The Relative Power of Employment-to-Employment Reallocation and Unemployment Exits in Predicting Wage Growth

We study the cyclical comovement nominal wage growth (either monthly earnings or hourly wage rate) and labor market flows. We use microdata from the Survey of Income and Program Participation over 1996-2013 to purge composition effects in worker and job characteristics and to isolate the reallocative effect of Employer-to-Employer (EE) transitions. We find an "EE wage Phillips curve": wage inflation comoves positively with EE as strongly as with the employment rate. This correlation holds for job stayers; we interpret the EE rate as a measure of labor demand. We find no analogous evidence for the job-finding rate from unemployment

Wage Posting and Business Cycles

The canonical framework of Burdett and Mortensen (1998) derives wage dispersion as the unique equilibrium outcome in a stationary environment with meeting frictions and random search. Firms derive monopsony power from search frictions and commit to wage offers. Workers earn rents: wages are not compressed to the opportunity cost of work, owing to the ability of employed workers to receive additional offers and quit directly from one job into another, without experiencing unemployment. In previous work (Moscarini and Postel-Vinay 2016), we explored the implications of this job ladder for the aggregate dynamics of unemployment, wages, and the firm size distribution at business cycle frequencies. The model establishes a natural connection between the average wage growth in the economy and the pace of Employer-to-Employer (EE) transitions, through two channels. First, a composition effect: workers typically quit a job when they receive a better offer, hence the faster these transitions the higher the pace of reallocation toward high wages, and the higher average wage growth. Second, a strategic effect: the more opportunities workers have to quit, the more aggressive are their employers with their wage responses, to try and retain them. The first effect benefits only job movers, the second both movers and stayers. Therefore, we expect wage growth to be positively related to the pace of EE reallocation for all workers, but especially for movers. We verify this empirically with longitudinal micro data from the Survey of Income and Program Participation (SIPP)

Enquête sur la distribution du crédit aux agriculteurs dans le département du Cantal : résultats pour la période 1970-1975

Diffusion du document : INRA Station d'Economie et Sociologie rurales 65 rue de Saint-Brieuc 35042 Rennes Cedex (FRA)Cette note se réduit à une présentation commenté des premiers résultats de l'enquête menée dans le cantal. La période étudiée couvre les années 1970 à 1975. La situation structurelle des exploitations est saisie au départ par les données du RGA puis par celles de l'EPEXA en 1975. La méthode employée consiste à utiliser pour le département du Cantal, un sous-échantillon EPEXA (le taux moyen de sondage est de 1/50) dont les exploitations sont analysées tant du point de vue de leur évolution structurelle que de celui de leur endettement. Les données sur ce point ont été recueillies par l'enquête auprès de la Caisse Régionale du Cantal

PARP inhibition enhances tumor cell-intrinsic immunity in ERCC1-deficient non-small cell lung cancer.

The cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway detects cytosolic DNA to activate innate immune responses. Poly(ADP-ribose) polymerase inhibitors (PARPi) selectively target cancer cells with DNA repair deficiencies such as those caused by BRCA1 mutations or ERCC1 defects. Using isogenic cell lines and patient-derived samples, we showed that ERCC1-defective non-small cell lung cancer (NSCLC) cells exhibit an enhanced type I IFN transcriptomic signature and that low ERCC1 expression correlates with increased lymphocytic infiltration. We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. Mechanistically, PARPi generated cytoplasmic chromatin fragments with characteristics of micronuclei; these were found to activate cGAS/STING, downstream type I IFN signaling, and CCL5 secretion. Importantly, these effects were suppressed in PARP1-null TNBC cells, suggesting that this phenotype resulted from an on-target effect of PARPi on PARP1. PARPi also potentiated IFN-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide a preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly selected populations

Early mortality and overall survival in oncology phase I trial participants: can we improve patient selection?

<p>Abstract</p> <p>Background</p> <p>Patient selection for phase I trials (PIT) in oncology is challenging. A typical inclusion criterion for PIT is 'life expectancy > 3 months', however the 90 day mortality (90DM) and overall survival (OS) of patients with advanced solid malignancies are difficult to predict.</p> <p>Methods</p> <p>We analyzed 233 patients who were enrolled in PIT at Princess Margaret Hospital. We assessed the relationship between 17 clinical characteristics and 90DM using univariate and multivariate logistic regression analyses to create a risk score (PMHI). We also applied the Royal Marsden Hospital risk score (RMI), which consists of 3 markers (albumin < 35g/L, > 2 metastatic sites, LDH > ULN).</p> <p>Results</p> <p>Median age was 57 years (range 21-88). The 90DM rate was 14%; median OS was 320 days. Predictors of 90DM were albumin < 35g/L (OR = 8.2, p = 0.01), > 2 metastatic sites (OR = 2.6, p = 0.02), and ECOG > 0 (OR = 6.3, p = 0.001); all 3 factors constitute the PMHI. To predict 90DM, the PMHI performed better than the RMI (AUC = 0.78 vs 0.69). To predict OS, the RMI performed slightly better (RMI ≥ 2, HR = 2.2, p = 0.002 vs PMHI ≥ 2, HR = 1.6, p = 0.05).</p> <p>Conclusions</p> <p>To predict 90DM, the PMHI is helpful. To predict OS, risk models should include ECOG > 0, > 2 metastatic sites, and LDH > ULN. Prospective validation of the PMHI is warranted.</p

Dose-Levels and First Signs of Efficacy in Contemporary Oncology Phase 1 Clinical Trials

PURPOSE: Phase 1 trials play a crucial role in oncology by translating laboratory science into efficient therapies. Molecular targeted agents (MTA) differ from traditional cytotoxics in terms of both efficacy and toxicity profiles. Recent reports suggest that higher doses are not essential to produce the optimal anti-tumor effect. This study aimed to assess if MTA could achieve clinical benefit at much lower dose than traditional cytotoxics in dose seeking phase 1 trials. PATIENTS AND METHODS: We reviewed 317 recent phase 1 oncology trials reported in the literature between January 1997 and January 2009. First sign of efficacy, maximum tolerated dose (MTD) and their associated dose level were recorded in each trial. RESULTS: Trials investigating conventional cytotoxics alone, MTA alone and combination of both represented respectively 63.0% (201/317), 23.3% (74/317) and 13.7% (42/317) of all trials. The MTD was reached in 65.9% (209/317) of all trials and was mostly observed at the fifth dose level. First sign of efficacy was less frequently observed at the first three dose-levels for MTA as compared to conventional cytotoxics or combinations regimens (48.3% versus 63.2% and 61.3%). Sign of efficacy was observed in the same proportion whatever the treatment type (73-82%). MTD was less frequently established in trials investigating MTA alone (51.3%) or combinations (42.8%) as compared to conventional cytotoxic agents (75.6%). CONCLUSION: First sign of efficacy was less frequently reported at the early dose-levels and MTD was less frequently reached in trials investigating molecular targeted therapy alone. Similar proportion of trials reported clinical benefit

DNA repair deficiency sensitizes lung cancer cells to NAD+ biosynthesis blockade.

Synthetic lethality is an efficient mechanism-based approach to selectively target DNA repair defects. Excision repair cross-complementation group 1 (ERCC1) deficiency is frequently found in non-small-cell lung cancer (NSCLC), making this DNA repair protein an attractive target for exploiting synthetic lethal approaches in the disease. Using unbiased proteomic and metabolic high-throughput profiling on a unique in-house-generated isogenic model of ERCC1 deficiency, we found marked metabolic rewiring of ERCC1-deficient populations, including decreased levels of the metabolite NAD+ and reduced expression of the rate-limiting NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). We also found reduced NAMPT expression in NSCLC samples with low levels of ERCC1. These metabolic alterations were a primary effect of ERCC1 deficiency, and caused selective exquisite sensitivity to small-molecule NAMPT inhibitors, both in vitro - ERCC1-deficient cells being approximately 1,000 times more sensitive than ERCC1-WT cells - and in vivo. Using transmission electronic microscopy and functional metabolic studies, we found that ERCC1-deficient cells harbor mitochondrial defects. We propose a model where NAD+ acts as a regulator of ERCC1-deficient NSCLC cell fitness. These findings open therapeutic opportunities that exploit a yet-undescribed nuclear-mitochondrial synthetic lethal relationship in NSCLC models, and highlight the potential for targeting DNA repair/metabolic crosstalks for cancer therapy