l-Amino Acid Based Phenol- and Catechol-Functionalized Poly(ester-urethane)s for Aromatic π-Interaction Driven Drug Stabilization and Their Enzyme-Responsive Delivery in Cancer Cells.

Exploiting aromatic π-interaction for the stabilization of polyaromatic anticancer drugs at the core of the polymer nanoassemblies is an elegant approach for drug delivery in cancer research. To demonstrate this concept, here we report one of the first attempts on enzyme-responsive polymers from aryl-unit containing amino acid bioresources such as l-tyrosine and 3,4-dihydroxy-l-phenylalanine (l-DOPA). A silyl ether protection strategy was adopted to make melt polymerizable monomers, which were subjected to solvent free melt polycondensation to produce silyl-protected poly(ester-urethane)s. Postpolymerization deprotection yielded phenol- and catechol-functionalized poly(ester-urethane)s with appropriate amphiphilicity and produced 100 ± 10 nm size nanoparticles in an aqueous solution. The aromatic π-core in the nanoparticle turns out to be the main driving force for the successful encapsulation of anticancer drugs such as doxorubicin (DOX) and topotecan (TPT). The electron-rich catechol aromatic unit in l-DOPA was found to be unique in stabilizing the DOX and TPT, whereas its l-tyrosine counterpart was found to exhibit limited success. Aromatic π-interactions between l-DOPA and anticancer drug molecules were established by probing the fluorescence characteristics of the drug-polymer chain interactions. Lysosomal enzymatic biodegradation of the poly(ester-urethane) backbone disassembled the nanoparticles and released the loaded drugs at the cellular level. The nascent polymer was nontoxic in breast cancer (MCF7) and WT-MEF cell lines, whereas its DOX and TPT loaded nanoparticles showed remarkable cell growth inhibition. A LysoTracker-assisted confocal microscopic imaging study directly evidenced the polymer nanoparticles' biodegradation at the intracellular level. The present investigation gives an opportunity to design aromatic π-interaction driven drug stabilization in l-amino acid based polymer nanocarriers for drug delivery applications.

Protocol for intranasal chemoprevention delivery in a urethane mouse lung cancer model.

Mouse iloprost lung cancer chemoprevention studies typically use oral delivery. Here, we present a protocol for intranasal iloprost delivery within a urethane lung adenocarcinoma mouse model. We detail steps for intraperitoneal urethane injection in mice, followed by nine-week monitoring, intranasal iloprost treatment, and lungs harvesting for analysis. This iloprost delivery approach parallels an ongoing phase II clinical trial of inhaled iloprost for lung cancer chemoprevention. This protocol diversifies options for chemoprevention studies and offers a relevant and translatable model. For complete details on the use and execution of this protocol, please refer to Sompel et al. (2022).

Investigation of effects of urethane foam mattress hardness on skin and soft tissue deformation in the prone position using magnetic resonance imaging.

AIM: In operating rooms, the occurrence of pressure ulcers caused by being in the prone position is the highest among that of pressure ulcers caused by being in other surgical positions. Thus, we investigated effects of hardness and shape of urethane foam mattresses for preventing pressure ulcers during surgery performed with patients in the prone position. We aimed to elucidate how mattresses of variable hardness and shapes affect compression and displacement of the skin and soft tissues with external force in the prone position. MATERIAL AND METHODS: We assessed effects of two shapes [rectangular cube (RC) and trapezoid cube (TC)] and four degrees of hardness (50, 87.5, 175, and 262.5 N) in each shape. We performed magnetic resonance imaging (MRI) of the iliac crests with external force while participants reclined in the prone position on eight different mattresses. RESULTS: Compression of the skin and soft tissue was significantly higher with 87.5-, 175-, and 262.5-N mattresses than that with 50-N mattresses. Skin and soft tissue displacement was higher with TC mattress than that with RC mattress, and the extent of skin surface and internal soft tissue displacement was different. CONCLUSIONS: Compression of the skin and soft tissue depends on mattress hardness; however, a threshold value (175 N) for hardness exists, above which no further changes in the parameters were observed. Skin and soft tissue displacement does not depend on mattress hardness, but rather on its shape. Furthermore, mattress inclination increases skin surface displacement.

Electrical Stimulation of the Spinal Dorsal Root Inhibits Reflex Bladder Contraction and External Urethra Sphincter Activity: Is This How Sacral Neuromodulation Works?

INTRODUCTION: Using a rat model, we aimed to confirm the inhibitory effect of dorsal spinal root (afferent) stimulation and test if bilateral stimulation is more effective than unilateral stimulation. External urethral sphincter (EUS) electromyography (EMG) is also assessed in conjunction with cystometrogram. MATERIALS AND METHODS: Eighteen female Sprague-Dawley rats were tested following urethane anesthesia. Via urethral catheterization, the bladder was infused with normal saline to evoke rhythmic bladder reflex contractions (BRC). L6 spinal nerves were isolated and stimulated. RESULTS: L6 stimulation was effective in inhibiting BRC. L6 bilateral dorsal root (DR) stimulation of 50% intensity was required to cause inhibition as compared to unilateral stimulation. In EUS EMG recordings, there was a strong association between EUS EMG activities and bladder contraction. When the bladder contraction was inhibited effectively by L6 DR stimulation, a considerable reduction was also found in the EUS EMG activities. CONCLUSIONS: L6 DR stimulation abolished BRC in our rat model. Bilateral L6 DR stimulation produced a 50% reduction in stimulation intensity, providing a similar BRC block. Abolishing BRC also appeared to coincide with a reduction in EUS EMG, implicating that sacral neuromodulation might act centrally, at least rostrally at the T8-9 spinal level.

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice.

Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.

Safety of the nonabsorbable dural substitute in decompressive craniectomy for severe traumatic brain injury.

BACKGROUND: Artificial dural substitutes are increasingly being used in decompressive craniectomy to prevent peridural fibrosis and facilitate cranioplasty for patients with head injury. The safety of the dural substitute should be systemically evaluated. We focus on Neuro-Patch (B. Braun, Boulogne, France), a nonabsorbable substitute and commonly used by neurosurgeons. METHODS: In this retrospective study, 132 patients undergoing 135 craniectomies and cranioplasties for traumatic brain injury were enrolled. We subdivided the operations into two groups on the basis of whether Neuro-Patch was used (N = 50) or not (N = 85). Risk factors of neurosurgical site infection were assessed first. Then, we compared the occurrence of infective, hemorrhagic, and hydrodynamic morbidities after craniectomy and cranioplasty between the two groups. RESULTS: The incidence of neurosurgical site infection after craniectomy or cranioplasty showed no intergroup difference (p = 1.000). Postoperatively, extra-axial hematoma, which consists of subdural or epidural hematoma, occurred in 9 of 50 craniectomies (18.00%) with Neuro-Patch and 3 of 85 craniectomies (3.53%) without Neuro-patch, which was significantly different (p = 0.009). The rates of hydrodynamic morbidities (subdural hygroma or cerebrospinal fluid leakage) after the procedures were similar between the two groups. CONCLUSIONS: The use of Neuro-Patch does not increase the incidence of neurosurgical site infection and hydrodynamic complications, including subdural hygroma and cerebrospinal fluid leakage, after decompressive craniectomy or cranioplasty for severe traumatic brain injury. However, extra-axial hematoma at the site of craniectomy is more often encountered in patients with Neuro-Patch and forms a compressive lesion on the adjacent brain.

History of multiple myeloma.

Multiple Myeloma has been recognized since Ancient Times. The first well-documented case was reported in 1844 by Samuel Solly. The most commonly recognized case is that of Thomas Alexander McBean, a highly respectable tradesman from London in 1850. Mr. McBean excreted a large amount of protein that was described by Henry Bence Jones in the middle of the 19th century. Jones was a well-known physician and made many contributions to medicine. One of the best known cases of multiple myeloma was that of Dr. Loos that was reported by Otto Kahler. The recognition of plasma cells and subsequently their product, a monoclonal protein has been described in detail. The authors have reviewed the treatment of multiple myeloma including the novel agents, thalidomide, bortezomib and lenalidomide.

Peptidomimetic inhibitors of HIV protease.

There are currently (July, 2002) six protease inhibitors approved for the treatment of HIV infection, each of which can be classified as peptidomimetic in structure. These agents, when used in combination with other antiretroviral agents, produce a sustained decrease in viral load, often to levels below the limits of quantifiable detection, and a significant reconstitution of the immune system. Therapeutic regimens containing one or more HIV protease inhibitors thus provide a highly effective method for disease management. The important role of protease inhibitors in HIV therapy, combined with numerous challenges remaining in HIV treatment, have resulted in a continued effort both to optimize regimens using the existing agents and to identify new protease inhibitors that may provide unique properties. This review will provide an overview of the discovery and clinical trials of the currently approved HIV protease inhibitors, followed by an examination of important aspects of therapy, such as pharmacokinetic enhancement, resistance and side effects. A description of new peptidomimetic compounds currently being investigated in the clinic and in preclinical discovery will follow.

Videographic assessment of the embolic characteristics of three polymeric compounds: ethylene vinyl alcohol, cellulose acetate, and liquid urethane.

BACKGROUND AND PURPOSE: Aneurysms have been clinically and experimentally treated with various surgical and endovascular methods, including endovascular polymer instillation. Additional tools may help to identify advantages and disadvantages of polymeric aneurysm treatment. We assessed the value of high-resolution videography to compare in vitro embolization characteristics of ethylene vinyl alcohol copolymer (VIN), cellulose acetate polymer (ACE), and urethane copolymer (UCO). METHODS: In a "neck-up" glass aneurysm model, solutions of 8% and 12% VIN, 8% and 12% ACE, and 8% UCO were introduced through a microcatheter into a xanthan gum solution at three flow rates: full physiological (62 cm/s), half physiological, and flow arrest. Each formulation was then introduced into a "neck-down" aneurysm model at flow arrest, for a total of 20 experiments. Results were tabulated for six different categories: outflow tail formation, inflow-zone polymer-mass deformation, inflow-zone migration, detachment tail formation, adherent mass pullout, and conjectural net effect. RESULTS: Of the 20 experiments, nine had unacceptable results because of potential clinical complications. The results were unacceptable in four of eight VIN experiments, four of eight ACE experiments, and one of four UCO experiments. VIN performance was more dependent on flow arrest than the more viscous ACE. The growth of the ACE solutions was most circumferential, with balloonlike growth characteristics, little inflow-zone effects, and fewer outflow tails than seen with VIN. All compounds had the potential for partial catheter adhesion and catheter-adhesing tails. UCO had the highest percentage of favorable results and the lowest percentage of unfavorable results. CONCLUSION: Videographic analysis allows detailed assessment of the dynamic embolization characteristics of polymers, revealing potential advantages of compounds such as UCO.

[Paramagnetic diethyleneimides of urethane phosphoric acids as antitumor agents]. / Paramagnitnye diétilenimidy uretanfosfornykh kislot kak protivoopukholevye agenty.

Under study were paramagnetic diethylene imides of urethan phosphoric acids containing three type groups showing carcinostatic activity. There was found small toxicity and a wide spectrum of the antitumor effect of the compounds, also the correlation between the chemical structure and carcinostatic effect was investigated. The nitroxyl radical was shown to participate in the antitumor effect manifestation.

Treatment of multiple myeloma and macroglobulinemai Waldenström: A long-term follow-up study.

Fifteen cases of multiple myeloma and 6 cases of macroglobulin emia Waldenstrom were followed up from 1957 to 1974. As for administration of drugs a low continuous dose regimen was mainly employed instead of a high intermittent dose regimen. 50% survival time from the onset of the disease was 18 months for multiple myeloma and 25 months for macroglobulinemia Waldenstrom. 3 cases of multiple myeloma are still living 44 months after the onset of symptoms. Cyclophosphamide and melphalan seem to have contributed much to the prolonged survival of these patients as well as improved supportive care.

[Effect of some N-alkyl-N-NO-carbamyl esters on leukemia L 5222]. / Wirkung einiger N-Alkyl-N-NO-carbamidsäureester auf die Leukámie L 5222

Contrary to N-methyl-N-NO-carbamyl esters, two N-ethyl-N-NO-urethanes have shown, at s.c. application, good chemotherapeutic effectiveness on the monocytic-myelogeneous rat leukaemia L 5222. It was possible to achieve definite healing. Single doses of N-ethyl-N-NO-n-butyl-urethane were equally effective as repeatedly applied smaller doses, the rate of curing amounting in both cases to 80 percent. N-Ethyl-N-NO-ethyl-urethane, however, can be compared to N-ethyl-N-NO-n-butyl-urethane only at repeated application. As suggested by orientative experiments, N-ethyl-N-NO-n-butyl urethane acts directly upon leukaemic cells and does not need any activation in the organism. Whether or not splitting by esterases, which are present in the cells of L 5222, should be decisive for the chemotherapeutic effectiveness of these substances can only be elucidated by further investigation. It is yet too early to form a definite opinion on the carcinogenicity of s.c. applied N-ethyl-N-NO-n-butyl-urethane.

Synthfsis of bis(aziridinyl)phosphinyl-N-hydroxyurethane derivatives as antineoplastic agents.

Several new "dual antagonists" were synthesized in which the 2,2-dimethyl (or ring C unsubstituted) aziridine phosphinyl function is linked to N-hydroxyurethane rather than the urethane moiety. Three of the new compounds showed very high activities against leukemia L1210 in mice.

Multiple myeloma: review of 869 cases.

A review of 869 cases of multiple myeloma seen at the Mayo Clinic from 1960 through 1971 revealed that 98% of patients were 40 years of age or older and that 61% of them were males. Inital findings were bone pain in 68% of patients, anemia in 62%, renal insufficiency in 55%, hypercalcemia in 30%, a palpable liver in 21%, and a palpable spleen in 5%. Proteinuria was noted in 88% and Bence Jones proteinuria was identified in 49%. Skeletal roentgenographic abnormalities were seen in 79%. Serum protein electrophoresis showed a spike in 76%, hypogammaglobulinemia in 9%, and minor or no abnormalities in 15%, and a globulin spike was seen 75% of the urinary electrophoretic patterns. Immunoelectrophoresis of the serum revealed a monoclonal heavy chain in 83% and a monoclonal light chain in the serum, in 8% (Bence Jones proteinemia). Three patients had no monoclonal protein in the serum or the urine ("nonsecretory"). Amyloidosis was found in 7% of the patients. Follow-up information was obtained in 99.7% ; 82% of the 869 patients have died. Infection and renal insufficiency were the most common specific causes of death. The median survival was 20 months; 66% of the patients were alive at 1 year and 18% at 5 years.