Quantifying time spent outdoors: A versatile method using any type of global positioning system (GPS) and accelerometer devices.

Spending time outdoors is associated with increased time spent in physical activity, lower chronic disease risk, and wellbeing. Many studies rely on self-reported measures, which are prone to recall bias. Other methods rely on features and functions only available in some GPS devices. Thus, a reliable and versatile method to objectively quantify time spent outdoors is needed. This study sought to develop a versatile method to classify indoor and outdoor (I/O) GPS data that can be widely applied using most types of GPS and accelerometer devices. To develop and test the method, five university students wore an accelerometer (ActiGraph wGT3X-BT) and a GPS device (Canmore GT-730FL-S) on an elastic belt at the right hip for two hours in June 2022 and logged their activity mode, setting, and start time via activity diaries. GPS trackers were set to collect data every 5 seconds. A rule-based point cluster-based method was developed to identify indoor, outdoor, and in-vehicle time. Point clusters were detected using an application called GPSAS_Destinations and classification were done in R using accelerometer lux, building footprint, and park location data. Classification results were compared with the submitted activity diaries for validation. A total of 7,006 points for all participants were used for I/O classification analyses. The overall I/O GPS classification accuracy rate was 89.58% (Kappa = 0.78), indicating good classification accuracy. This method provides reliable I/O clarification results and can be widely applied using most types of GPS and accelerometer devices.

A thematic analysis of alcohol and alcohol-related harm across health and social policy in Aotearoa New Zealand.

OBJECTIVE: This study aims to: 1) explore how alcohol and alcohol harm are framed in New Zealand national policy, strategy, and action plan documents; and 2) examine how these documents align with the WHO SAFER framework. METHODS: Keyword searches across government websites and Google were conducted in January 2021. Inclusion and exclusion criteria were applied to all identified documents, resulting in 22 being included for analysis in this study. An inductive and deductive thematic analysis of those documents was performed. RESULTS: Our inductive thematic analysis identified three themes, of which one is detailed in this study: 'Location of responsibility for addressing alcohol harms' with a focus on individuals and non-specific government agencies. Thematic results from the deductive analysis found that the most consistently referenced SAFER policies included brief interventions (68% of documents), followed by drink driving measures (45%), alcohol marketing (36%), alcohol availability (27%), and alcohol price (23%). The conversion rate from a document mentioning a SAFER framework policy area to making specific policy recommendations was usually less than or around 50%. CONCLUSIONS: The lack of alignment between New Zealand alcohol policy and the SAFER framework can be partially attributable to the absence of an updated national alcohol strategy (NAS). An updated NAS should identify responsible agencies, create a systematic monitoring and evaluation mechanism, and be consistent with the WHO SAFER framework. IMPLICATIONS FOR PUBLIC HEALTH: The analysis supports the need to update a national alcohol strategy to guide alcohol policy development.

Exploring jump experience, risk perception, anxiety and self-confidence in skydiving: A mixed methods approach.

Skydivers are required to interpret person-context characteristics to overcome inherent internal challenges (i.e., fear and anxiety) and external challenges (i.e., equipment malfunctions) to successfully perform. Research suggests that as skydiving experience increases, skydivers' self-confidence in their actions increases, while their perception of risk and anxiety decreases. However, there is a lack of research investigating the influence of experience and considerations of performance in extreme sports. This study examined the influence of skydiving experience on the interpretation of risk perception, anxiety and self-confidence. Participants comprised 503 experienced Australian skydivers (Mage = 40.10, SDage = 12.40; 79.5 % male). Using a mixed methods approach, skydivers completed measures of risk perceptions, anxiety, and self-confidence related to skydiving, as well as open-ended questions on their skydiving experiences. The findings indicated that increases in jumping experience led to greater self-confidence, and self-confidence mediated the relationship between all elements of jumping experience and cognitive and somatic anxiety associated with skydiving. Thematic analysis reinforced that skydivers understood the inherent risks associated with skydiving, and that skydivers adopted positive strategies that promoted self-confidence and mastery to perform successfully, while also managing their interpretations of risk and associated anxiety that potentially exists. Further research is needed to better understand the interpretation of person-context situations in extreme sports and recognize the important affordances for performance.

Identifying predictors of translocation success in rare plant species.

The fundamental goal of a rare plant translocation is to create self-sustaining populations with the evolutionary resilience to persist in the long term. Yet, most plant translocation syntheses focus on a few factors influencing short-term benchmarks of success (e.g., survival and reproduction). Short-term benchmarks can be misleading when trying to infer future growth and viability because the factors that promote establishment may differ from those required for long-term persistence. We assembled a large (n = 275) and broadly representative data set of well-documented and monitored (7.9 years on average) at-risk plant translocations to identify the most important site attributes, management techniques, and species' traits for six life-cycle benchmarks and population metrics of translocation success. We used the random forest algorithm to quantify the relative importance of 29 predictor variables for each metric of success. Drivers of translocation outcomes varied across time frames and success metrics. Management techniques had the greatest relative influence on the attainment of life-cycle benchmarks and short-term population trends, whereas site attributes and species' traits were more important for population persistence and long-term trends. Specifically, large founder sizes increased the potential for reproduction and recruitment into the next generation, whereas declining habitat quality and the outplanting of species with low seed production led to increased extinction risks and a reduction in potential reproductive output in the long-term, respectively. We also detected novel interactions between some of the most important drivers, such as an increased probability of next-generation recruitment in species with greater seed production rates, but only when coupled with large founder sizes. Because most significant barriers to plant translocation success can be overcome by improving techniques or resolving site-level issues through early intervention and management, we suggest that by combining long-term monitoring with adaptive management, translocation programs can enhance the prospects of achieving long-term success.

Identificación de pronosticadores del éxito de reubicación en especies raras de plantas Resumen El objetivo fundamental de la reubicación de plantas raras es la creación de poblaciones autosuficientes con resiliencia evolutiva que persistan a la larga. De todas maneras, la mayoría de las síntesis de estas reubicaciones se enfocan en unos cuantos factores que influyen sobre los parámetros a corto plazo del éxito (supervivencia y reproducción). Los parámetros a corto plazo pueden ser engañosos si se intenta inferir el crecimiento y la viabilidad en el futuro ya que los factores que promueven el establecimiento pueden diferir de aquellos requeridos para la persistencia a largo plazo. Ensamblamos un conjunto grande de datos representativos en general (n = 275) de las reubicaciones de plantas en riesgo bien documentadas y monitoreadas (7.9 años en promedio) para identificar los atributos de sitio más importantes, las técnicas de manejo y los rasgos de las especies para seis parámetros de ciclos de vida y medidas poblacionales del éxito de reubicación. Usamos el algoritmo de bosque aleatorio para cuantificar la importancia relativa de las 29 variables de pronosticadores para cada medida del éxito. Los factores en los resultados de las reubicaciones variaron con los marcos temporales y las medidas de éxito. Las técnicas de manejo tuvieron la mayor influencia relativa sobre la obtención de parámetros de ciclos de vida y tendencias poblacionales a corto plazo, mientras que los atributos de sitio y los rasgos de la especie fueron más importantes para la persistencia poblacional y las tendencias a largo plazo. En específico, las grandes cantidades de fundadores incrementaron el potencial de reproducción y reclutamiento de la siguiente generación, mientras que la declinación de la calidad del hábitat incrementó el riesgo de extinción y el trasplante de especies con baja producción de semillas redujo el rendimiento del potencial reproductivo a la larga. También detectamos interacciones novedosas entre algunos de los factores más importantes, como el aumento en la probabilidad del reclutamiento en la siguiente generación en especies con tasas mayores de producción de semillas, pero sólo cuando se emparejó con grandes cantidades de fundadores. Ya que las barreras más significativas para el éxito de la reubicación de plantas pueden superarse al mejorar las técnicas o resolver los temas a nivel de sitio por medio de un manejo y una intervención temprana, sugerimos que con la combinación del monitoreo a largo plazo con el manejo adaptativo los programas de reubicación pueden aumentar el prospecto de lograr el éxito a largo plazo.

Health empowerment scripts: Simplifying social/green prescriptions.

Social prescriptions are one term commonly used to describe non-pharmaceutical approaches to healthcare and are gaining popularity in the community, with evidence highlighting psychological benefits of reduced anxiety, depression and improved mood and physiological benefits of reduced risk of cardiovascular disease and reduced hypertension. The relationship between human health benefits and planetary health benefits is also noted. There are, however, numerous barriers, such as duration and frequencies to participate in activities, access, suitability, volition and a range of unpredictable variables (such as inclement weather, shifting interests and relocating home amongst others) impeding a comprehensive approach to their use on a wider scale. From a multidisciplinary perspective, this commentary incorporates a salutogenic and nature-based approach to health, we also provide a range of recommendations that can be undertaken at the patient level to assist in shifting the acknowledged systemic barriers currently occurring. These include using simple language to explain the purpose of health empowerment scripts, ensuing personal commitment to a minimum timeframe, enabling ease of access, co-designing a script program, providing ongoing motivational support and incorporating mindfulness to counter unexpected disruptions.

Anti-glioblastoma activity of monensin and its analogs in an organoid model of cancer.

Glioblastoma (GBM) remains the most frequently diagnosed primary malignant brain cancer in adults. Despite recent progress in understanding the biology of GBM, the clinical outcome for patients remains poor, with a median survival of approximately one year after diagnosis. One factor contributing to failure in clinical trials is the fact that traditional models used in GBM drug discovery poorly recapitulate patient tumors. Previous studies have shown that monensin (MON) analogs, namely esters and amides on C-26 were potent towards various types of cancer cell lines. In the present study we have investigated the activity of these molecules in GBM organoids, as well as in a host:tumor organoid model. Using a mini-ring cell viability assay we have identified seven analogs (IC50 = 91.5 ± 54.4-291.7 ± 68.8 nM) more potent than parent MON (IC50 = 612.6 ± 184.4 nM). Five of these compounds induced substantial DNA fragmentation in GBM organoids, suggestive of apoptotic cell death. The most active analog, compound 1, significantly reduced GBM cell migration, induced PARP degradation, diminished phosphorylation of STAT3, Akt and GSK3ß, increased É£H2AX signaling and upregulated expression of the autophagy associated marker LC3-II. To investigate the activity of MON and compound 1 in a tumor microenvironment, we developed human cerebral organoids (COs) from human induced pluripotent stem cells (iPSCs). The COs showed features of early developing brain such as multiple neural rosettes with a proliferative zone of neural stem cells (Nestin+), neurons (TUJ1 +), primitive ventricular system (SOX2 +/Ki67 +), intermediate zone (TBR2 +) and cortical plate (MAP2 +). In order to generate host:tumor organoids, we co-cultured RFP-labeled U87MG cells with fully formed COs. Compound 1 and MON reduced U87MG tumor size in the COs after four days of treatment and induced a significant reduction of PARP expression. These findings highlight the therapeutic potential of MON analogs towards GBM and support the application of organoid models in anti-cancer drug discovery.

Primary acute lymphoblastic leukemia cells are susceptible to microtubule depolymerization in G1 and M phases through distinct cell death pathways.

Microtubule targeting agents (MTAs) are widely used cancer chemotherapeutics which conventionally exert their effects during mitosis, leading to mitotic or postmitotic death. However, accumulating evidence suggests that MTAs can also generate death signals during interphase, which may represent a key mechanism in the clinical setting. We reported previously that vincristine and other microtubule destabilizers induce death not only in M phase but also in G1 phase in primary acute lymphoblastic leukemia cells. Here, we sought to investigate and compare the pathways responsible for phase-specific cell death. Primary acute lymphoblastic leukemia cells were subjected to centrifugal elutriation, and cell populations enriched in G1 phase (97%) or G2/M phases (80%) were obtained and treated with vincristine. We found death of M phase cells was associated with established features of mitochondrial-mediated apoptosis, including Bax activation, loss of mitochondrial transmembrane potential, caspase-3 activation, and nucleosomal DNA fragmentation. In contrast, death of G1 phase cells was not associated with pronounced Bax or caspase-3 activation but was associated with loss of mitochondrial transmembrane potential, parylation, nuclear translocation of apoptosis-inducing factor and endonuclease G, and supra-nucleosomal DNA fragmentation, which was enhanced by inhibition of autophagy. The results indicate that microtubule depolymerization induces distinct cell death pathways depending on during which phase of the cell cycle microtubule perturbation occurs. The observation that a specific type of drug can enter a single cell type and induce two different modes of death is novel and intriguing. These findings provide a basis for advancing knowledge of clinical mechanisms of MTAs.

"Like Nothing I've Seen Before": A Qualitative Inquiry Into the Lived Experience of Competing in a Trail Running Event.

Background: A recent upsurge in nature-based exercise research demonstrates the potential added benefits of exercising in this context compared to more urban ones. Yet there is a lack of qualitative research investigating the lived experiences of those who participate in nature-based exercise events. Objective: To explore the lived experience of individuals who were first-time participants in a nature-based running event. Method: Six participants who completed the Run Forrest trail run for the first time were individually interviewed. Semi-structured interviews were devised, and participants were invited to talk about their experiences of running in the event. Interviews were analysed using interpretative phenomenological analysis. Results: Following data analysis, two superordinate themes were constructed to resemble participant experiences. "Maintaining good health is vital" reflected participants' personal theory of health and their perceived benefits of exercise. "Nature as a special place" reflected the atmospheric characteristics of the event, including the pre-event set-up and the actual running event itself. Conclusion: Analysis suggests that participants considered the event and natural environment to provide unique value adding opportunities that encouraged positive experiences. These results also reaffirm the positive benefits associated with nature-based exercise, including potential benefits to individual wellbeing. Further research in this context may strengthen our collective understanding regarding individual motivation towards such events.

"Feels Good to Get Wet": The Unique Affordances of Surf Therapy Among Australian Youth.

Increasing prevalence rates of mental health problems among adolescents is an issue of growing concern. Surf therapy is a novel intervention that may provide tangible benefits to address this problem. Congruent with the ecological dynamics perspective (EDP), the existing research postulates that surf therapy yields psychological benefits in part due to the unique affordances of immersion in a blue space such as the ocean. Evidence worldwide has validated the use of surfing as a therapeutic mediator to achieve positive change, however, no such research has been conducted on Australian adolescents. The current study aimed to evaluate the impact of the Waves of Wellness (WOW) Foundation's 8 week surf therapy program on mental health outcomes in Australian at-risk youth. The study employed a mixed-methods design to examine the experiences of participants. Nine adolescents (M age = 14.9; SD = 1.2; 8 female) participated in the quantitative stage, with four completing the qualitative interview. Results indicated positive changes in resilience, self-esteem, social connectedness, and depressive symptoms post-intervention, however, improvements were not maintained at follow-up. Participants unanimously agreed that the program normalised their experiences with mental health through the unique leaning environment and fostered personal growth through mastery experiences and the development of healthy relationships. The EDP provided the most compelling explanation of the results denoting that benefits arise from the reciprocal relationship between individual, task, and environment. Despite the small and heterogenous sample, the findings provided preliminary evidence of the efficacy of surf therapy among Australian youth and offer a potential starting point for further research utilising larger more diverse samples.

Phosphoproteomics Provides Novel Insights into the Response of Primary Acute Lymphoblastic Leukemia Cells to Microtubule Depolymerization in G1 Phase of the Cell Cycle.

Microtubule targeting agents (MTAs) have been used for the treatment of cancer for many decades and are among the most successful chemotherapeutic agents. However, their application and effectiveness are limited because of toxicity and resistance as well as a lack of knowledge of molecular mechanisms downstream of microtubule inhibition. Insights into key pathways that link microtubule disruption to cell death is critical for optimal use of these drugs, for defining biomarkers useful in patient stratification, and for informed design of drug combinations. Although MTAs characteristically induce death in mitosis, microtubule destabilizing agents such as vincristine also induce death directly in G1 phase in primary acute lymphoblastic leukemia (ALL) cells. Because many signaling pathways regulating cell survival and death involve changes in protein expression and phosphorylation, we undertook a comprehensive quantitative proteomic study of G1 phase ALL cells treated with vincristine. The results revealed distinct alterations associated with c-Jun N-terminal kinase signaling, anti-proliferative signaling, the DNA damage response, and cytoskeletal remodeling. Signals specifically associated with cell death were identified by pre-treatment with the CDK4/6 inhibitor palbociclib, which caused G1 arrest and precluded death induction. These results provide insights into signaling mechanisms regulating cellular responses to microtubule inhibition and provide a foundation for a better understanding of the clinical mechanisms of MTAs and for the design of novel drug combinations. The mass spectrometry proteomics data have been deposited to the PRIDE Archive (http://www.ebi.ac.uk/pride/archive/) via the PRIDE partner repository with the data set identifier PXD027190 and 10.6019/PXD027190.

Motives for Dropout Among Former Junior Elite Caribbean Track and Field Athletes: A Qualitative Investigation.

Anecdotal reports within the Caribbean track and field fraternity have revealed that there is a high level of athlete dropout from competitive sport at the junior-elite level, and a poor transition to senior-elite status. Consequently, this qualitative investigation explored the key motives that may have contributed toward the unsuccessful transitions and ensuing dropout of Caribbean track and field athletes during the junior to senior transition period. Eleven former junior-elite track and field athletes (four males, seven females; Mage = 29, SD ± 4.2 years) from four English-speaking Caribbean islands participated in semi-structured interviews. Following an inductive and deductive thematic analysis, four higher order themes were identified: (1) "there's not enough support"; (2) "felt pressure to make sure I committed"; (3) "it's always competitive here"; and (4) "battle with the injuries." For these former junior-elite Caribbean athletes, the decision on whether to continue within the sport was influenced by a combination of factors, although inadequate financial and organizational support had the most bearing on athletes' decision to drop out during the crucial transition years. Implications for consideration by key stakeholders and policymakers within the region are discussed.

Single and double modified salinomycin analogs target stem-like cells in 2D and 3D breast cancer models.

Breast cancer remains one of the leading cancers among women. Cancer stem cells (CSCs) are tumor-initiating cells which drive progression, metastasis, and reoccurrence of the disease. CSCs are resistant to conventional chemo- and radio-therapies and their ability to survive such treatment enables tumor reestablishment. Metastasis is the main cause of mortality in women with breast cancer, thus advances in treatment will depend on therapeutic strategies targeting CSCs. Salinomycin (SAL) is a naturally occurring polyether ionophore antibiotic known for its anticancer activity towards several types of tumor cells. In the present work, a library of 17 C1-single and C1/C20-double modified SAL analogs was screened to identify compounds with improved activity against breast CSCs. Six single- and two double-modified analogs were more potent (IC50 range of 1.1 ± 0.1-1.4 ± 0.2 µM) toward the breast cancer cell line MDA-MB-231 compared to SAL (IC50 of 4.9 ± 1.6 µM). Double-modified compound 17 was found to be more efficacious than SAL against the majority of cancer cell lines in the NCI-60 Human Tumor Cell Line Panel. Compound 17 was more potent than SAL in inhibiting cell migration and cell renewal properties of MDA-MB-231 cells, as well as inducing selective loss of the CD44+/CD24/low stem-cell-like subpopulation in both monolayer (2D) and organoid (3D) culture. The present findings highlight the therapeutic potential of SAL analogs towards breast CSCs and identify select compounds that merit further study and clinical development.

Impact of shift work on sleep and fatigue in Maritime pilots.

This study examined how objective measures of sleep change across shift-cycles, and the impact of this on sleep quality and fatigue. Forty maritime pilots were recruited from Australian ports. Sleep wake-behaviour (timing and length), and self-reported sleep quality and fatigue, were assessed to determine any impact of roster status and 'on-call' status. On-roster pilots experienced reduced night time sleep duration compared to those off-roster (57 ± 8.8 min), while working on-call also diminished night time sleep duration (126 ± 11.3 min) and quality, compared to workers not on-call. Fatigue scores indicated that participants were not fully recovered prior to commencing rostered night shift, while sleep quality was significantly worse following sleep that occurred after a night shift, compared to after a day shift. These findings potentially support workplace negotiations to change future shift cycles, and to adopt monitoring systems that may mitigate the risk of fatigue-related accidents and chronic health outcomes. Practitioner summary: Long and irregular work hours of maritime pilotage can compromise worker performance and safety. This observational study found that on-roster pilots experience reduced sleep duration compared to those off-roster, while working on-call further diminishes sleep duration and quality. Future workload/fatigue monitoring systems may mitigate fatigue-related accidents and adverse chronic health outcomes. Abbreviations: ANOVA: analysis of variance; ANCOVA: analysis of covariance; BMI: body mass index; CVD: cardiovascular disease; h: hours; mins: minutes; SE: standard error of the mean; SD: standard deviation; SO: sleep opportunities; TST: total sleep time; WASO: wake after sleep onset.

Synthesis, anticancer activity and molecular docking studies of N-deacetylthiocolchicine and 4-iodo-N-deacetylthiocolchicine derivatives.

Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong ß-tubulin binding energies, lower than -8.70 kcal/mol, while the binding energy calculated for colchicine is -8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.

Interventions using behavioural insights to influence children's diet-related outcomes: A systematic review.

The global prevalence of children with overweight and obesity continues to rise. Obesity in childhood has dire long-term consequences on health, social and economic outcomes. Promising interventions using behavioural insights to address obesity in childhood have emerged. This systematic review examines the effectiveness and health equity implications of interventions using behavioural insights to improve children's diet-related outcomes. The search strategy included searches on six electronic databases, reference lists of previous systematic reviews and backward searching of all included studies. One-hundred and eight papers describing 137 interventions were included. Interventions using behavioural insights were effective at modifying children's diet-related outcomes in 74% of all included interventions. The most promising approaches involved using incentives, changing defaults and modifying the physical environment. Information provision alone was the least effective approach. Health equity implications were rarely analysed or discussed. There was limited evidence of the sustainability of interventions-both in relation to their overall effectiveness and cost-effectiveness. The limited evidence on health equity, long-term effectiveness and the cost-effectiveness of these interventions limit what can be inferred for policymakers. This review synthesises the use of behavioural insights to improve children's diet-related outcomes, which can be used to inform future interventions.

Limitations of an ex vivo breast cancer model for studying the mechanism of action of the anticancer drug paclitaxel.

Paclitaxel is widely used in the treatment of breast, ovarian, lung, and other cancers. Its primary mechanism is to prevent microtubule depolymerization causing loss of dynamic instability crucial for normal microtubule function leading to mitotic arrest. Prolonged mitotic arrest results in cell death as a secondary response. The effects of paclitaxel are typically studied in cell lines which precludes assessment of the possible influence of tumor-associated cells. We therefore examined paclitaxel action ex vivo in fresh explant cultures of human breast tumors. Surprisingly, we found that paclitaxel failed to induce tumor cell death in explant culture, in contrast to several other cytotoxic agents including salinomycin and vincristine. The lack of effect was not due to defective drug uptake, and furthermore, analysis of H&E stained tumor slices indicated that paclitaxel treatment caused defective (granular) mitosis and chromosomal condensation in 5-10% of tumor cells after 72 h. These results suggest that while paclitaxel was able to penetrate into the tumor slice and disrupt mitosis in cycling tumor cells, any ensuing cell death likely occurred beyond the useful lifetime of the tumor slices. We conclude that explant culture systems may be inappropriate for the study of cytotoxic drugs where a delay exists between the drug's primary and secondary modes of action.

Carbamate derivatives of colchicine show potent activity towards primary acute lymphoblastic leukemia and primary breast cancer cells-in vitro and ex vivo study.

Colchicine (COL) shows strong anticancer activity but due to its toxicity towards normal cells its wider application is limited. To address this issue, a library of 17 novel COL derivatives, namely N-carbamates of N-deacetyl-4-(bromo/chloro/iodo)thiocolchicine, has been tested against two types of primary cancer cells. These included acute lymphoblastic leukemia (ALL) and human breast cancer (BC) derived from two different tumor subtypes, ER+ invasive ductal carcinoma grade III (IDCG3) and metastatic carcinoma (MC). Four novel COL derivatives showed higher anti-proliferative activity than COL (IC50 = 8.6 nM) towards primary ALL cells in cell viability assays (IC50 range of 1.1-6.4 nM), and several were more potent towards primary IDCG3 (IC50 range of 0.1 to 10.3 nM) or MC (IC50 range of 2.3-9.1 nM) compared to COL (IC50 of 11.1 and 11.7 nM, respectively). In addition, several derivatives were selectively active toward primary breast cancer cells compared to normal breast epithelial cells. The most promising derivatives were subsequently tested against the NCI panel of 60 human cancer cell lines and seven derivatives were more potent than COL against leukemia, non-small-cell lung, colon, CNS and prostate cancers. Finally, COL and two of the most active derivatives were shown to be effective in killing BC cells when tested ex vivo using fresh human breast tumor explants. The present findings indicate that the select COL derivatives constitute promising lead compounds targeting specific types of cancer.

Synthesis, biological evaluation and molecular docking studies of new amides of 4-chlorothiocolchicine as anticancer agents.

Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC50 values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different ß tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.

Digital contact tracing technologies in epidemics: a rapid review.

BACKGROUND: Reducing the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global priority. Contact tracing identifies people who were recently in contact with an infected individual, in order to isolate them and reduce further transmission. Digital technology could be implemented to augment and accelerate manual contact tracing. Digital tools for contact tracing may be grouped into three areas: 1) outbreak response; 2) proximity tracing; and 3) symptom tracking. We conducted a rapid review on the effectiveness of digital solutions to contact tracing during infectious disease outbreaks. OBJECTIVES: To assess the benefits, harms, and acceptability of personal digital contact tracing solutions for identifying contacts of an identified positive case of an infectious disease. SEARCH METHODS: An information specialist searched the literature from 1 January 2000 to 5 May 2020 in CENTRAL, MEDLINE, and Embase. Additionally, we screened the Cochrane COVID-19 Study Register. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs, quasi-RCTs, cohort studies, cross-sectional studies and modelling studies, in general populations. We preferentially included studies of contact tracing during infectious disease outbreaks (including COVID-19, Ebola, tuberculosis, severe acute respiratory syndrome virus, and Middle East respiratory syndrome) as direct evidence, but considered comparative studies of contact tracing outside an outbreak as indirect evidence. The digital solutions varied but typically included software (or firmware) for users to install on their devices or to be uploaded to devices provided by governments or third parties. Control measures included traditional or manual contact tracing, self-reported diaries and surveys, interviews, other standard methods for determining close contacts, and other technologies compared to digital solutions (e.g. electronic medical records). DATA COLLECTION AND ANALYSIS: Two review authors independently screened records and all potentially relevant full-text publications. One review author extracted data for 50% of the included studies, another extracted data for the remaining 50%; the second review author checked all the extracted data. One review author assessed quality of included studies and a second checked the assessments. Our outcomes were identification of secondary cases and close contacts, time to complete contact tracing, acceptability and accessibility issues, privacy and safety concerns, and any other ethical issue identified. Though modelling studies will predict estimates of the effects of different contact tracing solutions on outcomes of interest, cohort studies provide empirically measured estimates of the effects of different contact tracing solutions on outcomes of interest. We used GRADE-CERQual to describe certainty of evidence from qualitative data and GRADE for modelling and cohort studies. MAIN RESULTS: We identified six cohort studies reporting quantitative data and six modelling studies reporting simulations of digital solutions for contact tracing. Two cohort studies also provided qualitative data. Three cohort studies looked at contact tracing during an outbreak, whilst three emulated an outbreak in non-outbreak settings (schools). Of the six modelling studies, four evaluated digital solutions for contact tracing in simulated COVID-19 scenarios, while two simulated close contacts in non-specific outbreak settings. Modelling studies Two modelling studies provided low-certainty evidence of a reduction in secondary cases using digital contact tracing (measured as average number of secondary cases per index case - effective reproductive number (R eff)). One study estimated an 18% reduction in R eff with digital contact tracing compared to self-isolation alone, and a 35% reduction with manual contact-tracing. Another found a reduction in R eff for digital contact tracing compared to self-isolation alone (26% reduction) and a reduction in R eff for manual contact tracing compared to self-isolation alone (53% reduction). However, the certainty of evidence was reduced by unclear specifications of their models, and assumptions about the effectiveness of manual contact tracing (assumed 95% to 100% of contacts traced), and the proportion of the population who would have the app (53%). Cohort studies Two cohort studies provided very low-certainty evidence of a benefit of digital over manual contact tracing. During an Ebola outbreak, contact tracers using an app found twice as many close contacts per case on average than those using paper forms. Similarly, after a pertussis outbreak in a US hospital, researchers found that radio-frequency identification identified 45 close contacts but searches of electronic medical records found 13. The certainty of evidence was reduced by concerns about imprecision, and serious risk of bias due to the inability of contact tracing study designs to identify the true number of close contacts. One cohort study provided very low-certainty evidence that an app could reduce the time to complete a set of close contacts. The certainty of evidence for this outcome was affected by imprecision and serious risk of bias. Contact tracing teams reported that digital data entry and management systems were faster to use than paper systems and possibly less prone to data loss. Two studies from lower- or middle-income countries, reported that contact tracing teams found digital systems simpler to use and generally preferred them over paper systems; they saved personnel time, reportedly improved accuracy with large data sets, and were easier to transport compared with paper forms. However, personnel faced increased costs and internet access problems with digital compared to paper systems. Devices in the cohort studies appeared to have privacy from contacts regarding the exposed or diagnosed users. However, there were risks of privacy breaches from snoopers if linkage attacks occurred, particularly for wearable devices. AUTHORS' CONCLUSIONS: The effectiveness of digital solutions is largely unproven as there are very few published data in real-world outbreak settings. Modelling studies provide low-certainty evidence of a reduction in secondary cases if digital contact tracing is used together with other public health measures such as self-isolation. Cohort studies provide very low-certainty evidence that digital contact tracing may produce more reliable counts of contacts and reduce time to complete contact tracing. Digital solutions may have equity implications for at-risk populations with poor internet access and poor access to digital technology. Stronger primary research on the effectiveness of contact tracing technologies is needed, including research into use of digital solutions in conjunction with manual systems, as digital solutions are unlikely to be used alone in real-world settings. Future studies should consider access to and acceptability of digital solutions, and the resultant impact on equity. Studies should also make acceptability and uptake a primary research question, as privacy concerns can prevent uptake and effectiveness of these technologies.