Efficacy of ruxolitinib for HAVCR2 mutation-associated hemophagocytic lymphohistiocytosis and panniculitis manifestations in children.

Frequent germline mutations of HAVCR2, recently identified in subcutaneous panniculitis-like T-cell lymphoma (SPTCL), are associated with an increased risk of hemophagocytic lymphohistiocytosis (HLH). However, SPTCL-HLH represents a challenge because of the difficulties in treatment with poor survival. Its malignant nature, specifically harbouring HAVCR2 mutations, has also been questioned. To better understand its pathology and treatment, we analysed the clinical data of six patients diagnosed at our centre. The median age at onset was 10.5 years (range, 0.8-12.4). Five patients presented with skin lesions of subcutaneous nodules/plaques and/or ulceration. All patients developed HLH; notably, one infant only had HLH without skin involvement. Histopathologically, only two patients were diagnosed with SPTCL and three were reported as panniculitis with no sufficient evidence of lymphoma. Genetically, germline homozygous mutation of HAVCR2 (p.Y82C) was identified in all patients, with a median diagnosis time of 4.6 months. All patients initially received corticosteroids, immunosuppressants or chemotherapy, achieving unfavourable responses. Strikingly, they responded well to ruxolitinib targeting inflammatory cytokines, allowing rapid disease resolution and/or long-term maintenance of remission. The excellent efficacy of ruxolitinib highlights this disease as an inflammatory condition instead of neoplastic nature and indicates novel agents targeting key inflammatory pathways as an encouraging approach for this disease entity.

Chryseobacterium reticulitermitis sp. nov., isolated from the gut of Reticulitermes aculabialis.

A Gram-stain-negative, non-motile, aerobic and rod-shaped bacterium, strain Ra1T, was isolated from the gut of a wood-feeding lower termite, Reticulitermes aculabialis. Phylogenetic analysis of 16S rRNA gene sequences showed that the strain was closely related to Chryseobacterium rigui JCM 18078T (96.7 % similarity). Growth was observed at 15-45 °C (optimum 30 °C), at pH 6.0-9.0 (optimum pH 8.0) and in the presence of 0-2 % (w/v) NaCl (optimum 0 %). The DNA G+C content of strain Ra1T was 39.9 mol%. Cells contained menaquinone MK-6 as the sole respiratory quinone and the major fatty acids were iso-C15 : 0, iso-C17 : 0, summed feature 3 (comprising C16 : 1ω6c and/or C16 : 1ω7c) and summed feature 9 (comprising C16 : 0 10-methyl and/or iso-C17 : 1ω9c). The predominant polyamine was sym-homospermidine. The cellular polar lipids consisted of one phosphatidylethanolamine, three unidentified aminolipids, one unidentified phospholipid and one unidentified lipid. Based on phenotypic, genotypic and phylogenetic studies, it is concluded that strain Ra1T represents a novel species of the genus Chryseobacterium, for which the name Chryseobacterium reticulitermitis sp. nov. is proposed. The type strain is Ra1T (=CCTCC AB 2015431T=KCTC 52230T).

S-1-based versus 5-FU-based chemotherapy as first-line treatment in advanced gastric cancer: a meta-analysis of randomized controlled trials.

To compare the efficacy, prognosis, and toxicity of S-1-based with fluorouracil (5-FU)-based chemotherapy in patients with advanced gastric cancer (AGC) as first-line treatment, we performed this meta-analysis of all eligible randomized controlled trials (RCTs). A comprehensive literature search of electronic databases (up to February 20, 2014) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology (ASCO) conferences held between January 2000 and February 2014 were searched to identify relevant trials. Overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Six RCTs with 2,264 patients of AGC were included. Meta-analysis demonstrated that S-1-based therapy was associated with better OS compared with 5-FU-based therapy (hazard ratio (HR) = 0.80, 95 % confidence interval (CI) 0.80-0.99, P = 0.03). Pooled estimate has showed the trend of superiority of S-1-based therapy in the aspect of ORR (odds ratio (OR) = 1.55, 95 % CI 0.87-2.77, P = 0.14) and TTF (HR = 0.73, 95 % CI 0.53-1.00, P = 0.05), but the difference was not significant. The incidence of toxicities of 5-FU-based regimens was significantly higher for thrombocytopenia (OR = 0.60, 95 % CI 0.42-0.88, P = 0.008) and stomatitis (OR = 0.22, 0, 95 % CI 0.05-0.9, P = 0.03). Based on the published studies, S-1-based therapy was superior to 5-FU-based therapy in OS and safety profile as first-line treatment in AGC. It was prone to improving ORR and TTF, though the difference was not significant. More high-quality randomized controlled trials should be performed to provide more information in comparing these two regimens.

Altered lipid acyl chain length controls energy dissipation in light-harvesting complex II proteoliposomes by hydrophobic mismatch.

In plants, the major light-harvesting antenna complex (LHCII) is vital for both light harvesting and photoprotection in photosystem II. Previously, we proposed that the thylakoid membrane itself could switch LHCII into the photoprotective state, qE, via a process known as hydrophobic mismatch. The decrease in the membrane thickness that followed the formation of ΔpH was a key fact that prompted this idea. To test this, we made proteoliposomes from lipids with altered acyl chain length (ACL). Here, we show that ACL regulates the average chlorophyll fluorescence lifetime of LHCII. For liposomes made of lipids with an ACL of 18 carbons, the lifetime was ∼2 ns, like that for the thylakoid membrane. Furthermore, LHCII appears to be quenched in proteoliposomes with an ACL both shorter and longer than 18 carbons. The proteoliposomes made of short ACL lipids display structural heterogeneity revealing two quenched conformations of LHCII, each having characteristic 77 K fluorescence spectra. One conformation spectrally resembles isolated LHCII aggregates, whilst the other resembles LHCII immobilized in polyacrylamide gels. Overall, the decrease in the ACL appears to produce quenched conformations of LHCII, which renders plausible the idea that the trigger of qE is the hydrophobic mismatch.

Photoinduced chlorophyll charge transfer state identified in the light-harvesting complex II from a marine green alga Bryopsis corticulans.

The light-harvesting complex II of Bryopsis corticulans (B-LHCII), a green alga, differs from that of spinach (S-LHCII) in chlorophyll (Chl) and carotenoid (Car) compositions. We investigated ultrafast excitation dynamics of B-LHCII with visible-to-near infrared time-resolved absorption spectroscopy. Absolute fluorescence quantum yield (Φ FL) of LHCII and spectroelectrochemical (SEC) spectra of Chl a and b were measured to assist the spectral analysis. Red-light excitation at Chl Qy-band, but not Car-band, induced transient features resembling the characteristic SEC spectra of Chl a ⋅+ and Chl b ⋅-, indicating ultrafast photogeneration of Chl-Chl charge transfer (CT) species; Φ FL and 3Car∗ declined whereas CT species increased upon prolonging excitation wavelength, showing positive correlation of 1Chl∗ deactivation with Chl-Chl CT formation. Moreover, ultrafast Chl b-to-Chl a and Car-to-Chl singlet excitation transfer were illustrated. The red-light induction of Chl-Chl CT species, as also observed for S-LHCII, is considered a general occurrence for LHCIIs in light-harvesting form.

The Structural and Spectral Features of Light-Harvesting Complex II Proteoliposomes Mimic Those of Native Thylakoid Membranes.

The major photosystem II light-harvesting antenna (LHCII) is the most abundant membrane protein in nature and plays an indispensable role in light harvesting and photoprotection in the plant thylakoid. Here, we show that "pseudothylakoid characteristics" can be observed in artificial LHCII membranes. In our proteoliposomal system, at high LHCII densities, the liposomes become stacked, mimicking the in vivo thylakoid grana membranes. Furthermore, an unexpected, unstructured emission peak at ∼730 nm appears, similar in appearance to photosystem I emission, but with a clear excimeric character that has never been previously reported. These states correlate with the increasing density of LHCII in the membrane and a decrease in its average fluorescence lifetime. The appearance of these low-energy states can also occur in natural plant membrane structures, which has unique consequences for the interpretation of the spectroscopic and physiological properties of the photosynthetic membrane.

A Possible Mechanism for Aggregation-Induced Chlorophyll Fluorescence Quenching in Light-Harvesting Complex II from the Marine Green Alga Bryopsis corticulans.

The light-harvesting complex II of a green alga Bryopsis corticulans (B-LHCII) is peculiar in that it contains siphonein and siphonaxathin as carotenoid (Car). Since the S1 state of siphonein and siphonaxathin lies substantially higher than the Qy state of chlorophyll a (Chl a), the Chl a(Qy)-to-Car(S1) excitation energy transfer is unfeasible. To understand the photoprotective mechanism of algal photosynthesis, we investigated the influence of temperature on the excitation dynamics of B-LHCII in trimeric and aggregated forms. At room temperature, the aggregated form showed a 10-fold decrease in fluorescence intensity and lifetime than the trimeric form. Upon lowering the temperature, the characteristic 680 nm fluorescence (F-680) of B-LHCII in both forms exhibited systematic intensity enhancement and spectral narrowing; however, only the aggregated form showed a red emission extending over 690-780 nm (F-RE) with pronounced blueshift, lifetime prolongation, and intensity boost. The remarkable T-dependence of F-RE is ascribed to the Chl-Chl charge transfer (CT) species involved directly in the aggregation-induced Chl deactivation. The CT-quenching mechanism, which is considered to be crucial for B. corticulans photoprotection, draws strong support from the positive correlation of the Chl deactivation rate with the CT state population, as revealed by comparing the fluorescence dynamics of B-LHCII with that of the plant LHCII.

Excitation dynamics and relaxation in the major antenna of a marine green alga Bryopsis corticulans.

The light-harvesting complexes II (LHCIIs) of spinach and Bryopsis corticulans as a green alga are similar in structure, but differ in carotenoid (Car) and chlorophyll (Chl) compositions. Carbonyl Cars siphonein (Spn) and siphonaxanthin (Spx) bind to B. corticulans LHCII likely in the sites as a pair of lutein (Lut) molecules bind to spinach LHCII in the central domain. To understand the light-harvesting and photoprotective properties of the algal LHCII, we compared its excitation dynamics and relaxation to those of spinach LHCII been well documented. It was found that B. corticulans LHCII exhibited a substantially longer chlorophyll (Chl) fluorescence lifetime (4.9 ns vs 4.1 ns) and a 60% increase of the fluorescence quantum yield. Photoexcitation populated 3Car* equally between Spn and Spx in B. corticulans LHCII, whereas predominantly at Lut620 in spinach LHCII. These results prove the functional differences of the LHCIIs with different Car pairs and Chl a/b ratios: B. corticulans LHCII shows the enhanced blue-green light absorption, the alleviated quenching of 1Chl*, and the dual sites of quenching 3Chl*, which may facilitate its light-harvesting and photoprotection functions. Moreover, for both types of LHCIIs, the triplet excitation profiles revealed the involvement of extra 3Car* formation mechanisms besides the conventional Chl-to-Car triplet transfer, which are discussed in relation to the ultrafast processes of 1Chl* quenching. Our experimental findings will be helpful in deepening the understanding of the light harvesting and photoprotection functions of B. corticulans living in the intertidal zone with dramatically changing light condition.