The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis.

BACKGROUND: The addition of HER2-targeted agents to standard treatment has been shown to improve outcomes for HER2 positive metastatic breast cancer patients. We undertook a meta-analysis to evaluate the efficacy of HER2-targeted therapy in addition to standard treatment in metastatic breast cancer patients. PATIENTS AND METHODS: Eligible trials were randomised controlled trials (RCTs) comparing the addition of HER2 therapy to standard treatment (hormone or chemotherapy) reporting overall survival (OS), time to progression (TTP), progression-free survival (PFS) and/or response rates. RESULTS: Eight trials comprising 1848 patients were eligible for inclusion. HER2-targeted agents were trastuzumab and lapatinib and therapeutic partners were taxanes (4 RCTs), anthracyclines (1), capecitabine (2), anastrozole (1) and letrozole (1). The addition of HER2-targeted agents improved OS [hazard ratios (HR) 0.78; 95% confidence interval (CI) 0.67-0.91], TTP (HR 0.56; 95% CI 0.48-0.64), PFS (HR 0.63; 95% CI 0.53-0.74) and overall response rate (relative risk 1.67; 95% CI 1.46-1.90). CONCLUSIONS: Our meta-analysis confirms the benefit of adding HER2-targeted therapy to standard treatment in HER2 positive metastatic breast cancer. Compared with OS, TTP, PFS and ORR overestimate treatment benefit. Trials in our meta-analysis differed in terms of partner drug or HER2 agents, yet delivered comparable outcomes.

Evidence of slow and variable choice-stepping reaction time in cancer survivors with chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is reported to affect up to 70 % of cancer survivors. Despite evidence that CIPN-related impairments often translate into balance and mobility deficits, the effects on stepping and quality of gait, well-documented risk factors for falls, are unclear. AIMS: (i) Establish choice-stepping reaction time (CSRT) performance in survivors with CIPN compared to young and older healthy controls and people with Parkinson's disease; (ii) document walking stability; (iii) investigate relationships between stepping and gait data to objective and patient-reported outcomes. METHODS: 41 cancer survivors with CIPN (mean (SD) age: 60.8 (9.7) years) who were ≥3months post chemotherapy, performed tests of simple and inhibitory CSRT. Walking stability measures were derived from 3-D accelerometry data during the 6-minute walk test. CIPN was assessed using neurological grading and patient-reported outcome measures (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire in CIPN Questionnaire scale EORTC CIPN20). RESULTS: In both stepping tests, CIPN participants performed at the level of adults aged 10 years older and people with mild to moderate Parkinson's disease. Mean (SD) total stepping response times in both CSRT (1160 (190) milliseconds) and inhibitory CSRT (1191 (164) milliseconds) tests were not associated with objective neurological grading but were correlated with increased difficulty feeling the ground. Participants with lower-limb vibration sensation deficit had slower and more variable CSRT times. There were no associations between walking stability and objective measures of CIPN, and limited correlations with the EORTC-CIPN20. CONCLUSIONS: Cancer survivors with CIPN showed deficits in voluntary stepping responses and seemed to compensate for their sensory and motor deficits by walking slower to maintain stability. Objective and patient-reported outcomes of CIPN were correlated with slower and more variable stepping response times. Future studies should aim to identify the causes of the apparent premature decline in cognitive-motor function and develop remediating interventions.

Interleukin (IL)-1 receptor-associated kinase (IRAK) requirement for optimal induction of multiple IL-1 signaling pathways and IL-6 production.

Interleukin (IL)-1 is a proinflammatory cytokine with pleiotropic effects in inflammation. IL-1 binding to its receptor triggers a cascade of signaling events, including activation of the stress-activated mitogen-activated protein (MAP) kinases, c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, as well as transcription factor nuclear factor kappaB (NF-kappaB). IL-1 signaling results in cellular responses through induction of inflammatory gene products such as IL-6. One of the earliest events in IL-1 signaling is the rapid interaction of IL-1 receptor-associated kinases, IRAK and IRAK-2, with the receptor complex. The relative roles of IRAK and IRAK-2 in IL-1 signaling pathways and subsequent cellular responses have not been previously determined. To evaluate the importance of IRAK in IL-1 signaling, IRAK-deficient mouse fibroblast cells were prepared and studied. Here we report that IL-1-mediated activation of JNK, p38, and NF-kappaB were all reduced in embryonic fibroblasts deficient in IRAK expression. In addition, IL-6 production in response to IL-1 was also dramatically reduced in IRAK-deficient embryonic fibroblasts and in skin fibroblasts prepared from IRAK-deficient mice. Our results demonstrate that IRAK plays an essential proximal role in coordinating multiple IL-1 signaling pathways for optimal induction of cellular responses.

Defective interleukin (IL)-18-mediated natural killer and T helper cell type 1 responses in IL-1 receptor-associated kinase (IRAK)-deficient mice.

Interleukin (IL)-18 is functionally similar to IL-12 in mediating T helper cell type 1 (Th1) response and natural killer (NK) cell activity but is related to IL-1 in protein structure and signaling, including recruitment of IL-1 receptor-associated kinase (IRAK) to the receptor and activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor (NF)-kappaB. The role of IRAK in IL-18-induced responses was studied in IRAK-deficient mice. Significant defects in JNK induction and partial impairment in NF-kappaB activation were found in IRAK-deficient Th1 cells, resulting in a dramatic decrease in interferon (IFN)-gamma mRNA expression. In vivo Th1 response to Propionibacterium acnes and lipopolysaccharide in IFN-gamma production and induction of NK cytotoxicity by IL-18 were severely impaired in IRAK-deficient mice. IFN-gamma production by activated NK cells in an acute murine cytomegalovirus infection was significantly reduced despite normal induction of NK cytotoxicity. These results demonstrate that IRAK plays an important role in IL-18-induced signaling and function.

Roles of LAP2 proteins in nuclear assembly and DNA replication: truncated LAP2beta proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopus laevis extracts.

Humans express three major splicing isoforms of LAP2, a lamin- and chromatin-binding nuclear protein. LAP2beta and gamma are integral membrane proteins, whereas alpha is intranuclear. When truncated recombinant human LAP2beta proteins were added to cell-free Xenopus laevis nuclear assembly reactions at high concentrations, a domain common to all LAP2 isoforms (residues 1-187) inhibited membrane binding to chromatin, whereas the chromatin- and lamin-binding region (residues 1-408) inhibited chromatin expansion. At lower concentrations of the common domain, membranes attached to chromatin with a unique scalloped morphology, but these nuclei neither accumulated lamins nor replicated. At lower concentrations of the chromatin- and lamin-binding region, nuclear envelopes and lamins assembled, but nuclei failed to enlarge and replicated on average 2. 5-fold better than controls. This enhancement was not due to rereplication, as shown by density substitution experiments, suggesting the hypothesis that LAP2beta is a downstream effector of lamina assembly in promoting replication competence. Overall, our findings suggest that LAP2 proteins mediate membrane-chromatin attachment and lamina assembly, and may promote replication by influencing chromatin structure.

Evaluation of potassium iodide (KI) and ammonium perchlorate (NH4ClO4) to ameliorate 131I- exposure in the rat.

Nuclear reactor accidents and the threat of nuclear terrorism have heightened the concern for adverse health risks associated with radiation poisoning. Potassium iodide (KI) is the only pharmaceutical intervention that is currently approved by the Food and Drug Administration for treating (131)I(-) exposure, a common radioactive fission product. Though effective, KI administration needs to occur prior to or as soon as possible (within a few hours) after radioactive exposure to maximize the radioprotective benefits of KI. During the Chernobyl nuclear reactor accident, KI was not administered soon enough after radiation poisoning occurred to thousands of people. The delay in administration of KI resulted in an increased incidence of childhood thyroid cancer. Perchlorate (ClO(4)(-)) was suggested as another pharmaceutical radioprotectant for 131I- poisoning because of its ability to block thyroidal uptake of iodide and discharge free iodide from the thyroid gland. The objective of this study was to compare the ability of KI and ammonium perchlorate to reduce thyroid gland exposure to radioactive iodide (131I-). Rats were dosed with 131I- tracer and 0.5 and 3 h later dosed orally with 30 mg/kg of either ammonium perchlorate or KI. Compared to controls, both anion treatments reduced thyroid gland exposure to 131I- equally, with a reduction ranging from 65 to 77%. Ammonium perchlorate was more effective than stable iodide for whole-body radioprotectant effectiveness. KI-treated animals excreted only 30% of the (131)I(-) in urine after 15 h, compared to 47% in ammonium perchlorate-treated rats. Taken together, data suggest that KI and ammonium perchlorate are both able to reduce thyroid gland exposure to 131I- up to 3 h after exposure to 131I-. Ammonium perchlorate may offer an advantage over KI because of its ability to clear 131I- from the body.

Physical activity uptake in patients with HIV: who does how much?

Regular physical activity is recommended for patients with human immunodeficiency virus (HIV) to help manage their disease. However, to date, little is known about levels of uptake of this advice. This study describes daily physical activity in HIV antibody-positive patients attending a public hospital infectious diseases clinic, compares them with those of patients attending the clinic for general infectious diseases and investigates compliance with the recommendations of the Centres for Disease Control and Prevention and American College of Sports Medicine physical activity guidelines. During April 2006, 261 patients completed the International Physical Activity Questionnaire short form. One hundred and ninety-one reported being HIV antibody-positive. Results showed that 1:4 HIV antibody-positive and 1:3 HIV antibody-negative respondents failed to meet the recommended guidelines. These findings are of concern, given the evidence-based benefits of regular physical activity. Further work is needed to identify barriers to participation and interventions that can improve uptake.

An assessment of the acute dietary exposure to glyphosate using deterministic and probabilistic methods.

Use of glyphosate in crop production can lead to residues of the active substance and related metabolites in food. Glyphosate has never been considered acutely toxic; however, in 2015 the European Food Safety Authority (EFSA) proposed an acute reference dose (ARfD). This differs from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR) who in 2016, in line with their existing position, concluded that an ARfD was not necessary for glyphosate. This paper makes a comprehensive assessment of short-term dietary exposure to glyphosate from potentially treated crops grown in the EU and imported third-country food sources. European Union and global deterministic models were used to make estimates of short-term dietary exposure (generally defined as up to 24 h). Estimates were refined using food-processing information, residues monitoring data, national dietary exposure models, and basic probabilistic approaches to estimating dietary exposure. Calculated exposures levels were compared to the ARfD, considered to be the amount of a substance that can be consumed in a single meal, or 24-h period, without appreciable health risk. Acute dietary intakes were <100% of the ARfD for all foodstuffs, except wild fungi, when calculated using the EFSA model. The model assumptions differ from those of the source model (German national model), resulting in the use of a higher variability factor. Intakes estimated with the German model represented only 18% of the ARfD. The impact of differing assumptions regarding variability and other input parameters is discussed. Probabilistic exposure estimates showed that the acute intake on no person-days exceeded 10% of the ARfD, even for the pessimistic scenario.

An assessment of dietary exposure to glyphosate using refined deterministic and probabilistic methods.

Glyphosate is a herbicide used to control broad-leaved weeds. Some uses of glyphosate in crop production can lead to residues of the active substance and related metabolites in food. This paper uses data on residue levels, processing information and consumption patterns, to assess theoretical lifetime dietary exposure to glyphosate. Initial estimates were made assuming exposure to the highest permitted residue levels in foods. These intakes were then refined using median residue levels from trials, processing information, and monitoring data to achieve a more realistic estimate of exposure. Estimates were made using deterministic and probabilistic methods. Exposures were compared to the acceptable daily intake (ADI)-the amount of a substance that can be consumed daily without an appreciable health risk. Refined deterministic intakes for all consumers were at or below 2.1% of the ADI. Variations were due to cultural differences in consumption patterns and the level of aggregation of the dietary information in calculation models, which allows refinements for processing. Probabilistic exposure estimates ranged from 0.03% to 0.90% of the ADI, depending on whether optimistic or pessimistic assumptions were made in the calculations. Additional refinements would be possible if further data on processing and from residues monitoring programmes were available.

The treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome.

Forty-four episodes of Pneumocystis carinii pneumonia (PCP) occurred in 36 of 70 patients with the acquired immunodeficiency syndrome. Thirty-four patients with 40 episodes of PCP were treated with trimethoprim-sulfamethoxazole. Therapy was successful in 18 episodes (45%), but was unsuccessful in 15 episodes (37.5%). In the latter cases, two patients died within 72 hours; 13, of whom nine died, had therapy changed to pentamidine. In seven additional episodes (17.5%), trimethoprim-sulfamethoxazole was changed to pentamidine due to adverse reactions; all patients survived. Seven patients (26% of survivors) developed recurrent PCP. Twenty-two patients (65%) developed adverse reactions to trimethoprim-sulfamethoxazole, including leukopenia (20), hepatotoxicity (12), fever (eight), rash (six), and immediate reactions (two). Reactions were most common during the second week of therapy. Patients with the acquired immunodeficiency syndrome who have PCP have a high trimethoprim-sulfamethoxazole failure rate, due either to adverse reactions or unresponsive infection. Late recurrence is common.

Molecular analysis of the recA gene of Agrobacterium tumefaciens C58.

The complete nucleotide sequence of the Agrobacterium tumefaciens recA gene was determined. A comparison of the translated open reading frame of the gene with other known recA sequences revealed significant sequence conservation. However, unlike its Escherichia coli equivalent, A. tumefaciens recA lacks the upstream 'SOS box', suggesting a different mechanism of regulation for this gene.

Cloning and characterisation of the human adenosine A3 receptor gene.

We have cloned the gene for the human adenosine A3 receptor and report characterisation of its intron/exon structure and upstream untranslated region. The open reading frame is interrupted by a single intron of approximately 2.2 kb, within the coding sequence for the second cytoplasmic loop. Sequence analysis of the upstream region reveals no TATA box but the transcriptional start site has been mapped to a common nucleotide in three tissues by 5'-RACE and RT-PCR analysis. Northern blotting, 5'-RACE PCR and analysis of upstream sequences, have provided no evidence for the occurrence of further introns in the upstream untranslated sequence or of transcriptional regulation by alternative splicing in this region.

Some aspects of the inhibition of the action of antidiuretic hormone by lithium ions in the rat kidney and bladder of the toad Bufo marinus.

1. The effect of intravenous infusions of various ions on the antidiuretic action of antidiuretic hormone has been studied in rats.2. Lithium (13 mmol/l.) reversibly inhibits the antidiuretic responses. Similar concentrations of potassium, rubidium, strontium, magnesium, choline and calcium do not. Lithium has a similar effect on the antidiuretic activity of oxytocin.3. The inhibition is not simply related to blood nor whole body lithium concentrations.4. Lithium (2 mmol/l.) in contact with the serosal surface also inhibits the transport of water facilitated by either 0.5 U/l. antidiuretic hormone or 1.1 mmol/l. cyclic adenosine monophosphate in the isolated toad bladder.5. Choline (2 mmol/l.) on the serosal surface also inhibits the transport of water facilitated by vasopressin in the toad bladder.

Modulation of striatal quinolinate neurotoxicity by elevation of endogenous brain kynurenic acid.

1. Nicotinylalanine, an inhibitor of kynurenine metabolism, has been shown to elevate brain levels of endogenous kynurenic acid, an excitatory amino acid receptor antagonist. This study examined the potential of nicotinylalanine to influence excitotoxic damage to striatal NADPH diaphorase (NADPH-d) and gamma-aminobutyric acid (GABA)ergic neurones that are selectively lost in Huntington's disease. 2. A unilateral injection of the N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid, into the rat striatum produced an 88% depletion of NADPH-d neurones. Intrastriatal infusion of quinolinic acid also produced a dose-dependent reduction in striatal GABA content. 3. Nicotinylalanine (2.3, 3.2, 4.6, 6.4 nmol 5 microl(-1), i.c.v.) administered with L-kynurenine (450 mg kg(-1)), a precursor of kynurenic acid, and probenecid (200 mg kg(-1)), an inhibitor of organic acid transport, 3 h before the injection of quinolinic acid (15 nmol) produced a dose-related attenuation of the quinolinic acid-induced loss of NADPH-d neurones. Nicotinylalanine (5.6 nmol 5 microl(-1)) in combination with L-kynurenine and probenecid also attenuated quinolinic acid-induced reductions in striatal GABA content. 4. Nicotinylalanine (4.6 nmol, i.c.v.), L-kynurenine alone or L-kynurenine administered with probenecid did not attenuate quinolinic acid-induced depletion of striatal NADPH-d neurones. However, combined administration of kynurenine and probenecid did prevent quinolinic acid-induced reductions in ipsilateral striatal GABA content. 5. Injection of nicotinylalanine, at doses (4.6 nmol and 5.6 nmol i.c.v.) which attenuated quinolinic acid-induced striatal neurotoxicity, when combined with L-kynurenine and probenecid produced increases in both whole brain and striatal kynurenic acid levels. Administration of L-kynurenine and probenecid without nicotinylalanine also elevated kynurenic acid, but to a lesser extent. 6. The results of this study demonstrate that nicotinylalanine has the potential to attenuate quinolinic acid-induced striatal neurotoxicity. It is suggested that nicotinylalanine exerts its effect by increasing levels of endogenous kynurenic acid in the brain. The results of this study suggest that agents which influence levels of endogenous excitatory amino acid antagonists such as kynurenic acid may be useful in preventing excitotoxic damage to neurones in the CNS.

The estrogenic activity of phthalate esters in vitro.

A large number of phthalate esters were screened for estrogenic activity using a recombinant yeast screen. a selection of these was also tested for mitogenic effect on estrogen-responsive human breast cancer cells. A small number of the commercially available phthalates tested showed extremely weak estrogenic activity. The relative potencies of these descended in the order butyl benzyl phthalate (BBP) > dibutyl phthalate (DBP) > diisobutyl phthalate (DIBP) > diethyl phthalate (DEP) > diisiononyl phthalate (DINP). Potencies ranged from approximately 1 x 10(6) to 5 x 10(7) times less than 17beta-estradiol. The phthalates that were estrogenic in the yeast screen were also mitogenic on the human breast cancer cells. Di(2-ethylhexyl) phthalate (DEHP) showed no estrogenic activity in these in vitro assays. A number of metabolites were tested, including mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mon-n-octyl phthalate; all were wound to be inactive. One of the phthalates, ditridecyl phthalate (DTDP), produced inconsistent results; one sample was weakly estrogenic, whereas another, obtained from a different source, was inactive. analysis by gel chromatography-mass spectometry showed that the preparation exhibiting estrogenic activity contained 0.5% of the ortho-isomer of bisphenol A. It is likely that the presence of this antioxidant in the phthalate standard was responsible for the generation of a dose-response curve--which was not observed with an alternative sample that had not been supplemented with o,p'-bisphenol A--in the yeast screen; hence, DTDP is probably not weakly estrogenic. The activities of simple mixtures of BBP, DBP, and 17beta-estradiol were assessed in the yeast screen. No synergism was observed, although the activities of the mixtures were approximately additive. In summary, a small number of phthalates are weakly estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vitro. No data has yet been published on whether these are also estrogenic in vivo; this will require tests using different classes of vertebrates and different routes of exposure.

bc1-1 rearrangement and cyclin D1 protein expression in multiple lymphomatous polyposis.

Multiple lymphomatous polyposis (MLP), characterized by multiple polyps involving long segments of the gastrointestinal (GI) tract, is believed to represent GI involvement by mantle cell lymphoma (MCL), primarily based on its histologic and immunophenotypic similarities with MCL. However, rearrangement of the bcl-1 locus, the molecular lesion characteristic of MCL, has not been investigated in this group of patients. The authors evaluated the morphologic, immunophenotypic, and molecular features of 18 cases of MLP and 8 B-cell lymphomas involving the GI tract (including 6 MALT lymphomas). All MLP cases presented with GI disease, and were histologically similar to MCL. DNA extracted from formalin-fixed, paraffin-embedded tissue was analyzed for evidence of bcl-1 rearrangement by PCR, using chromosome 11 specific and consensus JH primers. Amplifiable DNA was obtained in 24 of 26 cases (16 of 18 MLP cases and 8 of 8 controls). bcl-1 rearrangement was detected in 6 of 16 cases (38%), subsequently confirmed by sequencing of the breakpoint region, and in 0 of 8 controls. Immunostaining for cyclin D1 was positive in 14 of 18 MLPs, including the 6 bcl-1 rearranged cases and negative in 6 of 6 evaluable controls. The detection of bcl-1 rearrangement and cyclin D1 expression in cases of MLP supports the view that MLP represents primary MCL, of the GI tract. These techniques may also be helpful in differentiating MLP from other GI lymphomas, particularly low grade lymphomas of MALT, when only small routinely fixed endoscopic biopsies are available.

Potentiation of d-tubocurarine (d-Tc) neuromuscular blockade in cats by lithium chloride.

I.v. infusion of LiCl at 1.0 mEq/0.25 ml/min produced significant decrease in plasma Na+ from 158 +/- 4.5 mEq/l (p less than 0.025) and in Ca2+ from 7.8 +/- 0.34 to 6.8 +/- 0.24 mg% (p less than 0.01) with insignificant increase in K+. No significant changes in plasma electrolytes were observed on infusion of NaCl. The d-Tc induced neuromuscular blockade in Li Cl infused animals was significantly greater than that in Na Cl infused ones.