Somatic variation in normal tissues: friend or foe of cancer early detection?

BACKGROUND: Seemingly normal tissues progressively become populated by mutant clones over time. Most of these clones bear mutations in well-known cancer genes but only rarely do they transform into cancer. This poses questions on what triggers cancer initiation and what implications somatic variation has for cancer early detection. DESIGN: We analyzed recent mutational screens of healthy and cancer-free diseased tissues to compare somatic drivers and the causes of somatic variation across tissues. We then reviewed the mechanisms of clonal expansion and their relationships with age and diseases other than cancer. We finally discussed the relevance of somatic variation for cancer initiation and how it can help or hinder cancer detection and prevention. RESULTS: The extent of somatic variation is highly variable across tissues and depends on intrinsic features, such as tissue architecture and turnover, as well as the exposure to endogenous and exogenous insults. Most somatic mutations driving clonal expansion are tissue-specific and inactivate tumor suppressor genes involved in chromatin modification and cell growth signaling. Some of these genes are more frequently mutated in normal tissues than cancer, indicating a context-dependent cancer-promoting or -protective role. Mutant clones can persist over a long time or disappear rapidly, suggesting that their fitness depends on the dynamic equilibrium with the environment. The disruption of this equilibrium is likely responsible for their transformation into malignant clones and knowing what triggers this process is key for cancer prevention and early detection. Somatic variation should be considered in liquid biopsy, where it may contribute cancer-independent mutations, and in the identification of cancer drivers, since not all mutated genes favoring clonal expansion also drive tumorigenesis. CONCLUSION: Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.

Analysis of relationship of hormonal, hematological and biochemical parameters in Indian alcoholics with severity of alcohol dependence.

Background: Alcohol dependence syndrome (ADS) is a major problem in India. ADS is known to be a systemic disorder involving almost all organ-systems. The evaluation of ADS patients' needs successive assessment of severity of clinical condition. In this study, we attempted to explore Severity of Alcohol Dependence Questionnaire (SADQ-C) as a severity measure by studying its association with laboratory parameters. Methods: During the two months study period 155 diagnosed ADS male patients who had been admitted to the Psychiatric Ward of two zonal level hospitals were enrolled for the study. The participants were examined by the Psychiatrist and the severity of alcoholism ascertained by the SADQ-C scoring. Based on SADQ-C scoring they were divided into three groups: severe alcohol dependence, moderate dependence and mild physical dependence. The patients' blood samples were collected and tested. Results: In our study, morning and evening level of serum cortisol showed positive correlation with increasing SADQ-C scoring. The differences in morning and evening cortisol level also augmented with increasing severity score (r=0.257; p=0.001). Hemoglobin, mean corpuscular volume (MCV) and serum level of LH, FSH and testosterone levels were not shown any statistically significant alterations amongst the studied groups. Serum LH, total bilirubin, direct bilirubin, AST, ALT and GGT level showed positive correlation with SADQ-C scoring but AST/ALT ratio showed negative correlation. Conclusion: This study elaborated relationship between SADQ-C scoring and laboratory parameters in Indian male ADS patients. It highlighted the requirement of incorporation of serum cortisol along with presently evaluated laboratory parameters for ADS severity evaluation.

A Rare Case of Hemoglobin E Hemoglobinopathy with Gaucher's Disease.

Hemoglobin (Hb) E mutation is common in north-east part of our country. The natural history of Hb E thalassemia is highly variable. The phenotype, for patients with similar mutations, can range from asymptomatic to transfusion dependent. Our patient presented at 2 years of age with failure to thrive and hepatosplenomegaly. Routine work up revealed microcytic, hypochromic red blood cells. Hb E homozygous was indicated on electrophoresis and hemoglobin HPLC. Evaluation of parents revealed Haemoglobin E trait in both. Therapeutic splenectomy revealed Gaucher-like cells. ß-Glucocerebrosidase levels were low. Presence of Gaucher-like cells with normal ß-glucocerebrosidase (pseudo-Gaucher cells) are known in leukemia, multiple myeloma, thalassemia and mycobacterial infections. Co-existence of Gaucher's disease with Hb E mutation is not reported to the best of our knowledge.

Mercury speciation and transport via submarine groundwater discharge at a southern California coastal lagoon system.

We measured total mercury (Hg(T)) and monomethylmercury (MMHg) concentrations in coastal groundwater and seawater over a range of tidal conditions near Malibu Lagoon, California, and used (222)Rn-derived estimates of submarine groundwater discharge (SGD) to assess the flux of mercury species to nearshore seawater. We infer a groundwater-seawater mixing scenario based on salinity and temperature trends and suggest that increased groundwater discharge to the ocean during low tide transported mercury offshore. Unfiltered Hg(T) (U-Hg(T)) concentrations in groundwater (2.2-5.9 pM) and seawater (3.3-5.2 pM) decreased during a falling tide, with groundwater U-Hg(T) concentrations typically lower than seawater concentrations. Despite the low Hg(T) in groundwater, bioaccumulative MMHg was produced in onshore sediment as evidenced by elevated MMHg concentrations in groundwater (0.2-1 pM) relative to seawater (∼0.1 pM) throughout most of the tidal cycle. During low tide, groundwater appeared to transport MMHg to the coast, resulting in a 5-fold increase in seawater MMHg (from 0.1 to 0.5 pM). Similarly, filtered Hg(T) (F-Hg(T)) concentrations in seawater increased approximately 7-fold during low tide (from 0.5 to 3.6 pM). These elevated seawater F-Hg(T) concentrations exceeded those in filtered and unfiltered groundwater during low tide, but were similar to seawater U-Hg(T) concentrations, suggesting that enhanced SGD altered mercury partitioning and/or solubilization dynamics in coastal waters. Finally, we estimate that the SGD Hg(T) and MMHg fluxes to seawater were 0.41 and 0.15 nmol m(-2) d(-1), respectively - comparable in magnitude to atmospheric and benthic fluxes in similar environments.

Cord blood stem cell banking and transplantation.

Stem cells have the ability to divide for indefinite periods in culture and to give rise to specialized cells. Cord blood as a source of hematopoietic stem cells (HSC) has several advantages as it is easily available, involves non-invasive collection procedure and is better tolerated across the HLA barrier. Since the first cord blood transplant in 1988, over 2500 cord blood HSC transplants have been done world wide. Since then, the advantages of cord blood as a source of hematopietic stem cells for transplantation have become clear. Firstly, the proliferative capacity of HSC in cord blood is superior to that of cells in bone marrow or blood from adults. A 100 ml unit of cord blood contains 1/10th the number of nucleated cells and progenitor cells (CD34+ cells) present in 1000 ml of bone marrow, but because they proliferate rapidly, the stem cell in a single unit of cord blood can reconstitute the entire haematopoietic system. Secondly, the use of cord blood reduces the risk of graft vs host disease. Cord Blood Stem Cell banks have been established in Europe and United States to supply HSC for related and unrelated donors. Currently, more than 65,000 units are available and more than 2500 patients have received transplants of cord blood. Results in children have clearly shown that the number of nucleated cells in the infused cord blood influences the speed of recovery of neutrophils and platelets after myeloablative chemotherapy. The optimal dose is about 2 x 10(7) nucleated cells/kg of body weight. The present study was carried out for collection, separation, enumeration and cryopreservation of cord blood HSC and establishing a Cord Blood HSC Bank. 172 samples of cord blood HSC were collected after delivery of infant prior to expulsion of placenta. The average cord blood volume collected was 101.20 ml. Mononuclear cell count ranged from 7.36 to 25.6 x 10(7)/ml. Viability count of mononuclear cells was 98.1%. After 1 year of cryopreservation, the viability count on revival was over 82.1%. Related cord blood stem cell transplantation was carried out in three cases at Army Hospital (R&R), Delhi Cantt.

A prospective randomized trial of vagotomy in chronic duodenal ulceration: 4-year follow-up.

A total of 153 patients (124 male and 29 female) with uncomplicated chronic duodenal ulceration were studied in a prospective, randomized trial of proximal gastric vagotomy (PGV) and truncal vagotomy and pyloroplasty (TVP), conducted in four Manchester hospitals. Of these, 137 patients have now been followed up for 2.5 to 5.5 (mean 4.1) yr. There have been 15 (21 per cent) recurrent ulcers following PGV compared with 5 (7.5 per cent) after TVP (P less than 0.05). A satisfactory functional result was obtained in 82 per cent of patients after TVP compared with 73 per cent following PGV and there was little difference between the groups with regard to the incidence of dumping, heartburn and vomiting. There was significantly more diarrhoea following TVP (13 per cent) compared to PGV (1.4 per cent) but this represented only a minor clinical problem.

Randomized trial of elective highly selective or truncal vagotomy in chronic duodenal ulceration.

Between 1973 and 1976, 153 patients (124 men, 29 women) with uncomplicated, chronic, duodenal ulcer were entered into a prospective randomized trial of highly selective vagotomy (HSV) or truncal vagotomy and pyloroplasty (TVP). The study was conducted in four Manchester hospitals and the operations were performed by consultants or chief registrars. The follow-up was conducted by personal interview using a standardized questionnaire. The medical gastroenterologist did not know which type of operation the patient had had. The patients who had symptoms were referred back to the surgeon who performed the operation. The clinical laboratory and follow-up data were analysed by computer. There were no operative deaths. Three patients died from unrelated causes, 13 were lost to follow-up; 137 (89.5%) were followed up for a mean of 4.1 years (range from 2.5 to 5.5 years). A modified Visick grading was used to assess the results of surgery. The outcome was good in 82% after TVP and 73% after HSV. This difference and those in the incidences of early or late postprandial dumping, bilious vomiting, weight loss, anemia and heartburn were not significant. Diarrhea was more frequent after TVP (13.4%) than after HSV (1.4%); although the difference was significant (p less than 0.025), this complaint did not present a serious clinical problem. Ulcers recurred in 15 (21.4%) patients following HSV and in 5 (7.5%) after TVP; this difference was statistically significant (p less than 0.05).

Effect of urogastrone on gastric secretion and serum gastrin concentration in patients with duodenal ulceration.

A one-hour infusion of 0.25 micrograms/kg urogastrone administered to seven patients with duodenal ulceration resulted in significant reduction of basal acid secretion (p less than 0.05) but was without significant effect on basal pepsin and intrinsic factor secretion or on serum gastrin concentration. In another group of five patients with duodenal ulceration a one-hour infusion of urogastrone was given on five successive days. On day 1 and 5 urogastrone was administered after establishing a plateau response to intravenous pentagastrin 1.2 micrograms/kg/h. A mean reduction of 65% in acid output during the urogastrtone infusion was seen on day 1 and this was maintained during the next hour. On day 5 the pentagastrin-stimulated acid output was less than on day 1 and a further significant decrease was noted after urogastrone. Pepsin and intrinsic factor output were also significantly inhibited. There was no change in fasting serum gastrin or urogastrone concentration.

Binding of the anticancer drug cis-dichlorodiammineplatinum to 3'(2')-guanosine monophosphate and nucleic acids.

The UV-absorption spectral characteristics of cis[Pt(NH3)2(GMP)2]-2 ([Pt(NH3)2 (Guanosine-3'(2')-monophosphate)2]-2) (abbreviated Pt (GMP)2) and cis-[Pt(NH3)2(Guanine)2]+2 (abbreviated Pt(Gua)2) were studied at acidic, neutral and alkaline pH values. The compound Pt(GMP)2 was formed by reacting GMP with cis-Pt(NH3)2Cl2(= cis-platinum) in H2O(pH approximately 6) at 24 degrees C for 7 days in the dark. Hydrolysis of Pt(GMP)2 with HClO4 to remove its sugar-phosphate moiety followed by paper chromatographic separation yielded Pt(Gua)2. Exposure to alkali did not cause any irreversible change in the absorption spectrum of Pt(GMP)2 indicating the lack of imidazole ring fission. Spectral changes for Pt(Gua)2 as compared to control Gua at neutral and alkaline pH values were quantitatively less than those reported for 7-methyl guanine in the literature. Electronic perturbation of the guanine ring system was thus found to be considerably less for platinum than for alkylation of the N7 site. These subtle differences between the platination and alkylation of Gua are of interest in view of the apparent similarities between the biological effects of cis-platinum and bifunctional alkylating agents reported in the literature.

Long-term therapy with carbenoxolone in the prevention of recurrence of gastric ulcer. Natural history and evolution of important side-effects and measures to avoid them.

Between 1970 and 1979, 140 patients aged between 19 and 84 years with endoscopically confirmed gastric ulcer (GU), were treated with Biogastrone in reducing doses for 6 months. They received a daily dose of 300 mg for one week, 150 mg for 5 weeks, 100 mg for 6 weeks and 50 mg for the remainder of the 6 months. All the patients were reviewed at 2, 4, 6, 8, 12, 16, 20, 32, and 38 weeks and thereafter every 3 months or earlier in the event of significant dyspepsia. The anticipated recurrence rate of GU of approximately 42% at 2 years (3) was nearly halved to 26.7% over a median follow-up of 36 months in 140 cases completing the full six months course of treatment. The incidence of side effects was as follows: (i) A weight gain of 3.5 kg or more was seen in 23% of the patients at 2 weeks; this effect was maintained through the 6 month period. (ii) Oedema was noted in 14% of the patients at 2 weeks but declined to a 2% incidence by the end of the study. (iii) Elevated diastolic blood pressure in 14--18% of patients below 60 years and 20--27% patients above 60 years of age was noted throughout the study period. A high proportion of patients (38%) receiving other therapy had hypertension prior to the trial period; Carbenoxolone treatment had little further effect on blood pressure in these patients. (iv) Hypokalaemia was noted in the early stages of treatment especially in those over 60 years (43%). The incidence declined with the reduction in dosage through the 6 month treatment period. All side effects were successfully treated by diuretics and potassium supplements.

Preferential interstrand cross-linking of DNA rich in guanine and cytosine by cis-dichlorodiammineplatinum(II).

Two native DNAs differing in G + C content were bound equally with the antitumour drug cis-Pt(NH3)2Cl2 at increasing Pt/P ratios. Resulting changes in their ultraviolet absorption spectra show equal fractional decreases in the initially different values of A250/A270 for the two DNAs, and less prominent bathochromic and hyperchromic shifts for DNA richer in G + C. Changes in the absorbance (A260) observed before and after subjecting the DNA samples to the conditions of denaturation (with alkali) and renaturation, indicate the following effects of the platinum binding. Maximum renaturation occurs at 50% lower Pt/P ratio of 0.03 for Micrococcus lysodeikticus DNA (72% G + C) than 0.06 for salmon sperm DNA (41% G + C) and is maintained at higher Pt/P ratios. Interstrand cross-links that facilitate renaturation, cause an incomplete melting of DNA so that the platinum-DNA complex at pH 12.5 has a reduced absorbance. This effect is more evident for the platinum complex with DNA richer in G + C due to more interstrand cross-links. Platinum-induced destabilisation of DNA, shown by its hyperchromicity at the pre-melting state (pH 6--7, 25 degrees C) and also by a lowering of the pH corresponding to the mid-point of its melting, is less evident for DNA richer in G + C.

Cimetidine and gastric cancer.

Three patients with dyspeptic symptoms who were being treated with the H2-receptor blocking drug, cimetidine, were later found to have gastric carcinoma. It was not possible to determine whether the association was fortuitous, whether the drug had masked the neoplastic change, or whether it was involved in some other way. Repeated clinical and endoscopic evaluation is essential in patients on this treatment for any length of time.

A prospective randomized trial of vagotomy in chronic duodenal ulceration.

In a prospective, randomized trial, 76 patients with duodenal ulceration treated by truncal vagotomy and pyloroplasty were compared with 77 patients who underwent highly selective vagotomy. A total of 149 patients was followed up for from 1 to 4 years, the average follow-up period being 2.6 years. There was no operative mortality and no significant difference in postoperative morbidity between the two groups. The incidence of recurrent ulceration was greater after highly selective vagotomy, but this difference was not statistically significant. The clinical results were comparable in each group, and although the incidence of diarrhoea and dumping was greater after vagotomy and pyloroplasty, this difference was not statistically significant.

Comparison of an intragastric method of estimating acid output with the pentagastrin test in normal and duodenal ulcer subjects.

Using Fordtran's technique but substituting the meat extract Oxo for the steak meal we investigated gastric acid secretion in eight control subjects and nine patients with chronic duodenal ulcer. Intragastric titration was performed using a double lumen tube measuring the pH in the stomach every three minutes and adjusting it to 5.5 throughout the test by infusing 0.3-M sodium bicarbonate. On a separate day a pentagastrin test was performed using a conventional gastric aspiration technique. In the eight control subjects the mean acid output after pentagastrin was 13.7 +/- 2.1 (SEM) mmol/h, whereas the mean hourly acid output measured by intragastric titration was 20.1 +/- 3.1. The greater response to Oxo than to pentagastrin in the controls (deltaAO = + 46%) was significant (P less than 0.01). This is in contrast with our duodenal ulcer patients whose mean hourly acid outputs were 22.7 +/- 4.4 and 23.0 +/- 4.4 mmol/h in response to pentagastrin and Oxo respectively (r = 0.95). The findings, while clearly at variance with those of Fordtran and Walsh (1973), are more in keeping with the concept of increased endogenous secretory drive in duodenal ulcer patients compared to normal subjects.

Failure of oral bromocriptine to affect hypergastrinemia in two patients with the Zollinger-Ellison syndrome.

Bromocriptine was administered to 2 subjects with gastrin-secreting tumors of the pancreas. The absorption of the drug was confirmed by a rise in growth hormone levels but no change in the elevated serum gastrin levels were observed. Bromocriptine does not appear to affect gastrin hypersecretion in the way that it influences the hypersecretion of pituitary hormones.