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The application of tyrosine kinase inhibitors (TKIs) and novel immunotherapies has improved outcomes in patients with Ph + acute lymphoblastic leukaemia (ALL), and the issue of whether there is still a need for stem cell transplantation has become controversial. We performed a retrospective study to explore whether stem cell transplantation still held a place in patients with Ph + ALL if only imatinib and 2nd generation TKIs are available and affordable. A total of 292 patients were included. The median age was 38 years [range 14–64, IQR 28–48]. Patients receiving transplants (n = 216) had better rates of 4-year disease-free survival (DFS, 68% vs. 24%, P <.0001) and overall survival (OS, 72% vs. 47%, P <.0001) than those receiving continuous TKIs plus chemotherapy (TKI-chemo) (n = 76). In the multivariate analysis, male sex, WBC count ≥ 95 × 109/L and PLT count ≤ 154 × 109/L at diagnosis were significantly associated with poorer outcomes, and transplantation was significantly associated with favourable DFS and OS. In addition, the transplant outcomes were superior in any subgroup according to the number of risk variables. Furthermore, propensity score matching (PSM) analyses showed similar findings in the whole cohort and in age- and BCR-ABL1 level-based subgroups after the first or second consolidation. In conclusion, transplantation as a one-time procedure for adults with Ph + ALL patients remains important in countries lacking accessibility to third-generation TKIs or immunotherapies, regardless of the depth of the molecular response. [ABSTRACT FROM AUTHOR]

The therapeutic armamentarium of chronic myeloid leukemia (CML) has dramatically improved after small molecule tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 became available, with a life expectancy now close to that of the general population. Although highly effective, these drugs also have a toxicity profile that is often mild to moderate, but sometimes severe. Indeed, long‐term treatment with TKIs can lead to chronic adverse events that can negatively affect patients' quality of life and can promote significant morbidity and mortality, particularly in the case of second‐ or third‐generation TKIs. Treatment discontinuation has therefore become an emerging goal for CML patients and numerous studies have evaluated in off‐TKI subjects what requirements are appropriate for an attempt at treatment‐free remission (TFR). TFR eligibility is currently limited to a small population of subjects with both deep and sustained molecular responses to TKIs. For those attempting TFR, average success rates are promising, with 25%–30% of patients experiencing prolonged TFR. In case of failure to maintain sustained TFR, safety results to date are reassuring, with almost all patients responding successfully to resumption of TKIs, and advanced‐phase disease progression representing a very rare event. The purpose of this review is to discuss guidelines for TKI discontinuation, clinical advances from clinical trials and real‐life experiences, and describe areas of research, particularly regarding the biological factors capable of predicting the success of TFR. [ABSTRACT FROM AUTHOR]

Background: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL‐2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML‐CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. Methods: In this phase 2 trial, patients with CML‐CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single‐agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. Results: Sixty‐five patients were treated. Their median age was 46 years (range, 23–73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow‐up of 42 months, the 4‐year event‐free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single‐agent dasatinib (cumulative 12‐months MMR rate of 79% with both strategies). The incidence of grade 3‐4 neutropenia was 22% with the combination and 11% with single‐agent dasatinib (p <.001). Conclusions: Treatment with dasatinib and venetoclax was safe and effective in CML‐CP. The cumulative response rates with the combination were similar to those with single‐agent dasatinib. Further follow‐up is needed to evaluate the rates of durable deep molecular response and treatment‐free remission. Treatment with dasatinib and venetoclax was effective and well‐tolerated. By 12 months of combination, 86% and 53% of patients achieved a major molecular response and a deep molecular response, respectively. [ABSTRACT FROM AUTHOR]

Abstract The growth and productivity of crop plants are negatively affected by salinity-induced ionic and oxidative stresses. This study aimed to provide insight into the interaction of NaCl-induced salinity with Azolla aqueous extract (AAE) regarding growth, antioxidant balance, and stress-responsive genes expression in wheat seedlings. In a pot experiment, wheat kernels were primed for 21 h with either deionized water or 0.1% AAE. Water-primed seedlings received either tap water, 250 mM NaCl, AAE spray, or AAE spray + NaCl. The AAE-primed seedlings received either tap water or 250 mM NaCl. Salinity lowered growth rate, chlorophyll level, and protein and amino acids pool. However, carotenoids, stress indicators (EL, MDA, and H2O2), osmomodulators (sugars, and proline), antioxidant enzymes (CAT, POD, APX, and PPO), and the expression of some stress-responsive genes (POD, PPO and PAL, PCS, and TLP) were significantly increased. However, administering AAE contributed to increased growth, balanced leaf pigments and assimilation efficacy, diminished stress indicators, rebalanced osmomodulators and antioxidant enzymes, and down-regulation of stress-induced genes in NaCl-stressed plants, with priming surpassing spray in most cases. In conclusion, AAE can be used as a green approach for sustaining regular growth and metabolism and remodelling the physio-chemical status of wheat seedlings thriving in salt-affected soils.

The current study aimed to quantify the effects of two drought intensities achieved by deprivation of watering for 45 and 65% of the volumetric soil moisture content (VSMC) for 14 days after wheat anthesis to identify physio-biochemical and molecular changes associated with drought tolerance in six genotypes with different drought tolerance. Drought at 65% of VSMC induced a significant decrease in the chlorophyll a content in the drought-sensitive genotype, which indicated a strong loss of photosynthetic reaction centres. Further, in the drought-tolerant genotype, the content of carotenoids, which could play a vital role in resisting water shortage stress, tended to increase. The increased production of malondialdehyde showed that the antioxidant system in the drought-sensitive genotypes was not properly activated. A significant decrease in catalase (CAT; EC 1.11.1.6) was observed at a 45% reduction in VSMC, compared to the control, in the drought-sensitive genotype, and at a reduction in VSMC of 65%, in all medium sensitive genotypes. Further, the drought-tolerant and -medium tolerant genotypes responded to drought with a decline in total glutathione concentrations with the intention to reinforce their defence system. Thereby, dehydroascorbate reductase (DHAR; EC 1.8.5.1), monodehydroascorbate reductase (MDHAR; EC 1.6.5.4), and glutathione reductase (GR; EC 1.6.4.2) were critical enzymes involved in the ascorbate–glutathione cycle together with CAT, showing their main role in the detoxification of ROS produced with the reduction in VSMC by 65%. The results of gene expression analysis showed that severe drought increased the levels of the DHN5 and WZY2 genes (that were significantly positively correlated) in the drought-tolerant genotype, whose grain weight, area, and length did not change in maturity. Also, it was seen that DHN5 expression showed a significant positive correlation with grain length and proline content at a 45% reduction in VSMC. The identification of different mechanisms under drought can contribute to the selection of drought-tolerant genotypes. [ABSTRACT FROM AUTHOR]

An elevated sea temperature is considered a key abiotic stressor causing thermal stress to intertidal macroalgae and influencing their populations. Halimeda macroloba is an important CaCO3 producer that contributes to the carbonate budget in marine ecosystems. The population decline of this intertidal algal species could lead to considerable declines in both regional and global carbonate production. However, the impact of increasing temperature on the molecular mechanisms and protein profile of calcified H. macroloba is unclear and remains to be explored. In this study, H. macroloba was exposed to 30 °C and 35 °C for 7 days. The whole protein was then extracted using 0.5% SDS and digested using trypsin before an analysis using LC-MS. The protein profile of H. macroloba was characterized using the MaxQuant program aligned with the UniProt database. A total of 407 proteins were identified, and 12 proteins were found to be significantly upregulated or downregulated in response to the elevated temperature. Cell division protein, protein kinase domain-containing protein, phospholipid transport protein, and small ribosomal subunit protein were the significant proteins identified in our dataset. The proteins associated with cell division, cellular metabolic processes, localization, oxidoreductase activity, and biosynthetic process pathways were overexpressed with a more than 2-fold change at a high temperature. An interaction map generated using STITCH revealed that the significant protein change altered the other proteins related to abiotic stress, producing energy and inducing calcification. This information could be useful in understanding how H. macroloba responds to an elevated sea temperature. [ABSTRACT FROM AUTHOR]

This article discusses the case of a young patient with polycythemia vera (PV) who achieved a complete hematologic, cytogenetic, and molecular response to treatment with ropeginterferon alfa-2b (Ropeg). PV is a condition characterized by an elevated red blood cell count and an increased risk of thrombotic and hemorrhagic events. The patient in this case had a chromosomal abnormality, which disappeared after seven months of treatment with Ropeg. The article highlights the potential of Ropeg as a disease-modifying drug for improving the prognosis of PV patients, particularly those at high risk for disease progression. [Extracted from the article]

Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung cancer patients with a specific gene mutation often undergo tissue biopsies to guide treatment. But what if a simple blood test could do the same? This review explores "liquid biopsies", which detect circulating tumor DNA (ctDNA) in the blood, offering several advantages. For early-stage disease, it could help decide on treatment after surgery. In advanced stages, it can identify genetic changes in the tumor that might affect treatment response. Additionally, tracking ctDNA levels can monitor treatment progress and detect resistance early. While tissue biopsies remain standard, liquid biopsies are becoming a recommended alternative. Ongoing research aims to improve test sensitivity for early detection, refine treatment approaches based on ctDNA results, and explore other bodily fluids for even better detection. Making liquid biopsies more accessible and integrated into routine care could significantly improve lung cancer management. Circulating tumor DNA (ctDNA) offers a new paradigm in optimizing treatment strategies for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). Its potential spans early-stage disease, influencing adjuvant therapy, to advanced disease, where it aids in identifying genomic markers and resistance mechanisms. This review explores the evolving landscape of utilizing liquid biopsies, specifically circulating tumor DNA (ctDNA), in the management of NSCLC with EGFR mutations. While tissue-based genomic testing remains the cornerstone for clinical decision-making, liquid biopsies offer a well-validated, guideline-recommended alternative approach. Ongoing trials integrating ctDNA for EGFR-mutant NSCLC management are also discussed, shedding light on the potential of ctDNA in early-stage disease, including its applications in prognostication, risk stratification, and minimal residual disease detection post-curative intent treatment. For advanced disease, the role of ctDNA in identifying resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) is explored, providing insights into disease progression and guiding treatment decisions. This review also addresses the challenges, including the limitations in sensitivity of current assays for disease recurrence detection, and calls for future studies to refine treatment approaches, standardize reporting, and explore alternative biofluids for enhanced sensitivity. A systematic approach is crucial to address barriers to ctDNA deployment, ensuring equitable access, and facilitating its integration into routine clinical practice. [ABSTRACT FROM AUTHOR]

The introduction in 1998 of imatinib mesylate (IM), a first-generation BCR-ABL1 tyrosine kinase inhibitor (1G-TKI), to the treatment of chronic myelogenous leukemia patients in the chronic phase (CML-CP), significantly improved the prognosis of a previously incurable disease with a prognosed 5-year-long overall survival and progression-free survival of 91.7% and 94.7%, respectively. Long term follow-up studies of CML-CP patients verified the initial results, showing a 10-year overall response rate of 82-83.2%. In about one quarter of CML-CP patients, IM primary/secondary resistance or intolerance is diagnosed. After switching to a second generation BCR-ABL1 TKI (dasatinib, nilotinib, bosutinib), a complete cytogenetic response is obtained in only c. 50% of CML-CP patients. Also the frequency of deep molecular responses (DMR: MR4.0 and MR4.5) is relatively low. The results of 2G-TKI treatment are particularly unsatisfactory in patients carrying the TKI resistant BCR::ABL1 kinase domain mutants (BCR::ABL1 KD), especially BCR-ABL1 T315I. For this reason, other orally biocompatible compounds have been developed to target BCR-ABL T315I. One of these is ponatinib, which allows a major molecular response (MMR) and MR4.5 to be obtained in 40% and 24% of severely TKIs-pretreated CML-CP patients, respectively. The latter represent a new class of allosteric BCR-ABL1 tyrosine kinase inhibitor [asciminib (ABL001)], specifically targeting the ABL myristoyl pocket of BCR-ABL tyrosine kinase. Its application in CML-CP patients previously treated with at least two TKIs resulted in an MMR rate and a MR4.5 rate of 37.6% and 10.8%, respectively, at 96 weeks. The favorable asciminib response and tolerance profile was also confirmed in real--life conditions, even in subjects with previous ponatinib therapy failure (MR4.5 in 10.5%). Recent data suggests that asciminib may be used in the first line or in combination with a 1G- or 2G-TKI. This latter strategy may enhance the rate of DMR obtained and increase the number of patients eligible for an attempt at treatment-free remission. [ABSTRACT FROM AUTHOR]

Pesticides employed worldwide for crop protection easily reach aquatic systems, which act as the main reservoirs, and become a risk factor for aquatic fauna. Fipronil is a broad‐spectrum insecticide acting on the insect nervous system; however, other effects and systems unrelated to this mechanism could be affected in non‐target organisms. Thus, the present study aimed to assess the impact of fipronil on the suborganismal response (gene expression and enzymatic activity) of Chironomus riparius larvae as a model organism in ecotoxicology. To this end, short‐term toxicity tests were carried out with fourth‐instar larvae exposed to 0.001, 0.01, and 0.1 µg L−1 of fipronil for 24 and 96 h. Messenger RNA levels of 42 genes related to diverse metabolic pathways were analyzed by real‐time polymerase chain reaction, complemented with catalase (CAT), glutathione S‐transferase (GST), and acetylcholinesterase (AChE) activities. Few effects were observed at 24 h; however, after longer exposure (96 h), genes involved in the endocrine, detoxification, stress, and immune response pathways were altered. Moreover, fipronil at 96 h increased CAT and GST activity at 0.01 µg L−1 and AChE at the highest concentrations. The results demonstrate that even low environmentally relevant fipronil concentrations can modulate the molecular response of several cellular pathways in C. riparius after short‐term exposure. These results bring new information about the underlying response of fipronil and its mode of action on a key aquatic invertebrate. Despite no effects on mortality, strong modulation at the suborganismal level emphasizes the advantage of biomarkers as early damage responses and the harmful impact of this pesticide on freshwater organisms. Environ Toxicol Chem 2024;43:405–417. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. [ABSTRACT FROM AUTHOR]

Purpose: We investigated the potential clinical utility of short-term serial KRAS-mutated circulating cell-free tumor DNA (ctDNA) assessment for predicting therapeutic response in patients undergoing first-line chemotherapy for advanced pancreatic cancer. Methods: We collected 144 blood samples from 18 patients with locally advanced or metastatic cancer that were undergoing initial first-line chemotherapy of gemcitabine plus nab-paclitaxel (GEM plus nab-PTX). Analysis of KRAS-mutated ctDNA was quantified by digital droplet polymerase chain reaction (ddPCR) as mutant allele frequency (MAF). This study investigated pretreatment KRAS-mutated ctDNA status and ctDNA kinetics every few days (days 1, 3, 5 and 7) after initiation of chemotherapy and their potential as predictive indicators. Results: Of the 18 enrolled patients, an increase in KRAS-mutated ctDNA MAF values from day 0–7 after initiation of chemotherapy was significantly associated with disease progression (P < 0.001). Meanwhile, positive pretreatment ctDNA status (MAF ≥ 0.02%) (P = 0.585) and carbohydrate antigen 19-9 (CA19-9) values above the median (P = 0.266) were not associated with disease progression. In univariate analysis, this short-term increase in ctDNA MAF values (day 0–7) was found to be associated with significantly shorter progression free survival (PFS) (hazard ration [HR], 24.234; range, (2.761–212.686); P = 0.0002). Conclusion: This short-term ctDNA kinetics assessment may provide predictive information to reflect real-time therapeutic response and lead to effective refinement of regimen in patients with advanced pancreatic cancer undergoing systemic chemotherapy. [ABSTRACT FROM AUTHOR]

Drought stress is an annual global phenomenon that has devastating effects on crop production, so numerous studies have been conducted to improve crop drought resistance. Plant-associated microbiota play a crucial role in crop health and growth; however, we have a limited understanding of the key processes involved in microbiome-induced crop adaptation to drought stress. In this review, we summarize the adverse effects of drought stress on crop growth in terms of germination, photosynthesis, nutrient uptake, biomass, and yield, with a focus on the response of soil microbial communities to drought stress and plant-microbe interactions under drought stress. Moreover, we review the morpho-physiological, biochemical, and molecular mechanisms underlying the mitigation effect of microbes on crop drought stress. Finally, we highlight future research directions, including the characterization of specific rhizosphere microbiome species with corresponding root exudates and the efficiency of rhizobacteria inoculants under drought conditions. Such research will advance our understanding of the complex interactions between crops and microbes and improve crop resistance to drought stress through the application of beneficial drought-adaptive microbes. [ABSTRACT FROM AUTHOR]

Abstract Background “Red tides” are harmful algal blooms caused by dinoflagellate microalgae that accumulate toxins lethal to other organisms, including humans via consumption of contaminated seafood. These algal blooms are driven by a combination of environmental factors including nutrient enrichment, particularly in warm waters, and are increasingly frequent. The molecular, regulatory, and evolutionary mechanisms that underlie the heat stress response in these harmful bloom-forming algal species remain little understood, due in part to the limited genomic resources from dinoflagellates, complicated by the large sizes of genomes, exhibiting features atypical of eukaryotes. Results We present the de novo assembled genome (~ 4.75 Gbp with 85,849 protein-coding genes), transcriptome, proteome, and metabolome from Prorocentrum cordatum, a globally abundant, bloom-forming dinoflagellate. Using axenic algal cultures, we study the molecular mechanisms that underpin the algal response to heat stress, which is relevant to current ocean warming trends. We present the first evidence of a complementary interplay between RNA editing and exon usage that regulates the expression and functional diversity of biomolecules, reflected by reduction in photosynthesis, central metabolism, and protein synthesis. These results reveal genomic signatures and post-transcriptional regulation for the first time in a pelagic dinoflagellate. Conclusions Our multi-omics analyses uncover the molecular response to heat stress in an important bloom-forming algal species, which is driven by complex gene structures in a large, high-G+C genome, combined with multi-level transcriptional regulation. The dynamics and interplay of molecular regulatory mechanisms may explain in part how dinoflagellates diversified to become some of the most ecologically successful organisms on Earth.

Background: The authors assessed the clinical utility of patient‐reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy. Methods: The authors conducted an international prospective study that included patients with newly diagnosed, chronic‐phase CML. Before clinical consultation, patients were provided a tablet computer to self‐rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self‐reported questionnaire. The proportions of optimal responders at 3 and 6 months were assessed according to the European LeukemiaNet criteria. Results: Between July 2020 and August 2021, 94 patients with a median age of 57 years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6‐month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3 months and by 61 of 81 patients (75.3%) at 6 months. Conclusions: Patient‐reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848). Optimal adherence to tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia is critical to attain and maintain an optimal clinical response. The current findings suggest that systematic monitoring of patient‐reported symptoms is associated with high adherence rates. [ABSTRACT FROM AUTHOR]

Some wild cotton species are remarkably tolerant to salt stress, and hence represent valuable resources for improving salt tolerance of the domesticated allotetraploid species Gossypium hirsutum L. Here, we first detected salt-induced stress changes in physiological and biochemical indexes of G. anomalum, a wild African diploid cotton species. Under 350 mmol/L NaCl treatment, the photosynthetic parameters declined significantly, whereas hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents increased. Catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) activity and proline (PRO) content also significantly increased, reaching peak values at different stages of salt stress. We used RNA-Seq to characterize 15,476 differentially expressed genes in G. anomalum roots after 6, 12, 24, 72, and 144 h of salt stress. Gene Ontology enrichment analysis revealed these genes to be related to sequence-specific DNA and iron ion binding and oxidoreductase, peroxidase, antioxidant, and transferase activity; meanwhile, the top enriched pathways from the Kyoto Encyclopedia of Genes and Genomes database were plant hormone signal transduction, phenylpropanoid biosynthesis, fatty acid degradation, carotenoid biosynthesis, zeatin biosynthesis, starch and sucrose metabolism, and MAPK signaling. A total of 1231 transcription factors were found to be expressed in response to salt stress, representing ERF, MYB, WRKY, NAC, C2H2, bZIP, and HD-ZIP families. Nine candidate genes were validated by quantitative real-time PCR and their expression patterns were found to be consistent with the RNA-Seq data. These data promise to significantly advance our understanding of the molecular response to salt stress in Gossypium spp., with potential value for breeding applications. [ABSTRACT FROM AUTHOR]

The current study aimed to quantify the effects of two drought intensities achieved by deprivation of watering for 45 and 65% of the volumetric soil moisture content (VSMC) for 14 days after wheat anthesis to identify physio-biochemical and molecular changes associated with drought tolerance in six genotypes with different drought tolerance. Drought at 65% of VSMC induced a significant decrease in the chlorophyll a content in the drought-sensitive genotype, which indicated a strong loss of photosynthetic reaction centres. Further, in the drought-tolerant genotype, the content of carotenoids, which could play a vital role in resisting water shortage stress, tended to increase. The increased production of malondialdehyde showed that the antioxidant system in the drought-sensitive genotypes was not properly activated. A significant decrease in catalase (CAT; EC 1.11.1.6) was observed at a 45% reduction in VSMC, compared to the control, in the drought-sensitive genotype, and at a reduction in VSMC of 65%, in all medium sensitive genotypes. Further, the drought-tolerant and -medium tolerant genotypes responded to drought with a decline in total glutathione concentrations with the intention to reinforce their defence system. Thereby, dehydroascorbate reductase (DHAR; EC 1.8.5.1), monodehydroascorbate reductase (MDHAR; EC 1.6.5.4), and glutathione reductase (GR; EC 1.6.4.2) were critical enzymes involved in the ascorbate–glutathione cycle together with CAT, showing their main role in the detoxification of ROS produced with the reduction in VSMC by 65%. The results of gene expression analysis showed that severe drought increased the levels of the DHN5 and WZY2 genes (that were significantly positively correlated) in the drought-tolerant genotype, whose grain weight, area, and length did not change in maturity. Also, it was seen that DHN5 expression showed a significant positive correlation with grain length and proline content at a 45% reduction in VSMC. The identification of different mechanisms under drought can contribute to the selection of drought-tolerant genotypes.

An elevated sea temperature is considered a key abiotic stressor causing thermal stress to intertidal macroalgae and influencing their populations. Halimeda macroloba is an important CaCO3 producer that contributes to the carbonate budget in marine ecosystems. The population decline of this intertidal algal species could lead to considerable declines in both regional and global carbonate production. However, the impact of increasing temperature on the molecular mechanisms and protein profile of calcified H. macroloba is unclear and remains to be explored. In this study, H. macroloba was exposed to 30 °C and 35 °C for 7 days. The whole protein was then extracted using 0.5% SDS and digested using trypsin before an analysis using LC-MS. The protein profile of H. macroloba was characterized using the MaxQuant program aligned with the UniProt database. A total of 407 proteins were identified, and 12 proteins were found to be significantly upregulated or downregulated in response to the elevated temperature. Cell division protein, protein kinase domain-containing protein, phospholipid transport protein, and small ribosomal subunit protein were the significant proteins identified in our dataset. The proteins associated with cell division, cellular metabolic processes, localization, oxidoreductase activity, and biosynthetic process pathways were overexpressed with a more than 2-fold change at a high temperature. An interaction map generated using STITCH revealed that the significant protein change altered the other proteins related to abiotic stress, producing energy and inducing calcification. This information could be useful in understanding how H. macroloba responds to an elevated sea temperature.

Cadmium (Cd), one of the most toxic heavy metals, has been extensively studied by environmental scientists because of its detrimental effects on plants, animals, and humans. Increased industrial activity has led to environmental contamination with Cd. Cadmium can enter the food chain and pose a potential human health risk. Therefore, reducing the accumulation of Cd in plant species and enhancing their detoxification abilities are crucial for remediating heavy metal pollution in contaminated areas. One innovative technique is nano-phytoremediation, which employs nanomaterials ranging from 1 to 100 nm in size to mitigate the accumulation and detrimental effects of Cd on plants. Although extensive research has been conducted on using nanomaterials to mitigate Cd toxicity in plants, it is important to note that the mechanism of action varies depending on factors such as plant species, level of Cd concentration, and type of nanomaterials employed. This review aimed to consolidate and organize existing data, providing a comprehensive overview of the effects and mechanisms of nanomaterials in enhancing plant resistance to Cd. In particular, its deep excavation the mechanisms of detoxification heavy metals of nanomaterials by plants, including regulating Cd uptake and distribution, enhancing antioxidant capacity, regulating gene expression, and regulating physiological metabolism. In addition, this study provides insights into future research directions in this field.

Purpose: Postconcurrent chemoradiotherapy (CRT) response assessment has been challenging in locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) due to prevailing postradiation changes. Molecular response methods have been encouraging, although further clarifications and validations were needed. We tested the effectiveness of a proposed semi-quantitative molecular response criterion in these patients. Materials and Methods: Two subspecialty-trained physicians evaluated 18F-fluorodeoxyglucose positron emission tomography/computed tomography of LA-HNSCC patients (n = 83) post 3 months CRT using a five points Head and Neck Molecular Imaging-Reporting and Data System (HAN-MI-RADS) criterion. Where available, histopathology examination with clinical and imaging interpretation was taken as a reference for the disease. A diagnostic accuracy comparison was done with the existing Hopkins score. Further effectiveness was analyzed with disease-free survival (DFI) and overall survival (OS). Results: Metastasis was developed in 11/83 patients at 3 months of evaluation. Of 72 patients, 39, 2, and 31 patients had a complete response, equivocal response, and partial response as per HAN-MI-RADS. Per patient sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for predicting loco-regional disease up to 1 and 2 years was 93.3%, 92.5%, 90.3%, 94.9%, 92.9%, and 84.9%, 91.9%, 90.3%, 87.2%, and 88.6% respectively. One year and two years DFI for each HAN-MI-RADS score showed a statistically significant difference while it was not for OS. The receiver operating characteristic curve analysis showed significantly better outcome predictability of HAN-MI-RADS (area under the curve [AUC] 0.884) than Hopkins (AUC 0.699). Conclusions: A five points HAN-MI-RADS criterion was found promising for response assessment with less equivocal results and statistically significant higher AUC than Hopkins for loco-regional recurrence prediction. [ABSTRACT FROM AUTHOR]

Fusarium graminearum is among the most virulent pathogens attacking wheat plants and significantly lowering its production globally. The present work aims to shed light on the interactions between two priming solutions, calcium (Ca) or salicylic acid (SA), and F. graminearum inoculation depending on the growth rate, physiological attributes, and molecular responses in wheat seedlings. In a pot experiment, F. graminearum-pre-inoculated or inoculum-free sandy soil was used to germinate wheat kernels after priming them for 12 h in distilled water, 5-mM CaCl2, or 0.05-mM SA. The results demonstrated that F. graminearum inoculation decreased growth rate and chlorophyll content, but promoted carotenoids, stress markers (electrolytes leakage, lipid peroxidation, protein oxidation, hydrogen peroxide, and hydroxyl radical), antioxidant molecules (AsA, phenols, and flavonoids), osmolytes (GB, amino acids, and proline), and the antioxidant enzymes (CAT, GPX, SOD, PPO, and PAL). Additionally, the fungal infestation boosted the expression of CAT, GR, PR4, MT, and PCS genes. However, presoaking wheat kernels in Ca or SA solutions has contributed to mitigating the negative effects of fungal inoculation by restoring growth rate, chlorophyll content, and antioxidant capacity. It has also decreased the induced oxidative stress and downregulated the gene expression of F. graminearum-inoculated wheat seedlings. Consequently, by minimizing the negative repercussions of F. graminearum infestation, priming with Ca or SA could be used to appropriately stimulate growth and readjust the oxidative status of wheat seedlings. [ABSTRACT FROM AUTHOR]

Ponatinib may be effective in chronic myeloid leukemia (CML) patients after failure of first/second line therapies. Although its efficacy for minimum plasma concentrations (Cmin) is >21.3 ng/mL (equal to 40 nM), ponatinib may cause adverse events (AE) that require dose optimization. The present study was aimed at investigating any possible correlations among ponatinib dose, plasma concentration, molecular response (MR), and tolerability in a real-world setting. Clinical and laboratory records (including MR and drug plasma concentrations) of 32 CML patients treated with ponatinib were harvested and analyzed. Twenty-seven patients (71%) had ponatinib Cmin values > 21.3 ng/mL, but Cmin values > 10.7 ng/mL (considered efficacious in BCR-Abl unmutated patients) were achieved by 80% of the patients receiving ≥30 mg/day and 45% of the subjects treated with 15 mg/day. No significant correlations were identified among clinical efficacy, tolerability, daily dose, and plasma concentration. Notably, patients who underwent dose tapering for tolerability or safety reasons did not experience treatment failure. In a real-world setting, adjustment of ponatinib daily doses lower than those registered may maintain therapeutic efficacy while reducing the risk of vascular events and improving tolerability. Further studies are warranted to confirm the present results in a larger cohort of patients.

Circulating tumor DNA (ctDNA) offers a new paradigm in optimizing treatment strategies for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). Its potential spans early-stage disease, influencing adjuvant therapy, to advanced disease, where it aids in identifying genomic markers and resistance mechanisms. This review explores the evolving landscape of utilizing liquid biopsies, specifically circulating tumor DNA (ctDNA), in the management of NSCLC with EGFR mutations. While tissue-based genomic testing remains the cornerstone for clinical decision-making, liquid biopsies offer a well-validated, guideline-recommended alternative approach. Ongoing trials integrating ctDNA for EGFR-mutant NSCLC management are also discussed, shedding light on the potential of ctDNA in early-stage disease, including its applications in prognostication, risk stratification, and minimal residual disease detection post-curative intent treatment. For advanced disease, the role of ctDNA in identifying resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs) is explored, providing insights into disease progression and guiding treatment decisions. This review also addresses the challenges, including the limitations in sensitivity of current assays for disease recurrence detection, and calls for future studies to refine treatment approaches, standardize reporting, and explore alternative biofluids for enhanced sensitivity. A systematic approach is crucial to address barriers to ctDNA deployment, ensuring equitable access, and facilitating its integration into routine clinical practice.

We present the case of a 33-year-old male patient diagnosed with chronic phase chronic myeloid leukaemia in June 2008. According to treatment protocols enforced at that time, the patient started oral treatment with imatinib 400 mg/day, reaching a major molecular response (MMR) in 18-month time. The molecular response improved over the time, with an undetectable BCR-ABL1 transcript level after 36 -48 months of treatment. However, the profound molecular response did not last, requiring a switch to the second line of therapy after 75 months of imatinib. Taking nilotinib 400 mg x2/day, the patient achieved a major molecular response in 12 months, and after 18 months of treatment the level of BCR-ABL1 became undetectable. However, two vasooclusive events occurred in 2018 - a transient left parietal ischemic stroke and a left femoral artery occlusion - and in accordance with ESMO 2017 recommendations, nilotinib treatment was interrupted. The treatment free remission decision was made with monthly monitoring of the BCR-ABL1 transcript level, but since the 4th month of monitoring, the deep molecular response disappeared. Administration of dasatinib, the third tyrosine kinase inhibitor, resulted in a deep molecular response which currently lasted until now, during the 58 months of treatment. The presented case represents the evolution of the concept of treatment in this haemato-oncological disease during the last decade. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) with t (8;21) or inv (16), called core binding factor (CBF) AML, has a favourable prognosis. However, some CBF-AML patients have persistent measurable residual disease (MRD) and are more likely to relapse after standard chemotherapy treatment. The CAG regimen, composed of cytarabine, aclarubicin and granulocyte colony-stimulating factor, has been proven to be effective and safe in treating refractory AML patients. We performed a retrospective study to evaluate the efficacy of the CAG regimen to eliminate MRD detected by RUNX1::RUNX1T1 and CBFβ::MYH11 transcript levels by quantitative polymerase chain reaction (Q-PCR) among 23 patients. Molecular response was defined as the ratio of fusion transcript after treatment to that before treatment less than or equal to 0.5. The molecular response rate and median decrease ratio of fusion transcripts at the molecular level of the CAG regimen were 52% and 0.53, respectively. The median fusion transcripts before CAG treatment was 0.25% whereas after CAG was 0.11%. Among the 15 patients who had a poor molecular response to the high/intermediate-dose cytarabine regimen, the median decrease ratios of transcripts at the molecular level of high/intermediate-dose cytarabine and CAG were 1.55 and 0.53 (P = 0.028), respectively, and 6 of 15 patients achieved a molecular response to CAG (40%). The median disease-free survival was 18 months, and the overall survival rate at 3 years among all patients was 72.7% ± 10.7%. The common grades 3–4 adverse events were nausea (100%), thrombocytopenia (39%) and neutropenia (37.5%). The CAG regimen may have activity in CBF-AML patients and could provide a new option for patients who have a poor molecular response to high/intermediate-dose cytarabine. [ABSTRACT FROM AUTHOR]

The increasing ground‐level ozone (O3) pollution resulting from rapid global urbanization and industrialization has negative effects on many plants. Nonetheless, many gaps remain in our knowledge of how ornamental plants respond to O3. Rose (Rosa hybrida L.) is a commercially important ornamental plant worldwide. In this study, we exposed four rose cultivars ("Schloss Mannheim," "Iceberg," "Lüye," and "Spectra") to either unfiltered ambient air (NF), unfiltered ambient air plus 40 ppb O3 (NF40), or unfiltered ambient air plus 80 ppb O3 (NF80). Only the cultivar "Schloss Mannheim" showed significant O3‐related effects, including foliar injury, reduced chlorophyll content, reduced net photosynthetic rate, reduced stomatal conductance, and reduced stomatal apertures. In "Schloss Mannheim," several transcription factor genes—HSF, WRKY, and MYB genes—were upregulated by O3 exposure, and their expression was correlated with that of NCED1, PP2Cs, PYR/PYL, and UGTs, which are related to ABA biosynthesis and signaling. These results suggest that HSF, WRKY, and MYB transcription factors and ABA are important components of the plant response to O3 stress, suggesting a possible strategy for cultivating O3‐tolerant rose varieties. [ABSTRACT FROM AUTHOR]

In order to improve molecular response for a discontinuation attempt in chronic myeloid leukemia (CML) patients in chronic phase, who had not achieved at least a molecular response <0.01% BCR-ABL1IS (MR4.0) after at least 2 years of imatinib therapy, we prospectively evaluated whether they could attain MR4.0 after a switch to a combination of nilotinib and 9 months of pegylated interferon-α2b (PegIFN). The primary endpoint of confirmed MR4.0 at month 12 (a BCR-ABL1ISlevel ≤ 0.01% both at 12 and 15 months) was reached by 44% (7/16 patients, 95% confidence interval (CI): 23- 67%) of patients, with 81% (13/16 patients, 95% CI: 57-93%) of patients achieving an unconfirmed MR4.0. The scheduled combination was completed by 56% of the patients, with premature discontinuations, mainly due to mood disturbances after the introduction of PegIFN, questioning the feasibility of the combination of nilotinib and PegIFN for this patient population and treatment goal. A comprehensive clinical substudy program was implemented to characterize the impact of the treatment changes on the immunological profile. This trial was registered at www.clinicaltrials.gov as #NCT01866553. [ABSTRACT FROM AUTHOR]

Patulin (PAT), mainly produced by Penicillium expansum, is a potential threat to health. In recent years, PAT removal using antagonistic yeasts has become a hot research topic. Meyerozyma guilliermondii, isolated by our group, produced antagonistic effects against the postharvest diseases of pears and could degrade PAT in vivo or in vitro. However, the molecular responses of M. guilliermondii over PAT exposure and its detoxification enzymes are not apparent. In this study, transcriptomics is used to unveil the molecular responses of M. guilliermondii on PAT exposure and the enzymes involved in PAT degradation. The functional enrichment of differentially expressed genes indicated that the molecular response mainly includes the up-regulated expression of genes related to resistance and drug-resistance, intracellular transport, growth and reproduction, transcription, DNA damage repair, antioxidant stress to avoid cell damage, and PAT detoxification genes such as short-chain dehydrogenase/reductases. This study elucidates the possible molecular responses and PAT detoxification mechanism of M. guilliermondii, which could be helpful to further accelerate the commercial application of antagonistic yeast toward mycotoxin decontamination. [ABSTRACT FROM AUTHOR]

BackgroundDespite the intensity of hematopoietic stem cell transplantation (HCT), relapse remains the most common cause of death in juvenile myelomonocytic leukemia (JMML). In contrast to other leukemias where therapy is used to reduce leukemic burden prior to transplant, many patients with JMML proceed directly to HCT with active disease. The objective of this study was to elucidate whether pre-HCT therapy has an effect on the molecular burden of disease and how this affects outcome post-HCT.ProcedureTwenty-one patients with JMML who received pre-HCT therapy and were transplanted at UCSF were analyzed in this study. The mutant allele frequency of the driver mutation was assessed before and after pre-HCT therapy, using custom amplicon next-generation sequencing.ResultsOf the 21 patients, seven patients (33%) responded to therapy with a significant reduction in their mutant allele frequency and were classified as molecular responders. Six of these patients received moderate-intensity chemotherapy, one patient received only azacitidine. The 5-year progression-free survival after HCT of molecular responders was 100% versus 61% for nonresponders (P = .12). Survival of molecular nonresponders was not improved by use of high-intensity conditioning, but patients were salvaged if they experienced severe graft versus host disease. There were no baseline clinical characteristics that were associated with response to pre-HCT therapy.ConclusionsDespite the myelodysplastic nature of JMML, patients treated with pre-HCT therapy can achieve molecular remissions. These patients experienced a trend toward improved outcomes post-HCT. Importantly, molecular testing can be helpful to distinguish between responders and nonresponders and should become an integral part of clinical care.

Objective: Achieving an early molecular response (EMR) is crucial for improving the prognosis of patients with chronic myeloid leukemia (CML). The halving time (HT) and reduction ratio (RR) of BCR: : ABL1 transcript levels have recently emerged as additional prognostic indexes besides the BCR: : ABL1 International Scale (IS). We aimed to investigate the prognostic role of BCR: : ABL1 transcript levels, HT, and RR on molecular response kinetics at 3 months in patients with newly diagnosed chronic-phase (CP)-CML. Materials and Methods: Forty patients with CP-CML who received first-line imatinib treatment were included in this study. BCR: : ABL1 transcript levels and molecular responses at baseline and at 3, 6, 12, and 24 months of treatment were evaluated retrospectively. Major molecular response (MMR) at 12 months and event-free survival (EFS) were determined as primary endpoints and the effects of treatment kinetics on these parameters were examined. Results: Of the 40 patients, BCR: : ABL1 IS was ≤10% at 3 months in 72.5%, representing EMR. The rate of event occurrence was 45.5% in patients with BCR: : ABL1 IS of >10%, whereas it was 6.9% in those with BCR: : ABL1 IS of ≤10% (p=0.004). MMR was detected in 62.1% of the patients with EMR and in 9.1% of those without EMR (p=0.003). The cut-off value for achieving MMR was 24 days for HT and 0.04 for RR. Deep molecular response (DMR) at 24 months was associated with HT of ≤24 days and RR of ≤0.04. EFS was found to be significantly better in the group with BCR: : ABL1 IS of ≤10% and HT of ≤24 days (p=0.001) and in the group with BCR: : ABL1 IS of ≤10% and RR of ≤0.04 (p=0.007) compared to others. Conclusion: Our findings revealed that MMR could be predicted via EMR as well as by HT and RR. Additionally, HT of ≤24 days and RR of ≤0.04 were more important than BCR: : ABL1 IS of ≤10% in achieving DMR at 24 months, and the combination of BCR: : ABL1 IS of ≤10% with both HT of ≤24 days and RR of ≤0.04 has the best predictive value for EFS.

Background: Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. Objective: To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. Methods: Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. Results: Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. Conclusion: Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence. [ABSTRACT FROM AUTHOR]

Ropeginterferon α-2b is a mono-PEGylated proline-interferon for the treatment of polycythemia vera. This drug is used biweekly with a starting dose of 100 μg (50 μg if patients receiving hydroxyurea) and 50 μg increments up to a maximum dose of 500 μg. Increasing evidence indicates that patients can tolerate higher starting doses of ropeginterferon α-2b. This phase II trial utilizes 250 μg as the starting dose, 350 μg at week 2 and 500 μg at week 4 as the target dose. Doses can be adjusted according to tolerability. This study assesses the safety, efficacy and molecular response of ropeginterferon α-2b in Chinese patients with PV utilizing the 250–350–500 μg dosing schema. This study will be used to support the application of a biologics license for polycythemia vera treatment in China. Polycythemia vera (PV) is a slow-growing blood neoplasm (cells that grow and divide more than they should or do not die when they should). PV often has a mutation in the gene called JAK2, which causes changes in the DNA of genes that cause cells to become cancerous. PV is associated with an increased number of blood cells, debilitating symptoms, risks of thrombosis (blood clot) and bleeding and can progress to other diseases, including myelofibrosis and acute myeloid leukemia. Ropeginterferon α-2b is a new product with favorable properties, allowing a convenient dosing schedule of every 2–4 weeks. This drug has demonstrated good tolerability, safety and efficacy for PV treatment and has been approved for the treatment of PV in Europe and the USA. This article discusses the design of an ongoing study that looks at the safety and efficacy of ropeginterferon α-2b for the treatment of PV. The study follows a specific dosing schedule, with the aim of controlling the neoplasm faster, and plans to include 49 patients from 12–15 major hospitals in China. Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (identifier: NCT05485948) and in China (China National Medical Products Administration Clinical Trial Registration Number: CTR20211664). New #phaseII #trial to assess ropeginterferon α-2b in Chinese patients with polycythemia vera. [ABSTRACT FROM AUTHOR]

Graphene oxide (GO) materials possess physicochemical properties that facilitate their application in the industrial and medical sectors. The use of graphene may pose a threat to biota, especially aquatic life. In addition, the properties of nanomaterials can differentially affect cell and molecular responses. Therefore, it is essential to study and define the possible genotoxicity of GO materials to aquatic organisms and their ecosystems. In this study, we investigated the changes in the expression of 11 genes in the aquatic organism Chironomus riparius after 96 h of exposure to small GOs (sGO), large GOs (lGO) and monolayer GOs (mlGO) at 50, 500 and 3000 μg/L. Results showed that the different genes encoding heat shock proteins (hsp90, hsp70 and hsp27) were overexpressed after exposure to these nanomaterials. In addition, ATM and NLK—the genes involved in DNA repair mechanisms—were altered at the transcriptional level. DECAY, an apoptotic caspase, was only activated by larger size GO materials, mlGO and lGO. Finally, the gene encoding manganese superoxide dismutase (MnSOD) showed higher expression in the mlG O-treated larvae. The lGO and mlGO treatments indicated high mRNA levels of a developmental gene (FKBP39) and an endocrine pathway-related gene (DRONC). These two genes were only activated by the larger GO materials. The results indicate that larger and thicker GO nanomaterials alter the transcription of genes involved in cellular stress, oxidative stress, DNA damage, apoptosis, endocrine and development in C. riparius. This shows that various cellular processes are modified and affected, providing some of the first evidence for the action mechanisms of GOs in invertebrates. In short, the alterations produced by graphene materials should be further studied to evaluate their effect on the biota to show a more realistic scenario of what is happening at the molecular level. [ABSTRACT FROM AUTHOR]

Simple Summary: Oropharyngeal cancer (OPC) is one of the most common cancers in the head and neck region. The incidence of OPC is still growing, mostly due to the human papillomavirus (HPV), which has become the dominant etiological factor. HPV16 is the most relevant genotype for OPC, whereas other high-risk genotypes are rare and may be associated with a worse prognosis. The aim of this article is to discuss the molecular response (MR) obtained by assessing circulating tumor-related HPV DNA (ctHPV) in a liquid biopsy (LB). This quick and simple diagnostic tool reflects the presence of the tumor and thus, can support some clinical decisions. We provide a comprehensive overview of the clinical benefits of the blood-based molecular response, focusing on the decision-making process of the tumor response during the therapy, assessment of early treatment results, and post-treatment follow-up in patients with HPV-related OPC. Recent findings have shown that human papillomavirus (HPV) DNA is present in the blood as a tumor-specific biomarker (circulating tumor-related HPV; ctHPV) in patients with HPV-related oropharyngeal cancer (HPV-related OPC). The molecular response (MR) in patients with HPV-related OPC can be defined as the change in the number of ctHPV copies in relation to its initial quantity. The optimal model for assessing the MR using a liquid biopsy (LB) should be based on the E6/E7 sequences of the viral genome. MR assessment can help to evaluate the intensity of ongoing treatments in relation to the tumor response. The evaluation of the residual disease at the end of therapy may also be performed by MR assessment. If a partial MR (pMR) is found, caution is indicated and a subsequent LB should be considered, due to the likelihood of disease progression. Complete radiological and clinical responses together with a complete MR (cMR) convincingly indicate a low risk of treatment failure. Moreover, molecular recurrence (Mrec) during a follow-up, confirmed in two consecutive assays, even despite the lack of any other clinical or radiological symptoms of progression, indicates patients at high risk of disease recurrence. In conclusion, MR by ctHPV assessment may hasten the early detection of disease progression, at any stage of the management of the patient with HPV-related OPC. [ABSTRACT FROM AUTHOR]

Abstract The increasing ground‐level ozone (O3) pollution resulting from rapid global urbanization and industrialization has negative effects on many plants. Nonetheless, many gaps remain in our knowledge of how ornamental plants respond to O3. Rose (Rosa hybrida L.) is a commercially important ornamental plant worldwide. In this study, we exposed four rose cultivars (“Schloss Mannheim,” “Iceberg,” “Lüye,” and “Spectra”) to either unfiltered ambient air (NF), unfiltered ambient air plus 40 ppb O3 (NF40), or unfiltered ambient air plus 80 ppb O3 (NF80). Only the cultivar “Schloss Mannheim” showed significant O3‐related effects, including foliar injury, reduced chlorophyll content, reduced net photosynthetic rate, reduced stomatal conductance, and reduced stomatal apertures. In “Schloss Mannheim,” several transcription factor genes—HSF, WRKY, and MYB genes—were upregulated by O3 exposure, and their expression was correlated with that of NCED1, PP2Cs, PYR/PYL, and UGTs, which are related to ABA biosynthesis and signaling. These results suggest that HSF, WRKY, and MYB transcription factors and ABA are important components of the plant response to O3 stress, suggesting a possible strategy for cultivating O3‐tolerant rose varieties.

Some wild cotton species are remarkably tolerant to salt stress, and hence represent valuable resources for improving salt tolerance of the domesticated allotetraploid species Gossypium hirsutum L. Here, we first detected salt-induced stress changes in physiological and biochemical indexes of G. anomalum, a wild African diploid cotton species. Under 350 mmol/L NaCl treatment, the photosynthetic parameters declined significantly, whereas hydrogen peroxide (H2O2) and malondialdehyde (MDA) contents increased. Catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) activity and proline (PRO) content also significantly increased, reaching peak values at different stages of salt stress. We used RNA-Seq to characterize 15,476 differentially expressed genes in G. anomalum roots after 6, 12, 24, 72, and 144 h of salt stress. Gene Ontology enrichment analysis revealed these genes to be related to sequence-specific DNA and iron ion binding and oxidoreductase, peroxidase, antioxidant, and transferase activity; meanwhile, the top enriched pathways from the Kyoto Encyclopedia of Genes and Genomes database were plant hormone signal transduction, phenylpropanoid biosynthesis, fatty acid degradation, carotenoid biosynthesis, zeatin biosynthesis, starch and sucrose metabolism, and MAPK signaling. A total of 1231 transcription factors were found to be expressed in response to salt stress, representing ERF, MYB, WRKY, NAC, C2H2, bZIP, and HD-ZIP families. Nine candidate genes were validated by quantitative real-time PCR and their expression patterns were found to be consistent with the RNA-Seq data. These data promise to significantly advance our understanding of the molecular response to salt stress in Gossypium spp., with potential value for breeding applications.

Sexual dimorphism has commonly been found in many species. The phenotypes of Salix matsudana females and males are different under salinity stress. An F1 population was selected to compare the differences between males and females. As a result, males showed stronger roots and heavier dry weights than females. The unique molecular mechanisms of males and females under salinity stress were further analyzed based on the root transcriptome of males and females. Both males and females up-regulated systemic acquired resistance genes, such as ADH and oxygenase-related genes, to resist salt. Moreover, many other abiotic stress response genes were up-regulated in males to adjust to salinity stress, while females showed more down-regulation of nitrogen metabolism related genes to decrease the harm from salinity stress. The research on salinity tolerance in Salix matsudana males and females would help to further understand sexual dimorphism under selection pressure and provide benefits to the ecological environment. [ABSTRACT FROM AUTHOR]

Introduction: Interferon regulatory factor 4 (IRF4) is a transcriptional factor with a key role in the modulation of inflammation and immune surveillance. The IRF4 gene is downregulated in Philadelphia-negative myeloproliferative neoplasms, and its expression is associated with prognosis and response to treatment. Methods: We evaluated the IRF4 expression kinetics during tyrosine kinase inhibitor (TKI) treatment in a cohort of 116 chronic myeloid leukemia (CML) patients to elucidate its role in the disease course. Results: A relationship between the IRF4 expression and the disease burden was observed at various disease stages. A correlation analysis between the International Scale (IS) and IRF4 values confirmed this close association. A significant increase is detected after 3 months of TKI treatment. Patients achieving an early molecular response (EMR) had higher IRF4 values at both diagnosis and after 3 months of therapy as compared to those failing the EMR target. Patients achieving treatment-free remission did not show IRF4 fluctuations during monitoring, while a decreased IRF4 expression emerged at the time of molecular relapse. Conclusion: Our data seem to confirm the relevance of IRF4 in the pathogenesis of CML, suggesting a pivotal role at the disease onset and a predictive value during the CML course. [ABSTRACT FROM AUTHOR]

Cadmium is one of the major heavy metal pollutants in the environment. However, the toxicity targets and response mechanisms in photosynthetic organisms to cadmium are lacking. This study explored the physiological response of Synechocystis sp. PCC 6803 to cadmium stress; the toxicity targets and the resistance mechanism were screened. The results showed that cadmium led to an increase in reactive oxygen species content, superoxide dismutase activity, and the lipid peroxidation level, which damaged the cell's photosynthesis and ultrastructure. The cross-omics analysis found 1073 differentially expressed genes (DEGs), of which only 84 genes had the same expression trend at the mRNA and protein levels. The bioinformatics analysis found that the toxic effects of cadmium were inhibiting the expression of the proteins for the photosynthesis-antenna, photosynthesis, and ribosome pathway. The cell's response included the upregulation of proteins related to the two-component system, biosynthesis, and ABC transporter pathway. The study confirmed that the target sites of cadmium were chlorophyll a synthesis, photosynthetic electron transport chains, and ribosomes; the response mechanism to cadmium toxicity was the upregulation of the ABC transporter pathway and its protein expression. This study provides evidence to obtain insight into the toxicity targets and molecular response mechanism of Synechocystis sp. PCC 6803 to cadmium stress. [ABSTRACT FROM AUTHOR]

Aim: This study was carried out to assess the minimal residual disease in Tunisian patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors in routine clinical practice, to recognize potentially eligible carrier for treatment discontinuation, based on a molecular response (MR). Patients and Methods: A retrospective study was carried out in the Hospital University of Sfax, south of Tunisia from January 2016 to October 2020, including all CML patients in the chronic phase at diagnosis, treated with TKI (tyrosine kinase inhibitors) for a minimum duration of 6 months. Quantitative assessment of the BCR-ABL transcript was performed using the Cepheid Xpert BCR-ABL ultra-assay. Molecular response and outcome were evaluated, according to the European Leukemia Net guidelines. Results: A total of 162 CML patients were carried out. The median age was 50 years, the sex ratio M/F was 1.62. The rate of cumulative EMR; MMR and DMR was 80.8%; 73.8% and 55.9% respectively. According to the ELN criteria, 141 CML patients were evaluable. Optimal, suboptimal response and failure were noted in 81 (57.4%), 33(23.4%), and 27(19.1%) patients, respectively. Overall survival (OS) and progression-free survival (PFS) were 96.3% and 85%. Risk factors for an event (death/progression) were lack of EMR, MMR, and DMR (P < 0.05). Among 149 patients with sustained DMR; 14 (8.6%) CML patients have discontinued TKI therapy. Conclusion: Despite the limit of our study (duration and size), the available real-life molecular responses with TKI therapy should be considered to identify potentially CML patients eligible for discontinuation of TKI therapy. [ABSTRACT FROM AUTHOR]

Salinity affects the physiological activities of aquatic animals and determines the distribution of fish. In this study, we found that the naked carp survived under 0–15‰ salinity, but survival rates decreased to varying degrees under 20‰ and 25‰ salinity, which indicates that the safety threshold of salinity tolerance of Gymnocypris przewalskii is 0–15‰. Next, the response rate of NKAα1 in the gills and kidneys was significantly faster than in the livers, and the response intensity of NKAα1 and NKAα3 has certain tissue specificity under different salinity. NKA enzyme activity first increased, then gradually decreased and increased again in the gills and kidneys after 5‰ and 15‰ salinity stress. In contrast, the NKA enzyme activity gradually decreased and then gradually increased in the liver. Salinity stress also could lead to some pathological phenomena in the cytoplasm. These results indicated that changes in salinity can lead to differential expression of the NKA genes and enzyme in tissues. Also, the dynamic changes of the NKA gene, enzyme activities, and morphological characteristics in fish tissues are in response to the salinity changes in the living environment, thus maintaining a dynamic balance of ions inside and outside the cells. [ABSTRACT FROM AUTHOR]

Over the past decade, the gut microbiota has emerged as an important frontier in understanding the human body's homeostasis and the development of diseases. Gut flora in human beings regulates various metabolic functionalities, including enzymes, amino acid synthesis, bio-transformation of bile acid, fermentation of non-digestible carbohydrates (NDCs), generation of indoles and polyamines (PAs), and production of short-chain fatty acids (SCFAs). Among all the metabolites produced by gut microbiota, SCFAs, the final product of fermentation of dietary fibers by gut microbiota, receive lots of attention from scientists due to their pharmacological and physiological characteristics. However, the molecular mechanisms underlying the role of SCFAs in the interaction between diet, gut microbiota, and host energy metabolism is still needed in-depth research. This review highlights the recent biotechnological advances in applying SCFAs as important metabolites to treat various diseases and maintain colonic health. [ABSTRACT FROM AUTHOR]

Dasatinib is a potent second-generation tyrosine kinase inhibitor (TKI) used as a first-line treatment option for patients with chronic myeloid leukemia (CML). Currently, dose modification due to adverse events (AEs) is common in patients treated with dasatinib. This study compared the outcomes of two sequential prospective trials that enrolled patients with newly diagnosed chronic phase of CML (CP-CML) and initiated dasatinib at a starting dose of 100 mg daily. In the PCR-DEPTH study, CP-CML patients who started dasatinib 100 mg daily were enrolled and followed up, while in the DAS-CHANGE study, when patients achieved early molecular response with any grade of AEs were enrolled and treated with dasatinib 80 mg once daily. A total of 102 patients (PCR-DEPTH) and 90 patients (DAS-CHANGE) were compared. Although the median value of the relative dose intensity (RDI) of dasatinib was significantly higher in PCR-DEPTH than in DAS-CHANGE (99.6 % vs. 80.1 %, p <0.001), the MMR rate at 12months showed a trend toward superiority in DAS-CHANGE compared to PCR-DEPTH (77.1 % vs 65.2 %, p = 0.084). The frequencies of MR4.0 at 24 and 36 months were higher in DAS-CHANGE than in PCR-DEPTH (44.4 % vs 28.8 %, p = 0.052 and 63.6 % vs 40.3 %, p= 0.013, respectively). RDIs were not different according to the MMR, MR4.0 or MR4.5 in analyses using a pooled population. Our results suggest that early dose reduction of dasatinib does not compromise efficacy in patients achieving EMR at 3 months and could be an interventional strategy for improving long term outcomes. • Early dose reduction of dasatinib to 80 mg maintains efficacy in newly diagnosed chronic myeloid leukemia patients. • The DAS-CHANGE study showed higher rates of MR4.0 compared to the PCR-DEPTH study. • Median relative dose intensity was significantly lower in DAS-CHANGE compared to PCR-DEPTH. • Early dose reduction can be an effective strategy for improving long-term outcomes. [ABSTRACT FROM AUTHOR]