A study of skin marker alignment using different diamond-shaped light fields for prone breast external-beam radiation therapy.

For breast cancer patients treated in the prone position with tangential fields, a diamond-shaped light field (DSLF) can be used to align with corresponding skin markers for image-guided radiation therapy (IGRT). This study evaluates and compares the benefits of different DSLF setups. Seventy-one patients who underwent daily tangential kilovoltage (kV) IGRT were categorized retrospectively into four groups: (1) DSLF field size (FS) = 10 × 10 cm2 , gantry angle = 90° (right breast)/270° (left breast), with the same isocenter as treatment tangential beams; (2) same as group 1, except DSLF FS = 4 × 4 cm2 ; (3) DSLF FS = 4 × 4-6 × 8 cm2 , gantry angle = tangential treatment beam, off-isocenter so that the DSLF was at the approximate breast center; and (4) No-DSLF. We compared their total setup time (including any DSLF/marker-based alignment and IGRT) and relative kV-based couch shift corrections. For groups 1-3, DSLF-only dose distributions (excluding kV-based correction) were simulated by reversely shifting the couch positions from the computed tomography plans, which were assumed equivalent to the delivered dose when both DSLF and IGRT were used. For patient groups 1-4, the average daily setup time was 2.6, 2.5, 5.0, and 8.3 min, respectively. Their mean and standard deviations of daily kV-based couch shifts were 0.64 ± 0.4, 0.68 ± 0.3, 0.8 ± 0.6, and 1.0 ± 0.6 cm. The average target dose changes after excluding kV-IGRT for groups 1-3 were-0.2%, -0.1%, and +0.4%, respectively, whereas DSLF-1 was most efficient in sparing heart and chest wall, DSLF-2 had lowest lung Dmax ; and DSLF-3 maintained the highest target coverage at the cost of highest OAR dose. In general, the use of DSLF greatly reduces patient setup time and may result in smaller IGRT corrections. If IGRT is limited, different DSLF setups yield different target coverage and OAR dose sparing. Our findings will help DSLF setup optimization in the prone breast treatment setting.

Surgical Tracheostomy in a COVID-19 Positive Patient: A Case Study.

COVID-19 has caused a worldwide epidemic, essentially forcing healthcare workers to adapt and innovate in an effort to provide quality patient care while also protecting themselves from potential infection. Current clinical guidelines do not recommend the routine placement of tracheostomies in COVID-19 positive patients. Inevitably, patients who require intubation secondary to COVID-19 related pulmonary infections may require prolonged ventilation, placing the patients at risk for tracheal and laryngeal stenosis, vocal cord paralysis, and ventilation-associated pneumonias among other complications. This case study demonstrates the successful performance of a surgical tracheostomy in a COVID-19 positive patient while additionally discussing the personal protective equipment used by the anesthesia and surgical teams and reviewing recommendations for anesthetic care during tracheostomy in a COVID-19 positive patient.

Unprecedented frequency of mitochondrial introns in colonial bilaterians.

Animal mitogenomes are typically devoid of introns. Here, we report the largest number of mitochondrial introns ever recorded from bilaterian animals. Mitochondrial introns were identified for the first time from the phylum Bryozoa. They were found in four species from three families (Order Cheilostomatida). A total of eight introns were found in the complete mitogenome of Exechonella vieirai, and five, 17 and 18 introns were found in the partial mitogenomes of Parantropora penelope, Discoporella cookae and Cupuladria biporosa, respectively. Intron-encoded protein domains reverse transcriptase and intron maturase (RVT-IM) were identified in all species. Introns in E. vieirai and P. penelope had conserved Group II intron ribozyme domains V and VI. Conserved domains were lacking from introns in D. cookae and C. biporosa, preventing their further categorization. Putative origins of metazoan introns were explored in a phylogenetic context, using an up-to-date alignment of mitochondrial RVT-IM domains. Results confirmed previous findings of multiple origins of annelid, placozoan and sponge RVT-IM domains and provided evidence for common intron donor sources across metazoan phyla. Our results corroborate growing evidence that some metazoans with regenerative abilities (i.e. placozoans, sponges, annelids and bryozoans) are susceptible to intron integration, most likely via horizontal gene transfer.

Hypocalcemia-Induced Reversible Psychosis.

Hypocalcemia can manifest as a variety of presentations, ranging from neuromuscular irritability to seizures, and psychiatric manifestations such as emotional instability, anxiety, and depression. Here, we present a unique case of hypocalcemia-induced acute psychosis. A 24-year-old woman presented to the emergency department (ED) with confusion and agitation for four to five days. The patient was noted by the family to have decreased oral intake and sleep. Auditory and visual hallucinations prompted the family to bring the patient to the ED. The patient was mildly tachycardic. Initially, the patient was agitated, impulsive, and aggressive, exhibiting psychotic features including visual hallucinations, paranoid delusions, thought broadcasting, tangential and perseverative thought processes, and erotomanic delusions. She had mild leukocytosis and elevated procalcitonin on admission. A thorough workup ruled out infectious/inflammatory processes. Cerebrospinal fluid was negative for acute meningitis/encephalitis, autoimmune encephalitis antibodies, and paraneoplastic etiology. Thyroid-stimulating hormone was normal and thyroid antibodies were negative. The CT brain and MRI brain were unremarkable. The patient was severely hypocalcemic (6.7) with low parathyroid hormone (<6) on admission. To note, the patient has multiple endocrine neoplasia, type 2B (MEN2B). She underwent total thyroidectomy five months prior for metastatic medullary thyroid carcinoma complicated by postsurgical hypoparathyroidism. The patient had been non-compliant with calcium and calcitriol supplementation postoperatively. The patient was started on IV calcium gluconate and transitioned to calcitriol with calcium level improvement over the next three days. She experienced marked improvement, with the resolution of her psychosis. The patient's subacute onset psychosis with no personal or family psychiatric history and a rapid response to calcium correction supports hypocalcemia etiology. This case illustrates new-onset acute psychosis in a patient with calcium regulation imbalance. The development of hypocalcemia secondary to thyroidectomy with postsurgical hypoparathyroidism and calcium supplement non-compliance precipitated psychosis. A few similar cases have been reported, and here, we note that treatment of hypocalcemia promptly resolves symptoms. As per our review, this will be the first case of neuropsychiatric symptoms without associated cortical calcifications seen on imaging. It is important to recognize hypocalcemia as a rare cause of psychosis so as to not mistakenly categorize such presentations as primary psychotic disorders and miss a medically treatable illness.

Spatially Fractionated Radiotherapy (GRID) Prior to Standard Neoadjuvant Conventionally Fractionated Radiotherapy for Bulky, High-Risk Soft Tissue and Osteosarcomas: Feasibility, Safety, and Promising Pathologic Response Rates.

Spatially fractionated radiotherapy (GRID) has been utilized primarily in the palliative and definitive treatment of bulky tumors. Delivered in the modern era primarily with megavoltage photon therapy, this technique offers the promise of safe dose escalation with potential immunogenic, bystander and microvasculature effects that can augment a conventionally fractionated course of radiotherapy. At the University of Maryland, an institutional standard has arisen to incorporate a single fraction of GRID radiation in large (>8 cm), high-risk soft tissue and osteosarcomas prior to a standard fractionated course. Herein, we report on the excellent pathologic responses and apparent safety of this regimen in 26 consecutive patients.

Population health model for pharmacist assessment and independent prescribing of statins in an ambulatory care setting.

OBJECTIVE: This study aimed to evaluate the impact of a pharmacist population health initiative on the ability to increase the percentage of patients with atherosclerotic cardiovascular disease (ASCVD) who are on an appropriate statin. SETTING: Ten primary care clinics in Southwest Washington. The average payer mix across the included clinics is 47% Medicare, 26% commercial, 22% Medicaid, 2% self-pay, and 3% other. Reimbursement-tied statin quality metrics are present in 14.1% of patients' insurance contracts. PRACTICE DESCRIPTION: The primary care pharmacy collaborative drug therapy agreement allows pharmacists to act as prescribers by permitting initiation, adjustment, and monitoring of medication therapy, with the authority historically stemming from referral by the patient's primary care provider to the pharmacist. PRACTICE INNOVATION: A novel, population health protocolized prescriptive authority (PPA) initiative was implemented, of which a key component was expanding pharmacists' prescriptive authority to prescribe statins for population health initiatives. Without referral, pharmacists screened, directly outreached to, and prescribed statins for patients with ASCVD who were not on a moderate- or high-intensity statin. Electronic health record (EHR) documentation was updated to better reflect the patient's history and increase metric accuracy. EVALUATION: A retrospective analysis of a population health initiative from October 1 to December 31, 2018. The initiative was evaluated on the combined success of initiating patients with ASCVD on moderate- or high-intensity statins and the acceptance rate of EHR corrections. RESULTS: The pharmacy team screened 510 patients. Appropriately dosed statins were initiated for 40.0% of patients, and the EHR was accurately updated in 91.9% of instances. These combined efforts demonstrate 50.5% overall success of pharmacist interventions. CONCLUSION: Expanding pharmacists' authority to PPA for statin medications in patients not meeting quality metrics increased the number of successful interventions. Pharmacists make a major contribution on improving population health metrics for statins.

Delivery of TRAIL-expressing plasmid DNA to cancer cells in vitro and in vivo using aminoglycoside-derived polymers.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand that can preferentially induce apoptosis in cancer cells over normal cells. The transmembrane form of TRAIL has been shown to elicit much stronger activity than its soluble counterpart but delivery is a potential challenge. Here, we investigated the potential of aminoglycoside-derived polymers to enhance delivery of a plasmid (pEF-TRAIL) that expresses the transmembrane form of TRAIL in order to determine the effect on cell death in vitro and tumor growth in vivo. Transgene delivery efficacy and toxicity of aminoglycoside-derived polymers was first evaluated using a GFP-expressing plasmid (pEF-GFP) at different plasmid amounts and plasmid : polymer ratios in UMUC3 bladder cancer and HeLa cervical cancer cells. Delivery of the TRAIL plasmid using aminoglycoside-derived polymers resulted in up to 60% cell death in UMUC3 and HeLa cells; TRAIL protein expression was confirmed using Western blots. TRAIL plasmid delivery resulted in a decrease in cellular procaspase-8 and an increase in TRAIL receptor DR5 levels, suggesting a role for the death receptor and caspase cascade in TRAIL-mediated apoptosis. The TRAIL plasmid did not cause cell death in normal human or mouse fibroblasts. The in vivo delivery of the TRAIL plasmid using a paromomycin-derived polymer resulted in significant reduction in tumor burden and increased survival in tumor-bearing live mice.

Evaluation of Bivalirudin's Effect on International Normalized Ratio to Determine an Appropriate Strategy for Transitioning to Warfarin.

Background: Direct thrombin inhibitors are recommended in confirmed or suspected heparin-induced thrombocytopenia. False elevation of the international normalized ratio (INR) occurs with these agents making bridging to warfarin challenging. There is limited data regarding bivalirudin's effect on INR. Objective: To evaluate bivalirudin's effect on the INR and determine a strategy for transitioning to warfarin. Methods: This was a retrospective observational study. Included patients were >18 years old receiving primary bridging therapy with overlapping bivalirudin and warfarin for at least 72 hours. Patients with administration of alternate anticoagulants during the transition interval or active major bleeding within 48 hours prior to bivalirudin initiation were excluded. The primary endpoint was to determine the effect on INR at first therapeutic activated partial thromboplastin time after bivalirudin initiation and prior to warfarin initiation. Secondary endpoints included change in INR 12 and 24 hours after bivalirudin initiation, change in INR 4 hours after bivalirudin cessation, and incidence of major bleeding or new thrombotic events. Results: Thirty-four patients met study criteria. For the primary endpoint, the change in INR at first therapeutic activated partial thromboplastin time was 0.37 (range = 0.28-0.48), which occurred at 8.4 hours (range = 4.6-14.2; n = 14). INR increased at 12 and 24 hours by a median of 0.55 and 0.5 from baseline, respectively. Median change in INR 4 to 8 hours post-bivalirudin cessation was -0.48. Conclusion: Targeting an INR > 2.5 when bridging to warfarin will account for this false elevation and maintain an INR above 2.0 on bivalirudin discontinuation.

High-resolution studies of hydride transfer in the ferredoxin:NADP+ reductase superfamily.

Ferredoxin: NADP+ reductase (FNR) is an FAD-containing enzyme best known for catalysing the transfer of electrons from ferredoxin (Fd) to NADP+ to make NADPH during photosynthesis. It is also the prototype for a broad enzyme superfamily, including the NADPH oxidases (NOXs) that all catalyse similar FAD-enabled electron transfers between NAD(P)H and one-electron carriers. Here, we define further mechanistic details of the NAD(P)H ⇌ FAD hydride-transfer step of the reaction based on spectroscopic studies and high-resolution (~ 1.5 Å) crystallographic views of the nicotinamide-flavin interaction in crystals of corn root FNR Tyr316Ser and Tyr316Ala variants soaked with either nicotinamide, NADP+ , or NADPH. The spectra obtained from FNR crystal complexes match those seen in solution and the complexes reveal active site packing interactions and patterns of covalent distortion of the FAD that imply significant active site compression that would favour catalysis. Furthermore, anisotropic B-factors show that the mobility of the C4 atom of the nicotinamide in the FNR:NADP+ complex has a directionality matching that expected for boat-like excursions of the nicotinamide ring thought to enhance hydride transfer. Arguments are made for the relevance of this binding mode to catalysis, and specific consideration is given to how the results extrapolate to provide insight to structure-function relations for the membrane-bound NOX enzymes for which little structural information has been available. DATABASES: Structural data are available in the PDB database under the accession numbers 3LO8 (wild-type), 5VW4 [Y316S:nicotinamide (P32 21)], 5VW9 [Y316S:nicotinamide (P31 21)], 5VW3 [Y316S:NADP+ (P32 21)], 5VW8 [Y316S:NADP+ (P31 21)], 5VW2 [Y316S:NADPH (P32 21)], 5VW5 [Y316A:nicotinamide (P32 21)], 5VW6 [Y316A:NADP+ (P32 21)], 5VW7 [Y316A:NADPH (P32 21)], 5VWA [Y316F (P32 21)], and 5VWB [Y316F:NADP+ (P31 21)]. Enzyme Commission number: ferredoxin:NADP+ reductase - E C1.18.1.2.

Projected Improvements in Accelerated Partial Breast Irradiation Using a Novel Breast Stereotactic Radiotherapy Device: A Dosimetric Analysis.

Accelerated partial breast irradiation has caused higher than expected rates of poor cosmesis. At our institution, a novel breast stereotactic radiotherapy device has demonstrated dosimetric distributions similar to those in brachytherapy. This study analyzed comparative dose distributions achieved with the device and intensity-modulated radiation therapy accelerated partial breast irradiation. Nine patients underwent computed tomography simulation in the prone position using device-specific immobilization on an institutional review board-approved protocol. Accelerated partial breast irradiation target volumes (planning target volume_10mm) were created per the National Surgical Adjuvant Breast and Bowel Project B-39 protocol. Additional breast stereotactic radiotherapy volumes using smaller margins (planning target volume_3mm) were created based on improved immobilization. Intensity-modulated radiation therapy and breast stereotactic radiotherapy accelerated partial breast irradiation plans were separately generated for appropriate volumes. Plans were evaluated based on established dosimetric surrogates of poor cosmetic outcomes. Wilcoxon rank sum tests were utilized to contrast volumes of critical structures receiving a percentage of total dose (Vx). The breast stereotactic radiotherapy device consistently reduced dose to all normal structures with equivalent target coverage. The ipsilateral breast V20-100 was significantly reduced (P < .05) using planning target volume_10mm, with substantial further reductions when targeting planning target volume_3mm. Doses to the chest wall, ipsilateral lung, and breast skin were also significantly lessened. The breast stereotactic radiotherapy device's uniform dosimetric improvements over intensity-modulated accelerated partial breast irradiation in this series indicate a potential to improve outcomes. Clinical trials investigating this benefit have begun accrual.

Dosimetric Improvements with a Novel Breast Stereotactic Radiotherapy Device for Delivery of Preoperative Partial-Breast Irradiation.

OBJECTIVE: Partial-breast irradiation (PBI) with external-beam radiotherapy has produced higher than expected rates of fair-to-poor cosmesis. Worsened outcomes have been correlated with larger volumes of breast tissue exposed to radiation. A novel breast-specific stereotactic radiotherapy (BSRT) device (BSRTD) has been developed at our institution and has shown promise in delivering highly conformal dose distributions. We compared normal tissue sparing with this device with that achieved with intensity-modulated radiation therapy (IMRT)-PBI. METHODS: Fifteen women previously treated with breast conservation therapy were enrolled on an institutional review board-approved protocol. Each of them underwent CT simulation in the prone position using the BSRTD-specific immobilization system. Simulated postoperative and preoperative treatment volumes were generated based on surgical bed/clip position. Blinded planners generated IMRT-PBI plans and BSRT plans for each set of volumes. These plans were compared based on clinically validated markers for cosmetic outcome and toxicity using a Wilcoxon rank-sum test. RESULTS: The BSRT plans consistently reduced the volumes receiving each of several dose levels (Vx) to breast tissue, the chest wall, the lung, the heart, and the skin in both preoperative and postoperative settings (p < 0.05). Preoperative BSRT yielded particularly dramatic improvements. CONCLUSION: The novel BSRTD has demonstrated significant dosimetric benefits over IMRT-PBI. Further investigation is currently proceeding through initial clinical trials.

Educating emergency department nurses about trauma informed care for people presenting with mental health crisis: a pilot study.

BACKGROUND: Practicing with trauma informed care (TIC) can strengthen nurses' knowledge about the association of past trauma and the impact of trauma on the patient's current mental illness. An aim of TIC is to avoid potentially re-traumatising a patient during their episode of care. A TIC education package can provide nurses with content that describes the interplay of neurological, biological, psychological, and social effects of trauma that may reduce the likelihood of re-traumatisation. Although mental health nurses can be TIC leads in multidisciplinary environments, the translation of TIC into clinical practice by nurses working in emergency departments (EDs) is unknown. However, before ED nurses can begin to practice TIC, they must first be provided with meaningful and specific education about TIC. Therefore, the aims of this study were to; (1) evaluate the effectiveness of TIC education for ED nursing staff and (2) describe subsequent clinical practice that was trauma informed. METHODS: This project was conducted as exploratory research with a mixed methods design. Quantitative data were collected with an 18-item pre-education and post-education questionnaire. Qualitative data were collected with two one-off focus groups conducted at least three-months after the TIC education. Two EDs were involved in the study. RESULTS: A total of 34 ED nurses participated in the TIC education and 14 ED nurses participated in the focus groups. There was meaningful change (p < 0.01, r ≥ 0.35) in 9 of the 18-items after TIC education. Two themes, each with two sub-themes, were evident in the data. The themes were based on the perceived effectiveness of TIC education and the subsequent changes in clinical practice in the period after TIC education. CONCLUSION: Emergency department nurses became more informed of the interplay of trauma on an individual's mental health. However, providing care with a TIC framework in an ED setting was a considerable challenge primarily due to time constraints relative to the day-to-day ED environment and rapid turnover of patients with potentially multiple and complex presentations. Despite this, nurses understood the effect of TIC to reduce the likelihood of re-traumatisation and expressed a desire to use a TIC framework.

Protocol-Driven Allied Health Post-Discharge Transition Clinic to Reduce Hospital Readmissions in Heart Failure.

BACKGROUND: Heart failure (HF) patients have high rates of hospitalization and rehospitalization. METHODS AND RESULTS: A protocol-driven clinic staffed by an allied health care team was designed for patients discharged from the hospital with a diagnosis of congestive HF. The clinic provided follow-up visits 1 week and 4 to 6 weeks after hospital discharge. One-hundred and fourteen patients were observed at least 1 time, and 80% of these patients completed the 2-visit protocol. Clinical evaluations were provided by a nurse practitioner specializing in HF and a clinical pharmacist; these evaluations included physical examination, laboratory evaluation, medical education and reconciliation, medication adjustment and titration, and care coordination. Referrals to home health and appropriate services were provided. At visit 1, 25% of patients were hypervolemic and 13% were hypovolemic. At visit 2, 20% were hypervolemic and 13% were hypovolemic. Medicine reconciliation errors were common, with an average of 2.1 and 0.8 errors per person recorded for visits 1 and 2, respectively. Clinic participants showed a 44.3% reduction in 30-day readmission rates, as compared to the hospital's average 30-day readmission rates. CONCLUSIONS: Protocol-driven postdischarge transition care delivered by allied health staff addressed multiple transition issues and was associated with a dramatic reduction in readmission rates.

Adjuvant pelvic irradiation for cervical cancer in the setting of a transplanted pelvic kidney.

Postoperative radiation therapy is often needed following resection for gynecological cancers. A pelvic kidney, whether ectopic or transplanted, is considered an absolute contraindication for radiation if the organ is left in place. A 45-year-old, immunosuppressed patient with FIGO IB1 cervical adenocarcinoma was treated with intensity-modulated radiation therapy (IMRT) to 45 Gy to the modified whole pelvis with a boost to 59.4 Gy to high-risk areas despite having a transplanted kidney in the right iliac fossa. The irradiation prevented further local failure in the pelvis at 36-month follow-up with no decrement in renal function. Radiation to the modified pelvis using IMRT while avoiding the renal allograft is technically feasible and should be offered to more high-risk patients.

The crystal structure of the extracellular 11-heme cytochrome UndA reveals a conserved 10-heme motif and defined binding site for soluble iron chelates.

Members of the genus Shewanella translocate deca- or undeca-heme cytochromes to the external cell surface thus enabling respiration using extracellular minerals and polynuclear Fe(III) chelates. The high resolution structure of the first undeca-heme outer membrane cytochrome, UndA, reveals a crossed heme chain with four potential electron ingress/egress sites arranged within four domains. Sequence and structural alignment of UndA and the deca-heme MtrF reveals the extra heme of UndA is inserted between MtrF hemes 6 and 7. The remaining UndA hemes can be superposed over the heme chain of the decaheme MtrF, suggesting that a ten heme core is conserved between outer membrane cytochromes. The UndA structure has also been crystallographically resolved in complex with substrates, an Fe(III)-nitrilotriacetate dimer or an Fe(III)-citrate trimer. The structural resolution of these UndA-Fe(III)-chelate complexes provides a rationale for previous kinetic measurements on UndA and other outer membrane cytochromes.

ZraP is a periplasmic molecular chaperone and a repressor of the zinc-responsive two-component regulator ZraSR.

The bacterial envelope is the interface with the surrounding environment and is consequently subjected to a barrage of noxious agents including a range of compounds with antimicrobial activity. The ESR (envelope stress response) pathways of enteric bacteria are critical for maintenance of the envelope against these antimicrobial agents. In the present study, we demonstrate that the periplasmic protein ZraP contributes to envelope homoeostasis and assign both chaperone and regulatory function to ZraP from Salmonella Typhimurium. The ZraP chaperone mechanism is catalytic and independent of ATP; the chaperone activity is dependent on the presence of zinc, which is shown to be responsible for the stabilization of an oligomeric ZraP complex. Furthermore, ZraP can act to repress the two-component regulatory system ZraSR, which itself is responsive to zinc concentrations. Through structural homology, ZraP is a member of the bacterial CpxP family of periplasmic proteins, which also consists of CpxP and Spy. We demonstrate environmental co-expression of the CpxP family and identify an important role for these proteins in Salmonella's defence against the cationic antimicrobial peptide polymyxin B.

Ventricular arrhythmias and acute left ventricular dysfunction as a primary and life-threatening manifestation of a mitochondrial crisis: A novel management strategy.

Mitochondrial disorders are genetic diseases that result in a deficiency of energy metabolism (ATP production). A "mitochondrial crisis" can occur in the setting of infection, dehydration, or physiologic stress. The hallmark of a mitochondrial crisis is failure of multiple individual organ systems. The mortality of mitochondrial crisis is high and therapy is supportive but involves a specific strategy of hydration with dextrose-containing IV fluids, avoidance of many medications known to worsen mitochondrial function, and limitations of oxygenation as this can promote free radical production. We report a case of a patient with known mitochondrial disease that presented with a mitochondrial crisis with prominent and life-threatening cardiac manifestations including long QT, ventricular arrhythmias, and acute left ventricular systolic dysfunction in addition to rhabdomyolysis, lactic acidosis, and an acute kidney injury. This patient was managed successfully with a specifically tailored supportive strategy, a high-dose metabolic cocktail, permissive hypoxia, and low-protein diet. At 10 weeks post discharge all electrocardiographic abnormalities resolved and ventricular recovery has been observed. Given the increased survival of this population of patients into adulthood it is important that these adjunctive therapeutic strategies require consideration by clinicians treating this group of patients.

Overview of peroxiredoxins in oxidant defense and redox regulation.

Peroxiredoxins are important hydroperoxide detoxification enzymes, yet have only come to the fore in recent years relative to the other major players in peroxide detoxification, heme-containing catalases and peroxidases and glutathione peroxidases. These cysteine-dependent peroxidases exhibit high reactivity with hydrogen peroxide, organic hydroperoxides, and peroxynitrite and play major roles not only in peroxide defense, but also in regulating peroxide-mediated cell signaling. This overview focuses on important peroxiredoxin features that have emerged over the past several decades with an emphasis on catalytic mechanism, regulation, and biological function.

Dual pro-drugs of 2'-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus.

We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.