FTD is a unique condition which manifests with a range of behavioural symptoms,marked dysfunction in activities of daily living (ADL) and increased levels ofcarer burden as compared to carers of other dementias. No efficaciouspharmacological interventions to treat FTD currently exist, and research onpharmacological symptom management is variable. The few studies onnon-pharmacological interventions in FTD focus on either the carer or thepatients' symptoms, and lack methodological rigour. This paper reviews anddiscusses current studies utilising non-pharmacological approaches, exposing theclear need for more rigorous methodologies to be applied in this field. Finally,a successful randomised controlled trial helped reduce behaviours of concern indementia, and through implementing participation in tailored activities, theFTD-specific Tailored Activities Program (TAP) is presented. Crucially, thisprotocol has scope to target both the person with FTD and their carer. Thispaper highlights that studies in this area would help to elucidate the potentialfor using activities to reduce characteristic behaviours in FTD, improvingquality of life and the caregiving experience in FTD. With therevised criteria, a diagnosis of "possible" bvFTD requires three of the sixclinically discriminated characteristics: loss of inhibition, apathy/inertia, lossof empathy, perseveration/compulsive behaviours, hyperorality and dysexecutiveneuropsychological profile. "Probable" bvFTD requires the additional features offunctional disability and characteristic neuroimaging, whereas bvFTD "withdefinitive frontotemporal lobar degeneration" requires histopathologicalconfirmation or evidence of pathogenic mutation.13 In a previous study, we found that impairments in complex,instrumental ADLs (IADLs) such as managing finances and medications, are similarlyimpaired across FTD subtypes, while deficits in basic ADLs (BADLs) such asshowering, dressing and eating differ.12 Patients with nfv-PPA were found to present with the leastchange in BADL performance, followed by svPPA, with bvFTD patients being the mostimpaired subgroup. Over time, however, svPPA have been shown to decline at a slowerrate than both bvFTD and nfv-PPA.15Functional ability, as measured by ADLs, is more impaired in FTD than in Alzheimer'sdisease (AD).16 Behavioural symptoms are at the core of FTD and the severity ofbehavioural symptoms appears to be related to the setting in which the patientlives. People with FTD living at home present with more severe levels of behaviouraldisturbance than those living in care facilities;19 however, this is likely to be related to disease staging oruse of medication. A study by Mourik et al.18 found that carers of people with FTD living at home weremore distressed than carers of people living in residential care. This finding,however, is not universal, as demonstrated by a study in England where carers ofpeople with FTD living at home and of those living in residential care sharedsimilar levels of stress and depression.17 Finally, carers of people with FTD have been shown todemonstrate higher levels of depression, stress and burden than carers of othertypes of dementia such as AD.21Given the severe nature of both behavioural changes and functional deficits, it isnot surprising that disease severity, as measured by a combination of behaviour andfunctional impairments, should be the main contributor to burden in FTD carers,rather than just one of these aspects alone.22Impairments in function lead to progressive and marked dependence on the carer; inaddition, behavioural symptoms associated with FTD frequently make dementiacaregiving even more challenging.23 whichmay be related to the highly heterogeneous nature of FTD pathology.24 This lack of effective treatmentin FTD has been exemplified by a recent multi-centre, randomised, double-blind,placebo-controlled trial of the drug memantine.25 Results from this study found the intervention group tohave a greater decline in mental speed and more frequent adverse cognitive sideeffects than the placebo group. Pharmacological interventions currently used in FTDare therefore primarily targeted at treating specific behavioural symptoms such asagitation, aggression or obsessive behaviour.27 Large scale, randomised, double-blind, placebo-controlledtrials to prove the effectiveness of these pharmacological drugs have yet to beconducted.28 Investigations into several medications have had mixed resultsin FTD including some showing adverse side effects such as worsening ofsymptoms.28The unique devastating impact that FTD has on both the person with FTD and theircarers demonstrates the great need for interventions targeted to this specificdementia syndrome. Pharmacological interventions in FTD have yet to be shown toprovide any clear benefit,It is clear that the development of appropriate non-pharmacological interventions inFTD is of the utmost importance. This paper will argue for the importance ofnon-pharmacological interventions to improve patient function in FTD - through theintegration of addressing both patient behaviour and carer issues, while reviewingstudies which have been centred on carer issues or patient behaviour to date.th January 2013. The search terms frontotemporal dementia,frontotemporal lobar degeneration, and Pick's disease, were combined with the termstreatment, intervention, non-pharmacological, support, carer, caregiver, andtherapy. Articles were considered for inclusion if they discussednon-pharmacological interventions within an FTD cohort. Due to the lack of studieswith rigorous methodology for clinical trials, studies of all levels of evidence(n=16) which met these inclusion criteria were considered for review. In otherwords, the number of papers available was so small that we included them all in thisreview. It should be noted that two of these studies considered for review werewritten in Japanese and thus were not accessed in full text.A search of MEDLINE, PubMed, Cochrane database, and CINAHL was conducted up until30Non-pharmacological interventions in FTD. It is becoming increasinglyrecognised that people with FTD and their carers have unique needs for support.These include skills to manage profound behavioural and language changes, issuessurrounding finances and availability of appropriate care services as a result ofthe often younger onset of the disease, combined with greater levels of carer stressand burden than in other types of dementia such as AD.32 Perhaps not surprisingly, FTD carers appear significantlyless satisfied with support from specialist health care providers than ADcarers.33 This findinghighlights the lack of appropriate services that address specific issues in FTD, andthe pressing need for further investigation into FTD-specific non-pharmacologicalintervention strategies. Mendez34reported that non-pharmacological management strategies in FTD should primarilyinclude behavioural interventions, education and a focus on the carer. To date,crucially, no randomised controlled trials have taken place to evaluate the benefitof any non-pharmacological interventions in FTD. Carer-based interventions.Interventions promoting education. German studies36 have reported on an FTD-specificcarer support group (n=8) aimed at providing information, advice and support. Sevenphysician-facilitated structured sessions were conducted, which were designed to beboth educational and therapeutic. Outcomes were analysed immediately postintervention via interviews, and again after six months via mailed questionnaires,with a qualitative approach. Overall, carers reported improved understanding andknowledge of the disease, but less than half reported having learnt strategies tocare for themselves better as carers. Nonetheless, no control group was included inthe study.29 reported on an intervention based on a series ofFTD-specific conferences for FTD carers, which incorporated an educational lecturesession followed by a facilitated support group. Evaluation forms were used togather qualitative feedback from carers who attended these sessions. While somefeedback was positive regarding information and support provided at the sessions,other feedback was rather negative and stated that the lecture content wasimpractical. This study also did not have a control group, and lacked quantificationfrom which to obtain greater interpretation of the results.With similar aims to the German studies, Banks et al.37 This online intervention was based on evidence from efficaciousdementia carer support groups previously reported,39 where these groups were adapted to suit FTD cohorts.Qualitative analysis conducted post intervention (via interview) identified thatcarers reported social support and accessibility as positive aspects to theintervention. Reduced burden was also reported; levels of stress, however, remainedunchanged, and the study lacked a control group to avoid the Hawthorne effect, wherebias may have been introduced by participants knowingly receiving anintervention.40An online video-conferencing education and support group for FTD spousal carers(n=6), which involved 10 weekly one-hour sessions facilitated by a health-careprofessional was trialled in Canada.Structured interventions promoting carers' skills. Riedijk etal.19 reported that carerswho use passive coping strategies were more likely to have high levels of burden anddecreased health-related quality of life (QOL). The importance of carer educationand identifying support services was also highlighted by Mohandras andRajmohan.41 Following onfrom these, a recent study investigated the impact of a structured interventionprogram for FTD carers to specifically teach skills on cognitive appraisal andcoping strategies, including education on seeking support. The main outcomes werereduction of burden and enhancement of coping skills.42 The intervention was based on a previouslydeveloped intervention for general dementia carers,43 and adapted to suit FTD populations. The programinvolved an intervention group (n=9) and a control group (n=12), and was run inweekly sessions for 15 weeks (2 hours each). The study reported that both carerburden and carer reaction to behaviours decreased significantly in the interventiongroup, which persisted at 12 months follow-up.42 Transferability of the skills learnt in the interventionwas demonstrated through the qualitative analysis of a fictitious problem-solvingscenario.44 However,similarly to the qualitatively reported results from Marziali and Climans,37 no change in carer stress wasidentified, and the participants were similarly not randomised to intervention orcontrol groups.Despite these positive outcomes generated from carer-based interventions, the studiesmentioned above are of a limited transferability due to limitations in study design,such as lack of randomisation, and small sample sizes. Rigorous studies aretherefore required to reproduce the promising findings, and to further support theestablishment of carer-based interventions in FTD.Patient-based interventions. The current lack of randomised controlledtrials on non-pharmacological interventions in FTD extends to patient-basedinterventions. In this area, the majority of studies have been based on either casestudies or narratives and expert opinion articles.45 The aim of the program was very broad, offering individualisedactivities to patients, specific FTD-related training for staff members, as well asprovision of education and support to family carers. Preliminary outcomes of theprogram are reported to be positive. The authors also discussed frequent limitationsof such programs for people with FTD due to the frequent predominance of older groupmembers, or to distance.30 Thisimportant variable highlights the need for development of community-based FTD specific interventions to facilitate accessibility to carers.Behavioural modification interventions have been described, where a multidisciplinaryFTD-specific day-program was implemented within an existing day program at an adultday centre.46 reported on asingle-subject design study where an environmental intervention was used with an FTDpatient to restore sleep-wake cycles. The intervention of shutting doors during theday was shown to significantly reduce the patient's evening and night-timedisturbances. Lough and Hodges47also published a case report describing strategies for behavioural and psychologicalsymptoms of dementia (BPSD) management in a patient with FTD. In the study,behaviour modification techniques were found to be effective for altering theexpression of specific BPSD exhibited by the participant; quantitative outcomemeasures to support these findings were, however, missing. A recent casestudy48 reported on theuse of active music therapy to reduce BPSD in a patient with FTD. The result withthis case was the reduction of BPSD by more than 50%. Taken together, thesesingle-subject design studies suggest that interventions focused on patientbehaviours may be beneficial in FTD. Future studies should focus on rigorousmethodology.Yamakawa et al.49 highlighted the need forimproved carer management in FTD, recommending carer education, emotional support,treatment of psychiatric morbidities, and provision of respite care. The need tooffer appropriate support for FTD carers was also discussed by a Canadianexploratory study suggesting the internet as a platform for accessible FTDeducational resources.50Litvan32 In this model, brain atrophy is considered theantecedent [A]; behavioural symptoms secondary to this atrophy is considered thebehaviour [B], and carer response to this behaviour is the consequence [C]. Specificexamples of BPSD were used to explicate this behavioural modification basedintervention, with suggested interventions ranging from environmental, behavioural,pharmacologic and physical.51Although these approaches seem coherent in the FTD context, a pressing need forresearch studies to verify the efficacy of these recommendations exists.The antecedent-behaviour-consequences (ABC) model is an approach used by familycarers for management of behavioural symptoms in FTD.Improving function in FTD: an intervention that integrates patient and carerissues concomitantly. To date, most interventions in FTD have focused oneither carer burden or behavioural disturbances, with limited number of studies withinterventions focused on activity. Two Japanese studies aimed at promoting improvedfunction have been found in FTD. Ikeda et al.52 reported on the benefit of individualised activities basedon previous interests for reducing BPSD in people with FTD (n=4), while anotherstudy presented an OT approach53involving family education in conjunction with patient-based interventions toincrease QOL and improve care in FTD. However, limited information is available asboth studies were published in Japanese journals.54 TAP is acommunity-based occupational therapy based intervention designed to reduce BPSD byprescribing personalised activities. Importantly, these activities are based onpreserved capabilities and previous interests and roles, with scope fortransferability as the dementia progresses.A promising intervention, the Tailored Activities Program (TAP), has yet to betrialled in FTD. This approach incorporates the aforementioned concepts of usingindividualised activities with patients in conjunction with carer education, andthus shows great potential for success in this cohort. Developed by Gitlin etal.,54was a two-group randomised controlled trial (n=60) conducted with general dementiapatients. Results demonstrated a treatment effect for reduced incidences of BPSDoverall, with significant decreases in shadowing, repetitive questioning, agitationand argumentation. Following the intervention, carers reported greater activityengagement and ability for patients to keep busy, as well as fewer hours on duty ordoing things for the patient. Carer skills increased through increased mastery,self-efficacy using activities, and greater use of simplification techniques. Theseinitial outcomes of enhanced activity engagement and reduced BPSD along withenhanced caregiving skills, suggest TAP warrants consideration as a good candidatefor non-pharmacological intervention within FTD populations living in the community.FTD-specific services, as well as general services able to cater for FTD patientsare lacking.55 Development of anFTD-specific TAP protocol potentially provides translational opportunity for thedevelopment of an appropriate community-based intervention for people with FTD.Crucially, the TAP pilot study42 and Robinson.56 Both studies have highlighted the importance of FTD carers tolearn problem solving techniques to develop strategies to assist with patientfunction by themselves. This finding appears to be the key to success, becausecarers are instilled with an increased sense of control by taking an active approachto resolving specific problems. This concept was also suggested by Talerico andEvans,57 who proposedworking with carers to implement personalised environmental and behaviouralinterventions to promote improved function and QOL in a person with FTD.TAP requires active carer involvement, from activity development to generalisation ofstrategies and downgrading of activity for future decline in function. Similar useof problem solving strategies seem to have contributed to the positive careroutcomes reported by Mioshi et al.,59 The TAP intervention involves structuring activities based onsingle rather than multiple tasks,60 a strategy also suggested by Massimo and Grossman27 to assist with impairments inexecutive functioning in FTD.59Other studies61 have alsoadvocated the importance of providing interventions which match the functional levelof the person with FTD, while Robinson56 proposed the potential use of strategies to enhance attentionand use procedural/implicit learning strategies despite the degenerative nature ofFTD. Moreover, the TAP intervention also involves setting up the environment tofacilitate initiation and sequencing,60 another potentially important consideration in FTD where apathyfrequently prevents initiation of tasks,62 and executive dysfunction and utilisation behaviour may impedethe continuation of an activity.63One of the challenges to improve function in FTD is to address the marked frontaldeficits that characterise the disease, such as apathy and executivedysfunction.57 These studies have argued thatcarers need detailed information about the condition in order to improve theirunderstanding of the disease process, and thus better cope with their own emotionalreactions. This concept leads to the recommendation to involve professionals withexpert knowledge in FTD to work with affected families for greaterefficacy.61 The TAPintervention involves providing general dementia information to carers, which cantherefore be tailored for FTD-specific information.The paucity of reliable, accessible information regarding services for FTD dyadsliving in the community is an issue discussed by a number of studies.61especially in light of marked levels of stress reported by carers.65Finally, TAP also includes carer stress-reducing techniques, an importantconsideration in FTD interventions,Conclusions and future directions. FTD is a unique condition whichmanifests with a range of behavioural symptoms,59 marked ADL dysfunction12 and increased levels of carer burden as compared to carersof other dementias such as AD.22No efficacious pharmacological interventions to treat FTD exist, and researchinvolving non-pharmacological interventions to manage symptoms is variable. A fewstudies regarding non-pharmacological interventions in FTD have been published;however, the need for rigorous methodologies to be applied is clear. A promisingapproach is the use of an FTD-specific TAP protocol, which can target both theperson with FTD and their carer. Such a program has scope to elucidate the potentialfor using activity to improve patient function and reduce behavioural changes, whileimproving carers' skills and reducing difficulties in the caregiving experience inFTD.


Pten+/− mice, to build a feature-based machine learning model separating the early pathological lesions provoked by these genetic alterations. This work offers a set of computational methods for separation of early neoplastic lesions in the prostates of model mice, and provides proof-of-principle for linking specific tumor genotypes to quantitative histological characteristics. The results obtained show that separation between different spatial locations within the organ, as well as classification between histologies linked to different genetic backgrounds, can be performed with very high specificity and sensitivity.Cancer involves histological changes in tissue, which is of primary importance in pathological diagnosis and research. Automated histological analysis requires ability to computationally separate pathological alterations from normal tissue with all its variables. On the other hand, understanding connections between genetic alterations and histological attributes requires development of enhanced analysis methods suitable also for small sample sizes. Here, we set out to develop computational methods for early detection and distinction of prostate cancer-related pathological alterations. We use analysis of features from HE stained histological images of normal mouse prostate epithelium, distinguishing the descriptors for variability between ventral, lateral, and dorsal lobes. In addition, we use two common prostate cancer models, Hi-Myc and  Tissue histology is one of the main determinants in studying and diagnosing many pathologies, including cancer. Solid tumors change the structure of the tissue due to altered morphologies and localizations of tumor cells within the normal tissue. Histopathology is traditionally a very intuitive method, where decisions are most often based on visual inspection. Often, however, ability to objectively recognize and quantify pathological changes in tissue histology would be desired. Furthermore, gaining the decisive pathological information from basic histological stainings, most often hematoxylin and eosin (HE), would help to avoid using costly special stainings. Several current approaches aim to develop tools to help clinical pathologists to determine presence or state of a particular lesion from HE-stained images, e.g. to stage cancer for diagnostic and prognostic purposes1To be able to quantify changes in tissue morphology, measurable determinants of the pathology in question need to be determined. Key questions are how to differentiate between normal and pathological tissue, how to measure the stage of the pathological change, and even how to differentiate between several possible types of change, e.g. subtypes of cancer. For example, accurate separation of pathologies from normal tissue histology requires understanding and inclusion of all states and variables of the normal tissue, whether originating from characteristics of the tissue itself, or technical variation due to e.g. orientation of the histological section cut relative to tissue structures.In cancer research, recent years of next-generation sequencing have revealed the extent of genetic and gene expression alterations in cancer3Feature-based analysis combined with supervised learning has been a common approach in decision support systems and computer aided diagnosis based on whole slide images15PtenPten+/− or Hi-Myc-induced neoplasms from normal tissue, and 3) the two types of neoplasms from each other. Our study serves as the first step towards developing tools for automated analysis of early neoplastic changes in prostate tissue and their linkage to different genetic groups.We aim at improving histological recognition and quantification of pathological features in prostate cancer, and search for descriptors to differentiate early pathological lesions from normal prostate tissue. Furthermore, the goal is to separate genetically different types of early neoplastic changes from each other. In here, we use two classical and popular genetic prostate cancer mouse models, namely heterozygous First, we wanted to assess normal spatial variation in the histology of the prostate. Mouse core prostate can be divided in three lobular areas: ventral prostate (VP), lateral prostate (LP) and dorsal prostate (DP), which surround the urethra . All thrWe manually selected 227 acini to represent variation in prostate epithelium in histological sections, including both the heterogeneity in normal appearance of the tissue, and the technical variance (e.g. acini cut in different orientations). For these images, we performed preprocessing to, for example, correct color variation across the tissue samples, and to exclude areas not including tissue (e.g. empty and secretion-containg areas inside the acini) . We applPten form mouse prostatic intraepithelial neoplasia (mPIN) within 8–12 monthsPten+/− mice of 10-11 months, when recognizable mPIN is evident . Predictor importances of 20 most influential features in the model to distinquish between the morphology types are shown in To test whether the computed feature characteristics can be used to reliably separate mPIN lesions from normal epithelium, we applied machine learning. We developed a random forest based model and applied it in leave-one-out cross validation (LOOCV) to estimate the probability of a sample to belong to the group of PIN lesions based on the feature data. From the LOOCV experiment, used to validate the robustness of our random forest model, we collected altogether 426 models from which the average importances are shown in Pten+/− model mice, the number of mPIN samples in the analysis varied between lobes being greatest in LP and lowest in VP . PIN was distinguished from normal prostate most accurately in LP (AUC 0.997), likely due to the clear phenotypic difference in the histology. mPIN in VP and DP were similarly challenging, although with these, relatively small sample sets, a very high accuracy was still reached (AUC 0.972).We further tested the ability of the model to distinguish mPIN from normal epithelium in each lobe . AccordiPten+/− heterozygous mice which does not develop into carcinoma without additional genetic or carcinogenic manipulationPten+/− model mice , and manually selected samples from LP of Hi-Myc mice . Examples of representative histologies on normal and preneoplastic LP epithelium are shown in High expression of oncogenic Myc in the mouse prostate induces neoplastic lesions visible already at 1 month of agePten+/− mice compared to 1 month in Hi-Myc mice). Thus, to ensure consistency and comparability of the data from hiMyc and Pten+/− tissues, we selected features whose distributions did not show statistically significant difference (threshold α = 0.05) according to Kolmogorov-Smirnov test in the two control groups to use in the further analysis. Altogether 59 features fulfilled the criterion . The model is successful in predicting accurately the histological classes of the samples, as shown in a confusion matrix of the predictions . Similarly as in distinguishing mPIN from normal epithelium, the predictor importances of the most valuable features in this random forest model .Pten  and ImageJ software  with 20x objective and a CCD color camera  and a motorized specimen stage . The automated image acquisition was controlled by the Surveyor imaging system . Uncompressed bitmap output was converted by JVSdicom Compressor application to JPEG2000 WSI formatThe preprocessing of the images included histogram matching in order to remove the color variation between samples, exclusion of unwanted regions, color deconvolution to separate hematoxylin and eosin stains, and nuclei segmentation. These steps were implemented for bounding box areas around each ROI.Histogram matching was performed to balance staining variation between sections. For a reference histogram, a mean histogram was computed from a representative set of samples consisting of ROI images of preneoplastic lesions and normal prostate epithelium from all three lobular areas. After this, histogram matching was performed by using a transform function computed between the image’s histogram and the reference histogram.et al.To segment the effective tissue area within each ROI, a mask for secretion-filled regions and empty areas was obtained by subtracting different color channels and performing contrast limited mapping of the intensity values similarly as in Ruusuvuori A color deconvolution algorithmProperties of each ROI were described with extraction of 241 features . These fThe extracted texture based features included, e.g., mean intensity value, contrast, correlation, and energy, calculated from gray level co-occurrence matrix (GLCM). Properties of the texture within each ROI were also extracted using local binary patterns (LBP)28Features related to distribution of cell nuclei were calculated from a nuclei location map, generated by marking the center point of each segmented nucleus. Features included descriptors related to inter-nuclei distance, nuclei locations with respect to each other described with angular statistics, number of nuclei within a neighborhood, and density features. The density features were calculated from a Gaussian filtered nuclei location map.The angular statistic features were extracted using CircStat toolboxPten+/−, and Hi-Myc), a feature selection was performed by statistical testing between features extracted from both Hi-Myc and Pten+/− normal prostate epithelium samples. Two-sample Kolmogorov-Smirnov testα = 0.05) was used to determine if the feature data extracted from these two normal sample groups were from the same continuous distribution. Altogether 59 features not showing statistically significant differece between the two normal populations were included in further analysis .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Pseudocarcinomatous hyperplasia of the fallopian tube is a rare, benign disease characterized by florid epithelial hyperplasia.The authors present the history and details of a 22-year-old woman with bilateral pelvic masses and a highly elevated serum CA-125 level . Ultrasonography and magnetic resonance imaging (MRI) of the pelvis showed bilateral adnexal complex cystic masses with a fusiform or sausage-like shape. Contrast-enhanced fat-suppressed T1-weighted images showed enhancement of papillary projections of the right adnexal mass and enhancement of an irregular thick wall on the left adnexal mass, suggestive of tubal cancer. Based on MRI and laboratory findings, laparotomy was performed under a putative preoperative diagnosis of tubal cancer. The final pathologic diagnosis was pseudocarcinomatous hyperplasia of tubal epithelium associated with acute and chronic salpingitis in both tubes.The authors report a rare case of pseudocarcinomatous hyperplasia of the fallopian tubes mimicking tubal cancer. Various benign conditions of the female genital tract may be confused with malignant neoplasms. Pseudocarcinomatous hyperplasia of fallopian tubes is a rare, reactive response to an underlying inflammatory or neoplastic process, and can mimic adenocarcinoma clinically and pathologically. Epithelial hyperplasia of a tube has been reported in association with estrogen administration, estrogenic ovarian lesions, tuberculous salpingitis, and nontuberculous salpingitis . Mild toSince this condition has not been discussed extensively in the literature, its differentiation from tubal cancer can be problematic , and morHerein, we present a case of pseudocarcinomatous hyperplasia of fallopian tubes with chronic salpingitis and endometriosis in tubes mimicking tubal cancer.A 22-year-old nulliparous woman presented with persistent lower abdominal pain and vaginal spotting of 4 weeks’ duration. She was referred to our hospital due to bilateral adnexal masses and a highly elevated CA-125 level . Pelvic ultrasonography showed well defined bilateral adnexal cysts with irregular thickened walls  either grossly or microscopically, whereas carcinomas do not.No previous report has described the imaging appearance of pseudocarcinomatous hyperplasia of the fallopian tube. In our patient, it was visualized by pelvic ultrasonography and MRI as bilateral tubular cystic adnexal masses with papillary projections of the right mass and an irregular thick wall on the left mass. Furthermore, both of these features were intensely enhanced on contrast-enhanced MR images. The detection of a dilated fallopian tube by imaging aids determination that a cystic mass has a tubal origin, and is visualized as a thin-walled C- or S-shaped tubular cystic structure. The fluid is anechoic or shows low-level echoes by ultrasonography, and hyperintensity on T2-weighted images and hypointensity or hyperintensity (if hemorrhagic fluid is present) on T1-weighted images , 6. In oRadiologically, pseudocarcinomatous hyperplasia of fallopian tube may mimic tubal cancer, chronic salpingitis, or tubal tuberculosis. Tubal cancer also manifests as a solid, cystic adnexal mass, and the presence of enhancing intraluminal masses within a dilated tube is suggestive of its presence. On the other hand, thick-walled tubular adnexal cystic structures with intense enhancement and surrounding inflammation are indicative of salpingitis. However, thickened tube folding due to inflammation can be mistaken for enhancing mural nodules, and sometimes make it difficult to differentiate chronic salpingitis and tubal carcinoma , 6.Pseudocarcinomatous hyperplasia of the fallopian tube is a rare disease and its radiologic features overlap with other fallopian tube diseases, such as, tubal cancer and salpingitis, and thus, intraoperative frozen section is needed to confirm the diagnosis.Serum CA125 levels may provide information preoperatively that aid the differentiation of benign and malignant adnexal masses , and levIn conclusion, pseudocarcinomatous hyperplasia of the fallopian tube is a benign, reactive response to an underlying inflammatory process. Accurate discrimination is dependent on the identification of morphologic features, because there are no characteristic immunohistochemical findings that aid the differentiation of pseudocarcinomatous hyperplasia and tubal carcinoma. Thus, a meticulous morphological assessment is required to avoid an erroneous diagnosis of tubal cancer and subsequent overtreatment of this benign disease.


Recent advances in genomic sequencing and omics-based capabilities are uncovering tremendous therapeutic opportunities and rapidly transforming the field of cancer medicine. Molecularly targeted agents aim to exploit key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality. Additionally, immunotherapies targeting the host immune system are proving to be another promising and complementary approach. Owing to substantial tumor genomic and immunologic complexities, combination strategies are likely to be required to adequately disrupt intricate molecular interactions and provide meaningful long-term benefit to patients. To optimize the therapeutic success and application of combination therapies, systematic scientific discovery will need to be coupled with novel and efficient clinical trial approaches. Indeed, a paradigm shift is required to drive precision medicine forward, from the traditional “drug-centric” model of clinical development in pursuit of small incremental benefits in large heterogeneous groups of patients, to a “strategy-centric” model to provide customized transformative treatments in molecularly stratified subsets of patients or even in individual patients. Crucially, to combat the numerous challenges facing combination drug development—including our growing but incomplete understanding of tumor biology, technical and informatics limitations, and escalating financial costs—aligned goals and multidisciplinary collaboration are imperative to collectively harness knowledge and fuel continual innovation. The principle underlying combining therapeutic agents is to maximize efficacy and overcome treatment resistance by utilizing drugs with known activity, different mechanisms of action, and minimally overlapping toxicities. Cytotoxic chemotherapy combinations have had an indispensable impact in oncology and malignant hematology. Indeed, almost all curative cytotoxic regimens consist of combination agents . Many ofIn the past two decades, our growing genomic knowledge underlying oncogenesis has shifted the focus of developmental therapeutics to molecularly targeted agents (MTAs). This shift is coupled with advances and increasing availability of next-generation sequencing and other novel molecular techniques such as transcriptome analysis, RNA interference screening, and genome-editing tools. MTAs aim to optimize the therapeutic index by exploiting key tumor-specific vulnerabilities such as oncogenic or non-oncogenic addiction and synthetic lethality (Box 1). However, substantial genomic complexity exists, such that tumors are rarely reliant on one molecular aberrant pathway for survival, which, with a few notable exceptions, limits the efficacy and durability of response to single agent MTAs –4. BeyonAs in the case of cytotoxics, combinatorial approaches are needed for MTAs and immuno-oncology agents to adequately disrupt intricate molecular and immune interactions to provide long-term clinical benefit. However, progress in this field is hampered by a multitude of challenges. Foremost among these is the rational selection of combinations in the perplexing and dynamic disease context, which is characterized by tumor genomic redundancy and adaptability and considerable intra- and inter-patient heterogeneity , 19. SecThis review summarizes some of the past successes and failures in the development of combination therapies, explores the obstacles ahead, and suggests future directions to manage the evolving dynamics of cancer.MTAs can be combined to inhibit multiple components within a signaling network to evade resistance mechanisms or to target distinct and potentially complementary oncogenic processes. Combination strategies may include 1) additive or synergistic drug combinations of the same mechanism or connected mechanisms of action, (2) synthetic lethality pairings, and (3) the addition of a second agent with a different mechanistic activity to reverse resistance mechanisms. In addition, MTAs can be combined with other therapeutic modalities, such as radiotherapy, chemotherapy, and immuno-oncology therapy. Table  additiveBetween January 2006 and June 2016, four MTA–MTA and four MTA–endocrine-therapy combinations were approved by the US Food and Drug Administration (FDA) for use in adult solid malignancies, compared with approximately 40 approved single-agent MTAs and approximately 20 MTA–chemotherapy combinations  inhibit immune regulatory checkpoints, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1), respectively, producing durable tumor regression in multiple tumor types –11. MechThe scientific basis of these nine FDA-approved combinations is founded on proof of resistance mechanisms to an established therapy and/or evidence of synergistic or additive activity in animal models , 33–42. Approximately 75 % of investigational oncology compounds that enter clinical testing do not ultimately receive regulatory approval; these include 50 % of drugs tested in the phase III setting . In mostKRAS wild-type subpopulation, and toxicity was also increased [Failure to show benefit at the phase III stage is particularly disappointing during drug development given the immense financial cost and human resources involved. Importantly, a large number of patients may have been exposed to harm or unnecessary treatment. An example is the combination of anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab or panitumumab), anti-vascular endothelial growth factor (VEGF) antibody (bevacizumab), and chemotherapy in metastatic colorectal cancer. Both anti-EGFR and anti-VEGF mAbs have established antitumor activity in combination with chemotherapy in this setting –48. A lancreased , 53. Thencreased , 53. ThiCurrently, there are approximately 100 approved anticancer drugs and, according to the Pharmaceutical Research and Manufacturers of America’s 2015 report, approximately 1200 new anticancer drugs are in development in the United States, amounting to approximately 845,000 possible pairings and an exponential number of higher-order combinations . This, iIncreasingly, industry and academia are utilizing various methods of high-throughput screening, which leverage laboratory automation to simultaneously assay the biological activities of a vast number of compounds –59. IndeComplementary to these novel approaches, data-sharing efforts are imperative to promote scientific collaboration. Examples include publically available data repositories that catalogue protein–protein interactions and biological pathways such as Pathway Commons and Database of Interacting Proteins , 66. TheNonclinical studies of drug combinations often report synergy without appropriate evaluation of the combination index (Box 1) . AdditioIn response to the fundamental challenges of tumor molecular diversity and the expanding portfolio of novel MTA and immuno-oncology agents, clinical trial designs and statistical approaches are evolving to optimize the evaluation of combination therapeutics and streamline their clinical development. Despite considerable progress, more innovative precision medicine-based approaches are urgently needed to implement customized treatments and to bring truly durable benefit for molecularly stratified subsets of patients or even for individual patients.Traditional rule-based dose-escalation trial designs, which rely on the premise of dose-dependent toxicity, may have considerable limitations in defining the biological optimal dose and schedule of combination MTAs. Unlike cytotoxic chemotherapy, the relationship between dose, toxicity, target inhibition, and efficacy is less predictable with MTA therapy . PharmacAdaptive Bayesian model-based designs may be better placed to cater for the complex variables associated with combination MTAs, by incorporating pre-study probability of toxicity and updating such probability with real-time adverse event data to inform dose-escalation decisions –83. In sCurrently, there is no preferred dose-escalation design for combination MTAs. The choice of the most appropriate dose schedule selection and dose-finding method should be informed by knowledge of the nonclinical and clinical pharmacology of the agents of interest and based on consultation between experienced clinical researchers, sponsors, and statisticians. Comprehensive pharmacokinetic evaluation and pharmacodynamic assessment of tumors in early phase trials are vital to assess for target modulation and to mechanistically characterize on- and off-target toxicities. These are particularly pertinent in combination studies to delineate individual drug effects and to evaluate pharmacological interactions. Multiple targets may also need to be cross-examined to assess network inter-dependencies in identifying resistance mechanisms.Combinations of novel immune checkpoint and co-stimulatory molecules are actively being evaluated for additive or synergistic effects. Additionally, as multiple oncogenic pathways can foster immunosuppressive microenvironments, immuno-oncology agents are also being investigated in combination with MTAs, with pending efficacy data –17. AlthThe desire to expedite drug development has challenged the conventional three-phase clinical trial paradigm, in which safety and efficacy objectives are mandated at each distinct stage to fulfill regulatory requirements. Indeed, the time period from first-in-human testing to regulatory approval for oncology drugs typically averaged 7–9 years, substantially longer than agents of other therapeutic classes , 97. NovMultiple umbrella (histology-specific) and basket  clinical trials are currently ongoing, incorporating genomic testing results for treatment assignment to genotype-matched therapies and combinations  (Box 1) . The sizALK)-translocated non-small cell lung cancer, in which the identification of a molecular subset of patients helped accelerate drug registration [To support molecular-based patient selection strategies, biomarker development and validation are crucial, preferably in concert with drug discovery and testing. A successful example is the development of crizotinib in anaplastic lymphoma kinase fusion gene  or cell-free DNA (cfDNA) can be used at key treatment time points or regular intervals and present a less invasive alternative to tumor biopsies , 111. A The proposed individualized dynamic model offers the compelling potential to deliver immediate and durable benefit to patients, as well as an opportunity to study disease evolution and biology at an individual genetic level. However, the implementation and scaling-up of this approach may face a myriad of technical, resource, and culture issues. In Table p < 0.05), from 29.5 % in 2008 to 22.7 % in 2012. Furthermore, trials supported by the US National Institutes of Health are significantly more likely to use combinations than those supported by industry [A review of the characteristics of combination clinical trials listed on ClinicalTrials.gov between 2008 and 2013 found that 25.6 % of oncology trials were combination trials and, surprisingly, the ratio of combination trials to all trials decreased over time (industry . Barrierindustry , 118. Thindustry . Precompindustry . This maindustry .Cumbersome clinical trial operational systems can substantially hinder and add to the cost of drug development. A study found that opening a phase III cooperative group trial required a median of 2.5 years from the time of concept review by the cooperative groups to trial opening at individual cancer centers . The timThe limited utility of single agents provides the impetus to combine drugs early in their development, rather than delaying until one or both drugs is approved. In recognition of this, the FDA published their guidance on the co-development of two or more new investigational drugs in 2013, which emphasizes the need for a biological rationale for early co-development and outlines recommendations for nonclinical and clinical testing. It also provides direction for approval and marketing processes, with an emphasis on encouraging early and regular dialogue between commercial sponsors and the FDA to streamline and purpose-fit their efforts . These gTo adequately address the immense complexity and heterogeneity underlying oncogenesis and disease progression, innovative combination strategies will need to be customized to patients’ unique molecular and immune profiles and adaptively applied to respond to evolving changes over time. Moreover, in light of the current pace of scientific discovery and mounting financial costs, it is apparent that the existing framework of oncological drug development, with substantial attrition and lengthy timelines, is inefficient and ultimately unsustainable. Systematic high-throughput methods and computational network-based platforms can be utilized to explore novel therapeutic targets and identify synergistic or additive drug combinations. Clinical trial designs should be informed by comprehensive understanding of tumor biology and pharmacology and should leverage novel approaches to more effectively investigate new drug combinations. Throughout the nonclinical and clinical processes, co-development of biomarkers must be prioritized to refine and optimize patient selection. Importantly, meaningful collaborations and coordination of efforts are crucial among all stakeholders to collectively overcome technical, informatics, and logistical challenges, toward the shared goal of precision medicine.


As the production of non-traditional export (NTX) crops by smallholder households in developing countries expands, there is a compelling need to understand the potential effects of this type of agricultural production on household food security and nutrition. We use two household surveys with a sample of 52 households, interviews, and focus groups to examine whether smallholder farmers who produce broccoli for export in a rural Guatemalan community have different household food security than farmers in the same community who are still growing traditional maize and bean crops. We explore and compare the food security status of broccoli farmers (adopters) and traditional farmers (non-adopters) across four dimensions of food security: availability, access, utilization, and stability. Adopters earned significantly more income (40%) than non-adopters, but higher incomes did not coincide with improvements in food availability, food access, or food utilization. Results indicate that adopters and non-adopters alike struggle with access to food, while the intensity of broccoli production may be undermining the ability of local agricultural systems to naturally control pests and regulate nutrients. More systematic approaches to food security assessment, especially those that consider all four dimensions of food security, are needed to better target interventions designed to alleviate food insecurity among rural smallholders. The increased commercialization of agriculture and diversification into non-traditional export crops (NTXs) by smallholder farmers has been touted as a growth-oriented strategy to reduce rural poverty and combat food insecurity . NTXs inMuch of the literature on NTXs focuses on their potential to improve national economic performance ,7,8,9,10availability, food access, food utilization, and food system stability  concept are more important than others” . More woMeanwhile, policy-makers continue to promote NTX agriculture in Guatemala and across poor, food insecure parts of the world . These aSweeping arguments are often made either for or against the potential for NTX agriculture to improve the food security of smallholder farmers in developing countries. However, the results of our study–the first to systematically compare the food security status of adopters and non-adopters across four dimensions of food security–indicate that these arguments may be lacking in necessary nuance. Our results show that the food security status of adopters and non-adopters in Chilascó varies depending on the dimension of food security considered. It is therefore critically important to consider how NTX production may affect all four dimensions of food security, while recognizing that different indicators paint different pictures of household food security. Our research moves beyond a dualistic understanding of food security outcomes (better/worse) toward an analytical framework that considers food security within a matrix of interactions and potential trade-offs. As the commercialization of smallholder agriculture expands across Guatemala, understanding these interactions has important implications for the food security and wellbeing of the rural poor.S1 File(DOCX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.


To compare maternal and fetal effects of intravenous phenylephrine and ephedrine administration during spinal anesthesia for cesarean delivery in high-risk pregnancies.An extensive literature search was conducted using the US National Library of Medicine, MEDLINE search engine, Cochrane review, and Google Scholar using search terms “ephedrine and phenylephrine,” “preterm and term and spinal hypotension,” “preeclampsia and healthy parturients,” or “multiple and singleton gestation and vasopressor.” Society of Obstetric Anesthesia and Perinatology meeting abstracts for the past 4 years were also searched for relevant studies.Both phenylephrine and ephedrine can be safely used to counteract hypotension after spinal anesthesia in patients with uteroplacental insufficiency, pregnancy-induced hypertension, and in non-elective cesarean deliveries. Vasopressor requirements before delivery in high-risk cesarean sections are reduced compared to healthy parturients. Among the articles reviewed, there were no statistically significant differences in umbilical arterial pH, umbilical venous pH, incidence of fetal acidosis, Apgar scores, or maternal hypotension when comparing maternal phenylephrine and ephedrine use.From the limited existing data, phenylephrine and ephedrine are both appropriate selections for treating or preventing hypotension induced by neuraxial blockade in high-risk pregnancies. There is no clear evidence that either medication is more effective at maintaining maternal blood pressure or has a superior safety profile in this setting. Further investigations are required to determine the efficacy, ideal dosing regimens, and overall safety of phenylephrine and ephedrine administration in high-risk obstetric patients, especially in the presence uteroplacental insufficiency. Maintenance of hemodynamic stability from a sympathetic blockade after neuraxial anesthetic techniques for cesarean delivery remains a significant clinical problem . To counHistorically, ephedrine was considered the preferred vasopressor for management of spinal-induced hypotension in healthy parturients. Ephedrine has a relatively slow onset and long duration of action compared to phenylephrine and has a predominantly β-agonist effect . StudiesIn 2002, a quantitative systemic review by Lee et al. examined the role of ephedrine and phenylephrine in obstetric patients. The authors reported that phenylephrine use was associated with higher umbilical arterial (UA) pH values compared to ephedrine –9 and isThere is a paucity of evidence to guide clinical decisions regarding vasopressor use in non-elective cesarean deliveries or high-risk parturients. The majority of data that have shaped current practices of vasopressor use for spinal-induced hypotension have been done in healthy women undergoing elective cesarean deliveries. These results cannot necessarily be extrapolated to patients diagnosed with impaired uteroplacental blood flow or with pregnancy-induced hypertension. This review examines the available evidence regarding the efficacy and safety of phenylephrine and ephedrine administration in high-risk cesarean deliveries.In order to compare maternal and fetal effects of intravenous phenylephrine and ephedrine administration during spinal anesthesia for cesarean delivery in high-risk pregnancies, an extensive literature search was conducted through the United States National Library of Medicine using the MEDLINE search engine, Cochrane review, and Google Scholar. The search was limited to articles published in English prior to October 11, 2016. Search terms “ephedrine and phenylephrine,” “preterm and term and spinal hypotension,” “preeclampsia and healthy parturients,” or “multiple and singleton gestation and vasopressor” were used to identify relevant articles. Based on our review, 10 articles that investigated vasopressor use in high-risk human pregnancies were located, and 5 of these specifically compared the effects of phenylephrine and ephedrine in high-risk obstetric patients. Society of Obstetric Anesthesia and Perinatology meeting abstracts for the past 4 years were also searched for studies comparing phenylephrine and ephedrine in high-risk parturients.1-adrenergic agonists based on studies in healthy pregnant ewes and also pregnant ewes with uteroplacental insufficiency  ratio, the pulsatility index (PI), and the resistance index . AlahuhtBased on our review, there have not been any studies specifically examining the effects of phenylephrine or ephedrine on uteroplacental blood flow in patients with preeclampsia, uteroplacental insufficiency, or other high-risk conditions. Moreover, an association between prenatal stress and changes in Doppler waveform parameters remain inconclusive due to the methodological limitations of available studies . FurtherIn elective cesarean deliveries, phenylephrine has been associated with higher fetal pH compared with ephedrine –10, sugg2 in the phenylephrine group. It is important to note that patients with preexisting hypertension or pregnancy-induced hypertension were excluded from this investigation  or phenylephrine (100 mg) boluses to treat episodes of spinal-induced hypotension (systolic BP ≤100 mmHg) . The numAnother recent investigation by Jain et al. prospectively compared prophylactic ephedrine infusion (2.5 mg/min) to phenylephrine infusion (30 μg/min) to manage spinal-induced hypotension in 90 patients undergoing cesarean delivery due to signs of acute fetal compromise in the intrapartum period . The autHypertensive disorders in pregnancy are associated with maternal morbidity and mortality, accounting for 9.4% of pregnancy-related deaths in the United States during 2006–2010 . InadequThe incidence of spinal-induced hypotension and the need for vasopressor treatment has been noted to be reduced in patients with preeclampsia in comparison to both healthy term parturients  and pretFew studies have directly compared the use of ephedrine and phenylephrine for spinal-induced hypotension in preeclamptic patients. Cooper et al. reported that non-reassuring fetal HR tracing was the only variable associated with lower UA pH on multiple regression analysis, while the use of ephedrine, phenylephrine, or the presence of pregnancy-induced hypertension were not associated with alterations in UA pH . Ituk etBased on the limited data available, it appears that both ephedrine and phenylephrine are suitable options for managing spinal-induced hypotension in patients with hypertensive disorders of pregnancy. In women with preeclampsia, there are no apparent differences between phenylephrine and ephedrine with regard to UA or UV pH, and neonatal outcomes , 37, 38.In the studies reviewed, a variety of phenylephrine and ephedrine dosing regimens were used for either prevention of spinal-induced hypotension or to treat hypotension in high-risk obstetric patients, making it difficult to draw conclusions. Based on the limited available evidence, phenylephrine and ephedrine appear to be similarly effective in preventing and treating spinal-induced hypotension in parturients with potential uteroplacental insufficiency –32 or hyDuring spinal anesthesia, preeclampsia patients maintain a high vascular tone and typically display a limited decrease in mean arterial pressure. Preeclampsia-induced endothelial dysfunction leads to increases in endothelin and thromboxane production, decreased vasodilator synthesis, and sensitizes the vasculature to vasoconstrictors . PreviouP = 0.044), and the ephedrine requirement to restore blood pressure to baseline level was less than in the preterm group   .On the other hand, multiple gestations do not appear to be a risk factor for developing hypotension after regional anesthesia for cesarean deliveries, despite having a greater uterine mass . Ngan Ke1-adrenergic receptor agonist, phenylephrine-induced increases in blood pressure activate the baroreceptor reflex and cause bradycardia. However, these bradycardic events can be minimized or prevented by careful bolus dosing of phenylephrine, or minimizing the infusion rate. Furthermore, with these measures in place, no detrimental effects on maternal and neonatal outcome have been observed in normal (The maternal HR is significantly higher after ephedrine administration , 31, 32,n normal  or in hin normal , 31, 32.The management of hypotension during cesarean delivery under spinal anesthesia remains challenging. The administration of vasopressors is often necessary, despite other measures such as intravenous crystalloid infusions. Phenylephrine is currently the vasopressor of choice for preventing or treating spinal-induced hypotension in many practices, as many studies in elective cesarean deliveries have demonstrated phenylephrine to be associated with more favorable fetal acid–base status and greater effectiveness in preventing hypotension and IONV. However, phenylephrine use in the presence of preexisting fetal compromise continues to be controversial due to concern of potential uterine blood flow reduction.Based on limited available evidence, it appears that phenylephrine and ephedrine are similarly safe and effective, and both may be used to prevent or treat spinal-induced hypotension in the setting of potential uteroplacental insufficiency and preeclampsia. The current literature does not show any statistically significant differences in terms of maternal and neonatal outcomes between phenylephrine and ephedrine in these high-risk patients. Further randomized double-blind studies are required to further clarify the safety and efficacy and determine effective vasopressor dosing regimens in high-risk obstetric patients.SD and BH conducted a review of the literature. SD, MS, EB, BH, DS, and JC prepared the body of the manuscript. JC critically reviewed the publication. All the authors endorsed the final form of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Mexican immigrants in the United States suffer from poor oral health. The objective of the current study was to explore the utility of applying theory-based factors associated with seeking preventive dental care in a sample of Mexican American adults.Data were collected from a cross-sectional survey of a sample of 157 people of Mexican origin  recruited primarily from church congregations and lay community organizations in Central Indiana. Using the Integrative Model of Behavioral Prediction as the guiding framework, structural equation modeling was used to test factors associated with intention to seek preventive dental care.p < .0001) and self-efficacy for seeking preventive dental care  were associated with intention to seek preventive dental care. The association between dental beliefs and intention to seek preventive dental care was mediated by attitude and self-efficacy , and the association between past behavior and intention to seek preventive dental care was mediated by self-efficacy .Attitude towards seeking preventive dental care (estimate = 0.37; These findings suggest that interventions to increase preventive dental care seeking behavior among Mexican Americans should focus on changing attitudes toward seeking preventive dental care and on increasing self-efficacy to seek preventive dental care. Findings also support the use of interventions to influence dental beliefs. Multiple reasons contribute to the complex scenario of oral health disparities affecting people of Mexican origin in the United States (US)  for simplicity in this manuscript). With limited access to care, high-risk diet and lifestyle, and low ability to navigate health care systems in the list of likely reasons, oral health behaviors may be one major component in the MA oral health disparities scenario –6. AlthoGiven that the MA population makes up about two-thirds of Latinos in the US , and theHaving periodic preventive care delivered in the dental office is often cited as the hallmark of early identification of disease, timely implementation of secondary prevention measures, and appropriate management of risk to oral diseases . MoreoveWe recruited MA adults living in an urban environment through advertising at health fairs, churches and religious gatherings, the waiting room in the Mexican Consulate in Indianapolis, and community functions in 2014. Written informed consent from participants was obtained. Participants responded to the survey in English or Spanish, according to their preference, in sessions that lasted an average of 30–45 min. Participants received US $30 compensation.Of the 191 people approached who met the inclusion/exclusion criteria, (160) 84% agreed to participate. Those who did not agree to participate were usually pressed for time when attempted to be recruited. Inclusion criteria were 21 years of age or older, immigrant status with more than three years living in the US, and able to read and write either English or Spanish. Exclusion criteria were mental or physical conditions that impaired participation in the study. To assess the exclusion criteria, we asked potential participants if they were unable to read or hear sufficiently well to maintain a conversation, listen to instructions, or read a document.Intention to seek preventive dental care was a latent variable composed of two items . Attitude towards seeking preventive dental care was a latent variable composed of six items measured on five-point scales that assessed going to a dentist regularly for preventive care as good versus bad, harmful versus beneficial, unpleasant versus pleasant, foolish versus wise, unnecessary versus necessary, and a poor investment versus a good investment. Perceived norms regarding seeking preventive dental care was a latent variable composed of three indicators. The first two indicators were items measured on five-point scales from strongly disagree to strongly agree . The third indicator was computed by taking the mean of the available responses to four items measured on five-point scales .This procedure was followed because of missing data on these items, but each participant responded to at least one of these four items. Self-efficacy to seek preventive dental care was a latent variable composed of three items measured on five-point scales from strong disagree to strong agree . Dental beliefs was a latent variable composed of three items measured on five-point scales from strongly disagree to strongly agree . Finally, participants reported whether they had dental insurance and when they had last visited a dental office. For analyses, a binary variable was created for visited a dental office within the last year versus all other responses.Guided by the IM framework, structural equation modeling was used to test attitudes, perceived norms, and self-efficacy as predictors of intention to seek preventive dental care. In addition, demographics, having dental insurance, past behavior, and dental beliefs were tested as background variables that were hypothesized to influence intention to seek preventive dental care through attitudes, perceived norms, and self-efficacy. Analyses were conducted using SAS software, Version 9.4 for Windows .Of the 160 participants recruited, 3 were excluded from analyses due to missing data on one or more of the background variables included in the structural equation modeling analysis. This resulted in a final sample size of 157 .p = .001), and the association between past behavior and intention to seek preventive dental care was mediated by self-efficacy . Finally, we estimated another model that included the direct effects of sex, age, dental insurance, dental beliefs, and past behavior on intention. All of the statistically significant paths shown in Fig. Figure The first finding of note was that, of the three global IM constructs , attitude towards seeking preventive dental care and self-efficacy to seek preventive dental care were related to intention to seek preventive dental care in this sample of MAs. Perceived norms regarding seeking preventive dental care, however, was not associated with intention. These findings are consistent with earlier studies , 33 thatThe current study’s results have implications for the design of interventions to increase preventive dental care seeking behaviors among MAs. Specifically, interventions should focus on changing attitudes toward seeking preventive dental care and on enhancing self-efficacy to seek preventive dental care. While there is no unequivocal evidence supporting the effect of preventive visits on improved oral health outcomes, consistent and periodic preventive dental visits remain a centerpiece of professional recommendations . Indeed,The current study also examined the role of background variables on intention to seek preventive dental care. Based on the IM, we expected the background variables to influence intention through attitudes, perceived norms, or self-efficacy. Two of the background variables tested had statistically significant indirect effects on intention. First, the associations between dental beliefs and intention were mediated by attitude and self-efficacy. That is, our findings suggest that MAs’ dental beliefs are related to their attitude and to their self-efficacy about seeking preventive dental care. Therefore, messages that target dental beliefs of MAs could lead to meaningful changes in their intention to access preventive dental services through either an attitudinal pathway or by increasing self-efficacy. Second, the association between past behavior and intention was mediated by self-efficacy. Participants who had visited a dental office in the past year had higher self-efficacy, which in turn was related to intention to seek preventive dental care.This study has some limitations that should be considered. First, the sample size is relatively small. However, for an exploratory study, the sample size was adequate to identify statistically significant theory-based relationships among constructs. This represents an important first step in applying the IM framework to understanding oral health behaviors among MAs. Second, the sample is limited to MAs living in urban communities in Central Indiana who were recruited largely from Catholic parishes or other community-oriented groups. Thus, generalizing results beyond the current exploration of the IM framework to ascertain certain components of seeking preventive dental care is unwarranted. Third, our analyses are primarily based at the individual level and do not include important structural influences such as public policies and health care system factors. Fourth, the cross-sectional non-experimental design precludes solid suggestions about causality, and therefore possible bi-directional relationships must be acknowledged. For example, it is possible that higher (unmeasured) pre-visit self-efficacy influenced a completed visit to the dental office, post-visit self-efficacy, and intention to seek care in the future. Moreover, we acknowledge that because of the cross-sectional nature of the data, the background variables, theoretical mediators, and intention to seek preventive dental care were all measured at the same time. Future research with large, representative, longitudinal samples that include system-level as well as individual-level data is clearly warranted to overcome these limitations.This study is also characterized by multiple strengths. First, there are few studies in the new, evolving immigration entry point in the American Midwest; this has become a favored gateway for Hispanic immigrants, as opposed to other locations in which the Hispanic population has traditionally taken residence. As a consequence, the Midwest has recently experienced much faster growth than other Hispanic areas in the US , 37. SecThese findings suggest that interventions to increase preventive dental care seeking behavior among MAs should focus on changing attitudes toward seeking preventive dental care and increasing self-efficacy to seek preventive dental care. Findings also support the use of interventions to influence dental beliefs.


Technological advances in mass spectrometry instrumentation and proteomics methodologies are moving the field of clinical proteomics towards the analysis of large numbers of patient samples in a reasonable time. The Special Issue ‘Clinical proteomics’ reviews the current proteomic work flow from biological sample preparation to clinical exploitation with samples collected from human body fluids, tissues or isolated cells, and highlights the trend towards integrated omics approaches for clinical usage.Hernandez-Valladaras and colleagues  provide Sample processing and bioanalytical workflows dedicated to phosphoproteome analysis of traditional human biological fluids such as serum/plasma, urine, cerebrospinal fluid (CSF), saliva and broncoalveolar lavage fluid are discussed by Giorginanni and Beranova-Giorgianni , togetheSample handling procedures of non-traditional human samples such as ear wax, saliva, vitreous humor, aqueous humor, tears, nipple aspirate fluid, breast milk / colostrum, cervical-vaginal fluid, nasal secretions, bronco-alveolar lavage fluid, and stools for the utilization in quantitative proteomic studies for diagnostic and disease treatment purposes are reviewed by Licier et al. . The artTrenchevska et al.  discuss Apolipoproteins have also been shown to exist in vivo in several proteoisoforms, which are involved in lipid metabolism, and are associated with cardiovascular diseases, type 2 diabetes and Alzheimer Disease (AD). Martins  argues t2 concentrations are also associated with the multiprotein complexes besides oxygen. The combination of proteome and metabolome data alludes to a mechanism with central roles for molecular interactions at the red cell surface regulating cell shape, deformability, cell survival, and metabolism with oxygen and CO2 transport. Support for this proposed mechanism comes from observations that glycolysis and the pentose phosphate pathway are regulated by oxygen-driven interactions of key enzymes with the membrane, and that binding between cytoskeleton and membrane is controlled by oxygen-mediated interaction between band 3 and ankyrin. Recent studies further establish relations between metabolic changes and erythrocyte pathologies, which are likely caused by changes in membrane-associated protein complexes.The notion that detailed insights in cellular homeostasis and disease progression are generated from studies applying clinical proteomics with complementary omics technologies inspired Bosman for outlining the current perspective of red blood cell (RBC) homeostasis by integrating proteome with metabolome data . ComparaThe holistic view of the utilization of complementary mass spectrometry-based technologies in personalized proteomics for clinical diagnosis and treatment is seen by Duarte and Spencer  as the f


Rickettsia, Francisella, and Coxiella genera: while in medical and veterinary research these bacteria are traditionally recognized as highly virulent vertebrate pathogens, it is now clear to evolutionary ecologists that many (if not most) Coxiella, Francisella, and Rickettsia bacteria are actually non-pathogenic microorganisms exhibiting alternative lifestyles as mutualistic ticks symbionts. Consequently, ticks represent a compelling yet challenging system in which to study microbiomes and microbial interactions, and to investigate the composition, functional, and ecological implications of bacterial communities. Ultimately, deciphering the relationships between tick microorganisms as well as tick symbiont interactions will garner invaluable information, which may aid in the future development of arthropod pest and vector-borne pathogen transmission control strategies.Ticks are among the most important vectors of pathogens affecting humans and other animals worldwide. They do not only carry pathogens however, as a diverse group of commensal and symbiotic microorganisms are also present in ticks. Unlike pathogens, their biology and their effect on ticks remain largely unexplored, and are in fact often neglected. Nonetheless, they can confer multiple detrimental, neutral, or beneficial effects to their tick hosts, and can play various roles in fitness, nutritional adaptation, development, reproduction, defense against environmental stress, and immunity. Non-pathogenic microorganisms may also play a role in driving transmission of tick-borne pathogens (TBP), with many potential implications for both human and animal health. In addition, the genetic proximity of some pathogens to mutualistic symbionts hosted by ticks is evident when studying phylogenies of several bacterial genera. The best examples are found within members of the  Coxiella-like endosymbiont and the Francisella-like endosymbiont (Coxiella-LE and Francisella-LE hereafter), are actually non-pathogenic microorganisms hosted by ticks . The list of known or potential TBP is constantly evolving, and includes a variety of viruses, bacteria, and parasites afflicting humans and many other animals worldwide  mutualistic symbionts required to support normal host development, thus assisting their host in various essential functions. This includes nutritional diet upgrades by providing biosynthetic pathways absent from their hosts  symbionts not required for host survival. Some are defensive symbionts conferring protection against natural enemies or heat  have the capacity to frequently undergo evolutionary shifts between pathogenic and non-pathogenic forms, a process that may lead to the emergence of novel infectious diseases.In this article we review four major biological aspects where our views on tick microbes have undergone substantial change over the last decade. Firstly, we must emphasize that non-pathogenic microorganisms have much more complex effects on ticks than previously thought. Indeed, it is now evident that several maternally-inherited symbionts are required for tick survival and reproduction, while other symbionts can have multiple effects on tick life history traits. Secondly, whilst tick TBP transmission modes have been studied for decades, we now understand that certain non-pathogenic microorganisms may also interfere with TBP transmission. Thirdly, although microorganisms are often categorized as “TBP,” “commensals,” or “maternally-inherited symbionts,” both intermediate and transitional states frequently occur. In this context, it thus appears vital to not overlook the full range of potential effects, as have been recently described in microbiome studies. And finally, bacterial phylogeny demonstrates that several infectious agents have close genetic proximity with mutualistic tick symbionts. This indicates that some bacterial genera  and the distal part of Malpighian tubules, suggesting a possible role in nutrition, osmoregulation, or excretion , folic acid (B9), riboflavin (B2), and their cofactors, that are not usually obtainable in sufficient quantities from a uniquely blood-based diet  are also able to synthetize all major vitamins, suggesting that they may also confer a beneficial role in ticks when present  and in African blue tick Rhipicephalus decoloratus populations   showed increased engorgement weights, and decreased colonization by the causative agent of Lyme disease, Borrelia burgdorferi, when compared to normal specimens , and protect insects from parasite-induced mortality, possibly by up-regulating the insect's immune system  ticks are found worldwide and feed on many different vertebrate species, (ii) at least two thirds of tick species are infected by Coxiella-LE, and (iii) when present in a given tick species, Coxiella-LE are usually present in almost all specimens   and endosymbiotic forms . However, the evolutionary shifting pattern varies among genera Figure . In CoxiE Figure . This phRickettsia spp., recent evidence revealed that human pathogens—vectored by blood feeding arthropods such as ticks—emerged relatively late in the evolution of this genus  clearly indicate that switching between hosts  has been a common feature of Rickettsia evolution , along with two contrasting transmission modes , and variable host specificity (ticks vs. vertebrates), make the Coxiella-LE are important drivers of evolutionary change in ticks, as clearly shown by their role in driving their tick hosts to adapt to a strict hematophagous diet . In this context, comparative genomic approaches will be highly valuable in enhancing our understanding of the evolutionary ecology of both pathogenic and non-pathogenic intracellular bacteria, and in identifying novel candidate genes contributing to virulence and persistence in vertebrate cells.Extensive literature studies have now made it clear that TBP are not alone: an appreciable range of diverse non-pathogenic microorganisms has also been detected in almost all tick species examined so far. Perhaps the most important consideration for the future is not the incidence of these non-pathogenic microorganisms, but their phenotypes. The varied collection of non-pathogenic microorganisms includes intracellular maternally-inherited symbionts and microbes inhabiting the tick gut, and each could strongly influence—in very different ways—the biology of their tick hosts as well as TBP infection dynamics. Recent findings have shown that several maternally-inherited symbionts such as SB, AH, FB, and OD conducted the literature research, wrote the paper and prepared the figures and tables. All authors provided critical review and revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Intracerebral hemorrhage (ICH) accounts for 10%–30% of all types of stroke. Bleeding within the brain parenchyma causes gray matter (GM) destruction as well as proximal or distal white matter (WM) injury (WMI) due to complex pathophysiological mechanisms. Because WM has a distinct cellular architecture, blood supply pattern and corresponding function, and its response to stroke may vary from that of GM, a better understanding of the characteristics of WMI following ICH is essential and may shed new light on treatment options. Current evidence using histological, radiological and chemical biomarkers clearly confirms the spatio-temporal distribution of WMI post- ICH. Although certain types of pathological damage such as inflammatory, oxidative and neuro-excitotoxic injury to WM have been identified, the exact molecular mechanisms remain unclear. In this review article, we briefly describe the constitution and physiological function of brain WM, summarize evidence regarding WMI, and focus on the underlying pathophysiological mechanisms and therapeutic strategies. Intracerebral hemorrhage (ICH) accounts for approximately 10%–15% of all strokes in Western countries and 20%–30% of strokes in Asia and has a high mortality and poor functional outcome. Less than 30% of patients are independent 1 year after the stroke onset  and radial diffusivity (λ⊥), DTI can assess the integrity and connectivity of WM tracts, reconstruct the three-dimensional distribution of WM pathways in the brain, and help determine the WM microstructural pathophysiology. For instance, a decreased FA, a decreased λ//, and an increased λ⊥ reflect general WMI, axonal damage and myelin injury, respectively  has evolved considerably over the previous decade and can currently detect the magnitude and directionality of water molecules in WM with a higher sensitivity during WMI monitoring than conventional MRI. By calculating certain technical parameters such as the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity  sequence is sensitive to altered tissue water content and can be used to detect Wallerian degeneration (WD) after ICH. CST-WD changes have been observed 1 week following ICH as reduced diffusion on DWI that progresses rostrocaudally along the CST  grade who continue to suffer from neuropsychological deficits, because advanced MRI techniques may also provide more diagnostic information regarding cognitive function than conventional CT and MRI.WMI causes disintegration of axons and myelin, facilitating the outflow of intracellular contents into the extracellular space, their diffusion into the cerebrospinal fluid (CSF), and even their entry into the blood stream through a disrupted blood-brain barrier (BBB). Neurofilaments are the major components of WM, constituting the axonal cytoskeleton. Neurofilaments are mainly composed of heavy (NF-H) and light (NF-L) chains . MBP-like materials or fragments can be detected in the CSF in MS patients, and increase rapidly during acute exacerbation and subside over the following 4–6 weeks. Similarly, increases in the CSF and serum levels of MBP have been reported following TBI of various severities, and serum concentrations of MBP can predict the eventual GOS score  is rapidly activated, the pro-inflammatory cytokine genes are upregulated in the perihematomal WM  is considered to play a key role during this process. MMP-9 is produced by leukocytes, astrocytes and oligodendrocytes, and the MMP-9 promoter region contains activator protein-1 and NF-κB, both of which respond to inflammatory stimuli and specifically attack the basal lamina through the fibronectin binding domain  pathway. JNK is a member of the mitogen-activated protein kinase (MAPK) superfamily, which has already been widely investigated due to its active actions in response to various stimuli, such as the exposure to inflammatory cytokines , Nogo-A, and oligodendrocyte myelin glycoprotein (OMGP), can lead to growth cone collapse and inhibit axon regeneration  supports oligodendrogenesis and regeneration after WM damage  is an important posttranscriptional regulator of gene expression that has been implicated in the pathogenesis of many human diseases and has been suggested as a possible diagnostic and prognostic biomarker. Experimental studies showed a distinct miRNA profile after ICH, which was involved in inflammatory injury and apoptosis  allows for the noninvasive measurement of Although MRS-based techniques can detect changes in most cerebral metabolites, their spatio-temporal resolution is often insufficient for routine examinations of fast-evolving and heterogeneous acute stroke lesions  is a well-established laboratory tool that provides an on-line analysis of the brain biochemistry via a thin fenestrated dialysis catheter that is inserted into the brain parenchyma. In addition to the monitoring of energy metabolism, CMD can dynamically observe excitotoxicity, inflammation and oxidative stress by measuring the levels of glutamate, metalloproteinases, cytokines and 8-iso-PGFin vivo studies of WMI in patients are desperately needed.The importance of WMI in ICH is increasingly being recognized, and abundant evidence has confirmed the intimate relationship between WMI and poor functional outcomes. Although certain pathological factors, including inflammatory injury, oxidative stress and neuro-excitotoxicity, are responsible for ICH-induced WMI, the definite underlying mechanisms need to be further elucidated. However, both inflammatory and oxidative signaling pathways are involved in WMI partially due to the iron overload after ICH. Therefore, treatments targeting iron may be quite promising. From this perspective, the results of the ICH Deferoxamine (iDEF) trial, which will be revealed next year, are highly anticipated. Regarding WM restoration, regulating factors promoting/inhibiting axonal regeneration and remyelination should be defined under the background of ICH. Oligodendrocyte proliferation and differentiation play a central role in remyelination which is involved in the complex crosstalk among oligodendrocytes, astrocytes, microglia and cerebral endothelial cells. An understanding of the cell-cell interaction mechanisms will likely promote oligodendrogenesis. Regarding WMI diagnosis, novel biochemical and neuroimaging markers are expected to detect to assist in the early detection of WMI and the dynamic monitoring of WMI. Finally, for better clinical translation, future experimental treatment strategy designs should provide protection to both GM and WM by targeting multiple pathological factors in poly-gyrated animals rather than using only rodents, and more CY and CT conceived and designed the manuscript. All authors contributed to the writing of the manuscript. XH and HL edited the manuscript and all authors reviewed the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Tyrosine kinase inhibitors (TKIs) are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP) models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs. Tyrosine kinase inhibitors (TKIs) constitute a class of cancer therapeutics, many of which are known to cause cardiotoxicity as a major adverse event. Reported cardiotoxicities include heart failure, cardiomyopathy, conduction abnormalities, QT prolongation, and myocardial injury. The most common toxicity is systolic dysfunction or cardiomyopathy, potentially leading to heart failure, which is most likely mediated through direct toxicity of cardiomyocytes  signaling, via either gain-of-function (GOF) mutations or overexpression due to gene amplification, is found in about 70% of malignancies  humanized monoclonal antibodies (mAbs) and (2) small molecule inhibitors  direct or indirect modulation of cardiac ionic currents, resulting in pro-arrhythmic electrical activity , encoded by the gene traditionally known as hERG (subsequently renamed KCNH2), include crizotinib, sunitinib, and nilotinib. These drugs have been shown to block the channel in vitro and to prolong action potentials in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs)  evaluate the potential cardiotoxicity of new TKIs; (2) predict the mostly likely mechanisms involved; and (3) suggest strategies for mitigating and/or reversing toxicity. Systems approaches that perform large-scale measurements and quantitatively compare responses to multiple drugs are likely to be extremely useful for understanding the common and distinct features of cardiotoxicity caused by diverse TKIs.A common approach in systems-level pharmacology studies is to utilize a cell based, high-throughput drug screening assay. Although cardiovascular pharmacology has traditionally not been well-suited for high throughput studies, the development of hiPSC-CMs has expanded the possibilities. For instance, a recent study described the development of a comprehensive assay that evaluated cellular effects of TKIs in hiPSC-CMs  might either exacerbate or protect against cardiotoxicity. Although it is of course possible to expand the assay to treat cells with drug pairs and/or add relevant physiological stimuli, it is not clear in vitro data sets, as these studies may provide an important blueprint for future research on cardiotoxicity caused by kinase inhibitors.One way to address the aforementioned limitations is to use mathematical models that mechanistically describe biological dynamics. When the processes simulated by these models overlap with toxicity mechanisms, the simulations can be used to generate testable predictions, to guide experimental studies, and ultimately to make decisions about new drugs based on a quantitative understanding of benefits and risks. In this context, models that describe biological mechanisms through differential equations are frequently referred to as QSP models  initiative is highly relevant. This effort, part of the FDA's Critical Path Initiative, aims to improve the accuracy and cost effectiveness of screening for TdP risk. Whereas current in vitro methods for predicting TdP risk focus almost exclusively on block of Kv11.1 , an approach that is often inadequate, CiPA intends to both assess how drugs block multiple ion channels and to combine these measurements with recordings in hiPSC-CMs and mechanistic simulations , and the study suggested an experimental protocol for measuring drug block kinetics , the Comprehensive v11.1 but are nonetheless safe  Center at Mount Sinai has initiated a large-scale project to advance cellular assays and computational approaches that can improve our understanding of TKI-induced cardiotoxicity. One aspect of this project involves employing QSP models that describe biological processes potentially involved in this cardiotoxicity. We outline here an approach by which whole transcriptome expression assays can be integrated with mechanistic models to classify drugs and generate novel, experimentally-testable predictions.https://martip03.u.hpc.mssm.edu/sop.php) that captures early effects of drugs, as reflected in gene expression changes. The experiments treat cultured cardiomyocyte-derived cells with potentially cardiotoxic TKIs as well as drugs from different classes that are presumably safe. After 48 h, mRNA is harvested, and sequencing is performed to quantify drug-induced changes in gene expression (compared with vehicle-treated controls). Data are released at the DToxS website and can be freely-downloaded . The pipeline for integrating these released data with mechanistic mathematical models is shown in Figure For this part of the analysis, the project has designed a standard experimental protocol (DtoxS—Drug Toxicity Signature Generation Center—SOP, For example, results shown here are obtained with a QSP model that describes signaling events relevant to cardiac hypertrophy through a system of 106 ordinary differential equations, each one describing activity of a signaling component (Ryall et al., hypertrophy index, a summary statistic, condenses results by summing drug-induced changes across seven biomarkers in response to different stimuli applied in the model. The hypertrophy index confirms the impression from the simulated time courses, namely a pro-hypertrophic response to nilotinib contrasted with a slight anti-hypertrophic response to dasatinib (Figure These example simulation results, summarized in Figure b Figure .By simulating responses to stimuli, using gene expression changes induced by all drugs, patterns begin to emerge. Specifically, in myocytes that are not exposed to a physiological stimulus, TKIs and non-TKIs cause similar changes in hypertrophy biomarkers Figure . HoweverThese preliminary simulation results indicate the potential strengths of combining large scale measurements with mechanism-based mathematical models. First the simulations do not simply describe existing data—they can predict how drug-treated cells will respond to an additional stimulus that has not yet been applied experimentally. These predictions can be subsequently tested. Second, the simulation approach does not merely generate qualitative predictions; because the quantitative models predict that some drugs and/or stimuli may cause large effects whereas others cause only minor effects, this provides a means to prioritize experimental tests and use resources efficiently. Third, when clear differences are observed, for instance between individual drugs or between drug classes, the simulations predict the mechanisms responsible for the differences.Although the preliminary simulation results shown here are encouraging, they also hint at the future research that must be performed to fully realize the potential of this approach. First, although the simulations predict how drug-induced changes in gene expression may influence both baseline signaling and cellular responses to stimuli, they do not describe direct inhibition of kinase activity by drugs, which is of course the more traditional and straightforward method for simulating drug effects. We excluded these effects from initial simulations because many TKI targets are not included in the model, but future work will expand the model by systematically adding drug targets based on published protein-protein interaction databases (Warde-Farley et al., A second important extension of the work will be to simulate additional biological processes potentially involved in cardiotoxicity. For instance, cell death via apoptosis, which may be important in the development of toxicity caused by some TKIs, has been described mathematically by many previous models (Schleich and Lavrik, Here, we have discussed contemporary challenges in understanding TKI-induced cardiotoxicity and have illustrated how a QSP approach can be used to address unresolved questions and improve understanding. Previous successes of QSP in illuminating and predicting other forms of drug toxicity, including hepatotoxicity and drug-induced arrhythmia, demonstrate its potential utility for other drug toxicities. The initial results presented here show how mechanistic models can be integrated with “omics” measurements such as mRNA-seq, generating simulations that can suggest underlying mechanisms and help in prioritizing costly experiments. In the coming years, future work along these lines can be used to develop strategies to mitigate or reverse TKI-induced cardiotoxicity, thereby contributing to the development of therapeutic regimens that are both effective and safe.JVS and BC performed an extensive literature review and analysis of published clinical and experimental data. JVS performed simulations and analysis. JVS and ES wrote the initial draft of the manuscript. BC, JvH, MB, and JJS provided critical feedback and editorial suggestions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.