Beyond Trauma: High-Volume Critical Care Medicine in a Military Medical Center-Based Military-Civilian Partnership.

INTRODUCTION: Critical Care Internal Medicine (CCIM) is vital to the U.S. Military as evidenced by the role CCIM played in the COVID-19 pandemic response and wartime operations. Although the proficiency needs of military surgeons have been well studied, this has not been the case for CCIM. The objective of this study was to compare the patient volume and acuity of military CCIM physicians working solely at Military Treatment Facilities (MTFs) with those at MTFs also working part-time in a military-civilian partnership (MCP) at the University Medical Center of Southern Nevada (UMC). MATERIALS AND METHODS: We analyzed FY2019 critical care coding data from the Military Health System and UMC comparing the number of critical care encounters, the number of high-acuity critical care encounters, and the Abilities/Activity component of the Knowledge, Skills, and Abilities/Clinical Activity (KSA) score. This analysis was restricted to critical care encounters defined by Current Procedural Terminology codes for critical care (99291 and 99292). A critical care encounter was considered high acuity if the patient had ICD-10 codes for shock, respiratory failure, or cardiac arrest or had at least three codes for critical care in the same episode. RESULTS: The five AF CCIM physicians in the MCP group performed 2,019 critical care encounters in 206 days, with 63.1% (1,273) being defined as high acuity. The total number of MTF critical care encounters was 16,855 across all providers and services, with 28.9% (4,864) of encounters defined as high acuity. When limited to CCIM encounters, MTFs had 6,785 critical care encounters, with 32.0% being high acuity (2,171). Thus, the five AF CCIM physicians, while working 206 days at the UMC, equated to 12.0% (2,019/16,855) of the total critical care MTF encounters, 27.2% (1,273/4,684) of the total high-acuity MTF critical care encounters, and 29.8% (2,019/6,785) of the MTF CCIM encounters, with 58.6% (1,273/2,171) of the MTF CCIM high-acuity encounters.The USAF CCIM physicians in the MCP group performed 454,395 KSAs in 206 days, with a KSA density per day of 2,206. In the MTF group, CCIM providers generated 2,344,791 total KSAs over 10,287 days, with a KSA density per day of 227.9. Thus, the five CCIM physicians at the UMC accounted for 19.38% of the MTF CCIM KSAs, with a KSA density over 10 times higher (2,206 vs. 227.9). CONCLUSIONS: The volume and acuity of critical care at MTFs may be insufficient to maintain CCIM proficiency under the current system. Military-civilian partnerships are invaluable in maintaining clinical proficiency for military CCIM physicians and can be done on a part-time basis while maintaining beneficiary care at an MTF. Future CCIM expeditionary success is contingent on CCIM physicians and team members having the required CCIM exposure to grow and maintain clinical proficiency.Limitations of this study include the absence of off-duty employment (moonlighting) data and difficulty filtering military data down to just CCIM physicians, which likely caused the MTF CCIM data to be overestimated.

Inhalation Pneumonitis Caused by Nebulized Hydrogen Peroxide.

Hydrogen peroxide is a chemical commonly used as a household antiseptic for cleaning and disinfecting. No cases of acute hydrogen peroxide inhalation-induced lung injury are previously described. We present a case of acute chemical pneumonitis caused by mixing hydrogen peroxide in a nighttime continuous positive airway pressure device's humidifier used for obstructive sleep apnea to prevent COVID-19 infection. The patient endorsed mixing hydrogen peroxide with distilled water in his nighttime continuous positive airway pressure device's humidifier at a ratio of 1:3-1:2 for the previous week before admission based on a friend's advice in preventing COVID-19. The presenting chest X-ray showed new multifocal consolidations with interstitial markings and alveolar edema throughout both lungs. Chest computed tomography (CT) imaging demonstrated multifocal, bilateral, hazy consolidations with increased interstitial markings and bilateral pleural effusions. The patient was subsequently initiated on systemic glucocorticoid therapy, significantly improving hypoxemia and dyspnea. Inhalation of hydrogen peroxide may produce acute pneumonitis distinct from what has been described previously with chronic inhalation. Given this case, systemic glucocorticoid therapy may be considered a viable treatment option for acute hydrogen peroxide-associated inhalation lung injury causing pneumonitis.

Intensive care unit presentation of central corneal descemetocele secondary to Methicillin-Resistant staphylococcal infection superimposed by a hypopyon: a case report.

A descemetocele is a rare type of keratopathy that occurs when an intact descemet's membrane of the eye undergoes a herniation through an overlying stroma. Previous literature has documented corneal damage via bacterial enzymes, especially, Pseudomonas and Neisseria species. Most recent prospective interventional studies showed treatment of these infections. Case presentation: This report presents the first instance of a methicillin-resistant Staphylococcus aureus descemetocele presentation in a 51-year-old African American male, with co-presenting hypopyon sequelae successfully managed conservatively in an intensive care unit setting. Clinical discussion: An instance of a methicillin-resistant Staphylococcus aureus has not yet been documented in the literature. Likewise, a co-presentation with a hypopyon, which is known as a formation of inflammatory debris rich in white blood cells has not been studied. Conclusion: The presence of a hypopyon in the instances of bacterial descemetocele herniation should be further evaluated to see if there are associations with conservative, nonsurgical intervention outcomes.

Critical asthma syndrome in trauma patients - A case report and literature review.

Critical asthma syndrome (CAS) is an umbrella term for many acute, life-threatening, and treatment resistant variants of asthma exacerbation, including refractory asthma, near fatal asthma, and status asthmaticus. The asthma mortality rate has steadily increased through the last decade and disproportionately affects women, African-Americans, patients of low socioeconomic status, and adults over the age of 55. Increased awareness of the diagnosis and therapies for CAS can help establish a therapeutic strategy for asthma beyond corticosteroids, bronchodilators, and other conventional treatments. A 37 year-old African American woman presented to our Level 1 Trauma Center after a high-speed motor vehicle crash and was intubated on arrival for airway protection. The patient developed diffuse wheezing and persistent tachycardia, with elevated peak airway pressures and air trapping on mechanical ventilation. Her symptoms were refractory to inhaled steroids, systemic steroids, intravenous magnesium, continuous albuterol administration and ventilator optimization. Heliox, an admixture of 80:20 percent helium to oxygen, was initiated to assist with laminar flow. Throughout the next 24 h, the patient's air trapping improved, subsequently decreasing intrathoracic pressure, improving venous return and resolving her tachycardia. The patient's multiple orthopedic injuries were treated and she was eventually weaned off of Heliox, steroids, and continuous albuterol. She was extubated and endorsed a history of poorly controlled asthma requiring hospitalizations and multiple intubations. Recognition of CAS can be challenging in the trauma patient with distracting injuries. This case illustrates the utility of a stepwise approach to a trauma patient suffering from CAS, and should encourage further research into novel therapies when conventional treatment fails. Given that the populations most affected by CAS are often also subject to a disproportionate burden of trauma, trauma surgeons should maintain both a vigilance for the syndrome as well as a working knowledge of the treatment modalities available.

The Las Vegas military-civilian partnership: An origin story and call to action.

ABSTRACT: Military-civilian partnerships (MCPs) in urban American trauma centers have existed for more than 60 years to assist in the development and maintenance of wartime skills of military medical professionals. In the last 5 years, MCPs have gained congressional support, and their number and variety have grown substantially. The historical impact of these flagship trauma MCPs is well documented, with bidirectional benefit in the advancement of trauma care during the wars in Iraq and Afghanistan both deployed and stateside, and the future aim of MCPs lies primarily in mitigating the "peacetime effect." The majority of data regarding MCPs; however, focus on trauma care and are biased toward surgeons specifically. The Las Vegas (LV) MCP began in 2002 with the similar goal of sustaining Air Force (AF) expeditionary medical skills by embedding AF medics from nearby Nellis Air Force Base (AFB) into University Medical Center of Southern Nevada (UMC), the only Level 1 Trauma Center in Nevada. Over nearly 20 years, the LV-MCP has evolved into an innovative market-based collaboration composed of numerous relationships and programs that are designed to develop and sustain critical skills for military medical personnel in all aspects of expeditionary medicine. This includes AF medical personnel providing care to federal beneficiaries as well as civilian patients in a variety of medical settings. The partnership's central coordinating authority, the Office of Military Medicine-Las Vegas (OMM-LV), brings together military and civilian organizations with distinct and intersecting missions to support the greater LV population and the DoD mission of readiness. The LV-MCP is presented here as a model for the future of MCPs within the integrated local and national trauma and medical systems.

Experience Of A US Air Force Surgical And Critical Care Team Deployed In Support Of Special Operations Command Africa.

An eight-person team of conventional US Air Force (USAF) medical providers deployed to support US Special Operations Forces (SOF) in North and West Africa for the first time in November 2014. The predeployment training, operations while deployed, and lessons learned from the challenges of performing surgery and medical evacuations in the remote desert environment of Chad and Niger on the continent of Africa are described. The vast area of operations and far-forward posture of these teams requires cooperation between partner African nations, the French military, and SOF to make these medical teams effective providers of surgical and critical care in Africa. The continuous deployment of conventional USAF medical providers since 2014 in support of US Special Operations Command Africa is challenging and will benefit from more medical teams and effective air assets to provide casualty evacuation across the vast area of operations.

Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)?

OBJECTIVE: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. METHODS: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated. RESULT: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. CONCLUSION: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning.

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients.

PURPOSE: Image guided radiation therapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown. METHODS AND MATERIALS: A retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001 to 2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival, progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient- and treatment-related covariates and local failure. RESULTS: A total of 169 patients were treated with definitive radiation therapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was used in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs 49%, P = .63). The IGRT cohort had improved 2-year LFFS (80% vs 64%, P = .013) and LRFFS (75% and 62%, P = .04). Univariate analysis revealed IGRT and treatment year improved LFFS, whereas group stage, dose, and positron emission tomography/computed tomography planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio of 0.40 (P = .01). Distant failure-free survival (58% vs 59%, P = .67) did not differ significantly. CONCLUSION: IGRT with daily cone beam computed tomography confers an improvement in the therapeutic ratio relative to patients treated without this technology.

Reirradiation for second primary or recurrent cancers of the head and neck: Dosimetric and outcome analysis.

BACKGROUND: The purpose of this study was to examine outcomes, toxicity, and dosimetric characteristics of patients treated with reirradiation for head and neck cancers. METHODS: Fifty patients underwent ≥2 courses of radiation therapy (RT) postoperatively or definitively with or without chemotherapy. Composite dose volume histograms (DVHs) for selected anatomic structures were correlated with grade ≥3 late toxicity. RESULTS: Median initial and retreatment radiation dose was 64 and 60 Gy, respectively. Median overall survival (OS), progression-free survival (PFS), and 1-year PFS rates were 18 months, 11 months, and 45%, respectively, with 13 months median follow-up. Thirty-four percent of patients experienced grade ≥3 late toxicity with 1 death from carotid blowout. The DVH corresponding to the carotid blowout fell above the third quartile compared with other patients. CONCLUSION: Our analysis is the first to systematically evaluate the dose to the carotid artery using composite dosimetry in head and neck reirradiation patients, and demonstrates a promising technique for evaluating the dose to other normal tissue structures. © 2015 Wiley Periodicals, Inc. Head Neck 38: E961-E969, 2016.

Toward the Control of the Creation of Mixed Monolayers on Glassy Carbon Surfaces by Amine Oxidation.

A versatile and simple methodology for the creation of mixed monolayers on glassy carbon (GC) surfaces was developed, using an osmium-bipyridyl complex and anthraquinone as model redox probes. The work consisted in the electrochemical grafting on GC of a mixture of mono-protected diamine linkers in varying ratios which, after attachment to the surface, allowed orthogonal deprotection. After optimisation of the deprotection conditions, it was possible to remove one of the protecting groups selectively, couple a suitable osmium complex and cap the residual free amines. The removal of the second protecting group allowed the coupling of anthraquinone. The characterisation of the resulting surfaces by cyclic voltammetry showed the variation of the surface coverage of the two redox centres in relation to the initial ratio of the linking amine in solution.

Synthesis and evaluation of a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of Xaa-trans-Pro in poly-L-proline type II helix conformation.

We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of (1)H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by (1)H-(15)N HSQC NMR titration experiments.

Self-powered wireless carbohydrate/oxygen sensitive biodevice based on radio signal transmission.

Here for the first time, we detail self-contained (wireless and self-powered) biodevices with wireless signal transmission. Specifically, we demonstrate the operation of self-sustained carbohydrate and oxygen sensitive biodevices, consisting of a wireless electronic unit, radio transmitter and separate sensing bioelectrodes, supplied with electrical energy from a combined multi-enzyme fuel cell generating sufficient current at required voltage to power the electronics. A carbohydrate/oxygen enzymatic fuel cell was assembled by comparing the performance of a range of different bioelectrodes followed by selection of the most suitable, stable combination. Carbohydrates (viz. lactose for the demonstration) and oxygen were also chosen as bioanalytes, being important biomarkers, to demonstrate the operation of the self-contained biosensing device, employing enzyme-modified bioelectrodes to enable the actual sensing. A wireless electronic unit, consisting of a micropotentiostat, an energy harvesting module (voltage amplifier together with a capacitor), and a radio microchip, were designed to enable the biofuel cell to be used as a power supply for managing the sensing devices and for wireless data transmission. The electronic system used required current and voltages greater than 44 µA and 0.57 V, respectively to operate; which the biofuel cell was capable of providing, when placed in a carbohydrate and oxygen containing buffer. In addition, a USB based receiver and computer software were employed for proof-of concept tests of the developed biodevices. Operation of bench-top prototypes was demonstrated in buffers containing different concentrations of the analytes, showcasing that the variation in response of both carbohydrate and oxygen biosensors could be monitored wirelessly in real-time as analyte concentrations in buffers were changed, using only an enzymatic fuel cell as a power supply.

Management of mediastinal relapse after treatment with stereotactic body radiotherapy or accelerated hypofractionated radiotherapy for stage I/II non-small-cell lung cancer.

PURPOSE/OBJECTIVE(S): Regional failures occur in up to 15% of patients treated with stereotactic body radiotherapy (SBRT) for stage I/II lung cancer. This report focuses on the management of the unique scenario of isolated regional failures. METHODS: Patients treated initially with SBRT or accelerated hypofractionated radiotherapy were screened for curative intent treatment of isolated mediastinal failures (IMFs). Local control, regional control, progression-free survival, and distant control were estimated from the date of salvage treatment using the Kaplan-Meier method. RESULTS: Among 160 patients treated from 2002 to 2012, 12 suffered IMF and were amenable to salvage treatment. The median interval between treatments was 16 months (2-57 mo). Median salvage dose was 66 Gy (60-70 Gy). With a median follow-up of 10 months, the median overall survival was 15 months (95% confidence interval, 5.8-37 mo). When estimated from original treatment, the median overall survival was 38 months (95% confidence interval, 17-71 mo). No subsequent regional failures occurred. Distant failure was the predominant mode of relapse following salvage for IMF with a 2-year distant control rate of 38%. At the time of this analysis, three patients have died without recurrence while four are alive and no evidence of disease. High-grade toxicity was uncommon. CONCLUSIONS: To our knowledge, this is first analysis of salvage mediastinal radiation after SBRT or accelerated hypofractionated radiotherapy in lung cancer. Outcomes appear similar to stage III disease at presentation. Distant failures were common, suggesting a role for concurrent or sequential chemotherapy. A standard full course of external beam radiotherapy is advisable in this unique clinical scenario.

Design of maleimide-functionalised electrodes for covalent attachment of proteins through free surface cysteine groups.

Mixed two-component monolayers on glassy carbon are prepared by electrochemical oxidation of N-(2-aminoethyl)acetamide and mono-N-Boc-hexamethylenediamine in mixed solution. Subsequent N-deprotection, amide coupling and solid-phase synthetic steps lead to electrode-surface functionalisation with maleimide, with controlled partial coverage of this cysteine-binding group at appropriate dilution for covalent immobilisation of a model redox-active protein, cytochrome c, with high coverage (≈7.5 pmol cm(-2) ).

Local control and toxicity outcomes in brainstem metastases treated with single fraction radiosurgery: is there a volume threshold for toxicity?

Gamma Knife Radiosurgery (GKRS) has been reported in the treatment of brainstem metastases while dose volume toxicity thresholds remain mostly undefined. A retrospective review of 52 brainstem metastases in 44 patients treated with GKRS was completed. A median dose of 18 Gy (range 10-22 Gy) was prescribed to the tumor margin (median 50 % isodose). 25 patients had undergone previous whole brain radiation therapy. Toxicity was graded by the LENT-SOMA scale. Mean and median follow-up was 10 and 6 months. Only 3 of the 44 patients are living. Multiple brain metastases were treated in 75 % of patients. Median size of lesions was 0.134 cc, (range 0.013-6.600 cc). Overall survival rate at 1 year was 32 % (95 % CI 51.0-20.1 %) with a median survival time of 6 months (95 % CI 5.0-16.5). Local control rate at 6 months and 1 year was 88 % (95 % CI 70-95 %) and 74 % (95 % CI 52-87 %). Cause of death was neurologic in 17 patients, non-neurologic in 20 patients, and unknown in four. Four patients experienced treatment related toxicities. Univariate analysis of tumor volume revealed that volume greater than 1.0 cc predicted for toxicity. A strategy of using lower marginal doses with GKRS to brain stem metastases appears to lead to a lower local control rate than seen with lesions treated within the standard dose range in other locations. Tumor size greater than 1.0 cc predicted for treatment-related toxicity.

Thoracic re-irradiation using stereotactic body radiotherapy (SBRT) techniques as first or second course of treatment.

BACKGROUND AND PURPOSE: Management for in-field failures after thoracic radiation is poorly defined. We evaluated SBRT as an initial or second course of treatment re-irradiating in a prior high dose region. MATERIALS AND METHODS: Thirty-three patients were treated with re-irradiation defined by the prior 30 Gy isodose line. Kaplan-Meier estimates were performed for local (LC), regional (RC), distant control (DC), and overall survival (OS). The plans when available were summed to evaluate doses to critical structures. Patient and treatment variables were analyzed on UVA for the impact on control and survival measures. RESULTS: Median follow-up was 17 months. Treatment for sequential courses was as follows: (course1:course2) EBRT:SBRT (24 patients), SBRT:SBRT (7 patients), and SBRT:EBRT (3 patients). Median re-irradiation dose and fractionation was 50 Gy and 10 fractions (fx), with a median of 18 months (6-61) between treatments. Median OS was 21 months and 2 year LC 67%, yet LC for >1 fraction was 88% (p=0.006 for single vs. multiple). 10 patients suffered chronic grade 2-3 toxicity (6 chest wall pain, 3 dyspnea, 1 esophagitis) and 1 grade 5 toxicity with aorta-esophageal fistula after 54 Gy in 3 fx for a central tumor with an estimated EQD2 to the aorta of 200 Gy. CONCLUSION: Tumor control can be established with re-irradiation using SBRT techniques for in-field thoracic failures at the cost of manageable toxicity.

High-throughput synthesis and electrochemical screening of a library of modified electrodes for NADH oxidation.

We report the combinatorial preparation and high-throughput screening of a library of modified electrodes designed to catalyze the oxidation of NADH. Sixty glassy carbon electrodes were covalently modified with ruthenium(II) or zinc(II) complexes bearing the redox active 1,10-phenanthroline-5,6-dione (phendione) ligand by electrochemical functionalization using one of four different linkers, followed by attachment of one of five different phendione metal complexes using combinatorial solid-phase synthesis methodology. This gave a library with three replicates of each of 20 different electrode modifications. This library was electrochemically screened in high-throughput (HTP) mode using cyclic voltammetry. The members of the library were evaluated with regard to the surface coverage, midpeak potential, and voltammetric peak separation for the phendione ligand, and their catalytic activity toward NADH oxidation. The surface coverage was found to depend on the length and flexibility of the linker and the geometry of the metal complex. The choices of linker and metal complex were also found to have significant impact on the kinetics of the reaction between the 1,10-phenanthroline-5,6-dione ligand and NADH. The rate constants for the reaction were obtained by analyzing the catalytic currents as a function of NADH concentration and scan rate, and the influence of the surface molecular architecture on the kinetics was evaluated.

Mass transport controlled oxygen reduction at anthraquinone modified 3D-CNT electrodes with immobilized Trametes hirsuta laccase.

Carbon nanotubes covalently modified with anthraquinone were used as an electrode for the immobilization of Trametes hirsuta laccase. The adsorbed laccase is capable of oxygen reduction at a mass transport controlled rate (up to 3.5 mA cm(-2)) in the absence of a soluble mediator. The storage and operational stability of the electrode are excellent.

Selective anticancer activity of a hexapeptide with sequence homology to a non-kinase domain of Cyclin Dependent Kinase 4.

BACKGROUND: Cyclin-dependent kinases 2, 4 and 6 (Cdk2, Cdk4, Cdk6) are closely structurally homologous proteins which are classically understood to control the transition from the G1 to the S-phases of the cell cycle by combining with their appropriate cyclin D or cyclin E partners to form kinase-active holoenzymes. Deregulation of Cdk4 is widespread in human cancer, CDK4 gene knockout is highly protective against chemical and oncogene-mediated epithelial carcinogenesis, despite the continued presence of CDK2 and CDK6; and overexpresssion of Cdk4 promotes skin carcinogenesis. Surprisingly, however, Cdk4 kinase inhibitors have not yet fulfilled their expectation as 'blockbuster' anticancer agents. Resistance to inhibition of Cdk4 kinase in some cases could potentially be due to a non-kinase activity, as recently reported with epidermal growth factor receptor. RESULTS: A search for a potential functional site of non-kinase activity present in Cdk4 but not Cdk2 or Cdk6 revealed a previously-unidentified loop on the outside of the C'-terminal non-kinase domain of Cdk4, containing a central amino-acid sequence, Pro-Arg-Gly-Pro-Arg-Pro (PRGPRP). An isolated hexapeptide with this sequence and its cyclic amphiphilic congeners are selectively lethal at high doses to a wide range of human cancer cell lines whilst sparing normal diploid keratinocytes and fibroblasts. Treated cancer cells do not exhibit the wide variability of dose response typically seen with other anticancer agents. Cancer cell killing by PRGPRP, in a cyclic amphiphilic cassette, requires cells to be in cycle but does not perturb cell cycle distribution and is accompanied by altered relative Cdk4/Cdk1 expression and selective decrease in ATP levels. Morphological features of apoptosis are absent and cancer cell death does not appear to involve autophagy. CONCLUSION: These findings suggest a potential new paradigm for the development of broad-spectrum cancer specific therapeutics with a companion diagnostic biomarker and a putative functional site for kinase-unrelated activities of Cdk4.

Dimeric self-assembly of pyridyl guanidinium carboxylates in polar solvents.

A series of pyridyl guanidinium-carboxylates has been prepared and the dimeric self-assembly of these studied in H(2)O/DMSO mixtures, principally using dilution isothermal calorimetry. Compounds 5 and 6, incorporating an aromatic ring in the "tethering" region between the guanidinium and carboxylate groups, demonstrate the strongest dimerisation in neat DMSO. X-ray crystal structures of 5 and 6 reveal two different dimerisation architectures in the solid-state, but both involve carboxylate-guanidinium salt bridges as anticipated, and π-π interactions. Compounds 10-16 incorporating peptidic fragments between the guanidinium and carboxylate groups, showed reduced dimerisation strength with increased amino acid content, but also sustained dimerisation under increasingly aqueous conditions, up to 50% H(2)O/DMSO in the case of 14 and 15. The extent of our study in H(2)O/DMSO mixtures was determined by substrate solubility of 10-16, and not the limit of self-assembly.