Changing Concepts of Cancer Biology, Diagnosis and Treatment

Cancer is the number two killer in the United State and will probably account for some 400,000 deaths in 1982. The lung has now achieved the dubious distinction of being the most common site of cancer in men and causes the most deaths. Cancer of the colon and rectum is the second most common cancer in both males and females combined, whereas carcinoma of the breast and uterus predominate in women

HISTOPATHOLOGICAL EFFECTS IN MICE OF HETEROLOGOUS ANTILYMPHOCYTE SERUM

The effects of heterologous rabbit anti-mouse lymphocyte antiserum on the morphology of lymphoid and other tissues was investigated in CBA mice. The lymphoid tissues exhibited characteristic changes specific for ALS treatment, which were an invariable accompaniment to its immunosuppressive effects. These consisted of peripheral lymphopenia occurring at some time during a course of ALS treatment and persistent depletion of small lymphocytes in lymph node paracortical areas and splenic follicular periarteriolar zones. The thymic histology was generally well preserved. It is suggested that the relevant lesions reflect a rapid depletion of the pool of recirculating lymphocytes, possibly by a primary cytotoxic effect exerted on cells peripheral to lymphoid tissue. Other histologic features attendant to the administration of ALS were accounted for as consequences of immunization of ALS recipients to rabbit serum constituents or by the deleterious effects of antibodies directed against tissues other than lymphoid cells

Killing vectors in asymptotically flat space-times: I. Asymptotically translational Killing vectors and the rigid positive energy theorem

We study Killing vector fields in asymptotically flat space-times. We prove the following result, implicitly assumed in the uniqueness theory of stationary black holes. If the conditions of the rigidity part of the positive energy theorem are met, then in such space-times there are no asymptotically null Killing vector fields except if the initial data set can be embedded in Minkowski space-time. We also give a proof of the non-existence of non-singular (in an appropriate sense) asymptotically flat space-times which satisfy an energy condition and which have a null ADM four-momentum, under conditions weaker than previously considered.Comment: 30 page

DISTRIBUTION OF LABELED LYMPH NODE CELLS IN MICE DURING THE LYMPHOCYTOSIS INDUCED BY BORDETELLA PERTUSSIS

The mechanism by which Bordetella pertussis organisms and their products induce lymphocytosis in mice was analyzed in terms of the localization of syngeneic Cr-51-labeled lymph node cells. Labeled lymphoid cells incubated in vitro with the supernatant of B. pertussis cultures and then injected intravenously into normal recipients, or labeled cells injected into pertussis-treated recipients were unable to "home" to lymphoid organs but persisted for long periods in the blood. In animals "equipped" with a population of Cr-51-labeled lymphoid cells, administration of B. pertussis organisms or culture supernatant effected a shift of radioactivity from lymph nodes and spleen into the peripheral blood, coincident with the lymphocytosis. In in vitro experiments it was found that the active principle could bind to both erythrocytes and lymphocytes and could spontaneously elute from these cells onto labeled lymphocytes which were then unable to home efficiently. The data suggest that Bordetella pertussis-induced lymphocytosis involves a reversible attachment of the pertussis factor onto the surfaces of lymphocytes which prevents their recirculation to lymphoid organs. Recirculating lymphocytes are presumably affected as they emerge from lymphoid organs to enter the blood

Effect of alirocumab on lipids and lipoproteins in individuals with metabolic syndrome without diabetes: Pooled data from 10 phase 3 trials.

AimsThis analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials.Materials and methodsData from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo-controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe-controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL-C.ResultsLDL-C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non-MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non-MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), lipoprotein(a) and HDL-C. Overall, the percentage change at Week 24 in LDL-C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection-site reactions occurred more frequently in alirocumab vs control groups.ConclusionsAcross study pools, alirocumab-associated reductions in LDL-C, apolipoprotein B, and non-HDL-C were significant vs control, and did not vary by MetS status

Phase II Study of Temozolomide and Thalidomide in Patients with Unresectable or Metastatic Leiomyosarcoma

We assessed the efficacy of combined temozolomide and thalidomide in patients with unresectable or metastatic leiomyosarcoma in a phase II single-institution trial. Twenty-four patients were enrolled. Temozolomide (150 mg/m2/day for 7 days every other week) was administered with concomitant thalidomide (200 mg/day), and continued until unacceptable toxicity or disease progression. There were no complete responses and two (10%) partial responses. Five patients (24%) had stable disease for at least six months. Fourteen patients (67%) progressed after a median of two-month treatment. The median overall survival (twenty-two assessable patients) was 9.5 months [95% CI 7–28 months]. There were no treatment-related deaths or CTC grade 4 toxicities. Thirteen patients were dose-reduced or discontinued thalidomide due to toxicity. In conclusion, this combination of temozolomide and thalidomide provided disease stabilization in a subset of patients with advanced leiomyosarcoma. We hypothesize that temozolomide is the active agent in this regimen, and should be further studied

Direct and indirect effects of retinoic acid on human Th2 cytokine and chemokine expression by human T lymphocytes

BACKGROUND: Vitamin A (VA) deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s) involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMCs with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA) or 9-cis-RA. RESULTS: Stimulation of human PBMCs and purified T cells with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-γ, IL-2, IL-12p70 and TNF-α upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional proinflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment. CONCLUSION: These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses

Nuttier (A)dS Black Holes in Higher Dimensions

We construct new solutions of the vacuum Einstein field equations with cosmological constant. These solutions describe spacetimes with non-trivial topology that are asymptotically dS, AdS or flat. For a negative cosmological constant these solutions are NUT charged generalizations of the topological black hole solutions in higher dimensions. We also point out the existence of such NUT charged spacetimes in odd dimensions and we explicitly construct such spaces in 5 and 7 dimensions. The existence of such spacetimes with non-trivial topology is closely related to the existence of the cosmological constant. Finally, we discuss the global structure of such solutions and possible applications in string theory.Comment: latex, 30 pages, added reference

Early Diagnosis of Relapse in Acute Myeloblastic Leukemia — Serologic Detection of Leukemia-Associated Antigens in Human Marrow

Abstract We tested serial bone-marrow samples from 47 adults with acute myeloblastic leukemia in remission for reactivity with heteroantiserums to leukemia-associated antigens, to determine whether imminent relapse could be detected in patients with acute leukemia. Of 26 patients who relapsed by standard morphologic criteria, 21 had increased immunoreactivity of bone marrow for one to six months (mean, 3.7 months) before relapse. High concordance was observed between a positive test and relapse during the period of study (chi-square = 27.53,

Large N Phases, Gravitational Instantons and the Nuts and Bolts of AdS Holography

Recent results in the literature concerning holography indicate that the thermodynamics of quantum gravity (at least with a negative cosmological constant) can be modeled by the large N thermodynamics of quantum field theory. We emphasize that this suggests a completely unitary evolution of processes in quantum gravity, including black hole formation and decay; and even more extreme examples involving topology change. As concrete examples which show that this correspondence holds even when the space-time is only locally asymptotically AdS, we compute the thermodynamical phase structure of the AdS-Taub-NUT and AdS-Taub-Bolt spacetimes, and compare them to a 2+1 dimensional conformal field theory (at large N) compactified on a squashed three sphere, and on the twisted plane.Comment: 20 pages, three figures. (uses harvmac.tex and epsf.tex