Clinical characteristic and survival outcomes of patients with advanced NSCLC according to KRAS mutational status in the French real-life ESME cohort.

PURPOSE: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes. PATIENTS AND METHODS: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed. RESULTS: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients. CONCLUSION: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts.

Large-Scale Distribution of Total Mass versus Luminous Matter from Baryon Acoustic Oscillations: First Search in the Sloan Digital Sky Survey III Baryon Oscillation Spectroscopic Survey Data Release 10.

Baryon acoustic oscillations in the early Universe are predicted to leave an as yet undetected signature on the relative clustering of total mass versus luminous matter. A detection of this effect would provide an important confirmation of the standard cosmological paradigm and constrain alternatives to dark matter as well as nonstandard fluctuations such as compensated isocurvature perturbations (CIPs). We conduct the first observational search for this effect, by comparing the number-weighted and luminosity-weighted correlation functions, using the SDSS-III BOSS Data Release 10 CMASS sample. When including CIPs in our model, we formally obtain evidence at 3.2σ of the relative clustering signature and a limit that matches the existing upper limits on the amplitude of CIPs. However, various tests suggest that these results are not yet robust, perhaps due to systematic biases in the data. The method developed in this Letter used with more accurate future data such as that from DESI, is likely to confirm or disprove our preliminary evidence.

Birth of a relativistic outflow in the unusual γ-ray transient Swift J164449.3+573451.

Active galactic nuclei, which are powered by long-term accretion onto central supermassive black holes, produce relativistic jets with lifetimes of at least one million years, and the observation of the birth of such a jet is therefore unlikely. Transient accretion onto a supermassive black hole, for example through the tidal disruption of a stray star, thus offers a rare opportunity to study the birth of a relativistic jet. On 25 March 2011, an unusual transient source (Swift J164449.3+573451) was found, potentially representing such an accretion event. Here we report observations spanning centimetre to millimetre wavelengths and covering the first month of evolution of a luminous radio transient associated with Swift J164449.3+573451. The radio transient coincides with the nucleus of an inactive galaxy. We conclude that we are seeing a newly formed relativistic outflow, launched by transient accretion onto a million-solar-mass black hole. A relativistic outflow is not predicted in this situation, but we show that the tidal disruption of a star naturally explains the observed high-energy properties and radio luminosity and the inferred rate of such events. The weaker beaming in the radio-frequency spectrum relative to γ-rays or X-rays suggests that radio searches may uncover similar events out to redshifts of z ≈ 6.

Ultra-high-energy cosmic ray acceleration in engine-driven relativistic supernovae.

The origin of ultra-high-energy cosmic rays (UHECRs) remains an enigma. They offer a window to new physics, including tests of physical laws at energies unattainable by terrestrial accelerators. They must be accelerated locally, otherwise, background radiations would severely suppress the flux of protons and nuclei, at energies above the Greisen-Zatsepin-Kuzmin (GZK) limit. Nearby, gamma ray bursts (GRBs), hypernovae, active galactic nuclei and their flares have all been suggested and debated as possible sources. A local sub-population of type Ibc supernovae (SNe) with mildly relativistic outflows have been detected as sub-energetic GRBs, X-ray flashes and recently as radio afterglows without detected GRB counterparts. Here, we measure the size-magnetic field evolution, baryon loading and energetics, using the observed radio spectra of SN 2009bb. We place such engine-driven SNe above the Hillas line and establish that they can readily explain the post-GZK UHECRs.

[Routine use of serial plasmatic CA 15-3 determinations during the follow-up of patients treated for breast cancer. Evaluation as factor of early diagnosis of recurrence]. / Utilisation en routine du CA 15.3 dans la surveillance des patientes traitées pour un cancer du sein invasif. Impact en termes de diagnostic précoce de récidive.

PURPOSE: at our institution, CA 15-3 assays are routinely used for the early diagnosis of recurrence during the follow-up of patients treated for breast cancer, although published guidelines do not recommend this procedure. So, we decided to totally re-assess the usefulness of this policy. PATIENTS AND METHODS: all records of patients presenting a first recurrence, local (50 cases) or metastatic (88 cases), of breast cancer during 2003 were re-examined. An increase in CA 15-3 concentration of more than 25% was considered significant. RESULTS: an increase was observed in 18% of non metastatic recurrences. These increases had a prognostic value. CA 15-3 levels remained stable in 23% of metastasis cases and increased in 77%. In 14% of cases, the increase in CA 15-3 levels confirmed a clinically or radiologically suspected metastasis. Moreover, increased CA 15-3 levels in the absence of suggestive clinical or radiological signs led to the diagnosis in 18% of metastasis, 50% of which involved the bone. CONCLUSION: our study demonstrates that CA 15-3 is useful for the early diagnosis of recurrence. Eighteen per cent of metastases were diagnosed by a marker increase alone. CA 15-3 assays could be useful in the early management of these metastases in patients treated for breast cancer.

A comparison of Hispanic and African-American sexually abused girls and their families.

OBJECTIVE: To study the differential effects of sexual abuse on Hispanic (HN) and African-American (AA) girls. METHOD: Sexually abused girls and their caretakers (N = 159), of which 52% (n = 82) were AA (mean age 9.8 years, SD = 3.4, R = 6-17) and 48% (n = 77) were HN (mean age 10.1 years, SD = 3.8, R = 6-18), were included in the study. The mother/caretaker was administered a demographic form, the Achenbach's Child Behavior Checklist (CBCL), and the Family Assessment Measure (FAM-P). The child completed the FAM-C and the Trauma Symptom Checklist for Children (TSCC). The clinician completed the Parental Reaction to Incest Disclosure Scale (PRIDS). RESULTS: HN girls were found to have a greater number of sexually abusive episodes and waited longer to disclose their abuse while AA girls were more likely to have experienced vaginal penetration. The perpetrators of HN girls were older and more likely to be fathers or stepfathers. The mothers/ caretakers of HN girls perceived their children as having significantly more aggressive behavior, anxiety/depression, somatic complaints, internalizing and externalizing behaviors, and had a higher total score on the CBCL than did AA girls. The HN girls were more likely to see their family as dysfunctional with confusion regarding family values and rules. HN mothers/caretakers perceived their families as more conflicted regarding adaptability and family controls. CONCLUSIONS: HN girls experienced more emotional and behavioral problems, and both HN girls and their mothers/caretakers perceived their families as more disturbed and dysfunctional.

TeV neutrinos and GeV photons from shock breakout in supernovae.

We show that as a Type II supernova shock breaks out of its progenitor star, it becomes collisionless and may accelerate protons to energies >10 TeV. Inelastic nuclear collisions of these protons produce an approximately 1 h long flash of TeV neutrinos and 10 GeV photons, about 10 h after the thermal (10 MeV) neutrino burst from the cooling neutron star. A Galactic supernova in a red supergiant star would produce a photon and neutrino flux of approximately 10(-4) erg cm(-2) s(-1). A km(2) neutrino detector will detect approximately 100 muons, thus allowing to constrain both supernova models and neutrino properties.

Interactions between the Werner syndrome helicase and DNA polymerase delta specifically facilitate copying of tetraplex and hairpin structures of the d(CGG)n trinucleotide repeat sequence.

Werner syndrome (WS) is an inherited disorder characterized by premature aging and genomic instability. The protein encoded by the WS gene, WRN, possesses intrinsic 3' --> 5' DNA helicase and 3' --> 5' DNA exonuclease activities. WRN helicase resolves alternate DNA structures including tetraplex and triplex DNA, and Holliday junctions. Thus, one function of WRN may be to unwind secondary structures that impede cellular DNA transactions. We report here that hairpin and G'2 bimolecular tetraplex structures of the fragile X expanded sequence, d(CGG)(n), effectively impede synthesis by three eukaryotic replicative DNA polymerases (pol): pol alpha, pol delta, and pol epsilon. The constraints imposed on pol delta-catalyzed synthesis are relieved, however, by WRN; WRN facilitates pol delta to traverse these template secondary structures to synthesize full-length DNA products. The alleviatory effect of WRN is limited to pol delta; neither pol alpha nor pol epsilon can traverse template d(CGG)(n) hairpin and tetraplex structures in the presence of WRN. Alleviation of pausing by pol delta is observed with Escherichia coli RecQ but not with UvrD helicase, suggesting a concerted action of RecQ helicases and pol delta. Our findings suggest a possible role of WRN in rescuing pol delta-mediated replication at forks stalled by unusual DNA secondary structures.

Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo.

BACKGROUND: Isoprostanes (iPs) are free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. Several iPs exert biological effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF(2alpha)-III (8-iso PGF(2alpha)) and iPE(2)-III modulate platelet function and vascular tone. Although these effects are blocked by antagonists of the receptor (TP) for the cyclooxygenase product thromboxane A(2), it has been speculated that the iPs may activate a receptor related to, but distinct from, the TP. METHODS AND RESULTS: Transgenic mice (TPOEs) were generated in which the TP-beta isoform was under the control of the preproendothelin promoter. They overexpressed TP-beta in the vasculature but not in platelets and exhibited an exaggerated pressor response to infused iPF(2alpha)-III compared with wild-type mice. This was blocked by TP antagonism. The platelet response to the iP was unaltered in TPOEs compared with wild-type mice. By contrast, both the pressor response to iPF(2alpha)-III and its effects on platelet function were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE(2)-III on mean arterial pressure and platelet aggregation. CONCLUSIONS: Both iPF(2alpha)-III and iPE(2)-III exert their effects on platelet function and vascular tone in vivo by acting as incidental ligands at membrane TPs rather than via a distinct iP receptor. Activation of TPs by iPs may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after tissue ischemia.

Cosmic gamma-ray background from structure formation in the intergalactic medium

The Universe is filled with a diffuse background of gamma-ray radiation, the origin of which remains one of the unsolved puzzles of cosmology. Less than one-quarter of the gamma-ray flux can be attributed to unresolved discrete sources, such as active galactic nuclei; the remainder appears to constitute a truly diffuse background. Here we show that the shock waves induced by gravity in the gas of the intergalactic medium, during the formation of large-scale structures like filaments and sheets of galaxies, produce a population of highly relativistic electrons. These electrons scatter a small fraction of the cosmic microwave background photons in the local Universe up to gamma-ray energies, thereby providing the gamma-ray background. The predicted diffuse flux agrees with the observed background across more than four orders of magnitude in photon energy, and the model predicts that the gamma-ray background, though generated locally, is isotropic to better than five per cent on angular scales larger than a degree. Moreover, the agreement between the predicted and observed background fluxes implies a mean cosmological density of baryons that is consistent with Big Bang nucleosynthesis.

Functional interaction between the Werner Syndrome protein and DNA polymerase delta.

Werner Syndrome (WS) is an inherited disease characterized by premature onset of aging, increased cancer incidence, and genomic instability. The WS gene encodes a 1,432-amino acid polypeptide (WRN) with a central domain homologous to the RecQ family of DNA helicases. Purified WRN unwinds DNA with 3'-->5' polarity, and also possesses 3'-->5' exonuclease activity. Elucidation of the physiologic function(s) of WRN may be aided by the identification of WRN-interacting proteins. We show here that WRN functionally interacts with DNA polymerase delta (pol delta), a eukaryotic polymerase required for DNA replication and DNA repair. WRN increases the rate of nucleotide incorporation by pol delta in the absence of proliferating cell nuclear antigen (PCNA) but does not stimulate the activity of eukaryotic DNA polymerases alpha or epsilon, or a variety of other DNA polymerases. Moreover, we show that functional interaction with WRN is mediated through the third subunit of pol delta: i.e., Pol32p of Saccharomyces cerevisae, corresponding to the recently identified p66 subunit of human pol delta. Absence of the third subunit abrogates stimulation by WRN, and stimulation is restored by reconstituting the three-subunit enzyme. Our findings suggest that WRN may facilitate pol delta-mediated DNA replication and/or DNA repair and that disruption of WRN-pol delta interaction in WS cells may contribute to the previously observed S-phase defects and/or the unusual sensitivity to a limited number of DNA damaging agents.

Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation.

Thromboxane (Tx) A2 is a platelet agonist, smooth muscle cell constrictor, and mitogen. Urinary Tx metabolite (Tx-M) excretion is increased in syndromes of platelet activation and early in both normal pregnancies and in pregnancy-induced hypertension. A further increment occurs in patients presenting with severe preeclampsia, in whom Tx-M correlates with other indices of disease severity. TxA2 exerts its effects through a membrane receptor (TP), of which two isoforms (alpha and beta; refs. 5,6) have been cloned. Overexpression of TP in the vasculature under the control of the pre-proendothelin-1 promoter results in a murine model of intrauterine growth retardation (IUGR), which is rescued by timed suppression of Tx synthesis with indomethacin. IUGR is commonly associated with maternal diabetes or cigarette smoking, both conditions associated with increased TxA2 biosynthesis.

Functional evidence for inward-rectifier potassium channels in rat cremaster muscle arterioles.

Moderate increases in extracellular K(+) produce vasodilation in fourth order cremasteric arterioles in the anesthetized rat. We studied the contribution of different subtypes of K(+) channels to this response. Cremaster muscle arteriolar diameters were observed during superfusion with buffer containing 5-30 mM K(+) in the absence (control) and presence of barium (Ba(2+), 50 microM), glibenclamide (GLIB, 1 microM), or iberiotoxin (IBTX, 100 nM) to block inward-rectifier, ATP-sensitive, or Ca(2+)-activated K(+) channels, respectively. Under control conditions, vessels dilated in response to 10-25 mM K(+) and constricted at higher concentrations. At 5 mM K(+), vessel diameters were significantly decreased by GLIB and Ba(2+), but not IBTX, suggesting that basal diameter was regulated by inward-rectifier and ATP-sensitive K(+) channels. In contrast, Ba(2+), but not GLIB or IBTX, prevented K(+)-induced dilation. The data indicate that the inward-rectifier K(+) channel (blocked by low concentrations of Ba(2+), but not GLIB or IBTX) was most likely responsible for the K(+)-induced arteriolar dilation.

Child on child sexual abuse: psychological perspectives.

OBJECTIVE: This study describes the emotional and behavioral responses of children who have been sexually victimized by juveniles (CC) 17 years of age and younger compared to child victims of adults (CA) 18 years of age and older. METHOD: A total sample of N = 194 children and adolescents participated in the study, with 26% (n = 51) comprising CC and 74% (n = 143) encompassing CA. The mother/caretaker was administered a demographic form, Achenbach's Child Behavior Checklist (CBCL), and the Family Assessment Measure (FAM-P). The child was given the Family Assessment Measure (FAM-C) and the Trauma Symptom Checklist for Children (TSCC). The clinician completed the Parental Reaction to Incest Disclosure Scale (PRIDS). RESULTS: No differences were found between the two groups for the type of sexual abuse, penetration, or the use of force. CC were younger and more likely to be males who were abused in a school setting, home, or a relative's home by a sibling or a non-related male. CC endorsed clinically significant sexual preoccupations and manifested borderline clinically significant symptomatology. CONCLUSIONS: Children victimized by other children manifested elevated levels of emotional and behavioral problems and were not significantly different from those who had been sexually abused by adults.

WRN helicase expression in Werner syndrome cell lines.

Mutations in the chromosome 8p WRN gene cause Werner syndrome (WRN), a human autosomal recessive disease that mimics premature aging and is associated with genetic instability and an increased risk of cancer. All of the WRN mutations identified in WRN patients are predicted to truncate the WRN protein with loss of a C-terminal nuclear localization signal. However, many of these truncated proteins would retain WRN helicase and/or nuclease functional domains. We have used a combination of immune blot and immune precipitation assays to quantify WRN protein and its associated 3'-->5' helicase activity in genetically characterized WRN patient cell lines. None of the cell lines from patients harboring four different WRN mutations contained detectable WRN protein or immune-precipitable WRN helicase activity. Cell lines from WRN heterozygous individuals contained reduced amounts of both WRN protein and helicase activity. Quantitative immune blot analyses indicate that both lymphoblastoid cell lines and fibroblasts contain approximately 6 x 10(4)WRN molecules/cell. Our results indicate that most WRN mutations result in functionally equivalent null alleles, that WRN heterozygote effects may result from haploinsufficiency and that successful modeling of WRN pathogenesis in the mouse or in other model systems will require the use of WRN mutations that eliminate WRN protein expression.

Ecdysteroid titers in mated and unmated Drosophila melanogaster females.

Radioimmunoassay was used to determine ecdysteroid titers in mated or unmated Drosophila melanogaster females. Whole-body ecdysteroid titers increase after mating and this response is more pronounced after 12-24 hours than it is immediately after mating. In one experiment, females were mated to transgenic males deficient in accessory gland proteins to test whether these peptides mediate the observed increase in female whole-body ecdysteroid titers. Females mated to such transgenic males do not show a pronounced increase in whole-body ecdysteroid titers. The effect of mating on female hemolymph ecdysteroid titers was also investigated. Hemolymph ecdysteroid titers decrease after mating. The ecdysteroid titer change in the hemolymph may result from yolk protein uptake of ecdysteroids into developing vitellogenic oocytes as a consequence of male accessory gland protein stimulation of female oocyte maturation and yolk protein synthesis following mating.

Werner syndrome protein. I. DNA helicase and dna exonuclease reside on the same polypeptide.

Werner Syndrome (WS) is a human progeroid disorder characterized by genomic instability. The gene defective in WS encodes a 3' --> 5' DNA helicase (Gray, M. D., Shen, J.-C., Kamath-Loeb, A. S., Blank, A. , Sopher, B. L., Martin, G. M., Oshima, J., and Loeb, L. A.(1997) Nat. Genet. 17, 100-103). Sequence alignment analysis identified an N-terminal motif in WRN that is homologous to several exonucleases. Using combined molecular genetic, biochemical, and immunochemical approaches, we demonstrate that WRN also exhibits an integral DNA exonuclease activity. First, whereas wild-type recombinant WRN possesses both helicase and exonuclease activities, mutant WRN lacking the nuclease domain does not display exonucleolytic activity. In contrast, WRN proteins with defective helicase activity are active in exonucleolytic digestion of DNA. Second, the exonuclease co-purifies with the 160-kDa WRN protein and its associated DNA helicase and ATPase activities through successive steps of ion exchange and affinity chromatography, suggesting that all three activities are physically associated. Lastly, anti-WRN antiserum specifically co-precipitates the WRN helicase and exonuclease activities indicating that both activities reside on the same antigenic WRN polypeptide. The association of an exonuclease with WRN distinguishes it from other RecQ homologs and raises the possibility that the distinct phenotypic characteristics of WS may be due in part to a defective exonuclease.

Werner syndrome protein. II. Characterization of the integral 3' --> 5' DNA exonuclease.

In addition to its DNA helicase activity, Werner syndrome protein (WRN) also possesses an exonuclease activity (Shen, J.-C., Gray, M. D., Kamath-Loeb, A. S., Fry, M., Oshima, J., and Loeb, L. A. (1998) J. Biol. Chem. 273, 34139-34144). Here we describe the properties of nearly homogeneous WRN exonuclease. WRN exonuclease hydrolyzes a recessed strand in a partial DNA duplex but does not significantly digest single-stranded DNA, blunt-ended duplex, or a protruding strand of a partial duplex. Although DNA is hydrolyzed in the absence of nucleoside triphosphates, nuclease activity is markedly stimulated by ATP, dATP, or CTP. WRN exonuclease digests DNA with a 3' --> 5' directionality to generate 5'-dNMP products, and DNA strands terminating with either a 3'-OH or 3'-PO4 group are hydrolyzed to similar extents. A recessed DNA strand with a single 3'-terminal mismatch is hydrolyzed more efficiently by WRN than one with a complementary nucleotide, but the enzyme fails to hydrolyze a DNA strand terminating with two mismatched bases. WRN exonuclease is distinguished from known mammalian DNA nucleases by its covalent association with a DNA helicase, preference for a recessed DNA strand, stimulation by ATP, ability to equally digest DNA with 3'-OH or 3'-PO4 termini, and its preferential digestion of DNA with a single 3'-terminal mismatch.