)CD25(+) activated T-cell subsets from most of the RA patients displayed significantly higher apoptosis rates than did the PBMCs and total CD3(+) T cells. Furthermore, activated and effector CD4(+) T cells, including CD4(+)CD25(+) and CD4(+)CD45RO(+) T cells, had a tendency of being more susceptible to RosA-induced apoptosis than that of resting and na?ve T-cell subsets. RosA induced the release of cytochrome c from mitochondria and the blockage of mitochondrial depolarization inhibited apoptosis. Taken together, these results suggest that RosA induces apoptosis of activated T-cell subsets from RA patients via a mitochondrial pathway.     

The Atrial Electrogram During Clinical Electrophysiologic Studies: Onset versus the Local/Intrinsic Deflection

The Local Atrial Deflection. Introduction : As a wave front passes unfiltered bipolar recording electrodes, the point of local depolarization is marked by a maximal change in voltage, i.e., the intrinsic deflection. However, during electrophysiologic studies, the depolarization (A) on the lead recording the His-bundle potential traditionally has been measured at the first rapid reproducible deflection on a filtered electrogram. This methodology permits considerable latitude for subjective interpretation. The purpose of this study was to assess the timing of the atrial electrogram using the intrinsic deflection of relatively unfiltered electrograms (0.1-4.0 to 1,250 Hz) or the equivalent on filtered recordings. Methods and Results : To do this we studied 70 patients without evidence of atrial or atrioventricular (AV) nodal disease, documenting the difference in timing between the A wave as traditionally measured and as measured at its peak local deflection (A_L) determined from simultaneously recorded filtered and relatively unfiltered electrograms. New ranges based on the A_L were established for timing of intra-atrial and AV nodal conduction intervals. The P-A (41 ± 11 msec) was significantly shorter than the P-A_L (55 ± 12) and the A-H (80 ± 20) was longer than the A_L-H (66 ± 21 msec), both P <0.001. Interobserver differences in measurements were smaller when using the local (A_L) rather than traditional criteria. Conclusions : Conventional measurement of the A deflection provides only a rough estimate of local depolarization of the atrium near the AV node. The criteria proposed in the present article may (1) provide a better estimate of the timing of local depolarization; (2) have application in computerized timing of intervals; and (3) decrease technical problems and subjective error.     

Decrease in bispectral index prior to cardiovascular collapse during Caesarean sections

We report a case of significant reduction in bispectral index (BIS) associated with suspected amniotic fluid embolism (AFE) that occurred prior to change in haemodynamic variables. The patient was a 29‐year‐old nulliparous, who was admitted for Caesarean section under general anaesthesia in the 33rd week of pregnancy. After the baby was born, the BIS value suddenly decreased to 0, with suppression ratio of 100. One minute later, saturation decreased abruptly to 85%, end‐tidal carbon dioxide (EtCO₂) decreased to 5 mmHg, peak inspiratory pressure increased to 35 cm H₂O, and non‐invasive blood pressure (BP) failed to obtain a reading. After administration of vasoactive drugs, the systolic BP was maintained at 100 mmHg or higher, the BIS value rose to 10–20, and the EtCO₂ increased to 24–33 mmHg. In this case, the BIS monitoring may provide an earlier warning of impending cardiovascular collapse in the case of AFE.