[Non-clinical safety evaluations of next-generation therapeutic antibodies].

Since the first monoclonal antibody was approved by FDA in 1986, numerous therapeutic antibodies have been developed along with advances in antibody engineering and finally, the number of approved therapeutic antibodies by FDA exceeded 100 in 2021. Although therapeutic antibodies were thought to be safer than conventional small molecule drugs, non-clinical safety evaluations of antibodies become more important because antibody-specific toxicity has been found. The depletion of target molecules for antibody drugs is a problem due to the limited number of promising targets.

A novel mouse model of cutaneous T-cell lymphoma revealed the combined effect of mogamulizumab with psoralen and ultraviolet a therapy.

Mycosis fungoides (MF) is a subtype of cutaneous T-cell lymphoma (CTCL). Topical or systemic treatment with psoralen, such as 8-methoxypsoralen (8-MOP), followed by ultraviolet A (UVA) irradiation (PUVA therapy) is an effective phototherapy for early-stage MF. However, the efficacy of PUVA therapy for advanced-stage MF is not satisfactory, and the ideal combination partner for PUVA therapy has not yet been found.

Chimeric Mice With Humanized Livers Demonstrate Human-Specific Hepatotoxicity Caused by a Therapeutic Antibody Against TRAIL-Receptor 2/Death Receptor 5.

The activation of tumor necrosis factor (TNF)-related apoptosis-inducing ligand receptor 2 (TRAIL-R2)/death receptor 5 (DR5) induces apoptosis in various tumor cells but not in normal human cells. Because some therapeutic antibodies targeting TRAIL-R2 have demonstrated severe hepatotoxicity in clinical applications, novel in vivo models reflecting clinical hepatotoxicity are now required. In this study, we investigated the hepatotoxicity caused by KMTR2, an anti-human TRAIL-R2 monoclonal antibody, in chimeric mice with humanized livers (PXB-mice).

Potent Therapeutic Activity Against Peritoneal Dissemination and Malignant Ascites by the Novel Anti-Folate Receptor Alpha Antibody KHK2805.

Many ovarian cancer patients often show peritoneal metastasis with malignant ascites. However, unmet medical needs remain regarding controlling these symptoms after tumors become resistant to chemotherapies. We developed KHK2805, a novel anti-folate receptor α (FOLR1) humanized antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Mps1 phosphorylation of condensin II controls chromosome condensation at the onset of mitosis.

During mitosis, genomic DNA is condensed into chromosomes to promote its equal segregation into daughter cells. Chromosome condensation occurs during cell cycle progression from G2 phase to mitosis. Failure of chromosome compaction at prophase leads to subsequent misregulation of chromosomes.

An activation of LC3A-mediated autophagy contributes to de novo and acquired resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma.

The development of therapeutic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs, ie erlotinib or gefitinib) has been the major clinical problem when treating lung adenocarcinoma patients with these agents. However, its mechanisms have not necessarily been well studied to this date. Autophagy has been recently considered to play pivotal roles in escaping from the effects of anti-neoplastic agents.

An inhibition of p62/SQSTM1 caused autophagic cell death of several human carcinoma cells.

p62/SQSTM1 (p62) is a multifunctional protein implicated in several signal transduction pathways and selectively degraded by autophagy, a process for lysosomal degradation of both protein and organelle. p62 was also recently reported to be overexpressed in various malignancies and its inhibition to suppress carcinoma cell proliferation. However, its correlation with autophagy in carcinoma cells has remained largely unknown.

Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65.

Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory mechanisms in cellular responses to various stimuli. The NF-kappaB signaling pathway is controlled by the ubiquitin-mediated proteolysis. RelA/p65, which is a main subunit of NF-kappaB, is ubiquitinated for degradation by SOCS-1, but the functional mechanism of its ubiquitination remains poorly understood.

TTK/Mps1 controls nuclear targeting of c-Abl by 14-3-3-coupled phosphorylation in response to oxidative stress.

Upon exposure to genotoxic stress, the c-Abl tyrosine kinase is released from cytoplasmic 14-3-3 proteins and then is targeted to the nucleus. Phosphorylation of Thr735 in c-Abl is critical for binding to 14-3-3; however, kinases responsible for this phosphorylation are unknown. Here, we identify CLK1, CLK4, MST1, MST2 and TTK (also known as Mps1) as novel Thr735 kinases in vitro by expression cloning strategy using phosphospecific antibody.

DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage.

Genotoxic stress exerts biological activity by activating downstream effectors, including the p53 tumor suppressor. p53 regulates cell-cycle checkpoint and induction of apoptosis in response to DNA damage; however, molecular mechanisms responsible for committing to these distinct functions remain to be elucidated. Recent studies demonstrated that phosphorylation of p53 at Ser46 is associated with induction of p53AIP1 expression, resulting in commitment to apoptotic cell death.

Holding on and letting go: identity and acculturation among Chinese immigrants.

This study addresses the general question of whether ethnic identity and general acculturation would prove unique discriminators of quality of life for Chinese immigrants. Eighty-three Chinese immigrants served as participants. Survey data were collected regarding acculturation, Asian identity, and quality of life; observers provided ratings of certain home environment characteristics; and participants responded to open-ended interview questions about their immigration experiences that allowed for qualitative data analysis on perspectives of culture.

Ecocultural assessment in families of children with developmental delays: construct and concurrent validities.

Home interviews were conducted with 102 families of children with developmental delays to assess ecocultural family resources and constraints, values, and goals as well as proactive adaptive efforts to deal with their circumstances. Interview topics included (a) economic factors; (b) child safety, health, and education; (c) domestic and childcare workloads; (d) familial support networks; and (e) sociocultural influences. Factor analyses performed on the ecocultural measures revealed 12 salient factors.

Family responses to young children with developmental delays: accommodation activity in ecological and cultural context.

In this study 680 accommodations or proactive efforts to sustain a family environment in 10 ecocultural domains were reliably scored for 102 Euro-American families of young children with developmental delays. The families reported substantial accommodation activity. Results showed that accommodations (a) in the domains of child care and service access were correlated with children's problems that impact the daily routine; (b) in the domains of subsistence changes, seeking information, and roles of fathers were related to parents' job and career circumstances, with more modest links to socioeconomic status; and (c) were not associated with child developmental test scores.

Taxonomy of family life styles: III. Replication with families with severely mentally retarded children.

The home environment and behavior of 97 families with severely mentally retarded children was examined in order to determine the presence of family types. Cluster analysis was performed on 16 measures of proximal home environment. Five unique family clusters were identified: cohesive, control-oriented, responsive-to-child, moral-religious-oriented, nonachievement-oriented, and achievement-oriented.

Child-environment relationships: a cross-cultural study of educable mentally retarded children and their families.

A cross-cultural study was conducted to determine the generality of child-environment relationships in Japanese and American families with educable mentally retarded (EMR) children. A total of 90 families with EMR children in Japan and 93 families with EMR children in America participated. The Henderson Environment Learning and Process Scale, Family Environment Scale, and Home Quality Rating Scale were employed in home interviews and observations.

Direction of effects: family life styles and behavior of TMR children.

The direction of effects were examined between TMR children and their families in three previously determined family types: cohesive, harmonious; control oriented, somewhat unharmonious; and child-oriented, expressive. Child variables studied were measures of adaptive behavior, psychosocial adjustment, and self-esteem. Family variables included measures of cohesion and conflict, provision of cognitive stimulation, parental warmth and affection, quality of the residential environment, and openness with the interviewer.

Homes of TMR children: comparison between American and Japanese families.

A cross-cultural study was conducted to examine the extent to which certain environment-child development relationships can be generalized across two cultures. Participants were 103 trainable mentally retarded (TMR) children and their families in Japan and 88 TMR children and their families in the United States. The relation between cognitive stimulation and cultural opportunities at home and the children's social competence appeared to generalize across both cultures; however, the relation between affective and emotional aspects of parental behavior and the children's emotional adjustment appeared to be culture-specific.

Characteristics of home environment of families with mentally retarded children: comparison across levels of retardation.

To help fill the relative void of information about families of severely mentally retarded school children, we described 53 such families comparatively with 54 families of EMR and 50 of TMR children. All children resided in their natural homes; families were selected for study by identical means and interviewed at their home. Selection for comparison was made from larger samples to reduce mean age differences in the samples.

Taxonomy of family life styles: II. Homes with slow-learning children.

A battery of instruments dealing with family social environment and family and child characteristics and behavior was administered to 218 families with slow-learning children in EMR and educably handicapped programs. Cluster analysis was performed on family environment variables. Seven unique family clusters, each with distinctive patterns of characteristics, were identified: child-oriented, cohesive; learning-oriented, high residential quality; low disclosure, unharmonious; disadvantaged, noncohesive; achievement-oriented, low residential quality; expression-oriented with few sociocultural interests; and outerdirected with little achievement-orientation.

Predicting retarded students' short-term growth from home environment.

This investigation sought to determine whether change in mentally retarded students' developmental status and adjustment could be predicted by variables of the psychological home environment for periods of one and two years. Over 120 trainable mentally retarded (TMR) and over 220 educable mentally retarded and educationally handicapped (EMR-EH) children were subjects. Annual interviews were conducted in the homes.

Reciprocal relationship between home environment and development of TMR adolescents.

The reciprocal relationship between home environment and social competency of 112 TMR adolescents was examined over a period of 3 years. Assessment of home environment included child-rearing attitudes, educationally relevant stimuli and opportunities available at home, and general psychosocial climate among family members. Measures of social competency included the child's adaptive behavior, psychosocial adjustment, and self-concept.

Taxonomy of family life styles: I. Homes with TMR children.

A battery of instruments dealing with family social environment and family and child characteristics and behavior was administered to 115 families with children in TMR classes. Cluster analysis was performed on the social environment variables. Five distinctive clusters of families, each with distinctive patterns of characteristics, were identified: cohesive, harmonious; control-oriented, somewhat unharmonious; low-disclosure, unharmonious; child-oriented, expressive; and disadvantaged, low morale.

Relationship between home environment and school adjustment of TMR children.

The relationship between the home environment and school adjustment of 104 TMR children was examined. Assessment of home environment included measurement of environmental process variables with Caldwell's HOME Inventory and psychosocial climate with Moos, Insel, and Humphrey's Family Environment Scale. Certain child-rearing attitudes and relevant demographic characteristics were also investigated.

Dimensions of adaptive behavior in institutionalized mentally retarded children and adults: developmental perspective.

Factor analyses were performed utilizing the subscale scores of the AAMD Adaptive Behavior Scale, Part One, for 3,354 institutionalized mentally retarded children and adults. Eight different age groups were studied to determine (a) the underlying dimensions of adaptive behavior measured by the scale, (b) similarity of factor structure across ages, (c) whether there were developmental changes revealed by factor scores, and (d) the extent to which the above findings would be related to level of retardation. Three salient factorial dimensions--Personal Self-Sufficiency, Community Self-Sufficiency, and Personal-Social Responsibility--appeared across a wide span of age ranges from childhood through senility.