Predicting pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer: a systematic review.

AIM: Approximately 20% of patients treated with neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer achieve a pathological complete response (pCR) while the remainder derive the benefit of improved local control and downstaging and a small proportion show a minimal response. The ability to predict which patients will benefit would allow for improved patient stratification directing therapy to those who are likely to achieve a good response, thereby avoiding ineffective treatment in those unlikely to benefit. METHOD: A systematic review of the English language literature was conducted to identify pathological factors, imaging modalities and molecular factors that predict pCR following chemoradiotherapy. PubMed, MEDLINE and Cochrane Database searches were conducted with the following keywords and MeSH search terms: 'rectal neoplasm', 'response', 'neoadjuvant', 'preoperative chemoradiation', 'tumor response'. After review of title and abstracts, 85 articles addressing the prediction of pCR were selected. RESULTS: Clear methods to predict pCR before chemoradiotherapy have not been defined. Clinical and radiological features of the primary cancer have limited ability to predict response. Molecular profiling holds the greatest potential to predict pCR but adoption of this technology will require greater concordance between cohorts for the biomarkers currently under investigation. CONCLUSION: At present no robust markers of the prediction of pCR have been identified and the topic remains an area for future research. This review critically evaluates existing literature providing an overview of the methods currently available to predict pCR to nCRT for locally advanced rectal cancer. The review also provides a comprehensive comparison of the accuracy of each modality.

Does arousal enhance apical amplification and disamplification?

We summarize evidence that input to the apical tufts of neocortical pyramidal cells modulates their response to basal input. Because this apical amplification and disamplification provide intracortical mechanisms for prioritization, Mather and colleagues' arguments suggest that their effects are enhanced by noradrenergic arousal. Though that is likely, it has not yet been adequately studied. Their article shows that it should be.

Coherent Infomax as a computational goal for neural systems.

Signal processing in the cerebral cortex is thought to involve a common multi-purpose algorithm embodied in a canonical cortical micro-circuit that is replicated many times over both within and across cortical regions. Operation of this algorithm produces widely distributed but coherent and relevant patterns of activity. The theory of Coherent Infomax provides a formal specification of the objectives of such an algorithm. It also formally derives specifications for both the short-term processing dynamics and for the learning rules whereby the connection strengths between units in the network can be adapted to the environment in which the system finds itself. A central assumption of the theory is that the local processors can combine reliable signal coding with flexible use of those codes because they have two classes of synaptic connection: driving connections which specify the information content of the neural signals, and contextual connections which modulate that signal processing. Here, we make the biological relevance of this theory more explicit by putting more emphasis upon the contextual guidance of ongoing processing, by showing that Coherent Infomax is consistent with a particular Bayesian interpretation for the contextual guidance of learning and processing, by explicitly specifying rules for on-line learning, and by suggesting approximations by which the learning rules can be made computationally feasible within systems composed of very many local processors.

Fecal shedding of foodborne pathogens by Florida-born heifers and steers in U.S. beef production segments.

The objective in this study was to assess breed effects in fecal prevalence of Escherichia coli O157:H7 in heifers on a development program in Florida and in their steer half siblings in stocker and feedlot phases in Oklahoma. A secondary objective was to characterize fecal shedding of Campylobacter and Salmonella in subsets of the same samples. After weaning, heifers (n = 501; purebreds and F1 crosses of Angus, Brahman, and Romosinuano) were preconditioned and placed in a local development program. Steers (n = 481) were transported to Oklahoma, where they grazed wheat for 6 months and then were placed in feedlot pens. Fecal samples were obtained at least every 28 days for 12 months on most animals. None of the 10,982 samples tested positive for E. coli O157:H7. Overall fecal prevalences of Campylobacter and Salmonella in heifers were 1.7 and 0.04%, respectively. Corresponding overall prevalences in steer samples were 27.2 and 0.6%. Campylobacter isolates were mostly C. jejuni and were tetracycline resistant. Eight Salmonella isolates were Salmonella Typhimurium that were either quad or penta resistant, most often to ampicillin, chloramphenicol, sulfamexathole, and tetracycline. Feedlot steers had greater odds of positive detection of Campylobacter (odds ratio, 8.5; confidence interval, 3.7, 19.5) than when grazing winter wheat. No breed effect was detected for fecal prevalence of these pathogens.

Segregation by onset asynchrony.

We describe a simple psychophysical paradigm for studying figure-ground segregation by onset asynchrony. Two pseudorandom arrays of Gabor patches are displayed, to left and right of fixation. Within one array, a subset of elements form a figure, such as a randomly curving path, that can only be reliably detected when their onset is not synchronized with that of the background elements. Several findings are reported. First, for most participants, segregation required an onset asynchrony of 20-40 ms. Second, detection was no better when the figure was presented first, and thus by itself, than when the background elements were presented first, even though in the latter case the figure could not be detected in either of the two successive displays alone. Third, asynchrony segregated subsets of randomly oriented elements equally well. Fourth, asynchronous onsets aligned with the path could be discriminated from those lying on the path but not aligned with it. Fifth, both transient and sustained neural activity contribute to detection. We argue that these findings are compatible with neural signaling by synchronized rate codes. Finally, schizophrenic disorganization is associated with reduced sensitivity. Thus, in addition to bearing upon basic theoretical issues, this paradigm may have clinical utility.

ST7-mediated suppression of tumorigenicity of prostate cancer cells is characterized by remodeling of the extracellular matrix.

Multiple lines of evidence have provided compelling evidence for the existence of a tumor suppressor gene (TSG) on chromosome 7q31.1. ST7 may be the target of this genetic instability but its designation as a TSG is controversial. In this study, we show that, functionally, ST7 behaves as a tumor suppressor in human cancer. ST7 suppressed growth of PC-3 prostate cancer cells inoculated subcutaneously into severe combined immunodeficient mice, and increased the latency of tumor detection from 13 days in control tumors to 23 days. Re-expression of ST7 was also associated with suppression of colony formation under anchorage-independent conditions in MDA-MB-231 breast cancer cells and ST7 mRNA expression was downregulated in 44% of primary breast cancers. Expression profiling of PC-3 cells revealed that ST7 predominantly induces changes in genes involved in re-modeling the extracellular matrix such as SPARC, IGFBP5 and several matrix metalloproteinases. These data indicate that ST7 may mediate tumor suppression through modification of the tumor microenvironment.

Lipopolysaccharide priming of human neutrophils for an enhanced respiratory burst. Role of intracellular free calcium.

Lipopolysaccharide (LPS) pretreatment "primes" neutrophils to release increased amounts of superoxide anion (O2-) when stimulated. We investigated the molecular basis of this enhanced activity. Comparison of kinetic parameters of the respiratory burst NADPH oxidase in unstimulated LPS-primed and control neutrophils disclosed a similar Km for NADPH and no difference was seen in the content of cytochrome b. Pertussis toxin, which inhibits some G proteins, did not prevent priming. Change in membrane potential (delta psi) was five-fold greater in LPS-primed cells and paralleled the increased O2- release. Cytofluorographic analysis indicated that the increased change in delta psi was due to the creation of a new population of active cells. Changes in the concentration of intracellular free Ca2+ ([Ca2+]i) are believed to antecede changes in delta psi. There was a consistent increment (67 +/- 8%, n = 12) in resting [Ca2+]i in cells preincubated with LPS compared with control. When stimulated, the peak [Ca2+]i was significantly higher in LPS-primed cells. Ca2+-dependent protein kinase C activity was unaltered in resting and FMLP-stimulated neutrophils preexposed to LPS. Addition to cells of the intracellular Ca2+ chelator MAPTAM before preincubation with LPS blocked the changes in [Ca2+]i and the enhanced respiratory burst that characterize LPS priming. The increased resting [Ca2+]i in LPS-primed cells may enhance stimulus-induced cellular activity by modifying a Ca2+-dependent step in signal transduction.

Evaluation of tropically adapted straightbred and crossbred beef cattle: Cortisol concentration and measures of temperament at weaning and transport.

The objective of this research was to evaluate circulating concentrations of plasma cortisol and measures of temperament at weaning in calves (steers and heifers) and at transport in steers. Calves ( = 993) were produced from a 3-breed diallel mating design that included calves from 3 consecutive years. Breed types of calves were straightbred Angus (A), Brahman (B), and Romosinuano (R) and all F crossbred combinations (AB, BA, AR, RA, BR, and RB). At weaning (d 0) and at 24 and 72 h after weaning, blood was sampled from calves and the plasma was stored for later cortisol assay. Additionally, at each of these times, temperament was assessed as chute score, exit velocity, and pen score. About 1 mo later, steer calves ( = 471) were sampled before shipment, at arrival, and at 24 h, 72 h, 2 wk, and 4 wk after shipment (2,025 km; Brooksville, FL, to El Reno, OK). At each of these sampling times, blood was collected and plasma was stored for subsequent cortisol assay and temperament was assessed by measurement of exit velocity. At both weaning and transport, plasma concentrations of cortisol did not significantly differ ( > 0.05) among straightbreds or among crossbreds. Significant ( < 0.05) positive genetic effects were observed for plasma concentration of cortisol at weaning (heterosis for BA and direct Romosinuano effect) and transport (heterosis for RA, BR, and BA; direct Romosinuano effect; and maternal Angus effect). Assessment of temperament using the objective measurement of exit velocity or the subjective measures of chute score or pen score (1 [lowest] to 5 [highest excitability] scale, based on behavior in chute and behavior in pen with human observer, respectively) generally provided similar results: Brahman was higher than Brahman crosses, which were higher than Angus, Romosinuano, and their reciprocal crosses. For exit velocity, however, Brahman did not differ from Brahman crosses and Angus did not differ from Romosinuano or Brahman crosses. At transport, sire breed and dam breed affected exit velocity of steers, with higher ( < 0.05) estimates for Brahman than for Romosinuano or Angus. These data suggest that weaned calves and shipped steers of various breed types show a similar response to stressors in cortisol concentration. In contrast, in assessing temperament or behavioral response to humans, Romosinuano and Angus had better temperaments and were less excitable than Brahman.

The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors.

Phosphatidylinositol 3'-kinases (PI3ks) are a family of lipid kinases that play a crucial role in a wide range of important cellular processes associated with malignant behavior including cell growth, migration, and survival. We have used single-strand conformational polymorphism/heteroduplex analysis to demonstrate the presence of somatic mutations in the gene for the p85alpha regulatory subunit of PI3k (PIK3R1) in primary human colon and ovarian tumors and cancer cell lines. All of the mutations lead to deletions in the inter-SH2 region of the molecule proximal to the serine608 autoregulatory site. Expression of a mutant protein with a 23 amino acid deletion leads to constitutive activation of PI3k providing the first direct evidence that p85alpha is a new oncogene involved in human tumorigenesis.

The effects of arousal on apical amplification and conscious state.

Neocortical pyramidal cells can integrate two classes of input separately and use one to modulate response to the other. Their tuft dendrites are electrotonically separated from basal dendrites and soma by the apical dendrite, and apical hyperpolarization-activated currents (Ih) further isolate subthreshold integration of tuft inputs. When apical depolarization exceeds a threshold, however, it can enhance response to the basal inputs that specify the cell's selective sensitivity. This process is referred to as apical amplification (AA). We review evidence suggesting that, by regulating Ih in the apical compartments, adrenergic arousal controls the coupling between apical and somatic integration zones thus modifying cognitive capabilities closely associated with consciousness. Evidence relating AA to schizophrenia, sleep, and anesthesia is reviewed, and we assess theories that emphasize the relevance of AA to consciousness. Implications for theories of neocortical computation that emphasize context-sensitive modulation are summarized. We conclude that the findings concerning AA and its regulation by arousal offer a new perspective on states of consciousness, the function and evolution of neocortex, and psychopathology. Many issues worthy of closer examination arise.

Lipopolysaccharide- and interferon-gamma-induced expression of hck and lyn tyrosine kinases in murine bone marrow-derived macrophages.

We have examined the role of tyrosine phosphorylation during the course of macrophage activation. Initial experiments indicated that vanadate, a known phosphotyrosine phosphatase inhibitor, enhanced the phorbol 12-myristate 13-acetate (PMA)-triggered respiratory burst and potentiated the priming effects of bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma), suggesting that tyrosine phosphorylation may be important in these end cell functions. As src-related kinases have been implicated in the activation of cells of other haemopoietic lineages, we examined the relationship between the activity of two such kinases, hck and lyn, and priming of the respiratory burst. We found that the level of hck and lyn is increased following exposure of bone marrow-derived macrophages (BMM) to LPS or IFN-gamma. The induction of both of these kinases follows similar kinetics with maximal activity occurring at 24-48 h. Interestingly, the kinetics of induction of hck and lyn kinase activity in BMM demonstrated a close temporal relationship with the priming effects of LPS and IFN-gamma on the macrophage respiratory burst. Collectively, these observations raise the possibility that modulation of expression of hck and lyn is involved in the regulation of the respiratory burst.

Activation of the macrophage respiratory burst by phorbol myristate acetate: evidence for both tyrosine-kinase-dependent and -independent pathways.

We have investigated the relationship between tyrosine phosphorylation and respiratory-burst activity in murine bone-marrow-derived macrophages (BMM) stimulated with phorbol myristate acetate (PMA). In unprimed BMM, a good correlation was observed between the net level of tyrosine phosphorylation and the activity of the respiratory burst. The phosphotyrosine phosphatase inhibitor, vanadate, enhanced both tyrosine phosphorylation and respiratory-burst activity triggered by PMA. Furthermore, the tyrosine kinase inhibitor, ST638, abolished both tyrosine phosphorylation and respiratory-burst activity stimulated by PMA. However, in BMM primed by preexposure to TNF alpha, the correlation between net tyrosine phosphorylation and respiratory-burst activity triggered by PMA was not maintained. ST638 was found to only partially inhibit the PMA-triggered respiratory burst under conditions where PMA-stimulated tyrosine phosphorylation was abolished. We conclude that PMA can activate the macrophage respiratory burst by both tyrosine-kinase-dependent and -independent pathways.

Phosphotyrosine phosphatase activity in the macrophage is enhanced by lipopolysaccharide, tumor necrosis factor alpha, and granulocyte/macrophage-colony stimulating factor: correlation with priming of the respiratory burst.

Tyrosine phosphorylation is now recognised as a key event in the activation of the macrophage respiratory burst. Since vanadate, a phosphotyrosine phosphatase (PTP) inhibitor is able to enhance the respiratory burst, we proposed that agents which prime the macrophage for enhance respiratory burst activity may do so by suppressing cellular PTP activity. The level of PTP activity in murine bone marrow-derived macrophages (BMM) was assessed by the ability of cell lysates to dephosphorylate 32P-labelled RR-src peptide. In contrast to our hypothesis, pretreatment of BMM with bacterial lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF alpha) or granulocyte/macrophage-colony stimulating factor (GMCSF), agents which prime for enhanced respiratory burst activity, was found to dramatically increase the level of cellular PTP activity. The time-course for this increase correlated well with the time course of priming by these agents. In addition, colony stimulating factor-1, a cytokine which does not prime the macrophage respiratory burst, did not enhance PTP levels. The physiological relevance of the increased PTP activity was further supported by confirming it was active against endogenous tyrosine phosphorylated substrates. Interestingly, phorbol myristate acetate and zymosan, agents which trigger the macrophage respiratory burst, were found to inhibit the PTP activity of BMM. Our results demonstrate the regulation of cellular PTP activity by priming agents and further highlight the importance of tyrosine phosphorylation and dephosphorylation events in the regulation of macrophage function.

Changes in the incorporation of free fatty acids upon the stimulation of human polymorphonuclear leukocytes.

We have investigated the incorporation of free fatty acids into the cellular lipids of human polymorphonuclear leukocytes (PMN). Resting PMN incorporated both saturated and unsaturated fatty acids into triacylglycerol with only small amounts incorporated into the phospholipids. In contrast, PMN stimulated with the calcium ionophore A23187 incorporated significantly higher amounts of fatty acids, predominantly those other than arachidonic acid, into phosphatidylcholine and phosphatidylinositol, with reduced incorporation into triacylglycerol. Stimulation of PMN with serum-treated zymosan or the chemotactic peptide f-met-leu-phe but not phorbol myristate acetate, also increased the incorporation of fatty acids into these phospholipids. This stimulation-induced incorporation of fatty acids into cellular phospholipids was directed exlusively into position 2 of the lipid and probably reflects the reacylation of lysophospholipids after the release of arachidonic acid by phospholipase A2.

Expression of p47-phox and p67-phox proteins in murine bone marrow-derived macrophages: enhancement by lipopolysaccharide and tumor necrosis factor alpha but not colony stimulating factor 1.

We have investigated the relationship between the expression of the p47-phox and p67-phox cytosolic components of the NADPH oxidase and priming of the macrophage respiratory burst. Western blot analysis revealed that murine bone marrow-derived macrophages (BMM) contain immunoreactive proteins detected by antisera raised against recombinant human p47-phox and p67-phox. Priming BMM by exposure to tumor necrosis factor alpha (TNF-alpha) or lipopolysaccharide (LPS) increased the levels of p47-phox and p67-phox. Colony-stimulating factor 1 (CSF-1), which we previously found to have a negative effect on the priming of murine macrophages, had no effect on the level of p47-phox but down-regulated that of p67-phox. Our results suggest that the regulatory effects of LPS, TNF-alpha, and CSF-1 on the respiratory burst of BMM may be due to modulation of the expression of the p47-phox and p67-phox cytosolic components of the NADPH oxidase.

Role of YopH in the suppression of tyrosine phosphorylation and respiratory burst activity in murine macrophages infected with Yersinia enterocolitica.

Tyrosine phosphorylation is an important component of the signaling pathways responsible for the activation of the macrophage respiratory burst. Because the virulence plasmid of Yersinia enterocolitica encodes a phosphotyrosine phosphatase, YopH, it is possible that the pathogenic strategy of Y. enterocolitica involves the disruption of tyrosine phosphorylation in the macrophage leading to inhibition of respiratory burst activity. We have investigated the effects of Yersinia infection on tyrosine phosphorylation and respiratory burst activity in murine bone marrow-derived macrophages. Infection of macrophages with virulent [Ye(pYV+)] but not avirulent [Ye(pYV-)] strains of Y. enterocolitica was found to suppress both tyrosine phosphorylation and respiratory burst activity in response to zymosan. Mutational inactivation of YopH reversed the suppressive effect of Ye(pYV+) on zymosan-induced tyrosine phosphorylation, indicating that YopH is responsible for the dephosphorylation of macrophage phosphotyrosine-containing proteins observed in macrophages infected with the virulent strain of Y. enterocolitica. In contrast, mutational loss of YopH failed to reverse the inhibitory effect of Ye(pYV+) on the zymosan-triggered respiratory burst. We conclude that the inhibition of the macrophage respiratory burst by Y. enterocolitica involves a plasmid-encoded virulence protein(s) other than, or in addition to, YopH.

On the functions, mechanisms, and malfunctions of intracortical contextual modulation.

A broad neuron-centric conception of contextual modulation is reviewed and re-assessed in the light of recent neurobiological studies of amplification, suppression, and synchronization. Behavioural and computational studies of perceptual and higher cognitive functions that depend on these processes are outlined, and evidence that those functions and their neuronal mechanisms are impaired in schizophrenia is summarized. Finally, we compare and assess the long-term biological functions of contextual modulation at the level of computational theory as formalized by the theories of coherent infomax and free energy reduction. We conclude that those theories, together with the many empirical findings reviewed, show how contextual modulation at the neuronal level enables the cortex to flexibly adapt the use of its knowledge to current circumstances by amplifying and grouping relevant activities and by suppressing irrelevant activities.

Lipopolysaccharide-induced priming of the human neutrophil is not associated with a change in phosphotyrosine phosphatase activity.

The activation of the neutrophil respiratory burst is a two-step process involving an initial 'priming' phase followed by a 'triggering' event. The biochemical mechanisms which underlie these events are yet to be fully elucidated, but the evidence suggests a crucial role for stimulus-induced tyrosine phosphorylation. The enhanced tyrosine phosphorylation observed upon triggering primed cells may reflect an increase in tyrosine kinase activity or a reduction in the levels of the opposing phosphotyrosine phosphatases (PTPases). We have investigated the latter by examining the possibility that lipopolysaccharide (LPS)-induced priming of the neutrophil respiratory burst involves the suppression of cellular PTPase activity. Purified human neutrophils were incubated for 60 min with and without LPS. Priming of the respiratory burst was confirmed by fMet-Leu-Phe-induced cytochrome c reduction. The level of PTPase activity was assessed by dephosphorylation of [32P]RR-src peptide as substrate. Pretreatment of human neutrophils with 200 ng/ml LPS induced a 2.9 +/- 0.3 (mean +/- SEM, n = 3, P = 0.022) fold increase in the fMet-Leu-Phe-triggered respiratory burst. In the same cells, LPS did not induce a significant change in the total cellular PTPase activity (1.02 +/- 0.02-fold, mean +/- SEM, n = 3, P = 0.63). Similarly, stimulation of neutrophils with fMet-Leu-Phe or phorbol myristate acetate did not significantly affect the cellular PTPase activity (P = 0.94 and 0.68, respectively). Our results suggest that suppression of PTPase activity is not the mechanism underlying the priming and/or triggering of the neutrophil respiratory burst.

Histomorphometric and biochemical characterization of bone following acute severe burns in children.

Severe burns in adults is associated with an uncoupling of normal remodeling, low bone formation without reduced resorption. The risk of osteopenia that may occur under such circumstances is heightened by our detection in a cross-sectional study of low bone mass in severely burned children. We report here the acute histomorphometric and biochemical response of bone to severe burn injury, as well as bone mass in severely burned children. We enrolled 24 patients ages 5.8 to 17.5 years following burns of 63 +/- 16% (SD) body surface area. Serum and urine were collected weekly until iliac crest bone biopsy was obtained 26 +/- 10 days postburn. Seventeen of 18 patients, including 5 patients receiving growth hormone treatment to accelerate wound healing, failed to take up doxycycline in trabecular bone, and had no detectable osteoblasts at the osteoid seam, while eroded surface was normal and osteoblasts were documented by staining. Thus, bone formation was virtually absent. There was an eightfold elevation in urinary free cortisol excretion and high serum levels of acute phase reactants and interleukin-1 beta and -6. Biochemical markers of bone formation, osteocalcin, and type I procollagen propeptide were low, as were resorptive markers urinary pyridinoline and deoxypyridinoline. However, there was no correlation with resorptive surface. Mean age-related z-score for bone mass was -1.06 +/- 1.05, 40 days postburn. Immobilization and endogenous corticosteroid production may be the main factors responsible for acutely reduced bone formation while inflammatory cytokines may mediate resorption.

Activity of ethyl 5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate, a new hypocholesterolemic compound, in male rats and SEA Japanese quail.

Ethyl 5-(p-chlorophenoxy)-3-hydroxy-3-methylpentanoate (HMP), a new hypocholesterolemic compound, was evaluated in male rats at dosage levels ranging from 25-800 mg/kg/day and in SEA Japanese quail at approximately 200 mg/kg/day. In the rat, the atherogenic lipoprotein cholesterol, that is, the combination of very low density plus low density lipoprotein cholesterol (VLDL-C + LDL-C), was reduced 20-27% at dosage levels over 100 mg/kg/day, while high density lipoprotein cholesterol (HDL-C) and total serum cholesterol (TSC) were significantly decreased 25-46%, respectively, at all dose levels of HMP. Liver weights with HMP treatment were significantly elevated (11-26%) in the rat. HMP was not active in the SEA Japanese quail, since an initial reduction in artery cholesterol could not be confirmed in subsequent tests.