Prolonged Dormancy Research Articles

Environmental Pollutant Anthracene Induces ABA-Dependent Transgenerational Effects on Gemmae Dormancy in Marchantia polymorpha.

Anthracene, a polycyclic aromatic hydrocarbon (PAH) from fossil fuel combustion, poses significant environmental threats. This study investigates the role of abscisic acid (ABA) in the anthracene tolerance of the liverwort Marchantia polymorpha using mutants deficient in ABA perception (Mppyl1) or biosynthesis (Mpaba1). In this study, we monitored the role of ABA in the anthracene tolerance response by tracking two ABA-controlled traits: plant growth inhibition and gemmae dormancy. We found that the anthracene-induced inhibition of plant growth is dose-dependent, similar to the growth-inhibiting effect of ABA, but independent of ABA pathways. However, gemmae dormancy was differentially affected by anthracene in ABA-deficient mutants. We found that gemmae from anthracene-exposed WT plants exhibited reduced germination compared to those from mock-treated plants. This suggests that the anthracene exposure of mother plants induces a transgenerational effect, resulting in prolonged dormancy in their asexual propagules. While Mppyl1 gemmae retained a dormancy delay when derived from anthracene-exposed thalli, the ABA biosynthesis mutant Mpaba1 did not display any significant dormancy delay as a consequence of anthracene exposure. These results, together with the strong induction of ABA marker genes upon anthracene treatment, imply that anthracene-induced germination inhibition relies on ABA synthesis in the mother plant, highlighting the critical role of MpABA1 in the tolerance response. These findings reveal a complex interplay between anthracene stress and ABA signaling, where anthracene triggers ABA-mediated responses, influencing reproductive success and highlighting the potential for leveraging genetic and hormonal pathways to enhance plant resilience in contaminated habitats.

Semi-Markov process-driven maintenance scheduling for Tainter gate system considering multiplelimit states

In extended periods of operation, Taiwan’s reservoir electromechanical systems increasingly require substantial maintenance. This research adopts the semi-Markov process, which accommodates non-exponential distribution of state durations, to formulate optimal maintenance strategies for Tainter gate systems that are noted for their prolonged dormancy and significant operational uncertainties. The methodology initiates with the estimation of failure probabilities across four condition states, analyzing deterioration through the Weibull distribution for both general and latent limit states. The general limit state accounts for time-induced deterioration and effects of dormancy using a Bayesian–Weibull first-order reliability method, while the latent limit state addresses activation failures. Employing the semi-Markov process, an annual transition matrix is computed and combined with failure probabilities to assess the Tainter gates’ system reliability. To identify the most efficient maintenance schedule, a genetic algorithm is applied, targeting the minimization of failure probabilities for both limit states below predefined thresholds and cost reduction. Numerical simulations validate the framework’s efficacy, demonstrating its potential to enhance maintenance planning objectivity and decrease dependence on subjective assessments. The findings highlight the predominance of the general limit state in dictating system failure and underscore the risk Tainter gates face during transition from dormancy to activation, emphasizing the need for thorough monitoring.

Innate immune dynamics in the context of multisite EGFR mutations in lung adenocarcinoma.

Based on favorable outcomes and decreased propensity for lymph node and distant metastasis, multiple ground-glass nodules (GGNs) are now predominantly recognized as early-stage primary independent lung cancer. In this study, we discuss a case involving a patient with reoperative multifocal GGNs who was ultimately diagnosed with early multiple intrapulmonary metastases and multifocal primary lung cancers. This patient exhibited multisite epidermal growth factor receptor (EGFR) mutations, including the classical L858R, exon 19 deletion and the rare V834L variant. Despite a high tumor burden and the presence of various EGFR driver mutations, the patient experienced prolonged dormancy and exceptionally slow lesion growth, even without any systemic treatment. Our research indicates that the patient's immune response against the tumor remained robust throughout the disease course. Furthermore, we found that pathways associated with integrin-mediated cell extracellular matrix adhesion played a role in activating her innate immune responses and regulating tumor dormancy. Our findings suggest that the interplay between cancer cell mutations and the tumor microenvironment (TME) phenotype during tumor evolution contributed to this patient's prolonged survival. Integrating these aspects for lung tumor stratification is expected to improve predictions of growth potential and aid in clinical decision making.

Direct shoot regeneration from cotyledonary node of Uraria picta (Jacq.) Desv. ex DC., an important plant of dashmula drugs, and assessment of genetic fidelity, metabolic profiling, and anti-diabetic activity

Uraria picta root is used in the polyherbal product ‘Dashmula’. Its exploitation for formulation preparation has depleted its availability, leading to medicine adulteration. Direct shoot regeneration from the cotyledonary node holds promise as a source of raw material. This study aimed to develop a regeneration protocol for U. picta and validate its genetic and metabolic fidelity. The seeds of U. picta showed low germination rates, prolonged dormancy, and poor viability. Root exploitation in the wild poses a threat to its availability in nature. Seedling’s derived cotyledonary nodes cultured on B5 medium supplemented with BAP (0.5–3 mg L−1), Kinetin (0.5–3 mg L−1), Thidiazuron (0.01–1 mg L−1), and meta-Topolin (0.1–4 mg L1). To address hyperhydricity in regenerated shoots, cotyledonary nodes were cultured on high-agar concentration media. Microshoots were exposed to IBA solution (50–800 mg L−1) pulse treatment for rooting. Tissue-cultured plants genetic fidelity was assessed using ISSR and SCoT markers, while metabolic fidelity was studied with HRMS. The chlorophyll content, antioxidant, and antidiabetic activity of micropropagated plants were evaluated. The highest shoot regeneration frequency, with a maximum of 6.57±0.278 shoots per explant, was achieved using 2 mg L−1meta-Topolin. The shoots were elongated, had expanded leaves, and were hyperhydrated. BAP (2 mg L−1) induced a maximum of 9.83±0.333 shoot buds per explant. BAP caused explant browning, profuse callus formation, dwarfing, and hyperhydric shoots. Hyperhydricity was alleviated with a higher agar concentration (1 %). IBA (400 mg L−1) induced a maximum of 2.18±0.090 roots per shoot and a root length of 9.23±0.033 cm. Tissue-cultured and mother plants exhibited clonal fidelity, similar metabolite and chlorophyll content, strong antioxidant activity, and equal efficacy for inhibiting α-amylase and α-glucosidase. This method can propagate elite clones of U. picta and offer its improvement via genetic transformation.

Voltinism of a solitary bee was influenced by temperature but not provision size.

Changes in the timing and duration of life cycles are distinctive fingerprints of environmental change. Yet, the biotic and abiotic cues underpinning phenology and voltinism, i.e., number of generations per year, are poorly understood. Here, I experimentally test how temperature and provision size influence voltinism and survival to emergence in a solitary bee Colletes validus, and how temperature influences voltinism in the brood parasite Tricrania sanguinipennis. Within the same population, univoltine individuals emerge after 1 year (1-year form), whereassemivoltine individuals enter prolonged dormancy and emerge after 2 years (2-year form). I reared field-collected bees under 2 × 2 factorial experiments with cool (18.5°C ± 0.5°C) vs. warm (24°C ± 0.5°C) temperature treatments (bees and beetles) and no supplement vs. supplemental food treatments (+ 20% ± 5% pollen provision by mass); beetles were reared under temperature treatments only. Cool temperatures consistently increased the proportion of 2-year bees regardless of provision size, a finding that was consistent with three years of field observations. There was ademographic cost to prolonged dormancy in that both 1- and 2-year bees survived to emergence as adults, but survival of 2-year bees was approximately 50% lower than 1-year bees. Two-year beetles were produced under cooler temperatures, but unlike bees, beetles had nearly perfect survival to emergence in all treatments. This experiment advances our mechanistic understanding of the environmental drivers of voltinism in diverse insect taxa and underscores the importance of considering cryptic life stages when interpreting responses to environmental change.

Spatio-temporal variability in transmission risk of human schistosomes and animal trematodes in a seasonally desiccating East African landscape.

Different populations of hosts and parasites experience distinct seasonality in environmental factors, depending on local-scale biotic and abiotic factors. This can lead to highly heterogeneous disease outcomes across host ranges. Variable seasonality characterizes urogenital schistosomiasis, a neglected tropical disease caused by parasitic trematodes (Schistosoma haematobium). Their intermediate hosts are aquatic Bulinus snails that are highly adapted to extreme rainfall seasonality, undergoing prolonged dormancy yearly. While Bulinus snails have a remarkable capacity for rebounding following dormancy, we investigated the extent to which parasite survival within snails is diminished. We conducted an investigation of seasonal snail schistosome dynamics in 109 ponds of variable ephemerality in Tanzania from August 2021 to July 2022. First, we found that ponds have two synchronized peaks of schistosome infection prevalence and observed cercariae, though of lower magnitude in the fully desiccating than non-desiccating ponds. Second, we evaluated total yearly schistosome prevalence across an ephemerality gradient, finding ponds with intermediate ephemerality to have the highest infection rates. We also investigated dynamics of non-schistosome trematodes, which lacked synonymity with schistosome patterns. We found peak schistosome transmission risk at intermediate pond ephemerality, thus the impacts of anticipated increases in landscape desiccation could result in increases or decreases in transmission risk with global change.

Assessment of Various Gibberellic Acid Concentrations on Seed Germination and Seedling Growth of Chilgoza (Pinus gerardiana Wall. ex D. Don)

Chilgoza (Pinus gerardiana) forests naturally exist on the highest elevations of the Himalaya Mountains in the provinces of Paktia, Kunar, Nangarhar, Nuristan, and Paktika in the southeast of Afghanistan. These natural chilgoza forests provide a sizable source of income for the people living in these areas. The spread and natural regeneration of chilgoza pine forests is declining in the natural environment as a result of overharvesting, erratic annual seed production, and prolonged dormancy; therefore, it is necessary to find an effective method to enhance seed germination and seedling growth. Different Gibberellic Acid (GA3) hormone concentrations (50 ppm, 75 ppm, and 100 ppm), the removal of the seed coat, and control (untreated) treatments were used to conduct an experiment for this study. For each treatment, seedling growth parameters and the percentage of seeds that germinated were examined. The results showed that the T4 treatment had the highest average length of seedling, shoot, and root, measuring 13.34 cm, 8.1 cm, and 8.4 cm, respectively; whereas the T1 treatment had the shortest average lengths of seedling, shoot, and root, measuring 11.22 cm, 6.5 cm, and 6.2 cm, respectively. The greatest percentage of germination (78.66%) was observed in T4 (100 ppm), whereas the lowest percentage (26%) was documented in T1 (Control). The highest average number of leaves was recorded in T4 (22.25) and the lowest in T1 (15.02) treatment. The results indicated that treating chilgoza pine seeds in a 100 ppm solution of GA3 for 24 hours enhances both the seed germination and sprouting seedling growth.

Seasonal energetics: are insects constrained by energy during dormancy?

In seasonal environments, many animals, including insects, enter dormancy, where they are limited to a fixed energy budget. The inability to replenish energetic stores during these periods suggests insects should be constrained by pre-dormancy energy stores. Over the last century, the community of researchers working on survival during dormancy has operated under the strong assumption that energy limitation is a key fitness trait driving the evolution of seasonal strategies. That is, energy use has to be minimized during dormancy because insects otherwise run out of energy and die during dormancy, or are left with too little energy to complete development, reproductive maturation or other costly post-dormancy processes such as dispersal or nest building. But if energy is so strongly constrained during dormancy, how can some insects - even within the same species and population - be dormant in very warm environments or show prolonged dormancy for many successive years? In this Commentary, we discuss major assumptions regarding dormancy energetics and outline cases where insects appear to align with our assumptions and where they do not. We then highlight several research directions that could help link organismal energy use with landscape-level changes. Overall, the optimal energetic strategy during dormancy might not be to simply minimize metabolic rate, but instead to maintain a level that matches the demands of the specific life-history strategy. Given the influence of temperature on energy use rates of insects in winter, understanding dormancy energetic strategies is critical in order to determine the potential impacts of climate change on insects in seasonal environments.

Abstract A009: NR2F1 inhibits Gaq/11-YAP-TAZ signaling and limits reactivation of uveal melanoma disseminated cancer cells via induction of dormancy

Abstract Introduction: At the time of diagnosis, less than 5% of uveal melanoma (UM) patients have evidence of metastasis. However, up to 50% of UM patients will succumb to advanced metastatic in liver. UM cancer cells can persist undetected in liver for prolonged periods mainly and often take years-to-decades to grow out and do so without recurrence at the primary site. However, the mechanisms underlying the prolonged dormancy and why the liver is a preferred site for survival and eventual regrowth are a long-standing medical mystery. Results: GNAQ/11 are the main driving mutations in UM that activate downstream oncogenic YAP signaling. Using Gaq/11mut /BAPwt human uveal melanoma lines, we reveal that NR2F1, a neural cell commitment regulator is the main driver of regulating dormancy program. RNA-seq of rare UM disseminated cancer cells (DCCs) in livers identified that dormant DCCs upregulate the expression of neural differentiation genes, including NR2F1, while silencing Gaq downstream YAP/TAZ and cell cycle gene expression compared to proliferative cell clusters. Targeted pharmacological inhibition of Gaq/11mut signaling using YM-254890, an inhibitor of Gaq/11 resulted in NR2F1 upregulation and robust UM growth arrest. In contrast, inhibition of NR2F1 either by siRNA or CRISPR/cas9 upregulated YAP1 and its downstream targets at both transcript and protein levels along with increased colony growth in 3D culture. Importantly, UM solitary DCCs in nude mouse upregulated NR2F1 and in vivo CRISPR KO of NR2F1 results in dormant UM DCC awakening and massive metastatic growth in the murine liver. Immunofluorescence of UM patients’ liver metastatic lesions showed high expression of NR2F1 in solitary DCCs compared to the tumor mass. Chromatin-immunoprecipitation assays revealed that NR2F1 binds to the YAP1 promoter and regulates its gene expression. OMM1.3 CRISPR/Cas9 KO of NR2F1 cells showed increased recruitment of H3K4me3 and H3K27ac histone marks onto the YAP1 promoter while overexpression of NR2F1 decreased the recruitment of histone activating marks. Co-immunoprecipitation assay showed increased YAP1-TEAD1 complex formation in NR2F1 KO OMM1.3 cells while overexpression of NR2F1 reduced the abundance of this complex. Summary: Our work suggests that NR2F1 is required to maintain the single cell state of UM cells in the liver by inhibiting the YAP signally pathway. This study provides insight into the previously unrecognized mechanism of uveal melanoma dormancy opening a new space to design anti-metastatic therapies for UM patients. Citation Format: Rama Kadamb, Melisa Lopez Anton, Vivian Chua, Timothy Purwin, Maria Angelo Nieto Toledano, Andrew Aplin, Julio Aguirre-Ghiso. NR2F1 inhibits Gaq/11-YAP-TAZ signaling and limits reactivation of uveal melanoma disseminated cancer cells via induction of dormancy [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A009.

Fitness cost of Rhagoletis cerasi (Diptera: Tephritidae) adults emerged from pupae with different dormancy regimes: the case of prolonged chilling.

The European cherry fruit fly, Rhagoletis cerasi (Diptera: Tephritidae), is a univoltine species that overwinters at pupal stage. Under optimum overwintering conditions pupae will develop into adults the next spring. Shorter or longer than optimum chilling periods induce prolonged pupae dormancy. Pupae that enter prolonged dormancy due to a short chilling period exhibit high emergence rates after a second cycle of cold/warm periods. Adults found to be larger and less fecund compared to their counterparts from pupae with annual diapause. On the other hand, extreme long chilling periods at pupal stage results in high mortality rates. However, for one Greek population, a substantial number of adults emerged following prolonged chilling of pupae (ca. 18 consecutive months). In this study, we used three R. cerasi populations in order to address possible geographical variation in fitness cost of adults from pupae with prolonged dormancy. In addition, the fitness traits of these adults emerging after prolonged pupae chilling were compared with that of their counterparts from pupae with annual diapause or prolonged dormancy. Our results reveal no population-specific variation in fitness cost of adults from pupae with prolonged dormancy. Within a population, lifetime fecundity did not differ between adults emerged from pupae with prolonged dormancy and those emerged after prolonged pupae chilling. Adults emerged from pupae exposed to prolonged chilling suffer an additional reduction in adult longevity compared to adults from pupae with prolonged dormancy. Hence, fitness of R. cerasi adults is regulated by diapause regimes of pupae.

Review old bone, new tricks

Despite the significant progress made over the past decade with combination of molecular profiling data and the development of new clinical strategies, our understanding of metastasis remains elusive. Bone metastasis is a complex process and a major cause of mortality in breast and prostate cancer patients, for which there is no effective treatment to-date. The current review summarizes the routes taken by the metastatic cells and the interactions between them and the bone microenvironment. We emphasize the role of the specified niches and cues that promote cellular adhesion, colonization, prolonged dormancy, and reactivation. Understanding these mechanisms will provide better insights for future studies and treatment strategies for bone metastatic conditions.

Biological Flora of Britain and Ireland: Fritillaria meleagris

Abstract This account presents information on all aspects of the biology of Fritillaria meleagris L. (Snake's Head Fritillary). The main topics are presented within the standard framework of the Biological Flora of Britain and Ireland: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history, and conservation. Fritillaria meleagris is a perennial spring bulb that grows in wet mesotrophic meadows and wet openings in woodlands. In Britain, it is localised to floodplain meadows but occurs as an intentional introduction in a range of habitats. There are several large populations on the floodplains of the River Thames and its tributaries in Wiltshire, Berkshire and Oxfordshire. Fritillaria meleagris occurs on mesotrophic alluvium soils often overlaying calcareous gravel with a relatively wide pH range. It favours a high ground water table during winter months and spring followed by good drainage of the soil throughout the summer. Fritillaria meleagris plants regularly experience prolonged dormancy. From 30% to 99% of plants in a population can remain below‐ground for more than a year. Fritillaria meleagris produces nectar and is mainly pollinated in April by bumblebee queens in England. Other pollinators include insects of the orders Hymenoptera, Diptera and Lepidoptera, particularly bumblebees, hoverflies and butterflies. The release of the seeds from the pod in May–June can take a month. Seeds require warm and cold treatments for the embryo to fully form. Air pockets aid seed flotation on the surface of flood water for up to a month. The seeds of Fritillaria meleagris do not form a seed bank, germinating either during flotation or on bare ground. Fritillaria meleagris declined in Britain during the 20th century due to agricultural improvement and ploughing of floodplain grasslands. In all, 20 or so remaining populations survive in ancient hay meadows. Several of its British locations receive statutory protection as designated sites. However, recent work suggests that F. meleagris was probably introduced to Britain as an ornamental, and the level of protection it receives is therefore likely to change.

Host plant stimuli effects on survival and duration of dormancy of Rhagoletis zoqui, Rhagoletis completa (Diptera: Tephritidae) and associated parasitoids.

Tephritid fruit flies in the genus Rhagoletis bridge between predictable periods of fruit availability by becoming dormant. To cope with acyclic unpredictable events (e.g., frost, mast seeding, etc), a proportion of the population can undergo prolonged dormancy. In the case of walnut infesting Rhagoletis, host plant-derived cues such as juglone soil concentration vary seasonally in predictable patterns. Here, we examined the effects of host plant parts and derived compounds on emergence rates and dormancy duration of Rhagoletis completa (Cresson), Rhagoletis zoqui (Bush) (Diptera: Tephritidae), and associated parasitoids. Pupae of both species were exposed to walnut leaves, fruit, or fruit and leaves and compared to a control. In a second experiment, R. zoqui were exposed to 10 mg l-1 of juglone applied to pupation medium during four consecutive 4-week time periods under variable combinations of temperature and frequency of exposure. Overall, the presence of fruit resulted in greater overwintering survival of R. completa but had no effect on the duration of dormancy of either fly species. Application of juglone over two consecutive periods produced greater mortality of R. zoqui than the control. Three parasitoid species emerged from R. completa and one from R. zoqui. Duration of dormancy for parasitoids was longer than that of fly hosts. Regardless of treatment, 13.3-18.4% of R. completa pupae and 1.3-2.8% R. zoqui engaged in prolonged (>year) dormancy. Our results indicate that host plant derived cues have little or no effect on survival and duration of dormancy of walnut infesting Rhagoletis, and at the tested concentration juglone is toxic to R. zoqui pupae. Testing the effect of juglone at lower concentrations is necessary to rule out its role as an environmental cue for regulation of dormancy. So far, host plant fruiting phenology appears to play a greater role than host plant derived cues in selecting for fly eclosion times.

Applying Plant Hydraulic Physiology Methods to Investigate Desiccation During Prolonged Cold Storage of Horticultural Trees.

Plant nursery production systems are a multi-billion-dollar, international, and horticultural industry that depends on storing and shipping live plants. The storage environment represents potentially desiccating and even fatal conditions for dormant, bareroot, and deciduous horticulture crops, like orchard trees, forestry trees, ornamental trees, and grapevines. When tree mortality is considered within a plant hydraulic framework, plants experiencing water stress are thought to ultimately die from hydraulic failure or carbon starvation. We hypothesized that the hydraulic framework can be applied to stored crops to determine if hydraulic failure or carbon starvation could be attributed to mortality. We used deciduous trees as model species because they are important horticultural crops and provide a diversity of hydraulic strategies. We selected cultivars from six genera: Acer, Amelanchier, Gleditsia, Gymnocladus, Malus, and Quercus. For each cultivar, we measured stem hydraulic conductance and vulnerability to embolism. On a weekly basis for 14 weeks (March–June), we removed trees of each cultivar from cold storage (1–2°C). Each week and for each cultivar, we measured stem water potential and water content (n = 7) and planted trees to track survival and growth (n = 10). At three times during this period, we also measured non-structural carbohydrates. Our results showed that for four cultivars (Acer, Amelanchier, Malus, and Quercus), the stem water potentials measured in trees removed from storage did not exceed stem P50, the water potential at which 50% of stem hydraulic conductivity is lost. This suggests that the water transport system remains intact during storage. For two cultivars (Gleditsia and Gymnocladus), the water potential measured on trees out of storage exceeded stem P50, yet planted trees from all weeks survived and grew. In the 14 weeks, there were no significant changes or directional trends in stem water potential, water content, or NSC for most cultivars, with a few exceptions. Overall, the results show that the trees did not experience detrimental water relations or carbon starvation thresholds. Our results suggest that many young deciduous trees are resilient to conditions caused by prolonged dormancy and validate the current storage methods. This experiment provides an example of how a mechanistically based understanding of physiological responses can inform cold storage regimes in nursery tree production.

Bacterial Communities of Lab and Field Northern House Mosquitoes (Diptera: Culicidae) Throughout Diapause.

Diapause is a hormonally driven response which is triggered by environmental cues that signal impending adverse conditions and prompts metabolic, developmental, and behavioral changes to allow survival until the return of favorable conditions. Microbial symbionts have been shown to influence the metabolism, development, and behavior of their host organisms, all of which are common diapause-associated characteristics. Surveys of bacterial components in relation to diapause have been examined in few systems, of which the species are usually inactive during dormancy, such as eggs or pupae. This is specifically intriguing as adult female diapause in Culex pipiens (Diptera: Culicidae) can last between 4 and 7 mo and females remain mobile within their hibernacula. Furthermore, it is unknown how microbiota changes associated with prolonged dormancy are different between the lab and field for insect systems. This study aims to characterize how the microbiota of C. pipiens changes throughout diapause under both field and lab settings when provided identical food and water resources. Based on these studies, C. pipiens microbiota shifts as diapause progresses and there are considerable differences between field and lab individuals even when provided the same carbohydrate and water sources. Specific bacterial communities have more association with different periods of diapause, field and lab rearing conditions, and nutritional reserve levels. These studies highlight that diapausing mosquito microbiota studies ideally should occur in field mesocosms and at multiple locations, to increase applicability to wild C. pipiens as prolonged exposure to artificial rearing conditions could impact metrics related to diapause-microbiome interactions. Additionally, these findings suggest that it would be worthwhile to establish if the microbiota shift during diapause impacts host physiology and whether this shift is critical to diapause success.

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer.

Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations. We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019. Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use. Atorvastatin could be used during adjuvant chemotherapy and also in conjunction withmetastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.

Present era of drug safety in India: An overview

Introduction: Common Adverse Drug Reactions (ADR), evaluated by drug clinical trial studies, whereas an individual or specific population might suffer reactions after prolonged dormancy. Pharmacovigilance (PV) is a scientific investigation dealing with and keeping regular vigil on the drugs being used. Methods: The Indian Pharmacopoeia Commission (IPC) and other regulatory authorities like a National Coordination Committee (NCC) via the Central Drug Standard Control Organization (CDSCO) manage PV activity in synchronicity. Indian Pharmacovigilance (PV) system requires carving, therefore the Pharmacovigilance Program of India (PvPI) was enforced by the government in the year 2010, relying on exact ADR detection, evaluation, and reporting. Results: Thus, several regional, zonal and peripheral centers are developed for ADR reporting. Clinicians, Nurses, laypersons, pharmacists, and other healthcare professionals can fill ADR reporting forms online or offline at the nearest centers in suitable languages. Additionally, a toll-free number and mobile app could be used for reporting ADR. Every reported ADR gets collected and processed at the centers through Vigi-flow software, which detects and assesses the signal strength reported at CDSCO and World Health Organisation (WHO) for the required regulatory action. Conclusions: The final decision of CDSCO-WHO is passed by a suitable media source for the advancement of society's health.

Optimal resource allocation and prolonged dormancy strategies in herbaceous plants

Abstract Understanding the fitness consequences of different life histories is critical for explaining their diversity and for predicting effects of changing environmental conditions. However, current theory on plant life histories relies on phenomenological, rather than mechanistic, models of resource production. We combined a well‐supported mechanistic model of ontogenetic growth that incorporates differences in the size‐dependent scaling of gross resource production and maintenance costs with a dynamic optimization model to predict schedules of reproduction and prolonged dormancy (plants staying below ground for ≥1 growing season) that maximize lifetime offspring production. Our model makes three novel predictions: First, maintenance costs strongly influence the conditions under which a monocarpic or polycarpic life history evolves and how resources should be allocated to reproduction by polycarpic plants. Second, in contrast to previous theory, our model allows plants to compensate for low survival conditions by allocating a larger proportion of resources to storage and thereby improving overwinter survival. Incorporating this ecological mechanism in the model is critically important because without it our model never predicts significant investment into storage, which is inconsistent with empirical observations. Third, our model predicts that prolonged dormancy may evolve solely in response to resource allocation trade‐offs. Significance. Our findings reveal that maintenance costs and the effects of resource allocation on survival are primary determinants of the fitness consequences of different life history strategies, yet previous theory on plant life history evolution has largely ignored these factors. Our findings also validate recent arguments that prolonged dormancy may be an optimal response to costs of sprouting. These findings have broad implications for understanding patterns of plant life history variation and predicting plant responses to changing environments.

Abstract IA18: Molecular signatures of circulating tumor cells

Abstract Circulating tumor cells (CTCs) are shed from primary cancers, as well as from metastatic deposits, into the blood circulation, where they may travel either as single cells or as CTC clusters, facing both mechanical and oxidative stress. Only a small subset of CTCs remain sufficiently viable to initiate metastatic growth upon dissemination to distant organs; their detection in patients with localized invasive cancer may present an opportunity for early detection, while their analysis in advanced cases provides a “whole cell biomarker,” enabling single-cell DNA, RNA, and protein studies, as well as functional drug-sensitivity testing using cultured CTCs. We have applied microfluidic technologies to deplete normal hematopoietic cells from blood specimens of patients with cancer, enhancing the ability of unmanipulated CTCs to proliferate ex vivo and recapitulating features of metastatic-competent cancer cells. Cultured CTCs from patients with either breast cancer or melanoma are highly tumorigenic when injected orthotopically at low inoculum into immunosuppressed mice. However, they display sensitivity to ROS and appear to upregulate compensatory mechanisms that are not commonly observed in primary tumors. In addition, they may undergo prolonged dormancy when lodged within distant organs. By combining single-cell RNA seq of patient-derived CTCs together with CRISPR and other genome-wide screens for modulators of metastasis phenotypes, we have sought to identify novel vulnerabilities in these cellular initiators of metastasis. While CTCs transit only very briefly through the blood circulation, these exceptional conditions may present new therapeutic opportunities to suppress the metastatic recurrence of cancer. Citation Format: Daniel Haber, Xin Hong, Richard Ebright, Doug Micalizi, Aditya Bardia, Ryan Sullivan, Mehmet Toner, Shyamala Maheswaran. Molecular signatures of circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Liquid Biopsies; Jan 13-16, 2020; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(11_Suppl):Abstract nr IA18.

Dynamic expression of intra- and extra-cellular proteome and the influence of epiphytic bacteria for Nostoc flagelliforme in response to rehydration.

Nostoc flagelliforme is well known for its strong ecological adaptability in inhabiting desert biological soil crusts. However, the mechanism of its recovery from quiescent to active state after prolonged dormancy remains poorly characterized. Especially how exoproteome be related to the adaptive strategies and participate in the microalgae-bacteria interaction. In the present work, we analysed the intra- and extra-cellular proteome of N. flagelliforme over a complete rehydration period both in sterilization and in natural condition for the first time. The protein expression profile for N. flagelliforme has more fluctuations during the first 1 h after wetting but been relatively steady after fully hydrated. According to the extracellular proteomic datasets, we found a dynamic secretion of various extracellular hydrolytic enzymes and membrane transport proteins, which were related to peptidoglycan digestion and nutrient exchange respectively. Two-hundred and thirteen differentially expressed proteins induced by sterilization also reflect variation in nutrient exchange and highlight symbiosis between N. flagelliforme and surrounding bacteria. We also identified 112 phosphopeptides and 217 phosphorylation site of 95 protein of hydrated N. flagelliforme. The time course datasets we present here will be a reference for understanding the molecular processes underlying N. flagelliforme resuscitation and its potential role in microbial community diversification and soil desertification control.