Nevin Manimala

Eur J Cancer. 2021 Jun 19;153:142-152. doi: 10.1016/j.ejca.2021.05.023. Online ahead of print.

ABSTRACT

BACKGROUND: This phase 1 study evaluated safety, pharmacokinetics (PK), maximum tolerated dose (MTD), and antitumour activity of regorafenib in paediatric patients with solid tumours.

PATIENTS AND METHODS: Patients (aged 6 months to <18 years) with recurrent/refractory solid tumours received oral regorafenib once daily for 3 weeks on/1 week off. The starting dose (60 mg/m²) was derived from an adult physiology-based PK model and scaled to children; dose escalation was followed by safety expansion of the MTD cohort. Treatment-emergent adverse events (TEAEs) were evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Regorafenib PK was evaluated using a population PK model.

RESULTS: Forty-one patients (median age 13 years) received regorafenib (four cohorts: 60-93 mg/m²). Five of 23 evaluable patients experienced dose-limiting toxicities (Grade 4 thrombocytopenia, Grade 3 maculopapular rash, pyrexia, hypertension, and exfoliative dermatitis [each n = 1]). The MTD was defined as 82 mg/m². The most common Grade ≥3 drug-related TEAE was thrombocytopenia (10%). The incidence and severity of hypertension, diarrhoea, fatigue, hypothyroidism, and hand-foot skin reaction were lower than reported in adults. Regorafenib exposure increased with dose, with substantial overlap because of moderate-to-high interpatient variability. One patient with rhabdomyosarcoma experienced an unconfirmed partial response; 15 patients had stable disease, five for >16 weeks.

CONCLUSIONS: The recommended phase 2 dose of single-agent regorafenib in paediatric patients with solid malignancies is 82 mg/m². Regorafenib demonstrated acceptable tolerability and preliminary antitumour activity, supporting further investigation in paediatric patients.

CLINICAL TRIAL NUMBER: NCT02085148.

PMID:34157616 | DOI:10.1016/j.ejca.2021.05.023

Plant Physiol Biochem. 2021 Jun 16;166:427-436. doi: 10.1016/j.plaphy.2021.06.012. Online ahead of print.

ABSTRACT

Hotness or pungency is the major trait of genetically diverse and economically valuable chili (Capsicum sp.) cultivars. However, little is known about the influence of soil characteristics on genetic regulation of pungency vis-à-vis capsaicin formation in endemic chilies. Hence, the present work was conducted by growing two endemic chili cultivars in two types (alluvial and lateritic) of soil. Capsaicin content, pungency, and capsaicin synthase activity were significantly greater in chilies grown in alluvial soil than in lateritic soil. Correspondingly, Csy1, the gene that encodes capsaicin synthase, was significantly upregulated in alluvial soil grown plants. Interestingly, upregulation of Pun1, the gene responsible for capsaicin accumulation in fruits, was more in lateritic soil than in alluvial soil; but pungency was inhibited in lateritic soil by the overexpression of Pun1², a recessive allele of Pun1 locus. Statistical analyses revealed that high organic C, microbial activity, and NPK status in alluvial soil were responsible for high pungency, capsaicin synthase activity, capsaicin accumulation, and suppression of Pun1². Fruit yield, dry matter, crude protein, titratable acidity, and soluble solids were also significantly high in chilies grown in alluvial soil. Therefore, we postulate that soil quality attributes play vital roles in genetic regulation of pungency, capsaicin biosynthesis, fruit yield, and produce quality of endemic chili cultivars.

PMID:34157605 | DOI:10.1016/j.plaphy.2021.06.012

Food Chem. 2021 Jun 16;364:130381. doi: 10.1016/j.foodchem.2021.130381. Online ahead of print.

ABSTRACT

The objective of this study was to explore the potentiality and mechanism of visible and near-infrared (Vis-NIR) spectroscopy in estimating the freshness of komatsuna. We monitored the cumulative CO₂ production of komatsuna stored under different conditions as a freshness indicator and measured the Vis-NIR spectra of komatsuna as the predictor. Using the informative wavelengths (IW) selected using the stepwise selectivity ratio method, we constructed an accurate freshness prediction model through PLSR analysis. The IW in the visible region were attributed to pigments such as chlorophyll. In the NIR region, ten amino acids were identified as directly or indirectly contributing to the IW and were highly related to freshness. They were confirmed on the basis of the strong correlations between the informative NIR signals and NMR signals, which were determined using statistical heterospectroscopy. The results demonstrate the feasibility of Vis-NIR spectroscopy in estimating the freshness of komatsuna using the IW.

PMID:34157592 | DOI:10.1016/j.foodchem.2021.130381

Hum Mov Sci. 2021 Jun 19;78:102832. doi: 10.1016/j.humov.2021.102832. Online ahead of print.

ABSTRACT

Among adults, persons in control of a vehicle (i.e., drivers) are less likely to experience motion sickness compared to persons in the same vehicle who do not control it (i.e., passengers). This “driver-passenger effect” is well-known in adults, but has not been evaluated in children. Using a yoked-control design with seated pre-adolescent children, we exposed dyads to a driving video game. In each dyad, one child (the driver) drove the virtual vehicle. Their performance was recorded, and later shown to the other child (the passenger). Thus, visual motion stimuli were identical for the members of each dyad. During exposure to the video game, we monitored the quantitative kinematics of head and torso movements. Participants were instructed to discontinue participation immediately if they experienced any symptoms of motion sickness, however mild. Accordingly, the movements that we recorded preceded the onset of motion sickness. Results revealed that Passengers (73.08%) were more likely than Drivers (42.31%) to state that they were motion sick. Drivers tended to move more than passengers, and with a greater degree of multifractality. The magnitude of movement was greater among participants who later reported motion sickness than among those who did not. In addition, for the multifractality of movement a statistically significant interaction revealed that postural precursors of motion sickness differed qualitatively between Drivers and Passengers. Overall, the results reveal that control of a virtual vehicle reduces the risk of motion sickness among pre-adolescent children.

PMID:34157576 | DOI:10.1016/j.humov.2021.102832

J Environ Manage. 2021 Jun 19;295:113019. doi: 10.1016/j.jenvman.2021.113019. Online ahead of print.

ABSTRACT

Urban soils’ health is important to the community because of the soils’ potential use for recreational activities. A data quality-oriented approach to sampling design is proposed for performing soil representative surveys that gives support to defensible and statistically-based decisions. Krowoderski park in Cracow (Poland) was selected as a study case to investigate heavy metals (HMs) accumulation and to assess human risk exposure according to simulated scenarios. Statistical power was computed for optimizing the number of samples to compare HMs concentration against legal upper tolerance levels (LUTL). The samples’ location was iteratively designed as random spatial distribution throughout the study area, followed by K Ripley’s test for selecting the best sampling scheme and avoiding points of clustering or dispersion at several ranges. The total content of Cd, Cu, Pb, Zn, coarse size particles fraction and fine size particles texture, bulk density, pH, total C and S were measured in topsoil at each location using composite sampling. The hydraulic properties were estimated using pedotransfer functions. Statistical analysis of topsoil data shows low correlation between heavy metals, whereas high correlation was found between total S with Cu and Pb as well as total C with Cu and Pb. The concentration of all the HMs analysed was found to be under LUTL in all locations in the park, except for one point that is an outlier for Pb, although the values of several indexes for pooled HMs categorize the park as medium to highly polluted. Spatial autocorrelation was explored for every heavy metal and for elaborated pollution indexes, then maps were drawn using geostatistics. A human health risk assessment (HHRA) was computed for several simulated scenarios finding that risk exists for children from Pb through high ingestion of soil particles.

PMID:34157543 | DOI:10.1016/j.jenvman.2021.113019

Sci Total Environ. 2021 Jun 10;792:148406. doi: 10.1016/j.scitotenv.2021.148406. Online ahead of print.

ABSTRACT

BACKGROUND: Dengue is an endemic vector-borne disease influenced by environmental factors such as landscape and climate. Previous studies separately assessed the effects of landscape and climate factors on mosquito occurrence and dengue incidence. However, both factors concurrently coexist in time and space and can interact, affecting mosquito development and dengue disease transmission. For example, eggs laid in a suitable environment can hatch after being submerged in rain water. It has been difficult for conventional statistical modeling approaches to demonstrate these combined influences due to mathematical constraints.

OBJECTIVES: To investigate the combined influences of landscape and climate factors on mosquito occurrence and dengue incidence.

METHODS: Entomological, epidemiological, and landscape data from the rainy season (July-December) were obtained from respective government agencies in Metropolitan Manila, Philippines, from 2012 to 2014. Temperature, precipitation and vegetation data were obtained through remote sensing. A random forest algorithm was used to select the landscape and climate variables. Afterward, using the identified key variables, a model-based (MOB) recursive partitioning was implemented to test the combined influences of landscape and climate factors on ovitrap index (vector mosquito occurrence) and dengue incidence.

RESULTS: The MOB recursive partitioning for ovitrap index indicated a high sensitivity of vector mosquito occurrence on environmental conditions generated by a combination of high residential density areas with low precipitation. Moreover, the MOB recursive partitioning indicated high sensitivity of dengue incidence to the effects of precipitation in areas with high proportions of residential density and commercial areas.

CONCLUSIONS: Dengue dynamics are not solely influenced by individual effects of either climate or landscape, but rather by their synergistic or combined effects. The presented findings have the potential to target vector surveillance in areas identified as suitable for mosquito occurrence under specific climatic conditions and may be relevant as part of urban planning strategies to control dengue.

PMID:34157535 | DOI:10.1016/j.scitotenv.2021.148406

Clin Neurol Neurosurg. 2021 Jun 8;207:106739. doi: 10.1016/j.clineuro.2021.106739. Online ahead of print.

ABSTRACT

BACKGROUND: Non-Epileptic Paroxysmal Events (NEPE) are common clinical manifestations in pediatric age presenting with dysfunction of motor and behavioral activity mimicking features of epileptic seizures.

OBJECTIVE: To present and analyze number and clinical characteristic of a group of children/adolescents presenting with various types of NEPE; to compare clinical data of this group of NEPE affected children/adolescents with a group of children/adolescents affected by Epileptic Seizures (ES).

METHODS: The retrospective study was conducted at the Pediatric Clinic of University of Catania, Catania, Italy, in a period ranging from January 2005 and January 2018. Two groups of children/adolescents, aged from 1 month to 15 years, were selected: 312 affected by NEPE and 192 by ES. Number and percentage of the single type of NEPE were reported. Then, demographic characteristics, clinical manifestations, duration of the events, time of diagnosis, and age of onset of each type of NEPE and ES affected children/adolescents were analyzed and compared. Results of statistical analysis of the data were carried out between ES and some type of NEPEs including Sandifer syndrome, breath-holding spells, paroxysmal tremors, vertigo, and syncope.

RESULTS: Among the group of NEPE, vertigo, type of paroxysmal event clinically not classifiable, syncope, and Sandifer syndrome were the most common events; In the comparative analyzed samples, variability between NEPE and ES was found in the duration of the paroxysmal events, in number of episodes, in lag-time between the onset of symptoms and the diagnosis, and in age of onset. Analyzing clinical data of ES with some type of NEPE, statistical significant results were obtained in vertigo as regards the duration and average duration event, in paroxysmal tremors as number of events, in Sandifer syndrome as lag-time of diagnosis, and finally in all the types of NEPE as regards the age of onset, and loss of consciousness.

CONCLUSIONS: Analyzing the clinical features of each type of NEPE differences with ES are found. However, globally considered diagnostic differences between NEPE and ES remain difficult, questionable, and unrealizable without the support of correct parental report, direct clinical observations, and video-EEG monitoring.

PMID:34157509 | DOI:10.1016/j.clineuro.2021.106739

EBioMedicine. 2021 Jun 19;69:103436. doi: 10.1016/j.ebiom.2021.103436. Online ahead of print.

ABSTRACT

BACKGROUND: Due to the molecular mechanism complexity and heterogeneity of gastric cancer (GC), mechanistically interpretable biomarkers were required for predicting prognosis and discovering therapeutic targets for GC patients.

METHODS: Based on a total of 824 GC-specific fitness genes from the Project Score database, LASSOCox regression was performed in TCGA-STAD cohort to construct a GC Prognostic (GCP) model which was then evaluated on 7 independent GC datasets. Targets prioritization was performed in GC organoids. ARGLU1 was selected to further explore the biological function and molecular mechanism. We evaluated the potential of ARGLU1 serving as a promising therapeutic target for GC using patients derived xenograft (PDX) model.

FINDINGS: The 9-gene GCP model showed a statistically significant prognostic performance for GC patients in 7 validation cohorts. Perturbation of SSX4, DDX24, ARGLU1 and TTF2 inhibited GC organoids tumor growth. The results of tissue microarray indicated lower expression of ARGLU1 was correlated with advanced TNM stage and worse overall survival. Over-expression ARGLU1 significantly inhibited GC cells viability in vitro and in vivo. ARGLU1 could enhance the transcriptional level of mismatch repair genes including MLH3, MSH2, MSH3 and MSH6 by potentiating the recruitment of SP1 and YY1 on their promoters. Moreover, inducing ARGLU1 by LNP-formulated saRNA significantly inhibited tumor growth in PDX model.

INTERPRETATION: Based on genome-wide functional screening data, we constructed a 9-gene GCP model with satisfactory predictive accuracy and mechanistic interpretability. Out of nine prognostic genes, ARGLU1 was verified to be a potential therapeutic target for GC.

FUNDING: National Natural Science Foundation of China.

PMID:34157484 | DOI:10.1016/j.ebiom.2021.103436

J Stomatol Oral Maxillofac Surg. 2021 Jun 19:S2468-7855(21)00131-2. doi: 10.1016/j.jormas.2021.04.014. Online ahead of print.

ABSTRACT

PURPOSE: The aim of this study was to evaluate effects of extended maxillary advancement osteotomy on pharyngeal airway space (PAS) in mid-facial deficient cleft lip and palate (CLP) patients and mid-facial deficient non-CLP patients.

METHODS: Pharyngeal airway space (PAS) of 10 CLP and 10 non-CLP patients with the mean age of 19 years 10 months was measured on digitized lateral cephalograms taken shortly before maxillary advancement operation with Quadrangular Le Fort I osteotomy (QLF-I) (T0), early post-operative, (T1) and long term post-operative (T2). Two way repeated analysis of variance, independent samples t-test and correlations tests were used for statistical analysis of airway and skeletal changes.

RESULTS: Total PAS depth and area was significantly increased after the advancement and was stable in long term post-operative period for CLP and non-CLP patients. Nasopharyngeal and velopharyngeal airway space depth and area was statistically increased at T1 and T2 for both groups. Oropharyngeal airway depth and area showed no significant statistical difference at any of the time points. The effect of QLF-I osteotomy on (PAS) was similar in both CLP and non-CLP patients CONCLUSIONS: Nasopharyngeal, velopharyngeal, and total pharyngeal airway space depth and area increased after maxillary advancement with the QLF-I osteotomy; this increase was stable in long term follow up. Maxillary advancement with the QLF-I technique had no significant effect on oropharyngeal airway space depth and area in both CLP and non-cleft patients.

PMID:34157445 | DOI:10.1016/j.jormas.2021.04.014

J Proteomics. 2021 Jun 19:104306. doi: 10.1016/j.jprot.2021.104306. Online ahead of print.

ABSTRACT

In cyanobacteria, it is known that the excitation ratios of photosystem (PS) I and PSII changes with the wavelength of irradiated light due to mobile phycobilisome (PBS) and spillover, affecting the photosynthetic ATP/NADPH synthesis ratio and metabolic flux state. However, the mechanisms by which these changes are controlled have not been well studied. In this study, we performed a targeted proteomic analysis of Synechocystis sp. PCC 6803 under different spectral light conditions to clarify the regulation mechanisms of mobile PBS, spillover and metabolisms under different light qualities at the protein level. The results showed an increase in the amount of proteins mainly involved in CO₂ fixation under Red1 light conditions with a high specific growth rate, suggesting that the rate of intracellular metabolism is controlled by the rate of carbon uptake, not by changes in the amount of each enzyme. Correlation analysis between protein levels and PSI/PSII excitation ratios revealed that PsbQUY showed high correlations and significantly increased under Blue and Red2 light conditions, where the PSI/PSII excitation ratio was higher due to spillover. In the strains lacking the genes encoding these proteins, a decrease in the PSI/PSII excitation ratio was observed, suggesting that PsbQUY contribute to spillover occurrence. SIGNIFICANCE: In cyanobacteria, the photosynthetic apparatus’s responses, such as state transition [mobile PBS and spillover], occur due to the intensity and wavelength of irradiated light, resulting in changes in photosynthetic electron transport and metabolic flux states. Previous studies have analyzed the response of Synechocystis sp. PCC 6803 to light intensity from various directions, but only spectroscopic analysis of the photosynthetic apparatus has been done on the response to changes in the wavelength of irradiated light. This study analyzed the response mechanisms of mobile PBS, spillover, photosynthetic, and metabolic systems in Synechocystis sp. PCC 6803 under six different spectral light conditions by a targeted proteomic analysis. As a result, many proteins were successfully quantified, and the metabolic enzymes and photosynthetic apparatus were analyzed using an integrated approach. Principal component and correlation analyses and volcano plots revealed that the PSII subunits PsbQ, PsbU, and PsbY have a strong correlation with the PSI/PSII excitation ratio and contribute to spillover occurrence. Thus, statistical analysis based on proteome data revealed that PsbQ, PsbU, and PsbY are involved in spillover, as revealed by spectroscopic analysis.

PMID:34157441 | DOI:10.1016/j.jprot.2021.104306