抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1200690

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)04046-0.pdf

Inflammation and cancer: back to Virchow?

https://www.cell.com/cell/pdf/0092-8674(93)90509-O.pdf

Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death

CD40 stimulation promotes human secondary immunoglobulin responses in HuPBL-SCID chimeras

1.Introduction and Background 2. Diffuse Large B-Cell Lymphoma 3. Follicular Lymphoma 4. Peripheral T-cell Lymphomas 5. Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia 6. Mantle Cell Lymphoma 7. MALT Lymphoma (Extranodal Marginal-Zone B-Cell Lymphoma) 8. Burkitt's Lymphoma/Leukemia 9. Anaplastic Large T/null Cell Lymphoma 10. Primary Mediastinal Large B-Cell Lymphoma 11. Lymphoblastic Leukemia Lymphoma 12. Lymphoplasmacytic Lymphoma 13. Nodal and Splenic Marginal-Zone B-Cell Lymphomas 14. Lymphomas Involving Extranodal Sites 15. Hodgkin's Disease 16. Rare Subtypes 17. Summary

Text Atlas of Lymphomas

Interferon toxicity worse in retrospect; impact on q-twist?

ANEMIA as defined by World Health Organization criteria (i.e., ,12 g/dL in women; ,13 g/dL in men) is noted in 10%–11% of community-dwelling people aged 65 years or older (1). Iron-, B12-, and/or folate deficiency accounts for approximately 34% of cases, chronic disease (renal disease, chronic inflammatory disease, or both) accounts for approximately 32%, and the rest are unexplained. Among nursing home residents, the prevalence of anemia is 48% and the cause is unexplained in 45% of those individuals (2). Regardless of the mechanism, anemia is a poor prognostic factor for an enormous range of health outcomes. Patients with cardiovascular disease, renal disease, and cancer all have poorer quality of life and survival if they are anemic (3–5). Perioperative mortality is also adversely affected by anemia (6). In nursing home residents, 5-year survival is related to hemoglobin level as well as age; for the group aged 80–89 years, 5-year survival was 62% in the absence of anemia and 41% in its presence (7). Anemia is also associated with increased mortality in community-dwelling older women with moderate-to-severe disability (8). In this issue of the Journal, data are presented for the first time linking alterations in hemoglobin levels even within the low normal range to an increased risk of frailty in community-dwelling older women who were participants in the Women’s Health and Aging Studies (9). The relative risk of developing frailty was 7.1 for women with hemoglobin levels of 10 g/dL, 4.3 for women with hemoglobin levels of 10.5 g/dL, and 1.9 for women with hemoglobin levels of 11.5 g/dL compared with those with hemoglobin levels of 13.5 g/dL, the level at which frailty risk was lowest. The risk was increased 50% at hemoglobin levels of 12 g/dL. The presence of cardiovascular disease further augmented the risk. From one perspective, this important finding is a direct extension of prior work that has shown a relationship between anemia and most of the components of the frailty syndrome including reduced muscle strength and density (10), impaired mobility (11), disability, and poor physical performance (12). However, the novel promise of the work is that anemia may be a component of the pathophysiology of frailty and, if it is, correction of anemia may prevent or delay the onset of frailty. Although it is possible that heterogeneous mechanisms contribute to the unexplained anemia in elderly people, recent and ongoing studies suggest that a final common pathway involves erythropoietin production and responsiveness. We evaluated hemoglobin and erythropoietin levels longitudinally in participants of the Baltimore Longitudinal Study of Aging and found that, in participants who maintain normal hemoglobin levels over time, serum erythropoietin levels increase with age (13). The rising erythropoietin levels imply stress on the erythron. Is red cell life span shorter in older people with increased erythropoietin levels compensating for the increased red cell turnover? No definitive data are available, but it appears that reticulocyte counts are not increased in the setting of normal hemoglobin levels and elevated erythropoietin levels (unpublished observations). Red cell life-span studies in older people need to be performed. Are the erythroid progenitors less responsive to erythropoietin as we age, requiring higher concentrations of erythropoietin to generate the number of cells needed to maintain normal levels? No data have been published that address this question. Is the elevated erythropoietin level with normal hemoglobin a reflection of poorer oxygen delivery to the tissues a relative tissue hypoxia? The hemoglobin/oxygen dissociation curve has not been measured in red blood cells from older people. It is conceivable that 2,3-bisphosphoglycerate levels are lower in the red cells of older people or that the hemoglobin molecule is more susceptible to auto-oxidation, which inhibits its ability to deliver oxygen to the tissues. This question has not been addressed experimentally. The underlying physiology that leads to increased erythropoietin levels is unclear. However, in individuals who go on to develop frank anemia that is otherwise unexplained, they often have reduced serum erythropoietin levels even in the absence of detectable renal disease (13). Thus, at least some, and perhaps most of, the unexplained anemia in elderly people is related to inadequate erythropoietin production. The test of a causal linkage between anemia and frailty is not completely straightforward for a variety of reasons. First, frailty incidence is approximately 14% in the group older than 65 years. Studies aimed at showing a significant drop in incidence will need to enroll many participants. Furthermore, anemia has heterogeneous causes, and a single type of intervention will not be appropriate to all cases. In about one third of patients, repletion of a deficient nutritional component (and reversal of structural causes of blood loss) will be therapeutic. However, for the two thirds of patients with anemia of chronic disease and erythropoietin deficiency (this excludes the very small group with primary marrow disease such as myelodysplasia), the potential interventions each have associated problems. Transfusion has a low, but

/pdf/closing-in-on-a-killer-anemia-in-elderly-people-267htq165c.pdf

Closing in on a Killer: Anemia in Elderly People

The purpose of this trial was to determine the toxicity and antineoplastic activity of cisplatin, carboplatin, tamoxifen, and interferon-α (IFN-α) in patients with advanced melanoma. Eleven patients with metastatic melanoma were enrolled. The patients received carboplatin 400 mg/m2 IV on day 0; cisplatin 25 mg/m2 IV on days 7, 14, and 21; tamoxifen 20 mgp.o. b.i.d. on days 0-27; and interferon-α 5 million units/m2 subcutaneously 3 times per week Cycles were repeated every 28 days. Patients were assessed for tumor response at the end of 2 cycles. Toxicity was severe, with 14 of 24 cycles given requiring some form of dose reduction. Carboplatin dose reductions were related to bone-marrow toxicity, whereas IFN-α caused fatigue, arthralgias, myalgias, and fever. The overall response rate was 18% (2 partial responses [PRs]). The combination of cisplatin, carboplatin, tamoxifen, and IFN-a is active in advanced melanoma; however, the toxicity is unacceptable.

Dan L. Longo

Papers

CD40 stimulation promotes human secondary immunoglobulin responses in HuPBL-SCID chimeras

Text Atlas of Lymphomas

Interferon toxicity worse in retrospect; impact on q-twist?

Closing in on a Killer: Anemia in Elderly People

A phase II study of carboplatin, cisplatin, interferon-alpha, and tamoxifen for patients with metastatic melanoma.