Tolerable Toxicity Research Articles

Long-term survival of participants in the PASART-1 and PASART-2 trials of neo-adjuvant pazopanib and radiotherapy in soft tissue sarcoma

Objective: This study aims to assess the long-term safety and efficacy of adding pazopanib to neo-adjuvant radiotherapy followed by surgery in patients with high-risk non-metastatic soft tissue sarcoma of the trunk and extremities treated in the PASART-1 and PASART-2 trials, as well as to compare the PASART cohorts to a control cohort receiving standard treatment during the same time period from the Netherlands Cancer Registry (IKNL) to investigate if adding pazopanib improves Overall Survival (OS). Methods: Updated follow-up data on disease control, survival and long-term toxicities of the PASART-trials were extracted from electronic patient records. The effect of adding pazopanib to neo-adjuvant radiotherapy on OS was investigated by comparing the combined PASART cohorts to the IKNL cohort via direct comparison and exact matching analysis. Results: PASART-trials included 34 patients, IKNL cohort included 487 patients. After a median follow-up of 75.4 months (range: 30–131 months) the 1-year, 2-year and 5-year OS in the PASART-trials were 97% (95% confidence interval [CI]: 91.5–100), 85.3% (95% CI: 74.2–98.1), 79.3% (95% CI: 66.8–94.2), respectively. Matching resulted in 23 PASART and 89 IKNL patients. Adding pazopanib did not significantly improve OS when compared to standard treatment (IKNL) in a direct comparison (hazard ratio [HR]: 0.58; 95% CI: 0.30–1.13) or matched analysis (HR: 0.70; 95% CI: 0.29–1.73). Long-term toxicities, mainly fibrosis (n = 6) and edema (n = 2), were observed in 11 PASART patients and comparable to historical controls. Interpretation: The addition of pazopanib had tolerable long-term toxicity but did not improve OS when compared to a control cohort receiving standard treatment.

Complete response of gallbladder cancer treated with gemcitabine and cisplatin chemotherapy combined with durvalumab: A case report and review of literature

BACKGROUND Gallbladder cancer (GBC) is the most common and aggressive subtype of biliary tract cancer (BTC) and has a poor prognosis. A newly developed regimen of gemcitabine, cisplatin, and durvalumab shows promise for the treatment of advanced BTC. However, the efficacy of this treatment for GBC remains unclear. CASE SUMMARY In this report, we present a case in which the triple-drug regimen exhibited marked effectiveness in treating locally advanced GBC, thus leading to a long-term survival benefit. A 68-year-old man was diagnosed with locally advanced GBC, which rendered him ineligible for curative surgery. Following three cycles of therapy, a partial response was observed. After one year of combined therapy, a clinical complete response was successfully achieved. Subsequent maintenance therapy with durvalumab monotherapy resulted in a disease-free survival of 9 months for the patient. The patient experienced tolerable toxicities of reversible grade 2 nausea and fatigue. Tolerable adverse events were observed in the patient throughout the entirety of the treatment. CONCLUSION The combination of gemcitabine and cisplatin chemotherapy with durvalumab was proven to be an effective treatment approach for advanced GBC, with manageable adverse events. Further research is warranted to substantiate the effectiveness of the combined regimen in the context of GBC.

Effects of aluminum on metabolism of reactive oxygen species and reactive nitrogen species in root tips of different Eucalyptus species

On acidified soil, the growth of Eucalyptus is seriously restricted by aluminum (Al) stress. Therefore, breeding Eucalyptus species with excellent Al tolerance, developing the genetic potential of species, and improving tolerance to Al stress are important for the sustainable development of artificial Eucalyptus forests. By observing the occurrence and distribution of the main reactive oxygen species (ROS) and reactive nitrogen species (RNS) in root tips of Eucalyptus seedlings under Al stress, this study analyzed change in the growth and physiological indexes of Eucalyptus seedlings under Al stress. The antioxidant enzymes activities of the root tips of different Eucalyptus species induced by Al stress resulted in different ROS and RNS contents, ultimately resulting in differing degrees of membrane lipid peroxidation. In addition to suppressions of root relative elongation and root activity, the accumulations of soluble sugar, soluble protein, and proline can be used as indicators of Al sensitivity in Eucalyptus species. This may be an important determinant of the differences in Al tolerance among Eucalyptus species. The accumulation of ROS and RNS in the roots of E. grandis and E. tereticornis resulted in severe oxidative and nitrification stress. The tolerance of E. urophylla and E. urophylla × E. grandis to Al stress was stronger than that of E. grandis and E. tereticornis. Differences in Al toxicity tolerance were related to long-term selection of the original habitat of the species; moreover, the Al tolerance was hereditary. Eucalyptus urophylla × E. grandis had stronger Al tolerance than its parents, which is indicative of heterosis. These results provide theoretical support for the breeding of tree species in areas with acidic soil.

Zwitterionic polymers with high serum tolerance for intracellular protein delivery.

Cationic polymers have been widely developed as carriers for intracellular protein delivery, but face tough challenges such as poor serum tolerance and inevitable material toxicity. Here, we present a type of phase-separating polymer with an anionic surface to address the above issues. A cationic dendrimer is first modified with a hydrophobic moiety to obtain a pH-responsive amphiphilic polymer, which is further conjugated with anionic benzenesulphonate at different grafting degrees. The benzenesulphonate modification facilely changes the hydrophobicity of the polymer and reduces the material cytotoxicity. Interestingly, the polymer can co-assemble with cargo proteins to form nanovesicles for intracellular protein delivery. The benzenesulphonate on the polymer surface bolsters the resistance of polymers to serum proteins, allowing the materials to maintain high delivery efficacy in culture media containing abundant serum proteins. This study provides a facile strategy to design materials with high serum tolerance for intracellular protein delivery.

Novel anti-HER2 ADCs vs dual anti-HER2 antibody for HER2-positive metastatic breast cancer failed to tyrosine kinase inhibitor.

Both novel anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugates (ADCs) and pertuzumab and trastuzumab (HP) combined with chemotherapy(C) regimens are the choice of treatment for HER2 positive metastatic breast cancer (MBC) after tyrosine kinase inhibitors (TKIs). Our team's previous research has shown significant therapeutic effects of novel anti-HER2 ADCs in patients with TKIs treatment failure. Unfortunately, there is currently no data available to compare novel anti-HER2 ADCs with HP combined with chemotherapy regimens. This study was conducted to compare the efficacy and safety of novel anti-HER2 ADCs with that of the HP combined with chemotherapy regimen in patients for whom TKI treatment failed. HER2-positive MBC who used novel anti-HER2 ADCs and HP combined with a chemotherapy regimen from January 2019 to August 2023 were included, and all patients received TKIs. The primary study endpoint was progression-free survival (PFS), while the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety. A total of 150 patients, of which 83 are in the novel anti-HER2 ADCs group and 67 are in the HP combined with chemotherapy. Among these novel anti-HER2 ADCs, 36 patients received treatment with trastuzumab deruxtecan (T-Dxd), and 47 patients received treatment with other new types of ADCs. The median PFS of the novel anti-HER2 ADCs group and HP combined with the chemotherapy group were 7.0 months and 8.9 months, respectively, with ORR of 51.8% and 26.9%, and CBR of 69.9% and 65.7%, respectively. In subgroup, patients receiving T-Dxd showed improvement in PFS compared to the HP combined with chemotherapy group. The most common grade 3-4 adverse events in the novel anti-HER2 ADCs group and the HP combined with chemotherapy group were neutropenia and gastrointestinal symptoms. In HER2-positive MBC for whom TKI treatment has failed, novel anti-HER2 ADCs and the HP combined with chemotherapy regimen both showed moderate efficacy and tolerable toxicity. Novel anti-HER2 ADCs are the preferred treatment recommendation for TKI failure patients. Meanwhile, based on the results of this study, the HP combined with chemotherapy regimen may also be an option, especially for patients with low accessibility.

Efficient Bifunctional Electrocatalysts for Oxygen Evolution/Reduction Reactions in Two-Dimensional Metal-Organic Frameworks by a Constant Potential Method.

The evolution of bifunctional catalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) catalysts that are highly active, stable, and conductive is crucial for advancing metal-air batteries and fuel cells. We have here thoroughly explored the OER and ORR performance for a category of two-dimensional (2D) metal-organic frameworks (MOFs) called TM3(HADQ)2, and Rh3(HADQ)2 exhibits a promising bifunctional OER/ORR activity, with an overpotential of 0.31 V for both OER and ORR. The d-band center (εd) and crystal orbital Hamilton populations (COHP) are utilized to study the relationship between OER/ORR activity and the electronic structure of catalysts, and it is found that the elementary d-electron number (Ne) of the central TM for TM3(HADQ)2, as well as the electronegativity of the ligand TM-N4 and the intermediate O atom, are the main reason that affects the catalytic activity of OER/ORR. Additionally, Rh3(HADQ)2 can be proven through the constant potential method (CPM) and microkinetics method that it is an acidic OER/ORR bifunctional catalyst. Rh3(HADQ)2 has a high toxicity tolerance, making it a potential bifunctional catalyst. Our research contributes to both the rational design of SACs for various catalytic processes and the fabrication of bifunctional, cost-effective oxygen-electric catalysts.

Targeting autophagy plus high-dose CDK4/6 inhibitors in advanced HR+HER2- breast cancer: A phase 1b/2 trial.

The unmet needs of managing patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer who progress after cyclin-dependent kinase (CDK)4/6 inhibitor (CDK4/6i) treatment remain unclarified. This was a phase 1b/2, single-arm, open-label study that enrolled 29 patients with HR+/HER2- breast cancer who experienced first-line palbociclib treatment failure. The primary endpoint was the incidence of dose-limiting toxicity (DLT). The secondary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The clinical trial registration number is ClinicalTrials.gov: NCT05953350. The phase 1b study demonstrated no DLT in patients treated with hydroxychloroquine (HCQ; 600mg, bis in die [bid]) plus increasing doses of palbociclib (100, 150, or 200mg, quaque die [qd]). The plasma pharmacokinetics of palbociclib were not significantly affected by HCQ. The recommended phase 2 dose (RP2D) was HCQ (600mg, bid) plus palbociclib (200mg, qd). The dose-expansion cohort demonstrated that HCQ plus palbociclib (200mg, qd) treatment was tolerable. Grade 3 treatment-emergent adverse events (TEAEs) with an incidence higher than 15.0% included neutropenia (25.0%), leukopenia (25.0%), fatigue (20.0%), and back pain (15.0%). The ORR of all enrolled patients in our present trial was 41.4% (12/29). In the dose-expansion cohort, with the last enrolled patient having a follow-up duration of 32.3weeks, the median PFS was not reached. The clinical benefit rate (CBR) at 6months was 90.0% (95% confidence interval [CI]: 68.3%-98.8%). These findings were supported by preclinical data. Combined HCQ with high-dose CDK4/6i palbociclib (200mg, qd) showed tolerable toxicity and promising efficacy for patients with advanced HR+/HER2- breast cancer after CDK4/6i failure. This work was funded by the National Natural Science Foundation of China.

Partial Stereotactic Ablative Radiotherapy Boost Before Conventional Radiotherapy (P-SABR) for Large (> 5 cm) Unresectable Stage III Nonsmall Cell Lung Cancer.

Stereotactic ablative radiotherapy (SABR) is renowned for its high local control (LC) rates. Nonetheless, for tumors that are either large in volume or in close proximity to critical organs at risk, the application of SABR to the entire tumor becomes impractical. This study aims to evaluate the efficacy and safety of partial SABR boost before conventional radiotherapy (P-SABR) for the treatment of large (> 5 cm) unresectable stage III nonsmall cell lung cancer (NSCLC). From April 2014 to January 2024, 44 patients with > 5 cm unresectableT3-4N0-3M0 stage III NSCLC were analyzed. The median diameter was 9 cm (5.2-22.7 cm). The P-SABR plan is combined with a partial SABR boost part and a conventional fractionated radiotherapy (CFRT) part. In the partial SABR boost plan, the prescription dose for planning target volume (PTV) was 1.8-3 Gy per fraction over 3-4 fractions, and the artificially delineated gross tumor boost volume (GTVb) within GTV received a simultaneously integrated SABR dose (6 or 8 Gy per fraction). In the following CFRT plan, the median dose for the entire PTV was 54 Gy in 22 fractions. For the synthetic P-SABR plan, the median cumulative dose delivered to the PTV was 62.1 Gy, while the median cumulative dose to the GTVb was escalated to 78 Gy. The median follow-up time was 36 months (95% CI, 14.6-57.4 months). The LC rates at 1 and 2 years were 90.2% and 76.8%, respectively. The median OS was 47.0 months (95% CI, 16.8-77.2 months) and 15.0 months (95% CI, 6.0-24.0 months) for the chemoradiotherapy and radiotherapy groups, respectively. Univariate analysis showed that P-SABR combined with immunotherapy was associated with significantly longer OS (HR, 0.163; 95% CI, 0.038-0.704). Only one (2.3%) patient experienced grade 3 acute pneumonitis. The P-SABR treatment has shown a high rate of LC and tolerable toxicity in patients with large unresectable stage III NSCLC.

Macamides as Potential Therapeutic Agents in Neurological Disorders.

Therapeutic treatment of nervous system disorders has represented one of the significant challenges in medicine for the past several decades. Technological and medical advances have made it possible to recognize different neurological disorders, which has led to more precise identification of potential therapeutic targets, in turn leading to research into developing drugs aimed at these disorders. In this sense, recent years have seen an increase in exploration of the therapeutic effects of various metabolites extracted from Maca (Lepidium meyenii), a plant native to the central alpine region of Peru. Among the most important secondary metabolites contained in this plant are macamides, molecules derived from N-benzylamides of long-chain fatty acids. Macamides have been proposed as active drugs to treat some neurological disorders. Their excellent human tolerance and low toxicity along with neuroprotective, immune-enhancing, and and antioxidant properties make them ideal for exploration as therapeutic agents. In this review, we have compiled information from various studies on macamides, along with theories about the metabolic pathways on which they act.

Virus-bacterium interaction involved in element cycles in biological treatment of coking wastewater

Although prokaryotic microbes in coking wastewater (CWW) treatment have been comprehensively studied, the ecological functions of viruses remain unclear. A full-scale CWW biological treatment AOHO combination was studied for the virus-bacterium interactions involved in element cycles by metaviromics, metagenomics and physicochemical characteristics. Results showed the unique viromic profile with Cirlivirales and Petitvirales as the dominant viruses infecting functional bacteria hosts. The auxiliary metabolic genes (AMGs) focused on element cycles, including metabolisms of carbon (fadA), nitrogen (glnA), sulfur (mddA and cysK) and phosphorus (phoH). Other AMGs were involved in toxic tolerance of hosts, improving their cell membrane and wall robustness, antioxidant, DNA repair and cobalamin biosynthesis. Vice versa, the bloomed host provided fitness advantages for viruses. Dissolved oxygen was found to be the key factor shaping the distributions of viral community and AMGs. Summarizing, the study exposed the mutual virus-bacterium interaction in the AOHO combination providing stable treatment efficiency.

CTIM-08. FIRST IN HUMAN STUDY OF THE MRNA-BASED CANCER VACCINE CVGBM IN PATIENTS (PTS) WITH NEWLY-DIAGNOSED AND SURGICALLY RESECTED MGMT-UNMETHYLATED GLIOBLASTOMA (GBM): FIRST RESULTS FROM THE DOSE ESCALATION PHASE

Abstract INTRODUCTION CVGBM is an investigational therapeutic mRNA-based vaccine encoding 8 epitopes derived from tumor associated antigens with potential relevance in GBM. This is an ongoing, first-in-human study evaluating the safety of CVGBM in pts with newly-diagnosed MGMT-unmethylated GBM. METHODS HLA-A*02:01-positive pts with newly-diagnosed MGMT-unmethylated GBM (CNS WHO Grade [Gr] 4) who had a gross total or partial resection and completed radiotherapy ± concomitant temozolomide received CVGBM on Days 1, 8, 15, 29, 43, 57 and 71 + 6 optional doses at 6-week intervals. Primary endpoints are safety, tolerability and dose-limiting toxicities (DLTs). Immunogenicity is an exploratory endpoint. RESULTS As of 29/2/2024, 16 pts were enrolled in the dose-escalation part (Part A); 3 each in DL 1 (12 µg), DL 2 (25 µg), and DL 3 (50 µg), and 7 in DL 4 (100 µg). For all cohorts, mean time on study from 1st dose to last visit was 4.5 months (min: 1.5; max: 8). 109 doses were administered (mean: 6.8 doses per pt). All pts completed the 2-week DLT evaluation period without DLTs. Of 156 treatment-emergent adverse events (TEAEs), the majority (73%) were CTCAE Gr 1 (21% Gr 2, 6% Gr 3). The most common related TEAEs were chills (n=13), pyrexia (n=12), headache (n=12), fatigue (n=11) and malaise (n=5), mostly of mild to moderate severity. 7 pts had 9 ≥ Gr 3 AEs assessed as potentially related to CVGBM by the investigators outside the DLT period (cerebral edema [n=2], leukoencephalopathy, pseudoprogression with cerebral edema, structural epilepsy, ataxia, hypertension, malaise and fever [1 of each]), evenly distributed across cohorts. First immunogenicity data are planned to be presented. CONCLUSIONS CVGBM was generally well tolerated with an acceptable safety profile. The highest tolerated dose was not reached. Based on all available safety data, the selected dose for trial expansion was 100 µg. Previously presented at ESMO 2024, “FPN (Final Publication Number): 4400, Ghazaleh Tabatabai et al. - Reused with permission.

CTIM-21. FIRST-IN-HUMAN PHASE I CLINICAL TRIAL USING 8R-70CAR T CELLS FOR NEWLY DIAGNOSED ADULT GLIOBLASTOMA

Abstract BACKGROUND To address the challenges of chimeric antigen receptor (CAR) T cell therapy in GBM, we utilized IL-8 release from tumor cells as a ‘GPS homing signal’ to enhance T-cell trafficking with a novel CD70-specific CAR design (8R-70CAR) that targets GBM. The 8R-70CAR offers several advantages: 1) Improved CAR T-cell trafficking, enhancing antitumor efficacy; 2) Reduced CD70, reshaping the tumor microenvironment (TME) and boosting endogenous immunity; 3) Utilized CD27 as the CAR, a co-stimulatory molecule that enhances T-cell functions; 4) Enabled CAR T cells to act as a sink to neutralize or remove IL-8, a pro-cancer chemokine, from the TME; and 5) Required only 120 ml of whole blood (not leukapheresis) for CAR T cell production. Preclinically, 8R-70CAR significantly enhanced CAR-T cell tumor migration and persistence, leading to complete tumor regression and sustained immune memory in a chemo/radiation/PD-1-blockade-resistant GBM model. These findings led to a phase-I trial (IMPACT trial: FDA-IND#23881, NCT05353530) using 8R-70CAR T cells for CD70 -positive newly diagnosed adult GBM. METHODS We aim to recruit 18 adult patients (3 + 3 dose-escalation design) with CD70-positive (>20%) tumors. The CAR T cells will be given intravenously after completing standard-of-care (SOC) therapy. Primary endpoints: Evaluate safety, tolerability, and dose-limiting toxicities (DLTs) to determine the maximum tolerated dose. Secondary endpoints: Assess preliminary efficacy. Immune monitoring and correlative studies will also be conducted. RESULTS To date, four patients have been enrolled in the IMPACT trial, with 2 eligible patients participating in treatment at dose level 1 (1x10^6/kg). One patient has completed treatment with 8R-70CAR T cells, experienced no DLTs, and is currently in follow-up. The remaining patient is under SOC therapy before receiving CAR T cell treatment. CONCLUSIONS This study aims to address current therapeutic gaps and offers options for implementing a novel CAR design for the development of a more effective therapeutic modality for GBM.

Deciphering genetic mechanisms of Al toxicity tolerance through meta-QTL analysis in rice (Oryza sativa L.)

Rice is known for its tolerance to high aluminum (Al) concentrations in soil. However, the precise genetic and physiological mechanisms are yet to be fully understood. Recent research has identified several candidate genes (CGs) and quantitative trait loci (QTLs) associated with Al toxicity tolerance in rice. Nevertheless, many more QTLs/genes are yet to be precisely mapped. We employed meta-QTL (M-QTL) analysis, integrating 12 independent mapping studies and 5 Genome-Wide Association Studies (GWAS). The meta-analysis identified 53 M-QTLs from 157 projected QTLs, which were further narrowed down to 28 M-QTLs based on the number of overlapping QTLs on a consensus map. Gene identification through batch retrieval from the RAP database yielded 2765 non-redundant genes within the 28 M-QTL regions. Comparison of M-QTL CGs with six expression datasets associated with Al toxicity tolerance in rice resulted in the identification of 219 CGs with significant differential expression. Notably, 34 CGs were identified to be common across at least 2 studies. Further downstream analyses of CGs revealed the presence of cis-regulatory elements, transcription factors, and transporter proteins related to the Al toxicity tolerance response. Additionally, we analyzed the expression patterns of the four CGs, namely NRT2.3, ALMT4, MT1, and MTP11, which showed significant upregulation in the Al toxicity-tolerant rice genotype, Anjali. Conversely, in the sensitive genotype Swarna, only NRT2.3 exhibited upregulation, while ALMT4, MT1, and MTP11 were downregulated. Our study highlights significant meta-regions that hold the potential for improving rice genotypes for enhanced tolerance to Al toxicity in acidic soils.

Intraspecific diversity is critical to population-level risk assessments

Environmental risk assessment (ERA) is critical for protecting life by predicting population responses to contaminants. However, routine toxicity testing often examines only one genotype from surrogate species, potentially leading to inaccurate risk assessments, as natural populations typically consist of genetically diverse individuals. To evaluate the importance of intraspecific variation in translating toxicity testing to natural populations, we quantified the magnitude of phenotypic variation between 20 Daphnia magna clones exposed to two levels of microcystins, a cosmopolitan cyanobacterial toxin. We observed significant genetic variation in survival, growth, and reproduction, which increased under microcystins exposure. Simulations of survival showed that using a single genotype for toxicity tolerance estimates on average failed to produce accurate predictions within the 95% confidence interval over half of the time. Whole genome sequencing of the 20 clones tested for correlations between toxicological responses and genomic divergence, including candidate loci from prior gene expression studies. We found no overall correlations, indicating that clonal variation, rather than variation at candidate genes, predicts population-level responses to toxins. These results highlight the importance of incorporating broad intraspecific genetic variation, without focusing specifically on variation in candidate genes, into ERAs to more reliably predict how local populations will respond to contaminants.

Role of CCRT In T3n0 Squamous Cell Carcinoma Larynx, Pros Vs Cons

Objective: To assess the use and efficacy of Concurrent Chemoradiotherapy for a T3N0 Laryngeal Cancer as a Laryngeal Function Preservation modality.Study Design: Prospective Study designPlace and Duration of Study: CMH Rawalpindi, Pakistan from January 2022-January 2023.Methodology: The sample size was n=24, having TPF-CCRT from January 2022 to January 2023 was chosen by using a purposive sampling technique. Individuals were having abnormalities of T3 glottis without vocal cord fixation. Along with MRI, the pretreatment evaluation also comprised clinical, endoscopy, and ultrasound examinations with or without fine needle pick cytology samples. Moreover, F-fluoro-2-deoxy-D-glucose positron emitting tomography was used for whole-body CT scanning. The UICC TNM grading method was used to grade the tumors as grade 15.Results: Twelve out of 24 patients had grade 1 tumor (50%), eight had grade 2 tumors (25%), and four had grade 3 tumors (25%). There had been complete resolution among 17 (70%) of patients, while the disease remains persistent disease in 7 (30%) patients. 95% of patients found with good speech and breathing. 95% of patient organs remain preserved. All 24 patients received CCRT. Four individuals (20%) without tumor regression received surgery following 40 Gy of RT. Others received RT with a 66 Gy median total dose.Conclusion: The study found that effective cancer control is possible with CCRT, and its effects are manageable in 70% of patients with tolerable toxicity. However, in 30% of cases, it fails, requiring salvage laryngectomy. However, the search for a viable strategy with tolerabl

Phase II Study of Irinotecan, Trifluridine/tipiracil (TAS-102) plus Bevacizumab as a Later-line Therapy for Patients with Metastatic Colorectal Cancer (mCRC): a prospective single-center explorative study

PurposeTo explore the efficacy and safety of the combination of irinotecan, trifluridine/tipiracil (TAS-102), and bevacizumab in a later‐line setting for metastatic colorectal cancer (mCRC) patients.Patients and methodsThis was a single-center, phase II trial. The mCRC patients who are refractory to standard first-line and second-line treatment are eligible. Patients who previously received irinotecan while progressing during maintenance therapy are also eligible. The primary endpoint was the objective response rate (ORR).ResultsBetween August 1, 2022, and September 30, 2023, 35 patients were enrolled, and 31 of them were evaluable for efficacy. The ORR was 25.8% (8/31), and the disease control rate (DCR) was 93.5% (29/31). As of April 30, 2024, the median progression-free survival (PFS) was 9.2 months (95% CI 6.285-12.115), whereas the median overall survival (OS) was not reached with the 1-year OS rate of 73.5%. The most common grade 3/4 treatment-related adverse events were neutropenia (34.3%), anemia (17.1%), and thrombocytopenia (8.6%).ConclusionIrinotecan, TAS-102 plus bevacizumab regimen preliminarily demonstrated promising efficacy with tolerable toxicity for mCRC patients as later‐line treatment. This regimen warrants further exploration in refractory mCRC patients.

Transcription factor AtNAC002 positively regulates Cu toxicity tolerance in Arabidopsis thaliana

Copper (Cu) is an essential micronutrient for plant growth and development, but environmental Cu pollution has become increasingly severe, adversely affecting both ecosystems and crop productivity. In this study, we identified the AtNAC002 gene as a positive regulator of Cu toxicity in Arabidopsis thaliana. We found that AtNAC002 expression was induced by Cu excess, and the atnac002 mutant was Cu-sensitive, accumulating more Cu than the wild-type. Additionally, atnac002 mutants exhibit reduced activities of antioxidant enzymes (SOD, POD, and CAT), leading to increased levels of reactive oxygen species and malondialdehyde, which decrease Cu resistance. AtNAC002 might play a role in vacuolar and mitochondrial Cu compartmentalization by regulating genes involved in Cu detoxification, specifically COX11 and HCC1. Furthermore, AtNAC002 was implicated in flavone and flavanol biosynthesis, with the atnac002 mutant showing reduced flavonoid content. Our findings suggest that AtNAC002 is integral to the regulation of Cu toxicity tolerance in A. thaliana. This knowledge is critical for advancing our understanding and offers potential molecular breeding targets to enhance plant performance under Cu excess, which is significant for improving global food security and forest restoration.

Antidepressant Herbal Plants: An Updated Review

The symptoms of this illness include mood swings, protracted melancholy, disinterest, and diminished cognitive performance. These symptoms give the patient discomfort and have a substantial negative impact on their capacity to function and lead fulfilling personal, social, and professional lives. Depression treatment has to be comprehensive and involve medicine. For several centuries, herbal chemicals have been the subject of scientific inquiry, and ongoing studies are being conducted to explore their possible medical benefits. Herbs used in traditional medicine have been shown to be highly beneficial in lowering depression and its symptoms as well as enhancing patient function. Plants are used in biology and medicine in a variety of ways. They are an excellent resource for the creation of innovative drugs due to their high levels of safety, accessibility, availability, tolerance, and low levels of toxicity. Depression is caused by a multitude of variables, such as inflammation, brain-derived neurotropic factor (BDNF), hypothalamic-pituitary-adrenal (HPA) axis, and monoamine neurotransmitters (dopamine, serotonin (5-HT), noradrenaline, and 5-HT). Herbal medicines have gained a lot of attention lately since they are less costly and have less adverse effects than traditional depression treatments. Recent years have seen a significant amount of study on the possible application of sedative and antidepressant plants. The primary emphasis of this review has been herbal medications with antidepressant properties. Keywords: Depression, herbal medications. Herb, antidepressant plants

Screening and Identification of Aluminium Toxicity Tolerant Lentil (Lens culinaris Medik.) RILs based on Root Growth Studies and Organic Acid Exudation under Hydroponics

Background: Aluminium (Al) stress is among the prime limitations of crop production including Lentil, in acidic soils as Al solubilizes into phytotoxic forms at low pH causing root growth inhibition, minimizing plant-vigor and yield. The current study was performed to identify the Al tolerant RILs based on root-regrowth studies, short term growth culture and organic acid exudation in reaction to Al toxicity under hydroponics. Methods: The study involved screening for Al toxicity tolerance in recombinant inbred lines (RILs) population of lentil through root re-growth studies, short term growth response method under hydroponics treated with toxic concentration of Al (148 µM), organic acid exudation using HPLC and correlation analysis among the traits. Result: ANOVA for root and shoot traits revealed presence of highly significant genotypic differences for all the traits. High GCV along with high H2bs and GA% were observed for the traits revealing the influence of additive genes and suggested reliable selection of these traits for Al toxicity tolerance. Citric acid was exudated in highest amount in all the genotypes and was positively and significantly correlated with RRG. Based on the hydroponics study and organic acid exudation, RILs identified as tolerant were LRIL-10, LRIL-37, LRIL-68, LRIL-96, LRIL-97, LRIL-113, LRIL-125, LRIL-133, LRIL-143, LRIL-144 and LRIL-148. With further evaluation, these RILs may serve as important Al toxicity tolerant varieties suitable for acidic soil conditions. Also, these lines may serve as donors of Al toxicity loci and mapping of Al tolerance genes.

Chinese herbal formula in the treatment of metabolic dysfunction-associated steatotic liver disease: current evidence and practice.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, continues to rise with rapid economic development and poses significant challenges to human health. No effective drugs are clinically approved. MASLD is regarded as a multifaceted pathological process encompassing aberrant lipid metabolism, insulin resistance, inflammation, gut microbiota imbalance, apoptosis, fibrosis, and cirrhosis. In recent decades, herbal medicines have gained increasing attention as potential therapeutic agents for the prevention and treatment of MASLD, due to their good tolerance, high efficacy, and low toxicity. In this review, we summarize the pathological mechanisms of MASLD; emphasis is placed on the anti-MASLD mechanisms of Chinese herbal formula (CHF), especially their effects on improving lipid metabolism, inflammation, intestinal flora, and fibrosis. Our goal is to better understand the pharmacological mechanisms of CHF to inform research on the development of new drugs for the treatment of MASLD.