Know when and how to die: gaining insights into the molecular regulation of leaf senescence.

Senescence is the ultimate phase in the life cycle of leaves which is crucial for recycling of nutrients to maintain plant fitness and reproductive success. The earliest visible manifestation of leaf senescence is their yellowing, which usually commences with the breakdown of chlorophyll. The degradation process involves a gradual and highly coordinated disassembly of macromolecules resulting in the accumulation of nutrients, which are subsequently mobilized from the senescing leaves to the developing organs. Leaf senescence progresses under overly tight genetic and molecular control involving a well-orchestrated and intricate network of regulators that coordinate spatio-temporally with the influence of both internal and external cues. Owing to the advancements in omics technologies, the availability of mutant resources, scalability of molecular analyses methodologies and the advanced capacity to integrate multidimensional data, our understanding of the genetic and molecular basis of leaf ageing has greatly expanded. The review provides a compilation of the multitier regulation of senescence process and the interrelation between the environment and the terminal phase of leaf development. The knowledge gained would benefit in devising the strategies for manipulation of leaf senescence process to improve crop quality and productivity.

Linking of oxidative stress and mitochondrial DNA damage to the pathophysiology of idiopathic intrauterine growth restriction.

Objective: A common and serious pregnancy issue known as intrauterine growth restriction (IUGR) occurs when the fetus is unable to reach its full growth potential. Mitochondria are crucial to the development of the fetus and the placenta. We aimed to elucidate the role of oxidative stress parameters and markers of DNA damage. The integrity of the mitochondrial DNA (mtDNA) was studied. Materials and Methods: Blood samples were collected from 48 females (cases and controls, respectively). Oxidative stress parameters were analyzed. DNA was extracted followed by high-performance liquid chromatography to study 8-OH-dG and mt DNA by real-time polymerase chain reaction. Western blot analysis was performed for nuclear-encoded mitochondrial proteins and DNA damage markers. Results: When pregnant women were compared to non-pregnant women in their first, second, and third trimesters, a highly significant progressive drop in circulating mtDNA was found. In addition, mtDNA was considerably higher in mothers carrying IUGR fetuses than in healthy pregnancies. Sirtuin-3 protein expression was considerably suppressed in the IUGR placenta (P = 0.027), whereas Nrf1 expression was not statistically different from the control group in the IUGR. Increased oxidative stress led to greater DNA damage in IUGR. The highest concentrations of 8-OH-dG were found in IUGR with levels significantly higher than those in the non-pregnant group. Conclusion: Our research sets the path for further investigation into mitochondrial anomalies in IUGR pregnancies and offers evidence for disturbed mitochondrial homeostasis. The mtDNA might offer a fresh perspective on the processes involved in physiological gestation. In addition, the presence of mtDNA may aid in the diagnosis of IUGR during pregnancy.

Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) may be necessary throughout pregnancy by ensuring proper placentation and embryonic growth. The lack of standardized EPC quantification techniques has prevented conclusive proof of an increase in EPC during pregnancy. OBJECTIVES: The purpose of this study was to determine whether EPC levels change for healthy and idiopathic fetal growth restriction (FGR) pregnancies. MATERIALS AND METHODS: The study population consisted of 48 healthy pregnant females with no previous history of IUGR (10 in the first trimester, 15 in the second, and 23 in the third), 48 women with pregnancy complicated by idiopathic FGR, and 15 non-pregnant women. By using flow cytometry, EPCs in maternal blood were recognized as CD45dim/CD34/KDR cells. ELISA was used to measure plasmatic cytokines. RESULTS: We ascertained a progressive rise in EPCs in healthy pregnancies that was apparent in the first but more pronounced in the third trimester. At comparable gestational ages, FGR-complicated pregnancies had impaired EPC growth. Placental growth factor and stromal-derived factor-1 levels in the blood were significantly lower in FGR than in healthy pregnancies, which may have contributed to the degradation of the EPCs. CONCLUSION: The count in EPCs might hold considerable promise toward developing a peculiar authentication marker for observing pregnancies, and could be the focus of cutting-edge tactics for the prognosis and treatment of FGR pregnancies.

Audiological, Phonatory and Cardiac Correlates of Individuals Exposed to Low-Frequency Noise or at Risk of Vibroacoustic Disease.

Introduction Low-frequency noise (LFN) is hazardous to hearing. Long-term exposure to LFN may lead to vibroacoustic disease (VAD), which not only affects a specific organ but the physiological function of entire systems, such as the auditory, phonatory, respiratory, and cardiac systems. Moreover, VAD may lead to many psychological problems and hence affect the quality of life. Objective To investigate the adverse effects of LFN on hearing, acoustic and perceptual correlates of the voice, blood pressure, cardiac rate, and anxiety level. Method A total of 20 subjects exposed to LFN and 20 not exposed to LFN were included, and a detailed case history was recorded. The patients were submitted to pure tone audiometry, otoscopic examination, acoustic and perceptual analyses of the voice, maximum phonation time, and an assessment of the s/z ratio. We also assessed blood pressure, and the results of a voice-related quality of life questionnaire and of the Hamilton anxiety rating scale. Results The results indicate that LFN had an adverse impact on the high-frequency threshold. The present study found a significant difference in shimmer and harmonics-to-noise ratio (HNR) values. Few subjects had high blood pressure and showed the sign of anxiety on the Hamilton anxiety rating scale. Conclusion Low-frequency noise has adverse effects on entire systems of the body and causes many psychological issues, which, in turn negatively affect quality of life.

Generalized ComBat harmonization methods for radiomic features with multi-modal distributions and multiple batch effects.

Radiomic features have a wide range of clinical applications, but variability due to image acquisition factors can affect their performance. The harmonization tool ComBat is a promising solution but is limited by inability to harmonize multimodal distributions, unknown imaging parameters, and multiple imaging parameters. In this study, we propose two methods for addressing these limitations. We propose a sequential method that allows for harmonization of radiomic features by multiple imaging parameters (Nested ComBat). We also employ a Gaussian Mixture Model (GMM)-based method (GMM ComBat) where scans are split into groupings based on the shape of the distribution used for harmonization as a batch effect and subsequent harmonization by a known imaging parameter. These two methods were evaluated on features extracted with CapTK and PyRadiomics from two public lung computed tomography datasets. We found that Nested ComBat exhibited similar performance to standard ComBat in reducing the percentage of features with statistically significant differences in distribution attributable to imaging parameters. GMM ComBat improved harmonization performance over standard ComBat (- 11%, - 10% for Lung3/CAPTK, Lung3/PyRadiomics harmonizing by kernel resolution). Features harmonized with a variant of the Nested method and the GMM split method demonstrated similar c-statistics and Kaplan-Meier curves when used in survival analyses.

Resampling and harmonization for mitigation of heterogeneity in image parameters of baseline scans.

Our study investigates the effects of heterogeneity in image parameters on the reproducibility of prognostic performance of models built using radiomic biomarkers. We compare the prognostic performance of models derived from the heterogeneity-mitigated features with that of models obtained from raw features, to assess whether reproducibility of prognostic scores improves upon application of our methods. We used two datasets: The Breast I-SPY1 dataset-Baseline DCE-MRI scans of 156 women with locally advanced breast cancer, treated with neoadjuvant chemotherapy, publicly available via The Cancer Imaging Archive (TCIA); The NSCLC IO dataset-Baseline CT scans of 107 patients with stage 4 non-small cell lung cancer (NSCLC), treated with pembrolizumab immunotherapy at our institution. Radiomic features (n = 102) are extracted from the tumor ROIs. We use a variety of resampling and harmonization scenarios to mitigate the heterogeneity in image parameters. The patients were divided into groups based on batch variables. For each group, the radiomic phenotypes are combined with the clinical covariates into a prognostic model. The performance of the groups is assessed using the c-statistic, derived from a Cox proportional hazards model fitted on all patients within a group. The heterogeneity-mitigation scenario (radiomic features, derived from images that have been resampled to minimum voxel spacing, are harmonized using the image acquisition parameters as batch variables) gave models with highest prognostic scores (for e.g., IO dataset; batch variable: high kernel resolution-c-score: 0.66). The prognostic performance of patient groups is not comparable in case of models built using non-heterogeneity mitigated features (for e.g., I-SPY1 dataset; batch variable: small pixel spacing-c-score: 0.54, large pixel spacing-c-score: 0.65). The prognostic performance of patient groups is closer in case of heterogeneity-mitigated scenarios (for e.g., scenario-harmonize by voxel spacing parameters: IO dataset; thin slice-c-score: 0.62, thick slice-c-score: 0.60). Our results indicate that accounting for heterogeneity in image parameters is important to obtain more reproducible prognostic scores, irrespective of image site or modality. For non-heterogeneity mitigated models, the prognostic scores are not comparable across patient groups divided based on batch variables. This study can be a step in the direction of constructing reproducible radiomic biomarkers, thus increasing their application in clinical decision making.

Improved generalized ComBat methods for harmonization of radiomic features.

Radiomic approaches in precision medicine are promising, but variation associated with image acquisition factors can result in severe biases and low generalizability. Multicenter datasets used in these studies are often heterogeneous in multiple imaging parameters and/or have missing information, resulting in multimodal radiomic feature distributions. ComBat is a promising harmonization tool, but it only harmonizes by single/known variables and assumes standardized input data are normally distributed. We propose a procedure that sequentially harmonizes for multiple batch effects in an optimized order, called OPNested ComBat. Furthermore, we propose to address bimodality by employing a Gaussian Mixture Model (GMM) grouping considered as either a batch variable (OPNested + GMM) or as a protected clinical covariate (OPNested - GMM). Methods were evaluated on features extracted with CapTK and PyRadiomics from two public lung computed tomography (CT) datasets. We found that OPNested ComBat improved harmonization performance over standard ComBat. OPNested + GMM ComBat exhibited the best harmonization performance but the lowest predictive performance, while OPNested - GMM ComBat showed poorer harmonization performance, but the highest predictive performance. Our findings emphasize that improved harmonization performance is no guarantee of improved predictive performance, and that these methods show promise for superior standardization of datasets heterogeneous in multiple or unknown imaging parameters and greater generalizability.

Development of a robust radiomic biomarker of progression-free survival in advanced non-small cell lung cancer patients treated with first-line immunotherapy.

We aim to determine the feasibility of a novel radiomic biomarker that can integrate with other established clinical prognostic factors to predict progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC) undergoing first-line immunotherapy. Our study includes 107 patients with stage 4 NSCLC treated with pembrolizumab-based therapy (monotherapy: 30%, combination chemotherapy: 70%). The ITK-SNAP software was used for 3D tumor volume segmentation from pre-therapy CT scans. Radiomic features (n = 102) were extracted using the CaPTk software. Impact of heterogeneity introduced by image physical dimensions (voxel spacing parameters) and acquisition parameters (contrast enhancement and CT reconstruction kernel) was mitigated by resampling the images to the minimum voxel spacing parameters and harmonization by a nested ComBat technique. This technique was initialized with radiomic features, clinical factors of age, sex, race, PD-L1 expression, ECOG status, body mass index (BMI), smoking status, recurrence event and months of progression-free survival, and image acquisition parameters as batch variables. Two phenotypes were identified using unsupervised hierarchical clustering of harmonized features. Prognostic factors, including PDL1 expression, ECOG status, BMI and smoking status, were combined with radiomic phenotypes in Cox regression models of PFS and Kaplan Meier (KM) curve-fitting. Cox model based on clinical factors had a c-statistic of 0.57, which increased to 0.63 upon addition of phenotypes derived from harmonized features. There were statistically significant differences in survival outcomes stratified by clinical covariates, as measured by the log-rank test (p = 0.034), which improved upon addition of phenotypes (p = 0.00022). We found that mitigation of heterogeneity by image resampling and nested ComBat harmonization improves prognostic value of phenotypes, resulting in better prediction of PFS when added to other prognostic variables.

Radiogenomics in brain, breast, and lung cancer: opportunities and challenges.

The field of radiogenomics largely focuses on developing imaging surrogates for genomic signatures and integrating imaging, genomic, and molecular data to develop combined personalized biomarkers for characterizing various diseases. Our study aims to highlight the current state-of-the-art and the role of radiogenomics in cancer research, focusing mainly on solid tumors, and is broadly divided into four sections. The first section reviews representative studies that establish the biologic basis of radiomic signatures using gene expression and molecular profiling information. The second section includes studies that aim to non-invasively predict molecular subtypes of tumors using radiomic signatures. The third section reviews studies that evaluate the potential to augment the performance of established prognostic signatures by combining complementary information encoded by radiomic and genomic signatures derived from cancer tumors. The fourth section includes studies that focus on ascertaining the biological significance of radiomic phenotypes. We conclude by discussing current challenges and opportunities in the field, such as the importance of coordination between imaging device manufacturers, regulatory organizations, health care providers, pharmaceutical companies, academic institutions, and physicians for the effective standardization of the results from radiogenomic signatures and for the potential use of these findings to improve precision care for cancer patients.

Association Between PON1 (L55M and Q192R) Genetic Polymorphism and Recurrent Pregnancy Loss in North Indian Women Exposed to Pesticides.

OBJECTIVE: The aim of the present study was to examine the relation between the PON1 polymorphisms and recurrent pregnancy loss (RPL). METHODS: In a cross-sectional study, blood samples were collected from 100 females. DNA was extracted and PON1 genotypes were determined by polymerase chain reaction (PCR) amplification. RESULTS: Regarding PON1 L55M, the mutated allele (M) frequency was found in 70.5% in RPL and in 53.5% in controls; the M allele was significantly associated with an increased risk of RPL (adjusted odds ratio [ORadj] = 2.07; 95% confidence interval [CI]; p < 0.001). However, regarding PON1 Q192R, the R mutated allele frequency was found in 28.5% in RPL and in 33% in controls. The R allele did not show any risk for RPL (ORadj 0.81; 95%CI; p = 0.329). CONCLUSION: The present study suggests that there is an effect of genetic polymorphism on RPL and provides additional evidence that combines with the growing information about the ways in which certain PON1 genotypes can affect the development of the fetus in the uterus.

OBJETIVO: O objetivo deste estudo foi examinar a relação entre os polimorfismos PON1 e perda recorrente de gravidez PRG. MéTODOS: Em um estudo transversal, foram coletadas amostras de sangue de 100 mulheres. O DNA foi extraído e os genótipos PON1 foram determinados por amplificação por PCR. RESULTADOS: Com relação ao PON1 L55M, a frequência do alelo mutado (M) foi encontrada em 70,5% no PRG e em 53,5% nos controles; o alelo M foi significativamente associado a um risco aumentado de PRG (odds radio ajustado [ORadj] =2,07; intervalo de confiança [IC] 95%; p < 0,001). No entanto, em relação ao PON1 Q192R, a frequência do alelo mutado R foi encontrada em 28,5% no PRG e em 33% nos controles. O alelo R não mostrou qualquer risco para PRG (ORadj 0,81; IC 95; p = 0,329). CONCLUSãO: O presente estudo sugere que há um efeito do polimorfismo genético sobre PRG e fornece evidências adicionais que se combinam com as informações crescentes sobre as maneiras pelas quais certos genótipos PON1 podem afetar o desenvolvimento do feto no útero.

Audiological, Phonatory and Cardiac Correlates of Individuals Exposed to Low-Frequency Noise or at Risk of Vibroacoustic Disease

Abstract Introduction Low-frequency noise (LFN) is hazardous to hearing. Long-term exposure to LFN may lead to vibroacoustic disease (VAD), which not only affects a specific organ but the physiological function of entire systems, such as the auditory, phonatory, respiratory, and cardiac systems. Moreover, VAD may lead to many psychological problems and hence affect the quality of life. Objective To investigate the adverse effects of LFN on hearing, acoustic and perceptual correlates of the voice, blood pressure, cardiac rate, and anxiety level. Method A total of 20 subjects exposed to LFN and 20 not exposed to LFN were included, and a detailed case history was recorded. The patients were submitted to pure tone audiometry, otoscopic examination, acoustic and perceptual analyses of the voice, maximum phonation time, and an assessment of the s/z ratio. We also assessed blood pressure, and the results of a voice-related quality of life questionnaire and of the Hamilton anxiety rating scale. Results The results indicate that LFN had an adverse impact on the high-frequency threshold. The present study found a significant difference in shimmer and harmonics-to-noise ratio (HNR) values. Few subjects had high blood pressure and showed the sign of anxiety on the Hamilton anxiety rating scale. Conclusion Low-frequency noise has adverse effects on entire systems of the body and causes many psychological issues, which, in turn negatively affect quality of life.

Association Between PON1 (L55M and Q192R) Genetic Polymorphism and Recurrent Pregnancy Loss in North Indian Women Exposed to Pesticides / Associação entre o polimorfismo genético PON1 (L55M e Q192R) e a perda recorrente de gravidez emmulheres do norte da Índia expostas a pesticidas

Abstract Objective The aim of the present study was to examine the relation between the PON1 polymorphisms and recurrent pregnancy loss (RPL). Methods In a cross-sectional study, blood samples were collected from 100 females. DNA was extracted and PON1 genotypes were determined by polymerase chain reaction (PCR) amplification. Results Regarding PON1 L55M, the mutated allele (M) frequency was found in 70.5% in RPL and in 53.5% in controls; theMallele was significantly associated with an increased risk of RPL (adjusted odds ratio [ORadj]=2.07; 95% confidence interval [CI]; p<0.001). However, regarding PON1 Q192R, the R mutated allele frequency was found in 28.5% in RPL and in 33% in controls. The R allele did not show any risk for RPL (ORadj 0.81; 95%CI; p=0.329). Conclusion The present study suggests that there is an effect of genetic polymorphism on RPL and provides additional evidence that combines with the growing information about the ways in which certain PON1 genotypes can affect the development of the fetus in the uterus.

Resumo Objetivo O objetivo deste estudo foi examinar a relação entre os polimorfismos PON1 e perda recorrente de gravidez PRG. Métodos Em um estudo transversal, foramcoletadas amostras de sangue de 100 mulheres. O DNA foi extraído e os genótipos PON1 foram determinados por amplificação por PCR. Resultados Com relação ao PON1 L55M, a frequência do alelo mutado (M) foi encontrada em 70,5% no PRG e em 53,5% nos controles; o alelo M foi significativamente associado a um risco aumentado de PRG (odds radio ajustado [ORadj] =2,07; intervalo de confiança [IC] 95%; p<0,001). No entanto, em relação ao PON1 Q192R, a frequência do alelo mutado R foi encontrada em 28,5% no PRG e em 33% nos controles. O alelo R não mostrou qualquer risco para PRG (ORadj 0,81; IC 95; p=0,329). Conclusão O presente estudo sugere que há um efeito do polimorfismo genético sobre PRG e fornece evidências adicionais que se combinam com as informações crescentes sobre asmaneiras pelas quais certos genótipos PON1 podemafetar o desenvolvimento do feto no útero.

Pachyonychia congenita: A rare genodermatosis.

Pachyonychia congenita (PC) is a rare genodermatosis with only 450 cases reported since 1906. It is of two types, type I due to mutation in genes 6a and 16, and 6b and 17 in type II with an autosomal dominant inheritance in both types. A 22 yr old female patient presented in our OPD with hypertrophy of finger and toe nails, palmoplantar keratoderma, oral punctuate leukokeratosis, hyperhidrosis in palms and soles with maceration and malodour since childhood. She had a positive family history with father and grandfather affected but less severely. Microscopy and culture of nail clippings and scrapping were done to rule out fungal infection. On biopsy acanthotic epidermis, parakeratosis, orthokeratosis were seen. No evidence of any associated malignancy was found after thorough workup. She was diagnosed as PC Type 1. She was put on topical steroids and orally on acetretin 25 mg OD. Paring of the nails was done too reduce the thickness of nails & to provide symptomatic relief. She was on a regular treatment for 3-4 months and showed some improvement in the form of reduced palmoplantar hyperkeratosis and reduced oral punctate keratosis but was later lost on followup. She showed no adverse effect to therapy during this period. This case is being reported because of its rarity.