Developing a text message intervention for fathers with partners experiencing perinatal depression or anxiety.

BACKGROUND: Support from fathers to their partners is important to reduce distress in mothers during the perinatal period when conditions such as depression and anxiety can be common. The SMS4dads digital platform delivers text messages to fathers but has not previously addressed specific messages to fathers with partners who are experiencing perinatal depression and/or anxiety (PNDA). AIM: To develop messages, in collaboration with experienced parents and clinicians, that are suitable for fathers whose partner is experiencing PNDA. METHODS: Messages designed to enhance the quality of partner support for mothers experiencing PNDA were drafted by the SMS4dads team based on suggestions from mothers with lived experience of PNDA. Mothers and fathers with lived experience and expert clinicians rated the messages for importance and understanding. Clinicians additionally rated clinical relevance. Open response comments from parents and clinicians were collated for each message. Re-drafted messages were screened again and checked for literacy level. RESULTS: Forty-one draft messages received a total of 170 ratings from 24 parents and 164 ratings from 32 clinicians. Over three quarters of parents and clinicians agreed or strongly agreed that messages were understandable (parents 85.6%; clinicians 77.4%), important (parents 86.3%; clinicians 86.6%), and 85.5% of clinicians rated the messages as clinically relevant. Comments from clinicians (n = 99) and parents (n = 46) were reviewed and guided message development. Thirty re-drafted messages were screened and 16 edited based on a second round of ratings and comments from parents and clinicians. CONCLUSION: Messages for fathers whose partners are experiencing depression and anxiety can be developed and evaluated in collaboration with lived experience of parents and clinicians.

Equipping fathers to support distressed mothers: What do mothers want fathers to know and do?

ISSUE ADDRESSED: Up to one in five new mothers experience depression or anxiety, and their partners are often the first line of social and practical support. However, many fathers are unprepared for their role as support person. The SMS4dads program (www.sms4dads.com) provides text-based support to new fathers but lacks specific messages addressing maternal mental distress. METHODS: A mixed methods process engaged mothers with lived experience of perinatal mental distress to identify message content for co-designing texts in SMS4dads. Participants completed surveys derived from research literature and parenting websites using the theoretical framework of support domains: emotional or affectionate support, informational support, tangible support and positive social interaction. Mothers also indicated the most appropriate timing of support: at the point of identifying the distress (emerging), with ongoing symptoms (persistent) or during recovery (easing). Free text comments from mothers were linked to survey topics to provide examples of wording suitable for text messages to fathers. RESULTS: Fifty-five mothers with lived experience completed the surveys. All support items were more often endorsed as helpful rather than not helpful by mothers. Emotional support was thought helpful in the early stages, tangible support was valued with ongoing symptoms and social interaction appreciated as symptoms eased. CONCLUSIONS: Mothers experiencing perinatal depression and anxiety require a range of supportive actions by their partners, including household tasks and baby-care, encouragement, listening and managing relationships with family and friends. SO WHAT?: Information provided by distressed mothers can provide guidance to professionals when designing information for fathers/partners. Digital delivery of this co-designed information to fathers across urban and rural areas may enhance the competence of fathers working to support mothers experiencing mental distress in the perinatal period.

Accuracy of Parent-Reported Child Height and Weight and Calculated Body Mass Index Compared With Objectively Measured Anthropometrics: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: Electronic health (eHealth) interventions for children often rely on parent-reported child anthropometric measures. However, limited studies have assessed parental accuracy in reporting child height and weight via Web-based approaches. OBJECTIVE: The objective of this study was to determine the accuracy of parent-reported child height and weight, as well as body mass index and weight category that we calculated from these data. We also aimed to explore whether parent report was influenced by age, sex, weight status, or exposure to participation in a 12-week brief Web-based family lifestyle intervention. METHODS: This study was a secondary analysis of data from a 12-week childhood obesity pilot randomized controlled trial in families with children aged 4 to 11 years in Australia. We asked parents to report demographic information, including child height and weight, using an online survey before their child's height and weight were objectively measured by a trained research assistant at baseline and week 12. We analyzed data using the Lin concordance correlation coefficient (ρc, ranging from 0 [poor] to ±1 [perfect] concordance), Cohen kappa coefficient, and multivariable linear regression models. RESULTS: There were 42 families at baseline and 35 families (83%) at week 12. Overall, the accuracy of parent-reported child height was moderate (ρc=.94), accuracy of weight was substantial (ρc=.96), and accuracy of calculated body mass index was poor (ρc=.63). Parents underreported child height and weight, respectively, by 0.9 cm and 0.5 kg at baseline and by 0.2 cm and 1.6 kg after participating in a 12-week brief Web-based family lifestyle intervention. The overall interrater agreement of child body mass index category was moderate at baseline (κ=.59) and week 12 (κ=.54). The weight category calculated from 74% (n=31) and 70% (n=23) of parent-reported child height and weight was accurate at baseline and week 12, respectively. Parental age was significantly (95% CI -0.52 to -0.06; P=.01) associated with accuracy of reporting child height. Child age was significantly (95% CI -2.34 to -0.06; P=.04) associated with reporting of child weight. CONCLUSIONS: Most Australian parents were reasonably accurate in reporting child height and weight among a group of children aged 4 to 11 years. The weight category of most of the children when calculated from parent-reported data was in agreement with the objectively measured data despite the body mass index calculated from parent-reported data having poor concordance at both time points. Online parent-reported child height and weight may be a valid method of collecting child anthropometric data ahead of participation in a Web-based program. Future studies with larger sample sizes and repeated measures over time in the context of eHealth research are warranted. Future studies should consider modeling the impact of calibration equations applied to parent-reported anthropometric data on study outcomes.

Supporting men through their transition to fatherhood with messages delivered to their smartphones: a feasibility study of SMS4dads.

BACKGROUND: The transition to parenthood can be a challenging time, in which both mothers and fathers experience increased risk of distress and depression. Mothers are more likely than fathers to engage with services and have their mental health monitored and attended to during the perinatal period. The present study aimed to explore whether smartphone technology could be used to address fathers' needs across their transition to fatherhood. METHODS: A corpus of messages, including linked information and mood tracking software, was designed to support and enhance paternal relationships with their babies, their partners and themselves across the perinatal period. Messages were sent to project participants (N = 520) from 12-weeks' gestation to 24-weeks after birth. RESULTS: Of those fathers enrolled (N = 520), 21.5% scored >13 on K6 and completion rate (85%) was similar between these and other fathers. Most fathers (63.1%) clicked at least one link and responses were received for 20.5% of mood tracker questions. The probability of reporting worse mood scores decreased over time. Fathers completing post study surveys (N = 101) reported that messages helped them in their experience of becoming a new dad (92.8%), as well as helping them develop a strong relationship with their new child (54.9%), and in their relationship with their partner (79%). CONCLUSIONS: The present study has demonstrated that it is both feasible and acceptable to support new fathers with SMS4dads, a relationship-focused messaging system designed to be delivered to smartphones across fathers' transition to parenthood.

Antibiotic Stewardship for Non-Infectious Disease Physicians: Focusing on When to Withhold, Modify and Discontinue Antibiotics.

The multiple drug resistant organism (MDRO) and Clostridium difficile infection (CDI) epidemics are progressing relentlessly. Antibiotic stewardship (ABS) has evolved to confront these scourges. The Joint Commission has formulated a standard for its implementation and this should promote its use where others have failed. However, precisely how to intervene needs definition. Healthcare workers need practicable guidelines. The article discusses clinical scenarios where antibiotics should be withheld (Table 1), how they should be modified (Table 2) and when they should be discontinued (Table 3), three focal points of ABS.

An outcomes evaluation of an emergency department early pregnancy assessment service and early pregnancy assessment protocol.

BACKGROUND: Complications in early pregnancy, such as threatened or actual miscarriage is a common occurrence resulting in many women presenting to the emergency department (ED). Early pregnancy service delivery models described in the literature vary in terms of approach, setting and outcomes. Our objective was to determine outcomes of women who presented to an Australian regional ED with diagnoses consistent with early pregnancy complications following the implementation of an early pregnancy assessment service (EPAS) and early pregnancy assessment protocol (EPAP) in July 2011. METHODS: A descriptive, comparative (6 months before and after) study was undertaken. Data were extracted from the hospital ED information system and medical healthcare records. Outcome measures included: time to see a clinician, ED length of stay, admission rate, re-presentation rate, hospital admission and types of pathology tests ordered. RESULTS: Over the 12 -month period, 584 ED presentations were made to the ED with complications of early pregnancy (268 PRE and 316 POST EPAS-EPAP). Outcomes that improved statistically and clinically following implementation included: time to see a clinician (decreased by 6 min from 35 to 29 min), admission rate (decreased 6% from 14.5% to 8.5%), increase in ß-human chorionic gonadotrophin ordering by 10% (up to 80% POST), increase in ultrasound (USS) performed by 10% (up to 73% POST) and increase in pain score documentation by 23% (up to 36% POST). CONCLUSIONS: The results indicate that patient and service delivery improvements can be achieved following the implementation of targeted service delivery models such as EPAS and EPAP in the ED.

A synthetic cytotoxic T cell platform for rapidly prototyping TCR function.

Current tools for functionally profiling T cell receptors with respect to cytotoxic potency and cross-reactivity are hampered by difficulties in establishing model systems to test these proteins in the contexts of different HLA alleles and against broad arrays of potential antigens. We have implemented a granzyme-activatable sensor of T cell cytotoxicity in a universal prototyping platform which enables facile recombinant expression of any combination of TCR-, peptide-, and class I MHC-coding sequences and direct assessment of resultant responses. This system consists of an engineered cell platform based on the immortalized natural killer cell line, YT-Indy, and the MHC-null antigen-presenting cell line, K562. These cells were engineered to furnish the YT-Indy/K562 pair with appropriate protein domains required for recombinant TCR expression and function in a non-T cell chassis, integrate a fluorescence-based target-centric early detection reporter of cytotoxic function, and deploy a set of protective genetic interventions designed to preserve antigen-presenting cells for subsequent capture and downstream characterization. Our data show successful reconstitution of the surface TCR complex in the YT-Indy cell line at biologically relevant levels. We also demonstrate successful induction and highly sensitive detection of antigen-specific response in multiple distinct model TCRs. Additionally, we monitored destruction of targets in co-culture and found that our survival-optimized system allowed for complete preservation after 24 h exposure to cytotoxic effectors. With this bioplatform, we anticipate investigators will be empowered to rapidly express and characterize T cell receptor responses, generate knowledge regarding the patterns of T cell receptor recognition, and optimize therapeutic T cell receptors.

Developing text-messaging support for fathers after perinatal loss.

BACKGROUND: Perinatal loss is a devastating occurrence for expecting parents. Although both parents are affected, research on fathers' grief has not resulted in effective support services for fathers. AIM: To describe a multi-stage co-design process for developing text messaging support for fathers experiencing perinatal loss. METHODS: Co-designed text messages were developed in collaboration with a perinatal bereavement organisation, mothers and fathers with lived experience of perinatal loss, and clinicians working with bereaved parents. Bereaved parents responded to a survey about bereaved fathers' information needs (stage 1). A qualitative descriptive data analysis created topics for the generation of text messages (stage 2). Parents with lived experience and clinicians evaluated the messages on importance and clinical fit (stage 3). Messages were revised (stage 4), followed by parent and clinician evaluation and final message revision (stage 5). FINDINGS: There were 959 survey respondents; the majority agreed that support for fathers would have been useful; 539 provided comments. Qualitative analysis created twelve topics within three themes, leading to the generation of 64 text messages. Messages were evaluated by 27 lived experience parents and 19 clinicians as important (91.6%) and understandable (91.3%), and 92.5% of clinicians agreed the messages fitted clinical guidelines. Message revision resulted in 59 messages across three themes. The final evaluation by 12 parents and 14 clinicians led to a final revised set of 52 messages. CONCLUSION: Text-based support for bereaved fathers can be developed in a co-design process to accord with clinical practice, from topics suggested parents with lived experience.

Effectiveness of Father-Focused Interventions to Prevent or Reduce Intimate Partner Violence During Pregnancy and Early Parenthood: A Systematic Review.

During pregnancy and the early parenting period, women are especially vulnerable to intimate partner violence (IPV), with devastating impacts on women, children, and families. The aim of this systematic review was to determine the effectiveness of father-focused interventions to prevent or reduce IPV during pregnancy and early parenthood. Six databases were searched, using a combination of the concepts "fathers," "pregnancy/early parenthood," "IPV" and "intervention." Articles were double screened by title and abstract, and then full-text. Methodological and reporting quality was assessed using the Quality Assessment with Diverse Studies tool. Fifteen papers were eligible for inclusion; these articles were mostly of poor-to-moderate quality. Only three of the articles reported on interventions in lower- and middle-income countries. The most common forms of IPV addressed in these interventions were physical (10), psychological (8), sexual (4), and economic/financial (3). Of 12 articles reporting on data from both intervention and control groups, only six indicated statistically significant results; among these, only three reported robust analyses showing significantly greater reduction in IPV in intervention than in control groups. All three took place in lower- or middle-income countries. Two were underpinned by theoretical frameworks, which considered transforming traditional perceived gender norms. Therefore, interventions based on principles that address transformation of gender norms show promise but the success of such underlying principles needs to be confirmed, and better-quality evidence and reporting are needed for interventions targeting fathers to prevent or reduce IPV.

Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding.

Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ∼ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases.

Fathers with mental illness: implications for clinicians and health services.

A significant proportion of fathers living with their natural, adopted, step or foster children experience mental illness. Psychiatric illness among fathers can have a devastating impact on children's wellbeing, and even milder forms of paternal mental illness can have serious developmental effects on children. While several pathways linking paternal mental illness with poor child outcomes have been identified, fathers' impaired parenting is an important, potentially malleable factor. Clinicians can assist fathers with mental illness and their families by proactively inquiring about children and by exploring fathering-focused psychological support.

Comparison between shoulder computed tomography and clinical findings in 89 dogs presented for thoracic limb lameness.

Computed tomography (CT) is an established technique for detecting shoulder lesions in dogs, however the clinical significance of shoulder CT lesions often remains uncertain. The purposes of this retrospective study were to describe the prevalence of CT lesions in both shoulder joints for 89 dogs presenting with thoracic limb lameness and to compare CT lesions with clinical characteristics. For all included dogs, results of a full orthopedic examination, other diagnostic tests, and signalment data were available in medical records. Multilevel, multivariable logistic regression was used to test clinical significance of the most prevalent CT lesions and determine factors associated with their presence. Computed tomographic lesions were detected in one or both shoulder joints for 51/89 dogs (57.3%). Mineralization of one or more surrounding peri-articular soft-tissue structures was identified in 31.5% of dogs, with supraspinatus muscle/tendon mineralization being the most frequently identified (24.7%). The prevalence of humeral head osteochondrosis was 9 and 21.3% of dogs had shoulder osteoarthritis. Border collies (odds ratio [OR] 9.3; 95% CI 1.39-62.1, P = 0.02) and dogs with shoulder pain (OR 4.3; 95% CI 1.08-17.1, P = 0.04) had increased risk of osteochondrosis lesions. Border collies (OR 8.4; 95% CI 1.27-55.6; P = 0.03) and older animals (OR 1.04; 95% CI 1.02-1.1, P < 0.001) had increased risk of osteoarthritis lesions. Female entire dogs had an increased risk of supraspinatus mineralization lesions (OR 6.8; 95% CI 1.55-29.5, P = 0.01). Findings indicated that shoulder CT lesions are common in dogs with thoracic limb lameness, and that some CT lesions are not associated with shoulder pain.

Development of a Brief Coparenting Measure: The Coparenting Competence Scale.

Coparenting competence (CC) is a concept that describes the sense of collective efficacy that parents experience in raising children. An advantage of CC is that it bridges a gap between family systems thinking and efficacy theory, where extant research and theory have focused on the self-efficacy of one or both parents. This study aimed to develop a self-reported measure of CC. METHODOLOGY: Participants (n = 302), including cohabiting mothers (n = 240) and fathers (n = 62), completed an online survey (112 items) comprising demographic questions, the Coparenting Relationship Scale (CRS), the Parenting Sense of Competence Scale (PSOC), the Strengths and Difficulties Questionnaire (SDQ), and 36 items designed to explore perceptions of CC. RESULTS: Factor analyses on 36-CC items identified 10 items that reliably formed a brief Coparenting Competence Scale (CCS; Alpha = 0.89). Analysis of convergent and divergent validity demonstrated that the CCS measures a unique construct that is linked to parenting self-efficacy, measured by PSOC (r = 0.47), and coparenting quality, assessed by the CRS (r = 0.63). There was a significant association between CCS and SDQ across age groups and an association stronger than that found for the CRS and SDQ in the current cohort. CONCLUSIONS AND IMPLICATIONS: The study found support for the reliability and validity of the CCS. Coparenting competence, assessed by the CCS, was found to be distinct from factors previously used to represent coparenting quality in multivariate scales. The strength of associations between the CCS and SDQ suggests this new measure may have an important role in coparenting research.

A Synthetic Cytotoxic T cell Platform for Rapidly Prototyping TCR Function.

Current tools for functionally profiling T cell receptors with respect to cytotoxic potency and cross-reactivity are hampered by difficulties in establishing model systems to test these proteins in the contexts of different HLA alleles and against broad arrays of potential antigens. We have implemented and validated a granzyme-activatable sensor of T cell cytotoxicity in a novel universal prototyping platform which enables facile recombinant expression of any combination of TCR-, peptide-, and class I MHC-coding sequences and direct assessment of resultant responses. This system consists of an engineered cell platform based on the immortalized natural killer cell line, YT-Indy, and the MHC-null antigen-presenting cell line, K562. These cells were engineered using contemporary gene-editing techniques to furnish the YT-Indy/K562 pair with appropriate protein domains required for recombinant TCR expression and function in a non-T cell chassis, integrate a fluorescence-based target-centric early detection reporter of cytotoxic function, and deploy a set of protective genetic interventions designed to preserve antigen-presenting cells for subsequent capture and downstream characterization. Our data show successful reconstitution of the surface TCR complex in the YT-Indy cell line at biologically relevant levels. We also demonstrate successful induction and highly sensitive detection of antigen-specific response in multiple distinct model TCRs, with significant responses (p < 0.05 and Cohen's d >1.9) in all cases. Additionally, we monitored destruction of targets in co-culture and found that our survival-optimized system allowed for complete preservation after 24-hour exposure to cytotoxic effectors. With this bioplatform, we anticipate investigators will be empowered to rapidly express and characterize T cell receptor responses, generate new knowledge regarding the patterns of T cell receptor recognition, and optimize novel therapeutic T cell receptors for improved cytotoxic potential and reduced cross-reactivity to undesired antigenic targets.

Fathers Raising Children on the Autism Spectrum: Lower Stress and Higher Self-Efficacy Following SMS (Text2dads) Intervention.

This study explored potential influence of a text-based program for fathers of children on the autism spectrum. Fathers (N = 184) were recruited through autism services across Australia. Participants received messages focusing on five domains: (a) relationships with parenting partner; (b) formal support; (c) father-child interaction; (d) understanding autism; and, (e) coping. Surveys explored parenting stress, co-parenting quality and autism-specific parenting self-efficacy. Eighty-eight percent completed the program, 43.6% completed pre and post surveys. There was significant reduction in parenting stress (p < .01) and increase in autism-specific parenting self-efficacy (p < .01). Effect sizes indicate these may be clinically meaningful. This highly scalable intervention has potential to influence factors that shape and sustain relationships fathers share with their children on the autism spectrum, families and services.

Video Folding: Increased Framerate for Semi-Repetitive Sequences.

We introduce a technique to synthetically increase the framerate of semi-repetitive videos (i.e., videos of motion that repeats but not in an identical fashion) to aid in visualization. By reordering and combining frames from all repetitions, we produce a single non-repetitive sequence with much higher temporal resolution. Then, we use a novel frame warping technique based on a dense corrective flow to counteract differences between repetitions. The resulting video maintains smoothness of motion and additionally allows for seamless, infinite looping. We demonstrate the effectiveness of the proposed solution both quantitatively, by measuring the improvement over existing methods, and qualitatively, by performing a user evaluation and providing several examples in the article and accompanying video.

Fidelity and acceptability of a family-focused technology-based telehealth nutrition intervention for child weight management.

INTRODUCTION: Previous reviews of family-based interventions for childhood obesity treatment found that studies were of low methodological quality with inadequate details reported, especially related to intervention fidelity. The evaluation of fidelity is crucial to inform interpretation of the intervention outcomes. This study aimed to summarise intervention fidelity, participants' acceptability and satisfaction with a 12-week family-focused technology-based child nutrition and weight management intervention. METHODS: Families with children aged 4-11 years participated in a telehealth intervention with complementary components: website, Facebook group and text messages. Intervention fidelity was reported using National Institutes of Health Treatment Fidelity Framework. Delivery was measured using a dietitian-reported evaluation survey. Google Analytics and Bitly platform were used to objectively track data on frequency and pattern of intervention use. Participants' acceptability and satisfaction were measured using a process evaluation survey. RESULTS: Telehealth consultations delivered by trained dietitians had good adherence (≥83%) to the structured content. Process evaluation results indicated that parents (n = 30; mean age 41 years, 97% were female, body mass index 30 kg/m2) found the intervention components easy to use/understand (87-100%), the programme had improved their family/child eating habits (93%), and they wanted to continue using telehealth and the website, as well as recommending it to other parents (90-91%). DISCUSSION: In summary, a family-focused technology-based child nutrition and weight management intervention using telehealth, website, Facebook and SMS can be delivered by trained dietitians with good fidelity and attain high acceptability and satisfaction among families with primary-school-aged children in New South Wales, Australia.

Feasibility and efficacy of a web-based family telehealth nutrition intervention to improve child weight status and dietary intake: A pilot randomised controlled trial.

INTRODUCTION: Innovative eHealth solutions that improve access to child weight management interventions are crucial to address the rising prevalence of childhood obesity globally. The study aimed to evaluate the feasibility and preliminary efficacy of a 12-week online telehealth nutrition intervention to improve child weight and dietary outcomes, and the impact of additional text messages (SMS) targeted to mothers and fathers. METHODS: Families with children aged 4 to 11 were randomised across three groups: Telehealth, Telehealth+SMS, or Waitlist control. Telehealth and Telehealth+SMS groups received two telehealth consultations delivered by a dietitian, 12 weeks access to a nutrition website and a private Facebook group. The Telehealth+SMS group received additional SMS. Feasibility was assessed through recruitment, retention, and intervention utilisation. Efficacy was assessed through changes in measured child body mass index (BMI), waist circumference and diet. RESULTS: Forty-four (96%) and 36 (78%) families attended initial and second telehealth consultations, respectively. Thirty-six families (78%) completed week 12 assessments. Child BMI and waist circumference changes from baseline to week 12 were not statistically different within or between groups. Children in Telehealth+SMS had significantly reduced percentage energy from energy-dense nutrient-poor food (95% CI -21.99 to -0.03%E; p = .038) and increased percentage energy from healthy core food (95% CI -0.21 to 21.89%E; p = .045) compared to Waitlist control. DISCUSSION: A family-focused online telehealth nutrition intervention is feasible. While the modest sample size reduced power to detect between-group changes in weight status, some improvements in child dietary intakes were identified in those receiving telehealth and SMS.

Discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers.

We report the discovery of N-((benzo[d][1,3]dioxol-5-yl)methyl)-6-phenylthieno[3,2-d]pyrimidin-4-amine (2a) as an apoptosis inducer using our proprietary cell- and caspase-based ASAP HTS assay, and SAR study of HTS hit 2a which led to the discovery of 4-anilino-N-methylthieno[3,2-d]pyrimidines and 4-anilino-N-methylthieno[2,3-d]pyrimidines as potent apoptosis inducers. Compounds 5d and 5e were the most potent with EC(50) values of 0.008 and 0.004microM in T47D human breast cancer cells, respectively. Compound 5d was found to be highly active in the MX-1 breast cancer model. Functionally, compounds 5d and 5e both induced apoptosis through inhibition of tubulin polymerization.

Discovery and structure-activity relationships of (2-(arylthio)benzylideneamino)guanidines as a novel series of potent apoptosis inducers.

1-(2-(2,5-Dimethoxyphenylthio)benzylidene)semicarbazide (2a) was discovered as a potent apoptosis inducer through our cell based HTS assay. SAR study led to the discovery of a more aqueous soluble analog (2-(2,5-dimethoxyphenylthio)-6-methoxybenzylideneamino)guanidine (5e) with EC(50) value of 60 nM in the caspase activation assay and GI(50) value of 62 nM in the growth inhibition assay in T47D cells. Compound 5e was found to be an inhibitor of tubulin polymerization and efficacious in a MX-1 breast tumor model.