Tuning the performance of CAR T cell immunotherapies.

BACKGROUND: Simultaneous advances in gene editing, T cell engineering and biotechnology currently provide an opportunity for rapid progress in medicine. The approval of chimeric antigen receptor (CAR) T cell therapies by the US Food and Drug Administration (FDA) and the European Commission have generated substantial momentum for these first-in-class therapies to be used in patients with B cell malignancies. MAIN BODY: Considerable efforts focus on improved outcomes and reduced side effects of the newly approved therapies. Using innovative strategies, researchers aim to extend CAR T cell use to tackle difficulties inherent in solid tumors. Efforts are underway to broaden the applications of CAR T cells, and the strategy has been successful in chronic viral infections and preclinical models of autoimmunity. Research is in progress to generate "off-the-shelf" CAR T cells, an advance, which would greatly increase patient availability and reduce treatment cost. CONCLUSIONS: In this thematic review, we highlight advances that may help develop genetically engineered cells into a new category of medical therapies.

Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRL fas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell-treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.

Abuse among school going adolescents in three major cities of Pakistan: is it associated with school performances and mood disorders?

OBJECTIVE: To assess the proportion of various types of abuses and their association with school performances and psychological stress among adolescents from three major cities of Pakistan. METHODS: The cross-sectional school survey was conducted from March to September 2009, comprising adolescent students at six schools in Karachi, Lahore and Quetta. Data was collected using a self-administered and pre-tested questionnaire by trained medical students. SPSS 16 was used for statistical analysis. RESULTS: Of the 414 subjects in the study, there were 223 (54%) boys and 191 (46%) girls with an overall mean age of 14.36 ± 1.08 years. In all, 140 (33.7%) participants were physically abused and 236 (57%) participants were verbally abused in the preceding 12 months. Besides, 245 (59.2%) were involved in physical fight and 195 (47.1%) had suffered injury during the preceding year. There were 171 (41.4%) subjects having suffered bullying during the same period. Verbal abuse (p = 0.05), physical fight (p = 0.05) and bullying (p < 0.001) were significantly associated with poor school performances among adolescents. Physical abuse (p = 0.05), verbal abuse (p = 0.003), injury (p = 0.02) and bullying (p < 0.001) were significantly associated with psychological stress. CONCLUSION: Various types of abuse were quite prevalent in adolescents that were significantly associated with poor school performance and poor mental health.

Self-perceived health among school going adolescents in Pakistan: influence of individual, parental and life style factors?

BACKGROUND: Adolescents are at substantial risk of acquiring behaviors which might influence their health status. This study was aimed to assess the proportion of school going adolescents (both males and females) with poor self-perceived health and its associated factors. METHODOLOGY: A cross-sectional study was conducted in three major cities of Pakistan i.e. Karachi, Lahore and Quetta. From each city, six (6) secondary schools were randomly selected (3 public and 3 private). Pre-tested, self-administered questionnaire was distributed to students. Binary logistic regression analysis was conducted to determine independent factors associated with poor self-perceived health. RESULTS: Approximately 29% adolescents (119/414) reported poor self-perceived health. Individual and parental factors significantly associated with poor self-perceived health were being male (AOR = 1.75, 95% CI: 1.09 - 2.79), living in extended family (AOR = 2.65, 95% CI: 1.66 - 4.22), unskilled employment of father (AOR = 2.17, 95% CI: 1.35 - 3.48), lack of parental-child communication (AOR = 1.74, 95% CI: 1.03 - 2.91) and unfair treatment by parents (AOR = 1.80, 95% CI: 1.09 - 2.96). Life style factors such as use of smokeless tobacco (AOR = 2.14, 95% CI: 1.26 - 3.96) and unhealthy diet (AOR = 3.60, 95% CI: 1.76 - 7.33) were associated with poor self-perceived health. CONCLUSION: Better employment opportunities for father, parental counseling and increase awareness for adolescents about healthy diet are recommended to improve adolescent self-perceived health in Pakistan.

Warm autoimmune haemolytic anaemia and autoimmune hepatitis in an asymptomatic carrier of hepatitis B virus.

Warm antibody autoimmune haemolytic anaemia, a rare disease (0.2-1 per 100,000 populations), is due to the presence of warm agglutinins that react with protein antigens on the surface of red blood cells causing their premature destruction. Here, we present a case report of a 10 year old girl who came with features of haemolytic anaemia and history of blood transfusion since 3 years. On admission. laboratory test revealed that she had autoimmune hepatitis type 1 and was also an asymptomatic carrier of hepatitis B virus with positive HBs Ag. Steroid therapy resulted in clinical and laboratory remission. Direct antiglobulin test was negative after anaemia resolution, hepatitis B virus antigenemia persisted. To our knowledge, warm antibody autoimmune hemolytic anaemia has not previously been described in association with autoimmune hepatitis and asymptomatic carrier state of hepatitis B virus.

Preventable lifestyle risk factors for non-communicable diseases in the Pakistan Adolescents Schools Study 1 (PASS-1).

OBJECTIVES: The rising burden of preventable risk factors for non-communicable diseases (NCDs) among adolescents is a major public health challenge worldwide. We identified the preventable risk factors for NCDs in adolescents. METHODS: In a school-based study, pre-tested structured questionnaires were completed by 414 adolescents (14 to 17 years) at six schools in three cities in Pakistan. The chi-squared test and adjusted odds ratio (aOR) with 95% confidence interval (CI) were calculated in a multinomial logistic regression analysis. RESULTS: Over 80% of the adolescents had unhealthy diets, and 54% were physically inactive. Most adolescents were exposed to passive smoking, and 14% were also current smokers. More than one-third of participants chewed betel nut, and one-quarter used oral tobacco. More girls were physically inactive (OR, 4.07; 95% CI, 2.69 to 6.17), whereas a greater proportion of boys were current smokers (OR, 2.17; 95% CI, 1.19 to 3.91), exposed to passive smoking (OR, 2.57; 95% CI, 1.72 to 3.83), and using betel nut (OR, 2.03; 95% CI, 1.34 to 3.06). Only 3.1% of the participants were without any preventable lifestyle risk factor for NCDs, and over 80% had ≥2 factors. Co-existence of risk factors was independently associated with fathers being blue-collar workers (aOR, 3.57; 95% CI, 1.07 to 11.92) and parents not treating their child fairly (aOR, 5.05; 95% CI, 1.29 to 19.78). CONCLUSIONS: Most of the adolescents studied had preventable risk factors for NCDs. These results warrant comprehensive and integrated interventions to prevent lifestyle risk factors, and parents are front-line stakeholders.