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Twenty-two honeybee ( Apis mellifera) colonies were placed in four different cornfield areas in order to study the potential in situ effects of seed-coated systemic neonicotinoid pesticides used in cornfields ( Zea mays spp) on honeybee health. Two apiaries were located in two independent neonicotinoid-treated cornfield areas and two others in two independent untreated cornfield areas used as controls. These experimental hives were extensively monitored for their performance and health traits over a period of one year. Trapped pollen was collected and microscopically identified to define the visited flowers and the amount of corn pollen collected by bees. Liquid chromatography-mass spectrometry was performed to detect pesticide residues in honeybee foragers and trapped pollen. Honeybee colonies located in neonicotinoid-treated cornfields expressed significantly higher varroa mite loads than those in untreated cornfields. However, brood production and colony weight were less disturbed by the treatment factor. Sublethal doses of neonicotinoids were detected in the trapped corn pollen and none in bee foragers. Overall, our results show that forager bees collected 20% of corn pollen containing variable concentrations of neonicotinoids. Colonies located in treated cornfields expressed higher varroa loads and long-term mortality than those in untreated cornfields. On the other hand, no significant differences were observed regarding the brood production and colony weight. [ABSTRACT FROM AUTHOR]

African trypanosomes colonise the skin to ensure parasite transmission. However, how the skin responds to trypanosome infection remains unresolved. Here, we investigate the local immune response of the skin in a murine model of infection using spatial and single cell transcriptomics. We detect expansion of dermal IL-17A-producing Vγ6 + cells during infection, which occurs in the subcutaneous adipose tissue. In silico cell-cell communication analysis suggests that subcutaneous interstitial preadipocytes trigger T cell activation via Cd40 and Tnfsf18 signalling, amongst others. In vivo, we observe that female mice deficient for IL-17A-producing Vγ6 + cells show extensive inflammation and limit subcutaneous adipose tissue wasting, independently of parasite burden. Based on these observations, we propose that subcutaneous adipocytes and Vγ6 + cells act in concert to limit skin inflammation and adipose tissue wasting. These studies provide new insights into the role of γδ T cell and subcutaneous adipocytes as homeostatic regulators of skin immunity during chronic infection., (© 2023. Springer Nature Limited.)

Purpose: Angiogenesis plays a key role in glioblastoma, but most anti-angiogenic therapy trials have failed to change the poor outcome of this disease. Despite this, and because bevacizumab is known to alleviate symptoms, it is used in daily practice. We aimed to assess the real-life benefit in terms of overall survival, time to treatment failure, objective response, and clinical benefit in patients with recurrent glioblastoma treated with bevacizumab., Methods: This was a monocentric, retrospective study including patients treated between 2006 and 2016 in our institution., Results: 202 patients were included. The median duration of bevacizumab treatment was 6 months. Median time to treatment failure was 6.8 months (95%CI 5.3-8.2) and median overall survival was 23.7 months (95%CI 20.6-26.8). Fifty percent of patients had a radiological response at first MRI evaluation, and 56% experienced symptom amelioration. Grade 1/2 hypertension (n = 34, 17%) and grade one proteinuria (n = 20, 10%) were the most common side effects., Conclusions: This study reports a clinical benefit and an acceptable toxicity profile in patients with recurrent glioblastoma treated with bevacizumab. As the panel of therapies is still very limited for these tumors, this work supports the use of bevacizumab as a therapeutic option., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Rapidly spreading parasitic infections like amoebic gill disease (AGD) are increasingly problematic for Atlantic salmon reared in aquaculture facilities and potentially pose a risk to wild fish species in surrounding waters. Currently, it is not known whether susceptibility to AGD differs between wild and farmed salmon. Wild Atlantic salmon populations are declining and this emerging disease could represent an additional threat to their long-term viability. A better understanding of how AGD affects fish health is therefore relevant for the accurate assessment of the associated risk, both to farming and to the well-being of wild populations. In this study, we assessed the impact of natural exposure to AGD on wild, hybrid and farmed post-smolt Atlantic salmon reared in a sea farm together under common garden conditions., Results: Wild fish showed substantially higher mortality levels (64%) than farmed fish (25%), with intermediate levels for hybrid fish (39%) suggesting that AGD susceptibility has an additive genetic basis. Metabolic rate measures representing physiological performance were similar among the genetic groups but were significantly lower in AGD-symptomatic fish than healthy fish. Gut microbial diversity was significantly lower in infected fish. We observed major shifts in gut microbial community composition in response to AGD infections. In symptomatic fish the relative abundance of key taxa Aliivibrio, Marinomonas and Pseudoalteromonas declined, whereas the abundance of Polaribacter and Vibrio increased compared to healthy fish., Conclusions: Our results highlight the stress AGD imposes on fish physiology and suggest that low metabolic-rate fish phenotypes may be associated with better infection outcomes. We consider the role increased AGD outbreak events and a warmer future may have in driving secondary bacterial infections and in reducing performance in farmed and wild fish., (© 2022. The Author(s).)

Alpha mannose-oligosaccharide (MOS) prebiotics are widely deployed in animal agriculture as immunomodulators as well as to enhance growth and gut health. Their mode of action is thought to be mediated through their impact on host microbial communities and their associated metabolism. Bio-Mos is a commercially available prebiotic currently used in the agri-feed industry, but studies show contrasting results of its effect on fish performance and feed efficiency. Thus, detailed studies are needed to investigate the effect of MOS supplements on the fish microbiome to enhance our understanding of the link between MOS and gut health. To assess Bio-Mos for potential use as a prebiotic growth promoter in salmonid aquaculture, we have modified an established Atlantic salmon in vitro gut model, SalmoSim, to evaluate its impact on the host microbial communities. The microbial communities obtained from ceca compartments from four adult farmed salmon were inoculated in biological triplicate reactors in SalmoSim. Prebiotic treatment was supplemented for 20 days, followed by a 6-day washout period. Inclusion of Bio-Mos in the media resulted in a significant increase in formate ( P = 0.001), propionate ( P = 0.037) and 3-methyl butanoic acid ( P = 0.024) levels, correlated with increased abundances of several, principally, anaerobic microbial genera ( Fusobacterium, Agarivorans, Pseudoalteromonas ). DNA metabarcoding with the 16S rDNA marker confirmed a significant shift in microbial community composition in response to Bio-Mos supplementation with observed increase in lactic acid producing Carnobacterium . In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to complement in vivo trials of microbiome modulators. IMPORTANCE In this paper we report the results of the impact of a prebiotic (alpha-MOS supplementation) on microbial communities, using an in vitro simulator of the gut microbial environment of the Atlantic salmon. Our data suggest that Bio-Mos may be of value in salmonid production as it enhances volatile fatty acid production by the microbiota from salmon pyloric ceca and correlates with a significant shift in microbial community composition with observed increase in lactic acid producing Carnobacterium . In conjunction with previous in vivo studies linking enhanced volatile fatty acid production alongside MOS supplementation to host growth and performance, our data suggest that Bio-Mos may be of value in salmonid production. Furthermore, our data highlights the potential role of in vitro gut models to augment in vivo trials of microbiome modulators.

Purpose: Trastuzumab-emtansine (T-DM1), as well as lapatinib plus capecitabine were proven effective in two Phase III studies, following first-line trastuzumab plus a taxane. The introduction of dual HER2 blockade by trastuzumab and pertuzumab as first-line has positioned T-DM1 into second-line, and lapatinib plus capecitabine beyond, without formal evaluation of these strategies., Methods: ESME Data Platform (NCT03275311) included individual data from all patients aged ≥18 years, in whom first-line treatment for metastatic breast cancer (MBC) was initiated between January 1, 2008 and December 31, 2016 in one of the 18 French Comprehensive Cancer Centers. The efficacy of T-DM1 and lapatinib plus capecitabine combination, following double blockade associating trastuzumab and pertuzumab were evaluated in this national real-life database. Eligibility criteria were: female, MBC, HER2+ tumor, first-line taxane-based chemotherapy and dual HER2-blockage by trastuzumab plus pertuzumab. Cohort A received second-line T-DM1, and Cohort B second-line T-DM1 and third or fourth-line lapatinib plus capecitabine., Results: Cohort A comprised 233 patients, and Cohort B 47 patients. Median progression-free survival (PFS) was 7.1 months in Cohort A and 4.6 months in Cohort B. Median overall survival were 36.7 months and 12.9 months, respectively. PFS was significantly dependent on the preceding treatment line's duration. In cohort A, HER2 expression status was a significant predictive factor of PFS., Conclusion: First-line trastuzumab plus pertuzumab do not markedly diminish T-DM1's efficacy in second-line. Similarly, sequential treatment with trastuzumab plus pertuzumab then T-DM1 does not noticeably modify the efficacy of lapatinib plus capecitabine., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accurate prediction of vectors dispersal, as well as identification of adaptations that allow blood-feeding vectors to thrive in built environments, are a basis for effective disease control. Here we adopted a landscape genomics approach to assay gene flow, possible local adaptation, and drivers of population structure in Rhodnius ecuadoriensis, an important vector of Chagas disease. We used a reduced-representation sequencing technique (2b-RADseq) to obtain 2,552 SNP markers across 272 R. ecuadoriensis samples from 25 collection sites in southern Ecuador. Evidence of high and directional gene flow between seven wild and domestic population pairs across our study site indicates insecticide-based control will be hindered by repeated re-infestation of houses from the forest. Preliminary genome scans across multiple population pairs revealed shared outlier loci potentially consistent with local adaptation to the domestic setting, which we mapped to genes involved with embryogenesis and saliva production. Landscape genomic models showed elevation is a key barrier to R. ecuadoriensis dispersal. Together our results shed early light on the genomic adaptation in triatomine vectors and facilitate vector control by predicting that spatially-targeted, proactive interventions would be more efficacious than current, reactive approaches., Competing Interests: The authors have declared that no competing interests exist.

Pesticides are increasing honeybee ( Apis mellifera ) death rates globally. Clothianidin neonicotinoid appears to impair the microbe-immunity axis. We conducted cage experiments on newly emerged bees that were 4-6 days old and used a 16S rRNA metataxonomic approach to measure the impact of three sublethal clothianidin concentrations (0.1, 1 and 10 ppb) on survival, sucrose syrup consumption and gut microbiota community structure. Exposure to clothianidin significantly increased mortality in the three concentrations compared to controls. Interestingly, the lowest clothianidin concentration was associated with the highest mortality, and the medium concentration with the highest food intake. Exposure to clothianidin induced significant variation in the taxonomic distribution of gut microbiota activity. Co-abundance network analysis revealed local dysbiosis signatures specific to each gut section (midgut, ileum and rectum) were driven by specific taxa. Our findings confirm that exposure to clothianidin triggers a reshuffling of beneficial strains and/or potentially pathogenic taxa within the gut, suggesting a honeybee's symbiotic defense systems' disruption, such as resistance to microbial colonization. This study highlights the role of weak transcriptional activity taxa in maintaining a stable honeybee gut microbiota. Finally, the early detection of gut dysbiosis in honeybees is a promising biomarker in hive management for assessing the impact exposure to sublethal xenobiotics.

Background: The aquaculture sector now accounts for almost 50% of all fish for human consumption and is anticipated to provide 62% by 2030. Innovative strategies are being sought to improve fish feeds and feed additives to enhance fish performance, welfare, and the environmental sustainability of the aquaculture industry. There is still a lack of knowledge surrounding the importance and functionality of the teleost gut microbiome in fish nutrition. In vitro gut model systems might prove a valuable tool to study the effect of feed, and additives, on the host's microbial communities. Several in vitro gut models targeted at monogastric vertebrates are now in operation. Here, we report the development of an Atlantic salmon gut model, SalmoSim, to simulate three gut compartments (stomach, pyloric caecum, and midgut) and associated microbial communities., Results: The gut model was established in a series of linked bioreactors seeded with biological material derived from farmed adult marine-phase salmon. We first aimed to achieve a stable microbiome composition representative of founding microbial communities derived from Atlantic salmon. Then, in biological triplicate, the response of the in vitro system to two distinct dietary formulations (fishmeal and fishmeal free) was compared to a parallel in vivo trial over 40 days. Metabarcoding based on 16S rDNA sequencing qPCR, ammoniacal nitrogen, and volatile fatty acid measurements were undertaken to survey the microbial community dynamics and function. SalmoSim microbiomes were indistinguishable (p = 0.230) from their founding inocula at 20 days and the most abundant genera (e.g., Psycrobacter, Staphylococcus, Pseudomonas) proliferated within SalmoSim (OTUs accounting for 98% of all reads shared with founding communities). Real salmon and SalmoSim responded similarly to the introduction of novel feed, with majority of the taxa (96% Salmon, 97% SalmoSim) unaffected, while a subset of taxa (e.g., a small fraction of Psychrobacter) was differentially affected across both systems. Consistent with a low impact of the novel feed on microbial fermentative activity, volatile fatty acid profiles were not significantly different in SalmoSim pre- and post-feed switch., Conclusion: By establishing stable and representative salmon gut communities, this study represents an important step in the development of an in vitro gut system as a tool for the improvement of fish nutrition and welfare. The steps of the system development described in this paper can be used as guidelines to develop various other systems representing other fish species. These systems, including SalmoSim, aim to be utilised as a prescreening tool for new feed ingredients and additives, as well as being used to study antimicrobial resistance and transfer and fundamental ecological processes that underpin microbiome dynamics and assembly. Video abstract., (© 2021. The Author(s).)

Background: At diagnosis, tumor-infiltrating lymphocytes (TILs) are prognostic in epithelial ovarian cancer (EOC). We recently demonstrated that neoadjuvant chemotherapy (NACT) significantly increased stromal TILs. Here, we investigated the impact of NACT on immune subpopulations with a particular focus on the balance of immune-reactive to tolerant subpopulations., Materials and Methods: Tissue microarrays of EOC (145 pre-NACT, 139 post-NACT) were analyzed for CD3+, CD8+, FOXP3+, CD68+, and CD163+ by immunohistochemistry and CD4+ cells from deduction. Stromal TILs scored as percentage of stromal area, while intra-epithelial TILs scored as number of TILs in contact with tumor cells/HPF. Differences were evaluated by Wilcoxon or Chi square tests, Wilcoxon signed-rank for paired analyses, and cox model for PFS and OS., Results: NACT significantly increased stromal CD3+ (p = 0.003) and CD8+ (p = 0.001) and intra-epithelial CD8+ (p = 0.022) and CD68+ (p = 0.0003) infiltration in unmatched samples and among paired samples for stromal CD3+ and CD8+. Neither CD3+, CD8+, CD4+, and CD68+ nor CD163+ expression correlated with outcome at diagnosis or post NACT. Using median value as a cut-off, high stromal CD8+/FOXP3+ ratio (HR = 0.59; p = 0.017) and high stromal CD3+/FOXP3+ ratio post NACT were associated with prolonged PFS (p = 0.0226). The more the balance shifted in favor of effector versus regulatory TILs, the better the survival. Similarly, high CD68+/CD163+ ratio post NACT improved PFS (p = 0.0445)., Conclusion: NACT has a significant impact on the balance of immune-reactive to immune-tolerant subpopulations and a high ratio of CD8+/FOXP3+, CD3+/FOXP3+, and CD68+/CD163+ post NACT was significantly associated with improved outcomes. Whether this could select patients for immunotherapy in the post-operative setting should be investigated.

Background: Disentangling the dynamics of microbial interactions within communities improves our comprehension of metacommunity assembly of microbiota during host development and under perturbations. To assess the impact of stochastic variation of neutral processes on microbiota structure and composition under disturbance, two types of microbial habitats, free-living (water), and host-associated (skin and gut) were experimentally exposed to either a constant or gradual selection regime exerted by two sublethal cadmium chloride dosages (CdCl 2 ). Yellow Perch (Perca flavescens) was used as a piscivorous ecotoxicological model. Using 16S rDNA gene based metataxonomics, quantitative diversity metrics of water, skin and gut microbial communities were characterized along with development and across experimental conditions., Results: After 30 days, constant and gradual selection regimes drove a significant alpha diversity increase for both skin and gut microbiota. In the skin, pervasive negative correlations between taxa in both selection regimes in addition to the taxonomic convergence with the environmental bacterial community, suggest a loss of colonisation resistance resulting in the dysbiosis of yellow perch microbiota. Furthermore, the network connectivity in gut microbiome was exclusively maintained by rare (low abundance) OTUs, while most abundant OTUs were mainly composed of opportunistic invaders such as Mycoplasma and other genera related to fish pathogens such as Flavobacterium. Finally, the mathematical modelling of community assembly using both non-linear least squares models (NLS) based estimates of migration rates and normalized stochasticity ratios (NST) based beta-diversity distances suggested neutral processes drove by taxonomic drift in host and water communities for almost all treatments. The NLS models predicted higher demographic stochasticity in the cadmium-free host and water microbiomes, however, NST models suggested higher ecological stochasticity under perturbations., Conclusions: Neutral models agree that water and host-microbiota assembly promoted by rare taxa have evolved predominantly under neutral processes with potential involvement of deterministic forces sourced from host filtering and cadmium selection. The early signals of perturbations in the skin microbiome revealed antagonistic interactions by a preponderance of negative correlations in the co-abundance networks. Our findings enhance our understanding of community assembly host-associated and free-living under anthropogenic selective pressure.

Background: The eco-evolutionary processes ruling post-disturbance microbial assembly remain poorly studied, particularly in host-microbiome systems. The community recovery depends not only on the type, duration, intensity, and gradient of disturbance, but also on the initial community structure, phylogenetic composition, legacy, and habitat (soil, water, host). In this study, yellow perch (Perca flavescens) juveniles were exposed over 90 days to constant and gradual sublethal doses of cadmium chloride. Afterward, the exposure of aquaria tank system to cadmium was ceased for 60 days. The skin, gut and water tank microbiomes in control and treatment groups, were characterized before, during and after the cadmium exposure using 16s rDNA libraries and high throughput sequencing technology (Illumina, Miseq)., Results: Our data exhibited long-term bioaccumulation of cadmium salts in the liver even after two months since ceasing the exposure. The gradient of cadmium disturbance had differential effects on the perch microbiota recovery, including increases in evenness, taxonomic composition shifts, as well as functional and phylogenetic divergence. The perch microbiome reached an alternative stable state in the skin and nearly complete recovery trajectories in the gut communities. The recovery of skin communities showed a significant proliferation of opportunistic fish pathogens (i.e., Flavobacterium). Our findings provide evidence that neutral processes were a much more significant contributor to microbial community turnover in control treatments than in those treated with cadmium, suggesting the role of selective processes in driving community recovery., Conclusions: The short-term metallic disturbance of fish development has important long-term implications for host health. The recovery of microbial communities after metallic exposure depends on the magnitude of exposure (constant, gradual), and the nature of the ecological niche (water, skin, and gut). The skin and gut microbiota of fish exposed to constant concentrations of cadmium (CC) were closer to the control negative than those exposed to the gradual concentrations (CV). Overall, our results show that the microbial assembly during the community recovery were both orchestrated by neutral and deterministic processes. Video Abtract.

Introduction: HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens., Methods: We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting., Results: Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8-4] and median OS 7.3 months [95% CI 5.7-10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52-0.97], p = 0.028 for PFS and HR = 0.65 [0.46-0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77-1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88-1.37], p = 0.40 for OS)., Conclusion: Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

Adaptation of microbial communities to anthropogenic stressors can lead to reductions in microbial diversity and disequilibrium of ecosystem services. Such adaptation can change the molecular signatures of communities with differences in taxonomic and functional composition. Understanding the relationship between taxonomic and functional variation remains a critical issue in microbial ecology. Here, we assessed the taxonomic and functional diversity of a lake metacommunity system along a polymetallic pollution gradient caused by 60 years of chronic exposure to acid mine drainage (AMD). Our results highlight three adaptive signatures. First, a signature of taxon-function decoupling was detected in the microbial communities of moderately and highly polluted lakes. Second, parallel shifts in taxonomic composition occurred between polluted and unpolluted lakes. Third, variation in the abundance of functional modules suggested a gradual deterioration of ecosystem services (i.e., photosynthesis) and secondary metabolism in highly polluted lakes. Overall, changes in the abundance of taxa, function, and more importantly the polymetallic resistance genes such as copA, copB, czcA, cadR, cCusA , were correlated with trace metal content (mainly Cadmium) and acidity. Our findings highlight the impact of polymetallic pollution gradient at the lowest trophic levels.

Aquatic organisms are increasingly exposed to lowering of environmental pH due to anthropogenic pressure (e.g. acid rain, acid mine drainages). Such acute variations trigger imbalance of fish-associated microbiota, which in turn favour opportunistic diseases. We used the tambaqui (Colossoma macropomum), an Amazonian fish tolerant to significant pH variation in its natural environment, to assess the response of fish endogenous microbiota to acute short-term acid stress. We exposed 36 specimens of tambaquis to acidic water (pH 4.0) over 2 consecutive weeks and sampled cutaneous mucus, feces and water at 0, 7 &14 days. The 16S RNA hypervariable region V4 was sequenced on Illumina MiSeq. After two weeks of acidic exposure, fecal and skin microbiota taxonomic structures exhibited different patterns: skin microbiota was still exhibiting a significantly disturbed composition whereas fecal microbiota recovered a similar composition to control group, thus suggesting a stronger resilience capacity of the intestinal microbiota than cutaneous microbiota.

Background: Chagas disease results from infection with the diploid protozoan parasite Trypanosoma cruzi. T. cruzi is highly genetically diverse, and multiclonal infections in individual hosts are common, but little studied. In this study, we explore T. cruzi infection multiclonality in the context of age, sex and clinical profile among a cohort of chronic patients, as well as paired congenital cases from Cochabamba, Bolivia and Goias, Brazil using amplicon deep sequencing technology., Methodology/ Principal Findings: A 450bp fragment of the trypomastigote TcGP63I surface protease gene was amplified and sequenced across 70 chronic and 22 congenital cases on the Illumina MiSeq platform. In addition, a second, mitochondrial target--ND5--was sequenced across the same cohort of cases. Several million reads were generated, and sequencing read depths were normalized within patient cohorts (Goias chronic, n = 43, Goias congenital n = 2, Bolivia chronic, n = 27; Bolivia congenital, n = 20), Among chronic cases, analyses of variance indicated no clear correlation between intra-host sequence diversity and age, sex or symptoms, while principal coordinate analyses showed no clustering by symptoms between patients. Between congenital pairs, we found evidence for the transmission of multiple sequence types from mother to infant, as well as widespread instances of novel genotypes in infants. Finally, non-synonymous to synonymous (dn:ds) nucleotide substitution ratios among sequences of TcGP63Ia and TcGP63Ib subfamilies within each cohort provided powerful evidence of strong diversifying selection at this locus., Conclusions/significance: Our results shed light on the diversity of parasite DTUs within each patient, as well as the extent to which parasite strains pass between mother and foetus in congenital cases. Although we were unable to find any evidence that parasite diversity accumulates with age in our study cohorts, putative diversifying selection within members of the TcGP63I gene family suggests a link between genetic diversity within this gene family and survival in the mammalian host.

The phosphatidylinositol 3 kinase (PI3K) pathway is frequently altered in cancer, including ovarian cancer (OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (mTOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective mTOR complex-1 (mTORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual mTORC1/mTORC2, Akt, and PI3K inhibitors. Although it is likely that inhibition of the PI3K/Akt/mTOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and/or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3K signaling network, PI3K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3K pathway in OC and provide an up-to-date review of clinical trials of novel PI3K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.

DNA flows between chromosomes and mobile elements, following rules that are poorly understood. This limited knowledge is partly explained by the limits of current approaches to study the structure and evolution of genetic diversity. Network analyses of 119,381 homologous DNA families, sampled from 111 cellular genomes and from 165,529 phage, plasmid, and environmental virome sequences, offer challenging insights. Our results support a disconnected yet highly structured network of genetic diversity, revealing the existence of multiple "genetic worlds." These divides define multiple isolated groups of DNA vehicles drawing on distinct gene pools. Mathematical studies of the centralities of these worlds' subnetworks demonstrate that plasmids, not viruses, were key vectors of genetic exchange between bacterial chromosomes, both recently and in the past. Furthermore, network methodology introduces new ways of quantifying current sampling of genetic diversity.