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Summary For many commercial potato cultivars, tuber yield is optimal at average daytime temperatures in the range of 14–22 °C. Further rises in ambient temperature can reduce or completely inhibit potato tuber production, with damaging consequences for both producer and consumer. The aim of this study was to use a genetic screen based on a model tuberization assay to identify quantitative trait loci (QTL) associated with enhanced tuber yield. A candidate gene encoding HSc70 was identified within one of the three QTL intervals associated with elevated yield in a Phureja–Tuberosum hybrid diploid potato population (06H1). A particular HSc70 allelic variant was linked to elevated yield in the 06H1 progeny. Expression of this allelic variant was much higher than other alleles, particularly on exposure to moderately elevated temperature. Transient expression of this allele in Nicotiana benthamiana resulted in significantly enhanced tolerance to elevated temperature. An TA repeat element was present in the promoter of this allele, but not in other HSc70 alleles identified in the population. Expression of the HSc70 allelic variant under its native promoter in the potato cultivar Desiree resulted in enhanced HSc70 expression at elevated temperature. This was reflected in greater tolerance to heat stress as determined by improved yield under moderately elevated temperature in a model nodal cutting tuberization system and in plants grown from stem cuttings. Our results identify HSc70 expression level as a significant factor influencing yield stability under moderately elevated temperature and identify specific allelic variants of HSc70 for the induction of thermotolerance via conventional introgression or molecular breeding approaches.

Potato production is often constrained by abiotic stresses such as drought and high temperatures which are often present in combination. In the present work, we aimed to identify key mechanisms and processes underlying single and combined abiotic stress tolerance by comparative analysis of tolerant and susceptible cultivars. Physiological data indicated that the cultivars Desiree and Unica were stress tolerant while Agria and Russett Burbank were stress susceptible. Abiotic stress caused a greater reduction of photosynthetic carbon assimilation in the susceptible cultivars which was associated with a lower leaf transpiration rate. Oxidative stress, as estimated by the accumulation of malondialdehyde was not induced by stress treatments in any of the genotypes with the exception of drought stress in Russett Burbank. Stress treatment resulted in increases in ascorbate peroxidase activity in all cultivars except Agria which increased catalase activity in response to stress. Transcript profiling highlighted a decrease in the abundance of transcripts encoding proteins associated with PSII light harvesting complex in stress tolerant cultivars. Furthermore, stress tolerant cultivars accumulated fewer transcripts encoding a type-1 metacaspase implicated in programmed cell death. Stress tolerant cultivars exhibited stronger expression of genes associated with plant growth and development, hormone metabolism and primary and secondary metabolism than stress susceptible cultivars. Metabolite profiling revealed accumulation of proline in all genotypes following drought stress that was partially suppressed in combined heat and drought. On the contrary, the sugar alcohols inositol and mannitol were strongly accumulated under heat and combined heat and drought stress while galactinol was most strongly accumulated under drought. Combined heat and drought also resulted in the accumulation of Valine, isoleucine, and lysine in all genotypes. These data indicate that single and multiple abiotic stress tolerance in potato is associated with a maintenance of CO assimilation and protection of PSII by a reduction of light harvesting capacity. The data further suggests that stress tolerant cultivars suppress cell death and maintain growth and development fine tuning of hormone signaling, and primary and secondary metabolism. This study highlights potential targets for the development of stress tolerant potato cultivars.

In this study, a four-drug combination chemotherapy regimen was associated with objective responses in more than 30% of patients and increased survival by more than 4 months, as compared with standard gemcitabine. Pancreatic adenocarcinoma was the fourth leading cause of death from cancer in the United States in 2010, 1 and it carries a grim prognosis: the 5-year survival rate is 6% in Europe and the United States. 1 , 2 Gemcitabine became the reference regimen for advanced pancreatic cancer after a randomized trial showed significant improvement in the median overall survival as compared with fluorouracil administered as an intravenous bolus (5.6 vs. 4.4 months, P=0.002). 3 In the subsequent phase 3 trials of single-agent gemcitabine, 4 the median overall survival ranged from 5.0 to 7.2 months. The combination of gemcitabine with a variety of cytotoxic and . . .

Background Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) primarily relies on FOLFIRINOX (LV5FU- irinotecan – Oxaliplatine) and Gemcitabine – Nab-Paclitaxel in the first-line setting. However, second-lines remain less well-defined and there is limited data regarding third-line treatments. The objective of our study was to determine the proportion of patients advancing to third line chemotherapy, to outline the various third-line chemotherapy regimens used in routine practice and to evaluate their respective efficacy. Methods A retrospective single-center cohort from 2010-2022 compiled baseline characteristics, treatment outcomes and survival of PDAC patients who received at least one chemotherapy line in a French tertiary-center. Overall survivals (OS) were analyzed using a Cox multivariable model. Results In total, 676 patients were included, with a median follow-up time of 69.4 months, (Interquartile Range (IQR) = 72.1). Of these, 251 patients (37%) that proceeded to 3 rd -line chemotherapy. The median PFS in 3 rd line was 2.03 months, [CI95%: 1.83, 2.36]. The median 3 rd line overall survival was 5.5 months, [CI95%: 4.8, 6.3]. In multivariable analysis erlotinib-based chemotherapy was found to be deleterious (HR=2.38, [CI95%: 1.30, 4.34], p =0.005) compared to fluoropyrimidine-based chemotherapy in terms of 3 rd line overall survival while gemcitabine monotherapy showed a tendency towards negative outcomes. First and 2 nd line chemotherapies sequence didn’t influence 3 rd line outcome. Conclusion In our cohort, one-third of treated patients proceeded to 3 rd line chemotherapy resulting in a 5.5 months median 3 rd line OS, consistent with treatments at advanced stage. Our results argue against the use of erlotinib and gemcitabine monotherapy.

Potato, , is one of the most important global crops, but has high levels of waste due to tuber greening under light, which is associated with the accumulation of neurotoxic glycoalkaloids. However, unlike the situation in de-etiolating seedlings, the mechanisms underlying tuber greening are not well understood. Here, we have investigated the effect of monochromatic blue, red, and far-red light on the regulation of chlorophyll and glycoalkaloid accumulation in potato tubers. Blue and red wavelengths were effective for induction and accumulation of chlorophyll, carotenoids and the two major potato glycoalkaloids, α-solanine and α-chaconine, whereas none of these accumulated in darkness or under far-red light. Key genes in chlorophyll biosynthesis ( , encoding the rate-limiting enzyme glutamyl-tRNA reductase, , and and six genes ( , , , , and ) required for glycoalkaloid synthesis were also induced under white, blue, and red light but not in darkness or under far-red light. These data suggest a role for both cryptochrome and phytochrome photoreceptors in chlorophyll and glycoalkaloid accumulation. The contribution of phytochrome was further supported by the observation that far-red light could inhibit white light-induced chlorophyll and glycoalkaloid accumulation and associated gene expression. Transcriptomic analysis of tubers exposed to white, blue, and red light showed that light induction of photosynthesis and tetrapyrrole-related genes grouped into three distinct groups with one group showing a generally progressive induction by light at both 6 h and 24 h, a second group showing induction at 6 h in all light treatments, but induction only by red and white light at 24 h and a third showing just a very moderate light induction at 6 h which was reduced to the dark control level at 24 h. All glycoalkaloid synthesis genes showed a group one profile consistent with what was seen for the most light regulated chlorophyll synthesis genes. Our data provide a molecular framework for developing new approaches to reducing waste due to potato greening.

Strigolactones (SLs) are a class of phytohormones controlling shoot branching. In potato (Solanum tuberosum), tubers develop from underground stolons, diageotropic stems which originate from basal stem nodes. As the degree of stolon branching influences the number and size distribution of tubers, it was considered timely to investigate the effects of SL production on potato development and tuber life cycle. Transgenic potato plants were generated in which the CAROTENOID CLEAVAGE DIOXYGENASE8 (CCD8) gene, key in the SL biosynthetic pathway, was silenced by RNA interference (RNAi). The resulting CCD8-RNAi potato plants showed significantly more lateral and main branches than control plants, reduced stolon formation, together with a dwarfing phenotype and a lack of flowering in the most severely affected lines. New tubers were formed from sessile buds of the mother tubers. The apical buds of newly formed transgenic tubers grew out as shoots when exposed to light. In addition, we found that CCD8 transcript levels were rapidly downregulated in tuber buds by the application of sprout-inducing treatments. These results suggest that SLs could have an effect, solely or in combination with other phytohormones, in the morphology of potato plants and also in controlling stolon development and maintaining tuber dormancy.

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNA-mediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo , and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

In order to enhance the carotenoid content of potato tubers, transgenic potato plants have been produced expressing an Erwinia uredovora crtB gene encoding phytoene synthase, specifically in the tuber of Solanum tuberosum L. cultivar Désirée which normally produces tubers containing c. 5.6 μg carotenoid g−1 DW and also in Solanum phureja L. cv. Mayan Gold which has a tuber carotenoid content of typically 20 μg carotenoid g−1 DW. In developing tubers of transgenic crtB Désirée lines, carotenoid levels reached 35 μg carotenoid g−1 DW and the balance of carotenoids changed radically compared with controls: β-carotene levels in the transgenic tubers reached c. 11 μg g−1 DW, whereas control tubers contained negligible amounts and lutein accumulated to a level 19-fold higher than empty-vector transformed controls. The crtB gene was also transformed into S. phureja (cv. Mayan Gold), again resulting in an increase in total carotenoid content to 78 μg carotenoid g−1 DW in the most affected transgenic line. In these tubers, the major carotenoids were violaxanthin, lutein, antheraxanthin, and β-carotene. No increases in expression levels of the major carotenoid biosynthetic genes could be detected in the transgenic tubers, despite the large increase in carotenoid accumulation. Microarray analysis was used to identify a number of genes that were consistently up- or down-regulated in transgenic crtB tubers compared with empty vector controls. The implications of these data from a nutritional standpoint and for further modifications of tuber carotenoid content are discussed.

The factors that regulate storage organ carotenoid content remain to be fully elucidated, despite the nutritional and economic importance of this class of compound. Recent findings suggest that carotenoid pool size is determined, at least in part, by the activity of carotenoid cleavage dioxygenases. The aim of this study was to investigate whether Carotenoid Cleavage Dioxygenase4 (CCD4) activity affects potato (Solanum tuberosum) tuber carotenoid content. Microarray analysis revealed elevated expression of the potato CCD4 gene in mature tubers from white-fleshed cultivars compared with higher carotenoid yellow-fleshed tubers. The expression level of the potato CCD4 gene was down-regulated using an RNA interference (RNAi) approach in stable transgenic lines. Down-regulation in tubers resulted in an increased carotenoid content, 2- to 5-fold higher than in control plants. The increase in carotenoid content was mainly due to elevated violaxanthin content, implying that this carotenoid may act as the in vivo substrate. Although transcript level was also reduced in plant organs other than tubers, such as leaves, stems, and roots , there was no change in carotenoid content in these organs. However, carotenoid levels were elevated in flower petals from RNAi lines. As well as changes in tuber carotenoid content, tubers from RNAi lines exhibited phenotypes such as heat sprouting, formation of chain tubers, and an elongated shape. These results suggest that the product of the CCD4 reaction may be an important factor in tuber heat responses.