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Environmental Geochemistry and Health Jul 2024Pyrethroids are synthetic organic insecticides. Deltamethrin, as one of the pyrethroids, has high insecticidal activity against pests and parasites and is less toxic to... (Review)
Review
Pyrethroids are synthetic organic insecticides. Deltamethrin, as one of the pyrethroids, has high insecticidal activity against pests and parasites and is less toxic to mammals, and is widely used in cities and urban areas worldwide. After entering the natural environment, deltamethrin circulates between solid, liquid and gas phases and enters organisms through the food chain, posing significant health risks. Increasing evidence has shown that deltamethrin has varying degrees of toxicity to a variety of organisms. This review summarized worldwide studies of deltamethrin residues in different media and found that deltamethrin is widely detected in a range of environments (including soil, water, sediment, and air) and organisms. In addition, the metabolism of deltamethrin, including metabolites and enzymes, was discussed. This review shed the mechanism of toxicity of deltamethrin and its metabolites, including neurotoxicity, immunotoxicity, endocrine disruption toxicity, reproductive toxicity, hepatorenal toxicity. This review is aim to provide reference for the ecological security and human health risk assessment of deltamethrin.
Topics: Pyrethrins; Nitriles; Insecticides; Humans; Animals; Pesticide Residues; Risk Assessment; Environmental Pollutants
PubMed: 38954040
DOI: 10.1007/s10653-024-02043-x -
Cancer Immunology, Immunotherapy : CII Jul 2024Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these...
Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4 and CD8 T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.
Topics: Animals; Mice; Vaccines, DNA; Brain Neoplasms; Immune Checkpoint Inhibitors; Humans; Programmed Cell Death 1 Receptor; Cancer Vaccines; Mice, Inbred C57BL; Female; B7-H1 Antigen; Immunotherapy; Glioblastoma; Cell Line, Tumor; Intramolecular Oxidoreductases
PubMed: 38954031
DOI: 10.1007/s00262-024-03770-x -
Supportive Care in Cancer : Official... Jul 2024Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly...
PURPOSE
Continuous lenalidomide maintenance treatment after autologous stem cell transplantation delivers improvement in progression free and overall survival among newly diagnosed multiple myeloma patients and has been the standard of care in the UK since March 2021. However, there is scant information about its impact on patients' day-to-day lives. This service evaluation aimed to qualitatively assess patients receiving lenalidomide treatment at a cancer centre in London, in order that the service might better align with needs and expectations of patients.
METHODS
We conducted 20 semi-structured interviews among myeloma patients who were on continuous lenalidomide maintenance treatment at a specialist cancer centre in London. Members of the clinical team identified potentially eligible participants to take part, and convenience sampling was used to select 10 male and 10 female patients, median age of 58 (range, 45-71). The median treatment duration was 11 months (range, 1-60 months). Participants were qualitatively interviewed following the same semi-structured interview guide, which was designed to explore patient experience and insights of lenalidomide. Reflexive thematic analysis was used for data analysis.
RESULTS
Four overarching themes were as follows: (i) lenalidomide: understanding its role and rationale; (ii) reframing the loss of a treatment-free period to a return to normal life; (iii) the reality of being on lenalidomide: balancing hopes with hurdles; (iv) gratitude and grievances: exploring mixed perceptions of care and communication. Results will be used to enhance clinical services by tailoring communication to better meet patients' preferences when making treatment decisions.
CONCLUSION
This study highlights that most patients feel gratitude for being offered continuous lenalidomide and perceive it as alleviating some fears concerning relapse. It reveals variations in side effects in different age groups; younger patients reported no/negligible side effects, whilst several older patients with comorbidities described significant symptom burden, occasionally leading to treatment discontinuation which caused distress at the perceived loss of prolonged remission. Future research should prioritise understanding the unique needs of younger patients living with multiple myeloma.
Topics: Humans; Multiple Myeloma; Lenalidomide; Male; Female; Middle Aged; Aged; Qualitative Research; London; Maintenance Chemotherapy; Interviews as Topic; Quality of Life; Transplantation, Autologous; Antineoplastic Agents
PubMed: 38954025
DOI: 10.1007/s00520-024-08663-4 -
Cancer Immunology, Immunotherapy : CII Jul 2024Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are... (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized phase II clinical trial of stereotactic body radiation therapy (SBRT) and systemic pembrolizumab with or without intratumoral avelumab/ipilimumab plus CD1c (BDCA-1)/CD141 (BDCA-3) myeloid dendritic cells in solid tumors.
BACKGROUND
Radiotherapy (RT) synergizes with immune checkpoint blockade (ICB). CD1c(BDCA-1)/CD141(BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment are indispensable at initiating effector T-cell responses and response to ICB.
METHODS
In this phase II clinical trial, anti-PD-1 ICB pretreated oligometastatic patients (tumor agnostic) underwent a leukapheresis followed by isolation of CD1c(BDCA-1)/CD141(BDCA-3) myDC. Following hypofractionated stereotactic body RT (3 × 8 Gy), patients were randomized (3:1). Respectively, in arm A (immediate treatment), intratumoral (IT) ipilimumab (10 mg) and avelumab (40 mg) combined with intravenous (IV) pembrolizumab (200 mg) were administered followed by IT injection of myDC; subsequently, IV pembrolizumab and IT ipilimumab/avelumab were continued (q3W). In arm B (contemporary control arm), patients received IV pembrolizumab, with possibility to cross-over at progression. Primary endpoint was 1-year progression-free survival rate (PFS). Secondary endpoints were safety, feasibility, objective response rate, PFS, and overall survival (OS).
RESULTS
Thirteen patients (10 in arm A, eight non-small cell lung cancer, and five melanoma) were enrolled. Two patients crossed over. One-year PFS rate was 10% in arm A and 0% in arm B. Two patients in arm A obtained a partial response, and one patient obtained a stable disease as best response. In arm B, one patient obtained a SD. Median PFS and OS were 21.8 weeks (arm A) versus 24.9 (arm B), and 62.7 versus 57.9 weeks, respectively. An iatrogenic pneumothorax was the only grade 3 treatment-related adverse event.
CONCLUSION
SBRT and pembrolizumab with or without IT avelumab/ipilimumab and IT myDC in oligometastatic patients are safe and feasible with a clinically meaningful tumor response rate. However, the study failed to reach its primary endpoint.
TRIAL REGISTRATION NUMBER
Clinicaltrials.gov: NCT04571632 (09 AUG 2020).
EUDRACT
2019-003668-32. Date of registration: 17 DEC 2019, amendment 1: 6 MAR 2021, amendment 2: 4 FEB 2022.
Topics: Humans; Antibodies, Monoclonal, Humanized; Female; Male; Aged; Middle Aged; Radiosurgery; Dendritic Cells; Ipilimumab; Adult; Antineoplastic Combined Chemotherapy Protocols; Neoplasms; Thrombomodulin; Aged, 80 and over; Combined Modality Therapy; Myeloid Cells; Glycoproteins; Antigens, CD1
PubMed: 38954010
DOI: 10.1007/s00262-024-03751-0 -
Cancer Immunology, Immunotherapy : CII Jul 2024Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of...
BACKGROUND
Although nivolumab prolongs overall survival (OS) in pretreated patients with metastatic renal cell carcinoma (mRCC), underlining clinical and biological features of long-term responses are still to be determined. This study aims to investigate clinical and pathological characteristics of mRCC patients who achieved long-term responses during nivolumab treatment.
MATERIALS AND METHODS
A retrospective analysis was performed on mRCC patients receiving nivolumab as second or further therapy line between May 2016 and January 2019 in 34 Italian Oncology Centres. Outcome assessments and logistic regression were performed to evaluate factors influencing long-term responses.
RESULTS
A total of 571 patients with a median age of 61 years (range 17-85) were included in the analysis. With a median follow-up of 22.1 (1.0-89.0) months, 23.1% of patients were 2-year progression-free on treatment with nivolumab, hence they were categorized as long-term responders. Baseline characteristics, including age, gender, and histology, were similar between long- and short-term responders. Karnofsky Performance Status ≥ 80% was significantly associated with long-term response (p = 0.02), while bone metastases (p = 0.03), International mRCC Database Consortium intermediate-poor risk (p < 0.01) and Neutrophil-to-Lymphocyte Ratio ≥ 3.2 (p = 0.02) were associate with short-term responses. Long-term responders exhibited a median progression-free survival of 55.0 months versus 4.0 months of the short-term responders. The median OS was not reached in long-term responders while it was 17.0 months for short*term responders.
CONCLUSION
This retrospective analysis sheds light on factors associated with long-term response to nivolumab in mRCC. Understanding these clinical features will be essential for selecting patients who may mostly benefit from immunotherapy.
Topics: Humans; Nivolumab; Carcinoma, Renal Cell; Female; Male; Middle Aged; Aged; Adult; Kidney Neoplasms; Retrospective Studies; Aged, 80 and over; Young Adult; Adolescent; Antineoplastic Agents, Immunological; Follow-Up Studies
PubMed: 38954006
DOI: 10.1007/s00262-024-03741-2 -
Cancer Immunology, Immunotherapy : CII Jul 2024In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in...
In addition to their immunosuppressive effect, cytostatics conditioning prior to adoptive therapy such as chimeric antigen receptor (CAR) T cells may play a role in debulking and remodeling the tumor microenvironment. We investigated in vitro the killing efficacy and impact of treosulfan and fludarabine on ovarian cancer cells expressing mesothelin (MSLN) and effect on MSLN-targeting CAR T cells. Treosulfan and fludarabine had a synergetic effect on killing of SKOV3 and OVCAR4 cells. Sensitivity to the combination of treosulfan and fludarabine was increased when SKOV3 cells expressed MSLN and when OVCAR4 cells were tested in hypoxia, while MSLN cells surface expression by SKOV3 and OVCAR4 cells was not altered after treosulfan or fludarabine exposure. Exposure to treosulfan or fludarabine (10 µM) neither impacted MSLN-CAR T cells degranulation, cytokines production upon challenge with MSLN + OVCAR3 cells, nor induced mitochondrial defects. Combination of treosulfan and fludarabine decreased MSLN-CAR T cells anti-tumor killing in normoxia but not hypoxia. In conclusion, treosulfan and fludarabine killed MSLN + ovarian cancer cells without altering MSLN-CAR T cells functions (at low cytostatics concentration) even in hypoxic conditions, and our data support the use of treosulfan and fludarabine as conditioning drugs prior to MSLN-CAR T cell therapy.
Topics: Vidarabine; Humans; Female; Mesothelin; Ovarian Neoplasms; Receptors, Chimeric Antigen; GPI-Linked Proteins; Busulfan; Immunotherapy, Adoptive; Cell Line, Tumor; T-Lymphocytes; Tumor Microenvironment
PubMed: 38954005
DOI: 10.1007/s00262-024-03740-3 -
Cancer Immunology, Immunotherapy : CII Jul 2024Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a "hot tumor" which...
Tumor immunotherapies targeting PD-(L)1 exhibit anti-tumor efficacy in only 10-30% of patients with various cancers. Literature has demonstrated that a "hot tumor" which contains high T lymphocytes in the tumor microenvironment exhibits a better response to immunotherapies than a "cold tumor." This study aimed to investigate whether tumor-intrinsic IFNα and CXCL10 determine the recruitment and activation of CD8 T cells to become "hot tumor." In this study, we found that CXCL10 overexpressed in a variety of tumors including lung, colon, and liver tumors with a correlation with PD-L1. High PD-L1 and CXCL10 are associated with better survival rates in tumor patients receiving immunotherapies. IFNs-downstream transcriptional factor IRF-1 and STAT1 were correlated with PD-L1 and CXCL10 expression. We demonstrated that IRF-1 and STAT1 were both bound with the promoters of PD-L1 and CXCL10, sharing the same signaling pathway and determining IFNs-mediated PD-L1 and CXCL10 expression. In addition, IFNα significantly increased activation marker IFNγ in PBMCs, promoting M1 type monocyte differentiation, CD4 T, and CD8 T cell activation. Particularly, we found that CD8 T lymphocytes abundantly expressed CXCR3, a receptor of CXCL10, by flow cytometry, indicating that tumor-intrinsic CXCL10 potentially recruited CD8 T in tumor microenvironment. To demonstrate the hypothesis, immunotherapy-sensitive CT26 and immunotherapy-resistant LL/2 were used and we found that CT26 cells exhibited higher IFNα, IFNγ, CXCL10, and PD-L1 levels compared to LL/2, leading to higher IFNγ expression in mouse splenocytes. Moreover, we found that CD8 T cells were recruited by CXCL10 in vitro, whereas SCH546738, an inhibitor of CXCR3, inhibited T cell migration and splenocytes-mediated anti-tumor effect. We then confirmed that CT26-derived tumor was sensitive to αPD-L1 immunotherapy and LL/2-tumor was resistant, whereas αPD-L1 significantly increased T lymphocyte activation marker CD107a in CT26-derived BALB/c mice. In conclusion, this study revealed that CXCL10 expression is correlated with PD-L1 in tumors, sharing the same signaling pathway and associating with better immunotherapeutic efficacy. Further evidence in the syngeneic tumor models demonstrated that immunotherapy-sensitive CT26 intrinsically exhibited higher IFNα and CXCL10 compared to immunotherapy-resistant LL/2 to recruit and activate CD8 T cells in the tumor microenvironment, exhibiting "hot tumor" characteristic of sensitizing αPD-L1 immunotherapies.
Topics: Chemokine CXCL10; Tumor Microenvironment; Animals; Mice; Humans; Interferon-alpha; Immunotherapy; Neoplasms; Lymphocyte Activation; Cell Line, Tumor; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Female; STAT1 Transcription Factor
PubMed: 38953994
DOI: 10.1007/s00262-024-03761-y -
Cancer Immunology, Immunotherapy : CII Jul 2024To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed. (Meta-Analysis)
Meta-Analysis Review
PURPOSE
To compare the risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors, the meta-analysis was designed.
METHOD
The difference in risk of immune-associated pneumonitis between PD-1 and PD-L1 inhibitors was assessed by two different meta-analysis methods, the Mirror-pairing and the PRISMA guidelines.
RESULTS
A total of eighty-eight reports were used for meta-analysis, while thirty-two studies were used for the Mirror-pairing. Both PD-1 and PD-L1 inhibitors (used alone or combined with chemotherapy) increased the risk of developing immune-related pneumonitis (P < 0.00001; P < 0.00001). Based on indirect analyses results (subgroup analyses), the risk of PD-L1-induced pneumonitis was weaker than that of PD-1 inhibitors when the control group was chemotherapy (OR = 3.33 vs. 5.43) or placebo (OR = 2.53 vs. 3.19), while no obvious significant differences were found (P = 0.17; P = 0.53). For the Mirror-pairing-based meta-analysis, the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors (OR = 1.46, 95%CI [1.08, 1.98], I = 0%, Z = 2.47 (P = 0.01)). However, this difference was not significant, when they were combined with chemotherapy (OR = 1.05, 95%CI [0.68, 1.60], I = 38%, Z = 0.21 (P = 0.84)).
CONCLUSION
Both PD-1 and PD-L1 inhibitors increased the risk of immune-related pneumonitis, while the risk of PD-1-induced pneumonitis was significantly higher than that of PD-L1 inhibitors.
Topics: Humans; Pneumonia; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; B7-H1 Antigen; Neoplasms
PubMed: 38953977
DOI: 10.1007/s00262-024-03736-z -
Naunyn-Schmiedeberg's Archives of... Jul 2024Triple negative breast cancer is considered to be a malignancy of grave concern with limited routes of treatment due to the absence of specific breast cancer markers and... (Review)
Review
Triple negative breast cancer is considered to be a malignancy of grave concern with limited routes of treatment due to the absence of specific breast cancer markers and ambiguity of other potential drug targets. Poor prognosis and inadequate survival rates have prompted further research into the understanding of the molecular pathophysiology and targeting of the disease. To overcome the recurrence and resistance mechanisms of the TNBC cells, various approaches have been devised, and are being continuously evaluated to enhance their efficacy and safety. Chemo-Adjuvant therapy is one such treatment modality being employed to improve the efficiency of standard chemotherapy. Combining chemo-adjuvant therapy with other upcoming approaches of cancer therapeutics such as phytoconstituents and nanotechnology has yielded promising results in the direction of improving the prognosis of TNBC. Numerous nanoformulations have been proven to substantially enhance the specificity and cellular uptake of drugs by cancer cells, thus reducing the possibility of unintended systemic side effects within cancer patients. While phytoconstituents offer a wide variety of beneficial active constituents useful in cancer therapeutics, most favorable outcomes have been observed within the scope of polyphenols, isoquinoline alkaloids and isothiocyanates. With an enhanced understanding of the molecular mechanisms of TNBC and the advent of newer targeting technologies and novel phytochemicals of medicinal importance, a new era of cancer theranostic treatments can be explored. This review hopes to instantiate the current body of research regarding the role of certain phytoconstituents and their potential nanoformulations in targeting specific TNBC pathways for treatment and diagnostic purposes.
PubMed: 38953968
DOI: 10.1007/s00210-024-03234-0 -
Microbial Biotechnology Jul 2024Porcine epidemic diarrhoea virus (PEDV) infects pigs of all ages by invading small intestine, causing acute diarrhoea, vomiting, and dehydration with high morbidity and...
Porcine epidemic diarrhoea virus (PEDV) infects pigs of all ages by invading small intestine, causing acute diarrhoea, vomiting, and dehydration with high morbidity and mortality among newborn piglets. However, current PEDV vaccines are not effective to protect the pigs from field epidemic strains because of poor mucosal immune response and strain variation. Therefore, it is indispensable to develop a novel oral vaccine based on epidemic strains. Bacillus subtilis spores are attractive delivery vehicles for oral vaccination on account of the safety, high stability, and low cost. In this study, a chimeric gene CotC-Linker-COE (CLE), comprising of the B. subtilis spore coat gene cotC fused to the core neutralizing epitope CO-26 K equivalent (COE) of the epidemic strain PEDV-AJ1102 spike protein gene, was constructed. Then recombinant B. subtilis displaying the CLE on the spore surface was developed by homologous recombination. Mice were immunized by oral route with B. subtilis 168-CLE, B. subtilis 168, or phosphate-buffered saline (PBS) as control. Results showed that the IgG antibodies and cytokine (IL-4, IFN-γ) levels in the B. subtilis 168-CLE group were significantly higher than the control groups. This study demonstrates that B. subtilis 168-CLE can generate specific systemic immune and mucosal immune responses and is a potential vaccine candidate against PEDV infection.
Topics: Porcine epidemic diarrhea virus; Animals; Bacillus subtilis; Spores, Bacterial; Mice; Antibodies, Viral; Swine; Viral Vaccines; Coronavirus Infections; Swine Diseases; Antigens, Viral; Administration, Oral; Cytokines; Immunoglobulin G; Mice, Inbred BALB C; Female; Cell Surface Display Techniques; Spike Glycoprotein, Coronavirus
PubMed: 38953907
DOI: 10.1111/1751-7915.14518