Compromised BRCA1-PALB2 interaction is associated with breast cancer risk.

The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported. Here we report on the identification of a novel PALB2 variant, c.104T>C (p.L35P), that segregates in a family with a strong history of breast cancer. Functional analyses showed that L35P abrogates the PALB2-BRCA1 interaction and completely disables its abilities to promote HR and confer resistance to platinum salts and PARP inhibitors. Whole-exome sequencing of a breast cancer from a c.104T>C carrier revealed a second, somatic, truncating mutation affecting PALB2, and the tumor displays hallmark genomic features of tumors with BRCA mutations and HR defects, cementing the pathogenicity of L35P. Parallel analyses of other germline variants in the PALB2 N-terminal BRCA1-binding domain identified multiple variants that affect HR function to varying degrees, suggesting their possible contribution to cancer development. Our findings establish L35P as the first pathogenic missense mutation in PALB2 and directly demonstrate the requirement of the PALB2-BRCA1 interaction for breast cancer suppression.

A phase I trial of andrographolide in HIV positive patients and normal volunteers.

A phase I dose-escalating clinical trial of andrographolide from Andrographis paniculata was conducted in 13 HIV positive patients and five HIV uninfected, healthy volunteers. The objectives were primarily to assess safety and tolerability and secondarily to assess effects on plasma virion HIV-1 RNA levels and CD4(+) lymphocyte levels. No subjects used antiretroviral medications during the trial. Those with liver or renal abnormalities were excluded. The planned regimen was 5 mg/kg bodyweight for 3 weeks, escalating to 10 mg/kg bodyweight for 3 weeks, and to 20 mg/kg bodyweight for a final 3 weeks. The trial was interrupted at 6 weeks due to adverse events including an anaphylactic reaction in one patient. All adverse events had resolved by the end of observation. A significant rise in the mean CD4(+) lymphocyte level of HIV subjects occurred after administration of 10 mg/kg andrographolide (from a baseline of 405 cells/mm(3) to 501 cells/mm(3); p = 0.002). There were no statistically significant changes in mean plasma HIV-1 RNA levels throughout the trial. Andrographolide may inhibit HIV-induced cell cycle dysregulation, leading to a rise in CD4(+) lymphocyte levels in HIV-1 infected individuals.

Measuring knowledge of cancer.

At best, most individuals are able to recount two to three of the seven warning signs of cancer [1]. However, this finding is primarily based on free recall of symptoms personally experienced by the respondent. In the present study, a new approach is introduced as an alternative to traditional assessment of knowledge of cancer warning signs. The Knowledge of Cancer Warning Signs Inventory (KCWSI) is a 25 item self-report questionnaire which yields three scores concerning probability judgments about symptoms: basic recognition of the seven warning signs (BRCWS), the extent to which nonwarning signs are perceived to be warning signs (NSPWS), and the extent to which one can accurately discriminate between real and false positive warning signs (accurate knowledge of cancer: AKC). The KCWSI was given to a population who live in a community facing a perceived toxic waste hazard, based on the hypothesis that such a group should be cognizant of the warning signs of cancer because of the serious health threats posed by toxic exposure and the presumed need to engage in greater health preventative activities when living with such an environmental threat. Results show that basic knowledge of the seven cancer warning signs is predicted by AKC, fear of cancer, and a family history of cancer. Misperception of common distress symptoms (of anxiety, somatization, and depression) as symptoms of cancer (nonwarning signs perceived as warning signs: NSPWS) is predicted by fear of cancer, a composite scale of perceived susceptibility to cancer and other health-related problems, Global Symptom Distress, and higher order interactions among the demographic variables of race, gender, income and education. Accurate Knowledge of Cancer (AKC) is associated with lower fear of cancer and lower psychological distress than the other two knowledge measures. The Knowledge of Cancer Warning Signs Inventory yields complex information about how symptoms are perceived and may prove superior to other methods in understanding what people believe about the warning signs of cancer and how this understanding relates to health care behaviors. This study also illustrates the need to pay attention to how health information is measured.

Fear of cancer and knowledge of cancer: a review and proposed relevance to hazardous waste sites.

Cancer is a disease that is widely feared because of its prevalence and incidence, its widespread causes (heredity, environment, lifestyle) and the belief that 'everything causes cancer'. We review evidence on knowledge of cancer and find that knowledge is very limited. Then we examine factors that are related to knowledge of cancer and the pursuit of additional knowledge about cancer and factors that are related to health care behavior such as low rates of participation in cancer screening tests. This review leads us to conceptualize the essential, and perhaps central, role that fear of cancer has in the psychology of cancer. We then explore why cancer and fear of cancer have gained much attention in communities located near hazardous waste sites.