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DNA barcoding has been succesfully used for bio-surveillance of forest and agricultural pests in temperate areas, but has few applications in the tropics and particulary in Africa. Cacosceles newmannii (Coleoptera: Cerambycidae) is a Prioninae species that is locally causing extensive damage in commercially-grown sugarcane in the KwaZulu-Natal Province in South Africa. Due to the risk of spread of this species to the rest of southern Africa and to other sugarcane growing regions, clear and easy identification of this pest is critical for monitoring and for phytosanitary services. The genus Cacosceles Newman, 1838 includes four species, most being very similar in morphology. The damaging stage of the species is the larva, which is inherently difficult to distinguish morphologically from other Cerambycidae species. A tool for rapid and reliable identification of this species was needed by plant protection and quarantine agencies to monitor its potential abundance and spread. Here, we provide newly-generated barcodes for C. newmannii that can be used to reliably identify any life stage, even by non-trained taxonomists. In addition, we compiled a curated DNA barcoding reference library for 70 specimens of 20 named species of Afrotropical Prioninae to evaluate DNA barcoding as a valid tool to identify them. We also assessed the level of deeply conspecific mitochondrial lineages. Sequences were assigned to 42 different Barcode Index Numbers (BINs), 28 of which were new to BOLD. Out of the 20 named species barcoded, 11 (52.4%) had their own unique Barcode Index Number (BIN). Eight species (38.1%) showed multiple BINs with no morphological differentiation. Amongst them, C. newmannii showed two highly divergent genetic clusters which co-occur sympatrically, but further investigation is required to test whether they could represent new cryptic species., (Marion Javal, John S Terblanche, Desmond E Conlong, Norbert Delahaye, Elizabeth Grobbelaar, Laure Benoit, Carlos Lopez-Vaamonde, Julien M Haran.)

The success of anticancer chemotherapy relies at least in part on the induction of an immune response against tumor cells. Thus, tumors growing on mice that lack the pattern recognition receptor TLR4 or the purinergic receptor P2RX7 fail to respond to chemotherapy with anthracyclins or oxaliplatin in conditions in which the same neoplasms growing on immunocompetent mice would do so. Similarly, the therapeutic efficacy (measured as progression-free survival) of adjuvant chemotherapy with anthracyclins is reduced in breast cancer patients bearing loss-of-function alleles of TLR4 or P2RX7. TLR4 loss-of-function alleles also have a negative impact on the therapeutic outcome of oxaliplatin in colorectal cancer patients. Here, we report that loss-of-function TLR4 and P2RX7 alleles do not affect overall survival in non-small cell lung cancer (NSCLC) patients, irrespective of the administration and type of chemotherapy. The intrinsic characteristics of NSCLC (which near-to-always is chemoresistant and associated with poor prognosis) and/or the type of therapy that is employed to treat this malignancy (which near-to-always is based on cisplatin) may explain why two genes that affect the immune response to dying cells fail to influence the clinical progression of NSCLC patients.

Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18.

In response to stress, cells start transcriptional and transcription-independent programs that can lead to adaptation or death. Here, we show that multiple inducers of autophagy, including nutrient depletion, trigger the activation of the IKK (IkappaB kinase) complex that is best known for its essential role in the activation of the transcription factor NF-kappaB by stress. Constitutively active IKK subunits stimulated autophagy and transduced multiple signals that operate in starvation-induced autophagy, including the phosphorylation of AMPK and JNK1. Genetic inhibition of the nuclear translocation of NF-kappaB or ablation of the p65/RelA NF-kappaB subunit failed to suppress IKK-induced autophagy, indicating that IKK can promote the autophagic pathway in an NF-kappaB-independent manner. In murine and human cells, knockout and/or knockdown of IKK subunits (but not that of p65) prevented the induction of autophagy in response to multiple stimuli. Moreover, the knockout of IKK-beta suppressed the activation of autophagy by food deprivation or rapamycin injections in vivo, in mice. Altogether, these results indicate that IKK has a cardinal role in the stimulation of autophagy by physiological and pharmacological stimuli.

Cells respond to stress by activating cytoplasmic mechanisms as well as transcriptional programs that can lead to adaptation or death. Autophagy represents an important cytoprotective response that is regulated by both transcriptional and transcription-independent pathways. NFkappaB is perhaps the transcription factor most frequently activated by stress and has been ascribed with either pro- or anti-autophagic functions, depending on the cellular context. Our results demonstrate that activation of the IKK (IkappaB kinase) complex, which is critical for the stress-elicited activation of NFkappaB, is sufficient to promote autophagy independent of NFkappaB, and that IKK is required for the optimal induction of autophagy by both physiological and pharmacological autophagic triggers.

Unlabelled: Ciprofloxacin labeled with (99m)Tc specifically binds to various bacteria. Thus, it potentially constitutes a specific marker allowing discrimination between septic arthritis/osteomyelitis and aseptic osteoarticular diseases. The aim of this prospective study was to evaluate such properties in patients with skeletal diseases., Methods: We prospectively investigated 2 groups of patients: patients with suspected osteoarticular infections (G1, n = 16) and a control group of patients with a presentation of osteoarticular diseases and no sign suggestive of infection (G2, n = 11). All had clinical, biologic, and radiologic evaluations and had 1-, 4-, and 24-h images from (99m)Tc-ciprofloxacin scintigraphy (370 MBq) before planned biopsy or surgery. For 23 patients, the scintigraphic results were compared with histologic and bacteriologic analyses of biopsy tissue samples; for 4 patients, the scintigraphic results were compared with the findings from 23 +/- 5 mo of follow-up., Results: In G1, (99m)Tc-ciprofloxacin findings were true-positive in all 11 infected sites, true-negative in 2 cases, and false-positive in 3. In G2, (99m)Tc-ciprofloxacin was true-negative in 4 cases and false-positive in 7. Neither the location of (99m)Tc-ciprofloxacin activity nor its intensity or kinetics between 1, 4, and 24 h allowed discrimination between infection and aseptic diseases (sterile loosened joint replacement, pseudoarthrosis, or arthrosis). Sensitivity, specificity, and accuracy were 100%, 37.5%, and 63%., Conclusion: (99m)Tc-Ciprofloxacin scintigraphy showed good sensitivity and a high negative predictive value for the detection of bone and joint infection, but it did not discriminate between infected and aseptic osteoarticular diseases in symptomatic patients referred for surgery.

Unlabelled: A lack of specificity for myocardial perfusion imaging has been widely reported, mostly related to false-positive defects on the inferior wall. The application of depth-dependent resolution recovery (RR), attenuation correction (AC) using external source devices, and scatter correction has been proposed to resolve this pitfall., Methods: We studied the clinical benefit of depth-dependent RR, nonuniform AC using a scanning line source, and scatter correction (photon energy recovery [PER]) compared with filtered backprojection alone. Eighty-two patients were included: 40 healthy volunteers with a low likelihood of coronary artery disease (control group) and 42 patients with proven right or circumflex coronary artery disease but without involvement of the left anterior descending artery. Among these 82 patients, the images of 33 were also processed with PER., Results: RR did not alter the performance of filtered backprojection alone. AC + RR greatly improved specificity and the rate of normal (201)Tl SPECT findings in the control population (from 56% to 95% and from 53% to 100%, respectively) but significantly decreased sensitivity (from 92% to 54%). AC + RR generated a false anteroapical defect in 21% of patients and reverse redistribution of the apex in 23%. AC + RR significantly decreased the extent of the stress defect (from 4.09 to 3.21 segments, P < 0.003) and increased the perfusion score of the stress defect (from 0.78 +/- 0.72 to 1.47 +/- 1.11, P < 0.00061). Moreover, AC + RR generated overcorrection on the inferior wall, leading to false estimation of viability for 11 of 15 patients with an old inferior myocardial scar without evidence of residual viability. PER decreased overcorrection on the inferior wall, but without improving sensitivity. PER did not significantly reduce the number of anteroapical false-positives or the number of apical reverse distribution cases., Conclusion: AC + RR improved the specificity and normalcy rate of (201)Tl SPECT myocardial perfusion imaging but generated overcorrection on the inferior wall, leading to low sensitivity and to false evaluation of myocardial viability in 73% of the patients with inferior infarction. AC + RR also generated anteroapical artifacts. The addition of scatter correction did not significantly reduce these drawbacks.

Unlabelled: Exercise lung 201 TI uptake calculated with planar imaging has an important diagnostic and prognostic value in patients with coronary artery disease (CAD). However, its value with SPECT imaging raises methodological concerns and is controversial. We studied its value for the discrimination between extensive (E) and limited (L) angiographic CAD with exercise SPECT., Methods: Four methods of lung-to-heart ratio quantification were calculated in patients with a low likelihood (< 5%) of CAD (n = 62). Their dependent variables were defined, and corresponding correction equations were derived. Receiver operating characteristic (ROC) analysis was performed in a pilot group (L-CAD, n = 49; E-CAD, n = 126) to define the optimal method of calculation of the lung-to-heart ratio. Its best threshold providing the best sensitivity for a specificity of 90% was defined. After correction for dependent variables, the 4 methods were also compared by ROC analysis and the optimal corrected method was compared with the optimal uncorrected method using ROC analysis and the best threshold. The consistency of these results in the validation group (L-CAD, n = 41; E-CAD, n = 122) and of the results of visual analysis of lung 201TI uptake were then verified., Results: On ROC analysis in the pilot group, the optimal method of calculation of the lung-to-heart ratio was the mean activity in a region of interest drawn at the base of the lungs to the mean activity over the heart (Lb/H). For the best threshold, Lb/H presented a sensitivity of 34%. Corrected Lb/H still remained the best method of calculation on ROC analysis compared with the other corrected methods. On ROC analysis, there was no difference between corrected and uncorrected Lb/H. For the best threshold, corrected Lb/H presented a similar sensitivity of 37% compared with uncorrected Lb/H. When applied to the validation group (L-CAD, n = 41; E-CAD, n = 122), the best-defined threshold in the pilot group for corrected Lb/H presented a diagnostic value similar to that in the pilot group (sensitivity, 41%; specificity, 90%), but uncorrected Lb/H presented a higher sensitivity (47%; P < 0.04) and a slightly lower specificity (80%). Results of lung 201TI uptake visual analysis were inconsistent between pilot and validation groups (42% versus 58% sensitivity, P = 0.012; 86% versus 66% specificity, P = 0.023)., Conclusions: For evaluation of E-CAD versus L-CAD, quantification of the exercise lung-to-heart 201TI uptake ratio with SPECT is feasible, reproducible, more discriminate than simple visual analysis, and best calculated as Lb/H. It presents an intrinsic diagnostic value even after correction for other clinically valuable dependent variables.

Unlabelled: Scintigraphy with somatostatin analogs is a sensitive method for the staging and therapeutic management of patients with endocrine gastroenteropancreatic (GEP) tumors. The aim of this study was to compare prospectively somatostatin receptor scintigraphy (SRS) using 111n-pentetreotide with bone scintigraphy using 99mTc-hydroxymethylene diphosphonate for the detection of bone metastases., Methods: One-hundred-forty-five patients with proven endocrine GEP tumors were investigated. Patients were classified according to the presence of bone metastases as indicated by CT, MRI or histologic data. Group I included 19 patients with confirmed bone metastases, and group II included 126 patients without bone metastases., Results: In group I, SRS was positive in all 19 patients with bone metastases, and bone scintigraphy was positive in 17 patients. Bone metastases were found to occur predominantly in patients with liver metastases. In group 11, 5 patients had recent bone surgery for fracture or arthritis. SRS showed bone uptake in 4 of these patients, and bone scanning showed abnormal uptake in 5. In 7 of the remaining 121 group II patients, SRS was negative and bone scanning showed abnormal bone uptake suggesting bone metastases. The detection of bone metastases was of major prognostic value, because 42% of group 1 patients died during a 2-y follow-up., Conclusion: In patients with GEP tumors, the accuracy of SRS appears to be similar to that of bone scintigraphy for the detection of bone metastases.

Unlabelled: Norepinephrine (NE) reuptake function is impaired in heart failure and this may participate in myocyte hyperstimulation by the neurotransmitter. This alteration can be assessed by 123I-metaiodobenzylguanidine (MIBG) scintigraphy., Methods: To determine whether the impairment of neuronal NE reuptake was reversible after metoprolol therapy, we studied 18 patients (43+/-7 y) with idiopathic dilated cardiomyopathy who were stabilized at least for 3 mo with captopril and diuretics. Patients underwent, before and after 6 mo of therapy with metoprolol, measurements of radionuclide left ventricular ejection fraction (LVEF), maximal oxygen consumption and plasma NE concentration. The cardiac adrenergic innervation function was scintigraphically assessed with MIBG uptake and release measurements on the planar images obtained 20 min and 4 h after tracer injection. To evaluate whether metoprolol had a direct interaction with cardiac MIBG uptake and release, six normal subjects were studied before and after a 1-mo metoprolol intake., Results: In controls, neither cardiac MIBG uptake and release nor circulating NE concentration changed after the 1-mo metoprolol intake. Conversely, after a 6-mo therapy with metoprolol, patients showed increased cardiac MIBG uptake (129%+/-10% versus 138%+/-17%; P = 0.009), unchanged cardiac MIBG release and decreased plasma NE concentration (0.930+/-412 versus 0.721+/-0.370 ng/mL; P = 0.02). In parallel, patients showed improved New York Heart Association class (2.44+/-0.51 versus 2.05+/-0.23; P = 0.004) and increased LVEF (20%+/-8% versus 27%+/-8%; P = 0.0005), whereas maximal oxygen uptake remained unchanged., Conclusion: Thus, a parallel improvement of myocardial NE reuptake and of hemodynamics was observed after a 6-mo metoprolol therapy, suggesting that such agents may be beneficial in heart failure by directly protecting the myocardium against excessive NE stimulation.

Background: Congestive heart failure is associated with decreased stimulated myocardial adenylate cyclase activity, increased Gi-binding protein, attenuated parasympathetic tone, and increased modulation of beta-adrenergic inotropic left ventricular stimulation by parasympathetic agonists. Despite these abnormalities, changes in the density or affinity of ventricular muscarinic receptors have not been demonstrated in patients., Methods and Results: The density and affinity constants of myocardial muscarinic receptors were evaluated noninvasively by means of positron emission tomography with 11C-MQNB (methylquinuclidinyl benzilate), a specific hydrophilic antagonist, in 20 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (mean left ventricular ejection fraction, 22+/-9%) and compared with values in 12 normal subjects. The mean receptor concentration was significantly higher in patients than in control subjects (B'max, 34.5+/-8.9 versus 25+/-7.7 pmol/mL, P<.005), with no changes in affinity constants. The change in heart rate after injection of 0.6 mg of cold MQNB was lower in patients than in control subjects (34+/-20% versus 55+/-36%, P<.05), and receptor density correlated negatively with maximal heart rate in the patients (r=.45, P<.05)., Conclusions: Congestive heart failure is associated with an upregulation of myocardial muscarinic receptors. This may be an adaptive mechanism to beta-agonist stimulation and should increase the number of potential targets for pharmacological intervention.