Clathrin Light Chains negatively regulate plant immunity by hijacking the autophagy pathway.

The crosstalk between clathrin-mediated endocytosis (CME) and autophagy pathway has been reported in mammals. However, the interconnection of CME with autophagy has not been established in plants. In this report, we showed that Arabidopsis CLATHRIN LIGHT CHAIN (CLC) subunit 2 and 3 double mutant, clc2-1 clc3-1, phenocopied the Arabidopsis AUTOPHAGY-RELATED GENE (ATG) mutants both in auto-immunity and nutrient sensitivity. Accordingly, the autophagy pathway was significantly compromised in the clc2-1 clc3-1 mutant. Interestingly, we demonstrated with multiple assays that CLC2 directly interacted with ATG8h/ATG8i in a domain-specific manner. As expected, both GFP-ATG8h/GFP-ATG8i and CLC2-GFP were subjected to autophagic degradation and the degradation of GFP-ATG8h was significantly reduced in the clc2-1 clc3-1 mutant. Notably, simultaneously knocking out ATG8h and ATG8i by the CRISPR/CAS9 resulted in an enhanced resistance against Golovinomyces cichoracearum, supporting the functional relevance of the CLC2-ATG8h/8i interactions. In conclusion, our results uncovered a link between the function of CLCs and the autophagy pathway in Arabidopsis.

The Impact of Prior Single-Gene Testing on Comprehensive Genomic Profiling Results for Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Tissue-based broad molecular profiling of guideline-recommended biomarkers is advised for the therapeutic management of patients with non-small cell lung cancer (NSCLC). However, practice variation can affect whether all indicated biomarkers are tested. We aimed to evaluate the impact of common single-gene testing (SGT) on subsequent comprehensive genomic profiling (CGP) test outcomes and results in NSCLC. METHODS: Oncologists who ordered SGT for guideline-recommended biomarkers in NSCLC patients were prospectively contacted (May-December 2022) and offered CGP (DNA and RNA sequencing), either following receipt of negative SGT findings, or instead of SGT for each patient. We describe SGT patterns and compare CGP completion rates, turnaround time, and recommended biomarker detection for NSCLC patients with and without prior negative SGT results. RESULTS: Oncologists in > 80 community practices ordered CGP for 561 NSCLC patients; 135 patients (27%) first had negative results from 30 different SGT combinations; 84% included ALK, EGFR and PD-L1, while only 3% of orders included all available SGTs for guideline-recommended genes. Among patients with negative SGT results, CGP was attempted using the same tissue specimen 90% of the time. There were also significantly more CGP order cancellations due to tissue insufficiency (17% vs. 7%), DNA sequencing failures (13% vs. 8%), and turnaround time > 14 days (62% vs. 29%) than among patients who only had CGP. Forty-six percent of patients with negative prior SGT had positive CGP results for recommended biomarkers, including targetable genomic variants in genes beyond ALK and EGFR, such as ERBB2, KRAS (non-G12C), MET (exon 14 skipping), NTRK2/3, and RET . CONCLUSION: For patients with NSCLC, initial use of SGT increases subsequent CGP test cancellations, turnaround time, and the likelihood of incomplete molecular profiling for guideline-recommended biomarkers due to tissue insufficiency.

Patients with non-small cell lung cancer (NSCLC) should have their tumor tissue tested for all recommended biomarkers that can help identify their best treatment options. Traditional tests look at gene biomarkers one by one (single-gene testing), and doctors can order some or all these tests individually or in a group. However, some recommended biomarkers cannot be tested by traditional single-gene tests at all. Newer technology (next-generation sequencing) covers all current recommended treatment biomarkers in one test (comprehensive genomic profiling), but this testing is more expensive and can take more time. Our study shows that NSCLC patients do not get all recommended treatment biomarkers tested when a single-gene testing approach is taken. Single-gene testing also used up some patients' tumor tissue entirely, such that further testing by comprehensive genomic profiling could not be done at all (17% vs. 7% for patients with no prior single-gene tests), resulted in more sequencing failures (13% vs. 8%), and had turnaround time for results greater than 14 days for more patients (62% vs. 29%). When comprehensive genomic profiling was completed, 46% of patients with negative results from prior single-gene testing had positive results for recommended treatment biomarkers that were not included in the initial single-gene tests. To ensure that NSCLC patients receive testing for all recommended biomarkers, comprehensive genomic profiling must be performed first.

Soybean GmSAUL1, a Bona Fide U-Box E3 Ligase, Negatively Regulates Immunity Likely through Repressing the Activation of GmMPK3.

E3 ubiquitin ligases play important roles in plant immunity, but their role in soybean has not been investigated previously. Here, we used Bean pod mottle virus (BPMV)-mediated virus-induced gene silencing (VIGS) to investigate the function of GmSAUL1 (Senescence-Associated E3 Ubiquitin Ligase 1) homologs in soybean. When two closely related SAUL1 homologs were silenced simultaneously, the soybean plants displayed autoimmune phenotypes, which were significantly alleviated by high temperature, suggesting that GmSAUL1a/1b might be guarded by an R protein. Interestingly, silencing GmSAUL1a/1b resulted in the decreased activation of GmMPK6, but increased activation of GmMPK3 in response to flg22, suggesting that the activation of GmMPK3 is most likely responsible for the activated immunity observed in the GmSAUL1a/1b-silenced plants. Furthermore, we provided evidence that GmSAUL1a is a bona fide E3 ligase. Collectively, our results indicated that GmSAUL1 plays a negative role in regulating cell death and immunity in soybean.

Longitudinal Relationship between Bullying Victimization and Non-Suicidal Self-Injury among Chinese Adolescents: The Buffering Roles of Gratitude and Parental Autonomy Support.

Drawing on the resilience-oriented socioecological framework, the current study contributes to scarce scholarship by exploring intrapersonal (i.e., gratitude) and interpersonal (i.e., parental autonomy support) factors in the longitudinal association between bullying victimization and adolescent non-suicidal self-injury (NSSI). Participants were 238 Chinese adolescents (Mage at Time 1 (T1) = 13.45 years; 106 girls and 132 boys) based on a two-wave prospective design with data spanning one year. At T1, adolescents self-rated all study variables, and at Time 2 (T2), youth again reported their NSSI. The results showed a significant main effect (b = 0.12, SE = 0.05, p = 0.04), indicating that bullying victimization was positively related to T2 NSSI one year later, even controlling for T1 NSSI. Moderation analyses further indicated that parental autonomy support buffered against the positive association between bullying victimization and T2 NSSI, but only when adolescents experienced lower levels of gratitude. Specifically, for adolescents with lower levels of gratitude, high levels of parental autonomy support, in a compensatory way, prevented adolescents from NSSI after victimization occurred (b = -0.03, SE = 0.09, p = 0.78); by contrast, for those with higher levels of gratitude, bullying victimization was not significantly related to T2 NSSI, regardless of the levels of parental autonomy support (b = 0.07, SE = 0.04, p = 0.59 for higher parental autonomy support; b = 0.01, SE = 0.07, p = 0.93 for lower parental autonomy support). These findings suggest that gratitude and parental autonomy support, manifesting in a compensatory interaction pattern, could serve as targeted agents for breaking the vicious linkage between bullying victimization and NSSI.

meta-Allylation of Arenes via Ruthenium-Catalyzed Cross-Dehydrogenative Coupling.

A successful example of oxidative meta-dehydrogenative allylation of arenes with alkenes has been developed using Ru(PPh3)3Cl2 as a catalyst and DTBP as an oxidant. In the allylation process, pyrimidines, pyrazoles, and purines, found widely in nucleosides, were effective auxiliary groups. Gram-scale experiments took place smoothly under optimized conditions. Mechanistic studies indicated that ruthenium-catalyzed meta-dehydrogenative allylation was a free-radical process. The allylation process developed herein provides an efficient and practical strategy to prepare versatile meta-allylated arenes.

Relations between parental response to children's negative emotions and suicidal ideation in chinese adolescents: Internalizing problems, emotion regulation, and perceived relationship quality with parents as mediators.

Past work points to the crucial role of parents' responses to children's negative emotions (PRCNE) in adolescents' socioemotional adjustment. The presence of suicidal ideation (SI) is an important sign of significant distress and suicide risk. However, research on the relations between PRCNE and adolescents' SI is lacking. This research aimed to investigate whether parental reactions to children's negative emotions (PRCNE) was related to adolescents' SI and, if so, through which processes. This research utilized data from a sample of Chinese adolescent families (N = 4,574; Parents: 35.81% males, M = 44.07 years old; Adolescents: 55.40% males, M = 16.28 years old), with parents giving their reports on PRCNE and adolescents self-evaluating their psychosocial development (i.e., internalizing problems, emotion regulation, perceived relationship quality with parents) and SI. We examined the relations between six types of PRCNE and adolescents' SI, and analyzed the mediating roles of adolescents' internalizing problems, emotion regulation (i.e., cognitive reappraisal and expressive suppression), and perceived relationship quality with parents. The results showed that emotion-focused response, problem-focused response, and expression encouragement negatively predicted, while punitive response and distress response positively predicted adolescents' SI. However, no statistically significant association emerged between minimization and adolescents' SI. Moreover, adolescents' internalizing problems, usage of expressive suppression, and perceived relationship quality with parents could mediate the relations between PRCNE and adolescents' SI. Contrary to our hypothesis, the results did not support an indirect effect of PRCNE on adolescents' SI through adolescents' cognitive reappraisal. The present research illuminates adolescents' SI by emphasizing the roles of PRCNE. The findings also highlight the importance of paying attention to adolescents' internalizing problems, expressive suppression, and perceived relationship quality with parents in relation to PRCNE in interventions aimed at reducing adolescents' SI.

Silencing Autophagy-Related Gene 2 (ATG2) Results in Accelerated Senescence and Enhanced Immunity in Soybean.

Autophagy plays a critical role in nutrient recycling and stress adaptations. However, the role of autophagy has not been extensively investigated in crop plants. In this study, soybean autophagy-related gene 2 (GmATG2) was silenced, using virus-induced silencing (VIGS) mediated by Bean pod mottle virus (BPMV). An accelerated senescence phenotype was exclusively observed for the GmATG2-silenced plants under dark conditions. In addition, significantly increased accumulation of both ROS and SA as well as a significantly induced expression of the pathogenesis-related gene 1 (PR1) were also observed on the leaves of the GmATG2-silenced plants, indicating an activated immune response. Consistent with this, GmATG2-silenced plants exhibited a significantly enhanced resistance to Pseudomonas syringae pv. glycinea (Psg) relative to empty vector control plants (BPMV-0). Notably, the activated immunity of the GmATG2-silenced plants was independent of the MAPK signaling pathway. The fact that the accumulation levels of ATG8 protein and poly-ubiquitinated proteins were significantly increased in the dark-treated GmATG2-silenced plants relative to the BPMV-0 plants indicated that the autophagic degradation is compromised in the GmATG2-silenced plants. Together, our results indicated that silencing GmATG2 compromises the autophagy pathway, and the autophagy pathway is conserved in different plant species.

Different profiles with multiple risk factors of nonsuicidal self-injury and their transitions during adolescence: A person-centered analysis.

BACKGROUND: Nonsuicidal self-injury (NSSI) is a serious public health concern among adolescents. However, adolescents with different combinations of NSSI risk factors may constitute different subgroups that vary in subsequent risks of NSSI engagement, and the membership in these subgroups may change during early adolescence. Gender differences related to risk profiles and transition patterns may also exist. This study thus aimed to address these three questions. METHODS: A total of 2,942 participants ranging from 12 to 17 years old (55.2% females; Mage = 14.60, SD = 1.21) completed a series of questionnaires about NSSI and its risk factors on three occasions, every six months. Latent profile and latent transition analyses were used to examine NSSI risk profiles (subgroups), their transition patterns, and gender differences. RESULTS: Three distinct risk profiles were identified: Low-risk profile, Medium-risk profile, and High-risk profile. The profile membership was fairly stable over one year, and the shift across profiles represented a "resilient" pattern. Regarding gender differences, boys were less likely to be in either the Medium- or the High-risk groups, but more likely to transition from the Medium- to the Low-risk group, relative to girls. LIMITATIONS: This study relied upon self-report measures. Additional research is needed to investigate the generalizability of the results to other populations, and to examine more predictors of class membership and transitions. CONCLUSIONS: The results highlight the importance of considering subgroup differences in understanding NSSI risks. Differentiated interventions with multi-pronged approaches tailoring to different risk classes and gender groups may therefore prove more efficient and effective.

Dual Roles of GSNOR1 in Cell Death and Immunity in Tetraploid Nicotiana tabacum.

S-nitrosoglutathione reductase 1 (GSNOR1) is the key enzyme that regulates cellular homeostasis of S-nitrosylation. Although extensively studied in Arabidopsis, the roles of GSNOR1 in tetraploid Nicotiana species have not been investigated previously. To study the function of NtGSNOR1, we knocked out two NtGSNOR1 genes simultaneously in Nicotiana tabacum using clustered regularly interspaced short palindromic repeats (CRISPR)/caspase 9 (Cas9) technology. To our surprise, spontaneous cell death occurred on the leaves of the CRISPR/Cas9 lines but not on those of the wild-type (WT) plants, suggesting that NtGSNOR1 negatively regulates cell death. The natural cell death on the CRISPR/Cas9 lines could be a result from interactions between overaccumulated nitric oxide (NO) and hydrogen peroxide (H2O2). This spontaneous cell death phenotype was not affected by knocking out two Enhanced disease susceptibility 1 genes (NtEDS11a/1b) and thus was independent of the salicylic acid (SA) pathway. Unexpectedly, we found that the NtGSNOR1a/1b knockout plants displayed a significantly (p < 0.001) enhanced resistance to paraquat-induced cell death compared to WT plants, suggesting that NtGSNOR1 functions as a positive regulator of the paraquat-induced cell death. The increased resistance to the paraquat-induced cell death of the NtGSNOR1a/1b knockout plants was correlated with the reduced level of H2O2 accumulation. Interestingly, whereas the N gene-mediated resistance to Tobacco mosaic virus (TMV) was significantly enhanced (p < 0.001), the resistance to Pseudomonas syringae pv. tomato DC3000 was significantly reduced (p < 0.01) in the NtGSNOR1a/1b knockout lines. In summary, our results indicate that NtGSNOR1 functions as both positive and negative regulator of cell death under different conditions and displays distinct effects on resistance against viral and bacterial pathogens.

Bullying Experiences and Nonsuicidal Self-injury among Chinese Adolescents: A Longitudinal Moderated Mediation Model.

Bullying experiences play an important role in non-suicidal self-injury (NSSI). However, little is known about how and in what conditions different bullying experiences (i.e., experiences of being pure bullies, pure victims, and bully-victims) may influence NSSI. Guided by the transactional model of development and the integrated model of NSSI, the current study investigated two potential mediators (i.e., peer acceptance and depressive symptoms) and one potential moderator (i.e., psychological resilience) of the relations between different bullying experiences and NSSI. Participants were 812 Chinese adolescents (43% female; Mage at Wave 1 = 13.15 years) from a two-wave longitudinal study with data spanning 1 year. The results show that all three types of bullying experiences can relate to a higher likelihood of NSSI through two indirect pathways: (a) lower peer acceptance to more depressive symptoms, or (b) more depressive symptoms. These indirect effects were weaker for adolescents with higher (versus lower) levels of psychological resilience. Moreover, when bully-victims were distinguished from pure bullies and pure victims and the unique effects for all three groups were tested, the direct and indirect effects were most evident among bully-victims. These findings imply that it is necessary to distinguish bully-victims from pure bullies and pure victims. The results indicate that NSSI may be effectively reduced if interventions focus on promoting peer acceptance and reducing adolescent depressive symptoms, particularly for bully-victims with lower levels of psychological resilience.

Telemedicine in Community Cancer Care: How Technology Helps Patients With Cancer Navigate a Pandemic.

COVID-19 places unprecedented demands on the oncology ecosystem. The extensive pressure of managing health care during the pandemic establishes the need for rapid implementation of telemedicine. Across our large statewide practice of 640 practitioners at 221 sites of service, an aggressive multidisciplinary telemedicine strategy was implemented in March by coordinating and training many different parts of our healthcare delivery system. From March to September, telemedicine grew to serve 15%-20% of new patients and 20%-25% of established patients, permitting the practice to implement safety protocols and reduce volumes in clinic while continuing to manage the acute and chronic care needs of our patient population. We surveyed practice leaders, queried for qualitative feedback, and established 76% were satisfied with the platform. The common challenges for patients were the first-time use and technology function, and patients were, in general, grateful and happy to have the option to visit their clinicians on a telemedicine platform. In addition to conducting new and established visits remotely, telemedicine allows risk assessments, avoidance of hospitalization, family education, psychosocial care, and improved pharmacy support. The implementation has limitations including technical complexity; increased burden on patients and staff; and broadband access, particularly in rural communities. For telemedicine to improve as a solution to enhance the longitudinal care of patients with cancer, payment coverage policies need to continue after the pandemic, technologic adoption needs to be easy for patients, and broadband access in rural areas needs to be a policy priority. Further research to optimize the patient and clinician experience is required to continue to make progress.

Preparation and anti-cancer activity of transferrin/folic acid double-targeted graphene oxide drug delivery system.

In this study, a transferrin/folic acid double-targeting graphene oxide drug delivery system loaded with doxorubicin was designed. Graphene oxide was prepared by ultrasound improved Hummers method and was modified with Pluronic F68, folic acid, and transferrin to decrease its toxicity and to allow dual-targeting. The results show that the double target drug delivery system (TFGP*DOX) has good and controllable drug delivery performance with no toxicity. Moreover, TFGP*DOX has a better inhibitory effect on SMMC-7721 cells than does a single target drug delivery system (FGP*DOX). The results of drug release analysis and cell inhibition studies showed that TFGP*DOX has a good sustained release function that can reduce the drug release rate in blood circulation over time and improve the local drug concentration in or near a targeted tumor. Therefore, the drug loading system (TFGP*DOX) has potential application value in the treatment of hepatocellular carcinoma.

Ruthenium-Catalyzed meta-Selective CAr-H Bond Formylation of Arenes.

The meta-CAr-H bond formylation of arenes has been achieved using CHBr3 as a formyl source in the presence of [Ru(p-cym)(OAc)2] as a catalyst. This method provides efficient access to the preparation of various meta-substituted aromatic compounds, such as alcohols, ethers, amines, nitriles, alkenes, halogens, carboxylic acids, and their derivatives, through transformation of the versatile formyl group. Furthermore, mechanistic studies show that the key active species is a pentagonal ruthenacycle complex.

Peer Acceptance and Nonsuicidal Self-injury among Chinese Adolescents: A Longitudinal Moderated Mediation Model.

Peer relationship plays an important role in non-suicidal self-injury (NSSI). However, little is known about how and in what conditions peer relationship may influence NSSI. By integrating multiple theories (i.e., attachment theory, the emotional regulation model of self-compassion and NSSI, and the differential-susceptibility theory), the current study investigated two potential mediators (i.e., self-compassion and depressive symptoms) and one potential moderator (i.e., behavioral impulsivity) of the relation between peer acceptance and NSSI. Participants were 813 Chinese adolescents (43% female; Mage at Wave 1 = 13.15 years) from a two-wave longitudinal study with data spanning one year. The results revealed that the indirect pathways linking peer acceptance and NSSI were conditioned on the level of behavioral impulsivity. Specifically, for adolescents with lower levels of impulsivity, a higher level of peer acceptance was related to fewer depressive symptoms directly or indirectly through self-compassion; fewer depressive symptoms, in turn, were linked to fewer NSSI behaviors longitudinally. For adolescents with higher levels of behavioral impulsivity, peer acceptance was related to fewer NSSI behaviors only through self-compassion. Results indicate that increasing peer acceptance is important in reducing adolescent NSSI. Interventions designed to reduce adolescent NSSI may also be effective if they focus on promoting adolescent self-compassion, particularly for adolescents with higher levels of behavioral impulsivity.

Magnetic Graphene Oxide-Fe3O4-PANI Nanoparticle Adsorbed Platinum Drugs as Drug Delivery Systems for Cancer Therapy.

Graphene-based magnetic nanoparticles (NPs) were synthesized using a simple and effective chemical precipitation method. To determine the biocompatibility of GO-Fe3O4-PANI NPs with MTT assay, cytotoxicity testing from a low concentration (1 µg/mL) to a high concentration (125 µg/mL) was conducted using various cancer and normal cell lines. Cytotoxicity testing for cancer cell lines (SMMC-7721, HepG-2, RAW264.7) and normal cell lines (HL-7702) showed almost no toxicity within the 1~125 µg/mL concentration range. Carboplatin (CBP) and oxaliplatin (OXP) were then used as drug models to study the drug release of CBP and OXP loaded on GO-Fe3O4-PANI NPs in vitro. Results indicated that the release of CBP and OXP from GO-Fe3O4-PANI NPs were affected by pH, dose, and temperature. The release of CBP was more sensitive to pH, and the amounts released in neutral and acidic environments (pH 6.0 and 7.4, respectively) were higher than those released in alkaline environments (pH 8.0). Meanwhile, at different pH levels, the release of OXP was not as large. In addition, at a low temperature (27 °C), the amount released is small when the energy level does not meet that required by C═N. At a considerably higher temperature (47 °C), the energy required for C═N fracture is met, allowing the slow release of the drug over a longer period. The results of our studies suggest that GO-Fe3O4-PANI NPs are biocompatible with MTT assay, and as drug delivery systems, these particular NPs can lead to advances in cancer treatment.

Intergenerational Transmission of Educational Aspirations in Chinese Families: Identifying Mediators and Moderators.

Parents' educational aspirations for youth play an important role in shaping youth's own educational aspirations; however, little is known about how and in what context parents may transmit their aspirations to youth effectively. This is of particular interest and import to be examined in Chinese families, given Chinese cultural emphasis on educational achievement and Chinese youth's outstanding academic performance internationally. By integrating several key theories of motivation and parental socialization (i.e., the expectancy-value model of academic achievement, the two-step model of value transmission, the contextual model of parenting, and the self-determination theory), the current study investigated simultaneously the mediating roles of parental involvement in youth's learning and youth's perceptions of parental aspirations, as well as the moderating role of parental warmth in the intergenerational transmission process of educational aspirations in Chinese families. A two-wave longitudinal study spanning about half a year was conducted among 323 Chinese seventh graders (54% female; Mage = 13.25 years) and one of their parents (median educational attainment = completion of high school, median monthly income = USD 766-1226). It was found that parental educational aspirations for youth were related positively both indirectly through parental involvement and directly to youth's perceptions of parental aspirations, which in turn were associated positively with youth's own educational aspirations about half a year later. It was also found that parental educational aspirations for youth and youth's own educational aspirations were associated positively with each other only when youth reported experiencing high levels of parental warmth, but unrelated when youth reported experiencing low levels of parental warmth, whereas such moderating effects of parental warmth were absent on the links from parental aspirations to youth's perceptions of parental aspirations and parental involvement. These findings highlight the importance of integrating multiple theories to understand parent-to-youth transmission of educational aspirations in non-western cultures, which helps not only reveal generalizability, as well as boundary conditions for Western-originated theories, but also inform practical endeavors at promoting youth's educational achievement worldwide to draw on strengths of different cultures.

Pemetrexed-Associated Eyelid Edema: Effective Treatment by Excision of Lymphedematous Eyelid Tissue.

Pemetrexed is an antimetabolite agent that inhibits multiple folate-requiring enzymes and is used in the treatment of mesothelioma and non-small-cell lung cancer. One of its toxicities is isolated cutaneous swelling affecting the eyelids and/or orbit. The pathologic assessment or its management has not been addressed to date. Herein, the authors report a case of a 77-year-old woman treated with pemetrexed for non-small-cell lung adenocarcinoma who developed persistent, severe bilateral lower eyelid swelling for several months, despite compresses and oral diphenhydramine. Elective excision was performed with good results and no recurrence after 6 months' follow up. Histopathologically, the excised tissue showed changes typical of dermatochalasis with dissolution of collagen and elastic bundles and marked dilation of lymphatic vessels. The combination of pre-existing, localized lymphatic failure and capillary leakage secondary to pemetrexed therapy can explain the onset and worsening swelling with successive rounds of chemotherapy.

Systematic review of ICF core set from 2001 to 2012.

PURPOSE: This study systemically reviewed the published literature on the ICF core set. METHOD: A computer search of the MEDLINE, PubMed and SCOPUS databases was conducted between 2001 and December 2012. Articles reporting on the development of a set or sets of ICF categories for specific disease or health conditions were selected for a systematic review. RESULTS: The analysis included 116 articles from 36 journals, with the majority of papers having been published in 2011 and 2012. In these studies, spinal cord injury was the most frequently reported disease. The majority of the experts involved in the consensus process were physicians and physical therapists. CONCLUSION: This systematic review of studies on ICF core sets provided background information on the current developmental status of ICF core sets. Our findings also highlight possible directions for future research.

Phase I trial of oral estramustine and 3-hr infusional paclitaxel for the treatment of hormone refractory prostate cancer.

PRECIS: Estramustine 600 mg/m2 can be administered safely with 225 mg/m2 of paclitaxel if administered as a 3-hr infusion for the treatment of hormone refractory prostate cancer. Significant anti-tumor activity has been reconfirmed despite the change in schedule of administration of the paclitaxel. PURPOSE: This phase I study was conducted to identify the maximum tolerated dosage of paclitaxel administered as a 3-hr infusion combined with a stable dosage of estramustine capsules daily in men with hormone refractory prostate cancer. A secondary endpoint was to assess anti-tumor efficacy in this targeted patient population. PATIENTS AND METHODS: Twenty-six male patients, all with hormone refractory prostate cancer were enrolled in this trial. Estramustine was administered at a dosage of 600 mg/m2 daily, and paclitaxel was dose-escalated in cohorts from 125 to 250 mg/m2 administered as an infusion over 3 hr every 21 days. Patients were treated until maximum response was achieved, or toxicity or progressive disease precluded further treatment. Toxicity to determine maximum tolerated dose was assessed only during the first 3-week cycle. RESULTS: The maximum tolerated dose of paclitaxel on this schedule was 225 mg/m2 based on unacceptable dose-limiting fatigue observed at the next higher dosage level. Other grade 3 or 4 events included myelosuppression, left ventricular dysfunction, elevated liver function tests, deep venous thrombosis, vomiting, and development of depression. Using a response criteria of prostate specific antigen decline of > 50% persisting for a minimum of 6 weeks, eight of 26 patients responded (30.8%). Two of seven patients with documented soft-tissue disease experienced > 50% reductions in size of lesions or number of sites. The median response duration was 6 months, and the median survival time was 16 months. CONCLUSION: The recommended phase II dose of paclitaxel is 225 mg/m2 when administered over 3 hr in combination with estramustine. This regimen has an acceptable toxicity profile, is a convenient schedule, and results in significant antitumor activity even in a heavily pre-treated population of patients.