Vascularized Tissue Reconstruction in Previously Irradiated Sarcoma Defects.

INTRODUCTION: Radiation therapy (RT) is recommended for appropriately selected sarcoma patients to minimize the risk of local recurrence and to maximize outcomes of disease-free survival and function. The purpose of this study was to confirm the safety of vascularized tissue reconstruction in recently irradiated sarcoma defects. METHODS: A retrospective review of all patients treated by the senior author for sarcoma reconstruction from January 2005 to July 2017 was performed. Two independent reviewers collected data from both electronic and paper medical records. Patients were included if they underwent flap reconstruction (pedicled or free) following sarcoma resection. The safety of neoadjuvant RT was compared with a control group with no previous irradiation using χ(2) analysis. RESULTS: Fifty-seven patients were included in the study; 35 patients were included in the preoperative RT group, and 22 patients were included in the control group (no previous irradiation). There was no significant difference in wound complications between the 2 groups (infection, dehiscence, hematoma, and seroma). Microvascular complications (arterial thrombosis, venous thrombosis, partial/total flap loss) were also comparable in the free tissue transfer subgroup. CONCLUSIONS: The current study demonstrates the safety of both pedicled and free flap reconstruction in previously irradiated sarcoma defects. Judicious selection of reconstructive technique and recipient vessels is crucial in obtaining optimal outcomes given the devastating effects of RT on native tissues.

The surgical outcome and recurrence rate of tenosynovial giant cell tumor in the elbow: a literature review.

BACKGROUND: Tenosynovial giant cell tumor (TSGCT) is a rare proliferative disorder of the synovium. Because of its aggressive nature and recurrence potential, treatment of TSGCT involves surgical resection with or without synovectomy. There is currently a paucity of literature describing the surgical management of TSGCT at the elbow. The aim of this study was to evaluate clinical outcomes and recurrence rates following open and arthroscopic excision of TSGCT in the elbow. METHODS: Electronic databases were searched for relevant articles relating to surgical management of TSGCT of the elbow. We included all patients who received surgical treatment for TSGCT, with no age limitations. We excluded any nonsurgical treatment studies. Seventy-seven articles were identified for screening, and a total of 27 patients from 24 studies were included for the review. RESULTS: The patients' mean (standard deviation [SD]) age was 40.3 (21.7) years, and the most common presenting symptoms included pain (18/27, 66.7%), swelling (19/27, 70.4%), and decreased range of motion of the elbow (9/27, 33.3%). The majority of patients underwent open excision with or without synovectomy (23/27, 85.1%). Of those undergoing open procedures, 16 (16/23,69.6%) had diffuse TSGCT and 14 (14/23, 60.9%) remained symptom free for a mean (SD) follow-up of 38.9 (25.4) months. Four patients (4/27, 14.8%) were treated arthroscopically, all of whom had diffuse disease. CONCLUSIONS: Our review found that open synovectomy appears to be an effective treatment for both localized and diffuse TSGCT in the elbow, and arthroscopic synovectomy is emerging as a method of surgical management for diffuse TSGCT. However, because of the limited number of patients undergoing surgery for TSGCT, further studies are needed to make a definite conclusion.

Loss of the adipokine lipocalin-2 impairs satellite cell activation and skeletal muscle regeneration.

Lipocalin-2 (LCN2) is an adipokine previously described for its contribution to numerous processes, including innate immunity and energy metabolism. LCN2 has also been demonstrated to be an extracellular matrix (ECM) regulator through its association with the ECM protease matrix metalloproteinase-9 (MMP-9). With the global rise in obesity and the associated comorbidities related to increasing adiposity, it is imperative to gain an understanding of the cross talk between adipose tissue and other metabolic tissues, such as skeletal muscle. Given the function of LCN2 on the ECM in other tissues and the importance of matrix remodeling in skeletal muscle regeneration, we examined the localization and expression of LCN2 in uninjured and regenerating wild-type skeletal muscle and assessed the impact of LCN2 deletion (LCN2-/-) on skeletal muscle repair following cardiotoxin injury. Though LCN2 was minimally present in uninjured skeletal muscle, its expression was increased significantly at 1 and 2 days postinjury, with expression present in Pax7-positive satellite cells. Although satellite cell content was unchanged, the ability of quiescent satellite cells to become activated was significantly impaired in LCN2-/- skeletal muscles. Skeletal muscle regeneration was also significantly compromised as evidenced by decreased embryonic myosin heavy chain expression and smaller regenerating myofiber areas. Consistent with a role for LCN2 in MMP-9 regulation, regenerating muscle also displayed a significant increase in fibrosis and lower ( P = 0.07) MMP-9 activity in LCN2-/- mice at 2 days postinjury. These data highlight a novel role for LCN2 in muscle regeneration and suggest that changes in adipokine expression can significantly impact skeletal muscle repair.

Laminin-1 induces endocytosis of 67KDa laminin receptor and protects Neuroscreen-1 cells against death induced by serum withdrawal.

Although the function of laminin in the basement membrane is known, the function of soluble "neuronal" laminin is unknown. Since laminin is neuroprotective, we determined whether the soluble laminin-1 induces signaling for neuroprotection via its 67KDa laminin-1 receptor (67LR). Treatment of Neuroscreen-1 (NS-1) cells with laminin-1 or YIGSR peptide, which corresponds to a sequence in laminin-1 ß1 chain that binds to 67LR, induced a decrease in the cell-surface expression of 67LR and caused its internalization. Furthermore, intracellular cAMP-elevating agents, dibutyryl-cAMP, forskolin, and rolipram, also induced this internalization. Both soluble laminin-1 and YIGSR induced a sustained elevation of intracellular cAMP under defined conditions, suggesting a causal role of cAMP in the endocytosis of 67LR. This endocytosis was not observed in cells deficient in protein kinase A (PKA) nor in cells treated with either SQ 22536, an inhibitor for adenylyl cyclase, or ESI-09, an inhibitor for the exchange protein directly activated by cAMP (Epac). In addition, when internalization occurred in NS-1 cells, 67LR and adenylyl cyclase were localized in early endosomes. Under conditions in which endocytosis had occurred, both laminin-1 and YIGSR protected NS-1 cells from cell death induced by serum withdrawal. However, under conditions in which endocytosis did not occur, neither laminin-1 nor YIGSR protected these cells. Conceivably, the binding of laminin-1 to 67LR causes initial signaling through PKA and Epac, which causes the internalization of 67LR, along with signaling enzymes, such as adenylyl cyclase, into early endosomes. This causes sustained signaling for protection against cell death induced by serum withdrawal.

Prevalence and Risk Factors of Blindness Among Primary Angle Closure Glaucoma Patients in the United States: An IRIS Registry Analysis.

PURPOSE: To assess the prevalence and risk factors of blindness among patients newly diagnosed with primary angle closure glaucoma (PACG) in the United States. DESIGN: Retrospective cross-sectional study. METHODS: Eligible patients from the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry had newly diagnosed PACG, defined as: 1) observable during a 24-month lookback period from index date of PACG diagnosis; 2) no history of eye drops, laser, or cataract surgery unless preceded by a diagnosis of anatomical narrow angle (ANA); and 3) no history of glaucoma surgery. Logistic regression models were developed to identify risk factors for any (one or both eyes) or bilateral (both eyes) blindness (visual acuity ≤20/200) at first diagnosis of PACG. RESULTS: Among 43,901 eligible patients, overall prevalence of any and bilateral blindness were 11.5% and 1.8%, respectively. Black and Hispanic patients were at higher risk of any (odds ratios [ORs] 1.42 and 1.21, respectively; P < .001) and bilateral (ORs 2.04 and 1.53, respectively; P < .001) blindness compared with non-Hispanic White patients adjusted for ocular comorbidities. Age <50 or >80 years, male sex, Medicaid or Medicare insurance product, and Southern or Western practice region also conferred a higher risk of blindness (OR > 1.28; P ≤ .01). CONCLUSIONS: Blindness affects 1 of 9 patients with newly diagnosed PACG in the IRIS Registry. Black and Hispanic patients and Medicaid and Medicare recipients are at significantly higher risk. These findings highlight the severe ocular morbidity among patients with PACG and the need for improved disease awareness and detection methods.

Rates and Patterns of Diagnostic Conversion from Anatomical Narrow Angle to Primary Angle-Closure Glaucoma in the United States.

PURPOSE: To assess rates of diagnostic conversion from anatomical narrow angle (ANA) to primary angle-closure glaucoma (PACG) in the United States and identify factors associated with diagnostic conversion. DESIGN: Retrospective case-control study. PARTICIPANTS: Patients diagnosed with ANA between the years 2007 and 2019 were identified based on International Classification of Diseases (ICD) codes in the Optum Clinformatics Data Mart Database. Inclusion was limited to newly diagnosed ANA, defined as the following: (1) continuous enrollment during a 2-year look back period and 6-year study period from index (first) date of ANA diagnosis; (2) diagnosis by an ophthalmologist or optometrist and record of gonioscopy; and (3) no history of intraocular pressure (IOP)-lowering drops, laser peripheral iridotomy (LPI), or intraocular surgery. METHODS: Cox proportional hazards models were developed to assess factors associated with diagnostic conversion, defined as a change in ICD code from ANA to PACG. MAIN OUTCOME MEASURES: New diagnosis of PACG within the 6-year study period recorded after an index diagnosis of ANA. RESULTS: Among 3985 patients meeting inclusion criteria, 459 (11.52%) had detected diagnostic conversion to PACG within the study period. The conversion rate was stable at 3.54% per year after the first 6 months of ANA diagnosis. In the Cox proportional hazards model, age > 70 years and early (within 6 months of ANA diagnosis) need for LPI or IOP-lowering drops were positively associated with diagnostic conversion (hazard ratio [HR] > 1.59; P < 0.02). Cataract surgery at any time and late (after 6 months of ANA diagnosis) need for IOP-lowering drops appeared protective against diagnostic conversion (HR < 0.46; P < 0.004). CONCLUSIONS: Annual risk of diagnostic conversion from ANA to PACG is relatively low overall; elderly patients are at higher risk whereas patients receiving cataract surgery are at lower risk. The utility of long-term monitoring seems low for most patients with ANA, highlighting the need for improved clinical methods to identify patients at higher risk for PACG. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Refractive Error and Anterior Chamber Depth as Risk Factors in Primary Angle Closure Disease: The Chinese American Eye Study.

PRCIS: The risk of primary angle closure disease (PACD) rises rapidly with greater hyperopia while remaining relatively low for all degrees of myopia. Refractive error (RE) is useful for angle closure risk stratification in the absence of biometric data. PURPOSE: To assess the role of RE and anterior chamber depth (ACD) as risk factors in PACD. METHODS: Chinese American Eye Study participants received complete eye examinations including refraction, gonioscopy, amplitude-scan biometry, and anterior segment ocular coherence tomography imaging. PACD included primary angle closure suspect (≥3 quadrants of angle closure on gonioscopy) and primary angle closure/primary angle closure glaucoma (peripheral anterior synechiae or intraocular pressure >21 mm Hg). Logistic regression models were developed to assess associations between PACD and RE and/or ACD adjusted for sex and age. Locally weighted scatterplot smoothing curves were plotted to assess continuous relationships between variables. RESULTS: Three thousand nine hundred seventy eyes (3403 open angle and 567 PACD) were included. The risk of PACD increased with greater hyperopia [odds ratio (OR) = 1.41 per diopter (D); P < 0.001] and shallower ACD (OR = 1.75 per 0.1 mm; P < 0.001). Hyperopia (≥ + 0.5 D; OR = 5.03) and emmetropia (-0.5 D to +0.5 D; OR = 2.78) conferred a significantly higher risk of PACD compared with myopia (≤0.5 D). ACD (standardized regression coefficient = -0.54) was a 2.5-fold stronger predictor of PACD risk compared with RE (standardized regression coefficient = 0.22) when both variables were included in one multivariable model. The sensitivity and specificity of a 2.6 mm ACD cutoff for PACD were 77.5% and 83.2% and of a +2.0 D RE cutoff were 22.3% and 89.1%. CONCLUSION: The risk of PACD rises rapidly with greater hyperopia while remaining relatively low for all degrees of myopia. Although RE is a weaker predictor of PACD than ACD, it remains a useful metric to identify patients who would benefit from gonioscopy in the absence of biometric data.

Racial and Ethnic Differences in the Roles of Myopia and Ocular Biometrics as Risk Factors for Primary Open-Angle Glaucoma.

Purpose: Assess how the roles of refractive error (RE) and ocular biometrics as risk factors for primary open-angle glaucoma (POAG) differ by race and ethnicity. Methods: Data from the Los Angeles Latino Eye Study (LALES) and the Chinese American Eye Study (CHES), two population-based epidemiological studies, were retrospectively analyzed. Multivariable logistic regression and interaction term analyses were performed to assess relationships between POAG and its risk factors, including RE and axial length (AL), and to assess effect modification by race/ethnicity. Results: Analysis included 7601 phakic participants of LALES (47.3%) and CHES (52.7%) with age ≥ 50 years. Mean age was 60.6 ± 8.3 years; 60.9% were female. The prevalence and unadjusted risk of POAG were higher in LALES than CHES (6.0% and 4.0%, respectively; odds ratio [OR] = 1.55; P < 0.001). In the multivariable analysis, significant risk factors for POAG included Latino ethnicity (OR = 2.25; P < 0.001), refractive myopia (OR = 1.54 for mild, OR = 2.47 for moderate, OR = 3.94 for high compared to non-myopes; P ≤ 0.003), and longer AL (OR = 1.37 per mm; P < 0.001). AL (standardized regression coefficient [SRC] = 0.3) was 2.7-fold more strongly associated with POAG than high myopia status (SRC = 0.11). There was no modifying effect by race/ethnicity on the association between RE (per diopter) or AL (per millimeter) and POAG (P = 0.49). Conclusions: Although the POAG risk conferred by myopic RE and longer AL is similar between Latino and Chinese Americans, the difference in POAG prevalence between the two groups is narrowed by higher myopia prevalence among Chinese Americans. Racial/ethnic populations with higher myopia incidence may become disproportionately affected by POAG in the context of the global myopia epidemic.

A Retrospective Examination of Home PCA Use and Parental Satisfaction With Pediatric Palliative Care Patients.

INTRODUCTION: Home Patient-Controlled Analgesia (PCA) is an effective and often preferred therapy for the treatment of chronic pain symptoms in the pediatric palliative care patient. There is little previous research of patient experience with Home PCA. The purpose of this study was to investigate use of home PCA devices in pediatric patients to inform palliative care providers considering an alternative management option for the treatment of end-of-life or chronic pain. METHODS: A chart review was performed of patients prescribed home PCA. Surveys were sent to patients' guardians/caregivers. Questions referred to caregiver impression/satisfaction with information provided regarding use of the PCA machine, the medication used, the benefits and risks of PCA, monitoring of patient pain level and alertness, machine efficacy, and fears and concerns. RESULTS: Thirty-four patients met inclusion criteria, and 18 patient families completed surveys. Demographic data showed that the majority were Caucasian and had a cancer diagnosis. Patient age and duration of home PCA use varied greatly. Overall, participants were satisfied with information received and felt positively about home PCA, albeit expressing concerns. The majority described the machine as easy to use and were satisfied with their child's pain management and level of alertness. CONCLUSION: Responses indicated that home PCA is a manageable and effective alternative to traditional analgesic medications for management of chronic pain in the pediatric patient.

Age-Related Changes in Dynamic Iris Behavior Assessed Using a Programmable Closed-Loop Iris Control System.

Purpose: The purpose of this study was to develop and test a programmable closed-loop system for tracking, modulating, and assessing dynamic iris behavior, including in the mid-dilated position. Methods: A programmable closed-loop iris control system was developed by customizing an ANTERION OCT device (Heidelberg Engineering, Heidelberg, Germany). Custom software was developed to store camera and optical coherence tomography (OCT) images, track pupillary diameter (PD), control a light-emitting diode (LED), and modulate ambient lighting to maintain the iris in a dilated, constricted, or mid-dilated position in real-time. Study participants underwent 3 consecutive 65-second scan sessions. Dynamic iris behavior in the form of peak constriction velocity (PCV) and mid-dilated iris activity (MDIA) were calculated and analyzed offline. Results: Among 58 participants, 56 (96.6%) were eligible for analysis based on achieving and maintaining mean PD within ±10% of the calculated mid-dilated PD. Mean participant age was 49.8 ± 18.9 years. Mean PCV was 3.92 ± 0.83 mm/s, and mean MDIA was 0.37 ± 0.15 mm. The mean difference between the calculated and achieved mid-dilated PD was 0.166 ± 0.192 mm. There were significant negative correlations between PCV and age (slope = -0.022, P < 0.001) and MDIA and age (slope = -0.004, P < 0.001). Success rates were lower (69.0%) but relationships between dynamic iris behavior and age were similar based on achieving and maintaining mean PD within ±5% of the calculated mid-dilated PD. Conclusions: A programmable closed-loop iris control system can modulate dynamic iris behavior and maintain the iris in a mid-dilated position. Pupillary constriction velocity and iris activity in the mid-dilated position decrease with age. Translational Relevance: This system can be applied to study dynamic disease processes involving the iris and establish novel biometric measures that could serve as risk factors for acute and chronic primary angle closure glaucoma (PACG).

Conformational stability from variable temperature infrared spectra of xenon solutions, r0 structural parameters, and ab initio calculations of cyclopropylisocyanate.

Infrared spectra (4000 to 400 cm(-1)) of the gas and variable temperature xenon solutions, and the Raman spectrum of the liquid have been recorded for cyclopropylisocyanate. The enthalpy difference has been determined to be 77 ± 8 cm(-1) (0.92 ± 0.10 kJ/mol) with the trans form more stable than the cis conformer with 59 ± 2% present at ambient temperature. By utilizing three rotational constants for each conformer, combined with structural parameters predicted from MP2(full)/6-311+G(d,p) calculations, the adjusted r(0) parameters have been obtained. Heavy atom structural parameters for the trans [cis] conformers are the following: distances (Å) (C-C(2,3)) = 1.509(3) [1.509(3)], (C(2)-C(3)) = 1.523(3) [1.521(3)], (C-N) = 1.412(3) [1.411(3)], (N═C) =1.214(3) [1.212(3)], (C═O) = 1.163(3) [1.164(3)]; angles (°) ∠CCN = 116.7(5) [120.1(5)], ∠CNC = 136.3(5) [137.6(5)]. The centrifugal distortion constants have been predicted from ab initio and DFT calculations and are compared to the experimentally determined values.

Defining the Criteria for Reflex Testing for BRAF Mutations in Cutaneous Melanoma Patients.

Targeted therapy has been developed through an in-depth understanding of molecular pathways involved in the pathogenesis of melanoma. Approximately ~50% of patients with melanoma have tumors that harbor a mutation of the BRAF oncogene. Certain clinical features have been identified in BRAF-mutated melanomas (primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). While BRAF mutation testing is recommended for stage III-IV melanoma, guidelines differ in recommending mutation testing in stage II melanoma patients. To fully benefit from these treatment options and avoid delays in therapy initiation, advanced melanoma patients harboring a BRAF mutation must be identified accurately and quickly. To achieve this, clear definition and implementation of BRAF reflex testing criteria/methods in melanoma should be established so that patients with advanced melanoma can arrive to their first medical oncology appointment with a known biomarker status. Reflex testing has proven effective for a variety of cancers in selecting therapies and driving other medical decisions. We overview the pathophysiology, clinical presentation of BRAF-mutated melanoma, current guidelines, and present recommendations on BRAF mutation testing. We propose that reflex BRAF testing should be performed for every melanoma patient with stages ≥IIB.

Management of Osteomyelitis in Sickle Cell Disease: Review Article.

Sickle cell disease (SCD) is an autosomal recessive disorder that is characterized by abnormal "sickle-shaped" erythrocytes. Because of their shape, these erythrocytes are more likely to become trapped in small slow-flowing vessels, leading to vaso-occlusion. Because this commonly happens in the bones, patients with SCD are at an increased risk for orthopaedic manifestations such as osteomyelitis, septic joint, or osteonecrosis. Osteomyelitis is a serious and potentially disabling condition but can be difficult to differentiate from benign conditions of SCD, such as vaso-occlusive crisis. Diagnosis of osteomyelitis requires careful evaluation of the clinical presentation, laboratory testing, and imaging. Treatment of osteomyelitis in patients with SCD may be medical or surgical, but considerations in antibiotic selection and management preoperatively and postoperatively must be taken to ensure optimal outcomes.

A comparison of delayed versus immediate reconstruction following lower-extremity sarcoma resection.

BACKGROUND: Identifying patients who may be at high risk for wound complications postsarcoma resection and reconstruction is essential for improving functional outcomes and quality of life. Currently, the effect of timing on sarcoma reconstruction has been poorly investigated. The purpose of this study was to compare outcomes of delayed and immediate reconstruction in the setting of sarcoma resection requiring flap reconstruction in the lower extremity. METHODS: A retrospective review of the senior author's sarcoma reconstruction patients from January 2005 to July 2017 was completed. All patients undergoing flap reconstruction of the lower extremity were included. Complications in the early postoperative period were compared between delayed and immediate reconstructive procedures. RESULTS: A total of 32 patients (7 delayed, 25 immediate) were included in this study. There was a significantly increased rate of overall complications (100% vs. 28.0%, P=0.001) and rate of hematomas (28.6% vs. 0.0%, P=0.042) in the delayed reconstruction group. Other complications including dehiscence, seroma, infection, venous thrombosis, and total/partial flap loss were also increased in the delayed reconstruction group, but this was not considered to be significant. CONCLUSIONS: This study suggests that delayed reconstruction following sarcoma resection of the lower extremity had a higher incidence of overall complications and hematoma formation. We emphasize the importance of early plastic and reconstructive surgeon referral and the necessity to closely monitor delayed reconstruction patients for complications.

Analysis of Trends in the Selection and Production of U.S. Academic Plastic Surgery Faculty.

In academic plastic surgery, there is a paucity of data examining the relationship between program rank, faculty training history, and production of academic program graduates. The purpose of this study is to determine objective faculty characteristics that are associated with a high program reputation. METHODS: Accreditation Council for Graduate Medical Education-accredited integrated Plastic and Reconstructive Surgery (PRS) programs were ranked using Doximity and divided into Top-quartile programs and Other programs. Accredited medical schools were ranked using U.S. News and World Report. Individual faculty profiles were reviewed on program websites for information on prior training. RESULTS: Seventy-nine programs with 712 faculty were identified and objectively analyzed. Compared to Other PRS programs, Top-quartile programs had a higher proportion of faculty that trained at Top-quartile residency programs (P < 0.0001) and Top-quartile medical schools (P < 0.0001). Top-quartile programs also had the highest proportion of faculty that trained at the same institution for fellowship (P = 0.0001), residency (P = 0.03), medical school (P = 0.4), or any prior training (medical school, residency, or fellowship) (P = 0.002). Top-quartile programs were associated with the largest total faculty size (P < 0.0001) and the largest number of graduates entering the field of academic plastic surgery (P < 0.0001). CONCLUSIONS: Program reputation is associated with PRS faculty selection and production. Top-ranked programs are more likely to have faculty that previously trained at the same institution or at top-ranked programs. Top-ranked programs are more likely to graduate residents that will become academic plastic surgeons.

Aversive conditioning in the tardigrade, Dactylobiotus dispar.

Defensive responses to threatening events in the environment are displayed by a vast number of animals, both vertebrate and invertebrate. These defensive responses can be associated with salient neutral stimuli that are present along with the threatening stimulus. This is referred to as aversive conditioning. Animals with more simple nervous systems, such as Aplysia, C elegans, and Drosophila, have facilitated identification of some the physiological processes that support aversive conditioning. Perhaps even more basic information regarding the neurobiology of learning and memory may be gleaned from animals that have special characteristics not found in other species. Tardigrades, also known as "water bears," are microscopic eight-legged animals that live in various aquatic and terrestrial environments. They are known for their resilience to extreme conditions because of their ability to enter a cryptobiotic "tun" state during which they turn off their metabolism. Thus, tardigrades present an ideal model to study the metabolic requirements for memory storage. However, there is no prior research on tardigrade learning and memory. The purpose of this study was to demonstrate aversive conditioning in a tardigrade species, Dactylobiotus dispar. Associative learning was confirmed by numerous control conditions (unconditioned stimulus [US] only, conditional stimulus [CS] only, backward pairing, random pairing). Short-term memories were formed after a single pairing of the CS and US. This research introduces an important new animal model to the study of the neurobiology of aversive conditioning with important ramifications for understanding the metabolic influences on learning and memory. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Conformational stability from variable temperature FT-IR spectra of krypton solutions, r0 structural parameters, vibrational assignment, and ab initio calculations of 4-fluoro-1-butene.

Variable temperature (-115 to -155 degrees C) studies of the infrared spectra (3200-400 cm-1) of 4-fluoro-1-butene, CH2=CHCH2CH2F, dissolved in liquid krypton have been carried out. The infrared spectra of the gas and solid as well as the Raman spectra of the gas, liquid, and solid have also been recorded from 3200 to 100 cm-1. From these data, an enthalpy difference of 72 +/- 5 cm-1 (0.86 +/- 0.06 kJ x mol-1) has been determined between the most stable skew-gauche II conformer (the first designation refers to the position of the CH2F group relative to the double bond, and the second designation refers to the relative positions of the fluorine atom to the C-C(=C) bond) and the second most stable skew-trans form. The third most stable conformer is the skew-gauche I with an enthalpy difference of 100 +/- 7 cm-1 (1.20 +/- 0.08 kJ x mol-1) to the most stable form. Larger enthalpy values of 251 +/- 12 cm-1 (3.00 +/- 0.14 kJ x mol-1) and 268 +/- 17 cm-1 (3.21 +/- 0.20 kJ x mol-1) were obtained for the cis-trans and cis-gauche conformers, respectively. From these data and the relative statistical weights of one for the cis-trans conformer and two for all other forms, the following conformer percentages are calculated at 298 K: 36.4 +/- 0.9% skew-gauche II, 25.7 +/- 0.1% skew-trans, 22.5 +/- 0.2% skew-gauche I, 10.0 +/- 0.6% cis-gauche, and 5.4 +/- 0.2% cis-trans. The potential surface describing the conformational interchange has been analyzed and the corresponding two-dimensional Fourier coefficients were obtained. Nearly complete vibrational assignments for the three most stable conformers are proposed and some fundamentals for the cis-trans and the cis-gauche conformers have been identified. The structural parameters, dipole moments, conformational stability, vibrational frequencies, infrared, and Raman intensities have been predicted from ab initio calculations and compared to the experimental values when applicable. The adjusted r0 structural parameters have been determined by combining the ab initio predicted parameters with previously reported rotational constants from the microwave data. These experimental and theoretical results are compared to the corresponding quantities of some similar molecules.

Redox regulation of protein kinase C by selenometabolites and selenoprotein thioredoxin reductase limits cancer prevention by selenium.

The cancer-preventive mechanism of selenium should address the way low concentrations of selenometabolites react with cellular targets without being diffused from the sites of generation, the way selenium selectively kills tumor cells, and the intriguing U-shaped curve that is seen with dietary supplementation of selenium and cancer prevention. Protein kinase C (PKC), a receptor for tumor promoters, is well suited for this mechanism. Due to the catalytic redox cycle, low concentrations of methylselenol, a postulated active metabolite of selenium, react with the tumor-promoting lipid hydroperoxide bound to PKC to form methylseleninic acid (MSA), which selectively reacts with thiol residues present within the vicinity of the PKC catalytic domain to inactivate it. Given that lipid hydroperoxide levels are high in promoting cells, PKC inactivation selectively leads to death in these cells. A biphasic effect of MSA in inducing cell death was observed in certain prostate cancer cell lines; lower concentrations of MSA induced cell death, while higher concentrations failed to do so. Lower concentrations of selenium inactivate more sensitive antiapoptotic isoenzymes of PKC (ε and α), sparing less sensitive proapoptotic isoenzymes (PKCδ and PKCζ). Higher concentrations of selenium also inactivate proapoptotic isoenzymes and consequently make tumor cells resistant to apoptosis. Due to a high-affinity binding of thioredoxin to the PKC catalytic domain, this thiol oxidation is explicitly reversed by thioredoxin reductase (TXNRD), a selenoprotein. Therefore, overexpression of TXNRD in advanced tumor cells could make them resistant to selenium-induced death. Conceivably, this mechanism, at least in part, explains why selenium prevents cancer only in certain cases.

Imbalance in Protein Thiol Redox Regulation and Cancer-Preventive Efficacy of Selenium.

Although several experimental studies showed cancer-preventive efficacy of supplemental dietary selenium, human clinical trials questioned this efficacy. Identifying its molecular targets and mechanism is important in understanding this discrepancy. Methylselenol, the active metabolite of selenium, reacts with lipid hydroperoxides bound to protein kinase C (PKC) and is oxidized to methylseleninic acid (MSA). This locally generated MSA selectively inactivates PKC by oxidizing its critical cysteine sulfhydryls. The peroxidatic redox cycle occurring in this process may explain how extremely low concentrations of selenium catalytically modify specific membrane-bound proteins compartmentally separated from glutathione and selectively induce cytotoxicity in promoting cells. Mammalian thioredoxin reductase (TR) is itself a selenoenzyme with a catalytic selenocysteine residue. Together with thioredoxin (Trx), it catalyzes reduction of selenite and selenocystine by NADPH generating selenide which in the presence of oxygen redox cycles producing reactive oxygen species. Trx binds with high affinity to PKC and reverses PKC inactivation. Therefore, established tumor cells overexpressing TR and Trx may escape the cancer-preventive actions of selenium. This suggests that in some cases, certain selenoproteins may counteract selenometabolite actions. Lower concentrations of selenium readily inactivate antiapoptotic PKC isoenzymes e and a which have a cluster of vicinal thiols, thereby inducing apoptosis. Higher concentrations of selenium also inactivate proapoptotic enzymes such as proteolytically activated PKCd fragment, holo-PKCz, caspase-3, and c-Jun N-terminal kinase, which all have a limited number of critical cysteine residues and make tumor cells resistant to selenium-induced apoptosis. This may explain the intriguing U-shaped curve that is seen with dietary selenium intake and the extent of cancer prevention.