Treatment of Asthma by a Controlled-Release Theophylline Tablet Formulation: A Review of the North American Experience with Nocturnal Dosing

As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early ‘morning dip’. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr ‘symmetric’ theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow.

Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl® 400-mg tablets*) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur® tablets, ? B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to ‘dose dumping.’ Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing.

Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.     

A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness

Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a “stem-like state” that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from “maximal tolerated dose,” which may promote therapy induced-stemness, to repeated “minimally effective doses” (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.     

Proteomics advances for precision therapy in ovarian cancer

ABSTRACT

Introduction: Due to the relatively low mutation rate and high frequency of copy number variation, finding actionable genetic drivers of high-grade serous carcinoma (HGSC) is a challenging task. Furthermore, emerging studies show that genetic alterations are frequently poorly represented at the protein level adding a layer of complexity. With improvements in large-scale proteomic technologies, proteomics studies have the potential to provide robust analysis of the pathways driving high HGSC behavior.

Areas covered: This review summarizes recent large-scale proteomics findings across adequately sized ovarian cancer sample sets. Key words combined with ‘ovarian cancer’ including ‘proteomics’, ‘proteogenomic’, ‘reverse-phase protein array’, ‘mass spectrometry’, and ‘adaptive response’, were used to search PubMed.

Expert opinion: Proteomics analysis of HGSC as well as their adaptive responses to therapy can uncover new therapeutic liabilities, which can reduce the emergence of drug resistance and potentially improve patient outcomes. There is a pressing need to better understand how the genomic and epigenomic heterogeneity intrinsic to ovarian cancer is reflected at the protein level and how this information could be used to improve patient outcomes.     

Paradoxes of tumour complexity: somatic selection,vulnerability by design,or infectious aetiology?

The aetiology of cancer involves intricate cellular and molecular mechanisms that apparently emerge on the short timescale of a single lifetime. Some of these traits are remarkable not only for their complexity, but also because it is hard to conceive selection pressures that would favour their evolution within the local competitive microenvironment of the tumour. Examples include ‘niche construction’ (re‐programming of tumour‐specific target sites) to create permissive conditions for distant metastases; long‐range feedback loops of tumour growth; and remarkably ‘plastic’ phenotypes (e.g. density‐dependent dispersal) associated with metastatic cancer. These traits, which we term ‘paradoxical tumour traits’, facilitate the long‐range spread or long‐term persistence of the tumours, but offer no apparent benefit, and might even incur costs in the competition of clones within the tumour. We discuss three possible scenarios for the origin of these characters: somatic selection driven by specific selection regimes; non‐adaptive emergence due to inherent vulnerabilities in the organism; and manipulation by putative transmissible agents that contribute to and benefit from these traits. Our work highlights a lack of understanding of some aspects of tumour development, and offers alternative hypotheses that might guide further research.     

Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo

Due to the high level of heterogeneity and mutations inherent in human cancers, single agent therapies, or combination regimens which target the same pathway, are likely to fail. Emphasis must be placed upon the inhibition of pathways that are responsible for intrinsic and/or adaptive resistance to therapy. An active field of investigation is the development and testing of DNA repair inhibitors that promote the action of, and prevent resistance to, commonly used chemotherapy and radiotherapy. We used a novel protocol to evaluate the effectiveness of BRCA2 inhibition as a means to sensitize tumor cells to the DNA damaging drug cisplatin. Tumor cell metabolism (acidification and respiration) was monitored in real-time for a period of 72 hr to delineate treatment effectiveness on a minute by minute basis. In combination, we performed an assessment of metastatic frequency using a chicken embryo chorioallantoic membrane (CAM) model of extravasation and invasion. This protocol addresses some of the weaknesses of commonly used in vitro and in vivo methods to evaluate novel cancer therapy regimens. It can be used in addition to common methods such as cell proliferation assays, cell death assays, and in vivo murine xenograft studies, to more closely discriminate amongst candidate targets and agents, and select only the most promising candidates for further development.     

The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor’s volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. To this end, we simulated the impact of different fibroblast distributions on treatment outcomes. As a proof of principle, we focused on five types of distribution of fibroblasts characterized by different locations, shapes, and orientations of the fibroblast region with respect to the resistant cells. Our simulation shows that the spatial architecture of fibroblasts modulates tumor progression in both continuous and adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy of a virtual patient with four metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations. Our simulation highlights the importance of undetected metastatic lesions on adaptive therapy outcomes.     

Climatic adaptation of chromosomal inversions in <Emphasis Type="Italic">Drosophila subobscura</Emphasis>

Drosophila subobscura is a species with a rich chromosomal polymorphism which is adaptive to different climatic conditions. Five samples of the Font Groga population (Barcelona, Spain) were sampled in autumn during 5 consecutive years (2011–2015) to obtain their inversion chromosomal polymorphism, and climatic data of several meteorological variables were also collected. The aim was to analyze the adaptive potential of inversions with regard to climatic variables, being the most relevant: mean temperature (T_mean), maximum temperature (T_max), minimum temperature (T_min), humidity (Hm) and rainfall (Rf). As expected, no significant variation in inversion frequencies were detected over this short period of time. However, from a climatic point of view it was possible to differentiate ‘warm’ and ‘dry’ from ‘cold’ and ‘humid’ samples. The joint study of maximum (T_max) and minimum (T_min) temperatures was a key element to understand the effect on adaptation of many inversions. It was also observed that temperature had to be considered in conjunction with humidity and rainfall. All these factors would condition the biota of D. subobscura habitat, and chromosomal inversions could provide an adaptive response to it.     

Bioengineered Escherichia coli Nissle 1917 for tumour-targeting therapy

Bacterial vectors, as microscopic living ‘robotic factories’, can be reprogrammed into microscopic living ‘robotic factories’, using a top-down bioengineering approach to produce and deliver anticancer agents. Most of the current research has focused on bacterial species such as Salmonella typhimurium or Clostridium novyi. However, Escherichia coli Nissle 1917 (EcN) is another promising candidate with probiotic properties. EcN offers increased applicability for cancer treatment with the development of new molecular biology and complete genome sequencing techniques. In this review, we discuss the genetics and physical properties of EcN. We also summarize and analyse recent studies regarding tumour therapy mediated by EcN. Many challenges remain in the development of more promising strategies for combatting cancer with EcN.     

Structural heterogeneity of the plasmalemma of the yeast,Schwanniomyces occidentalis,induced by substrate

The growth of the yeast Schwanniomyces occidentalis on hydrocarbons (C₁₂?C₂₀) is followed by the formation of spherical invaginations. They are inwardly directed and border the ‘canals’ of the cell wall forming with them a single complex. The invaginations differ from the rest (smooth) part of the plasmalemma in the density of intramembrane particles. There is also a significant difference in the distribution of intramembrane particles in the plasmalemma of S. occidentalis grown on hydrocarbons and glucose. Invaginations and ‘canals’ are considered as a manifestation of the structural heterogeneity of the yeast cell envelope induced by a hydrocarbon substrate and, evidently, conditioned by adaptive processes.     

Role of age and tumour stage in the temporal pattern of 'cure' from stomach cancer: a population-based study in Osaka, Japan

Objectives: To evaluate progress in stomach cancer care in Japan since 1975. Design: Population-based study of data extracted from the Osaka Cancer Registry. Setting: Population-based cancer registry in the area of Osaka Prefecture. Participants: All 66,032 cases diagnosed with a stomach cancer in Osaka Prefecture, Japan between 1975 and 2000 and registered in the Osaka Cancer Registry. Main outcome measures: ‘Cure’ fraction and median survival time for ‘uncured’ patients were estimated with multivariable mixture ‘cure’ model. The role played by age and stage at diagnosis on the changes in ‘cure’ parameters between 1975 and 2000 was evaluated. Missing stage was handled by multiple imputation approach. Results: More than 50% of the patients diagnosed with a stomach cancer in 1996–2000 were estimated ‘cured’ from their cancer, corresponding to a 20% increase since 1975–1980. Median survival time for ‘uncured’ patients however remained unchanged at about 8 months. ‘Cure’ fraction was over 85% for localised tumours and 30% for regional tumours, but stayed as low as 2.5% for distant metastatic cancers. Improvement was underestimated by about 10% because of ageing of cancer patients. Changes in stage distribution explained up to 40% of the increase in ‘cure’ fraction among men and up to 13% in women. Overdiagnosis was unlikely to play any role in these patterns. Conclusions: ‘Cure’ fraction from stomach cancer dramatically increased in Osaka, Japan since 1975, partly because of earlier stage at diagnosis, but mostly due to improvement in treatment of stomach cancer patients. This study, based on a leading country in term of stomach cancer management, provides insightful results for other countries in which ‘cure’ fraction is usually much lower.     

Small molecules baicalein and cinnamaldehyde are potentiators of measles virus-induced breast cancer oncolysis

BackgroundAlthough the breast cancer mortality has slowed down from 2008 to 2017, breast cancer incidence rate continues to rise and thus, new and/or improved treatments are highly needed. Among them, oncolytic virotherapy which has the ability of facilitating the antitumor adaptive immunity, appears as a promising anticancer therapy. Oncolytic measles virus (MV) is particularly suitable for targeting breast cancer due to the upregulation of MV's receptor nectin-4. Nonetheless, with limited clinical success currently, ways of boosting MV-induced breast cancer oncolysis are therefore necessary. Oncolytic virotherapy alone and combined with chemotherapeutic drugs are two strategic areas with intensive development for the search of anticancer drugs. Considering that baicalein (BAI) and cinnamaldehyde (CIN) have demonstrated antitumor properties against multiple cancers including breast cancer, they could be good partners for MV-based oncolytic virotherapy.PurposeTo assess the in vitro effect of BAI and CIN with MV and assess their combination effects.MethodsWe examined the combinatorial cytotoxic effect of oncolytic MV and BAI or CIN on MCF-7 breast cancer cells. Potential anti-MV activities of the phytochemicals were first investigated in vitro to determine the optimal combination model. Synergism of MV and BAI or CIN was then evaluated in vitro by calculating the combination indices. Finally, cell cycle analysis and apoptosis assays were performed to confirm the mechanism of synergism.ResultsOverall, the viral sensitization combination modality using oncolytic MV to first infect MCF-7 breast cancer cells followed by drug treatment with BAI or CIN was found to produce significantly enhanced tumor killing. Further mechanistic studies showed that the combinations ‘MV-BAI’ and ‘MV-CIN’ display synergistic anti-breast cancer effect, mediated by elevated apoptosis.ConclusionWe demonstrated, for the first time, effective combination of oncolytic MV with BAI or CIN that could be further explored and potentially developed into novel therapeutic strategies targeting nectin-4-marked breast cancer cells.     

Active mixture of serum-circulating small molecules selectively inhibits proliferation and triggers apoptosis in cancer cells via induction of ER stress

Genetic and epigenetic regulation as well as immune surveillance are known defense mechanisms to protect organisms from developing cancer. Based on experimental evidence, we proposed that small metabolically active molecules accumulating in cancer cells may play a role in an alternative antitumor surveillance system. Previously, we reported that treatment with a mixture of experimentally selected small molecules, usually found in the serum (defined ‘active mixture’, AM), selectively induces apoptosis in cancer cells and significantly inhibits tumor formation in vivo. In this study, we show that the AM elicits gene expression changes characteristic of endoplasmic reticulum (ER) stress in HeLa, MCF-7, PC-3 and Caco-2 cancer cells, but not in primary human renal epithelial cells. The activation of the ER stress pathway was confirmed by the upregulation of ATF3, ATF4, CHAC1, DDIT3 and GDF15 proteins. Mechanistically, our investigation revealed that eIF2α, PERK and IRE1α are phosphorylated upon treatment with the AM, linking the induction of ER stress to the antiproliferative and proapoptotic effects of the AM previously demonstrated. Inhibition of ER stress in combination with BBC3 and PMAIP1 knockdown completely abrogated the effect of the AM. Moreover, we also demonstrated that the AM induces mIR-3189-3p, which in turn enhances the expression of ATF3 and DDIT3, thus representing a possible new feedback mechanism in the regulation of ATF3 and DDIT3 during ER stress. Our results highlight small molecules as attractive anticancer agents and warrant further evaluation of the AM in cancer therapy, either alone or in combination with other ER stress inducing agents.     

Honokiol: A review of its pharmacological potential and therapeutic insights

BackgroundHonokiol is a pleiotropic compound which been isolated from Magnolia species such as Magnolia grandiflora and Magnolia dealbata. Magnolia species Magnolia grandiflora is used in traditional medicine for the treatment of various diseases.PurposeThe objective of this review is to summarize the pharmacological potential and therapeutic insights of honokiol.Study designHonokiol has been specified as a novel alternative to treat various disorders such as liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties and others. Therefore, this study designed to represent the in-depth therapeutic potential of honokiol.MethodsLiterature searches in electronic databases, such as Web of Science, Science Direct, PubMed, Google Scholar, and Scopus, were performed using the keywords ‘Honokiol’, ‘Health Benefits’ and ‘Therapeutic Insights’ as the keywords for primary searches and secondary search terms were used as follows: ‘Anticancer’, ‘Oxidative Stress’, ‘Neuroprotective’, ‘Antimicrobial’, ‘Cardioprotection’, ‘Hepatoprotective’, ‘Anti-inflammatory’, ‘Arthritis’, ‘Reproductive Disorders’.ResultsThis promising bioactive compound presented an wide range of therapeutic and biological activities which include liver cancer, neuroprotective, anti-spasmodic, antidepressant, anti-tumorigenic, antithrombotic, antimicrobial, analgesic properties, and others. Its pharmacokinetics has been established in experimental animals, while in humans, this is still speculative. Some of its mechanism for exhibiting its pharmacological effects includes apoptosis of diseased cells, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6), amelioration of impaired hepatic enzymes and reversal of morphological alterations, among others.ConclusionAll these actions displayed by this novel compound could make it serve as a lead in the formulation of drugs with higher efficacy and negligible side effects utilized in the treatment of several human diseases.     

On the evolution of ‘Indian Bison type’ strains of Mycobacterium avium subspecies paratuberculosis

Mycobacterium avium subspecies paratuberculosis (MAP), the causative agent of Johne's disease (JD) in animals, has also been linked with Crohn's disease in human beings. Lack of indigenous diagnostics and vaccine hampered control of JD in India. Designing effective control strategies require thorough understanding of the etiological agent at phenotypic and molecular levels. On the basis of cultural phenotypes and IS1311 PCR-REA typing, MAP strains have been genotyped as ‘Cattle type’, ‘Sheep type’ and ‘Bison type’. Information exists on genetic differences and comparative evolution of ‘Cattle type’ and ‘Sheep type’ strains after divergence from M. avium; however, emphasis has been little on ‘Bison type’ strains. Recently, a new ‘Indian Bison type’ genotype has been reported as principal strain infecting different animal species and human beings in India. The study analyzed few genetic markers to have inferences on the molecular evolution of native MAP isolates belonging to ‘Bison type’ genotype. Results pointed towards recent evolution of ‘Bison type’ genotype.     

Gould and the fairies

This paper examines Stephen Jay Gould’s concept of science and religion as ‘nonoverlapping magisteria’ with reference to Spiritualism, specifically the case of the Cottingley fairies. It argues that this is a case in which the magisteria are neither separate nor overlapping but instead exist in a far more complex relationship. Through an exploration of this complexity, this paper offers discussion of the relationship between religion and science. In doing so, it problematises the common use of the terms ‘faith’ and ‘belief’ to characterise the experience of religious conviction.     

The impact of phenotypic heterogeneity of tumour cells on treatment and relapse dynamics

Intratumour heterogeneity is increasingly recognized as a frequent problem for cancer treatment as it allows for the evolution of resistance against treatment. While cancer genotyping becomes more and more established and allows to determine the genetic heterogeneity, less is known about the phenotypic heterogeneity among cancer cells. We investigate how phenotypic differences can impact the efficiency of therapy options that select on this diversity, compared to therapy options that are independent of the phenotype. We employ the ecological concept of trait distributions and characterize the cancer cell population as a collection of subpopulations that differ in their growth rate. We show in a deterministic model that growth rate-dependent treatment types alter the trait distribution of the cell population, resulting in a delayed relapse compared to a growth rate-independent treatment. Whether the cancer cell population goes extinct or relapse occurs is determined by stochastic dynamics, which we investigate using a stochastic model. Again, we find that relapse is delayed for the growth rate-dependent treatment type, albeit an increased relapse probability, suggesting that slowly growing subpopulations are shielded from extinction. Sequential application of growth rate-dependent and growth rate-independent treatment types can largely increase treatment efficiency and delay relapse. Interestingly, even longer intervals between decisions to change the treatment type may achieve close-to-optimal efficiencies and relapse times. Monitoring patients at regular check-ups may thus provide the temporally resolved guidance to tailor treatments to the changing cancer cell trait distribution and allow clinicians to cope with this dynamic heterogeneity.     

IL-12: a promising adjuvant for cancer vaccination

The clinical development of interleukin 12 (IL-12) as a single agent for systemic cancer therapy has been hindered by its significant toxicity and disappointing anti-tumor effects. The lack of efficacy was accompanied by, and probably related to, the declining biological effects of IL-12 in the course of repeated administrations at doses approaching the maximum tolerated dose (MTD). Nevertheless, IL-12 remains a very promising immunotherapeutic agent because recent cancer vaccination studies in animal models and humans have demonstrated its powerful adjuvant properties. Therefore, IL-12 may re-enter the arena of cancer therapy. Here, we review the immune modulating characteristics of IL-12 considered responsible for the adjuvant effects, as well as the results of animal and human cancer vaccination studies with IL-12 applied as an adjuvant. In addition, we discuss how studies with systemic IL-12 in cancer patients, and several other lines of evidence, indicate that IL-12 may exert optimal adjuvant effects only at low dose levels. Therefore, the MTD may not constitute the maximum effective dose of IL-12 for adjuvant application.     

Ecosystem spatial self-organization: Free order for nothing?

Ecosystems are complex adaptive systems (CAS) by nature, which means that macroscopic patterns and properties emerge from, and feed back to affect, the interactions among adaptive individual ecological agents. These agents then further adapt (genetically) to the outcomes of those interactions. The concept of self-organization has become increasingly important for understanding ecosystem spatial heterogeneity and its consequences. It is well accepted that ecosystems can self-organize, and that resulting spatial structures carry functional consequences. Feedbacks from the outcome of spatial pattern to the individual agents from which patterns emerge, are an essential component of the definition of CAS but have been rarely examined for ecosystems. We explore whether spatial self-organization provides a mechanism for such feedback for ecosystems as CAS, that is, whether ecosystem-level outcomes of self-organized patterning could feed back to affect or even reinforce local pattern-forming processes at the agent level. Diffuse feedbacks of ecological and evolutionary significance ensue as a result of spatial heterogeneity and regular patterning, whether this spatial heterogeneity results from an underlying template effect or from self-organization. However, feedbacks directed specifically at pattern-forming agents to enhance pattern formation—reinforcing feedback—depend upon the level of organization of agents. Reinforcing evolutionary feedbacks occur at the individual level or below. At the ecosystem level, evidence for mechanisms of feedback from outcomes to patterning to agents forming the patterning remain tenuous. Spatial self-organization is a powerful dynamic in ecosystem and landscape science but feedbacks have been only loosely integrated so far. Self-organized patterns influencing dynamics at the ecosystem level represent “order for free”. Whether or not this free order generated at the ecosystem level carries evolutionary function or is merely epiphenomenal is a fundamental question that we address here.     

Obligate annual and successive facultative diapause establish a bet‐hedging strategy of Rhagoletis cerasi (Diptera: Tephritidae) in seasonally unpredictable environments

To cope with temporal and spatial heterogeneity of habitats, herbivorous insects in the temperate zone usually enter diapause that facilitates synchronization of their life cycle with specific stages of host plants, such as fruit ripening. In the present study, we address those factors regulating dormancy responses as part of a ‘longer strategy’ to persist and thrive in temperate environments, focusing on Rhagoletis cerasi, a univoltine, oligophagous species, which overwinters as pupae and emerges when host fruits are available for oviposition at local scale. To ensure population survival and reproduction at habitats with ecological heterogeneity, R. cerasi has evolved a sophisticated diapause strategy based on a combination of local adaptation and diversified bet‐hedging strategies. Diapause duration is determined both by (i) the adaptive response to local host fruit phenology patterns (annual diapause) and (ii) the plastic responses to unpredictable inter‐annual (temporal) climatic variability that drives a proportion of the populations to extend dormancy by entering a second, successive, facultative cycle of prolonged diapause as part of a bet‐hedging strategy. Besides the dormant periods, post‐diapause development (which varies among populations) exerts ‘fine tune’ adjustments that assure synchronization and may correct possible errors. Adults emerging from pupae with prolonged diapause are larger in body size compared with counterparts emerging during the first year of diapause. However, female fecundity rates are reduced, followed by an extended post‐oviposition period, whereas adult longevity remains unaffected. Overall, it appears that R. cerasi populations are adapted to ecological conditions of local habitats and respond plastically to unpredictable environmental (climatic) conditions.     

Nano-Encapsulation of Arsenic Trioxide Enhances Efficacy against Murine Lymphoma Model while Minimizing Its Impact on Ovarian Reserve In Vitro and In Vivo

Advances in cancer therapy have increased the rate of survival of young cancer patients; however, female lymphoma patients frequently face a temporary or permanent loss of fertility when treated with traditional cytotoxic agents. The potential loss of fertility is an important concern that can influence treatment decisions for many premenopausal cancer patients. The negative effect of chemotherapeutic agents and treatment protocols to patients’ fertility–referred to as fertotoxicity–are thus an increasingly important cancer survivorship issue. We have developed a novel nanoscale formulation of arsenic trioxide, a potent drug for treatment of hematological malignancies, and demonstrate that it has significantly better activity in a murine lymphoma model than the free drug. In parallel, we have developed a novel in vitro assay of ovarian follicle function that predicts in vivo ovarian toxicity of therapeutic agents. Our results reveal that the nanotherapeutic agent is not only more active against lymphoma, but is fertoprotective, i.e., it is much less deleterious to ovarian function than the parent drug. Thus, our in vitro assay allows rapid evaluation of both established and experimental anticancer drugs on ovarian reserve and can inform the selection of efficacious and fertility-sparing treatment regimens for reproductive-age women diagnosed with cancer.