Correlation between changes in nutritional status and tumor response in patients receiving immunotherapy for lung cancer (NUTIMMUNO study).

Malnutrition is a common condition in lung cancer, and it is an independent prognostic factor. The main objective of this study was to determine whether an early improvement at 3 months in the nutritional status (NS) of patients undergoing immune checkpoint inhibitor (ICI) is associated with a tumor response to treatment at 6-month follow-up. The clinical data of 106 patients initiating ICI for bronchopulmonary non-small cell lung cancer (NCSLC) were retrospectively reviewed. NS was defined according to the HAS 2019 recommendation, depending on BMI, percentage of weight loss, and albuminemia. NS was assessed at baseline (M0) and 3 months (M3) after ICI treatment initiation according to 3 categories: well-nourished, malnourished, and very malnourished. The NS evolution of the 92 patients who were still alive at 3 months was determined. The proportion of patients with malnutrition at M0 and M3 was 39.6% and 43.3%. Median follow-up was 18.7 months. OS and PFS were longer for patients in the M0 well-nourished group than in the malnourished and very malnourished groups. Patients who remained well-nourished had a significantly better ICI success rate at 6 months than patients who remained malnourished or improved or deteriorated their NS. OS was significantly longer for remaining well-nourished patients compared to the amelioration group and the degradation group. PFS was not significantly modified between the 4 evolution groups. Maintaining good NS during the first months of ICI treatment leads to better OS and objective response rate than remaining malnourished or early deteriorating NS. However, an early improvement in NS does not seem to predict a good tumor response to treatment and not a better OS either.

Hydration by colonic enteroclysis: An alternative to parenteral hydration in patients with high-output double enterostomy.

BACKGROUND: High-output double enterostomies (DESs) result in sodium and fluid loss responsible for frequent episodes of dehydration and hospitalizations. Hydration by enteroclysis (HE) is an alternative to parenteral hydration when the small bowel, or the downstream colon, is accessible and functional. METHODS: A retrospective analysis was conducted on all consecutive patients admitted in our institution with high-output (≥1200 ml per 24 h) DES and access to downstream intestine (including colon), who were treated by enteroclysis between 2015 and 2019. A sodium chloride and bicarbonate solution was instilled through a tube inserted in the colon. The objectives were diuresis >1 L, natriuresis >40 mmol/24 h, and urinary sodium-to-potassium ratio >1. RESULTS: HE was conducted in 52 patients (24 female, 28 male). Initially, 30 patients received intravenous support. Fifteen patients (50%) were weaned from all parenteral support, of whom 11 of 12 (92%) received fluid and electrolyte support and 4 of 18 (22%) received parenteral nutrition (PN). When intravenous fluids were still required, daily volumes decreased from 2714 ± 1424 to 1578 ± 1000 ml per 24 h (P = .001), as did the energetic intake (NS), from 1439 ± 556 to 1230 ± 362 kcal per 24 h (P = .096). CONCLUSION: HE through the efferent intestine limits the requirement for parenteral hydration in patients with high-output DES. For patients with intestinal failure dependent on PN, it reduces daily infused volumes.

Chyme Reinfusion in Intestinal Failure Related to Temporary Double Enterostomies and Enteroatmospheric Fistulas.

Some temporary double enterostomies (DES) or entero-atmospheric fistulas (EAF) have high output and are responsible for Type 2 intestinal failure. Intravenous supplementations (IVS) for parenteral nutrition and hydration compensate for intestinal losses. Chyme reinfusion (CR) artificially restores continuity pending surgical closure. CR treats intestinal failure and is recommended by European Society for Clinical Nutrition and Metabolism (ESPEN) and American Society for Parenteral and Enteral Nutrition (ASPEN) when possible. The objective of this study was to show changes in nutritional status, intestinal function, liver tests, IVS needs during CR, and the feasibility of continuing it at home. A retrospective study of 306 admitted patients treated with CR from 2000 to 2018 was conducted. CR was permanent such that a peristaltic pump sucked the upstream chyme and reinfused it immediately in a tube inserted into the downstream intestine. Weight, plasma albumin, daily volumes of intestinal and fecal losses, intestinal nitrogen, and lipid absorption coefficients, plasma citrulline, liver tests, and calculated indices were compared before and during CR in patients who had both measurements. The patients included 185 males and 121 females and were 63 ± 15 years old. There were 37 (12%), 269 (88%) patients with EAF and DES, respectively. The proximal small bowel length from the duodeno-jejunal angle was 108 ± 67 cm (n = 232), and the length of distal small intestine was 117 ± 72 cm (n = 253). The median CR start was 5 d (quartile 25-75%, 2-10) after admission and continued for 64 d (45-95), including 81 patients at home for 47 d (28-74). Oral feeding was exclusive 171(56%), with enteral supplement 122 (42%), or with IVS 23 (7%). Before CR, 211 (69%) patients had IVS for nutrition (77%) or for hydration (23%). IVS were stopped in 188 (89%) 2 d (0-7) after the beginning of CR and continued in 23 (11%) with lower volumes. Nutritional status improved with respect to weight gain (+3.5 ± 8.4%) and albumin (+5.4 ± 5.8 g/L). Intestinal failure was cured in the majority of cases as evidenced by the decrease in intestinal losses by 2096 ± 959 mL/d, the increase in absorption of nitrogen 32 ± 20%, of lipids 43 ± 30%, and the improvement of citrulline 13.1 ± 8.1 µmol/L. The citrulline increase was correlated with the length of the distal intestine. The number of patients with at least one liver test >2N decreased from 84-40%. In cases of Type 2 intestinal failure related to DES or FAE with an accessible and functional distal small bowel segment, CR restored intestinal functions, reduced the need of IVS by 89% and helped improve nutritional status and liver tests. There were no vital complications or infectious diarrhea described to date. CR can become the first-line treatment for intestinal failure related to double enterostomy and high output fistulas.

Management of entero-atmospheric fistulas by chyme reinfusion: A retrospective study.

BACKGROUND & AIMS: High output entero-cutaneous fistulas may lead to intestinal failure with parenteral nutrition (PN) as the gold standard treatment to prevent dehydration and malnutrition. However in case of entero-atmospheric fistula (EAF) with the distal limb of the fistula accessible, chyme reinfusion (CR), a technique that restores artificially digestive continuity can be performed until the surgical repair. Our aim was to study the efficacy of CR in EAF regarding nutritional status, intestinal function, PN weaning and liver tests. METHODS: Retrospective study of 37 patients admitted for EAF and treated by CR from 1993 to 2017. Delays were expressed in median (25%-75% quartiles) and other data on mean ± SD. RESULTS: Location of EAF: jejunum (29), ileum (8). The length of the upstream intestine was estimated in 21 patients: 19 had a bowel length <150 cm of which 16 had less than 100 cm. During CR, mean digestive losses decreased from 1734 ± 578 to 443 ± 487 ml/24 h (p < 0.000001), nitrogen absorption increased from 45.3 ± 18.6 to 81.8 ± 12.9% of ingesta (p < 0.001). The percentage of patients with plasma citrulline <20 µmol/l decreased from 71 to 10%. PN was stopped in all patients within 3 (0-14) days after CR initiation, 2 patients required an intravenous hydration and 20 had an additional enteral support. The nutritional status improved: albumin (33.1 ± 5.1 g/L vs 28.4 ± 6.5, p < 0.001), NRI (decrease of the number of patients at risk of severe malnutrition from 22 to 10 (p < 0.001)). The number of patients who had one or several liver tests abnormalities (>2 N) decreased from 94 to 41% (p < 0.001). CONCLUSION: When the efferent part of the small bowel is accessible, CR is a safe and inexpensive method that restores bowel function. In most cases, it makes it possible to stop PN and helps to improve the nutritional status until surgical reconstruction.

Association study of the ubiquitin conjugating enzyme gene UBE2H in sporadic ALS.

Ubiquitin inclusions represent a cytopathological hallmark of ALS. The ubiquitin-dependent protein degradation pathway may also be involved in the pathophysiology of SOD1 mutated ALS cases as demonstrated in transgenic animals. UBE2H is an ubiquitin conjugating enzyme known to act on histones and cytoskeletal proteins, both involved in the degenerative pathway of the motor neuron. We screened the whole coding sequence of the UBE2H gene in 24 sporadic ALS (SALS) patients using single strand conformation polymorphism (SSCP). All variants detected by SSCP were analysed by genomic DNA sequencing. We found one known polymorphism (rs12539800) and two new synonymous single nucleotide polymorphisms (SNP) (nG78A and nG501A). The allele distribution of the rs12539800 (A336G) SNP were tested for association in 252 SALS patients and 357 controls. The allele and genotype distributions were identical in the two groups. The UBE2H gene is not implicated in SALS; however, the ubiquitin pathway is worthy of further investigation in ALS.

A second generation radiation hybrid map to aid the assembly of the bovine genome sequence.

BACKGROUND: Several approaches can be used to determine the order of loci on chromosomes and hence develop maps of the genome. However, all mapping approaches are prone to errors either arising from technical deficiencies or lack of statistical support to distinguish between alternative orders of loci. The accuracy of the genome maps could be improved, in principle, if information from different sources was combined to produce integrated maps. The publicly available bovine genomic sequence assembly with 6x coverage (Btau_2.0) is based on whole genome shotgun sequence data and limited mapping data however, it is recognised that this assembly is a draft that contains errors. Correcting the sequence assembly requires extensive additional mapping information to improve the reliability of the ordering of sequence scaffolds on chromosomes. The radiation hybrid (RH) map described here has been contributed to the international sequencing project to aid this process. RESULTS: An RH map for the 30 bovine chromosomes is presented. The map was built using the Roslin 3000-rad RH panel (BovGen RH map) and contains 3966 markers including 2473 new loci in addition to 262 amplified fragment-length polymorphisms (AFLP) and 1231 markers previously published with the first generation RH map. Sequences of the mapped loci were aligned with published bovine genome maps to identify inconsistencies. In addition to differences in the order of loci, several cases were observed where the chromosomal assignment of loci differed between maps. All the chromosome maps were aligned with the current 6x bovine assembly (Btau_2.0) and 2898 loci were unambiguously located in the bovine sequence. The order of loci on the RH map for BTA 5, 7, 16, 22, 25 and 29 differed substantially from the assembled bovine sequence. From the 2898 loci unambiguously identified in the bovine sequence assembly, 131 mapped to different chromosomes in the BovGen RH map. CONCLUSION: Alignment of the BovGen RH map with other published RH and genetic maps showed higher consistency in marker order and chromosome assignment than with the current 6x sequence assembly. This suggests that the bovine sequence assembly could be significantly improved by incorporating additional independent mapping information.

High-resolution comparative mapping among man, cattle and mouse suggests a role for repeat sequences in mammalian genome evolution.

BACKGROUND: Comparative mapping provides new insights into the evolutionary history of genomes. In particular, recent studies in mammals have suggested a role for segmental duplication in genome evolution. In some species such as Drosophila or maize, transposable elements (TEs) have been shown to be involved in chromosomal rearrangements. In this work, we have explored the presence of interspersed repeats in regions of chromosomal rearrangements, using an updated high-resolution integrated comparative map among cattle, man and mouse. RESULTS: The bovine, human and mouse comparative autosomal map has been constructed using data from bovine genetic and physical maps and from FISH-mapping studies. We confirm most previous results but also reveal some discrepancies. A total of 211 conserved segments have been identified between cattle and man, of which 33 are new segments and 72 correspond to extended, previously known segments. The resulting map covers 91% and 90% of the human and bovine genomes, respectively. Analysis of breakpoint regions revealed a high density of species-specific interspersed repeats in the human and mouse genomes. CONCLUSION: Analysis of the breakpoint regions has revealed specific repeat density patterns, suggesting that TEs may have played a significant role in chromosome evolution and genome plasticity. However, we cannot rule out that repeats and breakpoints accumulate independently in the few same regions where modifications are better tolerated. Likewise, we cannot ascertain whether increased TE density is the cause or the consequence of chromosome rearrangements. Nevertheless, the identification of high density repeat clusters combined with a well-documented repeat phylogeny should highlight probable breakpoints, and permit their precise dating. Combining new statistical models taking the present information into account should help reconstruct ancestral karyotypes.

Proteomic tools to characterize the protein fraction of Equidae milk.

The principal components of the protein fraction in pony mare's milk have been successfully identified and partially characterized using proteomic tools. Skimmed pony mare's milk was fractionated by either reversed phase-high-performance liquid chromatography (RP-HPLC) on a C4 column or a bi-dimensional separation technique coupling RP-HPLC in the first dimension and sodium dodecyl sulfate-polyacrylamide electrophoresis (SDS-PAGE) in the second dimension (two-dimensional RP-HPLC/SDS-PAGE). The fractions thus obtained were analyzed by Edman N-terminal microsequencing and mass determination, with or without tryptic digestion, on a matrix-assisted laser desorption/ionization-time of flight spectrometer. Based on the sequence and molecular mass information obtained, identifications were achieved through a protein database search using homology or pattern research algorithms. This methodological approach was shown to be rapid, efficient and reliable in identifying the principal proteins in pony mare's milk. kappa-, alpha(s1)-, alpha(s2)-, and beta-casein, lysozyme C, alpha-lactalbumin and beta-lactoglobulin I and II were thus identified. alpha(s1) and beta-caseins displayed polymorphic patterns, probably due to alternative splicing processes leading to casual exon skipping events involving exons 7 and 14 in alpha(s1)-casein and exon 5 in beta-casein. Edman N-terminal microsequencing over 35 amino acid residues, for pony alpha(s1)-casein, clearly demonstrated the occurrence, in Equidae, of a splicing pattern similar to that reported in rodents, characterized by the constitutive outsplicing of exon 5. Pony mare's milk SDS-PAGE and RP-HPLC patterns were compared with those obtained for other milks (cow, goat and human), as were the relative levels of caseins and major whey proteins in these milks. Our results provide further evidence to support the notion that Equidae milk is closer to human breast milk than milk from bovine and caprine with respect to the casein and lysozyme C contents and casein/whey proteins ratio.

A first generation bovine BAC-based physical map.

A first generation clone-based physical map for the bovine genome was constructed combining, fluorescent double digestion fingerprinting and sequence tagged site (STS) marker screening. The BAC clones were selected from an Inra BAC library (105,984 clones) and a part of the CHORI-240 BAC library (26,500 clones). The contigs were anchored using the screening information for a total of 1303 markers (451 microsatellites, 471 genes, 127 EST, and 254 BAC ends). The final map, which consists of 6615 contigs assembled from 100,923 clones, will be a valuable tool for genomic research in ruminants, including targeted marker production, positional cloning or targeted sequencing of regions of specific interest.

Localisation, dans la partie NH(2)-terminale de la caséine alpha(s1) bovine, d'une délétion de 13 acides aminés différenciant le variant a des variants B et C.

The A variant of bovine alpha(s1) casein is devoid of the segment of 13 amino acid residues which occupies the 14th to 26th position from the NH(2)-terminal in the polypeptide chain (198 residues) of the B and C variants.