Comparative analysis of molecular fingerprints in prediction of drug combination effects.

Application of machine and deep learning methods in drug discovery and cancer research has gained a considerable amount of attention in the past years. As the field grows, it becomes crucial to systematically evaluate the performance of novel computational solutions in relation to established techniques. To this end, we compare rule-based and data-driven molecular representations in prediction of drug combination sensitivity and drug synergy scores using standardized results of 14 high-throughput screening studies, comprising 64 200 unique combinations of 4153 molecules tested in 112 cancer cell lines. We evaluate the clustering performance of molecular representations and quantify their similarity by adapting the Centered Kernel Alignment metric. Our work demonstrates that to identify an optimal molecular representation type, it is necessary to supplement quantitative benchmark results with qualitative considerations, such as model interpretability and robustness, which may vary between and throughout preclinical drug development projects.

Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Comparison of Finnish meat inspection records and average daily gain for cattle herds differing in Mycoplasma bovis test-status.

Detecting Mycoplasma bovis on cattle farms represents a challenge in the absence of an outbreak or cases of M. bovis mastitis, yet identification of an infection is essential to control the spread of the disease successfully. The objectives of this study were: (1) to determine whether meat inspection records can aid identification of cattle farms supporting M. bovis infection, and (2) to compare the average daily weight gain estimated from carcass weight for cattle originating from farms differing in M. bovis test-status. Meat inspection records were collected from two abattoirs in 2015; 80 677 animals in total. All the dairy and mixed breed cows and bulls used for meat production were categorized according to known M. bovis infection status of the farms from which the cattle were derived; positive, contact or control farms. The associations between animals from different M. bovis categories and lung lesions of bulls and cows (pneumonia and pleuritis), identified during meat inspection, and estimated average daily gain (ADG) of bulls, were investigated. The odds ratios for lung lesions, especially pleuritis, were higher in M. bovis test-positive or contact farms compared with control farms. Additionally, odds ratios for pleuritis were higher among animals from M. bovis test-positive farms and animals from contact slaughtering farms originating from M. bovis-free rearing farms. Bulls originating from M. bovis test-positive farms had higher estimated average daily gain than cattle from control farms. Meat inspection records can be used alongside other methods to detect M. bovis-positive farms where M. bovis causes lung lesions.

Mannose, mannitol, fructose and 1,5-anhydroglucitol concentrations measured by gas chromatography/mass spectrometry in blood plasma of diabetic patients.

Gas chromatography/mass fragmentography was applied to measure sugars in the plasma of patients with diabetes mellitus (DM). The isotope-dilution technique was used in the calculation of 1,5-anhydro-D-glucitol (1,5-AG), whereas reductive deuterization of the samples and regression analysis of the reduction products were used to calculate the concentrations of mannose, fructose and mannitol. The concentrations of mannose and glucose were closely and positively correlated both in insulin-dependent (IDDM; r = 0.74, P = 0.001) and non-insulin-dependent (NIDDM; r = 0.89, P = 0.001) DM. The close correlation was also encountered in serial samples taken from patients with widely fluctuating plasma glucose concentrations. The mannose/glucose ratio was increased in NIDDM (P = 0.007). The concentration of 1,5-AG was decreased in both types of DM, but more markedly in IDDM. The concentration was negatively correlated with glucose concentration (r = 0.071, P = 0.02) and HbAtc (r = 0.84, P = 0.001) in NIDDM. It was postulated that both mannose and glucose, by competing with 1,5-AG of renal tubular sugar carrier sites, contribute to the high urinary excretion of 1,5-anhydroglucitol leading to depletion of the sugar in the diabetic organism. The high concentrations of circulating mannose suggested further that the contribution of mannose to the adverse effects of hyperglycaemia should be examined. The study demonstrated that parallel use of the isotope-dilution and reductive deuterization techniques is quite useful in the analysis of monosaccharides in biological fluids.

Changes in serum and urinary myo-inositol levels in chronic glomerulonephritis.

Serum and urinary myo-inositol and urinary glucose were estimated by means of gas-liquid chromatography in 54 patients with glomerulonephritis with and without renal failure. myo-Inositol clearance was calculated and an index was formulated which reflected changes in glomerular filtration, tubular reabsorption and catabolism of myo-inositol by the kidney. Serum and urinary myo-inositol levels were increased in glomerulonephritis with a close correlation to the degree of renal failure. In advanced forms of glomerulonephritis, glomerular filtration, tubular reabsorption and catabolism of myo-inositol were shown to be markedly deranged. Evidence obtained showed further that a derangement of tubular reabsorption and catabolism of myo-inositol also accompany milder forms of glomerulonephritis without decreased glomerular filtration. The myo-inositol index value, especially, was increased in patients with signs of disease activity as indicated by a histological examination of the kidney tissue. The index can also be regarded as a highly sensitive test of renal failure. Low grade glucosuria was shown to be frequently associated with glomerulonephritis with renal failure. Evidence was produced which suggested that the tubular reabsorption of myo-inositol was deranged earlier than glucose reabsorption in glomerulonephritis, although they may share a common step in the reabsorption process. The data suggest that the estimation of serum and urinary myo-inositol has advantages in the evaluation of kidney function.

The conversion of D-xylose into D-threitol in patients without liver disease and in patients with portal liver cirrhosis.

An oral D-xylose tolerance test was carried out on 12 patients with portal liver cirrhosis, on 7 patients with active fatty liver disease and on 29 subjects without liver diseases. D-Xylose and D-threitol were measured by means of gas-liquid chromatography. Fifteen percent of the D-xylose dose excreted in urine within five hours was recovered as D-threitol. The proportion of D-threitol was greater when the collection was extended to 24 h. The D-threitol excretion was markedly diminished in cirrhotic patients, suggesting that a substantial proportion of the D-xylose-D-threitol conversion occurs in the liver. No decrease was detected in patients with fatty liver disease. No significant change in D-xylose excretion was observed in liver cirrhosis or in fatty liver disease. D-Threitol can be regarded as the main end product of D-xylose metabolism in man. The role of the glucuronate pathway in the D-xylose-D-threitol conversion is discussed.

Proteinuria and plasma hexosugars in early-stage glomerulonephritis.

Marked changes in the plasma concentration of several non-glucose monosaccharides have been detected among patients++ with end-stage renal disease. To find changes specific to renal disease and not caused by a failing urinary excretion, we studied the plasma monosaccharide concentration in patients with early-stage glomerulonephritis whose renal function was normal or only mildly compromised. Plasma mannose, fructose and 1,5-anhydroglucitol (1,5-AG) concentrations were measured using gas chromatography/mass spectrometry and isotope-labelled sugar standard additions. The daily urinary protein excretion was positively correlated with the plasma cholesterol (r = 0.785), mannose (r = 0.550), triglyceride (r = 0.531 ) and fructose (r = 0.401) concentrations, while the correlation with 1,5-AG (r = -0.581) was inverse. The correlations were statistically significant. As previous studies have revealed a close positive correlation between the plasma mannose and glucose concentrations, we calculated the mannose/glucose concentration ratio to find out whether the increase in mannose concentration was or was not explained by ambient glucose. There was a strong correlation between the ratio and the urinary protein excretion (r = 0.704). It is inferred that the metabolic syndrome associated with glomerulonephritis and characterised by hyperlipidemia also involves a derangement in mannose and 1,5-AG metabolism.

1,5-Anhydro-D-glucitol--a novel type of sugar in the human organism.

1,5-Anhydroglucitol is a six-carbon chain monosaccharide in C1-chair conformation with an oxygen ring in pyran position. The compound is a component of normal human blood serum. The concentration in serum fluctuates within a narrow range in a normal population. Very low serum concentrations are found in patients with diabetes mellitus. In insulin-dependent (type 1) diabetes with a long history of disease the concentration of 1,5-anhydroglucitol remains low in spite of improvement of glycaemic control by intensification of treatment, whereas in non-insulin dependent (type 2) diabetes the concentration gradually increases towards normal levels concomitantly with improvement in glycaemic control. The serum 1,5-anhydroglucitol concentration may be useful as an indicator of glycaemic control in patients with non-insulin dependent diabetes. Urinary excretion of 1,5-anhydroglucitol in normal subjects is very low inferring that the compound is efficiently reabsorbed by tubular cells. During glucosuria, induced by glucose tolerance test in human or streptozotocin administration in rats the 1,5-anhydroglucitol excretion is temporarily increased, which may be attributable to a competition between 1,5-anhydroglucitol and glucose for renal tubular transporters. Data so far obtained indicate that 1,5-anhydroglucitol may be either actively or passively transported through the cell membrane, depending on the cell type. Gas-liquid chromatography is the method of choice in the measurement of the low concentrations of 1,5-anhydroglucitol present in biological samples.

Correction of haemodialysis-associated anaemia by deferoxamine. Effects on serum aluminum and iron overload.

Aluminium and iron overload is often seen among long-term haemodialysis patients. Untreated non-de-aluminized dialysis water or the intake of large amounts of aluminium hydroxide as phosphate binders are the most common reasons for hyper-aluminaemia. Iron overload is mainly a result of multiple blood transfusions given to correct renal anaemia. In chronic dialysis patients, hypochromic anaemia is one of the clinical manifestations of a long-term overload of aluminium and perhaps of other metals, e.g. iron. We used deferoxamine (DFO) to chelate aluminium and excessive iron in 17 patients on chronic haemodialysis. Two grams of DFO was administered weekly in the form of an i.v. infusion during the last hour of the dialysis session. The mean serum aluminum concentration decreased from 407.3 micrograms/l to 184.2 micrograms/l within 3 years of treatment, the mean serum ferritin concentration from 1,563 micrograms/l to 487 micrograms/l within 2 years. Anaemia was corrected concomitantly with an increase in the haemoglobin level, which rose from 71.7 g/l to 80.8 g/l. The mean corpuscular volume increased from 83.8 fl to 91.3 fl. The need for blood transfusion also decreased significantly in all patients after the institution of DFO therapy. The clinical manifestations of aluminium and iron overload disappeared and the quality of life improved. No major side-effects were observed.

[The role of the clinical laboratory in the evaluation of the tubular function of the kidneys]. / Rol' klinicheskoi laboratorii v otsenke kanal'tsevoi funktsii pochek.

Renal tubules contribute to maintenance of the body equilibrium by regulating urinary excretion of electrolytes and low molecular mass components. Many transport mechanisms for regulation of concentrations of various components of the tubular fluid are situated in the renal tubules. Studies on the specification and localization of subcellular mechanisms functioning in the renal tubules is a progressive borderline trend of investigation. A new approach has been used to solve the problems of clinical nephrology and maintenance of the body balance. Processes of calcium, sodium, and monosaccharide reabsorption in the tubular fluid are described in brief.

Serum 1,5-anhydroglucitol in normal subjects and in patients with insulin-dependent diabetes mellitus.

The serum levels of 1,5-anhydroglucitol were measured by gas chromatography in normal subjects and in patients with type 1 (insulin-dependent) diabetes mellitus and compared with those found in some other common diseases. The identity of the compound was checked by thin-layer chromatography and by means of mass fragmentography. The mean level was 81 mumol/l (range 10-146 mumol/l, n = 139) in normal subjects and comparable levels were found in patients with rheumatic disease (n = 20) and in several patients with circulatory diseases. The level was less than 10 mumol/l in 44 patients with insulin-dependent diabetes mellitus, both in newly diagnosed cases and in patients with a long history of the disease with or without nephropathy. The compound did not appear in serum during near normoglycaemic periods elicited by continuous subcutaneous insulin infusion therapy, nor after successful kidney transplantation.

Continuous blood glucose monitoring and characteristics of diabetes in patients on maintenance haemodialysis treatment.

The glucose metabolism of diabetes mellitus during maintenance haemodialysis treatment was studied in four patients with endstage renal failure. There was a large day-to-day variation in the predialysis blood glucose levels, which it was difficult to control by adjusting the insulin dose. In spite of very high blood glucose levels, blood lactate and beta-hydroxybutyrate were not elevated. Triglycerides were markedly and constantly elevated, in no apparent association with the predialysis blood glucose level. The patients were shown to release moderate amounts of glucose, beta-hydroxybutyrate and lactate into the dialysate during the dialysis period. A technique of continuous blood glucose monitoring during the haemodialysis period was applied. With this technique blood sugar levels were accurately determined during the whole dialysis period. A rapid drop in the blood glucose level was found in apparent association with an aggravation of symptoms. A very marked tendency to hypoglycaemia was also revealed. It is concluded that the technique is a valuable aid in the proper management of diabetes in these cases.