Synthesis of Poly(lauryl acrylate) by Single-Electron Transfer/Degenerative Chain Transfer Living Radical Polymerization Catalyzed by Na2S2O4 in Water

Living radical polymerization of lauryl acrylate was achieved by SET/DTLRP in water catalyzed by sodium dithionite. The work describes the synthesis of a highly hydrophobic and polar monomer in aqueous medium. The plots of versus conversion and ln[M]₀/[M] versus time are linear, indicating a controlled polymerization. This method leads to α,ω-diiodopoly(lauryl acrylate)s that can be further functionalized. The MWDs were determined using a combination of three detectors: RALLS, DV, and RI. The method studied in this work represents a possible route to prepare well-tailored macromolecules made of LA in environment friendly reaction medium. The syndiotactic content is 75%.

     

Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis

The role of Foxp3⁺ regulatory T (Treg) cells in the course of the early hyper-inflammatory and subsequent hypo-inflammatory phases of sepsis is ambiguous. Whereas Nrp1 expression has been reported to discriminate natural Treg cells from induced Treg cells, the Treg cell stability depends on the methylation status of foxp3-TSDR. To specifically evaluate the role of Foxp3⁺ Treg cells in the early and late phases of sepsis, we induced sepsis by caecal ligation and puncture and subsequent Pseudomonas aeruginosa lung infection in a DEREG (DEpletion of REGulatory T cells) mouse model. We found an increase of Foxp3⁺ Treg cells to all CD4⁺ T cells during murine sepsis. Using a new methylation-sensitive quantitative RT-PCR method and deep amplicon sequencing, we demonstrated that natural (Nrp1⁺ Foxp3⁺) Treg cells and most induced (Nrp1⁻ Foxp3⁺) Treg cells are stable and exhibit unmethylated foxp3-TSDR, and that both Treg populations are functionally suppressive in healthy and septic mice. DEREG mice depleted of Foxp3⁺ Treg cells exhibit higher disease scores, mortality rates and interleukin-6 expression levels than do non-depleted DEREG mice in early-phase sepsis, a finding indicating that Foxp3⁺ Treg cells limit the hyper-inflammatory response and accelerate recovery. Treg cell depletion before secondary infection with P. aeruginosa 1 week after caecal ligation and puncture does not influence cytokine levels or the course of secondary infection. However, a moderate Treg cell recurrence, which we observed in DEREG mice during secondary infection, may interfere with these results. In summary, Treg cells contribute to a positive outcome after early-phase sepsis, but the data do not support a significant role of Treg cells in immune paralysis during late-phase sepsis.     

Renal glomerular and tubular injury after gastric bypass in obese rats

Objective

Roux-en-Y gastric bypass (RYGB) surgery is the most common surgical intervention for long-term weight loss in morbidly obese patients. By decreasing obesity-associated hyperfiltration, diabetes, and hypertension, RYGB is touted to stabilize, if not prevent, progression of chronic renal disease. To test this, the renal histology of diet-induced obese rats that underwent RYGB surgery was compared with that of pair-fed and sham obese controls.

Methods

Sprague-Dawley rats, fed a high-fat, low-oxalate diet to induce gross obesity, were randomized to RYGB (n = 6), gastrointestinal-intact sham-operated obese controls (sham, n = 4), or gastrointestinal-intact sham-operated obese pair-fed controls (fed, n = 8). Daily body weight and food intake were recorded. On postoperative day 42, renal histology and immunohistochemistry were examined. Renal pathology was assessed by a categorical glomerular lesion score and a quantitative glomerular/tubular scoring system by experienced veterinary pathologists. Osteopontin and ED-1 (monocyte/macrophage cell) stainings were estimated by the percentage of stained area and the number of counted cells/high-power field, respectively.

Results

Compared with sham and fed controls, RYGB rats had significant decreases in body weight (P < 0.001), more glomerular lesions (P = 0.02), and received higher glomerular and tubular lesion scores (P < 0.01). RYGB rodents had significantly stronger staining for osteopontin within the inner medullary region (P < 0.005) and ED-1 within the outer medullary region (P < 0.02) compared with sham and fed controls.

Conclusion

In this diet-induced obese rat model, RYGB is associated with chronic glomerulosclerosis and tubulointerstitial nephritis, confirmed by histology and immunohistochemistry. Prospective studies to better define the injurious mechanisms in this model are underway.     

Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis

BACKGROUND AND AIMS: Primary biliary cirrhosis (PBC) has been reported in up to 4-6% of first degree relatives of patients with the disease. In addition, immune abnormalities, including hypergammaglobulinemia, autoantibodies and increased frequency of autoimmune disorders, were reported in family members of PBC patients. The aim of the present study was to investigate the prevalence of PBC in relatives of patients with PBC, and to investigate the occurrence of chronic liver disease (CLD) and immune abnormalities in these subjects. METHODS: One-hundred first degree relatives of 26 patients with PBC were interviewed and submitted to physical examination and determination of liver enzymes, gamma-globulin, bilirubin and auto-antibodies, including antinuclear (ANA), antismooth muscle (SMA), antimitochondrial antibodies (AMA) by indirect immunofluorescence (IIF) and anti-M2 antibody by immunoblotting (IB). RESULTS: Immune disturbances were rarely observed in relatives of PBC patients. Higher gamma-globulin levels, SMA and ANA were detected in four, eight and two family members, respectively. In most subjects, these autoantibodies were either in low titers or associated with concurrent diseases. Only four relatives had extrahepatic autoimmune diseases and another eight exhibited other CLD. Primary biliary cirrhosis was detected in a sister of one patient. Additionally, two other relatives of PBC patients who tested negative for AMA by IIF showed reactivity for anti-M2 by IB. CONCLUSIONS: Immune disturbances, including ANA and SMA, are uncommon in family members of PBC patients. Conversely, anti-M2 antibodies and overt PBC do occur in relatives of PBC patients, even in Brazil where the disease is quite rare.     

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

The phosphatidylinositol‐3‐kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2‐negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial ({"type":"clinical-trial","attrs":{"text":"NCT01980277","term_id":"NCT01980277"}}NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2‐negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell‐free DNA was sequenced using low‐coverage whole‐genome sequencing, and analysis was completed with droplet digital polymerase chain reaction (PCR) for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression‐free survival (PFS) and the overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 timepoints). All patients with tumor TP53, PI3KCA, or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated with PFS (6m‐PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; hazard ratio [HR] = 3.45, 95% confidence interval [CI] [1.34–8.90], P = 0.007). ctDNA status at week 7 was not correlated with prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post‐progression samples. In conclusion, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma‐based copy number analysis may help to identify alterations involved in resistance to treatment.     

Randomised proof-of-concept phase II trial comparing targeted therapy based on tumour molecular profiling vs conventional therapy in patients with refractory cancer: results of the feasibility part of the SHIVA trial

Background:

The SHIVA trial is a multicentric randomised proof-of-concept phase II trial comparing molecularly targeted therapy based on tumour molecular profiling vs conventional therapy in patients with any type of refractory cancer. Results of the feasibility study on the first 100 enrolled patients are presented.

Methods:

Adult patients with any type of metastatic cancer who failed standard therapy were eligible for the study. The molecular profile was performed on a mandatory biopsy, and included mutations and gene copy number alteration analyses using high-throughput technologies, as well as the determination of oestrogen, progesterone, and androgen receptors by immunohistochemistry (IHC).

Results:

Biopsy was safely performed in 95 of the first 100 included patients. Median time between the biopsy and the therapeutic decision taken during a weekly molecular biology board was 26 days. Mutations, gene copy number alterations, and IHC analyses were successful in 63 (66%), 65 (68%), and 87 (92%) patients, respectively. A druggable molecular abnormality was present in 38 patients (40%).

Conclusions:

The establishment of a comprehensive tumour molecular profile was safe, feasible, and compatible with clinical practice in refractory cancer patients.