Effects of Heavy Slow Resistance Training Combined With Corticosteroid Injections or Tendon Needling in Patients With Lateral Elbow Tendinopathy: A 3-Arm Randomized Double-Blinded Placebo-Controlled Study.

BACKGROUND: Lateral elbow tendinopathy is a disabling tendon overuse injury. It remains unknown if a corticosteroid injection (CSI) or tendon needling (TN) combined with heavy slow resistance (HSR) training is superior to HSR alone in treating lateral elbow tendinopathy. PURPOSE/HYPOTHESIS: The purpose was to investigate the effects of HSR combined with either (1) a CSI, (2) TN, or (3) placebo needling (PN) as treatment for lateral elbow tendinopathy. We hypothesized that 12 weeks of HSR in combination with a CSI or TN would have superior effects compared with PN at 12, 26, and 52 (primary endpoint) weeks' follow-up on primary (Disabilities of the Arm, Shoulder and Hand [DASH] score) and secondary outcomes in patients with chronic unilateral lateral elbow tendinopathy. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 60 patients with chronic unilateral lateral elbow tendinopathy were randomized to perform 12 weeks of home-based HSR with elastic band exercises combined with either (1) a CSI, (2) TN, or (3) PN, and at 12, 26, and 52 weeks, we assessed the primary outcome, the DASH score, and secondary outcomes: shortened version of the DASH (QuickDASH) score, pain (numerical rating scale [NRS] score), pain-free grip strength, and hypervascularization (power Doppler area). RESULTS: A CSI, TN, and PN improved patient outcomes equally based on the DASH (Δ20 points), QuickDASH (Δ21 points), and NRS (Δ2.5 points) scores after 12 weeks. Further, after 12 weeks, a CSI also resulted in decreased hypervascularization (power Doppler area) compared with PN (Δ-2251 pixels, P = .0418). Except for the QuickDASH score (CSI increased score by Δ15 points compared with PN; P = .0427), there were no differences between the groups after 52 weeks. CONCLUSION: These results suggest that 12 weeks of HSR improved symptoms in both the short and the long term and that a CSI or TN did not amplify this effect. In addition, a CSI seemed to impair patient-reported outcomes compared with HSR alone at long-term follow-up. REGISTRATION: NCT02521298 (ClinicalTrials.gov identifier).

Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers.

AXL, a tyrosine kinase receptor that is overexpressed in many solid and hematologic malignancies, facilitates cancer progression and is associated with poor clinical outcomes. Importantly, drug-induced expression of AXL results in resistance to conventional chemotherapy and targeted therapies. Together with its presence on multiple cell types in the tumor immune microenvironment, these features make it an attractive therapeutic target for AXL-expressing malignancies. ADCT-601 (mipasetamab uzoptirine) is an AXL-targeted antibody-drug conjugate (ADC) comprising a humanized anti-AXL antibody site specifically conjugated using GlycoConnect technology to PL1601, which contains HydraSpace, a Val-Ala cleavable linker and the potent pyrrolobenzodiazepine (PBD) dimer cytotoxin SG3199. This study aimed to validate the ADCT-601 mode of action and evaluate its efficacy in vitro and in vivo, as well as its tolerability and pharmacokinetics. ADCT-601 bound to both soluble and membranous AXL, and was rapidly internalized by AXL-expressing tumor cells, allowing release of PBD dimer, DNA interstrand cross-linking, and subsequent cell killing. In vivo, ADCT-601 had potent and durable antitumor activity in a wide variety of human cancer xenograft mouse models, including patient-derived xenograft models with heterogeneous AXL expression where ADCT-601 antitumor activity was markedly superior to an auristatin-based comparator ADC. Notably, ADCT-601 had antitumor activity in a monomethyl auristatin E-resistant lung-cancer model and synergized with the PARP inhibitor olaparib in a BRCA1-mutated ovarian cancer model. ADCT-601 was well tolerated at doses of up to 6 mg/kg and showed excellent stability in vivo. These preclinical results warrant further evaluation of ADCT-601 in the clinic.

Targeting HER2-positive cancer with dolastatin 15 derivatives conjugated to trastuzumab, novel antibody-drug conjugates.

PURPOSE: Targeting tubulin binders to cancer cells using antibody-drug conjugates (ADCs) has great potential to become an effective cancer treatment with low normal tissue toxicity. The nature of the linker used to tether the tubulin binder to the antibody and the conjugation sites on the antibody and the small molecule are important factors in the ADC stability and effectiveness. METHODS: We explored the use of tubulin-targeting dolastatin 15 derivatives (Dol15) tethered covalently to a representative antibody, trastuzumab, via cleavable and non-cleavable linkers at varying antibody reactive sites (i.e., lysine residues, partially reduced hinge region disulfide bonds) and drug coupling sites (i.e., C-terminus, N-terminus), to investigate which constructs were more effective in killing HER2-positive cells in vitro and in vivo. RESULTS: We found that Dol15 conjugated to trastuzumab via lysine residues at the drug C-terminus using a non-cleavable linker (trastuzumab-amide-C-term-Dol15) produced target-dependent growth inhibition of cells endogenously expressing high HER2 levels (i.e., SK-BR-3, SK-OV-3) in vitro. This ADC was effective at varying doses (i.e., 10 and 20 mg/kg) in the SK-OV-3 human ovarian cancer xenograft. CONCLUSIONS: Tethering Dol15 via partially reduced disulfide bonds at the drug C-terminus via a non-cleavable linker (trastuzumab-MC-C-term-Dol15) resulted in an equally effective ADC in vitro, showing that site of antibody conjugation did not influence ADC activity. However, tethering Dol15 at the drug N-terminus using non-cleavable and cleavable linkers (trastuzumab-MC-N-term-Dol15 and trastuzumab-MC-VC-PABC-N-term-Dol15, respectively) resulted in ineffective ADCs. Thus, Dol15 tethered at the C-terminus may be a useful tubulin-targeting agent for conjugation at various antibody reactive sites.

Synthetic studies on formamidopyrimidines related to clofarabine.

Degradation of clofarabine (3) in 0.9% saline solution at 100 degrees C afforded three degradation products which were determined to be formamidopyrimidines 4-6. Compounds 4 and 5 were assigned as C(1') anomers on the basis of one-dimensional and two-dimensional NMR experiments, whereas 6 was found to be the formamidopyrimidine lacking the sugar moiety. An improved procedure for the synthesis of formamidopyrimidines was developed, wherein benzoylated clofarabine (11) was treated with allyl chloroformate, followed by deprotection of the alloc group with catalytic Pd(PPh(3))(4) and dimedone. A synthesis of compound 6 from 4 is also described.

In vivo imaging of gene transfer to the respiratory tract.

Imaging of in vivo gene expression using luciferase expression in various organs has been used for several years. In contrast to other organs, in vivo imaging of the lung, particularly after non-viral gene transfer has not been extensively studied. The aim of this study was to address several questions: (1) Does in vivo light emission correlate with standard tissue homogenate-based luciferase detection in a dose-dependent manner? Recombinant Sendai virus (SeV) transduces airway epithelial cells very efficiently and was used to address this question, (2) Is the sensitivity of the assay sufficient to detect non-viral gene transfer? We treated mice with SeV-Lux vector using our standard "sniffing" protocol, a method that predominantly results in lung deposition. Dose-related in vivo light emission was visible in all animals. Importantly, there was a significant correlation (r>0.90, p<0.0001) between the in vivo and ex vivo assays in both the left and right lung. We next transfected the nasal epithelium via nasal perfusion or the lungs ("sniffing") of mice with a luciferase plasmid (pCIKLux) complexed to the cationic lipid GL67 (n=25-27/group) and imaged luciferase expression in vivo 24h after transfection. Gene expression was detectable in both organs. Correlation between the in vivo and ex vivo assays was significant (r=0.52, p<0.005) in the left, but not the right lung. The correlation in the nose was weaker (r=0.45, p<0.05). To our knowledge these studies show for the first time that this non-invasive method of assessing pulmonary gene transfer is viable for evaluating non-viral gene transfer agents.

Composites in armor.

Composite materials are traditionally regarded as materials that can save energy in large structures associated with transport. They are used to produce lightweight structures for fuel-efficient aircraft such as the new Boeing 787 Dreamliner; lightweight cars from Lotus, Ferrari and TVR; and high-speed trains, speedboats, and racing yachts. Now, however, some of the most interesting applications of composites are those where the materials are used to save lives and protect property by absorbing the energy of projectiles, impacts, and crashes.

Does the menstrual cycle influence the sensitivity of vagally mediated baroreflexes?

The menstrual cycle provokes several physiological changes that could influence autonomic regulatory mechanisms. We studied the carotid-cardiac baroreflex in ten healthy young women on four occasions over the course of their menstrual cycles (days 0-8, 9-14, 15-20 and 21-25). We drew blood during each session for analysis of oestrogen, progesterone and noradrenaline (norepinephrine) levels, and assessed carotid-cardiac baroreflex function by analysing R-R interval responses to graded neck pressure sequences. Oestrogen levels followed a classical two-peak (cubic) response, with elevated levels on days 9-14 and 21-25 compared with days 0-8 and 15-20 (P=0.0032), while progesterone levels increased exponentially from days 9-14 to days 21-25 (P=0.0063). Noradrenaline levels increased from an average of 137 pg/ml during the first three measurement periods to 199 pg/ml during days 21-25 (P=0.0456). Carotid-cardiac baroreflex gain and operational point were not statistically different at any of the time points during the menstrual cycle (P> or =0.18). These findings are consistent with the notion that beat-to-beat vagal-cardiac regulation does not change over the course of the normal menstrual cycle.