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BioRxiv : the Preprint Server For... May 2024Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like...
Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation without noticeable cytotoxicity Moreover, sequential cycles of albendazole and paclitaxel-a commonly used chemotherapeutic -displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.
PubMed: 38798673
DOI: 10.1101/2023.11.08.562798 -
International Journal of Surgery Case... Jun 2024Hydatid disease, caused by Echinococcus granulosus, is a zoonotic infection prevalent in specific regions, including Tunisia. Complications are rare but potentially...
INTRODUCTION AND IMPORTANCE
Hydatid disease, caused by Echinococcus granulosus, is a zoonotic infection prevalent in specific regions, including Tunisia. Complications are rare but potentially life-threatening. This case report highlights the significance of early diagnosis and intervention in a unique case where anaphylaxis resulted from minor abdominal trauma in a 17-year-old male with an undiagnosed hydatid cyst.
CASE REPORT
The patient arrived at the emergency department with syncope and hypotension after a classroom accident. Physical examination showed an urticarial rash and abdominal tenderness. Anaphylactic shock was diagnosed and promptly treated. A computed tomography scan confirmed a ruptured liver hydatid cyst. The patient received anthelmintic treatment and underwent conservative surgical management. Intraoperatively, a second anaphylactic shock occurred and was promptly treated. The post-operative course was uneventful, and histopathological analysis identified Echinococcus granulosus.
CLINICAL DISCUSSION
This case emphasizes the importance of recognizing hydatid disease as a potential cause of anaphylaxis post-trauma, even in asymptomatic patients. Early diagnosis through imaging is crucial for prompt intervention. Surgical management should be considered, with conservative approaches favored in acute cases. Post-surgical albendazole treatment is essential to prevent recurrence.
CONCLUSION
This report serves as a valuable reference for healthcare professionals, highlighting the need for heightened clinical suspicion in cases like this. It underscores the significance of considering hydatid cyst rupture in the differential diagnosis of anaphylaxis following blunt trauma. Awareness among pediatricians, emergency physicians, and primary care providers can lead to early diagnosis and better patient outcomes, preventing severe complications or fatalities associated with this rare condition.
PubMed: 38781844
DOI: 10.1016/j.ijscr.2024.109779 -
Scientific Reports May 2024Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic...
Metabolism of praziquantel (PZQ), a racemic mixture and the only drug approved to treat S. mansoni infection, is mediated by genetically polymorphic enzymes. Periodic school-based mass drug administration (MDA) with PZQ is the core intervention to control schistosomiasis. However data on the impact of pharmacogenetic variation, nutrition, and infection status on plasma PZQ exposure is scarce. We investigated genetic and non-genetic factors influencing PZQ plasma concentration and its metabolic ratios (trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ). Four hundred forty-six school children aged 7-15 years from four primary schools in southern Ethiopia who received albendazole and PZQ preventive chemotherapy through MDA campaign were enrolled. Genotyping for common functional variants of CYP3A4 (*1B), CYP3A5 (*3, *6), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3), and CYP2J2*7 was performed. Plasma concentrations of PZQ, trans-4-OH-PZQ, and cis-4-OH-PZQ were quantified using UPLCMS/MS. Carriers of CYP2C19 defective variant alleles (*2 and *3) had significantly higher mean PZQ plasma concentration than CYP2C19*1/*1 or *17 carriers (p = 0.005). CYP2C19*1/*1 and CYP2C19*17 carriers had higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios compared with CYP2C19*2 or *3 carriers (p < 0.001). CYP2J2*7 carriers had lower mean PZQ plasma concentration (p = 0.05) and higher trans-4-OH-PZQ/PZQ and cis-4-OH-PZQ/PZQ metabolic ratios. Male participants had significantly higher PZQ concentration (p = 0.006) and lower metabolic ratios (p = 0.001) than females. There was no significant effect of stunting, wasting, S. mansoni or soil-transmitted helminth infections, CYP3A4, CYP3A5, or CYP2C9 genotypes on plasma PZQ or its metabolic ratios. In conclusion, sex, CYP2C19 and CYP2J2 genotypes significantly predict PZQ plasma exposure among Ethiopian children. The impact of CYP2C19 and CYP2J2 genotypes on praziquantel treatment outcomes requires further investigation.
Topics: Humans; Praziquantel; Child; Male; Female; Ethiopia; Adolescent; Cytochrome P-450 CYP2C19; Genotype; Cytochrome P-450 Enzyme System; Anthelmintics; Schistosomiasis mansoni
PubMed: 38778126
DOI: 10.1038/s41598-024-62669-w -
PLoS Neglected Tropical Diseases May 2024Chronic infection by Loa loa remains an unsolved immunological paradox. Despite harboring subcutaneously migrating adult worms and often high densities of microfilariae,...
BACKGROUND
Chronic infection by Loa loa remains an unsolved immunological paradox. Despite harboring subcutaneously migrating adult worms and often high densities of microfilariae, most patients experience only relatively mild symptoms, yet microfilaricidal treatment can trigger life-threatening inflammation. Here, we investigated innate cell populations hypothesized to play a role in these two faces of the disease, in an endemic population in Gabon.
METHODOLOGY/PRINCIPAL FINDINGS
We analyzed numbers and activation of eosinophils and basophils, as well as myeloid-derived suppressor cell (MDSC) subsets and associated circulating cytokine levels by flow cytometry in sex- and age-matched L. loa-uninfected (LL-), -amicrofilaraemic (MF-) and -microfilaraemic (MF+) individuals (n = 42), as well as microfilaraemic individuals treated with albendazole (n = 26). The percentage of eosinophils was lower in LL- (3.0%) than in the combined L. loa-infected population, but was similar in MF+ (13.1%) and MF- (12.3%). Upon treatment of MF+, eosinophilia increased from day 0 (17.2%) to day 14 (24.8%) and had decreased below baseline at day 168 (6.3%). Expression of the eosinophil activation marker CD123 followed the same pattern as the percentage of eosinophils, while the inverse was observed for CD193 and to some extent CD125. Circulating IL-5 levels after treatment followed the same pattern as eosinophil dynamics. Basophil numbers did not differ between infection states but increased after treatment of MF+. We did not observe differences in MDSC numbers between infection states or upon treatment.
CONCLUSIONS/SIGNIFICANCE
We demonstrate that both chronic infection and treatment of L. loa microfilaraemia are associated with eosinophil circulation and distinct phenotypical activation markers that might contribute to inflammatory pathways in this setting. In this first ever investigation into MDSC in L. loa infection, we found no evidence for their increased presence in chronic loiasis, suggesting that immunomodulation by L. loa is induced through other pathways.
Topics: Humans; Loiasis; Male; Female; Adult; Eosinophils; Gabon; Basophils; Loa; Animals; Middle Aged; Myeloid-Derived Suppressor Cells; Young Adult; Albendazole; Chronic Disease; Flow Cytometry; Cytokines; Endemic Diseases; Adolescent
PubMed: 38771861
DOI: 10.1371/journal.pntd.0012203 -
Veterinary Research Forum : An... 2024The over-use of anti-parasitic compounds as a method of control has led to insufficient effectiveness and widespread drug resistance worldwide. The aim of this study was...
The over-use of anti-parasitic compounds as a method of control has led to insufficient effectiveness and widespread drug resistance worldwide. The aim of this study was to investigate the efficacy of albendazole and levamisole as anti-parasitic agents in a lung worm control program in goat flocks. During 2021 and 2022, a total of 110 goats (age of four months and above) were randomly selected from 11 herds in the north-western region of Iran including Saanen breed (both sexes of the same age). The results indicated that 3.60, 50.80 and 41.90% were respectively infected with , and , and generally all the lung parasites in goats of this region were resistant to albendazole and levamisole. Due to clinical importance of in goats, the molecular analysis of two samples was also done. Sequencing results showed that the identified parasites were 100% similar to the reference sequences registered in the GenBank. The results of this research showed low level of these anthelmintics efficacy against and . Generally, the lung parasites in goats of this region are resistant to albendazole and levamisole. The showed high resistance to these drugs. Totally, it can be concluded that the level of drug resistance varies in different parts of the world; but, the frequencies of drug resistance in different parts of the world are not the same, requiring more studies.
PubMed: 38770202
DOI: 10.30466/vrf.2023.2010062.3991 -
Frontiers in Pharmacology 2024The L. genus has been widely used in traditional medicine in many countries throughout the world. The study aimed to investigate the chemical composition and...
The L. genus has been widely used in traditional medicine in many countries throughout the world. The study aimed to investigate the chemical composition and bioactivity of the hydroethanolic extract (50% v/v) obtained by ultrasonication from the aerial flowering parts of L. (SSE) collected in Almaty region (Southern Kazakhstan). According to RP-HPLC/PDA analysis the leading metabolites of the SSE belonged to polyphenols: chlorogenic acid and its isomers (2.34 mg/g dry extract) and luteolin derivatives (1.49 mg/g dry extract), while HPLC-ESI-QTOF-MS/MS-based qualitative fingerprinting revealed the presence of 17 metabolites, mainly chlorogenic acid and its isomers, flavonoid glycosides, and verbascoside with its derivatives. GC-MS analysis of the volatile metabolites showed mainly the presence of diterpenoids and fatty acid esters. A reduction in the viability of nematodes sp. was obtained for the SSE concentration of 3.3 mg/mL, while 11.1 mg/mL showed activity comparable to albendazole. The SSE exhibited higher activity against Gram-positive (MIC = 0.5-2 mg/mL) than Gram-negative bacteria and yeast (MIC = 8 mg/mL), exerting bactericidal and fungicidal effects but with no sporicidal activity. The SSE showed some antiviral activity against HCoV-229E replicating in MRC-5 and good protection against the cytopathic effect induced by HHV-1 in VERO. The SSE was moderately cytotoxic towards human cervical adenocarcinoma (H1HeLa) cells (CC of 0.127 mg/mL after 72 h). This study provides novel information on the SSE extract composition and its biological activity, especially in the context of the SSE as a promising candidate for further antiparasitic studies.
PubMed: 38769997
DOI: 10.3389/fphar.2024.1386509 -
PLoS Pathogens May 2024Albendazole (a benzimidazole) and ivermectin (a macrocyclic lactone) are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs...
Albendazole (a benzimidazole) and ivermectin (a macrocyclic lactone) are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs worldwide. Despite emerging resistance, we do not fully understand the mechanisms of resistance to these drugs nor the consequences of delivering them in combination. Albendazole resistance has primarily been attributed to variation in the drug target, a beta-tubulin gene. Ivermectin targets glutamate-gated chloride channels (GluCls), but it is unknown whether GluCl genes are involved in ivermectin resistance in nature. Using Caenorhabditis elegans, we defined the fitness costs associated with loss of the drug target genes singly or in combinations of the genes that encode GluCl subunits. We quantified the loss-of-function effects on three traits: (i) multi-generational competitive fitness, (ii) fecundity, and (iii) development. In competitive fitness and development assays, we found that a deletion of the beta-tubulin gene ben-1 conferred albendazole resistance, but ivermectin resistance required the loss of two GluCl genes (avr-14 and avr-15). The fecundity assays revealed that loss of ben-1 did not provide any fitness benefit in albendazole conditions and that no GluCl deletion mutants were resistant to ivermectin. Next, we searched for evidence of multi-drug resistance across the three traits. Loss of ben-1 did not confer resistance to ivermectin, nor did loss of any single GluCl subunit or combination confer resistance to albendazole. Finally, we assessed the development of 124 C. elegans wild strains across six benzimidazoles and seven macrocyclic lactones to identify evidence of multi-drug resistance between the two drug classes and found a strong phenotypic correlation within a drug class but not across drug classes. Because each gene affects various aspects of nematode physiology, these results suggest that it is necessary to assess multiple fitness traits to evaluate how each gene contributes to anthelmintic resistance.
Topics: Animals; Caenorhabditis elegans; Anthelmintics; Drug Resistance; Ivermectin; Alleles; Genetic Fitness; Albendazole; Caenorhabditis elegans Proteins; Chloride Channels; Tubulin; Selection, Genetic
PubMed: 38768235
DOI: 10.1371/journal.ppat.1012245 -
Cureus Apr 2024We report two cases of diffuse unilateral subacute neuroretinitis (DUSN) where multimodal imaging was used to assist in locating the nematode. The first case presented...
We report two cases of diffuse unilateral subacute neuroretinitis (DUSN) where multimodal imaging was used to assist in locating the nematode. The first case presented with clusters of migrating choroiditis with a suspicious tiny visualized worm noted on serial fundus photography. The second case had an atypical presentation with extensive exudative retinal detachment and a suspicious coiled worm in the subretinal space noted on optical coherence tomography. Both cases received oral albendazole for six weeks while the first case received additional argon laser photocoagulation to the suspected nematode. Both cases showed resolution of the ocular inflammation upon completion of treatment with no further recurrences. DUSN should be suspected in young and healthy patients with unexplained unilateral inflammatory eye disease with severe loss of vision. This series highlights the challenges faced in identifying the nematode in cases with suspected DUSN.
PubMed: 38765355
DOI: 10.7759/cureus.58510 -
JPGN Reports May 2024This case report presents a rare complication of hepatic cystic echinococcosis in a 12-year-old Latino male, residing in a nonendemic region, who developed long-term...
This case report presents a rare complication of hepatic cystic echinococcosis in a 12-year-old Latino male, residing in a nonendemic region, who developed long-term sequelae of portal vein thrombosis accompanied by the emergence of a hyper-vascular sigmoid colon mass. Portal vein involvement in hepatic cystic echinococcosis is exceedingly uncommon, with limited documented cases. The presentation of the patient included intermittent hematochezia, abdominal pain, and fatigue. Imaging revealed liver cysts and chronic portal vein thrombosis with cavernous transformation, resulting in portal hypertension. Notably, the patient also exhibited mesenteric venous thrombosis, further complicating the clinical picture. The diagnosis was confirmed through echinococcus serology testing. Treatment involved a six month course of Albendazole, puncture-aspiration-injection-reaspiration procedure, splenectomy, and splenorenal shunt to alleviate portal hypertension. This case underscores the significance of considering portal hypertension secondary to hepatic cystic echinococcosis, even in nonendemic regions, particularly in pediatric patients with unique clinical presentations.
PubMed: 38756114
DOI: 10.1002/jpr3.12066 -
Cureus Apr 2024Hydatid disease, attributed to the tapeworm , poses a significant health threat in regions where it is endemic. Here, we present a case involving a 15-year-old boy from...
Hydatid disease, attributed to the tapeworm , poses a significant health threat in regions where it is endemic. Here, we present a case involving a 15-year-old boy from rural Pakistan who initially sought medical attention due to a persistent cough and hemoptysis. Despite initially testing negative for serological markers, imaging studies revealed well-defined cysts in both lungs. Confirmation of the diagnosis was achieved through histopathological examination. Management includes albendazole therapy and surgical excision of the cyst. Our case underscores the diagnostic challenges associated with seronegative cases and underscores the importance of considering hydatid disease in endemic regions, irrespective of typical serological markers. This report enhances understanding regarding the clinical presentation, diagnostic approach, and management strategies for pulmonary hydatid cysts.
PubMed: 38741845
DOI: 10.7759/cureus.57958