Digestive Toxicity Research Articles

Efficacy of Melia azedarach leaf extract in different solvents against Heterotermes indicola Wasmann (Blattodea: Rhinotermitidae) using non-durable wooden blocks under laboratory and field conditions

Hetertermes indicola Wasman (Blattodea: Rhinotermitidae) is a highly wood-destructive termite species in the urban settings of Pakistan. This study evaluated the biocidal action of Melia azedarach leaf extract in different solvents on H. indicola by conducting choice and no-choice feeding deterrence assays using impregnated palatable wood under field and laboratory conditions. Dose-dependent and time-dependent trends were observed in the leaf extracts of M. azedarach at different concentrations (500, 1000, and 1500 ppm) using solvent water and methanol with 80–100 % termite mortality after 6 days of exposure. A key outcome was the higher termiticidal efficacy of methanolic extract compared to aqueous extract under both field and laboratory conditions. The LC50 values of 358 ppm for methanol and 466 ppm for aqueous extract after 15 days in a laboratory no-choice experiment exhibit a quantitative measure of chinaberry leaf extract toxicity. A significant reduction in mean percent weight loss (8.26 %) of treated wood with 1500 ppm of M. azedarach leaf extract in methanol was observed under field conditions. In conclusion, triterpenoids and phytol present in methanolic leaf extract demonstrated higher efficacy in both lab and field conditions making a solid foundation for the further development of natural wood preservatives. Since they induced rapid lethargic conditions in termites and digestive toxicity which leads to minimum loss of treated wood.

Effect of a Novel Food Rich in Miraculin on the Oral Microbiome of Malnourished Oncologic Patients with Dysgeusia

Background/Objectives: Dysgeusia contributes to the derangement of nutritional status in patients with cancer as well as worsening the quality of life. There has been a lack of effective treatments for taste disorders provided by the pharmaceutical industry. Methods: This was a pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB or placebo tablet before each main meal. Using the nanopore methodology, we analyzed the oral microbiome of patients with cancer using saliva samples. Results: All patients with cancer and dysgeusia had dysbiosis in terms of lower bacterial diversity and richness. DMB consumption was associated with changes in oral microbiome composition. Neither selected bacteria nor taste perception, type of diet, and cytokine levels were associated with mucositis. Likewise, alcohol and tobacco consumption as well as general and digestive toxicity due to systemic therapy were not associated with specific changes of the oral microbiome, according to logistic binary regression. The standard dose of DMB resulted in a lower abundance of Veillonella compared with the high DMB dose and placebo at 3 months after intervention with DMB. In particular, some species such as Streptococcus parasanguinis, Veillonella parvula, and Streptococcus mutans were less abundant in the DMB standard-dose group. Additionally, the consumption of a standard dose of DMB revealed a negative association between the concentrations of TNF-α and the abundance of species such as Streptococcus thermophilus, Streptococcus pneumoniae, Streptococcus dysgalactiae and Streptococcus agalactiae. Conclusions: Accordingly, regular DMB consumption could modify the oral microbiome in patients with cancer and dysgeusia, which may contribute to maintaining an appropriate immune response. However, as the present pilot study involved a small number of participants, further studies are necessary to draw robust conclusions from the data.

Tolérance à court et moyen terme d’une radiothérapie prostatique hypofractionnée selon la technique du boost intégré

PurposeThis retrospective study was conducted to ensure that irradiation of the pelvic lymph node areas associated with simultaneous hypofractionated boost to the prostate according to the protocol implemented at the university hospital of Tours (France) does not result in excess urinary and digestive toxicity in the short and medium term. Materials and methodsThe study population included patients with localized unfavourable intermediate or high-risk prostate cancer. The dose delivered was 65Gy in 25 fractions of 2.6Gy to the prostate and seminal vesicles, and 50Gy in 25 fractions of 2Gy to the pelvic lymph nodes. Acute toxicity events (between the start of radiotherapy and the first follow-up consultation) and medium-term toxicity events (after the first follow-up consultation) were assessed using the CTCAE version 5.0 classification. ResultsSixty-three patients were treated according to the protocol between January 1st, 2020, and October 31st, 2022. The majority of them had high-risk prostate cancer (79%). The median follow-up was 15 months. Very few patients reported grade 3–4 toxicity acutely (6% urinary and 0% digestive toxicity) or in the medium term (7% urinary and 0% and digestive toxicity). ConclusionRadiotherapy of pelvic lymph node areas with simultaneous hypofractionated boost to the prostate is feasible, with low rates of severe acute and medium-term toxicity.

Development of cantharidin/baicalin co-delivery system based on mitochondrial targeting strategy for enhanced hepatocellular carcinoma therapy

Cantharidin (CTD) as a treatment for primary liver cancer are well known, and although structural alteration and nano-delivery are efficient in diminishing toxicity, its urinary and digestive toxicity has hindered its clinical application. Based on the synergistic effect of CTD and baicalin (BA) on proliferation inhibition of liver tumor cells, the highly expressed folic acid (FA) receptor of liver cancer cell membrane and the high negative membrane potential of tumor cell mitochondria, we synthesized CHEMS-FRFK and prepared a dual-ligand modified co-delivery liposomes (FA/FRFK-CTD/BA-Lips). Liposomes were spherical particles with uniform particle size, high encapsulation rate, good stability and no hemolysis. The results confirmed that FA/FRFK-CTD/BA-Lips had good targeting to mitochondria of tumor cells, and its target effect on mitochondria of HepG2 was better than that of Huh-7 cells. Compared with CTD, the cytotoxicity of liposomes on HepG2 is 7.0 times higher, while the cytotoxic effect on normal liver cells Thle-2 is 2.1 times lower. It may be related to increasing clathrin-mediated endocytosis, inhibiting tumor cell migration, arresting cell cycle in G1/G0 phase, and promoting mitochondria-mediated endogenous Bcl-2/Caspase 3 apoptosis pathway. Meanwhile, FA/FRFK-CTD/BA-Lips could alter the pharmacokinetic behavior of CTD and BA by increasing concentrations in vivo, slowing release and excretion, good anti-tumor with no obvious toxicity, and successfully delivered CTD/BA to liver tissue, tumor cells and mitochondria. Therefore, FA/FRFK-CTD/BA-Lips, as a delivery system targeting the mitochondria of liver cancer cells, has promising development potential, and could provide a new strategy for solving the problem of CTD toxicity and the treatment of hepatocellular carcinoma.

Effectiveness and safety of pembrolizumab as first-line treatment for non-small cell lung cancer in real clinical practice.

Pembrolizumab is currently the drug for the first-line treatment of stage-IV non-small cell lung cancer. The objective of this study is to measure the effectiveness of pembrolizumab as a first-line treatment and to analyze its safety in real clinical practice. This was a retrospective study that included patients with metastatic non-small cell lung cancer who had received pembrolizumab as a first-line treatment between 1 June 2018 and 31 January 2021. Variables related to the patients, treatment, and drug's efficacy and safety were collected. A total of 50 patients were analyzed. The median real-world progression-free survival and real-world overall survival of those who received pembrolizumab in monotherapy were 10.5 months (95% CI: 2.3-18.6) and 18.9 months (95% CI: 16.9-20.8), respectively. The median real-world progression-free survival and real-world overall survival of those who received the drug with chemotherapy was 7.9 months (95% CI: 4.1-11.7) and 13.3 months (95% CI: 0.0-27), respectively. Mostly digestive (48.3%) and endocrine (41.4%) immune-related adverse events were detected among the patients who received pembrolizumab in monotherapy, whereas mostly digestive immune-related adverse events (85.7%) and hematological toxicities (71.5%) were observed in those treated with pembrolizumab plus chemotherapy. Pembrolizumab has proven its effectiveness in terms of increasing real-world progression-free survival and real-world overall survival in real clinical practice. The main adverse events were digestive toxicities with pembrolizumab in monotherapy and with chemotherapy.

Selenium alleviates pancreatic fibrosis in chickens caused by mercuric chloride: Involvement of the MAPK signaling pathway and selenoproteins

Mercuric chloride (HgCl2) is a widespread inorganic mercury with digestive toxicity. The pancreas is an important digestive organ in animals, and pancreatic fibrosis (PF) is a major pathological feature of chronic pancreatitis, which can be caused by heavy metals. Selenium (Se) is an essential trace element for the animal organism, performing biological functions in the form of selenoproteins, as well as alleviating the toxicity of heavy metals. In this study, we explored the specific mechanisms underlying the protective effect of Se on HgCl2-induced pancreatic injury in chickens. Morphological observation and serum biochemical analysis showed that Se attenuated HgCl2-caused pancreatic tissue damage and elevated glucose concentration and α-amylase activity. Next, the expression of oxidative stress indicators such as MDA and GSH-Px as well as inflammation-related markers including IL-1β, IL-6, and TNF-α were detected. Results showed that Se had an inhibitory effect on HgCl2-induced oxidative stress and inflammation. Furthermore, we found that Se alleviated HgCl2-induced PF by detecting the expression of markers related to PF including TGF-β1, α-SMA, COL1A1, and FN1. Mechanistically, Se attenuated HgCl2-induced PF via the MAPK signaling pathway. Importantly, several selenoproteins, especially those with antioxidant activity, were involved in the protective effect of Se on HgCl2 toxicity. In conclusion, our findings demonstrated that Se inhibited HgCl2-induced oxidative stress and inflammation and alleviated chicken PF through the MAPK signaling pathway, in which some antioxidant selenoproteins were involved.

Identification of markers associated with toxicity of FOLFIRINOX in patients over 70 years with digestive cancers.

e16305 Background: mFOLFIRINOX (mFFX) is a chemotherapy regimen used for gastro-intestinal (GI) cancers, in colorectal (CCR) and pancreatic cancers (PDAC) but limited by grade ≥ 3 toxicities in 50% of cases. Little data is available regarding its use in elderly patients, rarely included in phase 3 trials, although most of patients in real-life setting have median age at diagnosis > 70 y-o for both CCR and PDAC. Methods: Using the ConSore (Continuum Soins Research) software based on of medical records data mining, we identified consecutive patients > 70 y-o, treated with mFFX in Paoli-Calmettes Institute, France, from 09/2011 to 07/2022. We recorded geriatric data, adverse events (AE), and dose reduction during mFFX. We analyzed factors associated mFFX’s toxicity in elderly population with GI cancers. Results: We included 161 patients. Median age was 74 y-o [range 71-83], including 43% >75 y-o. 82% had ECOG-PS 0-1 at diagnosis. 91% had PDAC and 9% had CCR, treated for a metastatic disease in 48%. Median number of mFFX cycles was 5 [range 1-15]. G8-ONCODAGE was calculated ≤14/17 for 77%. Multidimensional geriatric assessment (MGA) was performed in 29%, but 66% without MGA had a G8 ≤14. Sarcopenia (assessed by muscle mass in L3 CT-scan) was reported in 86% and malnutrition was moderate (57%) or severe (37%). Primary dose reduction was applied to 68%, dose reduction during mFFX in 69% and 32% discontinued 1 drug during mFFX’s courses. 53% experienced a grade ≥ 3 digestive AE or unplanned hospitalization, including 3 toxic deaths. Infections (23%), diarrhea (17% G3), peripheral neuropathy (16% G3), anorexia (15% G3), thrombopenia (12% G3) and vomiting (9% G3) were the most frequent AEs.Febrile neutropenia was reported in only 4%, due to systematic use of G-CSF. Median overall survival (mOS) was 15 months (51 months for CCR, 15 months for PDAC), and was 11 months for metastatic patients and 22 months for locally advanced disease. In multivariate analysis after backward selection, factors associated with grade > II digestive toxicity and/or hospitalization were MGA for patients with G8 ≤14 (OR 0.38 [0.15; 0.92] ; p = 0.036), polypharmacy (OR 2.70 [1.07; 7.22] ; p = 0.039), psychiatric comorbidity (OR 8.38 [1.57; 75.27] , p = 0.026) and past history of another cancer (OR 0.27 [0.07; 0.92], p = 0.04). A trend was found for sarcopenia (OR 2.70 [0.79; 10.13], p = 0.12) and cardiovascular comorbidity (OR 0.43 [0.17; 1.01] p = 0.058). Conclusions: Our data reported that mFFX is toxic and associated with similar survival in a highly selected > 70y-o patients with GI cancers, compared to their youngest counterpart included in pivotal trial. However, alternative regimens/strategies should be developed to enhance efficacy and reduce AEs. Particular attention to vulnerabilities detected using G8 and managed through MGA is of importance to reduce toxicity.

Abstract PO1-08-06: Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ breast cancer?

Abstract Background: The CHEK2 gene codes for checkpoint protein Kinase 2 (CHK2), an effector in the ATM-CHK2-p53 DNA damage repair pathway in double-stranded DNA breaks. Initially, germline pathogenic variants were associated with moderate risk for breast carcinoma, but later studies linked alterations in the gene to other types of cancer. The aim of our study was to establish a clinical-molecular correlation of profiles of patients carrying pathogenic variants and variants of uncertain significance (VUS) in CHEK2 with a diagnosis of breast carcinoma, in patients treated in our hospital. And to describe whether the pathogenic variant c.1100del present different clinical or immunohistochemical characteristics than the rest, also considering the particularity of being an island population. Methodology: We have collected data from genetic studies performed in patients from our hospital, covering a population of 580,000 inhabitants, in Santa Cruz de Tenerife ( Canary Islands, Spain), between 2017 and 2023.Out of 952 patients with suspected hereditary cancer, 81 had CHEK2 mutations. In patients with CHEK2 mutations and breast cancer we established three groups for clinical molecular analysis: 1) pathogenic variant c.1100del, 2) other pathogenic variants and 3) VUS, to be correlated with age, histology, ER, PR, Ki, grade (G), HER2, second tumour or recurrence, subtype, HER2 low, aggressive clinic, neuropathy, haematological and digestive toxicity. The germline genetic study performed covered 77 genes related to hereditary cancer using the SureSelect HS library preparation kit (Agilent Technologies). The classification of the variants identified was performed according to the American College of Medical Genetics (ACMG) criteria. Results: In the 952 genetic studies performed, 8.5% of cases had CHEK2 mutations, 2.62% were related to breast carcinoma (N=26) of which 54% had the pathogenic variant “c.1100del”, 16% “other” pathogenic variants and 30% VUS. The mean age at diagnosis was 42 years, being lower than 38 years in pathogenic variants other than c.1100del. Histologically, infiltrating ductal carcinoma (85%) and mucinous carcinomas (12%), ER+ (93%), PR+ (77%), HER 2+ (31%), HER2 low (44%), G2-3 (84%) and Ki >15% (70%) were predominant. Second diagnoses were tumour or recurrence in 40%, being higher in the group of pathogenic variants other than c.1100del (50%), and showing aggressive clinical course in 26%. The predominant subtype was luminal B (50%), HER2+ (31%), luminal A (12 %) and triple negative (7%), although in the cluster analysis patients with pathogenic variant c.1100del HER2+ were higher (38%) and luminal B (38%), while in pathogenic variants other than c.1100del and VUS the luminal subtype was predominant (75%). Chemotherapy toxicity: neuropathy (35%), haematological and digestive toxicity (50%). Conclusion: Our results are consistent with other reported series, being related with all breast carcinoma subtypes, mainly luminal B and HER2+ and with triple negative at a lesser extend. Considering HER2 low patients were about 75% of patients with CHEK2 mutations, a molecular mechanism that correlates a truncating mutation in CHK2 and HER2 overexpression can be hypothesized. In the cluster analysis, HER2+ (38%), and luminal B (38%) subtypes predominate in patients with pathogenic variant c.1100del, while in pathogenic variants other than c.1100del and VUS the luminal B subtype predominates (75%), as well as recurrence or second tumours in 50% of cases. On the other hand, considering that this is an island population, the possible effect of geographical isolation and the resulting inbreeding in the past, these facts do not seem to elicit differences comparing to the rest of the continental population, although the increase in pathogenic variants in CHEK2 were observed in patients from the small island of La Gomera. The relationship between CHEK2 and HER2 in breast cancer is an area of active research. Relative frequency in groups of CHEK2 variants Relative frequency in CHEK2 “ pathogenic variants c.1100 del (53%)”, “other”pathogenic variants no c.1100 del (15 %)" and VUS (30%). Relative frequency of breast cancer subtypes according to CHEK2 variants. HER2+: 30,8%. Luminal A: 11,5% . Luminal B: 50%. Triple negative: 7,7% . Histology, ER, PR, Ki, HER2 and HER2 low Histology , infiltrating ductal carcinoma (84%), ER+ (92%), PR (77%), Ki >15% (70%), HER2+ (31%), HER2 low (45%) Citation Format: Natalia Pérez-Rodríguez, Carol Prieto-Morin, Maria del Carmen Maeso, Lina Pérez-Mendez. Clinical-molecular correlation in breast cancer with pathogenic variants in CHEK2. Is there a relationship with HER2+ breast cancer? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-06.

Evaluation of the toxicity of prophylactic extended-field radiation therapy with volumetric modulated arc therapy in combination with concomitant chemoradiotherapy in patients with locally advanced stage IIIC1r cervical cancer according to the 2018 FIGO classification.

To evaluate the toxicity of prophylactic extended-field radiation therapy (EFRT) combined with volumetric modulated arc therapy (VMAT) in combination with cisplatin chemotherapy for locally advanced stage IIIC1r cervical cancer [2018 International Federation of Gynecology and Obstetrics (FIGO)]. Thirty patients with stage IIIC1r cervical cancer were treated with EFRT combined with concurrent cisplatin. Acute toxicities were evaluated according to the common terminology criteria for adverse events (CTCAE v.5). Delayed toxicities were evaluated according to the classification criteria of radiation damage toxicity of the Radiation Therapy Oncology Group (RTOG). The efficacy of the regimens was evaluated using response evaluation criteria in solid tumors (RECIST v1.1). Spearman correlation was used to analyze the correlation between acute gastrointestinal toxicity (nausea) and the small bowel V45. Predictive value analysis was performed using a receiver operating characteristic (ROC) curve. There were no grade ≥ 3 acute toxicities. The most common acute toxicity observed was nausea (grade 2 in 40%), which was positively correlated with the volume of the small intestine receiving 45 Gy. When the V45 of the small intestine was > 83.2 cc, the risk of grade 2 acute upper digestive tract toxicity (nausea) increased. The major late toxicities had the following distributions: Grade 1 diarrhea, 36.7%; Grade 1 abdominal pain, 13.3%; and Grade 1 radiation cystitis. No grade ≥ 2 late toxicities were observed. Treatment of locally advanced stage IIIC1r cervical cancer with EFRT combined with VMAT and concurrent cisplatin chemotherapy was well tolerated, and the acute toxicity profile was acceptable. Significant grade 3 acute/delayed toxicities were not observed.

Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity: FUSAFE individual patient data meta-analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7-13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2-2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

Phylogenetic conservation of Trop-2 across species-rodent and primate genomics model anti-Trop-2 therapy for pre-clinical benchmarks.

A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as pre-clinical benchmarks. Sequence divergence and incomplete conservation of expression patterns were observed in mouse and rat. Primate Trop-2 sequences were found to be 95%-100% identical to the human sequence. Comparative three-dimension primate Trop-2 structures were obtained with AlphaFold and homology modeling. This revealed high structure conservation of Trop-2 (0.66 ProMod3 GMQE, 0.80-0.86 ± 0.05 QMEANDisCo scores), with conservative amino acid changes at variant sites. Primate TACSTD2/TROP2 cDNAs were cloned and transfectants for individual ORF were shown to be efficiently recognized by humanized anti-Trop-2 monoclonal antibodies (Hu2G10, Hu2EF). Immunohistochemistry analysis of Macaca mulatta (rhesus monkey) tissues showed Trop-2 expression patterns that closely followed those in human tissues. This led us to test Trop-2 targeting in vivo in Macaca fascicularis (cynomolgus monkey). Intravenously injected Hu2G10 and Hu2EF were well tolerated from 5 to 10mg/kg. Neither neurological, respiratory, digestive, urinary symptoms, nor biochemical or hematological toxicities were detected during 28-day observation. Blood serum pharmacokinetic (PK) studies were conducted utilizing anti-idiotypic antibodies in capture-ELISA assays. Hu2G10 (t1/2 = 6.5days) and Hu2EF (t1/2 = 5.5days) were stable in plasma, and were detectable in the circulation up to 3weeks after the infusion. These findings validate primates as reliable models for Hu2G10 and Hu2EF toxicity and PK, and support the use of these antibodies as next-generation anti-Trop-2 immunotherapy tools.

Prospective results for 5-year survival and toxicity of moderately hypofractionated radiotherapy with simultaneous integrated boost (SIB) in (very) high-risk prostate cancer

PurposeHigh-risk (HR) prostate cancer patients usually receive high-dose radiotherapy (RT) using a two-phase sequential technique, but data on a simultaneous integrated boost (SIB) technique are lacking. We prospectively evaluated the long-term results of urinary (GU) and digestive (GI) toxicity and survival data for high-dose RT using a SIB technique in HR and very high-risk (VHR) prostate cancer. MethodsPatients were treated using an SIB technique in 34 fractions, at a dose of 54.4 Gy to the pelvis and seminal vesicles and 74.8 Gy to the prostate, combined with 36 months of androgen-depriving therapy in a prospective multicenter study. Acute and late GU and GI toxicity data were collected. Overall survival (OS), biochemical-relapse-free survival (bRFS), loco-regional-relapse-free survival (LRRFS), metastasis-free-survival (MFS) and disease-free-survival (DFS) were assessed. ResultsWe recruited 114 patients. After a median follow-up of 62 months, very few patients experienced acute (M0-M3) (G3-4 GU = 3.7 %; G3-4 GI = 0.9 %) or late (M6-M60) severe toxicity (G3-4 GU = 5.6 %; G3-4 GI = 2.8 %). The occurrence of acute G2 + GU or GI toxicity was significantly related to the consequential late G2 + toxicity (p < 0.01 for both GU and GI). Medians of OS, bRFS, LRRFS, MFS and DFS were not reached. At 60 months, OS, bRFS, LRRFS, MFS and DFS were 88.2 % [82.1; 94.7], 86.0 % [79.4 %;93.2 %], 95.8 % [91.8 %;99.9 %], 87.2 % [80.9 %;94.0 %] and 84.1 % [77.2 %;91.6 %] respectively. ConclusionSIB RT at a dose of 54.4 Gy to the pelvis and 74.8 Gy to the prostate is feasible, leading to satisfying tumor control and reasonable toxicity in HR and VHR prostate cancer.

Unraveling bioactive metabolites of mangroves as putative inhibitors of SARS-CoV-2 Mpro and RBD proteins: molecular dynamics and ADMET analysis

COVID-19 is a deadly pandemic caused by Corona virus leading to millions of deaths worldwide. Till today no medicine was available to cure this disease. This study selected 262 potential bioactive natural products derived from mangroves to inhibit the main protease (Mpro) and receptor-binding domain (RBD) protein of the COVID-19 virus. All the ligands were subjected to Adsorption Digestion Metabolism Excretion and Toxicity (ADMET) predictions and docking studies using AutodockVina. Among all the ligands, NP_143 (Shearinine A) and NP_242 (Amentoflavone), having the highest docking score of 10.2 and 10.1 Kj/mole, respectively, were picked for 100 ns of Molecular Dynamics using GROMACS. The trajectories generated were used to estimate Root mean square deviation (RMSD), Root mean square fluctuations (RMSF), Radius of Gyrations (RG), Solvent accessible surface area (SASA), and Hydrogen bonds. From the data generated, both the ligands have good binding ability at the active site of Mpro protein and do not deviate much. They have strong interactions with the amino acids during the 100 ns of simulations and can thus be considered potential drug candidates. Communicated by Ramaswamy H. Sarma

Enterosorbents in complex therapy of food allergies: a focus on digestive disorders and systemic toxicity in children.

The review analyzes mechanisms and concomitant factors in developing IgE-associated allergic diseases provoked by food allergens and discusses clinical symptoms and current approaches for the treatment of food allergies. The expediency of using enterosorbents in complex therapy of food allergies and skin and respiratory manifestations associated with gastroenterological disorders is substantiated. The review summarizes the experience of using enterosorbents in post-Soviet countries to detoxify the human body. In this regard, special attention is paid to the enterosorbent White Coal (Carbowhite) based on silicon dioxide produced by the Ukrainian company OmniFarma.

Acute renal failure during cisplatin-based chemotherapy: A prospective monocentric study.

Cisplatin is a widely used antineoplastic in the treatment of various types of solid cancers. The objectives of our study were to evaluate the prevalence of acute renal failure (ARF) during cisplatin-based chemotherapy and to determine the factors correlated with renal toxicity. This is a prospective study that was conducted over a period of 6 months. We included patients followed for histologically confirmed solid cancer and treated with cisplatin-based chemotherapy. Assessment of renal function was made by calculating renal creatinine clearance before starting cisplatin, before every cycle, at 3 months and at 6 months. Forty patients were included. The median age was 54 years (31-71 years). The mean cumulative dose received was 286 mg/m² (100-560 mg/m²). Twelve patients (30%) developed ARF which was grade 1 in 83% of cases. Cisplatin ARF was observed after a mean cumulative dose of 208 mg/m². Digestive toxicity (67%) and obstruction of the excretory tracts of tumoral origin (8%) were aggravating factors. Cisplatin cycle number >3 (p = 0.04) and dose ≥330 mg/m2 (p = 0.04) were the factors associated with cisplatin renal toxicity. This study concluded that ARF is dose-dependent with the predominance of grade 1 toxicity. A cumulative dose exceeding 330 mg/m2 was correlated with an increased risk of occurrence of ARF.

The impact of brachytherapy boost for anal canal cancers in the era of de-escalation treatments

PURPOSETo analyze clinical outcomes of high-dose-rate (HDR) interstitial brachytherapy boost (ISBT) after external beam radiation therapy (EBRT) or chemoradiotherapy (CRT) for the treatment of anal canal cancers (ACC). METHODS AND MATERIALSA total of 78 patients with ACC were treated at our institution by ISBT. Local Control (LC), disease-free survival (DFS), overall survival (OS), colostomy-free survival (CFS) and toxicity rates were analyzed. RESULTSWith a median followup (FU) of 59.8 months (95% CI [55.8–64.2]), six (7.7%) local recurrences with 2 patients (2.6%) having persistent disease at 3 months were observed. The 5-year rate of LC for the entire population was 92% [83–96%]. The 5-year DFS rate was 86% [76–93%]. The 5-year OS was 96% [88–99%]. In the univariate analysis, chemotherapy was significantly associated with morbidity grade ≥2. Late digestive toxicity grade ≥3 was reported in 8.9% patients, 1 patient underwent colostomy due to toxicity. The 5-year CFS rate was 88% [79–94%]. CONCLUSIONSHDR interstitial brachytherapy boost provide excellent rates of tumor control and colostomy-free survival with a favorable profile of GI toxicity. Continence in anal cancer survivors is a challenge and the boost technique must be discussed in a multidisciplinary approach as part of de-escalation treatments.

Dose-effect of polystyrene microplastics on digestive toxicity in chickens (Gallus gallus): Multi-omics reveals critical role of gut-liver axis

IntroductionMicroplastic pollution seriously threatens the health and safety of humans and wildlife. Avian is one of the main species endangered by microplastics. However, the damage mechanism of microplastics to the digestive system of avian is not clear. ObjectivesThe gut-liver axis is a bidirectional channel that regulates the exchange of information between the gut and the liver and is also a key target for tissue damage caused by pollutants. This study aimed to elucidate the digestive toxicity of microplastics in avian and the key role of the gut-liver axis in it. MethodsWe constructed an exposure model for microplastics in environmental concentrations and toxicological concentrations in chickens and reveal the digestive toxicity of polystyrene microplastics (PS-MPs) in avian by 16S rRNA, transcriptomics and metabolomics. ResultsPS-MPs changed the death mode from apoptosis to necrosis and pyroptosis by upregulating Caspase 8, disrupting the intestinal vascular barrier, disturbing the intestinal flora and promoting the accumulation of lipopolysaccharide. Harmful flora and metabolites were translocated to the liver through the liver-gut axis, eliciting hepatic immune responses and promoting hepatic lipid metabolism disorders and apoptosis. Liver injury involves multiple molecular effects of mitochondrial dynamics disturbance, oxidative stress, endoplasmic reticulum stress, and cell cycle disturbance. Furthermore, metabolomics suggested that caffeine and melanin metabolites may be potential natural resistance substances for microplastics. ConclusionTaken together, our data demonstrate the digestive damage of PS-MPs in avian, revealing a critical role of the liver-gut axis in it. This will provide a reference for protecting the safety of avian populations.

CML-337 Therapeutic Results of Second-Generation TKIs in a CML Multicentric Study in the West Region of Algeria

Historically, treatments for chronic myeloid leukemia (CML) are palliative, except for bone marrow allograft. Despite the results obtained using imatinib, a first-generation tyrosine kinase inhibitor (TKI), some patients (pts) have weak responses. The second-generation TKIs dasatinib and nilotinib are therapeutic alternatives in pts resistant to imatinib. This retrospective, multicenter study included 7 hematology centers in western Algeria. Pts older than 15 years treated with dasatinib or nilotinib as second-line therapy were included. The analysis of prognostic factors and the study of therapeutic responses were conducted according to ELN 2013. Event-free survival, progression-free survival, and overall survival (OS) were calculated according to the Kaplan-Meier method. Between January 2007 and December 2018, we collected 494 pts with CML, 154 of whom were treated with second-generation TKIs at a median age of 45 years (16, 83). The sex ratio was 0.87. The average splenic overflow was 8 cm. The average leukocytosis was 100 Giga/L. The average hemoglobin level was 10 g/dl (5.5-15). The average platelet rate was 35.5 Giga/L (27-1120). The majority of pts (120, 80%) had intermediate or high Sokal scores. The myelocytic phase was detected in 132 pts (86%), accelerated phase in 19 pts (13%), and acute transformation phase in 1 pt (1%). The indication for second-generation TKI was pts in accelerated phase in 70% of cases, failure to respond to first-generation TKI in 25% of cases, and intolerance in 5% of cases. Dasatinib was used in 75 pts (50%), nilotinib in 44 pts (30%), and dasatinib then nilotinib in 33 pts (20%). Evaluable pts (154) included 61% in MMR and 39% in failure, 25 pts died, and 25 pts were lost to follow-up. Toxicity was primarily hematological and digestive. OS was 80% at 5 years. The results obtained in our series are encouraging because second-generation TKIs as second-line therapy allowed treatment of 62% of pts who were intolerant or failing to respond to imatinib with acceptable digestive and hematological toxicity.

Docetaxel chemotherapy plus androgen-deprivation therapy in high-volume disease metastatic hormone-sensitive prostate cancer in Chinese patients: an efficacy and safety analysis

ObjectiveTo investigate the efficacy and safety of docetaxel chemotherapy combined with androgen-deprivation therapy for patients with high-volume disease metastatic hormone-sensitive prostate cancer.Methods153 cases of high-volume disease metastatic hormone-sensitive prostate cancer in Minhang Hospital between January 2018 and December 2019 were analyzed retrospectively, including the number of patients, age, initial PSA level, Gleason score, TNM stage and ECOG score. 90 patients in the endocrine therapy group received continuous ADT, and 63 patients in the combined chemotherapy group received docetaxel plus ADT. The progression-free survival time (time from initiation of prostate cancer treatment to progression to CRPC), PSA response rate, and adverse reactions were compared between the two groups.ResultsAll 153 cases were closely followed up for a period of 12.3–35.3 months, with a median follow-up time of 23.5 months. The median time to reach the lowest point of PSA in the two groups was 6.3 months and 7.9 months (P = 0.018) in the combination chemotherapy group and the ADT group alone, with 27 (42.9%) and 12 (13.3%) cases in the two groups Within 12 months of treatment, PSA decreased to below 0.2 ng/ml (P = 0.02), and progression-free survival was 16.9 months (6.5–28.5 months) and 11.2 months (4.3–22.7 months) in the two groups. (P < 0.001). There were 18 cases (28.6%) and 54 cases (60%) in the two groups with disease progression (P < 0.001). There were 6 cases (9.5%) and 15 cases (16.7%) in the combination chemotherapy group and the ADT group died of prostate cancer and related complications, respectively. All 63 cases in the combined chemotherapy group completed 6 cycles of chemotherapy. 39 (61.9%) cases experienced varying degrees of neutropenia, of which 12 (19%) experienced grade 3–4 neutropenia, with 6 cases (9.5%) developed febrile neutropenia. 30 cases (47.6%) had toxic reactions in the digestive system, and 3 case (4.3%) had grade 3 liver dysfunction. 27 cases (42.8%) had skin and mucosal toxicity. 9 cases (14.3%) had mild fluid retention. No blood and digestive toxicity were observed in the ADT group. 33 cases (52.4%) and 48 (53.3%) of the two groups had symptoms of afternoon hot flashes and fatigue, (P = 0.961).ConclusionDocetaxel chemotherapy combined with endocrine therapy could be one of effective treatments for delaying castration resistance of HVD-mHSPC, which could prolong PFS effectively and obtain a higher PSA response rate, high safety under close monitoring, and controllable adverse reactions.

Immediate Versus Salvage Postoperative Radiotherapy in High-Risk Prostate Cancer Patients: A Critical Review.

Radical prostatectomy in high-risk prostate cancer patients has long been followed by immediate adjuvant radiotherapy (IART) to increase biochemical relapse-free survival. However, the increased urinary and digestive radio-induced toxicities have raised questions about the safety of delaying radiotherapy until the occurrence of biochemical or clinical relapse. Recently, early salvage radiotherapy (ESRT) has been compared to IART, and results found equivalence in terms of efficiency outcomes, but increased toxicity was noted in patients receiving IART, leading to the proposal of ESRT as the new standard of care in high-risk patients after surgery. However, several confounding points are discussed in the present review regarding the methodology and results of these recent trials. Further follow-up is necessary to detect possible long-term advantages of one radiotherapy timing over the other.