Alimentation

Pour donner une image fidèle de l’alimentation des Berbères depuis les origines et suivre son évolution il aurait fallu disposer de documents et de textes qui font malheureusement défaut, aussi plutôt que de se livrer à une étude diachronique impossible à rédiger dans l’état actuel de la recherche nous avons choisi de présenter ce que l’on sait de l’alimentation des Paléoberbères des temps préhistoriques antérieurs à l’élevage et à l’agriculture puis de regrouper nos connaissances sur l’alime..

Immune microenvironment modulation unmasks therapeutic benefit of radiotherapy and checkpoint inhibition

Background Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. Methods Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. Results We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8+ T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8+ effector T cells. Conclusions Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors

Tumor microenvironment modulation enhances immunologic benefit of chemoradiotherapy

Background Chemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects. Methods Therefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes. Results We show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner. Conclusions Overall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation

Coercive Pressures and Anti-corruption Reporting: The Case of ASEAN Countries

This paper aims to investigate the extent of anti-corruption reporting by ASEAN companies and examine whether coercive factors influence the level of disclosure. The authors adopt indicators from the Global Reporting Initiative version 4.0 to measure the extent of anti-corruption disclosures in 117 companies’ reports. Informed by a coercive isomorphism tenet drawn from the institutional theory, the authors propose that several institutional factors influence the extent of their voluntary disclosures. The findings reveal that a large degree of variability difference between the average levels of anti-corruption disclosure in Thailand (434 words) and the Philippines (149 words). The dependence on government tenders and foreign ownership are associated with the level of disclosure. Surprisingly, the United Nation Global Compact membership is not a significant determinant of anti-corruption reporting. This signifies that the membership in the international initiative does not correspond to individual company’s commitment to disclose anti-corruption information. In spite of significant efforts undertaken by global organizations to combat corruption, the level of anti-corruption disclosure is significantly different among the four countries under study. The disclosure of sensitive information such as the confirmed incidences of corruption cases requires careful consideration by the top management as it is subjected to legal implications and reputational risks. Thus, impression management can complement the coercive pressure in explaining the level of anti-corruption reporting. This study is among the first studies which explores the association between coercive factors and the level of anti-corruption disclosure in ASEAN region

CHEMOTHERAPY POTENTIATES IMMUNE RESPONSES AGAINST MURINE TUMORS

De nombreuses études ont montré que l'effet de la chimiothérapie sur le rejet tumoral n'est pas seulement dû à son activité cytotoxique mais est dépendante du système immunitaire. En effet, les tumeurs murines et humaines répondent plus efficacement aux agents chimiothérapeutiques lorsque le système immunitaire de l'hôte est intact. En particulier, nous avons montré qu'un traitement au cyclophosphamide (CTX) dans des souris DBA/2 porteuses du mastocytome P815 induit une protection à long terme de façon dépendante des cellules T CD4+ et CD8+. Nous avons utilisé ce modèle tumoral d'une part parce qu'il est faiblement immunogénique et d'autre part parce qu'il permet l'identification de cellules T CD8+ spécifiques de l'antigène public P1A codé par un gène non muté et de l'antigène PIE spécifique de la tumeur codé par un gène muté. Nos résultats ont montré que le rejet tumoral induit par un traitement au CTX corrèle avec une augmentation, au sein de la tumeur, du pourcentage des lymphocytes T CD8 (PlE/H-2Kd)+, aux dépens des cellules T CD8 (PlA/H-2Ld)+. Nous avons tenté d'identifier les mécanismes par lesquels le CTX favorise une réponse immune dirigée contre un antigène provenant d'un gène muté. Nous avons observé que l'activation préférentielle des cellules T CD8 (P1E/H- 2Kd)+ n'est pas seulement due à la sélection thymique négative. Nous avons aussi caractérisé phénotypiquement et fonctionnellement les cellules T CD8+ (PlE/H-2Kd)+. Des expériences de cytométrie en flux et de single cell qPCR ont permis d'identifier, après traitement au CTX, l'émergence, au sein du mastocytome P815, d'une population de cellules T CD8 effectrices de mémoire spécifiques du complexe PlE/H-2Kd exprimant le marqueur de différentiation KLRG-1 à leur surface et le facteur de transcription Eomes. Nous avons ensuite tenté d'identifier les facteurs requis pour la différenciation de ces cellules. Nos résultats montrent une augmentation de l'expression de l'IL-15 et de l'IRF7 (un facteur de transcription qui régule les gènes codant pour l'IFN I) au sein de la tumeur en réponse au CTX. L'injection d'anticorps neutralisant la voie de signalisation de l'IFN I prévient le rejet tumoral chez 50% des souris et diminue l'infiltration des cellules T CD8 (PlE/H-2Kd)+ induits par le CTX, suggérant l'implication de cette cytokine dans l'induction et le recrutement des cellules T CD8 (PlE/H-2Kd)+ dans la tumeur in vivo. -- There is increasing evidence that the effect of chemotherapy on tumor rejection is not cell autonomous but relies on the immune system. Indeed, several reports have shown that human and murine tumors respond to chemotherapeutic agents more effïciently when the host immune system is intact. In particular, we have shown that cyclophosphamide treatment of DBA/2 mice bearing P815 mastocytoma induces rejection and long term protection in a CD4- and CD8-dependent mariner. We used this tumor model, as it is poorly immunogenic, expresses tumor-associated P1A and tumor-specifïc PIE antigens, encoded by germline and mutated genes, respectively, and allows the identification of some tumor-specifïc CD8+ T cells. We have previously reported that tumor régression correlates with selective infiltration of CD8+ T cells spécifié for PlE/H-2Kd antigen in tumor bed upon cyclophosphamide treatment. Unexpectedly, the proportion of CD8+ T cells specific for the tumor-associated antigen PI A in the context of H-2Ld decreases concomitantly, indicating that cyclophosphamide alters the repertoire of CD8+ T cells recognizing tumor antigens. Using PI A KO mice, we found that preferential activation of CD8+ T cells to PIE is not solely due to thymic negative selection. The major rôle of "mutated" antigens in tumor résistance has been recently highlighted in humans and raises an interesting question about the immune mechanisms of tumor rejection. Additionally to its effect on the specific immune response, cyclophosphamide promotes tumor infiltration by effector mernory (PlE/H-2Kd)+ CD8+ T cells which are characterized by higher expression of KLRG1 and Eomes. Our data point to a rôle of IL-15 and type 1 IFNs for their development, as increased levels of IL-15 and IRF7 were measured in tumor after cyclophosphamide. IFNAR1 blockade interferes with the tumor rejection in 50% of mice and decreases the (P1E/H-2K )+CD8+T cell infiltration induced by cyclophosphamide, suggesting a role of this cytokine in the expansion and/or recruitment of (PlE/H-2Kd)+ CD8+ T cells in vivo. Altogether, our results suggest that type 1 IFNs and IL-15 induced after cyclophosphamide promote the reprogramming of CD8+ T cells specific for the "mutated" PlE/H-2Kd antigen into effector memory lymphocytes

Essai de grammaire de la langue Tamachek : renfermant les principes du langage parlé par les Imouchar' ou Touareg, des conversations en Tamachek', des fac-simile d'écriture en caractères Tifinar', et une carte indiquant les parties de l'Algérie où la langue Berbère est encore en usage

PJ2381, ISO 639-3 : thv, Tamashek language--Gramma

Lobbying for Emissions Allowances: A New Perspective on the Political Economy of the US Acid Rain Program

This paper shows empirically that the choice between auction and grandfathering for the distribution of pollution permits is not neutral in presence of political market failures as it motivates rent-seeking. We model the distribution of free permits in the US sulfur emissions trading system as an endogenous sharing rule and we test this relation using PAC contribution as a measure of political influence. We find that shareholder interests of the US power sector influenced the distribution of permits as they were motivated by a windfall gain despite profit regulation in their sector and thanks to a climate of regulatory uncertainty when the law was discussed.

Synthesis of regioselectively deuterated cyclopropanes

International audienc

Cyclophosphamide treatment regulates the balance of functional/exhausted tumor-specific CD8(+) T cells.

An important question is how chemotherapy may (re-)activate tumor-specific immunity. In this study, we provide a phenotypic, functional and genomic analysis of tumor-specific CD8(+) T cells in tumor (P815)-bearing mice, treated or not with cyclophosphamide. Our data show that chemotherapy favors the development of effector-type lymphocytes in tumor bed, characterized by higher KLRG-1 expression, lower PD-1 expression and increased cytotoxicity. This suggests re-engagement of T lymphocytes into the effector program. IFN-I appears involved in this remodeling. Our findings provide some insight into how cyclophosphamide regulates the amplitude and quality of tumor-specific immune responses