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International Journal of Molecular... May 2024Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8)...
Tumor recurrence and drug resistance are responsible for poor prognosis in colorectal cancer (CRC). DNA mismatch repair (MMR) deficiency or elevated interleukin-8 (IL-8) levels are characteristics of CRCs, which have been independently correlated with treatment resistance to common therapies. We recently demonstrated significantly impaired therapeutical response and increased IL-8 release of CRC cell lines with reduced expression of MMR protein MLH1 as well as cytoskeletal non-erythrocytic spectrin alpha II (SPTAN1). In the present study, decreased intratumoral MLH1 and SPTAN1 expression in CRCs could be significantly correlated with enhanced serum IL-8. Furthermore, using stably reduced SPTAN1-expressing SW480, SW620 or HT-29 cell lines, the RASmediated RAFMEKERK pathway was analyzed. Here, a close connection between low SPTAN1 expression, increased IL-8 secretion, enhanced extracellular-signal-regulated kinase (ERK) phosphorylation and a mesenchymal phenotype were detected. The inhibition of ERK by U0126 led to a significant reduction in IL-8 secretion, and the combination therapy of U0126 with FOLFOX optimizes the response of corresponding cancer cell lines. Therefore, we hypothesize that the combination therapy of FOLFOX and U0126 may have great potential to improve drug efficacy on this subgroup of CRCs, showing decreased MLH1 and SPTAN1 accompanied with high serum IL-8 in affected patients.
Topics: Humans; Colorectal Neoplasms; Interleukin-8; Fluorouracil; Butadienes; Nitriles; Cell Line, Tumor; Organoplatinum Compounds; Leucovorin; Antineoplastic Combined Chemotherapy Protocols; Female; Male; Extracellular Signal-Regulated MAP Kinases; HT29 Cells; MAP Kinase Signaling System; MutL Protein Homolog 1; Middle Aged; Aged; Gene Expression Regulation, Neoplastic; Phosphorylation
PubMed: 38891846
DOI: 10.3390/ijms25115658 -
International Journal of Molecular... May 2024FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory...
FOLFOXIRI chemotherapy is a first-line therapy for advanced or metastatic colorectal cancer (CRC), yet its therapeutic efficacy remains limited. Immunostimulatory therapies like oncolytic viruses can complement chemotherapies by fostering the infiltration of the tumor by immune cells and enhancing drug cytotoxicity. In this study, we explored the effect of combining the FOLFOXIRI chemotherapeutic agents with the oncolytic coxsackievirus B3 (CVB3) PD-H in the CRC cell line Colo320. Additionally, we examined the impact of the drugs on the expression of microRNAs (miRs), which could be used to increase the safety of oncolytic CVB3 containing corresponding miR target sites (miR-TS). The measurement of cytotoxic activity using the Chou-Talalay combination index approach revealed that PD-H synergistically enhanced the cytotoxic activity of oxaliplatin (OX), 5-fluorouracil (5-FU) and SN-38. PD-H replication was not affected by OX and SN-38 but inhibited by high concentrations of 5-FU. MiR expression levels were not or only slightly elevated by the drugs or with drug/PD-H combinations on Colo320 cells. Moreover, the drug treatment did not increase the mutation rate of the miR-TS inserted into the PD-H genome. The results demonstrate that the combination of FOLFOXIRI drugs and PD-H may be a promising approach to enhance the therapeutic effect of FOLFOXIRI therapy in CRC.
Topics: Humans; Colorectal Neoplasms; Cell Line, Tumor; Fluorouracil; Oncolytic Virotherapy; MicroRNAs; Oncolytic Viruses; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Organoplatinum Compounds; Oxaliplatin; Enterovirus B, Human; Combined Modality Therapy; Irinotecan
PubMed: 38891807
DOI: 10.3390/ijms25115618 -
Proceedings. Biological Sciences Jun 2024Gene drive alleles that can bias their own inheritance could engineer populations for control of disease vectors, invasive species and agricultural pests. There are...
Gene drive alleles that can bias their own inheritance could engineer populations for control of disease vectors, invasive species and agricultural pests. There are successful examples of suppression drives and confined modification drives, but developing confined suppression drives has proven more difficult. However, CRISPR-based toxin-antidote dominant embryo (TADE) suppression drive may fill this niche. It works by targeting and disrupting a haplolethal target gene in the germline with its gRNAs while rescuing this target. It also disrupts a female fertility gene by driving insertion or additional gRNAs. Here, we used a reaction-diffusion model to assess drive performance in continuous space, where outcomes can be substantially different from those in panmictic populations. We measured drive wave speed and found that moderate fitness costs or target gene disruption in the early embryo from maternally deposited nuclease can eliminate the drive's ability to form a wave of advance. We assessed the required release size, and finally we investigated migration corridor scenarios. It is often possible for the drive to suppress one population and then persist in the corridor without invading the second population, a potentially desirable outcome. Thus, even imperfect variants of TADE suppression drive may be excellent candidates for confined population suppression.
Topics: Gene Drive Technology; Animals; CRISPR-Cas Systems; Models, Genetic; Clustered Regularly Interspaced Short Palindromic Repeats
PubMed: 38889790
DOI: 10.1098/rspb.2024.0500 -
Cancer Medicine Jun 2024Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to...
BACKGROUND
Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies.
METHODS
In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics.
RESULTS
By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively).
CONCLUSIONS
Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
Topics: Humans; Male; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged; Colorectal Neoplasms; Fluorouracil; Immune Checkpoint Inhibitors; Pilot Projects; Bevacizumab; Antibodies, Monoclonal, Humanized; Leucovorin; DNA Mismatch Repair; Adult; Microsatellite Instability; Oxaliplatin; Neoadjuvant Therapy; Tumor Microenvironment; Organoplatinum Compounds; Programmed Cell Death 1 Receptor; Treatment Outcome
PubMed: 38888366
DOI: 10.1002/cam4.7224 -
PeerJ 2024Biochar is increasingly gaining popularity due to its extensive recommendation as a potential solution for addressing the concerns of food security and climate change in...
Biochar is increasingly gaining popularity due to its extensive recommendation as a potential solution for addressing the concerns of food security and climate change in agroecosystems, with biochar application for increased carbon sequestration, enhanced soil fertility, improved soil health, and increased crop yield and quality. There have been multiple studies on crop yield utilizing various biochar types and application amounts; however, none have focused on the influence of diverse biochar types at various pyrolysis temperatures with different application amounts and the integration of fertilizer regimes in maize crops. Therefore, a two-year factorial field experiment was designed in a temperate Himalayan region of India (THRI) to evaluate the residual effect of different biochar on maize yield under different pyrolysis temperatures, various application rates and fertilizer regimes. The study included three factors , amendment type (factor 1), rate of application (factor 2) and fertilizer regime (factor 3). Amendment type included 7 treatments: No biochar- control (A1), apple biochar @ 400 °C pyrolysis temperature (A2), apple biochar @ 600 °C pyrolysis temperature (A3), apple residue biomass (A4), dal weed biochar @ 400 °C pyrolysis temperature (A5), dal weed biochar @ 600 °C pyrolysis temperatures (A6), and dal weed residue biomass (A7). The rate of application included 3 levels: Low (L- 1 t ha), medium (M- 2 t ha), and high (H- 3 t ha). At the same time, the fertilizer regimes included 2 treatments: No fertilizer (N) and recommended dose of fertilizer (F). The results revealed that among the various amendment type, rate of application and fertilizer regimes, the A3 amendment, H rate of application and F fertilizer regime gave the best maize growth and productivity outcome. Results revealed that among the different pyrolyzed residues used, the A3 amendment had the highest plant height (293.87 cm), most kernels cob (535.75), highest soil plant analysis development (SPAD) value (58.10), greatest cob length (27.36 cm), maximum cob girth (18.18 cm), highest grain cob yield (1.40 Mg ha), highest grain yield (4.78 Mg ha), higher test weight (305.42 gm), and highest stover yield (2.50 Mg ha). The maximum dry weight in maize and the number of cobs plant were recorded with amendments A4 (14.11 Mg ha) and A6 (1.77), respectively. The comparatively 2 year of biochar application than the 1 year, the H level of the rate of application than the L rate and the application and integration of the recommended dose of fertilizer in maize results in significantly higher values of growth and productivity in maize. Overall, these findings suggest that the apple biochar @ 600 °C pyrolysis temperature (A3) at a high application rate with the addition of the recommended dose of fertilizer is the optimal biochar for enhancing the growth and productivity of maize in the THRI.
Topics: Fertilizers; Zea mays; Charcoal; India; Pyrolysis; Soil; Biomass; Crops, Agricultural
PubMed: 38887617
DOI: 10.7717/peerj.17513 -
Nature Plants Jun 2024Synthetic gene drives, inspired by natural selfish genetic elements and transmitted to progeny at super-Mendelian (>50%) frequencies, present transformative potential...
Synthetic gene drives, inspired by natural selfish genetic elements and transmitted to progeny at super-Mendelian (>50%) frequencies, present transformative potential for disseminating traits that benefit humans throughout wild populations, even facing potential fitness costs. Here we constructed a gene drive system in plants called CRISPR-Assisted Inheritance utilizing NPG1 (CAIN), which uses a toxin-antidote mechanism in the male germline to override Mendelian inheritance. Specifically, a guide RNA-Cas9 cassette targets the essential No Pollen Germination 1 (NPG1) gene, serving as the toxin to block pollen germination. A recoded, CRISPR-resistant copy of NPG1 serves as the antidote, providing rescue only in pollen cells that carry the drive. To limit potential consequences of inadvertent release, we used self-pollinating Arabidopsis thaliana as a model. The drive demonstrated a robust 88-99% transmission rate over two successive generations, producing minimal resistance alleles that are unlikely to inhibit drive spread. Our study provides a strong basis for rapid genetic modification or suppression of outcrossing plant populations.
Topics: Arabidopsis; Pollen; CRISPR-Cas Systems; Germination; Arabidopsis Proteins; Plants, Genetically Modified; Gene Editing
PubMed: 38886523
DOI: 10.1038/s41477-024-01692-1 -
Scientific Reports Jun 2024Rice straw breakdown is sluggish, which makes agricultural waste management difficult, however pretreatment procedures and cellulolytic fungi can address this issue....
Rice straw breakdown is sluggish, which makes agricultural waste management difficult, however pretreatment procedures and cellulolytic fungi can address this issue. Through ITS sequencing, Chaetomium globosum C1, Aspergillus sp. F2, and Ascomycota sp. SM2 were identified from diverse sources. Ascomycota sp. SM2 exhibited the highest carboxymethyl cellulase (CMCase) activity (0.86 IU/mL) and filter-paper cellulase (FPase) activity (1.054 FPU/mL), while Aspergillus sp. F2 showed the highest CMCase activity (0.185 IU/mL) after various pretreatments of rice straw. These fungi thrived across a wide pH range, with Ascomycota sp. SM2 from pH 4 to 9, Aspergillus sp. F2, and Chaetomium globosum C1 thriving in alkaline conditions (pH 9). FTIR spectroscopy revealed significant structural changes in rice straw after enzymatic hydrolysis and solid-state fermentation, indicating lignin, cellulose, and hemicellulose degradation. Soil amendments with pretreated rice straw, cow manure, biochar, and these fungi increased root growth and soil nutrient availability, even under severe salt stress (up to 9.3 dS/m). The study emphasizes the need for a better understanding of Ascomycota sp. degradation capabilities and proposes that using cellulolytic fungus and pretreatment rice straw into soil amendments could mitigate salt-related difficulties and improve nutrient availability in salty soils.
Topics: Oryza; Soil; Cellulase; Salt Stress; Soil Microbiology; Cellulose; Chaetomium; Aspergillus; Hydrolysis; Hydrogen-Ion Concentration; Ascomycota; Fermentation; Manure; Charcoal
PubMed: 38886460
DOI: 10.1038/s41598-024-64705-1 -
Scientific Reports Jun 2024Co-pyrolysis of chicken manure with tree bark was investigated to mitigate salinity and potentially toxic element (PTE) concentrations of chicken manure-derived biochar....
Co-pyrolysis of chicken manure with tree bark was investigated to mitigate salinity and potentially toxic element (PTE) concentrations of chicken manure-derived biochar. The effect of tree bark addition (0, 25, 50, 75 and 100 wt%) on the biochar composition, surface functional groups, PTEs and polycyclic aromatic hydrocarbons (PAH) concentration in the biochar was evaluated. Biochar-induced toxicity was assessed using an in-house plant growth assay with Arabidopsis thaliana. This study shows that PTE concentrations can be controlled through co-pyrolysis. More than 50 wt% of tree bark must be added to chicken manure to reduce the concentrations below the European Biochar Certificate-AGRO (EBC-AGRO) threshold. However, the amount of PAH does not show a trend with tree bark addition. Furthermore, co-pyrolysis biochar promotes plant growth at different application concentrations, whereas pure application of 100 wt% tree bark or chicken manure biochar results in decreased growth compared to the reference. In addition, increased plant stress was observed for 100 wt% chicken manure biochar. These data indicate that co-pyrolysis of chicken manure and tree bark produces EBC-AGRO-compliant biochar with the potential to stimulate plant growth. Further studies need to assess the effect of these biochars in long-term growth experiments.
Topics: Animals; Manure; Charcoal; Chickens; Plant Bark; Arabidopsis; Pyrolysis; Polycyclic Aromatic Hydrocarbons
PubMed: 38886397
DOI: 10.1038/s41598-024-62468-3 -
Toxicology Research Jun 2024Aluminum phosphide (ALP) is a highly toxic rodenticide and the mortality rates caused by it have been demonstrated up to 70-100% in various studies. Unfortunately, there...
INTRODUCTION
Aluminum phosphide (ALP) is a highly toxic rodenticide and the mortality rates caused by it have been demonstrated up to 70-100% in various studies. Unfortunately, there is no specific antidote to manage its toxic effects. This study aimed to assess the biochemical and clinical efficacy and safety of intravenous lipid emulsion as an adjuvant therapy in acute aluminum phosphide poisoning.
PATIENTS AND METHODS
Sixty-four cases with acute ALP poisoning were stratified according to severity by the Poison Severity Score into severe and moderate groups (32 patients each). Patients were then randomly allocated into either receiving intravenous lipid emulsion in addition to the conventional treatment or receiving the conventional treatment only by using block randomization.
RESULTS
Treatment by ILE resulted in a significant improvement in the survival time, the mean arterial blood pressure, arterial blood gases, and a significant reduction in serum lactate levels. The need for intubation and mechanical ventilation was insignificantly lower in the intervention groups compared to control groups. However, the reduction in mortality rate in the patients of intervention groups compared with control groups was found to be non-significant. Intravenous lipid emulsion use in acute ALP poisoning significantly prolonged the survival time, improved the metabolic acidosis, decreased the serum lactate levels and increased the mean arterial blood pressure and hospital stay in the intervention groups. And insignificantly decreased the mortality rate, need of intubation and mechanical ventilation, and the total dose of vasopressors.
PubMed: 38883412
DOI: 10.1093/toxres/tfae090 -
Gan To Kagaku Ryoho. Cancer &... May 2024A 74-year-old man underwent laparoscopic-assisted high anterior resection with D3 lymph node dissection for rectal cancer, which was simultaneously accompanied by...
A 74-year-old man underwent laparoscopic-assisted high anterior resection with D3 lymph node dissection for rectal cancer, which was simultaneously accompanied by multiple liver metastases. The patient received mFOLFOX6 therapy for liver metastases 1 month after the surgery. Anorexia, nausea, and vomiting appeared on the second day of treatment. On the third day of treatment, impaired consciousness(JCS Ⅱ-20)and flapping tremors appeared. Blood tests revealed hyperammonemia, and the patient was diagnosed with impaired consciousness due to hyperammonemia, which was inferred to be caused by 5-fluorouracil(5-FU). Intravenous infusion and branched-chain amino acids were administered, and the patient recovered. The underlying disease of renal dysfunction, constipation, and dehydration due to chemotherapy might have induced the hyperammonemia. It is important to note that hyperammonemia can lead to a disturbance of consciousness during chemotherapy including 5-FU.
Topics: Humans; Hyperammonemia; Male; Fluorouracil; Aged; Rectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Leucovorin; Organoplatinum Compounds; Liver Neoplasms; Consciousness Disorders
PubMed: 38881070
DOI: No ID Found