Programmed death-1 immune checkpoint blockade in the treatment of hematological malignancies

The use of tumor-specific monoclonal antibodies (MAbs) has revolutionize the field of cancer immunotherapy. Although treatment of malignant diseases with MAbs is promising, many patients fail to respond or relapse after an initial response. Both solid tumors and hematological malignancies develop mechanisms that enable them to evade the host immune system by usurping immune checkpoint pathways such as PD-1, PD-2, PDL-1, or PDL-2 (programmed cell death protein-1 or 2 and PD-Ligand 1 or 2), which are expressed on activated T cells and on T-regulatory, B cells, natural killers, monocytes, and dendritic cells. One of the most exciting anticancer development in recent years has been the immune checkpoint blockade therapy by using MAbs against immune checkpoint receptor and/or ligands. Anti-PD1 antibodies have been tested in clinical studies that included patients with hematological malignancies and showed remarkable efficacy in Hodgkin lymphoma (HL). In our review, we will focus on the effect of PD-1 activation on hematological malignancies and its role as a therapeutic target.

• Key messages

• The programmed death 1 (PD1) immune checkpoint is an important homeostatic mechanism of the immune system that helps in preventing autoimmunity and uncontrolled inflammation in cases of chronic infections.

• However, PD1 pathway is also operated by a wide variety of malignancies and represents one of the most important mechanisms by which tumor cells escape from the surveillance of the immune system.

• Blocking of immune checkpoints by the use of monoclonal antibodies opened a new era in the field of cancer immunotherapy. Results from clinical trials are promising, and currently, this approach has been proven effective and safe in patients with solid tumors and hematological malignancies.

     

Site-directed tumor chemotherapy.

The therapeutic effect of drugs used in cancer chemotherapy has been augmented by their complexing or chemical linking to macromolecular carriers. The role of the carrier should be to deliver the drug preferentially to the tumor site. Potential carriers are either (1) nonspecific macromolecules whose preferential activity is due to the inherently higher permeability and pinocytic activity of tumor cells, (2) lysosomotropic agents such as DNA or liposomes, or (3) the more specific agents--antitumor antibodies. Conjugates of daunomycin to antitumor antibodies, prepared either by direct binding or by binding via dextran, were shown to retain both the antibody and the drug activity. Thus they exert specific cytotoxic activity toward tumor cells that the antibodies recognize. In vivo, these complexes are more active than the free drug in prolongation of survival of mice transplanted with the tumor cells. Conjugates of daunomycin with normal immunoglobulin or with dextran also show higher therapeutic efficacy in vivo, probably due to their capacity to reduce the cytotoxicity of daunomycin and/or to the higher permeability of neoplastic cells. But under certain conditions, mainly at low drug concentrations, the drug-antibody conjugates have an advantage over all others.     

Hexosaminidase A in amniotic fluid of Tay-Sachs fetuses

Hexosaminidase A is present in relatively low concentrations in cell-free amniotic fluids from pregnancies with Tay-Sachs fetuses. This isoenzyme was determined by an immunological procedure, radial immunodiffusion, by which hexosaminidase A can be directly and specifically detected, even in the presence of excess amounts of hexosaminidase B. No hexosaminidase A could be detected by the same procedure in Tay-Sachs fetal tissues, implying that this isoenzyme in the amniotic fluid originates from the mother.     

Nerve growth factor mediates hyperalgesia and cachexia in auto-immune arthritis

Pain and cachexia are two of the most debilitating aspects of rheumatoid arthritis. Despite that, the mechanisms by which they are mediated are not well understood. We provide evidence that nerve growth factor (NGF), a secreted regulatory protein that controls neuronal survival during development, is a key mediator of pain and weight loss in auto-immune arthritis. Function blocking antibodies to NGF completely reverse established pain in rats with fully developed arthritis despite continuing joint destruction and inflammation. Likewise, these antibodies reverse weight loss while not having any effect on levels of the pro-cachectic agent tumor necrosis factor (TNF). Taken together, these findings argue that pathological joint pain and joint destruction are mechanistically independent processes and that NGF regulates an alternative cachexia pathway that is independent or downstream of TNF.     

New Insights on Glucose Pathophysiology in Gestational Diabetes and Insulin Resistance

Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition of GDM does not preclude the possibility that unrecognized glucose intolerance may have existed before the pregnancy, and the definition applies whether insulin, oral antidiabetic agents, or dietary modification is used for treatment. Approximately 7% of all pregnancies in the United States are complicated by gestational diabetes resulting in more than 200,000 cases annually, but the prevalence ranges from 1% to 14% of all pregnancies depending on the population studied and the diagnostic tests used. Despite the better detection of GDM and recognition of its adverse consequences for mother and baby in many countries, there is still no consensus regarding GDM pathophysiology; as a result, diagnosis and treatment of GDM remain controversial. A better understanding of obesity along with new studies in GDM has identified the intra-abdominal metabolically active adipose tissue as a major factor in the pathophysiology of GDM. This review examines recent research regarding the link between obesity and glucose intolerance and highlights studies in the areas of genetics, glucose transport, and adipokines.     

Pregnancy outcome after in utero exposure to angiotensin converting enzyme inhibitors or angiotensin receptor blockers

ObjectiveTo examine first trimester safety of angiotensin-converting-enzyme-inhibitors (ACEIs) or angiotensin-receptor-blockers (ARBs).Study designProspective observational cohort regarding pregnancy ACEI/ARBs-exposure including contacts to two Teratology Information Services in Israel (1994–2007) and Italy (1990–2008), with two comparison groups: (1) exposed to other antihypertensives (OAH) (2) after non-teratogenic exposure (NTE) in similar time frames.Results252 ACEI/ARBs-exposed, 256 OAH-exposed and 495 NTE-exposed pregnancies were followed-up. The rate of major congenital anomalies was comparable between the groups (8/190, 4.2%, ACEI/ARB; 9/212, 4.2%, OAH; 18/471, 3.8% NTE; p = 0.954) among first trimester exposed pregnancies. The median gestational age at delivery was two weeks earlier, rate of preterm deliveries more than 2-fold higher, and median birth weight more than 200 g lower in the ACEI/ARB and OAH groups compared to the NTE group.ConclusionThe present study suggests that ACEI/ARBs are not major teratogens when used in the first trimester, and can reassure women with similar exposures.     

Periodontal care may improve endothelial function

BackgroundPeriodontitis is a chronic, infectious, insidious disease of the tooth-supporting structures that causes a general inflammatory response. The aims of this study were to determine whether periodontitis is associated with endothelial dysfunction leading to cardiovascular events and whether proper management of periodontal disease would improve endothelial function and prevent cardiovascular events in the future.MethodsTwenty-two patients (12 women, 10 men; 40 ± 5 years old) took part in the study. All had severe periodontitis (without systemic disorders) and were all treated conservatively. Thirteen patients returned for a second visit after 3 months of treatment. Endothelial function and periodontal status were evaluated on entry into the study and 3 months following treatment. Ten age-matched, healthy volunteers without periodontal disease served as the control group.ResultsThere was a significant difference between the patient group and the healthy controls: FMD% 4.12 ± 3.96 vs. 16.60 ± 7.86% (p = 0.0000). Periodontitis improved significantly in all 13 patients who completed 3 months of treatment, and their endothelial function improved as well: FMD% 4.12 ± 3.96% vs. 11.12 ± 7.22% (p = 0.007). No difference was found in FID% before and after 3 months of treatment: 20.97 ± 10.66% vs.17.94 ± 6.23% (p = NS).ConclusionsPeriodontitis may be an insidious cause of endothelial dysfunction and cardiovascular events. Treating periodontitis can improve endothelial function and be an important preventive tool for cardiovascular disease.     

The effect of music relaxation versus progressive muscular relaxation on insomnia in older people and their relationship to personality traits

A large percentage of older people suffer from chronic insomnia, affecting many aspects of life quality and well-being. Although insomnia is most often treated with medication, a growing number of studies demonstrate the efficiency of various relaxation techniques. The present study had three aims: first, to compare two relaxation techniques--music relaxation and progressive muscular relaxation--on various objective and subjective measures of sleep quality; second, to examine the effect of these techniques on anxiety and depression; and finally, to explore possible relationships between the efficiency of both techniques and personality variables. Fifteen older adults took part in the study. Following one week of base-line measurements of sleep quality, participants followed one week of music relaxation and one week of progressive muscular relaxation before going to sleep. Order of relaxation techniques was controlled. Results show music relaxation was more efficient in improving sleep. Sleep efficiency was higher after music relaxation than after progressive muscular relaxation. Moreover, anxiety was lower after music relaxation. Progressive muscular relaxation was related to deterioration of sleep quality on subjective measures. Beyond differences between the relaxation techniques, extraverts seemed to benefit more from both music and progressive muscular relaxation. The advantage of non-pharmacological means to treat insomnia, and the importance of taking individual differences into account are discussed.