ALBERT

Description: The analysis of ecological networks is generally bottom-up, where networks are established by observing interactions between individuals. Emergent network properties have been indicated to reflect the dominant mode of interactions in communities that might be mutualistic (e.g., pollination) or antagonistic (e.g., host–parasitoid communities). Many ecological communities, however, comprise species interactions that are difficult to observe directly. Here, we propose that a comparison of the emergent properties from detail-rich reference communities with known modes of interaction can inform our understanding of detail-sparse focal communities. With this top-down approach, we consider patterns of coexistence between termite species that live as guests in mounds built by other host termite species as a case in point. Termite societies are extremely sensitive to perturbations, which precludes determining the nature of their interactions through direct observations. We perform a literature review to construct two networks representing termite mound cohabitation in a Brazilian savanna and in the tropical forest of Cameroon. We contrast the properties of these cohabitation networks with a total of 197 geographically diverse mutualistic plant–pollinator and antagonistic host–parasitoid networks. We analyze network properties for the networks, perform a principal components analysis (PCA), and compute the Mahalanobis distance of the termite networks to the cloud of mutualistic and antagonistic networks to assess the extent to which the termite networks overlap with the properties of the reference networks. Both termite networks overlap more closely with the mutualistic plant–pollinator communities than the antagonistic host–parasitoid communities, although the Brazilian community overlap with mutualistic communities is stronger. The analysis raises the hypothesis that termite–termite cohabitation networks may be overall mutualistic. More broadly, this work provides support for the argument that cryptic communities may be analyzed via comparison to well-characterized communities. Many species–species interactions are difficult to observe directly. Here we propose that comparing the network topology of these obfuscated communities to the network topology of well-studied, detail-rich communities will provide insight into the structure of the obfuscated communities. We examine termite mound cohabitation as a case study; the analysis raises the hypothesis that the interactions contained therein may be overall mutualistic.

Description: Symbiosis, the living-together of unlike organisms, underlies every major transition in evolution and pervades most ecological dynamics. Among examples of symbioses, the simultaneous occupation of a termite nest by its builder termites and intruding invertebrate species (so-called termitophily) provides suitable macroscopic scenarios for the study of species coexistence in confined environments. Current evidence on termitophily abounds for dynamics occurring at the interindividual level within the termitarium, but is insufficient for broader scales such as the community and the landscape. Here, we inspect the effects of abiotic disturbance on termitophile presence and function in termitaria at these broader scales. To do so, we censused the termitophile communities inhabiting 30 termitaria of distinct volumes which had been exposed to increasing degrees of fire-induced disturbance in a savanna-like ecosystem in southeastern Brazil. We provide evidence that such an abiotic disturbance can ease the living-together of termitophiles and termites. Putative processes facilitating these symbioses, however, varied according to the invader. For nonsocial invaders, disturbance seemed to boost coexistence with termites via the habitat amelioration that termitaria provided under wildfire, as suggested by the positive correlation between disturbance degree and termitophile abundance and richness. As for social invaders (ants), disturbance seemed to enhance associational defenses with termites, as suggested by the negative correlation between the presence of ant colonies and the richness and abundance of other termitarium-cohabiting termitophiles. It is then apparent that disturbance-modulated distinct symbioses in these termite nests. Fire-induced disturbance boosted coexistence of termites and non-social termitophiles via the habitat amelioration that termitaria provided under wildfire. Simultaneously, harsh conditions enhanced termitaria defense by social termitophiles (ants).

Description: In this work, we investigate the generalized Hyers-Ulam stability of the Apollonius type additive functional equation in modular spaces with or without Δ 2 -conditions. We study the same problem in fuzzy Banach spaces and β -homogeneous Banach spaces. We show the hyperstability of the functional equation associated with the Jordan triple product in fuzzy Banach algebras. The obtained results can be applied to differential and integral equations with kernels of non-power types.

Description: In a phase I study, the sequentially administered combination of recombinant human interleukin-3 (rhIL-3) and rhGM-CSF was compared with treatment with rhIL-3 alone in 15 patients with advanced tumors but normal hematopoiesis. Patients were initially treated with rhIL-3 for 15 days. After a treatment-free interval, the patients received a second 5-day cycle of rhIL-3 at an identical dosage, immediately followed by a 10-day course of rhGM-CSF, to assess the toxicity and biologic effects of this sequential rhIL-3/rhGM-CSF combination. rhIL-3 doses tested were 125, and 250 micrograms/m2, whereas rhGM-CSF was administered at a daily dosage of 250 micrograms/m2. Both cytokines were administered by subcutaneous (SC) bolus injection. rhIL-3/rhGM-CSF treatment was more effective than rhIL-3 but equally effective to each other in increasing peripheral leukocyte counts, especially neutrophilic and eosinophilic granulocyte counts. In contrast, both modes of cytokine therapy raised the platelet counts to the same degree. rhIL-3/GM-CSF treatment was more effective than rhIL-3 in increasing the number of circulating hematopoietic progenitor cells BFU- E and CFU-GM. High-dose rhIL-3, but not low-dose rhIL-3, was as effective as the rhIL-3/rhGM-CSF combinations in increasing the number of circulating CFU-GEMM. The increase in absolute neutrophil counts correlated with the increase in the number of circulating CFU-GM. Side effects, mainly fever, headache, flushing, and sweating, were generally mild, but in two patients the occurrence of chills, rigor, and dyspnea after initiation of GM-CSF treatment necessitated dose reduction and discontinuation, respectively. These results indicate that sequential treatment with rhIL-3 and rhGM-CSF is as effective as single-factor treatment with rhIL-3 in stimulating platelet counts, whereas the effect of combination therapy on neutrophil counts and circulating progenitor cells is superior.

Description: In a phase I study, the sequentially administered combination of recombinant human interleukin-3 (rhIL-3) and rhGM-CSF was compared with treatment with rhIL-3 alone in 15 patients with advanced tumors but normal hematopoiesis. Patients were initially treated with rhIL-3 for 15 days. After a treatment-free interval, the patients received a second 5-day cycle of rhIL-3 at an identical dosage, immediately followed by a 10-day course of rhGM-CSF, to assess the toxicity and biologic effects of this sequential rhIL-3/rhGM-CSF combination. rhIL-3 doses tested were 125, and 250 micrograms/m2, whereas rhGM-CSF was administered at a daily dosage of 250 micrograms/m2. Both cytokines were administered by subcutaneous (SC) bolus injection. rhIL-3/rhGM-CSF treatment was more effective than rhIL-3 but equally effective to each other in increasing peripheral leukocyte counts, especially neutrophilic and eosinophilic granulocyte counts. In contrast, both modes of cytokine therapy raised the platelet counts to the same degree. rhIL-3/GM-CSF treatment was more effective than rhIL-3 in increasing the number of circulating hematopoietic progenitor cells BFU- E and CFU-GM. High-dose rhIL-3, but not low-dose rhIL-3, was as effective as the rhIL-3/rhGM-CSF combinations in increasing the number of circulating CFU-GEMM. The increase in absolute neutrophil counts correlated with the increase in the number of circulating CFU-GM. Side effects, mainly fever, headache, flushing, and sweating, were generally mild, but in two patients the occurrence of chills, rigor, and dyspnea after initiation of GM-CSF treatment necessitated dose reduction and discontinuation, respectively. These results indicate that sequential treatment with rhIL-3 and rhGM-CSF is as effective as single-factor treatment with rhIL-3 in stimulating platelet counts, whereas the effect of combination therapy on neutrophil counts and circulating progenitor cells is superior.

Description: This prospective multicenter study examined whether simultaneous administration of granulocyte colony-stimulating factor (G-CSF; Filgrastim) and induction chemotherapy for adult acute lymphoblastic leukemia (ALL) could prevent treatment-related neutropenia, infections, and resulting treatment delays. Seventy-six patients were randomly assigned to receive either G-CSF (n = 37) or no growth factor (n = 39) in conjunction with a uniform chemotherapy consisting of cyclophosphamide, cytarabine, mercaptopurine, intrathecal methotrexate, and cranial irradiation. The median duration of neutropenia (absolute neutrophil count 〈 1 x 10(9)/L) during chemotherapy was 8 days in patients receiving C-CSF, compared with 12.5 days in the control group (P 〈 .002). A similar reduction from 11.5 to 7 days was observed in patients with T-ALL receiving additional mediastinal irradiation (P = .13). Infections occurred in 43% and 56% of patients in the G-CSF and control arm, respectively (P = .25); the incidence of nonviral infections was reduced by 50%, from 32 episodes in the control arm to 16 episodes in the G-CSF arm. Prolonged interruptions of chemotherapy administration were less frequent, with delays of 2 weeks or more occurring in only 24% of patients receiving G-CSF as opposed to 46% in the control arm (P = .01). Accordingly, chemotherapy was completed significantly earlier with the use of G-CSF (39 v 44 days, P = .008). With a median follow-up of 20 months, the probability of disease-free survival was 0.45 in the G-CSF group and 0.43 in the control group (P = .34). In conclusion, adult ALL patients appear to benefit by the simultaneous administration of G-CSF with induction chemotherapy because of a significant reduction in the duration of neutropenia, a trend to fewer infections, and a more rapid completion of chemotherapy.

Description: In a phase I/II study, nine patients with aplastic anemia were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biologic effects of this multipotential hematopoietic growth factor. Doses ranging from 250 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injections daily for 15 days. An increase in platelet counts from 1,000/microL to 31,000/microL was induced by rhIL-3 in one patient, and an increase in reticulocyte counts by more than 10,000/microL in four patients. The blood leukocyte counts temporarily increased in eight patients 1.5- to 3.3-fold (median, 1.8-fold), mainly due to an increase in the number of neutrophils, eosinophils, lymphocytes, and monocytes. In two patients, bone marrow cellularity increased from 7% to 33% and from 10% to 80%, respectively, but without resulting in a substantial improvement of peripheral blood counts. Mild side effects (headache and flushing) were observed in some patients, while low-grade fever occurred in all patients. Transient thrombocytopenia necessitating discontinuation of rhIL-3 treatment occurred in one patient. In conclusion, rhIL-3 can stimulate hematopoiesis in patients with aplastic anemia; however, no lasting effects were obtained.

Description: To develop a sensitive and specific assay for minimal residual disease in acute lymphoblastic leukemia (ALL), we exploited the enormous diversity of genomic sequences created by immune receptor gene rearrangements. To isolate clone-specific sequences, we first synthesized oligonucleotides that match conserved variable (VH) and joining (JH) sequences flanking the third hypervariable region (HVR3) in the rearranged immunoglobulin heavy chain (IgH) locus. In polymerase chain reactions (PCR), these primers were then used to amplify the intervening HVR3 segments from leukemic DNA samples. Of 12 B-lineage ALLs studied, ten generated one or more fragments of the size expected for HVR3 gene segments. Thus, this single pair of amplimers was sufficient to isolate HVR3 sequences from a majority of acute lymphoblastic leukemias. To verify that the amplified fragments originated from HVR3 alleles and to assess their diversity, we sequenced 7 PCR products derived from 6 leukemias. In addition to elements of recognized D segments, each of the 7 fragments contained novel VH-D and D-JH junctional sequences, including N nucleotides, not known to be present in the germline. Each sequence was unique, and allele-specific oligonucleotide probes hybridized only to HVR3 segments from which the probes were derived. Therefore, as anticipated, these HVR3 segments appeared to possess the diversity required to serve as clonal markers for leukemic populations. To demonstrate that these amplified HVR3 alleles could serve as the basis for a sensitive and specific assay to detect rare leukemic cells, we analyzed in detail one pre-B leukemia that had rearranged 2 IgH alleles. The HVR3 sequences were shown to be linked to rearranged JH-containing restriction fragments in digests of genomic DNA, establishing their origin in the leukemic cells. We synthesized oligonucleotides corresponding to the unique junctional sequences in the HVR3 segments. Using these novel amplimers in an allele-specific amplification and hybridization procedure, we showed that this assay can detect 10 leukemic cells in a background of 10(6) normal blood mononuclear cells. In contrast, the leukemic HVR3 sequences were not detected in extracts of normal or unrelated remission leukemic leukocytes. We conclude that the assay for specific IgH HVR3 sequences is a realistic strategy for detection of minimal residual disease in B-lineage ALL.

Description: In a phase I/II study, 19 patients with advanced tumors but normal hematopoiesis and nine patients with bone marrow failure and prolonged severe cytopenias were treated with recombinant human interleukin-3 (rhIL-3) to assess the toxicity and biological effects of this multipotential hematopoietic growth factor. Doses ranging from 30 micrograms/m2 to 500 micrograms/m2 were administered as subcutaneous bolus injection daily for 15 days. A dose-dependent increase in platelet counts ranging from 1.3-fold at 60 micrograms/m2 to 1.9-fold at 250 micrograms/m2 was induced by rhIL-3 in 15 of 18 evaluable patients with normal hematopoiesis. An increase in reticulocyte counts was observed in 14 patients. The blood leukocyte counts dose dependently increased 1.4- to 3.0-fold. In patients with bone marrow failure, platelet counts increased by a mean of sixfold (range, 1.3- fold to 14.3-fold) in five of eight evaluable patients. Reticulocyte counts increased 4.4-fold in six patients, and neutrophil counts increased by a mean of 3.1-fold in all eight patients. Platelet transfusions could be discontinued after treatment with rhIL-3 in two of three transfusion-dependent patients. Only mild side effects, mainly fever, headache, and flushing, were observed. These results indicate that rhIL-3 functions as a multilineage hematopoietin in vivo in patients with normal bone marrow function and in patients with secondary bone marrow failure.

Description: We investigated the effects of interleukin-3 (IL-3), IL-7, IL-1, and IL- 6, of irradiated bone marrow-derived fibroblasts (Fb) and of in vitro matured peripheral blood macrophages (M phi), on the survival, proliferation, and maturation of purified blasts from nine common acute lymphoblastic leukemias (cALLs) in 7-day suspension culture. Exposure to IL-3, IL-7, IL-1, and IL-6 resulted in a mean 2.8-, 1.5-, 1.4-, and 1.6-fold stimulation of 3H-thymidine (3H-TdR) incorporation, respectively. Cocultures of cALL blasts with irradiated M phi, either allowing direct cell-cell contact or preventing it by membrane filters, or with irradiated Fb, resulted in a mean 31.7-, 4.1-, and 11.2-fold increase of 3H-TdR incorporation, respectively. Southern blot analysis of immunoglobulin and T-cell receptor (TCR) gene rearrangements before and after culture indicated exclusive proliferation of the leukemic clone in three of eight samples, whereas additional generation of nonleukemic cells was found in five samples. Polyclonal growth pattern corresponded to the detection of heterogeneous cell populations using FACS analysis. Survival of cALL blasts as defined by the detection of cells coexpressing both CD10 and CD19 after culture was supported by accessory cells in five of eight samples. No evidence of induced lymphoid maturation was found under any culture condition. Our data demonstrate supportive effects of stromal cells on cALL growth, which cannot be replaced by IL-3 or IL-7.