Complete pathological response in rectal cancer utilising novel treatment strategies for neo-adjuvant therapy: A systematic review.

BACKGROUND: Locally advanced rectal cancer is routinely treated with neo-adjuvant long course chemoradiotherapy or short course radiotherapy, followed by total mesorectal excision. Not all patients respond to this treatment and there has been an emergence of novel treatment strategies designed to improve outcomes for these patients. This systematic review aims to assess the current novel neo-adjuvant treatment strategies being utilised in the treatment of patients with rectal cancer and how these impact pathological complete response (pCR) rates. METHODS: A systematic review of the literature was performed to evaluate pathological response in patients with rectal cancer receiving novel neo-adjuvant therapy. EMBASE and Medline electronic databases were searched for relevant articles. Articles published between January 2008 and February 2019 were retrieved. Included studies underwent critical appraisal and complete pathological response rates were recorded. RESULTS: Of the initial 1074 articles identified, 217 articles fulfilled the inclusion criteria, of these 60 articles (4359 patients) were included. Neo-adjuvant therapy delivered included novel long course chemoradiation therapy, neoadjuvant chemotherapy alone, addition of a biological agent, total neo-adjuvant therapy, novel short course radiation therapy and studies utilising biomarkers to select patients for therapy. Complete pathological response rates ranged from 0 to 60%. CONCLUSION: A validated novel neo-adjuvant therapy that significantly increases pCR rates in patients with rectal cancer has not been identified.

Robotic transanal minimally invasive surgery - technical, oncological and patient outcomes from a single institution.

AIM: Robotic transanal minimally invasive surgery (R-TAMIS) is gaining traction around the globe as an alternative to laparoscopic conventional TAMIS for local excision of benign and early malignant rectal lesions. The aim was to analyse patient and oncological outcomes of R-TAMIS for consecutive cases in a single centre. METHODS: A prospective analysis of consecutive R-TAMIS procedures over a 12-month period was performed. Data were collated from hospital databases and theatre registers. RESULTS: Eleven patients (six men, five women), mean age 69.81 years (51-92 years), underwent R-TAMIS over 12 months utilizing a da Vinci Xi platform. The mean lesion size was 36 mm (20-60 mm) with a mean distance from the anal verge of 7.5 cm (3-14 cm). Five lesions were posterior in anatomical location, four anterior, one right lateral and one left lateral. All procedures were performed in the lithotomy position using a GelPOINT Path Platform. Mean operative time was 64 min (40-100 min). Complete resection was achieved in 10/11 patients with two patients being upgraded to a diagnosis of adenocarcinoma. Nine patients were diagnosed with dysplastic lesions. Four patients had a false positive diagnosis of an invasive tumour on MRI. Six patients required suturing for full-thickness resections. One patient had a postoperative bleed requiring repeat endoscopy and clipping. One patient (full-thickness resection of T3 tumour) proceeded to a formal resection without difficulty with no residual disease (T0N0, 0/22). One patient with a fully resected T2 tumour is undergoing a surveillance protocol. The mean length of stay was 1 day with two patients having a length of stay of 2 days and one patient of 4 days. CONCLUSION: R-TAMIS could potentially represent a safe novel approach for local resection of rectal lesions.

Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis.

AIM: Peritoneal metastases from colorectal cancer confer the worst survival among all metastatic sites. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with isolated colorectal peritoneal metastases (CRPM) a favourable long-term survival. There are numerous factors postulated to influence survival in patients undergoing CRS and HIPEC. The aim of this study was to identify the key perioperative prognostic factors that influence survival in patients undergoing CRS and HIPEC for isolated CRPM. METHOD: A systematic review and meta-analysis were conducted to evaluate prognostic factors influencing survival in patients undergoing CRS and HIPEC for isolated CRPM. RESULTS: Thirty-three studies fitted the inclusion criteria for the systematic review, with 25 studies included in the meta-analysis. On pooled analysis, incomplete cytoreduction, increasing peritoneal carcinoma index (PCI) and lymph node involvement were significantly associated with a worse survival. Additionally, a rectal primary [hazard ratio (HR) 1.93, 95% CI 1.10-3.37], adjuvant chemotherapy (HR 0.71, 95% CI 0.54-0.93) and perioperative grade III/IV morbidity (HR 1.59, 95% CI 1.17-2.16) were also found to significantly influence survival. Notably, tumour differentiation and signet ring cell histology did not influence survival on pooled analysis. CONCLUSION: This meta-analysis confirms that in patients undergoing CRS and HIPEC for isolated CRPM, incomplete cytoreduction, high PCI and lymph node involvement have a negative influence on survival. In addition, a rectal primary, adjuvant chemotherapy use and grade III/IV morbidity are important factors that also significantly influence survival.

Photon-enhanced thermionic emission from heterostructures with low interface recombination.

Photon-enhanced thermionic emission is a method of solar-energy conversion that promises to combine photon and thermal processes into a single mechanism, overcoming fundamental limits on the efficiency of photovoltaic cells. Photon-enhanced thermionic emission relies on vacuum emission of photoexcited electrons that are in thermal equilibrium with a semiconductor lattice, avoiding challenging non-equilibrium requirements and exotic material properties. However, although previous work demonstrated the photon-enhanced thermionic emission effect, efficiency has until now remained very low. Here we describe electron-emission measurements on a GaAs/AlGaAs heterostructure that introduces an internal interface, decoupling the basic physics of photon-enhanced thermionic emission from the vacuum emission process. Quantum efficiencies are dramatically higher than in previous experiments because of low interface recombination and are projected to increase another order of magnitude with more stable, low work-function coatings. The results highlight the effectiveness of the photon-enhanced thermionic emission process and demonstrate that efficient photon-enhanced thermionic emission is achievable, a key step towards realistic photon-enhanced thermionic emission based energy conversion.

Theoretical investigations of the experimentally observed selectivity of a cobalt imprinted polymer.

A cobalt imprinted polymer synthesised, for reducing the volume of radioactive waste generated during nuclear reactor decontaminations, using vinylbenzyl iminodiacetate (VbIDA) as the functional ligand, has been found to be selective for cobaltous ions over excess ferrous ions. The selectivity of the polymer has been investigated through theoretical calculation of the formation energies of complexes involved by using the ab-initio density functional theory (DFT) code SIESTA (Spanish Initiative for Electronic Simulations with Thousands of Atoms). The formation energies of complexes of Fe(2+), Co(2+), Cu(2+) and Ni(2+) with the free functional ligands as well as with ligands attached to the crosslinkers have been calculated. The calculations revealed that the ferrous forms an unstable complex with the ligands attached to the crosslinkers. The formation energy calculation results were found to corroborate the experimentally observed selectivity order.

Synthesis, characterization and thermolysis studies on 3,7-dinitro-1,3,5,7-tetraazabicyclo[3,3,1]nonane (DPT): A key precursor in the synthesis of most powerful benchmark energetic materials (RDX/HMX) of today.

This paper reports studies undertaken on 3,7-dinitro-1,3,5,7-tetraazabicyclo[3,3,1]nonane (DPT). The synthesis of DPT was carried out by the nitration of hexamine based on the lines of reported method with minor modification. DPT was characterized by elemental analysis, scanning electron microscopy (SEM), Fourier transform infrared (FTIR) and (1)H nuclear magnetic resonance (NMR) techniques. Thermal stability of DPT was studied using thermogravimetry (TG) and differential scanning calorimetry (DSC). The thermal analysis studies revealed that DPT undergoes decomposition at 211 degrees C. Decomposition of DPT using TG-FTIR indicated the evolution of carbon dioxide, water and oxides of nitrogen as main gaseous products. The electrochemical behavior of DPT was studied using cyclic voltammetric (CV) studies. The experimentally determined sensitivity parameters indicated the insensitive nature of DPT towards external stimuli. The performance parameters of DPT, RDX and HMX have been computed using Linear Output Thermodynamic User Friendly Software for Energetic Systems (LOTUSES) code. The predicted properties of DPT are interesting and important from the point of process technology and/or safety. The work reported in this paper enriches the existing scanty research and development data on one of the key precursor used for synthesis of important high energy materials (HEMs).

Molecular structure and activity toward DNA of baicalein, a flavone constituent of the Asian herbal medicine "Sho-saiko-to".

Baicalein (5,6,7-trihydroxyflavone, 1) is of interest because of its broad spectrum of biological activity. It is a constituent of the east Asian herbal remedy, "Sho-saiko-to". The 3D structure of 1 was determined using X-ray diffraction. The compound exists in an almost planar conformation with a C-2-C-1' bond distance of 1.476(5) A. Hydrogen-bonding interactions predominate in the crystal structure. The position of the three hydroxyl groups maximizes intramolecular hydrogen bonding, and each of the hydroxyl hydrogen atoms is a donor in a three-center hydrogen bond. The carbonyl oxygen, O-4, is an acceptor in an intramolecular hydrogen bond (with OH-5). Two molecules of 1 exist as hydrogen-bonded dimers related by inversion center (-x + 1, -y, -z + 1). O-4 is also an acceptor in an intermolecular hydrogen bond with OH-6. The planarity of the flavone framework is dependent on structural and/or electronic forces that stabilize the negative charge on the exocyclic oxygen atom, O-4. Compound 1, therefore, is planar in any situation where forces can stabilize the negative charge on O-4. Consistent with this, UV absorbance studies performed on 1-DNA complexes with varying concentrations of 1 strongly suggest intercalation of 1 within the double helix, followed by possible interstrand cross-links.

Impediments to global surveillance of infectious diseases: consequences of open reporting in a global economy.

Globalization has led to an increase in the spread of emerging and re-emerging infectious diseases. International efforts are being launched to control their dissemination through global surveillance, a major hindrance to which is the failure of some countries to report outbreaks. Current guidelines and regulations on emerging and re-emerging infectious diseases do not sufficiently take into account the fact that when developing countries report outbreaks they often derive few benefits and suffer disproportionately heavy social and economic consequences. In order to facilitate full participation in global surveillance by developing countries there should be: better and more affordable diagnostic capabilities to allow for timely and accurate information to be delivered in an open and transparent fashion; accurate, less sensationalist news reporting of outbreaks of diseases; adherence by countries to international regulations, including those of the World Trade Organization and the International Health Regulations; financial support for countries that are economically damaged by the diseases in question. The article presents two cases--plague in India and cholera in Peru--that illuminate some of the limitations of current practices. Recommendations are made on measures that could be taken by WHO and the world community to make global surveillance acceptable.

Deletion/insertion mutation that causes biotinidase deficiency may result from the formation of a quasipalindromic structure.

Biotinidase is responsible for recycling the vitamin biotin from biocytin that is formed after the proteolytic degradation of the biotin-dependent carboxylases. We have identified a deletion/insertion mutation within exon D of the human biotinidase gene in a child with biotinidase deficiency. The mutation causes a frame shift and premature termination which are predicted to result in a truncated protein. We propose that the mutation occurred during DNA replication by either of two mechanisms. Both mechanisms involve formation of a quasipalindromic hairpin loop in the template and dissociation of DNA polymerase alpha. This mutation supports the formation of palindromic structures as a possible cause of deletions in eukaryotes, and supports the proposal, derived from in vitro studies, that polymerase alpha may preferentially arrest or dissociate at specific template sequences.

Temperature induced interstrand crosslinks in cisplatin-DNA adducts detected by electrophoresis and UV spectrophotometer.

Thermal melting profiles of DNA samples complexed with the anti-tumor drug cisplatin exhibit significant hypochromicity at pre-melting temperatures while a reduction in total hyperchromicity is observed in the melting region. Densitometric analysis of agarose gel electrophoresis pattern of DNA-cisplatin adducts heated to different temperatures in the pre-melting region and frozen in their conformations reveals a gradual retardation of mobility as the temperature increases. We attribute these results to a temperature induced transition in the mode of binding of cisplatin to DNA from an initial intrastrand monofunctional binding to bifunctional interstrand crosslink formation which results in gradual bending of the helix.

The effects of the normal and oncogenic forms of the neu tyrosine kinase, and the corresponding forms of an immunoglobulin E receptor/neu tyrosine kinase fusion protein, on Xenopus oocyte maturation.

In this work, we have used Xenopus oocyte maturation as a read-out for examining the ability of the neu tyrosine kinase (p185neu) to participate with the epidermal growth factor (EGF) receptor in a common signal transduction pathway. We find that unlike the case for the EGF receptor, which elicits EGF-dependent maturation of these oocytes as reflected by their germinal vesicle breakdown (GVBD), neither the normal neu tyrosine kinase (p185val664) nor the oncogenic form of neu (p185glu664) are able to effectively trigger this maturation event. However, expression of p185glu664 causes a specific and significant promotion of the progesterone-induced GVBD, reducing the half-time for this maturation even from approximately 9 h to approximately 5 h. Stimulation of the progesterone-induced GVBD did not occur following the expression of a kinase-deficient p185neu protein (in which a lysine residue at position 758 was changed to alanine). Essentially identical results were obtained when the mRNAs coding for fusion proteins comprised of the extracellular domain of the receptor for immunoglobulin E (IgE), and the membrane-spanning and tyrosine kinase domains of normal or oncogenic p185neu (designated IgER/p185val664 and IgER/p185glu664, respectively), were injected into oocytes. Antigen-induced crosslinking of IgER/p185val164 proteins expressed in oocytes caused a reduction in the half-time for the progesterone-stimulated GVBD from approximately 9 h to approximately 7 h. Thus, the aggregation of the membrane-spanning and/or tyrosine kinase domains of p185val664 partially mimics the effects of the oncogenic forms of p185neu. Overall, the results of these studies suggest that the activation of the p185neu tyrosine kinase by a point mutation within its membrane-spanning helix, or an aggregation event, can result in the facilitation of oocyte maturation events that are elicited by other factors (e.g. progesterone). However, the activated p185neu tyrosine kinases are not able to mimic the EGF-stimulated EGF receptor tyrosine kinase in triggering oocyte maturation, which suggests that the EGF receptor and the p185neu tyrosine kinase do not input into identical signal transduction pathways in these cells.

Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus.

In mitogenically stimulated and tyrosine kinase-transformed cells, a substantial fraction of the ras GTPase-activating protein (GAP) forms a complex with a protein termed p190. We have cloned several cDNAs encoding the p190 protein. Analysis of the predicted protein sequence reveals three distinct domains with homology to previously described sequences. An N-terminal domain of p190 contains sequence motifs that are found in all of the known GTPases. At the C-terminus of the protein is a domain that contains sequences very similar to those found in the breakpoint cluster region gene product, n-chimerin, and rho GAP, all of which have been shown to possess intrinsic GAP activity on small GTPases. Finally, a 778 aa segment in the middle of p190 is nearly identical in sequence to a recently described transcriptional repressor. This raises the possibility that p190, acting via GAP, can transduce signals from p21ras to the nucleus, perhaps affecting expression of specific cellular genes.

Olfactory bulbectomy increases basal suprachiasmatic cyclic AMP levels in male rats.

For further characterization of the olfactory bulb's role in the medication of chronobiological phenomena, we examined basal cyclic- 3',5'-adenosine monophosphate (cAMP) levels in the suprachiasmatic nuclei (SCN) and lateral hippocampus (LHIP) following bilateral olfactory bulbectomy (OBX) to assess the effects of olfactory bulb removal on the biological clock. Two groups of adult Long-Evans rats underwent OBX or sham control surgery (SHAM). Eight weeks postoperative, the animals were decapitated at the time of maximal cAMP accumulation (circadian time 9-11 h), brains were removed, frozen in liquid nitrogen, and sectioned on a cryostat. Individual brain nuclei (SCN and LHIP) were microdissected using the Palkovits punch technique and analyzed by scintillation proximity assay for cAMP. We report a 83.6% increase in basal cAMP levels in the SCN following OBX (OBX = 63.7 pmol cAMP/mg protein, SHAM = 34.7 pmol cAMP/mg protein, p less than 0.01). No significant differences in LHIP cAMP levels were found. This specific increase in SCN cAMP, at the time of maximum cAMP accumulation, may give insight into the biochemical basis for altered activity levels following OBX.

Altered restriction patterns of microwave irradiated lambdaphage DNA.

Samples of lambdaphage DNA exposed to short pulses of microwave irradiation were subjected to restriction fragmentation by Eco RI and Bam HI. Eco RI digests of microwaved DNA samples yielded three additional fragments ranging in base pair lengths between 24,226 and 7,421 besides the six expected fragments. While Bam HI digests of the microwaved samples did not yield any additional fragments, mobilities of the Bam HI fragments from the microwaved DNA samples were slower and the bands were broader in comparison to those from native samples. We attribute these altered restriction patterns to the conformational anomolies in DNA resulting from single strand breaks and localized strand separations induced by microwave irradiation.

Molecular cloning of the gene for the human placental GTP-binding protein Gp (G25K): identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42.

We have isolated cDNA clones from a human placental library that code for a low molecular weight GTP-binding protein originally designated Gp (also called G25K). This identification is based on comparisons with the available peptide sequences for the purified human Gp protein and the use of two highly specific anti-peptide antibodies. The predicted amino acid sequence of the protein is very similar to those of various members of the ras superfamily of low molecular weight GTP-binding proteins, including the N-, Ki-, and Ha-ras proteins (30-35% identical), the rho proteins (approximately 50% identical), and the rac proteins (approximately 70% identical). The highest degree of sequence identity (80%) is found with the Saccharomyces cerevisiae cell-division-cycle protein CDC42. The human placental gene, which we designate CDC42Hs, complements the cdc42-1 mutation in S. cerevisiae, which suggests that this GTP-binding protein is the human homolog of the yeast protein.

Microfilaments regulate the rate of exocytosis in rat basophilic leukemia cells.

Disruption of microfilaments in rat basophilic leukemia (RBL) cells by exposure to cytochalasin B is observed to potentiate the rate of antigen-stimulated secretion from these cells. Under these conditions, cytochalasin B is without effect on the antigen-stimulated production of inositol phosphates or 45Ca2(+)-influx. In streptolysin-O-permeabilized RBL cells, cytochalasin B is observed to potentiate the rate of secretion in response both to guanosine 5'-(2-thio)-O-triphosphate (GTP gamma S) and to Ca2+ (buffered between 0.1 and 10 microM). However, under these conditions, cytochalasin B does not affect to antigen-stimulated production of inositol phosphates. Consistent with these data, microfilaments are proposed to regulate a terminal step in exocytosis, in a physiologically relevant manner.

A guanine nucleotide-binding protein participates in IgE receptor-mediated activation of endogenous and reconstituted phospholipase A2 in a permeabilized cell system.

Activation of phospholipase A2 (PLA2) by the aggregation of receptors for immunoglobulin E (IgE) can be studied in streptolysin O-permeabilized rat basophilic leukemia cells. Under these conditions, 40 microM guanosine 5'-O-(3-thio)triphosphate (GTP gamma S) stimulates PLA2 activity 5-6-fold when free Ca2+ concentrations are buffered at 10(-7)-10(-5) M. Antigen-mediated cross-linking of receptors for IgE synergizes with low concentrations of GTP gamma S (0.1 microM) to cause similar stimulation. When the endogenous PLA2 activity is inactivated by chemical modification, we find that exogenously supplied PLA2 from porcine pancreas and Naja naja venom is also activated by the aggregation of cell-surface IgE receptors in these permeabilized cells. As with endogenous PLA2, GTP gamma S synergizes with IgE receptor-aggregation to activate exogenous PLA2 approximately 10-fold at 10(-7)-10(-6) M free Ca2+. These data indicate that receptor-mediated activation of a guanine nucleotide-binding protein can shift the Ca2+ dependence of PLA2 activity resulting in greatly enhanced activity at physiological concentrations of intracellular free Ca2+. The partial reconstitution of various PLA2 forms into such a broken-cell system offers a new approach for studying the mechanisms of G-protein-mediated activation of PLA2.

Cholera toxin increases the rate of antigen-stimulated calcium influx in rat basophilic leukemia cells.

Cholera toxin pretreatment has been found to cause a 3-fold increase in the initial rate of antigen-stimulated secretion of serotonin from rat basophilic leukemia (RBL) cells. Under similar conditions, cholera toxin enhances the antigen-stimulated rise in cytoplasmic free ionized calcium levels and causes a 2-3-fold increase in the rate of antigen-stimulated influx of 45Ca. In intact RBL cells cholera toxin pretreatment potentiates the antigen-stimulated production of inositol phosphates, but in permeabilized cells, with strongly buffered free calcium levels, no effect of cholera toxin pretreatment on the antigen-stimulated activation of cellular phospholipase activities is observed. In addition, pretreatment of cells with tetradecanoylphorbol acetate inhibits antigen-stimulated production of inositol phosphates by greater than 95%, while the stimulated influx of 45Ca remains unaffected. These data indicate that the antigen-stimulated influx of calcium into RBL cells can be dissociated from the production of inositol phosphates in these cells. The observed effects of cholera toxin on exocytosis and Ca2+ influx in RBL cells are not due to the elevation of cellular cyclic AMP levels since a variety of agents capable of elevating cellular cyclic AMP levels do not mimic these effects. Together, these data suggest that a cholera toxin-sensitive guanine nucleotide-binding protein is involved in the pathway responsible for the antigen-stimulated influx of calcium into RBL cells.

Conformational flexibility of poly (dG-m5dC) under very low salt conditions.

The methylated DNA polymer poly (dG-m5dC) which exhibits a B helical conformation in solutions containing 20 mM NaCl, undergoes a gradual and reversible transition to the Z conformation as the NaCl concentration is lowered. The midpoint of this transition occurs around 5-6 mM NaCl. The conformational flexibility of this polymer at such low NaCl concentrations opens up the possibility of studying the effects of other perturbants with negligible interference from salt concentration effects.