Severe Toxic Effects Research Articles

Network analysis and experimental pharmacology study explore the protective effects of Isoliquiritigenin on 5-fluorouracil-Induced intestinal mucositis.

5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs for malignant tumors. However, intestinal mucositis caused by 5-FU is a severe dose-limiting toxic effect and even leads to treatment interruption. Isoliquiritigenin (ISL) is one of the main active compounds of licorice, which is a traditional Chinese herbal medicine commonly used in inflammation and gastrointestinal diseases. It is speculated that ISL have protective effects on intestinal mucositis. However, no such studies have been reported. Therefore, to investigate the impact of ISL on 5-Fu-induced intestinal mucositis, a strategy based on network prediction and pharmacological experimental validation was proposed in this study. Firstly, the targets and mechanism of ISL in alleviating 5-Fu-induced gastrointestinal toxicity were predicted by network analysis. And the results were further confirmed by molecular docking. Then, a mouse model of intestinal mucositis was established by intraperitoneal injection of 5-FU (384 μmol/kg) to verify the prediction of network analysis. The network analysis results suggested that PTGS2 (Prostaglandin G/H synthase 2) and NOS2 (Nitric oxide synthase, inducible) might be the critical targets of ISL for reducing the intestinal toxicity of 5-FU. In addition, KEGG and GO enrichment analysis revealed that the HIF-1, TNF, MAPK, IL-17, PI3K-Akt, Ras, NF-kappa B signaling pathway, and biological processes of the inflammatory response, apoptosis regulation, NO production and NF-kappa B transcription factor activity might be involved in the mechanism of ISL against intestinal mucositis. Subsequent animal experiments showed that ISL could reduce the weight loss, leukopenia and mucosal damage caused by 5-FU. Compared with the intestinal mucositis model, the protein expressions of PTGS2, NOS2, TNFα (Tumor necrosis factor-alpha) and NF-κB p65 (nuclear factor kappa-B P65) were decreased after ISL treatment. In conclusion, this study is the fist time to find that ISL can attenuate 5-FU-induced intestinal mucositis in mice. Its anti-mucositis effect may be through regulating TNF/NF-κB pathway and inhibiting inflammatory mediators PTGS2 and NOS2. It will provide a potential candidate for the prevention and treatment of chemotherapy-induced intestinal mucositis.

Synergistic anticancer effect of flavonoids from Sophora alopecuroides with Sorafenib against hepatocellular carcinoma.

Sorafenib (SF), a multi-kinase inhibitor, is the first FDA-approved systemic chemotherapy drug for advanced hepatocellular carcinoma (HCC). However, its clinical application is limited by severe toxicity and side effects associated with high applied doses. Sophora alopecuroides L. is traditionally used as Chinese herbal medicine for treating gastrointestinal diseases, bacillary dysentery, viral hepatitis, and other diseases, and exerts an important role in anti-tumor. Hence, we investigated the synergistic actions of seventeen flavonoids from this herb combined with SF against HCC cell lines and their primary mechanism. In the experiment, most compounds were found to prominently enhance the inhibitory effects of SF on HCC cells than their alone treatment. Among them, three compounds leachianone A (1), sophoraflavanone G (3), and trifolirhizin (17) exhibited significantly synergistic anticancer activities against MHCC97H cells at low concentration with IC50 of SF reduced by 5.8-fold, 3.6-fold, and 3.5-fold corresponding their CI values of 0.49, 0.66, and 0.46 respectively. Importantly, compounds 3 or 17 combined with SF could synergistically induce MHCC97H cells apoptosis via the endogenously mitochondrial-mediated apoptotic pathway, involving higher Bax/Bcl-2 expressions with the activation of caspase-9 and -3, and arrest the cell cycle in G1 phases. Strikingly, this synergistic effect was also closely related to the co-suppression of ERK and AKT signaling pathways. Furthermore, compound 3 significantly enhanced the suppression of SF on tumor growth in the HepG2 xenograft model, with a 79.3% inhibition ratio at high concentration, without systemic toxicity, compared to either agent alone. These results demonstrate that the combination treatment of flavonoid 3 and SF at low doses exert synergistic anticancer effects on HCC cells in vitro and in vivo.

Conservative treatment of Head and Neck hemangiomas using Intralesional Bleomycin.

Hemangiomas are vascular tumours and commonly occur in head and neck region. Complete treatment of these vascular swellings are often challenging. As surgical excision carries high risk of complications and poor cosmetic outcome, treatment is shifted more towards non-surgical modalities like steroid therapy, radiotherapy, chemotherapy and sclerotherapy. To study the efficacy of intralesional Bleomycin sclerotherapy for head and neck hemangiomas. Seventeen patients ( 9 males and 8 females) with head and neck hemangiomas were treated with sclerotherapy using intralesional bleomycin injection ( 0.1-0.5mg/kg/ dose) in a medical college of India. Details of the patients were recorded along with serial photographs of lesion. Post injection outcomes in form of reduction of lesion size, patient satisfaction and complications were also recorded. 11 patients were completely cured, 3 had more than 50% reduction in size, one patient showed minimal reduction and two had no response. One patient had superficial ulceration, one case of slough and fever was reported. None of the patients developed severe toxic side effects and pulmonary fibrosis with follow up of 18 months. Bleomycin injection is safe, easy and well tolerated method for treatment of head and neck hemangiomas. We recommend surgery only if there is no response to other conservative treatment modalities.

Combination therapy regimens in the treatment of metastatic renal cell carcinoma: A review

Renal cell carcinoma (RCC) is one of the most common tumor types in urologic oncology practice. Despite the improvement of diagnostics methods, about 1/3 of patients with renal cell carcinoma have distant metastases at presentation resulting in an extremely high death rate. For many years, treatment of advanced forms of RCC was utterly ineffective. Standard chemotherapy regimens with fluoropyrimidines and antitumor antibiotics, cytokine therapy with interleukin-2, and interferon- only slightly prolonged the life of patients while causing severe toxic side effects and anemia. Attempts to treat the tumor with radiation therapy have also failed and have been used only for symptomatic treatment of distant metastases. The introduction of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic RCC (mRCC) has enabled much more significant results. Thus, a landmark event was the approval of TKIs sunitinib and then sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, and mammalian target of rapamycin (mTOR) inhibitors: everolimus and temsirolimus. Subsequent combined therapy using bevacizumab with low-dose interferon- and lenvatinib with everolimus improved recurrence-free survival and objective response rates but contributed to increased toxicity of therapy. The next step in RCC therapy was the approval of the combination of the immuno-oncology agents ipilimumab and nivolumab for the treatment of mRCC by the U.S. Food and Drug Administration in April 2018. Later, combinations of immune checkpoint inhibitors with targeted agents were approved, which increased the life expectancy of patients and reduced the toxicity of antitumor therapy. One of the most effective regimens is the combination of a TKI axitinib or lenvatinib with the PD-1 inhibitor pembrolizumab. This article addresses the current progress in the treatment of patients with mRCC, reviewing the results of completed clinical trials on the use of combination therapy with targeted and immuno-oncology agents.

Antipyretic drugs: benefits and undesirable consequences

Fever is a defensive and adaptive reaction of the body that develops in response to the action of pathogenic stimuli. It often accompanies various infectious, autoimmune, oncohematological and other diseases. Due to the frequent significant deterioration of children's general health, the occurrence of fever in children gives rise to concern not only in parents, but also in pediatricians. According to temperature level, fever can be classified into different categories: subfebrile - 37.1 to 37.9 °C, moderate -38 to 39 °C, febrile - 39.1 to 41 °C and hyperthermic - above 41 °C. By clinical manifestation distinguish benign, or rose, and malignant, or white, fever. The need to use antipyretic drugs depends not only on the hight of the body temperature elevation, but also on the patient's general health. The clinical guidelines state that the use of acetylsalicylic acid, nimesulide and met-amizole to lower the body temperature in children is not recommended, due to high risk of adverse reactions. Ibuprofen and paracetamol are the drugs of choice to lower body temperature in children both in Russia and abroad. Over 120 comparative studies of these two drug formulations have shown their close efficacy, but ibuprofen is most preferred for the treatment of fever and pain. In order to lower body temperature, parents can uncontrollably use antipyretic drugs in various combinations and incorrect dosages, which leads to severe toxic effects. The article presents a clinical case of Reye's syndrome in a 10-year-old girl, which is most likely associated with the use of aspirin as an antipyretic.

Mercury levels in North Atlantic seabirds: A synthesis

Mercury (Hg) is globally-distributed, with severe toxic effects on wildlife. Methylmercury biomagnifies within food webs, so long-lived, top predators such as seabirds are prone to high mercury concentrations. We synthesized historical and contemporary data on mercury concentrations in seabirds from the North Atlantic. We collected 614 values determined from 39 species and 115 locations, ranging from 1895 to 1940 and from 1970 to 2020. Highest blood-equivalent Hg values were in Phalacrocoracidae. For the same species/tissue/collection site, blood-equivalent values were lower during pre-1940 than post-1970 period. In almost 5 % of post-1970 values, mean blood-equivalent Hg concentrations were above those considered to pose severe risks of adverse effects, and 21 % were above the high-risk effect. We found an imbalance in sample effort and did not find Hg values for many species. We argue that stronger, trans-Atlantic Hg monitoring schemes are required to coordinate research and better compare trends across a wide scale.

Alcohol and the young: how does the press face the problem?


 Background: alcohol is an important component of the Mediterranean diet and its moderate use is protective against cardiovascular risk. Binge drinking, i.e. the heavy consumption of alcohol over a short period of time, is the main consumption pattern of young people in Western countries and may lead to severe toxic effects in many organs. Mass media often address the issue by suggesting prevention measures; however, they may also have the unintended effect of encouraging alcohol misuse. This study aims to assess how the Italian press faces excessive alcohol consumption in young people, comparing the messages given by the press with scientific recommendations.
 Methods: articles published by the 6 best-selling Italian newspapers and the 4 best-selling Italian magazines were collected from October 15th to November 14th 2009. Medline database, governmental and non-governmental sources were searched for scientific recommendations regarding primary prevention of alcohol misuse. Press articles were described and analysed by filling out a predefined form.
 Results: fourteen newspaper articles regarding alcohol were found, 79% belonging to the news section. Six quotations of scientific recommendations were found: two about drink-driving, two about raising public awareness, one about Monitoring and Evaluation, and one about community and workplace action.
 Conclusions: scientific recommendations were often inadequately reported by the Italian press. The most covered recommendations, designed driver and public educational intervention, are also the least effective according to international literature. Therefore, a further effort is needed to tackle this issue in a more scientifically sound way.

Comparable Long-Term Tumor Control for Hypofractionated FLASH Versus Conventional Radiation Therapy in an Immunocompetent Rat Glioma Model

PurposeTo ensure a clinical translation of FLASH radiation therapy (FLASH-RT) for a specific tumor type, studies on tumor control and toxicity within the same biological system are needed. In this study, our objective was to evaluate tumor control and toxicity for hypofractionated FLASH-RT and conventional radiation therapy (CONV-RT) in an immunocompetent rat glioma model. Methods and MaterialsFisher 344 rats (N = 68) were inoculated subcutaneously with NS1 glioma cells and randomized into groups (n = 9-10 per group). CONV-RT (∼8 Gy/min) or FLASH-RT (70-90 Gy/s) was administered in 3 fractions of either 8 Gy, 12.5 Gy, or 15 Gy using a 10-MeV electron beam. The maximum tumor diameter was measured weekly, and overall survival was determined until day 100. Long-term tumor control was defined as no evident tumor on day 100. Animals were evaluated for acute dermal side effects at 2 to 5 weeks after completed RT and for late dermal side effects at 3 months after initiation of treatment. ResultsSurvival was significantly increased in all irradiated groups compared with control animals (P < .001). In general, irradiated tumors started to shrink at 1 week post–completed RT. In 40% (23 of 58) of the irradiated animals, long-term tumor control was achieved. Radiation-induced skin toxic effects were mild and consisted of hair loss, erythema, and dry desquamation. No severe toxic effect was observed. There was no significant difference between FLASH-RT and CONV-RT in overall survival, acute side effects, or late side effects for any of the dose levels. ConclusionsThis study shows that hypofractionated FLASH-RT results in long-term tumor control rates similar to those of CONV-RT for the treatment of large subcutaneous glioblastomas in immunocompetent rats. Neither treatment technique induced severe skin toxic effects. Consequently, no significant difference in toxicity could be resolved, suggesting that higher doses may be required to detect a FLASH sparing of skin.

Intercropping in Walnut Orchards – Assessing the Toxicity of Walnut Leaf Litter on Barley and Maize Germination and Seedlings Growth

Intercropping arable crops between tree rows has proven to be a great alternative to conventional agriculture in terms of food production sustainability and climate change adaptation. However, close interactions between species in these systems sometimes yield adverse allelopathic effects. In this study, the possibility of intercropping barley and maize in the walnut orchard was investigated in terms of walnut leaf litter toxicity. Leaves from 15 and 30 years old walnut trees were used to prepare water extracts out of freshly fallen leaves and soil with leaves decomposed within. Barley and maize seeds were germinated in these extracts using between paper towels method. Fresh leaf litter extracts slightly reduced barley germination but significantly inhibited both barley and maize seedlings’ growth. The extract from older walnut tree leaves had the most severe toxic effect, and seedlings shoot was more sensitive than root for both species. A significant correlation was observed between extracts pH and seedlings lengths, suggesting the hydrogen-induced injury to the root, which consequently influenced growth. Decomposed leaf litter extract had a promotional effect on barley and maize germination and growth, which shows that appropriate walnut litter management could improve the performance of intercropped walnut systems.

Preliminary Analysis Of Early And Late Radiation Responses In 3D Image-Guided Brachytherapy For Cervical Cancer

Rationale – The use of 3D image-guided brachytherapy (3D-IGBT) allows adequately optimizing the dose distribution to bring a target therapeutic dose to clinical target volume (CTV), thereby minimizing an impact on critical organs, while ensuring a decrease in the incidence and severity of radiation-caused complications. Use of 3D-IGBT also allows improving the quality of life in patients with cervical cancer. Objective – To conduct a preliminary analysis of the incidence of early and late radiation responses in 3D-IGBT of locally advanced cervical cancer (LACC). Materials and Methods – The objects of our study were female patients with stages IIB and IIIB of cervical squamous cell carcinoma, without confirmed metastases, preceding chemotherapy (CHT) and/or radiation therapy (RT), and surgical interventions in this localization, who underwent combined chemoradiotherapy during the study. Results – Statistically significant results were obtained when analyzing the incidence of late radiation responses. It is important to point out that when assessing early toxicity in the main group with 3D-IGBT, grade 3 responses were not diagnosed, while in the control group, they were observed in 4 (9.1%) women. For instance, the manifestation of grade 3 delayed radiation injuries in the rectum was diagnosed in 3 (6.8%) women in the control group, while in the main group, they were not detected. Grade 2 cystitis was observed in a smaller number of women in the group with 3D-IGBT, compared with the control group (9.1% vs. 13.6%, p&lt;0.05). Grade 3 delayed radiation responses in the bladder were diagnosed in 4 (9.1%) women in the control group, whereas among the patients of the main group with 3D-IGBT, they were not recorded at all (p &lt;0.05). Grade II reactions in the vaginal mucosa and cervix were diagnosed more often in the control group (16.7% vs. 13.6%, p&lt;0.05). Conclusion – Hence, the method we have used to optimize the treatment of LACC by means of 3D planning in accordance with toxicity criteria exhibited a definite advantage, compared with RT with 2D planning. Based on the results of our research, we concluded that optimization of RT for LACC using 3D-IGBT created clinically favorable conditions for effective therapy: it reduced the risk of displacement of the applicators and decreased an impact on the patient via reducing the total radiation doses and incidence of severe early and late toxic effects, providing good outcomes of local control regardless of tumor size and clinical stage.

Abstract 2093: PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile

Abstract Introduction: Interleukin-2 (IL-2) can activate and expand tumor killing lymphocytes. High doses of IL-2 are needed to activate CD8+ T cells. Severe toxic side effects associated with high doses, as well as the poor PK profile of IL-2, have limited its clinical usage. Various strategies have been employed to prolong half-lives of IL-2 and enable selectivity or bias towards receptor binding to reduce toxicity and maintain good efficacy. Among these, certain PEGylation strategies have generated promising clinical results, but also showed some major limitations. We report a unique PEGylation strategy to produce PEGylated IL-2 with a therapeutic window more than two times larger than the reference PEGylated IL-2. Methods: CT26 murine syngeneic model was used for evaluation of in vivo efficacy and safety. Each 6-8 weeks old female BALB/c mouse was inoculated subcutaneously in the right front flank region with CT26 tumor cells (5 x 105). Tumors were allowed to grow to mean size ~110 mm3 before randomization and treatment. Body weights and tumor volumes were measured three times per week. The tumor-free mice at the end of the study were re-challenged with CT26 colon tumor cells on the left side. Results: Utilizing our proprietary PEGylation technology, rhIL-2 was covalently connected with multiple PEG polymers through releasable linkers (RL). The releasable linkers are designed to modulate the release rate of the active IL-2 species. In CT26 syngeneic mouse model, CS-PEG-IL-2 showed significantly enhanced efficacy and safety over IL-2 and reference PEGylated IL-2. rhIL-2 (2 mg/kg, bid x 5, two cycles, i.p.) resulted in complete response (CR) in one out of eight (1/8) mice, while 3 mg/kg dose resulted in death in 8/8 mice. With the reference PEGylated IL-2, 3/8 CR were obtained at 3 mg/kg dose (q1w x 4, i.v.), and 6 mg/kg dose resulted in death in 8/8 mice. Whereas, with three CS PEGylated IL-2 analogs, 5/8 and 6/8 CR were achieved at 3 mg/kg and 6 mg/kg dose respectively, and no obvious toxicity was observed even at the highest dose. After re-challenged with another inoculation of CT26 cancer cells, the CR mice remained tumor-free until the end of the study at day 158. Conclusions: CS unique PEGylation strategy generated PEG-IL-2 with superior anti-tumor efficacy and safety profiles. Preclinical results support clinical evaluation of this novel class of PEGylated IL-2 analogs. Citation Format: Yuntao Song, Hui Li, Wei Zhang, Dayan Fu, Meng Xu. PEGylated IL-2 with enhanced anti-tumor efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2093.

Definitive Local Consolidative Therapy for Oligometastatic Solid Tumors: Results From the Lead-in Phase of the Randomized Basket Trial EXTEND

The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase. Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0. From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects. The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease.

Orally delivered solid lipid nanoparticles of irinotecan coupled with chitosan surface modification to treat colon cancer: Preparation, in-vitro and in-vivo evaluations

Irinotecan-loaded solid lipid nanoparticles (IRI-SLNs) was formulated and tested for its potential activity against colon cancer. IRI-SLNs were prepared by applying the principles of DoE. Nanoparticles were further surface modified using chitosan. Characterizations such as size, poly-dispersity, surface charge, morphology, entrapment, drug release pattern, cytotoxicity were conducted. In-vivo studies in male Wistar rats were carried to ascertain distribution pattern of SLNs and their acute toxicity on various vital organs. Lastly, stability of the SLNs were evaluated. Particles had a size, polydispersity and zeta potential of 430.77 ± 8.69 nm, 0.36 ± 0.02 and −40.06 ± 0.61 mV, respectively. Entrapment of IRI was 62.24 ± 2.90% in IRI-SLNs. Sustained drug release was achieved at a colonic pH and long-term stability of NPs was seen. Cytotoxicity assay results showed that SLNs exhibited toxicity on HCT-116 cells. Biodistribution studies confirmed higher concentration of drug in the colon after surface modification. An acute toxicity study conducted for 7 days showed no severe toxic effects on major organs. Thus, we picture that the developed SLNs may benefit in delivering IRI to the tumour cells, therefore decreasing the dose and dose-associated toxicities.

Smart dual responsive nanocarriers with reactive oxygen species amplification assisted synergistic chemotherapy against prostate cancer

Conventional chemotherapy efficacy is impeded by poor water solubility, inferior tissue targeting, and severe systemic toxic effect. Synergistic chemotherapy has become prominent with the stimulus–response drug delivery system (DDS) to treat solid malignancies. The most popularly employed responsive stimulus is reactive oxygen species (ROS), which is proven to primarily sensitize chemotherapy and enhance antitumor impact. In this study, we have successfully developed smart dual responsive nanocarriers with ROS self-amplification, particularly responding to disassemble under the high levels of ROS and esterase in the tumor microenvironment (TME) and to release docetaxel (DTX) efficiently. Additionally, we utilized palmitoyl ascorbate (PA) as a stabilizer by taking advantage of its amphiphilic structure. PA is also an excellent ROS generator that produces a large amount of hydrogen peroxide (H2O2) in TME to achieve ROS self-amplification. Also, elevated levels of ROS could continue to activate ROS-sensitive thioketal and make the remaining nanocarriers disassemble for sustaining the release of chemotherapeutics, realizing a positive feedback loop for ROS generation and ROS amplification, as well as sensitizing chemotherapy efficacy. The smart dual responsive nanocarriers may serve as a promising and prospective strategy for treating prostate cancer and promoting synergistic cancer therapy.

Effects of Dietary Aflatoxin B1 on Hybrid Striped Bass (Morone chrysops × M. saxatilis) and Assessment of Supplemental Arginine as a Potential Aflatoxicosis Alleviator

Aflatoxin contamination of feeds poses a significant threat to aquaculture. This six-week study was conducted to evaluate the impact of aflatoxin B1 (AFB1) in diets with and without supplemental arginine (Arg) on the production performance, somatic indices, body composition, and immune responses of hybrid striped bass (HSB). Six experimental diets were formulated to contain different levels of AFB1 (0, 1, or 2 mg/kg) and supplemental Arg (0 or 2%) following a 3 × 2 factorial arrangement. Triplicate groups of HSB (~5.44 g/fish) stocked in 18 glass aquaria were randomly assigned each diet and fed at a rate approaching apparent satiation twice daily. At the conclusion of the feeding trial, no interactions among dietary AFB1 and Arg were found. However, both medium (~1 mg/kg) and high (~2 mg/kg) levels of dietary AFB1 caused severe toxic effects on HSB directly affecting performance. Relative to control groups without AFB1 supplementation, steep reductions in weight gain (from 553% to 120% of initial weight), feed efficiency ratio (from 0.96 to 0.36), and protein retention (from 43% to 12%) were found in fish fed diets containing medium AFB1, and further reductions were observed in groups exposed to high AFB1. Dietary AFB1 also negatively affected condition factor and somatic indices and reduced whole-body protein and lipid contents relative to control groups. Significantly lower plasma hemolytic and lysozyme activities were found in fish exposed to dietary AFB1. Despite no significant protective effect of supplemental Arg being observed for most response parameters, reduced levels of Arg in plasma and muscle of AFB1-fed HSB indicated increased catabolism under nutritional stress. In conclusion, this study demonstrated that exposure to dietary AFB1 concentrations of ~1 and 2 mg/kg severely affected HSB and that supplemental Arg above requirement levels may be ineffective in alleviating aflatoxicosis.

Acute Tumor Lysis Syndrome: A Review of 100 Patients with Acute Lymphoblastic Leukemia

Background: ALL is a malignancy of B or T lymphoblasts which is characterized by unrestrained spread of abnormal, immature lymphocytes and their progenitors which results in the replacement of bone marrow and other lymphoid organs subsequently. Methods: This study was a observational cross sectional study conducted at the Department of Hematology, in Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka, Bangladesh. The study period was from October 2019- September 2020. The sample size for this study was 100. Result: Most of the respondents 53(53%) were from &lt;20 years and the mean age was 30±11.18. The female was 68(68%) and male was 32(32%). Fever was found in 100% cases and Progressive pallor in 98%. Bony tenderness was found in 58 cases and followed by Splenomegaly 48, Lymphadenopathy in 46, Oral ulcer in 46, Hepatomegaly in 36. The range of Total WBC count (x109/L) was (6-435) and the Mean±SD was 52.51±78.70 and followed by Hb% (gm/dl) was (4.1-13.4) and 9.25±1.49, Platelet (x109/L) was (5-20000) and 505.20±2815.29. S. uric acid (mg/dL) was (1.40-30.03) and 5.76±4.61. S. inorganic phosphate (mg/dL) was (2.30-7.70) and 4.19±1.20. S. potassium (mmol/L) (2.50-5.40) and 3.92±0.56. S. calcium (mg/dL) was (1.10-11.80) and 8.33±2.08. S. creatinine (mg/dL) was (0.19-3.59) and 89±0.55. In 72% TLS was absent and in 28% was present. Conclusions: Rapid spread of TLS often causes severe toxic effects on organs, which leads to renal impairment, epilepsy, cardiac arrhythmias, pulmonary edema, and even death.

Meta-analysis of Elective Pelvic Nodal Irradiation Using Moderate Hypofractionation for High-Risk Prostate Cancer

Despite several advances in planning and delivery of radiation therapy (RT) for prostate cancer, the role of elective pelvic nodal irradiation (EPNI) remains controversial for high-risk disease. We performed a meta-analysis to evaluate the outcomes of patients treated with moderate hypofractionated RT (MHF-RT) with EPNI using modern RT techniques. Eligible studies were identified on MEDLINE, Embase, the Cochrane Library, and proceedings of annual meetings through October 2021. We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and MOOSE (Meta-analyses of Observational Studies in Epidemiology) guidelines. A metaregression analysis was performed to assess a possible correlation between selected variables and outcomes. A P value <.05 was considered significant. Eighteen studies with a total of 1745 patients (median follow-up, 61 months) treated with EPNI using MHF-RT were included. The biochemical relapse-free survival at 5, 7, and 10 years was 90% (95% confidence interval [CI], 88%-94%), 83% (95% CI, 78%-91%), and 78% (95% CI, 68%-88%). The 5-year prostate cancer-specific survival, disease-free survival, distant metastases-free survival, and overall survival were 98% (95% CI, 97%-99%), 88.7% (95% CI, 85%-93%), 91.2% (95% CI, 88%-92%), and 93% (95% CI, 90%-96%), respectively. The rates of local, pelvic, and distant recurrence were 0.38% (95% CI, 0%-2%), 0.13% (95% CI, 0%-1.5%), and 7.35% (95% CI, 2%-12%), respectively. The rate of late grade ≥2 gastrointestinal and genitourinary toxic effects were 6.7% (95% CI, 4%-9%) and 11.3% (95% CI, 7.6%-15%), with heterogeneity, but with rare cases of grade 3 to 5 toxic effects. EPNI with concomitant MHF-RT provides satisfactory biochemical relapse-free survival in long-term follow-up, with low rates of genitourinary and gastrointestinal severe toxic effects and minimal pelvic and local failure.

Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer.

Pancreatic cancer is a highly fatal disease that is becoming an increasingly leading cause of cancer-related deaths. In clinic, the most effective approach to treat pancreatic cancers is the combination treatment of several chemotherapeutic drugs, including fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), but this approach is not adequate to manage patients due to their severe toxic side effects. Herein, we proposed light-activated monomethyl auristatin E (MMAE) prodrug nanoparticles for combinational photo-chemotherapy and optimized its applications for pancreatic cancer treatment. The photosensitizer (Ce6) and chemotherapeutic drug (MMAE) were conjugated through caspase-3-specific cleavable peptide (KGDEVD). The resulting CDM efficiently promoted the reactive oxygen species (ROS) under visible light irradiation and thereby induced caspase-3 overexpression in pacreatic cancers, which subsequently released the MMAE from the system. Importantly, MMAE released from CDM further amplified the activation of CDM into MMAE by inducing extensive apoptotic cell death in tumor microenvironment for treatment of tumor cells in deep in the tumor tissues as far visible light cannot reach. In addition, CDM formed prodrug nanoparticles via intermolecular π-π stacking and hydrophobic interactions, allowing durable and reliable treatment by preventing fast leakage from the pancreatic cancers via the lymphatic vessels. The CDM directly (intratumoral) injected into pancreatic cancers in orthotopic models through an invasive approach significantly delayed the tumor progression by combinational photo-chemotherapy with less toxic side effects. This study offers a promising and alternative approach for safe and more effective pancreatic cancer treatment via prodrug nanoparticles that combine photodynamic therapy and chemotherapy.

Pathological effects of graded doses of aflatoxin B1 on the development of the testes in juvenile white leghorn males.

Current experiment was planned to investigate the deleterious effects of the graded doses of aflatoxin B1 (AFB1) on white leghorn male birds. For this purpose, one-hundred birds of 8weeks of age were divided into 4 equal groups and reared on feed contaminated with different doses of AFB1 for 10weeks. Group A was kept as a control group and was fed with normal toxin-free diet; groups B, C, and D were offered feed containing 100ppb, 200ppb, and 400ppb of AFB1, respectively. The birds were euthanized at the 4th and 10th week of the experiment. Clinical signs, behavioral changes, absolute and relative organ weight of the testes, and sperm motility were measured. Cellular immune response was observed through carbon clearance assay (CCA), P-HAP, and antibody response against sheep red blood cells (SRBC). Results showed a dose-dependent decline in the immune response of birds with the increase in the level of AFB1 in the feed. A significant decrease in the serum levels of testosterone, prolactin, and LH were observed at the end of the study. Grossly, testicular size and volume were reduced in ABF1 fed birds, while histological examination showed moderate to severe necrosis of testicular parenchyma, with partial to complete arrest of spermatogenesis. Very few spermatozoa were found in group C, while they were almost absent in group D which was offered a diet containing 400ppb AFB1. The motility of sperms was reduced in all treated groups except control. The abovementioned results showed that AFB1 had severe toxic effects on the reproductive and immunological parameters of WLH male birds in a dose-dependent manner.

New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining.

Glycosylated polyene macrolides include effective antifungal agents, such as pimaricin, nystatin, candicidin, and amphotericin B. For the treatment of systemic mycoses, amphotericin B has been described as a gold-standard antibiotic because of its potent activity against a broad spectrum of fungal pathogens, which do not readily become resistant. However, amphotericin B has severe toxic side effects, and the development of safer alternatives remains an important objective. One approach towards obtaining such compounds is to discover new related natural products. Advances in next-generation sequencing have delivered a wealth of microbial genome sequences containing polyene biosynthetic gene clusters. These typically encode a modular polyketide synthase that catalyzes the assembly of the aglycone core, a cytochrome P450 that oxidizes a methyl branch to a carboxyl group, and additional enzymes for synthesis and attachment of a single mycosamine sugar residue. In some cases, further P450s catalyze epoxide formation or hydroxylation within the macrolactone. Bioinformatic analyses have identified over 250 of these clusters. Some are predicted to encode potentially valuable new polyenes that have not been uncovered by traditional screening methods. Recent experimental studies have characterized polyenes with new polyketide backbones, previously unknown late oxygenations, and additional sugar residues that increase water-solubility and reduce hemolytic activity. Here we review these studies and assess how this new knowledge can help to prioritize silent polyene clusters for further investigation. This approach should improve the chances of discovering better antifungal antibiotics.