Genetic variations that influence paclitaxel pharmacokinetics and intracellular effects that may contribute to chemotherapy-induced neuropathy: A narrative review.

Taxanes, particularly paclitaxel and docetaxel, are chemotherapeutic agents commonly used to treat breast cancers. A frequent side effect is chemotherapy-induced peripheral neuropathy (CIPN) that occurs in up to 70% of all treated patients and impacts the quality of life during and after treatment. CIPN presents as glove and stocking sensory deficits and diminished motor and autonomic function. Nerves with longer axons are at higher risk of developing CIPN. The causes of CIPN are multifactorial and poorly understood, limiting treatment options. Pathophysiologic mechanisms can include: (i) disruptions of mitochondrial and intracellular microtubule functions, (ii) disruption of axon morphology, and (iii) activation of microglial and other immune cell responses, among others. Recent work has explored the contribution of genetic variation and selected epigenetic changes in response to taxanes for any insights into their relation to pathophysiologic mechanisms of CIPN20, with the hope of identifying predictive and targetable biomarkers. Although promising, many genetic studies of CIPN are inconsistent making it difficult to develop reliable biomarkers of CIPN. The aims of this narrative review are to benchmark available evidence and identify gaps in the understanding of the role genetic variation has in influencing paclitaxel's pharmacokinetics and cellular membrane transport potentially related to the development of CIPN.

A Multimodal Approach to Discover Biomarkers for Taxane-Induced Peripheral Neuropathy (TIPN): A Study Protocol.

Introduction: Taxanes are a class of chemotherapeutics commonly used to treat various solid tumors, including breast and ovarian cancers. Taxane-induced peripheral neuropathy (TIPN) occurs in up to 70% of patients, impacting quality of life both during and after treatment. TIPN typically manifests as tingling and numbness in the hands and feet and can cause irreversible loss of function of peripheral nerves. TIPN can be dose-limiting, potentially impacting clinical outcomes. The mechanisms underlying TIPN are poorly understood. As such, there are limited treatment options and no tools to provide early detection of those who will develop TIPN. Although some patients may have a genetic predisposition, genetic biomarkers have been inconsistent in predicting chemotherapy-induced peripheral neuropathy (CIPN). Moreover, other molecular markers (eg, metabolites, mRNA, miRNA, proteins) may be informative for predicting CIPN, but remain largely unexplored. We anticipate that combinations of multiple biomarkers will be required to consistently predict those who will develop TIPN. Methods: To address this clinical gap of identifying patients at risk of TIPN, we initiated the Genetics and Inflammatory Markers for CIPN (GENIE) study. This longitudinal multicenter observational study uses a novel, multimodal approach to evaluate genomic variation, metabolites, DNA methylation, gene expression, and circulating cytokines/chemokines prior to, during, and after taxane treatment in 400 patients with breast cancer. Molecular and patient reported data will be collected prior to, during, and after taxane therapy. Multi-modal data will be used to develop a set of comprehensive predictive biomarker signatures of TIPN. Conclusion: The goal of this study is to enable early detection of patients at risk of developing TIPN, provide a tool to modify taxane treatment to minimize morbidity from TIPN, and improved patient quality of life. Here we provide a brief review of the current state of research into CIPN and TIPN and introduce the GENIE study design.

A unifying network modeling approach for codon optimization.

MOTIVATION: Synthesizing genes to be expressed in other organisms is an essential tool in biotechnology. While the many-to-one mapping from codons to amino acids makes the genetic code degenerate, codon usage in a particular organism is not random either. This bias in codon use may have a remarkable effect on the level of gene expression. A number of measures have been developed to quantify a given codon sequence's strength to express a gene in a host organism. Codon optimization aims to find a codon sequence that will optimize one or more of these measures. Efficient computational approaches are needed since the possible number of codon sequences grows exponentially as the number of amino acids increases. RESULTS: We develop a unifying modeling approach for codon optimization. With our mathematical formulations based on graph/network representations of amino acid sequences, any combination of measures can be optimized in the same framework by finding a path satisfying additional limitations in an acyclic layered network. We tested our approach on bi-objectives commonly used in the literature, namely, Codon Pair Bias versus Codon Adaptation Index and Relative Codon Pair Bias versus Relative Codon Bias. However, our framework is general enough to handle any number of objectives concurrently with certain restrictions or preferences on the use of specific nucleotide sequences. We implemented our models using Python's Gurobi interface and showed the efficacy of our approach even for the largest proteins available. We also provided experimentation showing that highly expressed genes have objective values close to the optimized values in the bi-objective codon design problem. AVAILABILITY AND IMPLEMENTATION: http://alpersen.bilkent.edu.tr/NetworkCodon.zip. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Comparison of temporal muscle fascia and tragal cartilage perichondrium in endoscopic type 1 tympanoplasty with limited elevation of tympanomeatal flap / Comparação entre fáscia do músculo temporal e pericôndrio de cartilagem tragal na timpanoplastia endoscópica tipo 1 com descolamento limitado do retalho timpanomeatal

Abstract Introduction Elevation of tympanomeatal flap is one of the basic steps of tympanoplasty. A satisfactory level of anatomic and functional success can be achieved by using different grafts with limited tympanomeatal flap elevation. Objectives We aimed to compare the anatomic and functional success of tragal cartilage perichondrium and temporal muscle fascia in cases of endoscopic type 1 tympanoplasty performed with limited tympanomeatal flap elevation. Methods In total, 81 cases (33 females, 48 males, mean age 22.1<±<10.1 years, interval 18-49 years) which underwent transcanal endoscopic type 1 tympanoplasty with limited elevation of tympanomeatal flap were included the present study. All cases were divided into two groups as tragal cartilage perichondrium (group A) and temporal muscle fascia (group B). The comparison of the groups were made considering the pre- and postoperative air-bone gap and the tympanic membrane status. Results There was no statistically significant difference between Group A and Group B in preoperative and in postoperative air-bone gap values (p<=<0.608 and 0.529, respectively). In Group A and B, postoperative air-bone gap values demonstrated significant decrease compared to the preoperative values (p<=<0.0001). Group A and group B did not demonstrate significant differences between postoperative improvements of air-bone gap values (p<=<0.687). Graft retention success was 92.6% in group A while it was 90.0% in group B. There was no statistically significant difference between the groups in terms of graft retention success (p<=<0.166). Conclusion In accordance with the results of this study, we believe that both tragal cartilage perichondrium and temporal muscle fascia, and also in limited tympanomeatal flap elevation in endoscopic tympanoplasty are all eligible for result in safe and successful surgery.

Resumo Introdução O descolamento do retalho timpanomeatal é uma das etapas básicas da timpanoplastia. Um nível satisfatório de sucesso na restauração anatômica e funcional pode ser alcançado com o uso de diferentes enxertos e descolamento limitado do retalho timpanomeatal. Objetivos Comparar os resultados anatômicos e funcionais entre o uso de pericôndrio de cartilagem tragal e de fáscia do músculo temporal em timpanoplastias endoscópicas tipo 1 feitas com descolamento limitado do retalho timpanomeatal. Método Foram incluídos no estudo 81 pacientes (33 mulheres, 48 homens, média de 22,1 ± 10,1 anos, variação de 18-49 anos), submetidos a timpanoplastia endoscópica transcanal tipo 1 com descolamento limitado do retalho timpanomeatal. Todos os casos foram divididos em dois grupos: pericôndrio da cartilagem tragal (grupo A) e fáscia do músculo temporal (grupo B). Na comparação dos grupos consideraram-se o gap aéreo-ósseo, pré e pós-operatório, e a condição da membrana timpânica. Resultados Não houve diferença estatisticamente significante entre os grupos A e B no pré e pós-operatório (p = 0,608 e 0,529, respectivamente). Nos grupos A e B, os valores do gap aéreo-ósseo no pós-operatório demonstraram redução significante em relação aos valores pré-operatórios (p = 0,0001). Os grupos A e B não demonstraram diferenças significantes entre as medidas pré e pós-operatórias dos valores dos gaps (p = 0,687). O sucesso da retenção do enxerto foi de 92,6% no grupo A, enquanto no grupo B foi de 90,0%, não ocorreu diferença estatisticamente significante entre os grupos (p = 0,166). Conclusão De acordo com os resultados deste estudo, acreditamos que tanto o pericôndrio da cartilagem tragal como a fáscia do músculo temporal, usados com descolamento limitado do retalho timpanomeatal na timpanoplastia endoscópica, são elegíveis para uma cirurgia segura e bem-sucedida.

Codon optimization: a mathematical programing approach.

MOTIVATION: Synthesizing proteins in heterologous hosts is an important tool in biotechnology. However, the genetic code is degenerate and the codon usage is biased in many organisms. Synonymous codon changes that are customized for each host organism may have a significant effect on the level of protein expression. This effect can be measured by using metrics, such as codon adaptation index, codon pair bias, relative codon bias and relative codon pair bias. Codon optimization is designing codons that improve one or more of these objectives. Currently available algorithms and software solutions either rely on heuristics without providing optimality guarantees or are very rigid in modeling different objective functions and restrictions. RESULTS: We develop an effective mixed integer linear programing (MILP) formulation, which considers multiple objectives. Our numerical study shows that this formulation can be effectively used to generate (Pareto) optimal codon designs even for very long amino acid sequences using a standard commercial solver. We also show that one can obtain designs in the efficient frontier in reasonable solution times and incorporate other complex objectives, such as mRNA secondary structures in codon design using MILP formulations. AVAILABILITY AND IMPLEMENTATION: http://alpersen.bilkent.edu.tr/codonoptimization/CodonOptimization.zip.

Comparison of temporal muscle fascia and tragal cartilage perichondrium in endoscopic type 1 tympanoplasty with limited elevation of tympanomeatal flap.

INTRODUCTION: Elevation of tympanomeatal flap is one of the basic steps of tympanoplasty. A satisfactory level of anatomic and functional success can be achieved by using different grafts with limited tympanomeatal flap elevation. OBJECTIVES: We aimed to compare the anatomic and functional success of tragal cartilage perichondrium and temporal muscle fascia in cases of endoscopic type 1 tympanoplasty performed with limited tympanomeatal flap elevation. METHODS: In total, 81 cases (33 females, 48 males, mean age 22.1 ±â€¯10.1 years, interval 18-49 years) which underwent transcanal endoscopic type 1 tympanoplasty with limited elevation of tympanomeatal flap were included the present study. All cases were divided into two groups as tragal cartilage perichondrium (group A) and temporal muscle fascia (group B). The comparison of the groups were made considering the pre- and postoperative air-bone gap and the tympanic membrane status. RESULTS: There was no statistically significant difference between Group A and Group B in preoperative and in postoperative air-bone gap values (p = 0.608 and 0.529, respectively). In Group A and B, postoperative air-bone gap values demonstrated significant decrease compared to the preoperative values (p = 0.0001). Group A and group B did not demonstrate significant differences between postoperative improvements of air-bone gap values (p = 0.687). Graft retention success was 92.6% in group A while it was 90.0% in group B. There was no statistically significant difference between the groups in terms of graft retention success (p = 0.166). CONCLUSION: In accordance with the results of this study, we believe that both tragal cartilage perichondrium and temporal muscle fascia, and also in limited tympanomeatal flap elevation in endoscopic tympanoplasty are all eligible for result in safe and successful surgery.

The effect of age on ossiculoplasty results: A retrospective evaluation of 60 cases.

OBJECTIVE: There are only a few studies evaluating ossiculoplasty results in the pediatric age group. Although the effect of different factors on the results of ossiculoplasty is investigated, the effect of age on ossiculoplasty results is not known. In this study, the effect of age on ossiculoplasty results has been investigated. METHODS: This retrospective clinical study was performed in 60 patients (30 female, 30 male; mean age 15.5±14.3 years, range 9-57 years) who underwent ossiculoplasty. The cases were divided into two groups according to their age. Group A consisted of pediatric cases younger than 18 years of age and group B consisted of adult subjects (>18 years). The comparison of the groups was made by taking into consideration the air-bone gap in the 3rd and 12th weeks of the pre- and postoperative period. RESULTS: There was no statistically significant difference between preoperative air-bone gaps of the groups (p=0.086). In the third postoperative month, the air-bone gap gain of group A was statistically significantly higher than group B (p=0.0001). The air-bone gap gain of group A was significantly higher than group B in the postoperative 12th month (p=0.026). The air-bone gap gain of the patients with malleus in group A and group B was higher in the postoperative 3rd month than in the patients without malleus (all p values <0.05). There was no statistically significant difference between the air-bone gap gain in patients with the stapes suprastructure and the air-bone gap gain of the patients without stapes suprastructure in group A and group B in the postoperative 3rd month (p values >0.05). CONCLUSION: The results of ossiculoplasty were found better in the pediatric age group. We think that ossiculoplasty should be carried out without delay in the pediatric age group.

Comparison of the anatomical and functional success of fascia and perichondrium grafts in transcanal endoscopic type 1 tympanoplasty.

BACKGROUND: There are no studies in the literature, comparing the functional and anatomical successes of the use of fascial and perichondrial grafts in endoscopic type 1 tympanoplasties. OBJECTIVES: To compare the anatomical and functional outcomes of grafting with the fascia of the temporalis muscle and with the perichondrium of the tragal cartilage in patients undergoing primary transcanal type 1 tympanoplasty with endoscopy. METHODS: We enrolled a total of 151 patients (80 females and 71 males with a mean age of 26.0 ± 9.3 years in the age range between 18-57) with MERI scores ranging from 1 to 3 and who underwent a transcanal endoscopic type 1 tympanoplasty without tympanomeatal flap elevation. The patients were assigned to two groups according to the type of the graft used. The patients were assigned to either the tragal cartilage perichondrium group (Group A) or the fascia of the temporal muscle (Group B). The groups were compared according to the pre- and postoperative air-bone gaps and to the status of the tympanic membrane. RESULTS: There were no statistically significant differences in the distribution of the age, gender, localization, MERI scores, the duration of the operation, and the size of the perforation (all p values> 0.05). The pre-operative air-bone gap values of Group A and B did not show a statistically significant difference (p = 0.073). The postoperative improvement in the air-bone gap value did not demonstrate a significant difference between Group A and B (p = 0.202). The graft retention rates were 94.9 and 97.2% in Group A and in Group B respectively. There were no statistically significant differences between the two groups in terms of the graft retention success rates (p = 0.743). CONCLUSION: Perichondrium and fascia were suitable for use in endoscopic tympanoplasties.

Assessment of Oxidative Stress in Patients with Sudden Hearing Loss: A Non-randomized Prospective Clinical Study.

The etiology of sudden hearing loss (SHL) has not been fully elucidated. Previous studies claimed that different etiological factors may play a role in the pathogenesis of SHL. The aim of the present study is to investigate the presence of oxidative stress (OS) in SHL cases using thiol-disulfide balance. In addition, total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI) and lipid hydroperoxide levels (LOOH) were investigated. A total of 30 cases (15 female, 15 male, mean age 48.9 ± 8.1 years, age range: 36-68 years) were included in the study. Thiol and disulfide amounts, thiol/disulfide ratios, TOS, TAS, OSI and LOOH scores of the case group and control group were compared. Native thiol (SH) and total thiol (SH + SH) values were significantly lower in the SHL group than in the control group (p = 0.028 and p = 0.044, respectively). The LOOH value, TOS value and OSI value were significantly higher in the SHL group than in the control group (all p values < 0.05). The TAS value was significantly lower in the SHL group than in the control group (p = 0.0001). The present study has presented that the thiol-disulfide balance was impaired in SHL cases. OS may play a role in the development of SHL.

Plasma-Free Amino Acid Profiling of Nasal Polyposis Patients.

AIM AND OBJECTIVE: To determine the mechanisms present in the etiopathogenesis of nasal polyposis. It is not clear whether amino acids contribute in a causal way to the development of the disease. Therefore, the aim of this study was to determine the plasma-free amino acid profile in patients with nasal polyposis and to compare the results with a healthy control group. MATERIALS AND METHODS: This was a prospective controlled study that took place in the Otolaryngology Department at the Harran University Faculty of Medicine between April 2017 and April 2018. Plasmafree amino acid profile levels were studied in serum samples taken from a patient group and a healthy control group. Patients who were diagnosed with bilateral diffuse nasal polyposis and were scheduled for surgical interventions were included in this study. Individuals whose age, gender, and body mass index values were compatible with that of the patient group and who did not have any health problems were included in the control group. All the participants whose levels of plasma-free amino acid were thought to be affected by one or more of the following factors were excluded from the study: smoking and alcohol use, allergic rhinitis presence, the presence of acute or chronic sinusitis, a history of endoscopic sinus surgery, unilateral nasal masses, a history of chronic drug use, systemic or topical steroid use in the last three months for any reason, and liver, kidney, hematological, cardiovascular, metabolic, neurological, or psychiatric disorders or malignancies. RESULTS: In patients with nasal polyposis, 3-methyl histidine (3-MHIS: nasal polyposis group (ng) = 3.22 (1.92 - 6.07); control group (cg) = 1.21 (0.77 - 1.68); p = 0.001); arginine (arg: ng = 98.95 (70.81 - 117.75); cg = 75.10 (54.49 - 79.88); p = 0.005); asparagine (asn: ng = 79.84 (57.50 - 101.44); cg = 60.66 (46.39 - 74.62); p = 0.021); citrulline (cit: ng = 51.83 (43.81 - 59.78); cg = 38.33 (27.81 - 53.73); p = 0.038); cystine (cys: ng = 4.29 (2.43 - 6.66); cg = 2.41 (1.51 - 4.16); p = 0.019); glutamic acid (glu: ng = 234.86 (128.75 - 286.66); cg = 152.37 (122.51 - 188.34); p = 0.045); histidine (his: ng = 94.19 (79.34 - 113.99); cg = 74.80 (62.76 - 98.91); p = 0.018); lysine (lys: ng = 297.22 (206.55 - 371.25); cg = 179.50 (151.58 - 238.02); p = 0.001); ornithine (ng = 160.62 (128.36 - 189.32); cg = 115.91 (97.03 - 159.91); p = 0.019); serine (ser: ng = 195.15 (151.58 - 253.07); cg = 83.07 (67.44 - 92.44); p = 0.001); taurine (tau: ng = 74.69 (47.00 - 112.13); cg = 53.14 (33.57 - 67.31); p = 0.006); tryptophan (trp: ng = 52.31 (33.81 - 80.11); cg = 34.44 (25.94 - 43.07); p = 0.005), homocitrulline (ng = 1.75 (1.27 - 2.59); cg = 0.00 (0.00 - 0.53); p = 0.001); norvaline (ng = 6.90 (5.61 - 9.18); cg = 4.93 (3.74 - 7.13); p = 0.021); argininosuccinic acid (ng = 14.33 (10.06 - 25.65); cg = 12.22 (5.77 - 16.87) p = 0.046); and plasma concentrations were significantly higher than in the healthy control group (p <0.05). However, the gamma-aminobutyric acid (gaba: ng = 0.16 (0.10 - 0.24); cg = 0.21 (0.19 - 0.29); p = 0.010) plasma concentration was significantly lower in the nasal polyposis group than in the healthy control group. CONCLUSION: In this study, plasma levels of 15 free amino acids were significantly higher in the nasal polyposis group than in the healthy control group. A plasma level of 1 free amino acid was found to be significantly lower in the nasal polyposis group compared to the healthy control group. Therefore, it is important to determine the possibility of using the information obtained to prevent the recurrence of the condition and to develop effective treatment strategies. This study may be a milestone for studies of this subject. However, this study needs to be confirmed by further studies conducted in a larger series.

Endoscopic tympanoplasty with limited tympanomeatal flap elevation in pediatric cases: comparison of anatomic and audiological results of grafts.

OBJECTIVES: The anatomical and functional success rates of tragal cartilage perichondrium and temporal muscle fascia, in pediatric patients who underwent endoscopic type 1 tympanoplasty with limited tympanomeatal flap elevation, were compared. METHODS: In total, 35 pediatric patients (21 females, 14 males; mean age 11.0 ± 1.5 years; range 8-14 years) who underwent transcanal endoscopic type 1 tympanoplasty with limited elevation of the tympanomeatal flap were included in this study. Patients in group A received a tragal cartilage perichondrium graft and those in group B received a temporal muscle fascia graft. The groups were compared with respect to the pre- and postoperative air-bone gap (ABG) and tympanic membrane status. RESULTS: The mean preoperative and postoperative ABG were 27.0 ± 9.2 and 9.0 ± 8.5 dB in group A, and 26.8 ± 8.8 and 11.6 ± 9.2 dB in group B, respectively. The group differences in pre- and postoperative ABG values were not significant (p = 0.882 and p = 0.417, respectively). However, in both groups, the postoperative ABG was significantly lower than the preoperative ABG (both p = 0.0001). The graft retention rate was 100% in group A and 88.2% in group B; the difference was not statistically significant (p = 0.134). There was also no statistically significant difference between the pre- and postoperative bone conduction values of the patients at 0.5, 1, 2, 3 or 4 kHz (all p > 0.05). CONCLUSIONS: Our study demonstrated that in pediatric patients undergoing endoscopic tympanoplasty, both the tragal cartilage perichondrium and the temporal muscle fascia can be used successfully and safely as grafts in endoscopic type 1 tympanoplasty performed by limited tympanomeatal flap elevation.

Which graft should be used for the pediatric transcanal endoscopic type 1 tympanoplasty? A comparative clinical study.

OBJECTIVES: To compare the functional and anatomical success rates of the fascial versus perichondrial grafts in pediatric endoscopic type 1 tympanoplasties. METHODS: This retrospective clinical study was conducted on 40 pediatric patients (23 females and 17 males; mean age: 10.0 ±â€¯1.7 years; the age range: 6-13) who were operated with a transcanal endoscopic type 1 tympanoplasty. The study participants were assigned to two groups by graft types. The patients were assigned to either the tragal cartilage perichondrium group (Group A) or the fascia of the temporal muscle (Group B). The groups were compared according to the pre- and postoperative air-bone gaps and to the status of the tympanic membrane. RESULTS: There were not any statistically significant differences between the groups in terms of the distribution of age, gender, the operation sites, the duration of the operation, MERI scores or the size of the perforation (all p values > 0.05). The graft retention success rates were 94.7% and 90.5% in Group A and Group B, respectively. There were no statistically significant differences between the two groups in terms of the graft retention success rates (p = 0.609). The functional (audiological) success rate was statistically higher in Group B compared to Group A (p = 0.044). CONCLUSION: Perichondrium and fascia grafts were found out to be acceptable for use in pediatric endoscopic tympanoplasties. The functional success rates were higher in the fascia group. We also recommended the fascia as a graft in pediatric transcanal endoscopic type 1 tympanoplasties.

Programming an Artificial Neural Network Tool for Spatial Interpolation in GIS - A Case Study for Indoor Radio Wave Propagation of WLAN.

Wireless communication networks offer subscribers the possibilities of free mobility and access to information anywhere at any time. Therefore, electromagnetic coverage calculations are important for wireless mobile communication systems, especially in Wireless Local Area Networks (WLANs). Before any propagation computation is performed, modeling of indoor radio wave propagation needs accurate geographical information in order to avoid the interruption of data transmissions. Geographic Information Systems (GIS) and spatial interpolation techniques are very efficient for performing indoor radio wave propagation modeling. This paper describes the spatial interpolation of electromagnetic field measurements using a feed-forward back-propagation neural network programmed as a tool in GIS. The accuracy of Artificial Neural Networks (ANN) and geostatistical Kriging were compared by adjusting procedures. The feedforward back-propagation ANN provides adequate accuracy for spatial interpolation, but the predictions of Kriging interpolation are more accurate than the selected ANN. The proposed GIS ensures indoor radio wave propagation model and electromagnetic coverage, the number, position and transmitter power of access points and electromagnetic radiation level. Pollution analysis in a given propagation environment was done and it was demonstrated that WLAN (2.4 GHz) electromagnetic coverage does not lead to any electromagnetic pollution due to the low power levels used. Example interpolated electromagnetic field values for WLAN system in a building of Yildiz Technical University, Turkey, were generated using the selected network architectures to illustrate the results with an ANN.