Polo-like kinase 1 expression in medullary carcinoma of the thyroid: its relationship with clinicopathological features.

OBJECTIVE: Polo-like kinase 1 (PLK1) is one of the serine-threonine kinases that contributes to cell mitosis and is regarded as a marker of cellular proliferation. However, its protein expression in human carcinoma has not been studied in depth. In this study, we investigated PLK1 expression in medullary thyroid carcinoma by means of immunohistochemistry. METHODS: We immunohistochemically investigated PLK1 expression in 67 cases of medullary thyroid carcinoma. RESULTS: The PLK1 expression level was elevated in 43 of the 67 cases (64.1%). Furthermore, the expression level was directly linked to lymph node metastasis, advanced stage and male sex. All patients who were negative for PLK1 expression are currently alive without tumor recurrence, while 6 of the 43 PLK1-positive patients showed recurrence and 3 have already died of this disease. CONCLUSIONS: These findings suggest that PLK1 expression significantly reflects aggressive characteristics of medullary thyroid carcinoma.     

Cytogenetics and molecular genetics of lung cancer

The development and progression of lung cancer is a multistep process characterized by the accumulation of numerous genetic and epigenetic alterations, some of which occur early in the course of disease. In this review, we summarize cytogenetic imbalances and molecular genetic/epigenetic changes seen in human small-cell and non-small-cell lung cancer. Alterations of tumor suppressor genes and oncogenes leading to perturbations of key cell-regulatory and growth-control pathways are highlighted. The translational implications of molecular biomarkers for risk assessment, early detection, and monitoring of chemoprevention trials are discussed.     

Astroglial responses against Abeta initially occur in cerebral primary cortical cultures: species differences between rat and cynomolgus monkey.

In the present study, we investigated how amyloid beta (Abeta) peptides initially affect neuronal cells in primary cerebral cortical cultures from rat and cynomolgus monkey. In these cultures, complicated interactions between glial and neuronal cells occur; moreover, synaptic interactions similar to those observed in vivo also occur between neuronal cells in these cultures. In this study, we applied low concentrations of Abeta to these well-characterized primary cultures to investigate how Abeta initially affects neurons or astroglial cells. In both rat and monkey cortical cultures, treatment with low concentrations of Abeta failed to drastically change or damage of neurons. Abeta treatment, however, significantly activated astrocytes, resulting in increased apolipoprotein E (ApoE) production. Rat astrocytes were more sensitive to Abeta than monkey astrocytes, and responded to Abeta via a different mechanism. In monkey astrocyte cultures, only direct treatment with Abeta increased ApoE production. In rat astrocyte cultures, however, treatment with conditioned media from cortical cultures grown with Abeta increased ApoE production, indicating that some sort of neuron-derived soluble factor(s) was also involved in activating rat astrocytes. These species differences suggest that monkey cortical cultures would be more useful as an in vitro model system to understand the details of how Abeta accumulates in the human brain, since monkeys are phylogenetically more similar to humans.     

The cyclo-copolymerization of diallyl compounds and sulfur dioxide, 5. Copolymerization of some 4-substituted 1,6-heptadiene derivatives with sulfur dioxide

Copolymers of sulfur dioxide with N-substituted 4-(1,6-heptadiene-4-yl)pyridinium chlorides and bromides ( 1 ) and N-substituted 4-(3-butenyl)pyridinium chlorides and bromides, and some other 1,6-heptadiene derivatives 3 substituted in 4-position were prepared. The effects of the copolymerization conditions on the conversions and viscosities of the copolymers were studied and their structures by elemental analyses, IR and ¹H NMR spectroscopy. The thermal stabilities of the copolymers were also examined.     

Mechanoenergetics characterizing oxygen wasting effect of caffeine in canine left ventricle

Caffeine causes a considerable O(2) waste for positive inotropism in myocardium by complex pharmacological mechanisms. However, no quantitative study has yet characterized the mechanoenergetics of caffeine, particularly its O(2) cost of contractility in the E(max)-PVA-VO(2) framework. Here, E(max) is an index of ventricular contractility, PVA is a measure of total mechanical energy generated by ventricular contraction, and VO(2) is O(2) consumption of ventricular contraction. The E(max)-PVA-VO(2) framework proved to be powerful in cardiac mechanoenergetics. We therefore studied the effects of intracoronary caffeine at concentrations lower than 1 mmol/l on left ventricular (LV) E(max) and VO(2) for excitation-contraction (E-C) coupling in the excised cross-circulated canine heart. We enhanced LV E(max) by intracoronary infusion of caffeine after beta-blockade with propranolol and compared this effect with that of calcium. We obtained the relation between LV VO(2) and PVA with E(max) as a parameter. We then calculated the VO(2) for the E-C coupling by subtracting VO(2) under KCl arrest from the PVA-independent (or zero-PVA) VO(2) and the O(2) cost of E(max) as the slope of the E-C coupling VO(2)-E(max) relation. We found that this cost was 40% greater on average for caffeine than for calcium. This result, for the first time, characterized integratively cardiac mechanoenergetics of the O(2) wasting effect of the complex inotropic mechanisms of intracoronary caffeine at concentrations lower than 1 mmol/l in a beating whole heart.     

Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): Mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor

Congenital insensitivity to pain with anhidrosis (CIPA), also referred to as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self‐mutilating behavior, and mental retardation. The TRKA (NTRK1) gene located on chromosome 1 (1q21‐q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and is the gene responsible for CIPA. Defects in NGF signal transduction at the TRKA receptor lead to failure to support survival of sympathetic ganglion neurons and nociceptive sensory neurons derived from the neural crest. Thirty‐seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal‐transduction domain. Extensive analysis of CIPA mutations and associated intragenic polymorphisms should facilitate detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications. In addition, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure–function relationship in the RTK family. Further, molecular pathology of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans. Hum Mutat 18:462–471, 2001. © 2001 Wiley‐Liss, Inc.     

Physiological characterization of the renal-sympathetic reflex in rabbits

In urethane-anesthetized and vagotomized rabbits, electrical stimulation of the afferent renal nerve (RN) elicited reflex changes in renal nerve activity (RNA) and arterial pressure (AP). The responses were attributable mostly to excitation of nonmyelinated afferent fibers, although, in about 30% of the animals, they were contributed slightly by myelinated afferents. In about 70% of rabbits, the peristimulus time histogram (PTH) of RNA following stimulation of the RN consisted of a long-lasting inhibitory (I) component occasionally accompanied, during its recovery phase, by a transient excitatory (E) component. In these animals, tetanic stimulation of the RN resulted in a depressor response, either alone or, if an E component was present in the PTH, followed by a slight pressor response. In the remaining rabbits, the PTH was composed exclusively of an E component and tetanic stimulation caused a pressor response. Stimulation of the RN evoked reflex changes in cardiac sympathetic discharges comparable to that of RNA, whereas the change in cervical sympathetic discharges was much smaller. The sympathetic response remained intact after a total transection of the rostral medulla near the ponto-medullary junction; the I component was even augmented. However, it usually disappeared following a transection at the high cervical cord. Bilateral lesions of the nucl. tractus solitarius (NTS) near the obex failed to appreciably affect the response. Among chemical and mechanical stimuli examined, nociceptive stimulation of the kidney elicited a sympathetic response comparable to that following nerve stimulation. In conclusion, the renal-sympathetic reflex in rabbits (1) originates predominantly from nonmyelinated afferent renal fibers activated effectively by nociceptive stimulation applied to the kidney; (2) depends critically on medullary structures other than the NTS; and (3) evokes changes of the same temporal pattern but of nonuniform magnitude in sympathetic discharges to different organs.