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PubMed1999

Improved survival and local control after total mesorectal excision or D3 lymphadenectomy in the treatment of primary rectal cancer: an international analysis of 1411 patients.

AIMS: Improved local control and survival in the treatment of rectal cancer have been reported after total mesorectal excision and after extended lymphadenectomy. Comparison of published results is difficult because of differences in patient populations and definitions. We compared three series of patients who underwent standardized surgery [i.e. total mesorectal excision (TME) or D3 lymphadenectomy] with patients who underwent conventional surgery, using actual patient data and uniform definitions. METHODS: TME was performed at Memorial Sloan-Kettering Cancer Center, New York, USA (n=254) and the North Hampshire Hospital, Basingstoke, UK (n=204). D3 lymphadenectomy was performed at the National Cancer Center, Tokyo (n=233). Conventional surgery was used in hospitals in Norway (n=366) and in hospitals of the Comprehensive Cancer Center West, The Netherlands (n=354). Only patients with a curatively resected primary TNM Stage II or Stage III rectal cancer within 12 cm from the anal verge were included. RESULTS: Five-year overall survival and cancer-specific survival were 62-75% and 75-80%, respectively, in the standardized surgery groups and 42-44% and 52%, respectively, in the conventional surgery groups. Local recurrence rates ranged from 4 to 9% in the standardized surgery groups and 32-35% in the conventional surgery groups. CONCLUSIONS: A 30% survival difference and 25% local recurrence difference is not likely to be caused by the shortcomings which are inherent in a non-randomized study: selection bias, assessment variability or stage migration. This study suggests that standardized surgery gives superior survival and local control when compared to conventional surgery.

Aged↗

PubMed2002

[The Transverse Coloplasty Pouch (TCP)--function and subjective judgement in comparison with the surgically more complicated J-Pouch].

The present study shows the comparison of function and subjective judgement between two pouch-constructions after TME as treatment for rectal cancer. In 61 cases we constructed a J-Pouch, in 25 cases a transverse coloplasty pouch (TCP). The sex distribution was nearly the same. The influence of additional treatment like neoadjuvant radiotherapy or adjuvant chemo-radiatio was considered. Patients were asked about stool frequency, -consistency, continence, quality of life etc. 9 patients were not alive at follow up. 54 patients (70 %) could be interviewed and examined. 6 months after operation patients with a J-Pouch had a daily stool frequency of 4 times versus 6 times with a TCP. 19 % of patients with a J-Pouch suffered from incontinence problems compared to 33 % with a TCP. Obstipation was only a problem after J-Pouch-construction (12 %). The question on a "good" quality of life was positively answered by 56 % of patients in the J-pouch-group versus 39 % in the TCP-group. 17 % after J-pouch-construction versus 6 % after TCP-construction judged the quality of life as "bad". The results of this study show the TCP being a good alternative pouch-construction instead of the surgically more complicated J-pouch after TME.

Aged↗

PubMed1989

Reliability of different temporary myocardial pacing leads.

Temporary myocardial pacing leads are routinely used for diagnosis and treatment of postoperative arrhythmias following open-heart surgery. The intention of this study is to compare five different electrodes for reliability during the postoperative period. A standardised technique of implantation was used to place 147 ventricular and 81 atrial wire electrodes in 149 patients. During operation and then daily over the next ten days, the stimulation threshold, P- and R-wave sensing, and impedance were measured with a pacing system analyser to evaluate the reliability of the pacing and sensing function. Five measurements were taken at each time; the mean values were statistically analysed. The number of failures in pacing and sensing and the course of the tested parameters during the postoperative period were compared. As a result, bipolar pacing leads (Osypka TME 64a/66a) proved to be more reliable than unipolar wires (Ethicon HD 12S, Osypka TME 60/60a), particularly in atrial sensing. Also the Medtronic 6400/6500 showed good reliability for the ventricle, so that they can be recommended for VVI-mode pacing. In conclusion, for reliable function during the postoperative course up to 10 days a specially developed bipolar temporary pacemaker electrode can be recommended for both atrial and ventricular or sequential pacing.

Differential Threshold↗

PubMed1997

Effects of amino acid balance and energy:protein ratio on energy and nitrogen metabolism in male broiler chickens.

1. An experiment was performed with growing broiler chickens (14 to 21 d old) to examine 3 diet characteristics which have been implicated in regulatory elevation of metabolic rate: an imbalanced amino acid mixture, high dietary energy concentration and low protein concentration. 2. Differences in energy expenditure could be explained almost entirely (93%) by differences in quantities, and therefore costs, of protein and fat accretion. There was no indication of regulatory diet-induced thermogenesis. Heat production was not significantly correlated with CP:TME ratio and was negatively correlated (P < 0.01) with dietary TME concentration. 3. Heat production was closely correlated (P < 0.001) with rate of protein accretion, which in turn was more strongly associated with intake of the first-limiting amino acid (lysine) than with total protein intake. Heat production on an imbalanced, lysine-limited, amino acid mixture was no greater than on a balanced amino acid source with the same lysine concentration. 4. There was no indication of a stimulation of heat production by excess amino acids. Heat production, adjusted for body weight by covariance analysis, was similar on paired diets which had identical lysine concentrations but a 1.5- or 2-fold difference in crude protein concentration. 5. There was a strong negative correlation (P < 0.001) between protein retention per g of lysine consumed and lysine: CP ratio, suggesting that, in this case, response to a limiting amino acid was improved by the presence of a super-abundance of other amino acids.

Adipose Tissue↗

PubMed1999

Effects of ambient temperature on heat increment of feeding and energy retention in growing broilers maintained at different food intakes.

Zero-activity heat production (HP), body temperature (Tb) and energy retention were measured in growing broilers maintained at 5 ambient temperatures (Ta) (14 degrees , 17 degrees , 22 degrees , 27 degrees and 32 degrees C) and at 5 feeding rates (ad libitum intake and 75%, 50%, 25% and 0% (fasting) of ad libitum). Zero-activity HP increased with decreasing Ta and increasing food intake. However, at 14 degrees C, zero-activity HP in birds fed ad libitum and 75% did not show further increase, but those in birds fed less than 75% of ad libitum increased rapidly. Results of the regression of zero-activity HP on Ta ranging from 32 degrees to 17 degrees C indicated that the slope was affected little by food intake, but the intercept decreased with decreasing food intake. Tb increased significantly with increasing food intake. There was little variation with Ta but, at and above 27 degrees C, a slightly increased Tb was observed only in birds fed ad libitum. Overall effects of Ta and food intake on HIF (% TME intake) were not found, but HIF tended to increase with decreasing food intake at 14 degrees C. Total energy retention and energy retention as fat decreased with decreasing Ta and food intake, although energy retention as protein decreased only with decreasing food intake. Results obtained here suggest that availability of TME is affected little by Ta ranging from 32 degrees to 17 degrees C and that HIF is utilised, in part, to maintain Tb at any Ta.

Animal Feed↗

PubMed1998

The residence time of the bound water in the hydrophobic minor groove of the carbocyclic-nucleoside analogs of Dickerson-Drew dodecamers.

The residence time of the bound water molecules in the antisense oligodeoxyribonucleotides containing 7'-alpha-methyl (TMe) carbocyclic thymidines in duplex (I), d5'(1C2G3C4G5A6A7TMc8TMe9C10G11C12G)23', and 6'-alpha-hydroxy (TOH) carbocyclic thymidines in duplex (II), d5'(1C2G3C4G5AOH6AOH7TOH8 TOH9C10G11C12G)2(3), have been investigated using a combination of NOESY and ROESY experiments. Because of the presence of 7'-alpha-methyl groups of TMe in the centre of the minor groove in duplex (I), the residence time of the bound water molecule is shorter than 0.3 ns. The dramatic reduction of the residence time of the water molecule in the minor groove in duplex (I) compared with the natural counterpart has been attributed to the replacement of second shell of hydration and disruption of hydrogen-bonding with 04' in the minor groove by hydrophobic alpha-methyl groups, as originally observed in the X-ray study. This effect could not be attributed to the change of the width of the minor groove because a comparative NMR study of the duplex (I) and its natural counterpart showed that the widths of their minor grooves are more or less unchanged (r.m.s.d change in the core part is <0.63A). For duplex (II) with polar 6'-alpha-hydroxyl groups pointed to the minor groove, the correlation time is much longer than 0.36 ns as a result of the stabilising hydrogen-bonding interaction with N3 or 02 of the neighbouring nucleotides.

Acids, Carbocyclic↗

PubMed2003

Other animal prion diseases.

In addition to bovine spongiform encephalopathy (BSE) of cattle and scrapie of sheep and goats, a few other animal prion diseases have been reported. These include feline spongiform encephalopathy of zoological and domestic cats (FSE) and transmissible spongiform encephalopathy (TSE) of zoological ruminants and non-human primates, as well as chronic wasting disease of deer and elk (CWD) and transmissible mink encephalopathy of farmed mink (TME). The origins of TSE in cats, zoo bovids, and non-human primates are clearly linked to the BSE epidemic; however, the origins of CWD and TME are less clear, but are not epidemiologically linked to the BSE epidemic. Here we review the epidemiology, transmission, clinical features and pathology of these other animal prion diseases.

Animals↗

PubMed1984

Characterization of a recombinant mouse T haplotype that expresses a dominant lethal maternal effect.

The twLub2 chromosome was generated by rare recombination between a complete t haplotype and a wild-type form of mouse chromosome 17. This recombinant chromosome expresses a dominant lethal effect in all embryos that inherit the mutant chromosome from their mothers. The phenotype of this maternal effect is indistinguishable from that expressed by the previously described Thp deletion chromosome. It appears likely that the crossing over event that gave rise to twLub2 was unequal and resulted in the alteration or deletion of a gene (which is named the T-associated maternal effect locus, Tme) that must be inherited from the mother in order for normal development to proceed through late stages of gestation. The results presented here allow a mapping of the Tme locus between the quaking and tufted loci which are 3 cM apart within the proximal region of chromosome 17.

Animals↗

PubMed2001

Additivity and associative effects of metabolizable energy and amino acid digestibility in barley and canola meal for White Pekin ducks.

An experiment was conducted using the TMEn bioassay method to investigate the additivity and associative effects of metabolizable energy and amino acid digestibility in barley and canola meal for White Pekin ducks. Additivity was tested by comparing the difference between observed values determined in a complete diet and predicted values from measurements determined with individual ingredients (barley and canola meal). Six ducks each were assigned to diets of barley, canola meal, the complete diet, and dextrose. Dextrose-fed ducks were used for estimation of endogenous losses for calculation of true amino acid digestibility. The observed AME, TME, AMEn, and TMEn values in the complete diet were 0.065, 0.083, 0.016, and 0.023 (kcal/g), respectively, numerically higher than predicted values. Differences between observed and predicted values were not significant (P > 0.05), indicating that the AME, AMEn, TME, and TMEn in barley and canola meal were all additive. In general, observed values for apparent amino acid digestibility (AAAD) and true amino acid digestibility (TAAD) in the complete diet were higher than those predicted from individual ingredients. Observed AAAD for lysine, histidine, tryptophan, alanine, and aspartate were higher (P < 0.05) than predicted values, indicating that digestibilities of these amino acids were not additive. The mean of AAAD in canola meal (77.29%) was higher (P < 0.05) than the observed values of barley (52.2%) and complete diet (64.55%). For TAAD values, differences between observed and predicted values were significant for lysine, histidine, and tryptophan (P < 0.05). The mean of TAAD in canola meal, barley, and complete diet were 85.88, 80.87, and 81.33%, respectively. The average difference between observed and predicted values for TAAD (1.18 %) was smaller than that of AAAD (5.41%). These results indicated that ME values for barley and canola meal were additive in the complete diet but that digestibilities of some amino acids were not additive; they further suggested that there were some associative effects of amino acids in barley and canola meal for ducks.

Amino Acids↗

PubMed2003

Comparisons of amino acid availability by different methods and metabolizable energy determination of a Chinese variety of high oil corn.

TME, true amino acid availability (TAAA), AME, and apparent amino acid availability (AAAA) were determined in Chinese high oil corn (CHOC) and conventional corn (CC). The CC and CHOC contained 4.58 and 8.44% ether extract (DM basis), respectively. A precision-fed rooster assay was used in which each corn sample was tube-fed (50 g) to 16 roosters and excreta were collected for 48 h. A N-free diet and fasting methods were used to evaluate endogenous amino acid (AA) losses. Endogenous losses of 10 AA were different (P < 0.05) with the N-free and fasting methods; in most cases the mean value for the N-free treatment was greater (P < 0.05) than for the fasting treatment. The TME value for CHOC was greater than for CC (4,193 vs. 3,961 cal/g DM; P < 0.05). The true availability of aspartic acid, threonine, isoleucine, and leucine of CC and CHOC was higher (P < 0.05) for the N-free method than for the fasting method. When compared within the N-free or within the fasting method, the true availabilities of lysine, methionine, and proline were higher (P < 0.05) in CHOC than in CC, but the true availability of phenylalanine was lower (P < 0.05) in CHOC than in CC. The AAAA values, although lower, followed similar patterns as the TAAA values. The results of this study indicated that availability of AA in CHOC is equal or superior to that in CC and that the available energy for poultry is higher in CHOC than in CC.

Amino Acids↗

PubMed2005

The modern abdominoperineal excision: the next challenge after total mesorectal excision.

OBJECTIVES: Examine the cause of local recurrence (LR) and patient survival (S) following abdominoperineal resection (APR) and anterior resection (AR) for rectal carcinoma and the effect of introduction of total mesorectal excision (TME) on APR. METHODS: A total of 608 patients underwent surgery for rectal cancer in Leeds from 1986 to 1997. CRM status and follow-up data of local recurrence and patient survival were available for 561 patients, of whom 190 underwent APR (32.4%) and 371 AR (63.3%). Also, a retrospective study of pathologic images of 93 specimens of rectal carcinoma. RESULTS: Patients undergoing APR had a higher LR and lower survival (LR, 22.3% versus 13.5%, P = 0.002; S, 52.3% versus 65.8%, P = 0.003) than AR. LR free rates were lower in the APR group and cancer specific survival was lowered (LR, 66% versus 77%, log rank P = 0.03; S, 48% versus 59%, log rank P = 0.02). Morphometry: total area of surgically removed tissue outside the muscularis propria was smaller in APR specimens (n = 27) than AR specimens (n = 66) (P < 0.0001). Linear dimensions of transverse slices of tissue containing tumor, median posterior, and lateral measurements were smaller (P < 0.05) in the APR than the AR group. APR specimens with histologically positive CRM (n = 11) had a smaller area of tissue outside the muscularis propria (P = 0.04) compared with the CRM-negative APR specimens (n = 16). Incidence of CRM involvement in the APR group (41%) was higher than in the AR group (12%) (P = 0.006) in the 1997 to 2000 cohort. Similar results (36% and 22%) were found in the 1986 to 1997 cohort (P = 0.002). CONCLUSIONS: Patients treated by APR have a higher rate of CRM involvement, a higher LR, and poorer prognosis than AR. The frequency of CRM involvement for APR has not diminished with TME. CRM involvement in the APR specimens is related to the removal of less tissue at the level of the tumor in an APR. Where possible, a more radical operation should be considered for all low rectal cancer tumors.

Adenocarcinoma↗

PubMed1994

Physicochemical and biological characterizations of distinct strains of the transmissible mink encephalopathy agent.

Inoculation of the Stetsonville, Wisconsin source of transmissible mink encephalopathy (TME) into Syrian hamsters has identified two strains of the TME agent having distinct biological properties and producing disease-specific prion proteins (PrPTME) having different physicochemical properties. Although several strains of the sheep scrapie agent have been identified in Great Britain, this is the first indication that agents producing transmissible spongiform encephalopathies in the United States also are capable of producing distinct strains.

Animals↗

PubMed1991

Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy.

Epidemiological investigation of a new incident of transmissible mink encephalopathy (TME) in Stetsonville, Wisconsin, U.S.A. in 1985 revealed that the mink rancher had never fed sheep products to his mink but did feed them large amounts of products from fallen or sick dairy cattle. To investigate the possibility that this occurrence of TME may have resulted from exposure to infected cattle, two Holstein bull calves were injected intracerebrally with mink brain from the Stetsonville ranch. Each bull developed a fatal spongiform encephalopathy 18 and 19 months after inoculation, respectively, and both bovine brains passaged back into mink were highly pathogenic by either intracerebral or oral inoculation. These results suggest the presence of a previously unrecognized scrapie-like infection in cattle in the United States.

Animal Feed↗

PubMed1994

Experimental infection of mink with bovine spongiform encephalopathy.

To determine whether the aetiological agent of bovine spongiform encephalopathy (BSE) is pathogenic for mink, standard dark mink were inoculated with coded homogenates of bovine brain from the U.K. Two homogenates were from cows affected with BSE. The third was from a cow that came from a farm with no history of having had BSE or having been fed ruminant-derived, rendered by-products, the proposed vehicle for introduction of the BSE agent. Each homogenate was inoculated intracerebrally into separate groups of mink and a pool of the three was fed to a fourth group. Signs of neurological disease appeared in mink an average of 12 months after intracerebral inoculation and 15 months after feeding. Decreased appetite, lethargy and mild to moderate pelvic limb ataxia were the predominant clinical signs, quite unlike the classic clinical picture of transmissible mink encephalopathy (TME). Microscopic changes in brain sections of most affected mink were those of a scrapie-like spongiform encephalopathy. Vacuolar change in grey matter neuropil was accompanied by prominent astrocytosis. Varying greatly in severity from one mink to another, the degenerative changes occurred in the cerebral cortex, dorsolateral gyri of the frontal lobe, corpus striatum, diencephalon and brainstem. Although resembling TME, the encephalopathy was distinguishable from it by less extensive changes in the cerebral cortex, by more severe changes in the caudal brainstem and by sparing of the hippocampus. The results of this study extend the experimental host range of the BSE agent and demonstrate for the first time the experimental oral infection of mink with a transmissible spongiform encephalopathy agent from a naturally infected ruminant species.

Animals↗

PubMed1997

The cleavage activities of aphthovirus and cardiovirus 2A proteins.

The primary 2A/2B polyprotein cleavage of aphtho-and cardioviruses is mediated by their 2A proteins cleaving C-terminally. Whilst the aphthovirus 2A region is only 16 aa (possibly 18 aa) long, the cardiovirus 2A protein is some 150 aa. We have previously shown that foot-and-mouth disease virus (FMDV) 2A is able to mediate cleavage in an artificial (chloramphenicol acetyltransferase/FMDV 2A/beta-glucuronidase [CAT-2A-GUS]) polyprotein system devoid of any other FMDV sequences with high (approximately 85%), although not complete, cleavage. In this paper we show that insertion of upstream FMDV capsid protein 1 D sequences increases the activity. In addition, we have demonstrated that the cardiovirus Theiler's murine encephalomyelitis virus(TME) 2A protein, when linked to GUS in a single ORF, is able to cleave at its own C terminus with high efficiency--if not completely. The C-terminal 19 aa of TME 2A, together with the N-terminal proline residue of protein 2B, were inserted into the CAT/GUS artificial polyprotein system (in a single ORF). This recombinant [CAT-deltaTME2A-GUS] polyprotein was able to mediate cleavage with high (approximately 85%) efficiency--directly comparable to the activity observed when FMDV 2A was inserted. A similar insertion into [CAT-GUS] of the C-terminal 19 aa of the cardiovirus encephalomyocarditis virus (EMC) 2A, together with the N-terminal proline residue of protein 2B, produced a [CAT-delta EMC2A-GUS] polyprotein which also mediated cleavage at approximately 85%. Analysis of the products of expression of these artificial polyproteins in a prokaryotic translation system did not, apparently, reveal any GUS cleavage product.

Amino Acid Sequence↗

PubMed2025

Discovery of a Linked Constellation of Gene Expression Revealed by Local Editing of Fibroblasts in Tumors.

Fibroblasts play critical roles in regulating cellular relationships during tissue homeostasis, immunity, and tumor biology at multiple sites. However, tools to perturb fibroblasts at just one site in vivo are limited, restricting our understanding of how these cellular relationships develop on a local level. We optimized local gene editing of fibroblasts in multiple mouse tumor models to investigate how locally restricted fibroblast perturbations affect the cellular tumor microenvironment (TME). By knocking out surface receptors Osmr, Tgfbr2, or Il1r1 on cancer-associated fibroblasts (CAFs), we uncover that TGFBR2 signaling loss uniquely induces the emergence of a Col18a1 hi CAF cell state that is distinct from previously described fibroblast states and is associated with worse survival in human PDAC patients. Further application of a local as well as combinatorial gene knockout technology in CAFs reveals a circuit in which these Col18a1 hi CAFs reshape the TME by recruiting Siglec-Fhi neutrophils via Cxcl5 expression; and that the Col18a1 hi CAF cell state is further dependent on TNFR1 and canonical Wnt signaling. Together, a fast, affordable, and modular engineering method is demonstrated, allowing discovery of a modified fibroblast identify, as well as the network details of a local inter-cellular circuitry in a tumor.

Journal Article↗

PubMed2025

Installation of Dominant-Negative Mutations in FAS and TGFβR2 via Base Editing in Primary T Cells.

Adoptive cell transfer (ACT) of engineered T cells is effective against B-cell malignancies but has faltered against solid tumors due to the immunosuppressive tumor microenvironment (TME). FASL and TGFβ are key mediators of T cell dysfunction in the TME and overexpressing dominant negative (dn) forms of their receptors in T cells increases anti-tumor efficacy in solid tumor models. However, an approach which directly targets the endogenous genes would be more amenable to multiplex editing and reduce competition with WT alleles. Here, we employ base editing (BE) in primary human T cells to install naturally occurring dominant negative FAS and TGFβR2 mutations. In vitro survival and proliferation assays demonstrate that BE T cells are resistant to pro-apoptotic and anti-proliferative effects of FAS and TGFβ signaling. CAR-T cells with BE-installed dn TGFβR2 or dn FAS exhibit improvements in cytotoxicity, while dn TGFβR2 CAR T demonstrate increased persistence and reduced expression of phenotypic markers of exhaustion compared to controls. Moreover, BE-engineered dn CAR T outperform lentiviral-engineered cDNA over expression counterparts in several functional assays. Considering the efficiency of BE and its amenability for multiplex editing, our novel approach lends itself to engineering strategies necessary to overcome T cell dysfunction in solid tumors.

CAR T↗

PubMed2025

Spatially organized lymphocytic microenvironments in high grade primary prostate tumors.

The spatial organization and composition of the tumor-immune microenvironment (TME) play a critical role in shaping the progression of many solid cancers, but the organization of the TME in primary prostate cancer (PCa) remains poorly characterized. We therefore profiled the abundance and spatial distributions of major cell types involved in adaptive immunity in 29 radical prostatectomy specimens stratified into high (HGG; n=14) and low Gleason-grade (LGG; n=15). Compared to LGG, HGG PCa exhibited significantly greater B and T cell infiltration with many immune cells organized into clusters, some of which resembled tertiary lymphoid structures (TLSs). In HGG tumors, these clusters were dense, symmetric, rich in PD-1+ T cells, and frequently proximate to the tumor compartment. LGG clusters were less well organized, and T cell depleted. Thus, a subset of high-grade PCa harbor organized immune clusters that may play a role in tumor control and contain therapeutically targetable T and B cells.

Prostate cancer↗