Prophylaxis and Treatment of <i>Pneumocystis jiroveci</i> Pneumonia in Lymphoma Patients Subjected to Rituximab-Contained Therapy: A Systemic Review and Meta-Analysis

<div><p><i>Pneumocystis jiroveci</i> pneumonia (PCP) is frequently reported in lymphoma patients treated with rituximab-contained regimens. There is a trend toward a difference in PCP risk between bi- and tri-weekly regimens. The aims of this systemic review and meta-analysis were to estimate the risk for PCP in these patients, compare the impact of different regimens on the risk, and evaluate the efficacy of prophylaxis. The cohort studies with incept up to January 2014 were retrieved from the Cochrane Library, Medline, Embase, and Web of Science databases. Studies that compared the incidence of PCP in patients with and without rituximab treatment were conducted. Studies that reported the results of prophylaxis were concentrated to evaluate the efficacy of prophylaxis. Fixed effect Mantel-Haenszel model was chosen as the main analysis method. Funnel plots were examined to estimate the potential selection bias. Egger’s test and Begg’s test were used for the determination of possible small study bias. Eleven cohort studies that met the inclusion criteria were finally included. Results indicated that rituximab was associated with a significantly increased risk for PCP (28/942 vs 5/977; risk ratio: 3.65; 95% confidence interval 1.65 to 8.07; <i>P</i>=0.001), and no heterogeneity existed between different studies (<i>I²</i>=0%). Little significant difference in PCP risk was found between bi-weekly and tri-weekly regimens (risk ratio: 3.11; 95% confidence interval 0.92 to 10.52, <i>P</i>=0.068). PCP risk was inversely associated with prophylaxis in patients treated with rituximab (0/222 vs 26/986; risk ratio: 0.28; 95% confidence interval 0.09 to 0.94; <i>P</i>=0.039). In conclusion, PCP risk was increased significantly in lymphoma patients subjected to rituximab-contained chemotherapies. Difference in PCP risk between bi-weekly and tri-weekly regimens was not significant. Additionally, prophylaxis was dramatically effective in preventing PCP in rituximab-received lymphoma patients, suggesting that rituximab should be recommended for these patients.</p></div

Effect of rituximab treatment on PCP risk.

<p>M-H pooled risk ratio = 3.65, fixed effect model method. R: rituximab. Rituximab increased the risk for PCP in lymphoma patients significantly.</p

Flow diagram of identification process for eligible studies.

<p>Flow diagram of identification process for eligible studies.</p

Effect of prophylaxis on PCP risk in rituximab-received lymphoma patients.

<p>M-H pooled risk ratio = 0.28, fixed effect model method. Prophylaxis dramatically reduced PCP risk in rituximab-received patients.</p

PCP risk in bi-weekly and tri-weekly regimens.

<p>M-H pooled risk ratio = 3.11; fixed effect model method. R-C-14: rituximab-added chemotherapy bi-weekly; R-C-21: rituximab-added chemotherapy tri-weekly. Patients treated with bi-weekly regimen seemed to have a higher risk for PCP but the difference between the two regimens was not statistically significant.</p

Funnel plot (with pseudo 95% confidence limits) for rituximab on PCP risk.

<p>Funnel plot (with pseudo 95% confidence limits) for rituximab on PCP risk.</p

Functional Validation of an Alpha-Actinin-4 Mutation as a Potential Cause of an Aggressive Presentation of Adolescent Focal Segmental Glomerulosclerosis: Implications for Genetic Testing - Fig 1

<p>(A), histologic findings in the patient’s kidney biopsy. Periodic acid–Schiff (PAS) staining (magnification 200X) shows segmental glomerulosclerosis and interstitial fibrosis with multiple foci of microcystic tubular dilation. (B), Electron microscopy images shows glomerular podocyte foot processes effacement (arrows) (magnification 20000X). (C), serum creatinine and urine protein/creatinine ratio of the patient over a period of a year.</p

Design, Synthesis, and Insecticidal Activity of Novel Isoxazoline Compounds That Contain <i>Meta</i>-diamides against Fall Armyworm (Spodoptera frugiperda)

Fall armyworm (Spodoptera frugiperda) is a major migratory pest around the entire world that causes severe damage to agriculture. We designed and synthesized a series of novel isoxazoline derivatives based on the previously discovered active compound H13 to find new and effective candidates against S. frugiperda. Most of them showed excellent insecticidal activity. In addition, a three-dimensional quantitative structure–activity relationship model was established, and compound F32 was designed and synthesized based on the results. The bioassay result showed that compound F32 exhibited excellent activity against S. frugiperda (LC50 = 3.46 mg/L), which was substantially better than that of the positive control fipronil (LC50 = 78.8 mg/L). Furthermore, an insect γ-aminobutyric acid (GABA) enzyme-linked immunosorbent assay indicated that F32 can upregulate the content of GABA in insects in a manner similar to that of fipronil. Molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are vital factors between the binding of F32 and receptors. All of these results suggest that compound F32 could be employed as a novel isoxazoline lead compound to control S. frugiperda

Characterization of Tetratricopeptide Repeat-Containing Proteins Critical for Cilia Formation and Function

<div><p>Cilia formation and function require a special set of trafficking machinery termed intraflagellar transport (IFT), consisting mainly of protein complexes IFT-A, IFT-B, BBSome, and microtubule-dependent molecular motors. <u>T</u>etra<u>t</u>ri<u>c</u>opeptide repeat-containing (TTC) proteins are widely involved in protein complex formation. Nine of them are known to serve as components of the IFT or BBSome complexes. How many TTC proteins are cilia-related and how they function, however, remain unclear. Here we show that twenty TTC genes were upregulated by at least 2-fold during the differentiation of cultured mouse tracheal epithelial cells (MTECs) into multiciliated cells. Our systematic screen in zebrafish identified four novel TTC genes, <i>ttc4</i>, <i>-9c</i>, <i>-36</i>, and <i>-39c</i>, that are critical for cilia formation and motility. Accordingly, their zebrafish morphants displayed typical ciliopathy-related phenotypes, including curved body, abnormal otolith, hydrocephalus, and defective left-right patterning. The morphants of <i>ttc4</i> and <i>ttc25</i>, a known cilia-related gene, additionally showed pronephric cyst formation. Immunoprecipitation indicated associations of TTC4, -9c, -25, -36, and -39c with components or entire complexes of IFT-A, IFT-B, or BBSome, implying their participations in IFT or IFT-related activities. Our results provide a global view for the relationship between TTC proteins and cilia.</p></div

The expression profiles of TTC genes upregulated during MTEC differentiation into multiciliated cells.

<p>(A) Typical differentiation progression of MTECs cultured <i>in vitro</i>. MTECs were isolated from mice of 8-week old and were induced to differentiate into multiciliated cells by culturing at an air-liquid interface (ALI) for the indicated time. Approximately 90% of MTECs were multiciliated at ALI day 5. Acetylated tubulin (Ace-tub) was used to mark cilia. ZO-1 labels the tight junctions. (B) The gene expression profiles of known cilia-related TPR-containing proteins following the MTEC differentiation. The data were from cDNA microarray analyses on MTECs samples from ALI d0 to ALI d5. The gene expression pattern of Deup1, a protein critical for centriole amplification, is also included for comparison. (C) The expression profiles of ten novel TTC genes. (D) Expression profiles of the indicated genes, based on quantitative PCR (qPCR) results. One set of typical results of two independent experiments is presented (Please see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0124378#pone.0124378.s002" target="_blank">S2 Fig</a> for the second set of results). The mRNA levels at ALI d0 were set as 1.</p