Let
k
be an integer such that
k
≥
3
.
Let
H
k
denote the set of
k
-connected graphs each
G
of which has a vertex
x
such that
G
-
x
is a
(
k
-
1
)
-connected
(
k
-
1
)
-regular graph. Note that
H
3
is ...the set of wheels. Let
G
be a
k
-connected graph where
k
≥
2
is an integer. An operation on
G
is defined as follows. (I) Delete a vertex
x
of degree at least
2
(
k
-
1
)
from
G
, (II) Add new two vertices
x
1
and
x
2
,
(III) Join
x
i
to
N
i
∪
{
x
3
-
i
}
for
i
=
1
,
2
where
N
G
(
x
)
=
N
1
∪
N
2
,
|
N
i
|
≥
k
-
1
for
i
=
1
,
2
and
N
1
∩
N
2
=
∅
.
We call this operation “proper vertex-splitting”. Two edges of a graph are said to be “independent” if they have no common end vertex and a set of edges is said to be “independent” if each two of it are independent. Let
G
be a 2
k
-connected graph where
k
is a positive integer. We define an operation on
G
as follows. (I) Choose independent
k
edges of
G
, (II) Subdivide each of the chosen
k
edges by one vertex, (III) Identify the new
k
vertices arising from the subdivisions. We call this operation “edge-binding”.
Tutte gave a constructive characterization of 3-connected graphs.
Theorem
(Tutte’s wheel theorem, 1961)
Every
3-
connected graph can be obtained from a graph in
H
3
by repeated applications of edge addings and proper vertex-splittings.
In this paper we prove the following 4-connected analogue of Tutte’s Wheel Theorem.
Theorem
Every
4-
connected graph can be obtained from a graph in
H
4
by repeated applications of edge addings, proper vertex-splittings and edge-bindings.
Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based ...chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma.
We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival.
A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval CI, 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died.
Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).
Four known Malayan species described by Fairmaire and Kraatz are redescribed;
Gauromaia approximans
Fairmaire, 1897 and
G. femoralis
Fairmaire, 1893 are transferred to the genus
Phaedis
and also ...redescribed herein. A lectotype is designated for
Pseudeumorpus decretus
Fairmaire, 1893. The following new synonymies are established:
Phaedis superbus
(Kraatz, 1880) =
Ph. semiarmatus
(Fairmaire, 1893),
syn. n.;
Phaedis pretiosus
(Kraatz, 1880) =
Ph. decretus
(Fairmaire, 1893),
syn. n.
Six new species are described from the Malay Peninsula:
Phaedis azureus
sp. n.
,
Ph.
hatayamai
sp. n.
,
Ph. marginipennis
sp. n.
,
Ph. medvedevi
sp. n.
,
Ph. propinquus
sp. n.
, and
Ph. viridistriatus
sp. n.
Genetic variants in C5 and poor response to eculizumab Nishimura, Jun-ichi; Yamamoto, Masaki; Hayashi, Shin ...
New England journal of medicine/The New England journal of medicine,
02/2014, Letnik:
370, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The ...molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).
Anti-CD38 monoclonal antibody (MoAb) treatments including daratumumab (DARA) are effective therapies for both newly diagnosed and relapsed multiple myeloma (MM). In this study, we examined the ...soluble factors that modulate CD38 expression and are associated with sensitivity to DARA-mediated antibody-dependent cellular cytotoxicity (ADCC) in the bone marrow (BM) microenvironment. Importantly, primary BM stromal cell (BMSC) culture supernatant (BMSC-sup) and interleukin-6 (IL-6) downregulated CD38 expression and reduced DARA-mediated ADCC. Both cytokine profiling of the BMSC-sup and genome-scale clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) knockout screening in MM cell lines identified and validated the JAK-STAT3 signaling pathway mediating CD38 downregulation, whereas the JAK-STAT1 pathway mediated CD38 upregulation. STAT3 knockdown abrogated BMSC-sup- and IL-6-induced CD38 downregulation on MM cell lines. We also confirmed that STAT3 and CD38 is negatively correlated in primary MM cells. To assess potential clinical relevance, pharmacological inhibition of the JAK-STAT pathway on BMSC-sup-induced CD38 downregulation was further examined. JAK inhibitor ruxolitinib inhibited STAT3 phosphorylation in MM cell lines, upregulated CD38 expression in MM cell lines and primary patient MM cells, and augmented DARA-mediated ADCC against MM cell lines. Taken together, our results suggest that CD38 expression on MM cells in the BM microenvironment is regulated by both STAT1 (positively) and STAT3 (negatively), and that inhibition of the JAK-STAT3 pathway represents a novel therapeutic option to enhance CD38 expression and anti-CD38 MoAb-mediated MM cytotoxicity.
Platybolium watanai sp. nov., the second species of the genus, is described from Thailand, with illustrations of the diagnostic characters, including the defensive glands and the cuticular structures ...of females. The type species of the genus, Platybolium alvearium Blair, 1938, is known from beehives in a wide range of the Oriental region, but the new species was found in an ant nest of Pheidole singaporensis Özdikmen, 2010. Myrmecophily in the new species is discussed.
In classical Hodgkin lymphoma (cHL)-characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells-tumor-associated macrophages (TAMs) play a pivotal role in tumor formation. However, the ...significance of direct contact between HRS cells and TAMs has not been elucidated. HRS cells and TAMs are known to express PD-L1, which leads to PD-1
CD4
T cell exhaustion in cHL. Here, we found that PD-L1/L2 expression was elevated in monocytes co-cultured with HRS cells within 1 h, but not in monocytes cultured with supernatants of HRS cells. Immunofluorescence analysis of PD-L1/L2 revealed that their upregulation resulted in membrane transfer called "trogocytosis" from HRS cells to monocytes. PD-L1/L2 upregulation was not observed in monocytes co-cultured with PD-L1/L2-deficient HRS cells, validating the hypothesis that there is a direct transfer of PD-L1/L2 from HRS cells to monocytes. In the patients, both ligands (PD-L1/L2) were upregulated in TAMs in contact with HRS cells, but not in TAMs distant from HRS cells, suggesting that trogocytosis occurs in cHL patients. Taken together, trogocytosis may be one of the mechanisms that induces rapid upregulation of PD-L1/L2 in monocytes to evade antitumor immunity through the suppression of T cells as mediated by MHC antigen presentation.
Let
G
be a 3-connected graph. An edge (a triangle) of
G
is said to be a 3-contractible edge (a 3-contractible triangle) if the contraction of it results in a 3-connected graph. We denote by
E
c
(
G
)
...and
T
c
(
G
)
the set of 3-contractible edges of
G
and the set of 3-contractible triangles of
G
, respectively. We prove that if
|
V
(
G
)
|
≥
7
, then
|
E
c
(
G
)
|
+
15
14
|
T
c
(
G
)
|
≥
6
7
|
V
(
G
)
|
.
We also determine the extremal graphs.
Extracellular vesicles (EVs) including exosomes act as intercellular communicators by transferring protein and microRNA cargoes, yet the role of EV lipids remains unclear. Here, we show that the ...pro-tumorigenic action of lymphoma-derived EVs is augmented via secreted phospholipase A2 (sPLA2)-driven lipid metabolism. Hydrolysis of EV phospholipids by group X sPLA2, which was induced in macrophages of Epstein-Barr virus (EBV) lymphoma, increased the production of fatty acids, lysophospholipids, and their metabolites. sPLA2-treated EVs were smaller and self-aggregated, showed better uptake, and increased cytokine expression and lipid mediator signaling in tumor-associated macrophages. Pharmacological inhibition of endogenous sPLA2 suppressed lymphoma growth in EBV-infected humanized mice, while treatment with sPLA2-modified EVs reversed this phenotype. Furthermore, sPLA2 expression in human large B cell lymphomas inversely correlated with patient survival. Overall, the sPLA2-mediated EV modification promotes tumor development, highlighting a non-canonical mechanistic action of EVs as an extracellular hydrolytic platform of sPLA2.
Display omitted
•sPLA2-X is induced in EBV-induced B cell lymphoma in humanized mice•sPLA2-X hydrolyzes EV membranes to increase lipid mediator cargo•sPLA2-X alters the morphology and function of EVs•sPLA2-X facilitates EBV lymphomagenesis via a lipid-driven non-canonical mechanism
EVs act as intercellular communicators by transferring miRNAs and proteins. Kudo et al. find the importance of EV lipids in EBV lymphoma development. Hydrolysis of phospholipids in tumor-cell-derived EVs by sPLA2-X increases vesicle aggregation, produces immunoregulatory lipid mediators, and facilitates EV uptake by recipient macrophages, thereby exacerbating lymphomagenesis.
Stem cells of highly regenerative organs including blood are susceptible to endogenous DNA damage caused by both intrinsic and extrinsic stress. Response mechanisms to such stress equipped in ...hematopoietic stem cells (HSCs) are crucial in sustaining hematopoietic homeostasis but remain largely unknown. In this study, we demonstrate that serial transplantation of human HSCs into immunodeficient mice triggers replication stress that induces incremental elevation of intracellular reactive oxygen species (ROS) levels and the accumulation of persistent DNA damage within the human HSCs. This accumulation of DNA damage is also detected in HSCs of clinical HSC transplant patients and elderly individuals. A forced increase of intracellular levels of ROS by treatment with a glutathione synthetase inhibitor aggravates the extent of DNA damage, resulting in the functional impairment of HSCs in vivo. The oxidative DNA damage activates the expression of cell-cycle inhibitors in a HSC specific manner, leading to the premature senescence among HSCs, and ultimately to the loss of stem cell function. Importantly, treatment with an antioxidant can antagonize the oxidative DNA damage and eventual HSC dysfunction. The study reveals that ROS play a causative role for DNA damage and the regulation of ROS have a major influence on human HSC aging.
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