(4+1) vs (4+2): Catalytic Intramolecular Coupling between Cyclobutanones and Trisubstituted Allenes via C–C Activation

Herein we describe a rhodium-catalyzed (4+1) cyclization between cyclobutanones and allenes, which provides a distinct [4.2.1]-bicyclic skeleton containing two quaternary carbon centers. The reaction involves C–C activation of cyclobutanones and employs allenes as a one-carbon unit. A variety of functional groups can be tolerated, and a diverse range of polycyclic scaffolds can be accessed. Excellent enantioselectivity can be obtained, which is enabled by a TADDOL-derived phosphoramidite ligand. The bridged bicyclic products can be further functionalized or derivatized though simple transformations

Timing of sleep in the break between two consecutive night-shifts: The effect of different strategies on daytime sleep and night-time neurobehavioural function

Objective: The aim of this study was to examine whether the timing of sleep in the break between consecutive night-shifts affects the quantity and quality of sleep obtained during the daytime and/or neurobehavioural function and self-perceived capacity during the night-time. Methods: Participants (n = 12, all male, aged 22.9±5.2 y) completed three randomised, counterbalanced conditions in a sleep laboratory, consisting of two consecutive 12-hour night-shifts (18:00–06:00) with 7 hours in bed in the break between shifts. The three conditions differed only in the timing of the sleep opportunities – immediate (07:00–14:00), delayed (10:00–17:00), split (07:00–10:30 and 13:30–17:00). Neurobehavioural function (attention, memory, throughput) and self-perceived capacity (sleepiness, alertness, fatigue, mood) were assessed at 2-hour intervals during the night-shifts. Results: Condition did not affect total sleep time (p = 0.465), but it did affect sleep onset latency (p < 0.001; W = 0.780; large effect), wake after sleep onset (p = 0.018; W = 0.333; moderate effect) and the amount of Stage N3 sleep (p < 0.001; η2 =0.510; small effect). Compared to the immediate and delayed sleep conditions, the split sleep condition had less wake after sleep onset and more Stage N3 sleep; and compared to the delayed condition, the split sleep condition had longer latency to sleep onset. There was no effect of condition on measures of neurobehavioural function or self-perceived capacity during the second night-shift. Conclusion: None of the three sleep strategies examined here – immediate, delayed or split – are clearly superior or inferior to the others in terms of the capacity to sleep during the daytime or to work at night. Therefore, those who work consecutive night-shifts should employ the strategy that best suits their personal preferences and/or circumstances

Subgroup analysis according to sex.

<p>Male patients benefit more in EFS than female from rituximab maintenance therapy.</p

Rituximab maintenance therapy for patients with diffuse large B-cell lymphoma: A meta-analysis

<div><p>Purpose</p><p>The addition of rituximab to standard chemotherapy has significantly improved survival in patients with lymphoma. Recently, maintenance therapy with rituximab has been shown to prevent relapse and provide survival benefits for patients with follicular or mantle cell lymphoma. However, the effects of rituximab in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear. Two new studies involving rituximab in the treatment of DLBCL were performed this past year. We performed a meta analysis to evaluate the effects of rituximab maintenance treatment of patients with DLBCL.</p><p>Methods</p><p>Several databases (PubMed, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) databases were reviewed for relevant randomized controlled trials published prior to May, 2016. Two reviewers assessed the quality of the included studies and extracted data independently. The hazard ratios (HRs) for time-to-event data and relative risks (RRs) for the other data were pooled and estimated.</p><p>Results</p><p>Totally 5 studies including 1740 patients were eligible for the meta-analysis. Compared to the observation group, patients who received rituximab maintenance therapy had significantly improved event-free survival (EFS) (HR = 0.80, 95% CI: 0.65–0.98) and progression-free survival (PFS) (HR = 0.72, 95% CI: 0.54–0.94). However, there was no statistically significant difference in overall survival (OS) (HR = 0.66, 95% CI: 0.27–1.29). A subgroup analysis suggested that male patients may benefit from rituximab maintenance therapy with a better EFS (HR = 0.53, 95% CI: 0.34–0.82-), while this advantage was not observed in female patients (HR = 0.99, 95% CI: 0.64–1.52).</p><p>Conclusions</p><p>Rituximab maintenance may provide survival benefits beyond that afforded by first- and second-line chemotherapy alone, especially in male patients. However, maintenance rituximab treatment may cause more adverse events. It is recommended that both survival benefits and adverse events should be taken into consideration when making treatment decisions.</p></div

Flowchart of selection of studies for inclusion in meta-analysis.

<p>Flowchart of selection of studies for inclusion in meta-analysis.</p

Forest plot of the HR.

<p>PFS is improved in patients in the maintenance arm.</p

Forest plot of the RRs of main adverse events.

<p>The size of the squares reflects each study’s relative weight, and the diamond (◊) represents the aggregate RR and 95% CI. MR, rituximab maintenance; OBS, observation.</p

RhoA is necessary for BAFF-mediated B cell survival but not proliferation.

<p>(A) Splenic B220⁺ B cells from <i>CD19^Cre/+; RhoA^+/+</i> (control) and <i>CD19^Cre/+; RhoA^flox/flox</i> (<i>RhoA^−/−</i>) mice were cultured for 48 hours on 96-well plates (4×10⁵ cells/well) with or without (−) 2 µg/mL anti-IgM F(ab')₂ antibody or LPS. Cell growth rate was analyzed using the CellTiter 96® AQ_ueous Non-Radioactive Cell Proliferation Assay (MTS) kit. Data are expressed as absorbance OD₄₉₀. n = 5. (B) Splenocytes from control and <i>RhoA^−/−</i> mice were stained with anti-B220, -CD21, and -CD23 antibodies followed by Annexin V staining. The cells were then analyzed by flow cytometry. T: transitional B cells, FO B: follicular B cells, and MZ B: marginal zone B cells. n = 5. (C) Splenic B220⁺ B cells from control and <i>RhoA^−/−</i> mice were cultured for 72 hours on 96-well plates (2×10⁵ cells/well) with or without (−) 2 µg/mL anti-IgM F(ab')₂ antibody or indicated concentrations of BAFF (left). Alternatively, control B cells were incubated with or without (−) BAFF and/or Y27632 (10 µM) (right). The cells were then stained with Annexin V and analyzed by flow cytometry. n = 5. (D) Splenocytes from control and <i>RhoA^−/−</i> mice were stained with antibodies against B220, CD21, CD23 and BAFFR, and then analyzed by flow cytometry. The numbers above bracketed lines indicate the percentage of BAFFR⁺ cells in each B cell subset and the numbers below the bracketed lines indicate mean fluorescence intensity (MFI) of BAFFR in each B cell subset (left). The percentage of BAFFR⁺ cells and MFI of BAFFR were averaged from 5 mice for each genotype (right). (E) Splenic B220⁺ B cells from control and <i>RhoA^−/−</i> mice were subjected to Western blot for BAFFR and IgM (left). β-actin serves as loading control (left). The protein expression was quantified and normalized to β-actin and the data are expressed as fold of expression (right). n = 3. (F) Splenic B220⁺ B cells from control and <i>RhoA^−/−</i> mice were analyzed for BAFFR mRNA levels by quantitative RT-PCR. The expression of GAPDH was used to normalize samples and the relative fold of expression is shown. n = 4. (G) Splenic B220⁺ B cells from control and <i>RhoA^−/−</i> mice were stimulated with or without BAFF(100 ng/mL) for 30 min and then subjected to Western blot (left). Phospho (p)-Akt (S473) is quantified and normalized to total Akt and the data are expressed as relative fold of p-Akt (right). n = 3. Error bars represent mean ± SD. **p<0.01. *p<0.05. Statistical analysis was performed using a Student's unpaired t-test with a two-tailed distribution.</p

B cell-specific deletion of RhoA impairs splenic B cell development.

<p>(A) Generation of <i>RhoA^−/−</i> B cells. Left, the loxP/Cre-mediated gene targeting strategy to generate the <i>RhoA</i> knockout allele (<i>RhoA⁻</i>) in B cells. Right, Western blot showing RhoA expression in B220⁺ B cells purified from bone marrow and spleen of <i>CD19^Cre/+; RhoA^+/+</i> (control) and <i>CD19^Cre/+; RhoA^flox/flox</i> (<i>RhoA^−/−</i>) mice. (B) Bone marrow cells from control and <i>RhoA^−/−</i> mice were stained with antibodies against B220 and IgM and analyzed by flow cytometry (left). The number of B cell subsets was calculated by multiplying the total number of bone marrow cells by the percentage of each subset of cells (right). n = 5. (C) Splenocytes from control and <i>RhoA^−/−</i> mice were stained with antibodies against B220, CD21 and CD23 and analyzed by flow cytometry (left). The number of B cell subsets was calculated by multiplying the total number of splenocytes by the percentage of each subset of cells (right). T: transitional B cells, FO B: follicular B cells, and MZ B: marginal zone B cells. n = 5. (D) Spleen sections from control and <i>RhoA^−/−</i> mice, stained with hematoxylin and eosin. Data are representative of 3 mice. Error bars represent mean ± SD. **p<0.01. Statistical analysis was performed using a Student's unpaired t-test with a two-tailed distribution.</p

Characteristics of included studies.

<p>Characteristics of included studies.</p