Ulnar-sided wrist pain. II. Clinical imaging and treatment

Pain at the ulnar aspect of the wrist is a diagnostic challenge for hand surgeons and radiologists due to the small and complex anatomical structures involved. In this article, imaging modalities including radiography, arthrography, ultrasound (US), computed tomography (CT), CT arthrography, magnetic resonance (MR) imaging, and MR arthrography are compared with regard to differential diagnosis. Clinical imaging findings are reviewed for a more comprehensive understanding of this disorder. Treatments for the common diseases that cause the ulnar-sided wrist pain including extensor carpi ulnaris (ECU) tendonitis, flexor carpi ulnaris (FCU) tendonitis, pisotriquetral arthritis, triangular fibrocartilage complex (TFCC) lesions, ulnar impaction, lunotriquetral (LT) instability, and distal radioulnar joint (DRUJ) instability are reviewed

Regression and Eradication of Triple-Negative Breast Carcinoma in 4T1 Mouse Model by Combination Immunotherapies

Triple-negative breast carcinoma (TNBC) is one of the most aggressive types of solid-organ cancers. While immune checkpoint blockade (ICB) therapy has significantly improved outcomes in certain types of solid-organ cancers, patients with immunologically cold TNBC are afforded only a modest gain in survival by the addition of ICB to systemic chemotherapy. Thus, it is urgently needed to develop novel effective therapeutic approaches for TNBC. Utilizing the 4T1 murine model of TNBC, we developed a novel combination immunotherapeutic regimen consisting of intratumoral delivery of high-mobility group nucleosome binding protein 1 (HMGN1), TLR2/6 ligand fibroblast-stimulating lipopeptide (FSL-1), TLR7/8 agonist (R848/resiquimod), and CTLA-4 blockade. We also investigated the effect of adding SX682, a small-molecule inhibitor of CXCR1/2 known to reduce MDSC trafficking to tumor microenvironment, to our therapeutic approach. 4T1-bearing mice responded with significant tumor regression and tumor elimination to our therapeutic combination regimen. Mice with complete tumor regressions did not recur and became long-term survivors. Treatment with HMGN1, FSL-1, R848, and anti-CTLA4 antibody increased the number of infiltrating CD4+ and CD8+ effector/memory T cells in both tumors and draining lymph nodes and triggered the generation of 4T1-specific cytotoxic T lymphocytes (CTLs) in the draining lymph nodes. Thus, we developed a potentially curative immunotherapeutic regimen consisting of HMGN1, FSL-1, R848, plus a checkpoint inhibitor for TNBC, which does not rely on the administration of chemotherapy, radiation, or exogenous tumor-associated antigen(s)

LD-Aminopterin in the Canine Homologue of Human Atopic Dermatitis: A Randomized, Controlled Trial Reveals Dosing Factors Affecting Optimal Therapy

<div><p>Background</p><p>Options are limited for patients with atopic dermatitis (AD) who do not respond to topical treatments. Antifolate therapy with systemic methotrexate improves the disease, but is associated with adverse effects. The investigational antifolate LD-aminopterin may offer improved safety. It is not known how antifolate dose and dosing frequency affect efficacy in AD, but a primary mechanism is thought to involve the antifolate-mediated accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). However, recent <i>in vitro</i> studies indicate that AICAR increases then decreases as a function of antifolate concentration. To address this issue and understand how dosing affects antifolate efficacy in AD, we examined the efficacy and safety of different oral doses and schedules of LD-aminopterin in the canine model of AD.</p><p>Methods and Findings</p><p>This was a multi-center, double-blind trial involving 75 subjects with canine AD randomized to receive up to 12 weeks of placebo, once-weekly (0.007, 0.014, 0.021 mg/kg) or twice-weekly (0.007 mg/kg) LD-aminopterin. The primary efficacy outcome was the Global Score (GS), a composite of validated measures of disease severity and itch. GS improved in all once-weekly cohorts, with 0.014 mg/kg being optimal and significant (43%, <i>P</i><0.01). The majority of improvement was seen by 8 weeks. In contrast, GS in the twice-weekly cohort was similar to placebo and worse than all once-weekly cohorts. Adverse events were similar across all treated cohorts and placebo.</p><p>Conclusions</p><p>Once-weekly LD-aminopterin was safe and efficacious in canine AD. Twice-weekly dosing negated efficacy despite having the same daily and weekly dose as effective once-weekly regimens. Optimal dosing in this homologue of human AD correlated with the concentration-selective accumulation of AICAR <i>in vitro</i>, consistent with AICAR mediating LD-aminopterin efficacy in AD.</p></div

Base‐Modified Nucleic Acids as a Powerful Tool for Synthetic Biology and Biotechnology

International audienceThe ability of various nucleoside triphosphate analogues of deoxyguanosine and deoxycytidine with 7-deazadeoxyadenosine (A1) and 5-chlorodeoxyuridine (T1) to serve as substrates for Taq DNA polymerase was evaluated. The triphosphate set composed of A1, T1, and 7-deazadeoxyguanosine with either 5-methyldeoxycytidine or 5-fluorodeoxycytidine was successfully employed in the polymerase chain reaction (PCR) of 1.5 kb fragments as well as random oligonucleotide libraries. Another effective combination of triphosphates for the synthesis of a 1 kb PCR product was A1, T1, deoxyinosine, and 5-bromodeoxycytidine. In vivo experiments using an antibiotic-resistant gene containing the latter set demonstrated that the bacterial machinery accepts fully modified sequences as genetic templates. Moreover, the ability of the base-modified segments to selectively protect DNA from cleavage by restriction endonucleases was shown. This approach can be used to regulate the endonuclease cleavage pattern

Subject demographics and baseline AD characteristics.

<p>Abbreviations: GS, Global Score; CADESI, Canine Atopic Dermatitis Extent and Severity Index 03; PVAS, Pruritus Visual Analogue Scale.</p><p>Data are mean ± SD for continuous variables.</p>a<p><i>P</i>-values were calculated by chi-square test for categorical data and one-way ANOVA for continuous data.</p><p>Subject demographics and baseline AD characteristics.</p

Effect of placebo and LD-aminopterin on canine AD disease measures.

<p>Subjects (<i>N</i> = 75) with AD were randomized equally to receive placebo, or LD-aminopterin once-weekly (0.007, 0.014 or 0.021 mg/kg) or twice-weekly (0.007×2 mg/kg). Improvement in baseline disease measures were determined for (A) GS, (B) PVAS and (C) CADESI (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#s2" target="_blank">Materials and Methods</a>). GS and PVAS improved significantly in the 0.014 mg/kg cohort. *<i>P</i><0.05. Horizontal bars are medians. Abbreviations: GS, Global Score; PVAS, Pruritus Visual Analogue Scale; CADESI, Canine Atopic Dermatitis Extent and Severity Index 03.</p

LD-Aminopterin composition and mechanistic model in anti-inflammation.

<p>(A) Chemical structure of L-aminopterin (<i>top</i>) and D-aminopterin (<i>bottom</i>). (B) The anti-inflammatory activity of L-aminopterin and methotrexate have been attributed to inhibition of thymidylate (<i>red</i>) and purine (<i>green</i>) <i>de novo</i> biosynthesis. In the <i>de novo</i> pathway of thymidylate (dTMP) synthesis, serine hydroxymethyltransferase (SHMT) catalyzes the conversion of serine and tetrahydrofolate polyglutamates (THF) to 5,10-CH₂-THF and glycine. Thymidylate synthase (TYMS) converts 5,10-CH₂-THF and deoxyuridine monophosphate (dUMP) to dihydrofolate polyglutamates (DHF) and dTMP. Dihydrofolate reductase (DHFR) completes the cycle by catalyzing the conversion of DHF to THF in an NADPH-dependent reaction. The purine, inosine monophosphate (IMP), is synthesized <i>de novo</i> in 10 chemical steps (shown numbered) catalyzed by six enzymes. The six enzymes are phosphoribosylpyrophosphate amidotransferase (PPAT; 1); a trifunctional enzyme composed of glycinamide ribonucleotide synthetase (GARS; 2), GAR formyltransferase (GART; 3) and aminoimidazole ribonucleotide synthetase (AIRS; 5); formylglycinamidine ribonucleotide synthase (FGAMS; 4); a bifunctional enzyme composed of carboxyaminoimidazole ribonucleotide synthase (CAIRS; 6) and succinoaminoimidazolecarboxamide ribonucleotide synthetase (SAICARS; 7); adenylosuccinate lyase (ASL; 8); and a bifunctional enzyme composed of aminoimidazolecarboxamide ribonucleotide transformylase (AICART; 9) and inosine monophosphate cyclohydrolase (IMPCH; 10). Evidence indicates that 10-formyl-7,8-dihydrofolate (10-CHO-DHF) is the predominant <i>in vivo</i> substrate for AICART, making AICART and TYMS the only enzymes to produce the DHFR substrate DHF <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Baggott4" target="_blank">[69]</a>. Inside the cell, L-aminopterin and methotrexate and their polyglutamate metabolites (antifol) bind with high affinity to DHFR, resulting in accumulation of DHF and depletion of the reduced folate pool. Depletion of folates, as well as the direct inhibition by antifol and DHF, have all been implicated in the inhibition of PPAT, GART, AICART and TYMS <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Sant1" target="_blank">[22]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Allegra2" target="_blank">[33]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Lyons1" target="_blank">[54]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Seither1" target="_blank">[70]</a>. In the case of AICART, the accumulation of DHF may cause this reaction to run backwards, since AICAR is normally driven towards the biosynthesis of FAICAR and IMP by the DHFR-catalyzed reduction of DHF to THF, as the equilibrium of this step actually lies in the direction of AICAR formation <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#pone.0108303-Wall1" target="_blank">[60]</a>.</p

Summary of laboratory AEs by cohort^a.

<p>Abbreviations: RBC, red blood cell; BUN, blood urea nitrogen; ALT, alanine transaminase.</p>a<p>Expressed as <i>N</i> and percent of 75 total subjects.</p><p>Summary of laboratory AEs by cohort<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0108303#nt111" target="_blank">^a</a>.</p