Thrombopoietin: biology and potential clinical applications

After an almost 40-year search for a primary regulatory of platelet production, thrombopoietin has recently been purified and cloned. Thrombopoietin regulates all stages in the production of platelets by promoting both the proliferation of megakaryocyte progenitors and their maturation into platelet-producing megakaryocytes. In preclinical studies in normal mice and non-human primates, administration of thrombopoietin resulted in a rapid rise in platelet counts to levels previously unattainable with other thrombopoietic cytokines. In myelosuppressed animal models, use of thrombopoietin following chemotherapy, radiation, or stem-cell transplantation accelerated megakaryocyte and platelet recovery. Thrombopoietin has rapidly moved from the laboratory to the clinic in the last 3 years. Preliminary results of clinical trials using truncated or full-length forms of the molecule indicate that thrombopoietin is a powerful stimulus in the production of megakaryocytes and normal platelets in humans and enhances platelet recovery following chemotherapy. Although the peripheral effect is selective on platelet lineage, thrombopoietin mediates stimulatory effects on progenitors of multiple cell lineages at the bone marrow level and mobilizes progenitor cells into the peripheral blood. These biological effects suggest that thrombopoietin holds promise as a useful agent for the prevention and treatment of thrombocytopenia in cancer patients and for other disorders of thrombocytopenia.     

The molecular and cellular biology of pancreatic cancer

Adenocarcinoma of the pancreas carries a grave prognosis for affected patients. Certain oncogenes (K-ras and HER-2/neu) are mutated in a large proportion of these aggressive tumors. Adenocarcinoma of the pancreas has also been associated with loss of tumor suppressor genes (p53, DPC4, p16/MTS), either by deletion or by mutation and loss of function. Growth factors (EGF, TGF-alpha, HGF) and growth factor receptors (EGF-R, c-met, CCK) are expressed at levels not found in the normal pancreas. Finally, factors important for angiogenesis (FGF, integrins, selectins) are likely to play an important role in the growth and metastasis of clinically relevant tumors. This review attempts to summarize and assimilate current research into the molecular and cellular biology of pancreatic cancer.     

Telomerase in cancer: clinical applications

The biology of telomeres and telomerase has been the subject of intensive investigative effort since it became evident that they play a significant role in two important biological processes, the loss of cellular replicative capacity inherent to organismal ageing and the unrestricted cell proliferation characteristic of carcinogenesis. Telomere shortening in normal cells is a result of DNA replication events, and reduction beyond a critical length is a signal for cellular senescence. One of the cellular mechanisms used to overcome proliferative restriction is the activation of the enzyme telomerase, which replaces the loss of telomeric DNA that occurs at each cell division. Studies have demonstrated that tumours have shorter telomeres than normal tissue and that telomerase is activated in up to 90% of all human cancers while it is present only in a limited range of normal adult tissues. The role of telomerase in the extension of the cellular replicative lifespan has recently been shown by ectopic expression of the enzyme, being consistent with the oncogenesis model whereby the acquisition of an 'immortal' phenotype is a requirement for advanced tumour progression. In this article we review the present knowledge of telomeres and telomerase in cancer and discuss the potential use of this enzyme as a diagnostic and prognostic tumour marker and as a target for cancer therapy.     

Vitamin D-retinoid association: molecular basis and clinical applications

BACKGROUND AND PURPOSE: The role of single-photon emission CT (SPECT) in the prognosis of cerebral infarction is controversial, but most studies report that SPECT using a variety of radiopharmaceutical agents gives useful prognostic information. Only one study has questioned whether acute perfusion deficits independently add to a valid clinical prognostic score. This study was limited to middle cerebral artery territory infarcts and was negative. We present data on the prognostic utility of SPECT using 99mTc-hexamethylpropyleneamine oxime (HMPAO) in cerebral infarction, unselected by site. METHODS: Fifty consecutive unselected patients admitted to the hospital with acute cerebral infarction, of whom 10 died and 7 withdrew, had SPECT performed serially at onset and at 1 week and 3 months after stroke onset using 99mTc-HMPAO and the NOVO 810 dedicated high-resolution head tomograph. Clinical severity at presentation and outcome was measured with the Canadian Neurological Scale and the Barthel Index. Infarct volumes were measured from both the SPECT and CT scans. The data for the 43 subjects who completed the study or died were evaluated to determine the most powerful prognostic measures. Predictors were the Canadian Neurological Scale score at onset and 1 week, the Barthel Index at 1 week, the CT infarct volume typically done between 3 and 7 days after stroke onset, and the infarct volumes at the first and second SPECT. Outcome measures were the Canadian Neurological Scale score and Barthel Index score at 3 months, scored as zero for those patients who died. RESULTS: The clinical prognostic indicators correlated with the outcome measures, with coefficients between .617 and .821 (P < .0006 in all cases). The Canadian Neurological Scale score measured at 1 week was the best of these. Infarct volumes measured from SPECT correlated less well (coefficients between -.518 and -.683, P < .0019 in all cases). CT infarct volume was the poorest predictor. Although SPECT infarct volumes predicted outcome, they did so less well than clinical examination. Spontaneous infarct reperfusion did not affect outcome. CONCLUSIONS: Although the measurement of infarct volume on SPECT using 99mTc-HMPAO provides a predictor of stroke outcome, it is not a better predictor than the Canadian Neurological Scale score.     

New contributions to clinical hypertension from molecular biology

The authors constructed a new dynamic guiding splint assisting the active mobilisation after flexor tendon repair distal to the wrist. In these cases, the "inverse" wrist position seems to be the best position for mobilisation. This means that finger flexion should be carried out during wrist extension, and finger extension during wrist flexion. The splint guides and co-ordinates the movements of the wrist and the fingers, and it limits the free usage of the hand.     

Peripheral blood stem cells in acute myeloid leukemia: biology and clinical applications

Fifteen persons with profound mental retardation were divided into two groups. One group was identified with chronic training needs by habilitative staff and the other group served as a control. In an attempt to identify a reinforcer, each participant received a preference assessment and a simple, low-effort treatment procedure. In Experiment 1, only individuals who approached at least one stimulus on 80% or more of the preference assessment trials ("high preference") showed reinforcement effects in treatment. However, three individuals showing high preference failed to show treatment effects. All persons identified with chronic training needs failed to show reinforcement effects. Experiment 2 analyzed characteristics of the two groups and found significant differences in overall movement and response latency. Limitations of the current reinforcement technology were apparent for identifying reinforcers in the group with chronic training problems. Research is suggested for evaluating training alternatives for people with profound multiple disabilities who move very little or who respond with very long latencies.     

The molecular biology of bladder carcinoma

OBJECTIVE: The clinical course of transitional cell carcinoma of the bladder can be difficult to predict due to its potential to invade the muscle layer and/or develop to a high grade lesion. Bladder carcinoma can arise from genetic changes that may activate the oncogenes (-c-erbB2, c-erbB1, c-myc, ras, etc.) and/or inactivate the suppressor genes (p53, Rb). The aim of the present study is to continue a study protocol on the molecular biology of bladder tumors. METHODS/RESULTS: From January, 1993 to January, 1995, 85 patients were studied. These patients were divided into two groups: the first group comprised 14 controls of urothelial tissue and the second comprised 65 cases of transitional cell carcinoma of the bladder. p53 expression was determined by an immunohistochemical method (NCL-p53-DO7 monoclonal antibody). Quantification of the p8 oncoprotein in cytosol and EGFR (epidermal growth factor receptor) in membrane was performed by ELISA (Oncogene Science) and RIA (Vienna Lab), respectively. A statistically significant relationship between the expression of p53 and EGFR with tumor stage and grade was found. Quantification of p185 and EGFR showed higher values in the tumor tissue than in the control samples, but a worse survival could not be determined. CONCLUSIONS: The present study shows that p53 expression can be considered to be a prognostic factor. It provides useful information on the aggressive behaviour of the tumor and has a direct relation with the survival rates.     

The molecular biology of chitin digestion

A beneficial effect in blood pressure control is presumed for patients on an intensive preoperative antihypertensive regimen who undergo empiric renal revascularization. Nonetheless, a noticeable decline in surgical cure rates for hypertension has been recently observed in patients with generalized atherosclerosis. The outcome of patients on multiple preoperative antihypertensive agents who underwent combined aortic and renal artery reconstruction was reviewed. The study population comprised 43 patients who underwent concomitant renal artery and aortic reconstruction for atherosclerotic disease between 1983 and 1995 and who were taking two or more antihypertensive medications and had a serum creatinine of less than or equal to 1.7 mg/dL. Operative management included an aortic reconstruction with either unilateral (n = 22) or bilateral (n = 19) aortorenal bypass or renal endarterectomy (n = 2). Operative mortality was 4.7% (2 of 43). The estimated 5-yr probability of survival was 83% (95% C.I. 0.70, 0.99). Late follow-up data on blood pressure control were available for review in 32 patients at a median follow-up of 37 months. Hypertension was cured in 1 (3%) and improved in an additional 15 (47%) patients. The numbers of antihypertensive medications taken preoperatively (mean = 2.7) declined at late follow-up (mean = 1.6). Notably, the largest reduction was observed with beta blockers (p = 0.006), central sympatholytics (p = 0.041), and angiotensin converting enzyme (ACE) inhibitors (p = 0.052). The number of preoperative antihypertensive medications was not significantly related to survival or to blood pressure improvement. However, uncontrolled preoperative hypertension despite antihypertensive therapy was associated with a favorable blood pressure response to operation (p < 0.001). Patients on an intensive antihypertensive regimen can safely undergo concomitant renal artery and aortic reconstruction for the empiric management of hypertension. Poorly controlled preoperative hypertension in the presence of multiple antihypertensive agents is a favorable marker for improved postoperative blood pressure control.     

The alleged association between induced abortion and risk of breast cancer: biology or bias?

The alleged association between induced abortion and breast cancer is one of the most controversial and important questions in women's health today. To help clinicians provide appropriate counseling, we reviewed both the primary data and review articles on this topic. We identified the studies and reviews by using Medline and the reference lists of articles and texts. We then used the U.S. Preventive Services Task Force rating system to evaluate the evidence. Many case-control studies have addressed this question, but their results have been inconsistent. Persistent problems in the case-control studies include selection of an appropriate control group, recall bias (under-reporting of induced abortion by controls), and confounding by other risk factors. Two recent, large cohort studies, which are less susceptible to bias, showed either protection or no effect on breast cancer risk from an induced abortion. At present, level II-2 evidence (cohort and case-control studies) supports a class B recommendation (fair evidence) that induced abortion does not increase a woman's risk of breast cancer later in life.     

The myth of Eve: molecular biology and human origins

It has been proposed that modern humans descended from a single woman, the "mitochondrial Eve" who lived in Africa 100,000 to 200,000 years ago. The human immune system DRB1 genes are extremely polymorphic, with gene lineages that coalesce into an ancestor who lived around 60 million years ago, a time before the divergence of the apes from the Old World monkeys. The theory of gene coalescence suggests that, throughout the last 60 million years, human ancestral populations had an effective size of 100,000 individuals or greater. Molecular evolution data favor the African origin of modern humans, but the weight of the evidence is against a population bottleneck before their emergence. The mitochondrial Eve hypothesis emanates from a confusion between gene genealogies and individual genealogies.     

Prognostic factors of colon cancer from a molecular biology standpoint

It has been reported that several genes may be good indicators for determining biological behavior, including the prognosis, of colorectal cancers. We have summarized these reported genes, such as tumor suppressor gene, oncogenes, metastasis suppressor gene, adhesion molecules, growth factors, proteinases, and others, including microsatellite instability. Some of the genes such as p53, DCC, c-met, or matrix metalloproteinase are considered to be reliable for determining biological aggressiveness. We introduced several interesting genes which we are focusing using cDNA subtraction library analysis. We hope that these genes are well combined for best analysis of the biological behavior of colorectal cancers and use for practical clinical analysis. In addition, we hope that novel important genes indicative for prognosis will be found.     

The molecular biology of polycystic kidney disease

In recent years there have been a number of developments in polycystic kidney disease (PKD) research. The genes associated with the predominant forms of autosomal dominant PKD have been cloned, and the gene associated with a mouse model for autosomal recessive PKD has been identified and characterized. Other studies have yielded new information regarding the role of the epidermal growth factor receptor gene in promoting renal cyst formation. In this review article we summarize recent published data on the molecular genetics of autosomal dominant and autosomal recessive PKD and provide a working model of how multiple genes participate in the PKD disease pathway.