Additional Toxicity Research Articles

Selinexor (KPT-330) in Combination with Immune Checkpoint Inhibition in Uveal Melanoma: A Phase 1B Trial

Introduction Uveal melanoma remains a disease with aggressive behavior and poor prognosis despite advances in clinical management. Because monotherapy with immune checkpoint inhibitors has led to limited improvement in response rates, combination with other agents that act on the biological basis of oncogenesis has been proposed as a possible therapeutic strategy. Methods We designed a phase 1b trial to test the safety and tolerability of selinexor in combination with immune checkpoint inhibitors in patients with advanced uveal melanoma. Patients received selinexor 60 mg PO twice weekly with standard of care, commercially available immune checkpoint inhibitor of the investigator’s choice. In one patient receiving nivolumab and ipilimumab as the immunotherapy backbone, selinexor 60 mg PO was given once weekly. Results We included 10 patients with uveal melanoma who received treatment with either selinexor plus pembrolizumab (n = 9) or selinexor plus nivolumab and ipilimumab (n = 1). The most common adverse events of any grade were neutropenia, thrombocytopenia, leukopenia, and anemia. Additional common nonhematological toxicities included hyponatremia, nausea, and vomiting. Dose reductions were required in six patients (60%). Among nine patients with evaluable disease, eight had stable disease as the best response. The median progression-free and overall survival were 6 months (95% CI: 4, not reached and 17 months (95% CI: 7, not reached), respectively. Conclusion The combination of selinexor and immunotherapy was safe and showed a side effect profile consistent with previous reports. Clinical benefit was achieved in most patients and should be validated in larger phase 2 trials. ClinicalTrials.gov ID: NCT02419495.

Диффузная В-крупноклеточная лимфома с высоким риском поражения центральной нервной системы (обзор литературы, вопросы профилактики, лечение, прогноз)

AIM. To assess the feasibility of preventing the CNS damage in intermediate/high risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) in accordance with CNS-IPI criteria. MATERIALS & METHODS. The trial was based on the clinical data from 60 patients with newly diagnosed DLBCL treated at the NN Blokhin National Medical Cancer Research Center from 2018 to 2024. The patients were 29–80 years of age (median 59 years); there were 34 women and 26 men. In accordance with the immunohistochemical algorithm of C.P. Hans, GCB subtype of DLBCL was identified in 18 (30 %) patients, non-GCB subtype was detected in 35 (58 %), and in 7 (12 %) patients subtype was not specified. By the time of primary DLBCL diagnosis, in 58 out of 60 patients tumor stage 4 was found, in 56 patients LDH increase was reported, and 22 patients showed ECOG ≥ 2. Extranodal lesions (> 1 zone) were identified in 53/60 patients. In accordance with the CNS-IPI score, with respect to CNS damage there were 22 (37 %) intermediate and 36 (60 %) high risk patients. In first-line therapy, R-CHOP (n = 40; 67 %) was most commonly used, R-DA-EPOCH (n = 10; 17 %) and Pola-R-CHP (n = 7; 11 %) were administered less often; 3 patients (5 %) received R-B. In 18 (30 %) patients, the initial lesions were treated with radiotherapy after completing drug chemotherapy. Different variants of CNS damage prevention in DLBCL included intrathecal (IT) administration of 3 drugs (methotrexate, cytarabine, and dexamethasone) and/or 2 methotrexate (МТХ) 3–3,5 g/m2 infusions. The trial identified two clinically comparable groups of DLBCL patients with CNS-IPI intermediate/high risk of CNS damage, who received chemotherapy throughout different periods of time (2018–2021 and 2022–2024). During the first period (n = 30), to prevent possible CNS damage, both methods were used as monotherapy or combined regimens consecutively. МТХ IT + МТХ HD (high dose) as prevention was administered to 20 (67 %) patients, 2 (7 %) patients received only МТХ HD, and 8 (26 %) patients received only МТХ IT. In the second group, CNS damage prevention was not provided for this category of DLBCL patients. RESULTS. In the total group (n = 60), with the follow-up median of 24 months, the 2-year progression-free survival (PFS) was 76 % (median 44 months), whereas the 2-year overall survival (OS) was 87 % (median 49 months). Age > 60 years was associated with the worst rate of the 2-year PFS (72 %) compared with patients ≤ 60 years (90 %) (p = 0.04). Besides, the 2-year OS in women was 77 % and 100 % in men, whereas in the groups of patients with ECOG ≥ 2 vs. < 2 it was 63 % and 95 %, respectively (p = 0.04). In patients with prevention of CNS damage, the 2-year PFS was 95 % vs. 64 % in patients without it (p = 0.001), and the 2-year OS in them was 95 % and 77 %, respectively (p = 0.05). In the course of this trial, the rate of DLBCL relapses with CNS involvement was 5 % (n = 3). Relapses were detected in 6, 18, and 46 months from the beginning of chemotherapy. CNS damage prevention was not performed in 3 patients with relapses. CONCLUSION. The data obtained in this ambispective trial support systemic and intrathecal use of methotrexate to increase the overall PFS rate and to reduce the relapse rate, also in CNS. The methods of CNS damage prevention are not associated with additional toxicity in DLBCL patients with intermediate/high CNS-IPI risk score.

Rapid determination of chemical losses in a microplate bioassay using fluorescence spectroscopy.

The increase in production and innovation of chemicals that humans interface with has enhanced the need for rapid toxicity testing of new and existing chemicals. This need, along with efforts to reduce animal testing, has led to the development of high-throughput bioassays typically conducted in microplates. These bioassays offer time and resource advantages over traditional animal models; however, significant chemical losses can occur in microplates. Current methods for measuring chemical losses in microplates require extensive sample preparation and highly sensitive instruments. We propose the use of fluorescence spectroscopy to measure chemical losses in high-throughput bioassays as a low resource alternative to the existing methods. A fluorescent plate reader was used to develop methods for quantifying the aqueous concentrations of two chemicals, 2-hydroxynaphthalene and acridine, in microwells of a 96-well microplate. A high-throughput, 5 day embryonic zebrafish bioassay was used as the model bioassay for method development. Chemical losses were attributed to a combination of photodegradation, sorption, and uptake by the zebrafish embryos, kinetics of which were derived from a pseudo-first order model. Chemical uptake amount was calculated to be approximately 50% and 21% of the total chemical amount added for 2-hydroxynaphthalene and acridine, respectively. Unexpected cranial deformities were observed in the embryonic zebrafish, suggesting further investigation of potential additive toxicity of the ultraviolet radiation exposure from fluorescence measurements and chemical exposure is needed. Nonetheless, this novel method provides a rapid, low resource approach to measuring chemical losses in microplates that can be extended to a variety of autofluorescent chemicals and microplate-based bioassays.

The Effects of Polystyrene Microplastics and Copper Ion Co-Contamination on the Growth of Rice Seedlings.

Microplastics (MPs) are emerging pollutants of global concern, while heavy metals such as copper ions (Cu2+) are longstanding environmental contaminants with well-documented toxicity. This study investigates the independent and combined effects of polystyrene microplastics (PS-MPs) and Cu on the physiological and biochemical responses of rice seedlings (Oryza sativa L.), a key staple crop. Hydroponic experiments were conducted under four treatment conditions: control (CK), PS-MPs (50 mg·L-1), Cu (20 mg·L-1 Cu2+), and a combined PS-MPs + Cu treatment. The results showed that PS-MPs had a slight stimulatory effect on root elongation, while Cu exposure mildly inhibited root growth. However, the combined treatment (PS-MPs + Cu) demonstrated no significant synergistic or additive toxicity on growth parameters such as root, stem, and leaf lengths or biomass (fresh and dry weights). Both PS-MPs and Cu significantly reduced peroxidase (POD) activity in root, stem, and leaf, indicating oxidative stress and disrupted antioxidant defenses. Notably, in the combined treatment, PS-MPs mitigated Cu toxicity by adsorbing Cu2+ ions, reducing their bioavailability, and limiting Cu accumulation in rice tissues. These findings reveal a complex interaction between MPs and heavy metals in agricultural systems. While PS-MPs can alleviate Cu toxicity by reducing its bioavailability, they also compromise antioxidant activity, potentially affecting plant resilience to stress. This study provides a foundation for understanding the combined effects of MPs and heavy metals, emphasizing the need for further research into their long-term environmental and agronomic impacts.

Personalized genotype-directed antitumor therapy for newly diagnosed diffuse large B-cell lymphoma: efficacy and toxicity of the R-CHOP-X protocol in a single-center, non-randomized, prospective clinical trial (first results)

Background. Diffuse large cell lymphoma (LCL) is a potentially curable biologically heterogeneous lymphatic tumor. Standard RCHO therapy shows disappointing results, both immediate and longterm. To improve efficacy without additional toxicity, it is worth considering the possibility of using biologically oriented therapy.Aim. To evaluate the clinical efficacy and toxicity of the genotypedirected RCHO in patients with newly diagnosed LCL in real clinical practice.Materials and methods. A singlecenter prospective interventional clinical study included 30 patients with newly diagnosed LCL between September 2023 and September 2024. The median age was 60 (38–78) years. According to the international prognostic index, 23 (77 %) patients were classified as having a high risk of progression. Genotype incidence in the study cohort: MC– 7 %, N1 – 20 %, N2 – 7 %, EZ– 16 %, ST2 – 7 %, NOS – 43 %.Results. 30 patients received personalized genotypedirected therapy. Of these, 21 (70 %) patients completed treatment: the overall response rate was 100 % (complete metabolic response – 100 %). 9 (30 %) patients continue therapy: the overall response rate is 100 %. At 12 months, overall survival and progressionfree survival were 100 % (95 % confidence interval 100 %). Hematological toxicity was assessed depending on the number of cycles (n = 144): grade III–I neutropenia was detected in 7 % of cycles, grade III–I anemia and grade III–I thrombocytopenia in 1.4 and 3.5 % of cycles, respectively. Nonhematological toxicity was generally grade ≤I–II.Conclusion. The results of this clinical trial are promising and provide preliminary evidence for the benefit of personalized genotypedirected antitumor therapy in newly diagnosed LCL. This therapeutic strategy demonstrates high clinical efficacy, particularly in the main target group – LCL with a high risk of progression with low toxicity. Further randomized studies are needed to confirm the effectiveness and implement the new approach in routine clinical practice.

To consolidate or not to consolidate: the role of autologous stem cell transplantation in MCL.

An Ara-C-containing intensified induction therapy followed by autologous stem cell transplantation (ASCT) is considered a highly effective treatment strategy in younger mantle cell lymphoma (MCL) patients, inducing long-lasting remissions. However, ASCT is also hampered by acute and delayed toxicity. Thus, alternative first-line treatment strategies without ASCT but including novel agents are under investigation. With the recently published results of the TRIANGLE trial, showing superiority of an ibrutinib-containing immunochemotherapy induction followed by ASCT compared with the standard therapy and, more strikingly, a noninferiority of an ibrutinib-containing regimen without ASCT compared with the standard regimen with ASCT, we consider the addition of ibrutinib to first-line therapy in younger MCL patients as a new standard of care. Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined. In addition, it remains unclear how effective Bruton's tyrosine kinase inhibitor (BTKi) therapy will be in the relapsed setting for patients who received BTKi as part of first-line therapy. It also remains unclear whether the TRIANGLE data can be extrapolated to other BTKi, which is particularly relevant considering it is no longer FDA approved for MCL. Until then, individual patient characteristics and preferences, disease biology, and estimation of risk of toxicity needs to be taken into account when deciding about the addition of ASCT to an ibrutinib-containing induction therapy. For patients with TP53 aberrations, ASCT should not be recommended due to potential toxicity and limited efficacy in this high-risk subgroup. Large randomized clinical trials such as ECOG-ACRIN 4151 will help to ultimately clarify the role of ASCT.

The Evolution of Lupus Nephritis Treatment; from Conventional to Targeted and Biologics Therapy

Lupus nephritis (LN) is a common and severe organ manifestation in patients with systemic lupus erythematosus (SLE). LN can present alone or with accompanying extra-renal symptoms. The prevalence and severity vary depending on ethnicity, genetics, and environmental exposure. However, the presence of LN in SLE is a surrogate indicator of disease severity, frequent relapse, increased chronic kidney disease (CKD), and mortality risks. The current conventional standard treatments for LN include corticosteroids, immunosuppressive drugs, and antimalarial drugs. Despite an optimal standard treatment regimen, the outcomes of renal remission, decreased CKD risk, and quality of life are unsatisfactory. In addition, corticosteroid and immunosuppressive drug toxicity are of primary concern. Thus, two dozen promising biological and targeted drugs are being studied in the LN treatment pipeline to improve renal outcomes and mitigate the side effects of conventional therapy. This article aims to review the pathogenesis of LN, summarise the current conventional strategy, and highlight the candidate novel drugs in LN included in Phase II and III clinical trials. These biologics, or targeted therapies, are hoped to facilitate the advancement of the LN treatment paradigm in the era of precision medicine.

PPARγ and COX1 Inhibition of Linoleic Acid as Potential Bioactive Molecule in Aqueous Extract of Tinospora cordifolia (Wild.): A in silico based Approach

In this work, the ethyl acetate extract of Tinospora cardifolia was analyzed using GC-MS and phytochemical analysis. The FTIR analysis and UV spectroscopy were used to further validate the structures of the isolated compounds. For the selected compounds, the computational methods were used to conduct an in silico analysis on their molecular, physico-chemical and druglikeliness properties. Moreover, the pharmacokinetic profile and additional toxicity potential were ascertained. Swiss ADME tools and OSIRIS data warrior were used in the investigation. The docking experiment was used to examine the anti-inflammatory and antidiabetic characteristics. The α-glucosidase, peroxisome proliferator-activated receptor, glucose transporter-1 and cyclooxygenases 1 and 2 were targeted for inhibition. Approximately 23 chemicals were found during GC-MS analysis. Each of the compounds have shown the pharmacokinetic potential and moderate to good drug likeliness. The compounds bioactivity score against enzyme receptors was high. The least harmful profile of PGP and CYP inhibitory actions was indicated by the ADMET prediction. Linoleic acid (molecule-12) has a strong binding affinity for PPARγ and COX1 targeted proteins under inquiry as demonstrated by the docking studies.

Core-Shell Chitosan Particles Targeting Membrane-Bound Heat Shock Protein 70 for Cancer Therapy.

Anti-cancer targeted therapy is a promising approach. However, the identification of target molecules over-expressed in a wide range of tumors remains a significant challenge. The aim of this study was to analyze the expression of cell membrane-exposed heat shock protein 70 kDa (mHSP70) on different tumor cells and to develop a nanoscale delivery system based on a monoclonal antibody (mAb) that recognizes mHSP70 and uses chitosan core-shell nanoparticles (NPs). Several types of tumor cells (breast, pancreas, colon, prostate cancers, and some lymphomas) expressed mHSP70 as was determined by flow cytometry and confocal microscopy both in 2D and 3D cultures. Core NPs were formed by chitosan (C) conjugated to allocolchicinoid, which was used as a model drug (D). mAbs (A) targeting mHSP70 were complexed with succinylchitosan and used as NP shells forming final CAD-NPs. These NPs were characterized by size, charge, and functional activity. CAD-NPs were shown to have additional toxicity in comparison with CD-NPs in mHSP7-positive cells. Taken collectively, this study shows that mAb to mHSP70 can be used as a targeting vector in antitumor therapy.

Calcium nanoparticles target and activate T cells to enhance anti-tumor function

Calcium signaling plays a crucial role in the activation of T lymphocytes. However, modulating calcium levels to control T cell activation in vivo remains a challenge. In this study, we investigate T cell activation using 12-myristate 13-acetate (PMA)-encapsulated CaCO3 nanoparticles. We find that anti-PD-1 antibody-conjugated CaCO3 nanoparticles can be internalized by T cells via receptor-mediated endocytosis and then gradually release calcium. This results in an increase in cytosolic calcium, which triggers the activation of NFAT and NF-κB pathways, especially when the surface of the CaCO3 nanoparticles is loaded with PMA. Animal studies demonstrate that the PMA-loaded calcium nanoparticles enhance the activation and proliferation of cytotoxic T cells, leading to improved tumor suppression without additional toxicity. When tested in metastatic tumor models, T cells loaded with the calcium nanoparticles prior to adoptive cell transfer control tumor growth better, resulting in prolonged animal survival. Our approach offers an alternative T cell activation strategy to potentiate immunotherapy by targeting a fundamental signaling pathway.

A Comparison of Stereotactic Radiation Therapy in Elderly Patients with Central or Peripheral Stage I-II (T1-3 N0 M0) Non-Small Cell Lung Cancer.

The objective of this study was to compare the clinical outcomes of stereotactic body radiation therapy (SBRT) in elderly patients aged 65 or older with clinical stage I-II non-small-cell lung cancer (NSCLC), specifically examining the differences between centrally located lung tumors and peripherally located lung tumors. From April 2009 to January 2020, a total of 136 patients with 136 tumors (65 central, 71 peripheral; NSCLC) at an early stage (T1-3N0M0) were treated with SBRT at a single institution. Central/peripheral location was assessed retrospectively on planning CT scans. A propensity score matching analysis was utilized to compare the two groups. In addition, the prognosis and related toxicity were compared between the two study arms. A total of 33 central tumors and 33 peripheral tumors were matched and analyzed. The results showed no significant differences in overall survival (OS) and progression-free survival (PFS) between the two groups. The 2-year OS was 71.88% (95% CI, 57.87%-89.27%) in the central lung cancer group, while it was 93.94% (95% CI, 86.14%-100.00%) in the peripheral lung cancer group (P=0.462). The 2-year PFS was 43.75% in the central lung cancer group, while it was 78.79% in the peripheral lung cancer group (P=0.279). Further subgroup analysis indicated that the location of peripheral tumor have a positive impact on OS in patients with adenocarcinoma. The occurrence of local failure, regional failure, or distant failure was comparable between central and peripheral tumors. There was no statistically significant difference in toxicity between the central and the peripheral tumor groups. The outcomes of SBRT for central tumors versus peripheral lung tumors in elderly patients with early-stage NSCLC were similar. SBRT demonstrated a similar level of safety in terms of toxicity for both central and peripheral lung tumors.

Are Repeat-Dose Toxicity Studies Informative for Safety Assessment of Vaccine Candidates? A Survey of Vaccine Developers.

A BioSafe-sponsored survey investigated how vaccine companies (n = 12) perceive the value of the repeat-dose toxicity studies for safety assessment of vaccine candidates. As all major vaccine developers were part of the survey, it was considered representative for the industry practices up to 2022. Vaccine developers indicated that they see scientific value in performing repeat-dose toxicity studies with vaccines, especially when novel components (e.g., adjuvant) or technology is being used. However, a few (3/12) also indicated that repeat-dose toxicity studies could be replaced by a pharmacology study with additional toxicity parameters. For the majority of companies (9/12), findings from the repeat-dose toxicity studies never prevented or postponed a first-in-human (FIH) trial. In the remaining 3 companies, a total of 4 occurrences of postponement or prevention of clinical development occurred and in only 2 of these cases was the finding considered related to the vaccine. A platform approach has been successfully implemented for influenza vaccines already in 2016, and an outline of the regulatory requirements for a platform approach has been recently documented in the latest infectious disease mRNA-LNP vaccine guideline, as well as in the guidance on the development and licensure of COVID-19 vaccines presented by the FDA. Vaccine developers are seeking to extend this platform approach to the development of new vaccines, building on established technologies and using well-defined manufacturing processes. This approach could support reduction of animal use (a principle of 3Rs) while still providing reassurance of the nonclinical safety of these products.

Echinacoside inhibits tumor immune evasion by downregulating inducible PD-L1 and reshaping tumor immune landscape in breast and colorectal cancer

BackgroundTargeting PD-L1 has become a crucial approach in tumor immunotherapy. Echinacoside (ECH) is a natural compound known for its extensive biological activities, its impact on antitumor immunity remains uncertain. PurposeThis work was designed to assess the effects of ECH on the PD-L1/PD-1-mediated tumor immune evasion and its underlying mechanisms. MethodsFlow cytometry and RT-qPCR were utilized to explore the influence of ECH on PD-L1 expression. Western blot was employed to examine the mechanism by which ECH might modulate PD-L1 expression. Flow cytometry was conducted to evaluate the influence of ECH therapy, or the synergistic effects of ECH combined with immune checkpoint blockade (ICB) on tumor immune microenvironment (TIME) in tumor-burden mice. Blood biochemistry tests were used to evaluate the safety of ECH treatment. ResultsECH downregulated both the protein and mRNA expression levels of IFN-γ-induced PD-L1 through JAK/STAT1/IRF1 signaling pathway. ECH treatment upregulated the infiltration of IFN-γ+CD8+ T cells and Ki-67+CD8+ T cells, lowered the frequency of TIM-3+PD-1+ T cells, promoted the infiltration of effector CD4+ T cells and total CD8+ T cells while suppressed the percentage of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Moreover, the combination of ECH and anti-PD-1 or anti-CTLA-4 therapy exhibited synergistic anti-tumor effects, reshaping TIME. Blood biochemistry tests unveiled that ECH did not show additional toxicity. ConclusionECH upregulates the expression of inducible PD-L1 through the JAK/STAT1/IRF1 signaling pathway, enhances T cell function, and reshapes the tumor immune landscape into an anti-tumor phenotype. Importantly, ECH markedly enhances the efficacy of ICB treatment, indicating its potential application in anti-tumor therapy.

Long-chain perfluoroalkylether carboxylic acids PFO5DoA and PFO4DA alter glucose, bile acid, and thyroid hormone homeostasis in fetal rats from 5-day maternal oral exposure

Chemical monitoring studies in North Carolina, USA and Shandong, China have reported detections of perfluoroalkylether carboxylic acids of increasing chain length with ether bonds between each fluorinated carbon. Despite detection there is limited hazard data available to inform risk assessment. Here, we exposed pregnant Sprague-Dawley rats to two of these compounds, perfluoro-3,5,7,9-butaoxadecanoic acid (PFO4DA) and perfluoro-3,5,7,9,11-pentaoxadodecanoic acid (PFO5DoA), from gestation days 18–22 across a series of doses (0.3–62.5 mg/kg/d) via oral gavage. PFO5DoA was acutely toxic to rat dams and fetuses at the top two doses (30 and 62.5 mg/kg), while PFO4DA did not cause acute toxicity at any doses tested. PFO5DoA significantly increased maternal liver weight (≥3 mg/kg; 28% increase at 10 mg/kg) while PFO4DA did not affect maternal liver weight up to 62.5 mg/kg. PFO4DA and PFO5DoA both significantly reduced serum total thyroxine in maternal (≥10 mg/kg for both) and fetal (≥1 mg/kg) rats. Both compounds significantly reduced fetal liver glycogen concentrations, increased fetal serum total bile acids, and altered expression levels of multiple genes associated with glucose metabolism in the fetal liver. Serum concentrations of PFO5DoA were higher than PFO4DA in both rat dams and fetuses at equivalent maternal oral doses indicating greater accumulation. Dose response modelling of several fetal endpoints as a function of serum molar concentration indicates PFO5DoA was ∼3-4-fold more potent than PFO4DA. PFO5DoA and PFO4DA produced maternal and fetal toxicity from short-term oral maternal exposure indicating need for additional toxicity data to evaluate potential human health risks.

Optimising hypoxia PET imaging and its applications in guiding targeted radiation therapy for non-small cell lung cancer: a scoping review.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Definitive treatment includes chemotherapy and radiation therapy. Tumour hypoxia impacts the efficacy of these treatment modalities. Novel positron-emission tomography (PET) imaging has been developed to non-invasively quantify hypoxic tumour subregions, and to guide personalised treatment strategies. This review evaluates the reliability of hypoxia imaging in NSCLC in relation to various tracers, its correlations to treatment-related outcomes, and to assess if this imaging modality can be meaningfully applied into radiation therapy workflows. A literature search was conducted on the Medline (Ovid) and Embase databases. Searches included terms related to 'hypoxia', 'positron-emission tomography', 'magnetic resonance imaging' and 'lung cancer'. Results were filtered to exclude studies prior to 2011, and animal studies were excluded. Only studies referring to a confirmed pathology of NSCLC were included, while disease staging was not a limiting factor. Full-text English language and translated literature examined included clinical trials, clinical cohort studies and feasibility studies. Quantification of hypoxic volumes in a pre-treatment setting is of prognostic value, and indicative of treatment response. Dosimetric comparisons have highlighted potential to significantly dose escalate to hypoxic volumes without risk of additional toxicity. However, clinical data to support these strategies are lacking. Heterogenous study design and non-standardised imaging parameters have led to a lack of clarity regarding the application of hypoxia PET imaging in NSCLC. PET imaging using nitroimidazole tracers is the most investigated method of non-invasively measuring tumour hypoxia and has potential to guide hypoxia-targeted radiation therapy. Further clinical research is required to elucidate the benefits versus risks of dose-escalation strategies.

Macro- and microplastics leachates: Characterization and impact on seed germination

Although plastic mulch enhances crop yield, its removal and disposal present significant challenges, contributing to macro- and microplastic pollution in agricultural soils. The adverse effects of this pollution on soil and plant health are not fully understood but may stem from the plastic particles or the toxicity of leached chemical additives. This study assessed the impact of macro- and microplastics from nondegradable LDPE-based (LDPEb) and biodegradable PBAT-based (PBATb) mulch films, along with their leachates, on the germination of three plant species. After seven days of incubation, PBAT mulch leached compounds that significantly inhibited Arabidopsis germination, while cotton and tomato exhibited notable tolerance. Notably, PBATb mulch released a higher concentration of compounds, whereas LDPEb mulch exhibited a greater diversity of leached chemicals. Microplastic particles alone did not hinder seed germination, indicating that plastic toxicity primarily arises from the leachates. Many of these leached compounds lack global regulation and hazard information, underscoring the urgent need for further investigation into their environmental impacts and the development of appropriate regulatory frameworks to mitigate the potential toxicity of chemicals from conventional and biodegradable mulches.

Protective and Therapeutic Effects of Medicinal Plants Against Food Additive-Induced Toxicity.

For thousands of years, people have used medicinal plants and in many parts of the world, traditional medicines continue to play a significant role in the standard treatment of a wide range of illnesses. With changes in modern eating patterns, there has recently been an increase in the use of processed foods. Furthermore, the use of food additives has increased in tandem with the production of processed foods. The dosage levels used for these additives are determined using empirical analyses. However, some additives have demonstrated long-term toxic effects on the human body in toxicity tests. Plants are one of the main sources of biologically active substances and in recent years, many studies have focused on the health benefits of phytochemicals and plant-derived extracts in the treatment and prevention of food additive toxicity. This review clarified studies on several medicinal plants, such as <i>Physalis peruviana</i> L., <i>Jatropha tanjorensis</i>, <i>Cymbopogon citratus</i>,<i> Ficus carica</i>, <i>Rosmarinus officinalis</i> L. and others. The findings presented here demonstrate these plants' efficiency and success in preventing and lowering the toxicity of food additives through antioxidant activity reducing oxidative stress, and reduction in renal and hepatic toxicity. Therefore, these plant extracts have a preventive and therapeutic effect in reducing toxicity and may be the best option for reducing the toxicity of food additives in the future. Moreover, additional research is required to confirm the biologically active components found in medicinal plants that are effective in reducing this toxicity.

NEW INSIGHTS INTO THE THIAZOLIDINEDIONES AS AN ADD-ON THERAPY TO METFORMIN AND GLIMEPIRIDE IN PATIENTS WITH UNCONTROLLED TYPE 2 DIABETES MELLITUS

Diabetes mellitus is a complex metabolic disorder that requires multifaceted management, including frequent blood glucose monitoring, polypharmacy, and timely therapeutic adjustments. Thiazolidinediones have been proposed as an effective add-on therapy to existing regimens to improve glycemic control in patients with Type 2 Diabetes Mellitus (T2DM). Objective: To evaluate the effectiveness of Thiazolidinediones as add-on therapy in diabetic patients already taking metformin and glimepiride. Methods: This observational, comparative, and follow-up cohort study was conducted in a tertiary care hospital in Pakistan. A total of 90 patients with poorly controlled T2DM were enrolled and randomly divided into two groups: Group A (n=45) received standard oral therapy with metformin and glimepiride, while Group B (n=45) received metformin, glimepiride, and Thiazolidinediones. The study outcomes included changes in Hemoglobin A1c (HbA1c), fasting blood sugar (FBS), and body mass index (BMI) throughout the study. Statistical analyses were performed using appropriate methods, with significance at p < 0.05. Results: The addition of Thiazolidinediones in Group B resulted in superior glycemic control compared to Group A. Group B exhibited a 16.1% reduction in HbA1c versus an 8.2% reduction in Group A (p < 0.05). FBS levels decreased by 28.8% in Group B compared to a 14.6% decrease in Group A (p < 0.05). Additionally, BMI decreased by 1.5% in Group B, whereas Group A showed a slight increase of 0.06% (p < 0.05). Significantly, the addition of Thiazolidinediones did not exacerbate the toxicity of the existing drug regimen. Conclusion: The study demonstrates that Thiazolidinediones, when added to standard therapy with metformin and glimepiride, offer significant improvements in glycemic control without additional toxicity. This combination therapy may be a beneficial strategy for managing poorly controlled Type 2 diabetes mellitus in the Pakistani population.

Phase II Trial of HER-Vaxx, a B-cell Peptide-Based Vaccine, in HER2-Overexpressing Advanced Gastric Cancer Patients Under Platinum-Based Chemotherapy (HERIZON).

A multicenter, randomized, open-label, phase II study (HERIZON; NCT02795988) was conducted to evaluate the clinical and immunologic efficacy of HER-Vaxx (IMU-131), a B-cell, peptide-based vaccine targeting HER2 overexpressed in 6% to 30% of gastroesophageal adenocarcinomas (GEA). Patients (n = 36) with GEA were treated with standard-of-care chemotherapy (n = 17) or HER-Vaxx plus chemotherapy (n = 19), using the recommended phase 2 dose for the vaccine. Overall survival (OS; primary endpoint), safety, progression-free survival (PFS), clinical response (secondary endpoints), and vaccine-induced HER2-specific antibody levels in serum and correlation with tumor response rates (exploratory endpoints) were investigated. A 40% OS benefit [HR, 0.60; median OS, 13.9 months; 80% confidence interval (CI), 7.52-14.32] for patients treated with HER-Vaxx plus chemotherapy compared with OS of 8.31 months (80% CI, 6.01-9.59) in patients that received chemotherapy alone. A 20% PFS difference was obtained for the vaccination arm (HR, 0.80; 80% CI, 0.47, 1.38). No additional toxicity due to HER-Vaxx was observed. The vaccine-induced high levels of HER2-specific total IgG and IgG1 antibodies (P < 0.001 vs. controls) that significantly correlated with tumor reduction (IgG, P = 0.001; IgG1, P = 0.016), had a significant capacity in inhibiting phosphorylation of the intracellular HER2-signaling pathways, mediated antibody-dependent cellular cytotoxicity, and decreased immunosuppressive FOXP3+ regulatory T cells. HER-Vaxx plus standard chemotherapy exhibits an excellent safety profile and improves OS. Furthermore, vaccine-induced immune response was significantly associated with reduced tumor size compared with standard-of-care chemotherapy. The presented vaccination approach may substitute for treatment with trastuzumab, upon unavailability or toxicity, based on further evidence of equivalent treatment efficacy.

Exploring the feasibility of preoperative tumor-bed boost, oncoplastic surgery, and adjuvant radiotherapy schedule in early-stage breast cancer: A phase II clinical trial.

Oncoplastic breast-conserving surgery (OBCS) improves satisfaction in patients who would fare otherwise sub-optimal cosmetic outcome, while brings challenge in tumor-bed identification during adjuvant radiotherapy. The ultra-hypofractionated breast radiotherapy further shortens treatment sessions from moderately hypofractionated regimens. To circumscribe the difficulty in tumor-bed contouring and the additional toxicity from larger boost volumes, we propose to move forward the boost session preoperatively from the adjuvant radiation part. Thus, the present study aims to evaluate the feasibility of a new treatment paradigm of preoperative primary-tumor boost before breast-conserving surgery (BCS) or OBCS followed by adjuvant ultra-hypofractionated whole-breast irradiation (u-WBRT) for patients with early-stage breast cancer. There was a phase II study. Patients younger than 55 years old, with a biopsy confirmed mono-centric breast cancer, without lymph node involvement were enrolled. Preoperative primary-tumor boost was given by a single 10Gy in 1 fraction, and BCS or OBCS was conducted within two weeks afterwards. Adjuvant u-WBRT (26Gy/5.2Gy/5f) was given in 6 weeks postoperatively without any boost, after the full recovery from surgery. Surgical complications and patient-reported outcomes, as assessed via Breast-Q questionnaires, were documented. A propensity score matching approach was employed to identify a control group at a 1:1 ratio for BREAST-Q outcomes comparison. From May 2022 to September 2023, 36 patients were prospectively enrolled. Surgical complications were observed in 7 cases (19.4%), including 3 cases with Clavien-Dindo (CD) grade 1-2 and 4 cases with CD grade 3 complications. All but four patients (11.1%) started the planned u-WBRT within one week after the pre-defined due dates postoperatively (≤49d). Four patients (11.1%) developed grade 2 radiodermatitis after chemotherapy initiation. Compared to the study group, the control patients reported higher scores in chest physical well-being (P=0.045) and in their attitudes towards arm swelling (P=0.01). No significant difference was detected in the other of domains (Satisfaction with Breasts, Sexual and Psychosocial Well-Being, and Adverse Effects of Radiation). With a median follow-up period of 9.8 months (2.4-18.9mo), none had any sign of relapse. This Phase II clinical trial confirmed the technical and safety feasibility of novel radiation schedule in patients undergoing BCS or OBCS. According to the BREAST-Q questionnaire, patients who underwent novel radiation schedules reported lower satisfaction in chest physical well-being. A randomized controlled trial is necessary to further investigate these findings. Additionally, long-term follow-up is required to assess oncological outcomes.