Antibody targeting of Cathepsin S induces antibody-dependent cellular cytotoxicity.

BACKGROUND: Proteolytic enzymes have been implicated in driving tumor progression by means of their cancer cell microenvironment activity where they promote proliferation, differentiation, apoptosis, migration, and invasion. Therapeutic strategies have focused on attenuating their activity using small molecule inhibitors, but the association of proteases with the cell surface during cancer progression opens up the possibility of targeting these using antibody dependent cellular cytotoxicity (ADCC). Cathepsin S is a lysosomal cysteine protease that promotes the growth and invasion of tumour and endothelial cells during cancer progression. Our analysis of colorectal cancer patient biopsies shows that cathepsin S associates with the cell membrane indicating a potential for ADCC targeting. RESULTS: Here we report the cell surface characterization of cathepsin S and the development of a humanized antibody (Fsn0503h) with immune effector function and a stable in vivo half-life of 274 hours. Cathepsin S is expressed on the surface of tumor cells representative of colorectal and pancreatic cancer (23%-79% positive expression). Furthermore the binding of Fsn0503h to surface associated cathepsin S results in natural killer (NK) cell targeted tumor killing. In a colorectal cancer model Fsn0503h elicits a 22% cytotoxic effect. CONCLUSIONS: This data highlights the potential to target cell surface associated enzymes, such as cathepsin S, as therapeutic targets using antibodies capable of elicitingADCC in tumor cells.

Differences in compassion fatigue, symptoms of posttraumatic stress disorder and relationship satisfaction, including sexual desire and functioning, between male and female detectives who investigate sexual offenses against children: a pilot study.

Law enforcement detectives who work with traumatized individuals, especially children who were victims of sexual abuse or assault, are likely to experience job-related emotional distress. The purpose of this study was to examine the relations among compassion fatigue, probable PTSD symptoms, and personal relationship satisfaction, including communication and sexual satisfaction, in a sample of 47 male and female detectives. Responses to the administered questionnaires indicated a relation between compassion fatigue symptoms and probable PTSD symptoms. There also were compelling gender differences. For example, for male detectives, open communication with their spouse or significant other was negatively correlated with burnout, indicating the more open the communication, the lower the reported burnout. However for female detectives there was a negative correlation between open communication with spouse or significant other and compassion satisfaction, suggesting that more open communication was related to lower levels of satisfaction with their ability to be a professional caregiver Furthermore, although stepwise regression analysis indicated that years of service as a detective is independently associated with sexual desire, female detectives evidenced less sexual desire and more difficulty with sexual functioning than did male detectives. Implications of these preliminary findings are discussed and limitations addressed.

Stable expression and purification of a functional processed Fab' fragment from a single nascent polypeptide in CHO cells expressing the mCAT-1 retroviral receptor.

Monoclonal antibodies and derivative formats such as Fab' fragments are used in a broad range of therapeutic, diagnostic and research applications. New systems and methodologies that can improve the production of these proteins are consequently of much interest. Here we present a novel approach for the rapid production of processed Fab' fragments in a CHO cell line that has been engineered to express the mouse cationic amino acid transporter receptor 1 (mCAT-1). This facilitated the introduction of the target antibody gene through retroviral transfection, rapidly producing stable expression. Using this system, we designed a single retroviral vector construct for the expression of a target Fab' fragment as a single polypeptide with a furin cleavage site and a FMDV 2A self-cleaving peptide introduced to bridge the light and truncated heavy chain regions. The introduction of these cleavage motifs ensured equimolar expression and processing of the heavy and light domains as exemplified by the production of an active chimeric Fab' fragment against the Fas receptor, routinely expressed in 1-2mg/L yield in spinner-flask cell cultures. These results demonstrate that this method could have application in the facile production of bioactive Fab' fragments.

PTSD reactions and functioning of American Airlines flight attendants in the wake of September 11.

The authors explore the psychological reactions and functional coping responses of American Airlines (AA) flight attendants, a unique at-risk group of people in the war on terrorism, in the aftermath of the September 11 attacks. Demographic characteristics and standardized questionnaires, including the Posttraumatic Stress Disorder Checklist and the Psychotherapy Outcome Assessment and Monitoring System--Trauma Version, were sent in June 2002 to approximately 26,000 AA flight attendants. Of the 2050 respondents, 18.2% reported symptoms consistent with probable posttraumatic stress disorder (PTSD). Those living alone were 1.48 times more likely to have a probable PTSD diagnosis than those living with someone else. Age or years of service as a flight attendant did not predict probable PTSD; however, marital status did. Substance abuse was not endorsed as a coping strategy. Given the traumatic events experienced by AA flight attendants, and persistent threats of future terrorist attacks, these results reveal that additional assessment and treatment interventions for stress-related symptoms in this population seem warranted.

PTSD reactions and coping responses of East Coast and West Coast American Airlines flight attendants after September 11: a possible psychological contagion effect?

Psychological reactions and functional coping of East Coast and West Coast-based flight attendants were compared after the attacks on September 11. Demographics and standardized questionnaires were sent in June 2002 to approximately 26,000 flight attendants. The 2,050 returned surveys were separated into East Coast-based flight crews (513 from Boston, New York, and Washington, DC) and West Coast-based flight crews (353 from Los Angeles and San Francisco). Despite demographic differences between the flight crews, most notably that the East Coast members were more than twice as likely to know someone who perished in the wake of September 11, there was no difference between them regarding probable PTSD (19.1% and 18.3%, respectively) or life functioning. We suggest that a psychological contagion effect occurred in this at-risk group of workers in the war on terrorism. Public health implications, including multicomponent treatment interventions, are suggested.