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The Journal of Pharmacology and... Jun 2024Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease...
Ovarian cancer is the most lethal gynecological malignancy, with a 5-year survival rate of approximately 50%. The dismal prognosis is due in part to metastatic disease and acquired drug resistance to conventional chemotherapies such as taxanes. Colchicine binding site inhibitors (CBSIs) are attractive alternatives to taxanes because they could potentially achieve oral bioavailability and overcome drug resistance associated with the prolonged use of taxanes. VERU-111 is one of the most advanced CBSIs that is orally available, potent, well-tolerated, and has shown good efficacy in several preclinical solid tumor models. Here, we demonstrate for the first time the potency of VERU-111 as well as its efficacy at inhibiting tumor growth and metastasis in an orthotopic ovarian cancer mouse model. VERU-111 has nanomolar potency against ovarian cancer cell lines and strongly inhibits colony formation, proliferation, invasion, and migration. VERU-111 disrupts microtubule formation to induce mitotic catastrophe and, ultimately, apoptosis in a concentration-dependent manner. The efficacy of VERU-111 was comparable with standard chemotherapy paclitaxel, the current first-line treatment for ovarian cancer, with no observed synergy with combination paclitaxel + VERU-111 treatment. , VERU-111 markedly suppressed ovarian tumor growth and completely suppressed distant organ metastasis. Together, these results support VERU-111 for its potential as a novel therapy for ovarian cancer, particularly for late-stage metastatic disease. VERU-111 is an investigational new drug and has comparable efficacy as paclitaxel in suppressing tumor cell proliferation, colony formation, and migration in ovarian cancer models and has potent anti-tumor and anti-metastatic activity in an orthotopic ovarian cancer mouse model. VERU-111 has low systemic toxicity and, unlike paclitaxel, is orally bioavailable and is not a substrate for the major drug efflux transporters, making it a promising and attractive alternative to taxane-based therapy.
PubMed: 38936977
DOI: 10.1124/jpet.124.002298 -
Indian Journal of Dental Research :... Jan 2024Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth...
Melanoma is the ninth most prevalent and the second most lethal tumour. The aetiology and pathogenesis remain uncertain. It occurs in elderly people, over the fifth decade, and is predominant in males. Clinically, they present as an asymptomatic macular or nodular growth. The prognosis is impacted by the size of the tumour and distant metastases. Patients with distant metastases have a 5-year survival rate of less than 30%, constituting metastasis as the major cause of melanoma-related fatality. Currently, the mainstay of treatment for metastatic melanoma is immunotherapy due to the inoperable state, radioresistant nature of the tumour and high chances of cytotoxicity in chemotherapy. A senile male patient, who was diagnosed with oral malignant melanoma of the maxillary buccopalatal gingiva with distant metastasis to the liver and the prostate, is reported here. Although metastasis to the liver is common among malignant melanomas, in this case metastasis to the prostate gland highlights the rarity.
Topics: Humans; Male; Melanoma; Prostatic Neoplasms; Mouth Neoplasms; Liver Neoplasms; Gingival Neoplasms; Aged
PubMed: 38934760
DOI: 10.4103/ijdr.ijdr_376_23 -
MSystems Jun 2024Hypersaline ecosystems display taxonomically similar assemblages with low diversities and highly dense accompanying viromes. The ecological implications of viral...
UNLABELLED
Hypersaline ecosystems display taxonomically similar assemblages with low diversities and highly dense accompanying viromes. The ecological implications of viral infection on natural microbial populations remain poorly understood, especially at finer scales of diversity. Here, we sought to investigate the influence of changes in environmental physicochemical conditions and viral predation pressure by autochthonous and allochthonous viruses on host dynamics. For this purpose, we transplanted two microbiomes coming from distant hypersaline systems (solar salterns of Es Trenc in Spain and the thalassohaline lake of Aran-Bidgol lake in Iran), by exchanging the cellular fractions with the sterile-filtered accompanying brines with and without the free extracellular virus fraction. The midterm exposure (1 month) of the microbiomes to the new conditions showed that at the supraspecific taxonomic range, the assemblies from the solar saltern brine more strongly resisted the environmental changes and viral predation than that of the lake. The metagenome-assembled genomes (MAGs) analysis revealed an intraspecific transition at the ecotype level, mainly driven by changes in viral predation pressure, by both autochthonous and allochthonous viruses.
IMPORTANCE
Viruses greatly influence succession and diversification of their hosts, yet the effects of viral infection on the ecological dynamics of natural microbial populations remain poorly understood, especially at finer scales of diversity. By manipulating the viral predation pressure by autochthonous and allochthonous viruses, we uncovered potential phage-host interaction, and their important role in structuring the prokaryote community at an ecotype level.
PubMed: 38934645
DOI: 10.1128/msystems.00538-24 -
Frontiers in Oncology 2024Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is...
Thyroid-like follicular renal cell carcinoma (TLFRCC), also known as thyroid-like follicular carcinoma of the kidney or thyroid follicular carcinoma like renal tumor, is an exceedingly rare variant of renal cell carcinoma that has only recently been acknowledged. This neoplasm exhibits a distinct follicular morphology resembling that of the thyroid gland. Immunohistochemical analysis reveals positive expression of PAX8, Vimentin, and EMA, while thyroid-specific markers TG and TTF1 are consistently absent. Furthermore, there is a notable absence of any concurrent thyroid pathology on clinical evaluation. Previous reports have suggested that TLFRCC is an indolent, slow-growing malignancy with infrequent metastatic potential. In this report, we present a case of TLFRCC characterized by remarkable ossification and widespread metastasis, including multifocal pulmonary lesions, involvement of the abdominal wall, and infiltration into the psoas muscle. To our knowledge, this represents only the third documented instance of distant metastasis in thyroid follicular renal carcinoma. The current case demonstrates a therapeutic approach that combines radiotherapy with the utilization of toripalimab, a programmed cell death 1 (PD-1) receptor inhibitor, and pazopanib. This treatment regimen was tailored based on comprehensive genomic profiling, which identified mutations in the POLE (catalytic subunit of DNA polymerase epsilon) and ATM (ataxia-telangiectasia mutated) genes, both of which have been implicated in the pathogenesis of various malignant tumors. These findings represent a novel discovery, as such mutations have never been reported in association with TLFRCC. Thus far, this therapeutic approach has proven to be the most efficacious option for treating metastatic TLFRCC among previously reported, and it also marks the first mention of the potential benefits of radiotherapy in managing this particular subtype of renal cell carcinoma.
PubMed: 38933440
DOI: 10.3389/fonc.2024.1352865 -
World Journal of Nuclear Medicine Jun 2024Differentiated thyroid carcinoma (DTC) usually is slow growing and carries a good prognosis. It most commonly tends to spread locally to regional lymph nodes in 20 to...
Unusual Metastatic Sites and Radioiodine Uptake in Patients of Differentiated Thyroid Carcinoma with Atypical Clinical Presentations: Utilization of I-Whole-Body Scintigraphy with Regional SPECT/CT.
Differentiated thyroid carcinoma (DTC) usually is slow growing and carries a good prognosis. It most commonly tends to spread locally to regional lymph nodes in 20 to 60% of patients. The presence of distant metastasis impacts overall survival and prognosis. The lungs, bones, and the brain are typically involved in distant sites with less common metastatic sites that include the liver, kidney, skeletal muscle, adrenal glands, bladder, and skin. These unusual sites are rare and pose a diagnostic challenge and impact clinical decision-making to a great extent. The radioiodine I whole-body scintigraphy with single-photon emission computed tomography/computed tomography can provide a thorough investigation of unusual sites of uptake leading to diagnosis of these metastases. We present a case series of DTC showing unusual sites of metastasis and/or radioiodine uptake in urinary bladder, in the third metacarpal bone of left hand and lastly in the forearm at postoperative hypertrophic scar area.
PubMed: 38933072
DOI: 10.1055/s-0044-1779750 -
Vaccines Jun 2024Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an...
Oligodeoxynucleotides (ODNs) containing unmethylated cytosine-phosphate-guanosine (CpG) motifs are readily recognized by Toll-like receptor 9 on immune cells, trigger an immunomodulatory cascade, induce a Th1 -biased immune milieu, and have great potential as an adjuvant in cancer vaccines. In this study, a green one-step synthesis process was adopted to prepare an amino-rich metal-organic nanoplatform (FN). The synthesized FN nanoplatform can simultaneously and effectively load model tumor antigens (OVA)/autologous tumor antigens (dLLC) and immunostimulatory CpG ODNs with an unmodified PD backbone and a guanine quadruplex structure to obtain various cancer vaccines. The FN nanoplatform and immunostimulatory CpG ODNs generate synergistic effects to enhance the immunogenicity of different antigens and inhibit the growth of established and distant tumors in both the murine E.G7-OVA lymphoma model and the murine Lewis lung carcinoma model. In the E.G7-OVA lymphoma model, vaccination efficiently increases the CD4, CD8, and tetramerCD8 T cell populations in the spleens. In the Lewis lung carcinoma model, vaccination efficiently increases the CD3CD4 and CD3CD8 T cell populations in the spleens and CD3CD8, CD3CD8, and CD11bCD80 cell populations in the tumors, suggesting the alteration of tumor microenvironments from cold to hot tumors.
PubMed: 38932378
DOI: 10.3390/vaccines12060649 -
Pharmaceutics Jun 2024The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis....
The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL's engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis.
PubMed: 38931953
DOI: 10.3390/pharmaceutics16060833 -
Plants (Basel, Switzerland) Jun 2024Long-distance transfer of genetic material and metabolites between rootstock and scions is well documented in homo-grafted hybrids but has rarely been reported in...
Long-distance transfer of genetic material and metabolites between rootstock and scions is well documented in homo-grafted hybrids but has rarely been reported in genetically-distant grafts where the rootstock and scion belong to different families. In this study, we grafted scions onto stocks and obtained 20 vegetative hybrids, / (Vs). After 25 years of growth, we found that the phenotypes of the leaves, internodes, and fruits of the Vs hybrids above the graft union resembled an intermediate phenotype between and and the new traits were stable when propagated vegetatively. We further analyzed genetic differences between Vv plants and Vs hybrids using high-throughput sequencing, while metabolomes were analyzed by liquid chromatography-mass spectrometry (LC-MS). We found a total of 2113 differentially expressed genes (DEGs). GO annotation and KEGG pathway enrichment analysis showed that these DEGs enriched mainly in oxidation-reduction and metabolic processes. Seventy-nine differentially expressed miRNAs (DEMs) containing 27 known miRNAs and 52 novel miRNAs were identified. A degradation analysis detected 840 target genes corresponding to 252 miRNAs, of which 12 DEMs and their corresponding target gene expression levels were mostly negatively correlated. Furthermore, 1188 differential metabolic compounds were identified. In particular, in Vs hybrids, the abundance of the metabolites schizandrin and gomisin as the main medicinal ingredients in were down-regulated and up-regulated, respectively. Our data demonstrated the effects of interfamily grafts on the phenotype, transcript profile and metabolites of the scion, and also provided new insight into the genetic, phenotypic, and metabolic plasticity associated with genetically distant grafted hybrids.
PubMed: 38931108
DOI: 10.3390/plants13121676 -
Journal of Clinical Medicine Jun 2024: Although the role of PET/CT imaging is well established in oncology, its diagnostic value in routine monitoring for recurrent colorectal cancer (CRC) is still...
: Although the role of PET/CT imaging is well established in oncology, its diagnostic value in routine monitoring for recurrent colorectal cancer (CRC) is still controversial. The aim was to evaluate the diagnostic value of F-18 FDG PET/CT in detecting recurrent CRC in correlation with CEA, CA 19-9 levels, and conventional imaging modalities (CIM). Between 2009 and 2023, a retrospective study was performed including 134 CRC patients referred for PET/CT imaging on the suspicion of recurrence, based on elevated CEA and/or CA 19-9 and/or equivocal CIM findings. According to our institution's Tumor Board CRC protocol, after the initial treatment, which was dependent on the TNM stage (neoadjuvant therapy, primary resection, or adjuvant treatment), patients underwent a standard 5-year surveillance including CEA and CA 19-9 measurements, CIM, and colonoscopy, every six months. The statistics, including univariate and multivariate analyses were conducted using the IBM SPSS 20.0 statistical software. -values < 0.05 were considered statistically significant. Recurrent CRC was confirmed in 54/134 (40.3%) patients with elevated tumor markers. PET/CT showed high diagnostic performance in detecting recurrent CRC with sensitivity, specificity, PPV, NPV, and accuracy of 94.4%, 82.5%, 78.5%, 95.7%, and 87.3%, respectively. The CEA showed a high sensitivity of 98.1% but both low specificity and accuracy of 15% and 48.5%, respectively. The sensitivity, specificity, and accuracy for CA 19-9 and CIM for diagnosis of CRC recurrence were 44.4%, 67.5%, 58.2%, and 51.9%, 98.8%, 79.9%, respectively. The AUC for PET/CT, elevated CEA levels, CIM, and elevated CA 19-9 levels was 0.885 (95% CI: 0.824-0.946; < 0.001), 0.844 (95% CI: 0.772-0.916; < 0.001), 0.753 (95% CI: 0.612-0.844; < 0.001), and 0.547 (95% CI: 0.442-0.652; = 0.358), respectively. Univariate analysis showed that both PET/CT and CIM positive results were highly associated with CRC recurrence ( < 0.001 and < 0.001, respectively). At the same time, gender, mucinous tumor type, presence of initial lymph node metastasis (N+), and presence of initial distant metastasis (M+) had no significance ( = 0.211, = 0.158, = 0.583, and = 0.201, respectively). Our multivariate analysis showed that independent predictors for CRC recurrence are positive PET/CT scans ( < 0.001), positive CIM results ( = 0.001), and elevated CA 19-9 levels ( = 0.023). Although CA 19-9 was not detected as a statistically significant predictor in the univariate analysis ( = 0.358), in a multivariate analysis it was recognized as a significant predicting factor in detecting the CRC recurrence ( = 0.023). F-18 FDG PET/CT showed high diagnostic efficacy in CRC recurrence detection, in correlation with CEA levels, CA 19-9 levels, and CIM. This imaging modality should be routinely integrated into the post-operative follow-op in patients with elevated tumor markers.
PubMed: 38930131
DOI: 10.3390/jcm13123602 -
Journal of Personalized Medicine Jun 2024We conducted a retrospective, longitudinal study on a single-center series of patients who underwent parotidectomy in the management of advanced head and neck...
We conducted a retrospective, longitudinal study on a single-center series of patients who underwent parotidectomy in the management of advanced head and neck non-melanoma skin cancer (hnNMSC). The aim of this study was to identify prognostic factors associated with worse outcomes. Forty-one men and nine women were included. The mean age at the time of surgery was 78.9 years. The 5-year overall survival, disease-specific survival, locoregional recurrence-free survival, and distant metastasis-free survival calculated with Kaplan-Meier curves were 39.9%, 56.3%, 58.6%, and 82.1%, respectively. A univariate analysis showed that the status of the margins, facial nerve direct involvement, lymph vascular invasion, and histological grading were associated with worse outcomes ( < 0.05). Positive margins were associated with worse disease-specific survival also in a multivariate analysis ( = 0.001, HR = 32.02, and CIs 4.338 to 351.3). Because the resection in free margins is the most important prognostic factor, early diagnosis or, in the case of advanced disease, extensive surgical resection with concomitant reconstruction is needed. Adjuvant therapy is indicated in selected cases.
PubMed: 38929852
DOI: 10.3390/jpm14060631