Peers' Emotionality and Children's Academic Achievement in Second Grade: Testing the Moderating Role of Children's Behavioral Self-Regulation.

Although there is interest in the role of peers in children's schooling experiences, few researchers have examined associations and related underlying processes between peers' emotionality, an aspect of temperament, and children's academic achievement. This study evaluated whether target children's (N = 260) own self-regulation, assessed with two behavioral measures, served a moderating function for associations between peers' emotionality and children's own academic achievement in second grade. There was a positive association between peers' positive emotionality and reading scores for children with higher self-regulation. Peers' negative emotionality was negatively related to target children's reading scores, particularly for children with higher self-regulation levels, but was unrelated to math scores. Peers' positive and negative emotionality did not predict math scores, and there was no strong evidence for the moderating role of target children's self-regulation in this association. This study highlights the potential role of children's self-regulation in modulating peer effects on academic achievement, particularly reading.

An Introduction to Artificial Intelligence in Developmental and Behavioral Pediatrics.

ABSTRACT: Technological breakthroughs, together with the rapid growth of medical information and improved data connectivity, are creating dramatic shifts in the health care landscape, including the field of developmental and behavioral pediatrics. While medical information took an estimated 50 years to double in 1950, by 2020, it was projected to double every 73 days. Artificial intelligence (AI)-powered health technologies, once considered theoretical or research-exclusive concepts, are increasingly being granted regulatory approval and integrated into clinical care. In the United States, the Food and Drug Administration has cleared or approved over 160 health-related AI-based devices to date. These trends are only likely to accelerate as economic investment in AI health care outstrips investment in other sectors. The exponential increase in peer-reviewed AI-focused health care publications year over year highlights the speed of growth in this sector. As health care moves toward an era of intelligent technology powered by rich medical information, pediatricians will increasingly be asked to engage with tools and systems underpinned by AI. However, medical students and practicing clinicians receive insufficient training and lack preparedness for transitioning into a more AI-informed future. This article provides a brief primer on AI in health care. Underlying AI principles and key performance metrics are described, and the clinical potential of AI-driven technology together with potential pitfalls is explored within the developmental and behavioral pediatric health context.

White children's empathy-related responding and prosocial behavior toward White and Black children.

Relations among White (non-Latinx) children's empathy-related responding, prosocial behaviors, and racial attitudes toward White and Black peers were examined. In 2017, 190 (54% boys) White 5- to 9-year-old children (M = 7.09 years, SD = 0.94) watched a series of videos that depicted social rejection of either a White or Black child. Empathy-related responses, prosocial behaviors, and racial attitudes were measured using multiple methods. Results showed that younger children showed less facial concern toward Black than White peers and greater increases with age in concern and prosocial behaviors (sharing a desirable prize) for Black, compared to White, targets. Children's facial anger increased with age for White but not Black targets. The findings can extend our understanding children's anti-racism development.

Parents' color-blind racial ideology and implicit racial attitudes predict children's race-based sympathy.

We examined the relation of White parents' color-blind racial attitudes (a global composite score and its subscales) and their implicit racial attitudes to their young children's race-based sympathy toward Black and White victims. One hundred and nighty non-Hispanic White children (54% boys, Mage = 7.13 years, SD = 0.92) reported their sympathy in response to short films depicting bullying toward White or Black children. Their primary caregivers' (mostly mothers') color-blind racial ideology (CBRI) was assessed through a questionnaire (reflecting global color blindness, as well as denial of institutional racism, White privilege, and blatant racial issues), and their implicit racial attitudes were assessed with a computerized test. Children's sympathy toward Black victims and their equitable sympathy (difference score toward Black vs. White victims) was predicted by parents' color blindness, implicit racial attitudes, and their interaction. Results indicated several interaction effects, such that parents' denial of blatant racial attitudes and global CBRI were negatively related to children's sympathy toward Black victims and equitable sympathy toward Black versus White victims, only when the parents held implicit racial attitudes that favored White people. In addition, parents' denial of White privilege was negatively related to children's sympathy toward Black victims. The findings are discussed in terms of potential ways to shape children's race-based sympathy and compassion, particularly with an eye toward ways White parents might socialize sympathy toward historically marginalized youth. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Self-Assembling Injectable Hydrogel for Controlled Drug Delivery of Antimuscular Atrophy Drug Tilorone.

A two-component injectable hydrogel was suitably prepared for the encapsulation and prolonged release of tilorone which is an antimuscular atrophy drug. The rapid (7-45 s, depending on the polymer concentration) in situ solidifications of the hydrogel were evoked by the evolving Schiff-base bonds between the aldehyde groups of modified PVA (4-formyl benzoate PVA, PVA-CHO, 5.9 mol% functionalization degree) and the amino groups of 3-mercaptopropionate chitosan (CHIT-SH). The successful modification of the initial polymers was confirmed by both FTIR and NMR measurements; moreover, a new peak appeared in the FTIR spectrum of the 10% w/v PVA-CHO/CHIT-SH hydrogel at 1647 cm-1, indicating the formation of a Schiff base (-CH=N-) and confirming the interaction between the NH2 groups of CHIT-SH and the CHO groups of PVA-CHO for the formation of the dynamic hydrogel. The reaction between the NH2 and CHO groups of the modified biopolymers resulted in a significant increase in the hydrogel's viscosity which was more than one thousand times greater (9800 mPa·s) than that of the used polymer solutions, which have a viscosity of only 4.6 and 5.8 mPa·s, respectively. Furthermore, the initial chitosan was modified with mercaptopropionic acid (thiol content = 201.85 ± 12 µmol/g) to increase the mucoadhesive properties of the hydrogel. The thiolated chitosan showed a significant increase (~600 mN/mm) in adhesion to the pig intestinal membrane compared to the initial one (~300 mN/mm). The in vitro release of tilorone from the hydrogel was controlled with the crosslinking density/concentration of the hydrogel; the 10% w/v PVA-CHO/CHIT-SH hydrogel had the slowest releasing (21.7 h-1/2) rate, while the 2% w/v PVA-CHO/CHIT-SH hydrogel had the fastest releasing rate (34.6 h-1/2). Due to the characteristics of these hydrogels, their future uses include tissue regeneration scaffolds, wound dressings for skin injuries, and injectable or in situ forming drug delivery systems. Eventually, we hope that the developed hydrogel will be useful in the local treatment of muscle atrophy, such as laryngotracheal atrophy.

Longitudinal relations between behavioral engagement and academic achievement: The moderating roles of socio-economic status and early achievement.

This study investigated developmental trajectories of observationally coded engagement across the early elementary years and whether these trajectories were associated with children's academic achievement. Furthermore, we evaluated if these relations varied as a function of children's family socio-economic status and early reading and math skills. Data were collected from 301 children who were studied from kindergarten (Mage = 65.74 months; 49% boys) to 2nd grade. Children's behavioral engagement was observed in kindergarten, 1st, and 2nd grade. Reading and math skills were assessed via standardized tests in kindergarten and 2nd grade. Growth mixture models identified two classes of behavioral engagement: most children (87.0%) displayed relatively high behavioral engagement in the fall of kindergarten and decreased significantly across time (referred to below as high-decreasing class), and other children (13.0%) exhibited moderate behavioral engagement in the fall of kindergarten that was stable across time (referred to below as moderate-stable class). After controlling for academic skills in kindergarten and demographic variables (i.e., child age, sex, ethnicity, and family socio-economic status), children in the high-decreasing class displayed higher reading skills, but not math skills, than children in the moderate-stable class. Additional analyses revealed that differences in reading skills between the two classes were present only for children from low socio-economic status families or for children low in kindergarten reading skills. The findings suggest that economically or academically at-risk students might benefit more than their peers from high behavioral engagement.

Functionalized Mesoporous Silica Nanoparticles for Drug-Delivery to Multidrug-Resistant Cancer Cells.

Background: Multidrug resistance is a common reason behind the failure of chemotherapy. Even if the therapy is effective, serious adverse effects might develop due to the low specificity and selectivity of antineoplastic agents. Mesoporous silica nanoparticles (MSNs) are promising materials for tumor-targeting and drug-delivery due to their small size, relatively inert nature, and extremely large specific surfaces that can be functionalized by therapeutic and targeting entities. We aimed to create a fluorescently labeled MSN-based drug-delivery system and investigate their internalization and drug-releasing capability in drug-sensitive MCF-7 and P-glycoprotein-overexpressing multidrug-resistant MCF-7 KCR cancer cells. Methods and Results: To track the uptake and subcellular distribution of MSNs, particles with covalently coupled red fluorescent Rhodamine B (RhoB) were produced (RhoB@MSNs). Both MCF-7 and MCF-7 KCR cells accumulated a significant amount of RhoB@MSNs. The intracellular RhoB@MSN concentrations did not differ between sensitive and multidrug-resistant cells and were kept at the same level even after cessation of RhoB@MSN exposure. Although most RhoB@MSNs resided in the cytoplasm, significantly more RhoB@MSNs co-localized with lysosomes in multidrug-resistant cells compared to sensitive counterparts. To examine the drug-delivery capability of these particles, RhoB@Rho123@MSNs were established, where RhoB-functionalized nanoparticles carried green fluorescent Rhodamine 123 (Rho123) - a P-glycoprotein substrate - as cargo within mesopores. Significantly higher Rho123 fluorescence intensity was detected in RhoB@Rho123@MSN-treated multidrug-resistant cells than in free Rho123-exposed counterparts. The exceptional drug-delivery potential of MSNs was further verified using Mitomycin C (MMC)-loaded RhoB@MSNs (RhoB@MMC@MSNs). Exposures to RhoB@MMC@MSNs significantly decreased the viability not only of drug-sensitive but of multidrug-resistant cells and the elimination of MDR cells was significantly more robust than upon free MMC treatments. Conclusion: The efficient delivery of Rho123 and MMC to multidrug-resistant cells via MSNs, the amplified and presumably prolonged intracellular drug concentration, and the consequently enhanced cytotoxic effects envision the enormous potential of MSNs to defeat multidrug-resistant cancer.

Use of Self-Assembled Colloidal Prodrug Nanoparticles for Controlled Drug Delivery of Anticancer, Antifibrotic and Antibacterial Mitomycin.

Herein we present the synthesis of a polymeric prodrug nanomaterial capable of spontaneous, self-assembled nanoparticle formation and of the conjugation (encapsulation) of drugs with amino and/or carboxyl and/or hydroxyl groups via ester and/or amide linkage. Mitomycin C (MMC) a versatile drug with antibiotic, antibacterial and antineoplastic properties, was used to prove this concept. The in vitro drug release experiments showed a fast release for the pure MMC (k = 49.59 h-n); however, a significantly lower MMC dissolution rate (k = 2.25, 1.46, and 1.35 h-n) was obtained for the nanoparticles with increased cross-link density (3, 10, 21%). The successful modification and conjugation reactions were confirmed using FTIR and EDX measurements, while the mucoadhesive properties of the self-assembled particles synthesized in a simple one-pot reaction were proved by rheological measurement. The prepared biocompatible polymeric prodrugs are very promising and applicable as a drug delivery system (DDS) and useful in the area of cancer treatment.

Evaluation of an artificial intelligence-based medical device for diagnosis of autism spectrum disorder.

Autism spectrum disorder (ASD) can be reliably diagnosed at 18 months, yet significant diagnostic delays persist in the United States. This double-blinded, multi-site, prospective, active comparator cohort study tested the accuracy of an artificial intelligence-based Software as a Medical Device designed to aid primary care healthcare providers (HCPs) in diagnosing ASD. The Device combines behavioral features from three distinct inputs (a caregiver questionnaire, analysis of two short home videos, and an HCP questionnaire) in a gradient boosted decision tree machine learning algorithm to produce either an ASD positive, ASD negative, or indeterminate output. This study compared Device outputs to diagnostic agreement by two or more independent specialists in a cohort of 18-72-month-olds with developmental delay concerns (425 study completers, 36% female, 29% ASD prevalence). Device output PPV for all study completers was 80.8% (95% confidence intervals (CI), 70.3%-88.8%) and NPV was 98.3% (90.6%-100%). For the 31.8% of participants who received a determinate output (ASD positive or negative) Device sensitivity was 98.4% (91.6%-100%) and specificity was 78.9% (67.6%-87.7%). The Device's indeterminate output acts as a risk control measure when inputs are insufficiently granular to make a determinate recommendation with confidence. If this risk control measure were removed, the sensitivity for all study completers would fall to 51.6% (63/122) (95% CI 42.4%, 60.8%), and specificity would fall to 18.5% (56/303) (95% CI 14.3%, 23.3%). Among participants for whom the Device abstained from providing a result, specialists identified that 91% had one or more complex neurodevelopmental disorders. No significant differences in Device performance were found across participants' sex, race/ethnicity, income, or education level. For nearly a third of this primary care sample, the Device enabled timely diagnostic evaluation with a high degree of accuracy. The Device shows promise to significantly increase the number of children able to be diagnosed with ASD in a primary care setting, potentially facilitating earlier intervention and more efficient use of specialist resources.

Effortful Control and Extensive Observations of Negative Emotion as Joint Predictors of Teacher-Student Conflict in Childhood.

Studies with extensive observations of real-life emotions at school are rare but might be especially useful for predicting school-related outcomes. This study evaluated observations of negative emotion expressivity in lunch and recreation settings across kindergarten, first grade, and second grade (N = 301), kindergarten teachers' reports of children's effortful control, and kindergarten and second grade teachers' reports of their perceived conflict with children. In latent growth curve analyses, we tested whether individual trajectories of negative expressivity from kindergarten to second grade, based on estimated slopes, predicted teacher-student conflict in second grade, and whether effortful control in kindergarten moderated this association. RESEARCH FINDINGS: Negative expressivity levels in kindergarten significantly predicted higher levels of teacher-student conflict in second grade, controlling prior teacher-student conflict. Furthermore, greater increases in negative expressivity from kindergarten to second grade were associated with higher teacher-student conflict in second grade especially for children who had difficulties with effortful control in kindergarten. PRACTICE OR POLICY: Results from this study have the potential to inform programs focused on reducing teacher-student conflict. The findings highlight the possibility of targeting both effortful control and negative emotion in the early elementary school transition as a means to improve teacher-student relationships.

Racial, Ethnic, and Sociodemographic Disparities in Diagnosis of Children with Autism Spectrum Disorder.

ABSTRACT: This special article uses a biosocial-ecological framework to discuss findings in the literature on racial, ethnic, and sociodemographic diagnostic disparities in autism spectrum disorder. We draw explanations from this framework on the complex and cumulative influences of social injustices across interpersonal and systemic levels.

The relations of White parents' implicit racial attitudes to their children's differential empathic concern toward White and Black victims.

The goal of this study was to investigate the relations between White parents' implicit racial attitudes and their children's racially based bias in empathic concern toward White and Black victims of injustice as well as the moderating role of children's age in this relation. Children aged 5-9 years (N = 190) reported how sorry (i.e., sympathy) and nervous (i.e., personal distress) they felt after watching sympathy-inducing videos in which either a White (non-Hispanic) child or a Black child was teased by peers. Participants' primary caregivers (mostly mothers) completed a computerized Implicit Association Test to assess their implicit racial attitudes. Parents' implicit race bias was associated with their children's reported sympathy toward Black victims and their sympathetic bias (i.e., relative sympathy toward White vs. Black victims); however, results were moderated by children's age. Specifically, parents with higher implicit race bias tended to have children with lower levels of sympathy toward Black victims for younger children and higher levels of sympathetic bias for younger and average-aged children but not for older children. Older children tended to report relatively high levels of sympathy toward Black victims and low levels of sympathetic bias regardless of their parents' implicit attitudes. The importance of parents' implicit attitudes in understanding young children's race-based moral emotional responses and the implications for intervention work are discussed.

Children's mu suppression is sensitive to witnessing others' social victimization.

Empathy has been a key focus of social, developmental, and affective neuroscience for some time. However, research using neural measures to study empathy in response to social victimization is sparse, particularly for young children. In the present study, 58 children's (White, non-Hispanic; five to nine years old) mu suppression was measured using electroencephalogram methods (EEG) as they viewed video scenarios depicting social injustices toward White and Black children. We found evidence of increased mu suppression in response to social victimization; however, contrary to well-documented findings of ingroup racial bias in empathic responses among adults, we found no evidence of racial bias in mu suppression in young children. Implications of these findings for neuroscience research on empathy and the development of ingroup bias are discussed.

[Nasolabial suspension of the malar fat pad: a new, minimally invasive and reversible technique for facial symmetrization in permanent facial paralysis]. / A középarc lágy részeinek nasolabialis függesztése: új, minimálinvazív és reverzibilis módszer az arc statikus szimmetrizálására végleges arcidegbénulásban.

Introduction: For the treatment of asymmetry of the midface due to permanent peripheral facial nerve palsy of different etiologies - which means a great psychical burden for the patients - several surgical solutions have been described. Aim: Our goal was to elaborate a minimally invasive surgical technique, that, on one hand, restores an adequate nasolabial fold, which is the most determinative keystone of facial symmetry. On the other hand, our technique can give an appropriate lift for the malar fat pad with shorter operative time and burden, with much lower complication rate and shorter recovery period compared to the classic static sling suspension techniques. Method: Out method is based on the formation of a neo-nasolabial fold, which is then suspended to the temporal fascia by permanent threads thus restoring facial symmetry and giving a lifting effect on the midfacial soft tissues as well. Results: Between 2014 and 2017, six patients had been operated with this nasolabial lifting technique of the malar fat pad without any major complications under local anesthesia on an outpatient basis at our Department. Conclusions: As our surgical exploration is minimal, the postoperative period is shorter, no visible scars remain on the face and the complication rate is negligible. If necessary, suspension could easily be adjusted, and as the technique is reversible, no other possible facial reconstruction methods are excluded. Our method can symmetrize the face in resting position completely on the long term, which is the most important issue for our patients according to their feedback. Orv Hetil. 2019; 160(22): 869-872.

Antifibrotic effect of mitomycin-C on human vocal cord fibroblasts.

OBJECTIVE: Acquired laryngotracheal stenosis is a potentially life-threatening situation and a very difficult and challenging problem in laryngology. Therefore, new trends and innovative approaches based on antifibrotic drugs and minimally invasive regimens are being developed to attenuate laryngotracheal fibrosis and scarring. The purpose of this study was to examine the efficacy of mitomycin-C (MMC) to reverse the transforming growth factor (TGF)-ß-induced differentiation of MRC-5 fibroblast and human primary vocal cord fibroblasts to reveal the possible applicability of MMC to laryngotracheal fibrotic conditions. METHODS: Human primary fibroblast cells were isolated from vocal cord specimens of patients undergoing total laryngectomy. The established primary vocal cord fibroblast cell cultures as well as the MRC-5 human fibroblast cells were treated with 5 ng/mL TGF-ß alone and then with 0.5 µg/mL MMC for 24 hours. Differentiation of fibroblasts was characterized by α-smooth muscle actin (α-SMA) immunhistochemistry, Western blot analysis, and real-time polymerase chain reaction. Cell motility was assessed by wound-healing assay. RESULTS: Elevated α-SMA mRNA and protein expression as well as increased cell motility were observed upon TGF-ß exposures. However, after MMC treatments the TGF-ß-induced fibroblasts exhibited a significant decrease in α-SMA expression and wound-healing activity. Therefore, TGF-ß-stimulated fibroblast-myofibroblast transformation was reversed at least in part by MMC treatment. Histopathological examinations of tissue specimens of a laryngotracheal stenosis patient supported these findings. CONCLUSION: Antifibrotic effects of MMC were demonstrated on the human MRC-5 cell line and on primary vocal cord fibroblast cultures. These results verify that MMC can be used with success to reverse upper airway stenosis by reverting the myofibroblast phenotype. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E255-E262, 2019.

Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus.

A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks.

Self-Regulation and Academic Measures Across the Early Elementary School Grades: Examining Longitudinal and Bidirectional Associations.

This study evaluated the association between children's (N = 301) self-regulation and math and reading achievement in kindergarten, first grade, and second grade. Children's self-regulation was assessed using the Head-Toes-Knees-Shoulders (HTKS) task (involving control of gross body movements) and a computerized continuous performance task (CPT; assessing primarily inhibitory control) in kindergarten, first grade, and second grade. Research findings: Based on cross-lagged structural equation panel models, HTKS task performance positively predicted later math and reading achievement. Math achievement significantly and positively predicted later HTKS and CPT scores. Earlier math and reading achievement moderated the association between CPT scores and later math and reading achievement; inhibitory control-based self-regulation assessed with the CPT predicted higher math or reading achievement in subsequent grades for children with lower math or reading achievement in prior grades. Performance on the CPT moderated the paths from HTKS scores to later reading achievement; behavioral self-regulation assessed with the HTKS task predicted higher reading achievement in subsequent grades for children with low or average CPT performance in prior grades. Practice: Results from this study have the potential to inform targeted academic interventions focused on enhancing self-regulation in school contexts. The findings highlight the utility of assessing multiple measures of self-regulation.

Isolation of Chlorogenic Acid from Soil Borne Fungi Screlotium rolfsii, their Reversal of Multidrug Resistance and Anti-proliferative in Mouse Lymphoma Cells.

BACKGROUND: Fungi performing a wide range of function in soil by secreting low molecular weight compound known as secondary metabolites. S. rolfsii is a soil borne phytopathogenic fungi was used for the production of bioactive compounds. OBJECTIVE: The present study belongs to evaluate the anticancer potentials of a secondary metabolites isolated from S. rolfsii, their multidrug resistance (MDR), and molecular docking study. METHOD: (1S,3R,4R,5R,E)-3-(3-(3,4-Dihydroxyphenyl)acryloyloxy)-1,4,5 trihydroxycyclohexanecarboxylic acid (1), or best known as chlorogenic acid, was isolated from the ethyl acetate fraction of crude secondary metabolites produced by the soil borne Fungus Screlotium rolfsii. Structure of chlorogenic acid (1) was confirmed by means of FT-IR, 1H NMR, 13C NMR, and mass spectrometry as well as by melting point. RESULTS: Effect of compound 1 on the reversion of multidrug resistant (MDR) mediated by Pglycoprotein (P-gp) against cancer cells was evaluated with a rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma. Compound 1 was also evaluated for Anti-proliferative effect on the L5178 mouse Tcell lymphoma cell line. CONCLUSION: Results from the present investigation revealed that compound 1 exhibits excellent MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Compound 1 also showed anti-proliferative effect on L5178Y mouse T-lymphoma cell line.

Isolation and Structure Elucidation, Molecular Docking Studies of Screlotiumol from Soil Borne Fungi Screlotium rolfsii and their Reversal of Multidrug Resistance in Mouse Lymphoma Cells.

A new compound namely (13-(3,3-dihydroxypropyl)-1,6-dihydroxy-3,4-dihydro-1H-isochromen-8(5H)-one (1) was isolated from an ethyl acetate extract of the borne fungi Screlotium rolfsii. Its chemical structure was elucidated by spectroscopic analysis. Screlotiumol 1 were evaluated for their effects on the reversion of multidrug resistant (MDR) mediated by P-glycoprotein (P-gp) of the soil borne fungi. The multidrug resistant P-glycoprotein is a target for chemotherapeutic drugs in cancer cells. In the present study rhodamine-123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell lymphoma which showed excellent MDR reversing effect in a dose dependent manner against mouse T-lymphoma cell line. Moreover, molecular docking studies of compound-1 also showed better results as compared with the standard. Therefore the preliminary results obtained from this study suggest that screlotiumol 1 could be used as a potential agent for the treatment of cancer.