Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation.

The administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8(+) CD11c(+) T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b(-/-) ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b(-/-) ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8(+) T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8(+) CD11c(+) T cells with regulatory properties and prolong graft survival.

Copy number variation in chemokine superfamily: the complex scene of CCL3L-CCL4L genes in health and disease.

Genome copy number changes (copy number variations: CNVs) include inherited, de novo and somatically acquired deviations from a diploid state within a particular chromosomal segment. CNVs are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. CNVs are distributed widely in the genomes of apparently healthy individuals and thus constitute significant amounts of population-based genomic variation. Human CNV loci are enriched for immune genes and one of the most striking examples of CNV in humans involves a genomic region containing the chemokine genes CCL3L and CCL4L. The CCL3L-CCL4L copy number variable region (CNVR) shows extensive architectural complexity, with smaller CNVs within the larger ones and with interindividual variation in breakpoints. Furthermore, the individual genes embedded in this CNVR account for an additional level of genetic and mRNA complexity: CCL4L1 and CCL4L2 have identical exonic sequences but produce a different pattern of mRNAs. CCL3L2 was considered previously as a CCL3L1 pseudogene, but is actually transcribed. Since 2005, CCL3L-CCL4L CNV has been associated extensively with various human immunodeficiency virus-related outcomes, but some recent studies called these associations into question. This controversy may be due in part to the differences in alternative methods for quantifying gene copy number and differentiating the individual genes. This review summarizes and discusses the current knowledge about CCL3L-CCL4L CNV and points out that elucidating their complete phenotypic impact requires dissecting the combinatorial genomic complexity posed by various proportions of distinct CCL3L and CCL4L genes among individuals.

Optimal duration of first-line chemotherapy for advanced gastric cancer: data from the AGAMENON registry.

BACKGROUND: The optimal duration of first-line chemotherapy for patients with advanced gastric cancer is unknown. Diverse clinical trials have proposed different strategies including limited treatment, maintenance of some drugs, or treatment until progression. METHOD: The sample comprises patients from the AGAMENON multicenter registry without progression after second evaluation of response. The objective was to explore the optimal duration of first-line chemotherapy. A frailty multi-state model was conducted. RESULTS: 415 patients were divided into three strata: discontinuation of platinum and maintenance with fluoropyrimidine until progression (30%, n = 123), complete treatment withdrawal prior to progression (52%, n = 216), and full treatment until progression (18%, n = 76). The hazard of tumor progression decreased by 19% per month with the full treatment regimen. However, we found no evidence that fluoropyrimidine maintenance (hazard ratio [HR] 1.07, confidence interval [CI] 95%, 0.69-1.65) worsened progression-free survival (PFS) with respect to treatment until progression. Predictive factors for PFS were ECOG performance status, ≥ 3 metastatic sites, prior tumor response, and bone metastases. Toxicity grade 3/4 was more common in those who continued the full treatment until progression vs fluoropyrimidine maintenance (16% vs 6%). CONCLUSION: The longer duration of the full initial regimen exerted a protective effect on the patients of this registry. Platinum discontinuation followed by fluoropyrimidine maintenance yields comparable efficacy to treatment up to PD, with a lower rate of serious adverse events.

Bull effect on the reproductive performance of mature and first calf-suckled Zebu cows in the tropics.

This experiment was designed to determine if continuous bull exposure of heifers 2 wk post partum to a first calf (30 to 36 m old) or mature (42 to 72 m old) Zebú Brahman suckled cows reduces the interval to first estrus and the number of days open. Post partum first calf cows were randomly assigned to be exposed continuously to epidectomized bulls with surgical ablation of the dorsal ligament of the penis (Group 35 FBE, n = 25) or not exposed to bulls (Group FNE, n = 22). Post partum mature cows were likewise assigned to be continuously exposed (Group MBE, n = 24) or not exposed to bulls (Group MNE, n = 25). Milk samples were collected twice a week for progesterone assays to determine resumption of ovarian cyclic activity. All the cows were artificially inseminated for 120 d while in their respective treatment groups. The first postpartum estrus percentages were 60 < 90 d, 24.4%; and > 90 d, 33.7%. The interval to first estrus f-or Groups FBE and FNE was 75.4 and 104.2 d, respectively, and differed significantly (P < 0.01). For Groups MBE and MNE the interval to first estrus was 76.3 and 95.0 d, respectively (P < 0.05). The number of open days for Groups FBE and FNE was 77.3 and 114.9, respectively (P < 0.01); while for Groups MBE and MNE it was 73.0 and 98.6 d, respectively (P < 0.01). The results of the present study indicate that introduction of bulls to first calving cows or mature Zebú Brahman cows after parturition provides a practical and economical option for reducing the extended post partum anestrus interval and days open under tropical conditions.

Factors affecting postpartum ovarian activity in crossbred primiparous tropical heifers.

The relationship between postpartum ovarian activity and a total of 9 variables was studied in a dry tropical environment. Primiparous cows (n=61) that had shown no peripartum abnormalities, and were not suckled but milked twice daily, were used in the study. Independent variables included crossbreeding, sex of the calf, season, body condition, weight of cow at calving, age of dam at calving, uterine involution, calf weight and accumulated milk yield. Diet was a controlled variable. Dependent variables were first estrus postpartum and/or first milk progesterone elevation prior to first estrus. A bull fitted with a chin ball marker was used to detect first estrus postpartum, while ovarian structures were palpated per rectum once a week. Progesterone was measured by RIA in milk samples collected twice weekly. First postpartum estrus was detected at 56 +/- 32 days postpartum, a first milk progesterone elevation was observed in 50.8% of cows at 42 +/- 27 days. Cows calving in the dry season had longer intervals and those who calved males had shorter postpartum intervals. Accumulated milk yield affected both intervals significatly (p < 0.01). Weight, age and uterine involution were asociated with first milk progesterone elevation, while crossbreeding, weight at calving and weight postpartum change were associated with the dependent variables.

Improvement of reproductive performance in crossbred zebu anestrous primiparous cows by treatment with norgestomet implants or 96 h calf removal.

The aim of the present study was to compare the effect of norgestomet implants (NI) and calf removal (CR) for 96 h on estrus induction and first service fertility in crossbred zebu primiparous anestrous cows after 120 days postpartum. A total of 152 cows in a tropical environment were allotted to three experimental groups: CR for 96 h (n = 51), NI for 9 days plus 500 IU of PMSG at implant removal (n = 51) and a control group (CG) without treatment (n = 50). Estrous rate (%) and mean interval to first estrus (days) were 50.9 and 26.3+/-6.8; 60.7 and 13.8+/-6.8; 16.0% and 61.8+/-5.9 days for groups CR, NI and CG, respectively. CR and NI were statistically similar, however, both groups were different (P < 0.01) when compared with CG. Calving interval to first service and to conception were: CR: 151.2+/-8.4 and 157.8+/-21.4; NI: 145.2+/-8.5 and 150.9+/-21.3; CG: 186.8+/-7.3 and 201.0+/-18.5. A difference (P < 0.01) was found in both intervals when comparing the CR and NI with CG, with longer intervals for cows in the CG group. First service conception rates were 61.5, 67.7 and 62.5% for groups CR, NI and CG, respectively, and were not different (P > 0.05). These results demonstrate the efficacy of NI + PMSG or temporary CR for 96 h in inducing a fertile estrus and shortening the interval to estrus and to conception in primiparous crossbred anestrous zebu cows in the tropics.

Factores demográficos y socioeconómicos asociados con malaria en cuatro localidades del Estado Barinas, Venezuela / Demographic and socio-economic factors associated with malaria in four localities of Barinas State, Venezuela

Se determinó la asociación entre factores demográficos y socioeconómicos y la tasa de incidencia de la malaria, entre enero de 1993 y diciembre de 1994, en cuatro localidades del municipio Ciudad Bolivia, del estado Barinas, Venezuela. De cada habitante, se registró la información pertinente incluyendo una descripción de las viviendas y el material usado en su construcción. La malaria, ocasionada por Plasmodium vivax, registró una incidencia anual de 5,8 por ciento y 3,6 por ciento. La incidencia de la malaria fue significativamente diferente (p<0.05 por ciento) (DS), entre los diferentes tipos de vivienda, con mayor proporción de casos (10,09 por ciento-1993 y 6,0 por ciento-1994) en los habitantes de casas incompletas y de pobre construcción. Otros factores demográficos y socioeconómicos no mostraron asociación con la incidencia de la enfermedad. Se estudió la distribución de casos en relación a las localidades, al tipo de vivienda y a su proximidad con cuerpos de agua; encontrándose que los casos de malaria estaban agrupados en ciertas casas. Fue observada una asociación entre el tipo de construcción de las viviendas y el índice de casos de malaria (ICM). Las mejor construidas tenían un ICM significativamente menor (0,26) que aquellas pobremente construidas (2,10,p<0,05). Aunque el ICM no mostró DS entre localidades, fue superior para habitantes de casas de pobre construcción e incompletas. El ICM también fue superior y SD para las viviendas con cuerpos de agua cercanos y de pobre construcción con respecto a las otras. En conclusión, se detectó un mayor ICM en los habitantes de casas incompletas y con cuerpos de agua cercanos