scholarly journals Suppression of Metastatic Melanoma Growth in Lung by Modulated Electro-Hyperthermia Monitored by a Minimally Invasive Heat Stress Testing Approach in Mice

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3872
Author(s):  
Mbuotidem Jeremiah Thomas ◽  
Enikő Major ◽  
Anett Benedek ◽  
Ildikó Horváth ◽  
Domokos Máthé ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Cells ◽  
Therapeutic Option ◽  
Complementary Therapy ◽  
Primary Objective ◽  
Growth Potential ◽  
Normal Lung ◽  
Repeated Treatment ◽  
Dna Double Strand Breaks ◽  
Macrophage Density

Modulated electro-hyperthermia (mEHT) is a novel complementary therapy in oncology which is based on the higher conductivity and permittivity of cancerous tissues due to their enhanced glycolytic activity and ionic content compared to healthy normal tissues. We aimed to evaluate the potential of mEHT, inducing local hyperthermia, in the treatment of pulmonary metastatic melanoma. Our primary objective was the optimization of mEHT for targeted lung treatment as well as to identify the mechanism of its potential anti-tumor effect in the B16F10 mouse melanoma pulmonary metastases model while investigating the potential treatment-related side effects of mEHT on normal lung tissue. Repeated treatment of tumor-bearing lungs with mEHT induced significant anti-tumor effects as demonstrated by the lower number of tumor nodules and the downregulation of Ki67 expression in treated tumor cells. mEHT treatment provoked significant DNA double-strand breaks indicated by the increased expression of phosphorylated H2AX protein in treated tumors, although treatment-induced elevation of cleaved/activated caspase-3 expression was insignificant, suggesting the minimal role of apoptosis in this process. The mEHT-related significant increase in p21waf1 positive tumor cells suggested that p21waf1-mediated cell cycle arrest plays an important role in the anti-tumor effect of mEHT on melanoma metastases. Significantly increased CD3+, CD8+ T-lymphocytes, and F4/80+CD11b+ macrophage density in the whole lung and tumor of treated animals emphasizes the mobilizing capability of mEHT on immune cells. In conclusion, mEHT can reduce the growth potential of melanoma, thus offering itself as a complementary therapeutic option to chemo- and/or radiotherapy.

scholarly journals Current Advancements and Novel Strategies in the Treatment of Metastatic Melanoma

2021 ◽  
Vol 20 ◽  
pp. 153473542199007
Author(s):  
Siddhartha Sood ◽  
Rahul Jayachandiran ◽  
Siyaram Pandey
Keyword(s):  
Metastatic Melanoma ◽  
Complementary Therapy ◽  
Natural Health Products ◽  
Combination Therapies ◽  
Natural Health ◽  
The Past ◽  
Health Products ◽  
Melanoma Treatment ◽  
New Research

Melanoma is the deadliest form of skin cancer in the world with a growing incidence in North America. Contemporary treatments for melanoma include surgical resection, chemotherapy, and radiotherapy. However, apart from resection in early melanoma, the prognosis of patients using these treatments is typically poor. In the past decade, there have been significant advancements in melanoma therapies. Immunotherapies such as ipilimumab and targeted therapies such as vemurafenib have emerged as a promising option for patients as seen in both scientific and clinical research. Furthermore, combination therapies are starting to be administered in the form of polychemotherapy, polyimmunotherapy, and biochemotherapy, of which some have shown promising outcomes in relative efficacy and safety due to their multiple targets. Alongside these treatments, new research has been conducted into the evidence-based use of natural health products (NHPs) and natural compounds (NCs) on melanoma which may provide a long-term and non-toxic form of complementary therapy. Nevertheless, there is a limited consolidation of the research conducted in emerging melanoma treatments which may be useful for researchers and clinicians. Thus, this review attempts to evaluate the therapeutic efficacy of current advancements in metastatic melanoma treatment by surveying new research into the molecular and cellular basis of treatments along with their clinical efficacy. In addition, this review aims to elucidate novel strategies that are currently being used and have the potential to be used in the future.

scholarly journals Sonodynamic Therapy for the Treatment of Intracranial Gliomas

2021 ◽  
Vol 10 (5) ◽  
pp. 1101
Author(s):  
Antonio D’Ammando ◽  
Luca Raspagliesi ◽  
Matteo Gionso ◽  
Andrea Franzini ◽  
Edoardo Porto ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Therapeutic Option ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
High Grade ◽  
Sonodynamic Therapy ◽  
Treatment Protocols ◽  
Ultrasound Waves ◽  
High Grade Gliomas ◽  
Preclinical And Clinical Studies

High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas.

Phase I/II Study of Ipilimumab for Patients With Metastatic Melanoma

2008 ◽  
Vol 26 (36) ◽  
pp. 5950-5956 ◽  
Author(s):  
Jeffrey S. Weber ◽  
Steven O’Day ◽  
Walter Urba ◽  
John Powderly ◽  
Geoff Nichol ◽  
...  
Keyword(s):  
Phase I ◽  
Metastatic Melanoma ◽  
Complete Response ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Multiple Doses ◽  
Group A ◽  
Group B

PurposeThe primary objective of this phase I/II study was to determine the safety and pharmacokinetic profile of either transfectoma- or a hybridoma-derived ipilimumab. Secondary objectives included determination of a maximum-tolerated dose and assessment of clinical activity.Patients and MethodsEighty-eight patients with unresectable stage III or IV melanoma with at least one measurable lesion were treated. Mean age was 59 years, with 65% male and 35% female patients, and 79% of patients had received prior systemic therapy. Single doses of ipilimumab up to 20 mg/kg (group A, single dose), multiple doses up to 5 mg/kg (group A, multiple dose), and multiple doses up to 10 mg/kg (group B) were administered.ResultsSingle dosing up to 20 mg/kg of transfectoma antibody was well tolerated, as were multiple doses up to 10 mg/kg without a maximum-tolerated dose. In group B, dose-limiting toxicity was seen in six of 23 melanoma patients. Grade 3 or 4 immune-related adverse events (irAEs) were observed in 14% of patients (12 of 88 patients), and grade 1 or 2 irAEs were seen in an additional 58%. The half-life of ipilimumab was 359 hours. In group B, there was one partial response (23+ months), one complete response (21+ months), and seven patients with stable disease (SD), for a disease control rate of 39%. Two patients in group B with SD had slow, steady decline in tumor burden that was ongoing at 1 year of observation.ConclusionIpilimumab has activity in patients with metastatic melanoma. Late responses were observed in patients with prolonged SD.

Vaccination With Irradiated, Autologous Melanoma Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor by Adenoviral-Mediated Gene Transfer Augments Antitumor Immunity in Patients With Metastatic Melanoma

2003 ◽  
Vol 21 (17) ◽  
pp. 3343-3350 ◽  
Author(s):  
Robert Soiffer ◽  
F. Stephen Hodi ◽  
Frank Haluska ◽  
Ken Jung ◽  
Silke Gillessen ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Metastatic Melanoma ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Melanoma Cells ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Purpose: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer.Patients and Methods: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 × 106, 4 × 106, or 1 × 107tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals.Results: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease.Conclusion: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

scholarly journals Lamin A/C Mechanosensor Drives Tumor Cell Aggressiveness and Adhesion on Substrates With Tissue-Specific Elasticity

2021 ◽  
Vol 9 ◽  
Author(s):  
Enrica Urciuoli ◽  
Valentina D’Oria ◽  
Stefania Petrini ◽  
Barbara Peruzzi
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Lung Parenchyma ◽  
Normal Lung ◽  
Lamin A ◽  
Osteosarcoma Cell ◽  
Adhesion Properties ◽  
Tissue Specific ◽  
Definition Of ◽  
High Level

Besides its structural properties in the nucleoskeleton, Lamin A/C is a mechanosensor protein involved in perceiving the elasticity of the extracellular matrix. In this study we provide evidence about Lamin A/C-mediated regulation of osteosarcoma cell adhesion and spreading on substrates with tissue-specific elasticities. Our working hypothesis is based on the observation that low-aggressive and bone-resident SaOS-2 osteosarcoma cells express high level of Lamin A/C in comparison to highly metastatic, preferentially to the lung, osteosarcoma 143B cells, thereby suggesting a role for Lamin A/C in tumor cell tropism. Specifically, LMNA gene over-expression in 143B cells induced a reduction in tumor cell aggressiveness in comparison to parental cells, with decreased proliferation rate and reduced migration capability. Furthermore, LMNA reintegration into 143B cells changed the adhesion properties of tumor cells, from a preferential tropism toward the 1.5 kPa PDMS substrate (resembling normal lung parenchyma) to the 28 kPa (resembling pre-mineralized bone osteoid matrix). Our study suggests that Lamin A/C expression could be involved in the organ tropism of tumor cells, thereby providing a rationale for further studies focused on the definition of cancer mechanism of metastatization.

scholarly journals Inhibition of Rac1 attenuates radiation-induced lung injury while suppresses lung tumor in mice

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Ni An ◽  
Zhenjie Li ◽  
Xiaodi Yan ◽  
Hainan Zhao ◽  
Yajie Yang ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Lung Injury ◽  
Mouse Model ◽  
Tumor Cells ◽  
Nuclear Translocation ◽  
Lung Tumor ◽  
Lung Epithelial Cells ◽  
Normal Lung ◽  
Limiting Factor ◽  
Radiation Induced

AbstractThe lung is one of the most sensitive tissues to ionizing radiation, thus, radiation-induced lung injury (RILI) stays a key dose-limiting factor of thoracic radiotherapy. However, there is still little progress in the effective treatment of RILI. Ras-related C3 botulinum toxin substrate1, Rac1, is a small guanosine triphosphatases involved in oxidative stress and apoptosis. Thus, Rac1 may be an important molecule that mediates radiation damage, inhibition of which may produce a protective effect on RILI. By establishing a mouse model of radiation-induced lung injury and orthotopic lung tumor-bearing mouse model, we detected the role of Rac1 inhibition in the protection of RILI and suppression of lung tumor. The results showed that ionizing radiation induces the nuclear translocation of Rac1, the latter then promotes nuclear translocation of P53 and prolongs the residence time of p53 in the nucleus, thereby promoting the transcription of Trp53inp1 which mediates p53-dependent apoptosis. Inhibition of Rac1 significantly reduce the apoptosis of normal lung epithelial cells, thereby effectively alleviating RILI. On the other hand, inhibition of Rac1 could also significantly inhibit the growth of lung tumor, increase the radiation sensitivity of tumor cells. These differential effects of Rac1 inhibition were related to the mutation and overexpression of Rac1 in tumor cells.

scholarly journals Bone Marrow Lymphoid Niche Adaptation to Mature B Cell Neoplasms

2021 ◽  
Vol 12 ◽  
Author(s):  
Erwan Dumontet ◽  
Stéphane J. C. Mancini ◽  
Karin Tarte
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Tumor Cells ◽  
Stromal Cells ◽  
Therapeutic Option ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Niche Adaptation ◽  
Functional Features

B-cell non-Hodgkin lymphoma (B-NHL) evolution and treatment are complicated by a high prevalence of relapses primarily due to the ability of malignant B cells to interact with tumor-supportive lymph node (LN) and bone marrow (BM) microenvironments. In particular, progressive alterations of BM stromal cells sustain the survival, proliferation, and drug resistance of tumor B cells during diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The current review describes how the crosstalk between BM stromal cells and lymphoma tumor cells triggers the establishment of the tumor supportive niche. DLBCL, FL, and CLL display distinct patterns of BM involvement, but in each case tumor-infiltrating stromal cells, corresponding to cancer-associated fibroblasts, exhibit specific phenotypic and functional features promoting the recruitment, adhesion, and survival of tumor cells. Tumor cell-derived extracellular vesicles have been recently proposed as playing a central role in triggering initial induction of tumor-supportive niches, notably within the BM. Finally, the disruption of the BM stroma reprogramming emerges as a promising therapeutic option in B-cell lymphomas. Targeting the crosstalk between BM stromal cells and malignant B cells, either through the inhibition of stroma-derived B-cell growth factors or through the mobilization of clonal B cells outside their supportive BM niche, should in particular be further evaluated as a way to avoid relapses by abrogating resistance niches.

scholarly journals CRISPR/Cas9 Editing of the Polyomavirus Tumor Antigens Inhibits Merkel Cell Carcinoma Growth In Vitro

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1260 ◽  
Author(s):  
Arturo Temblador ◽  
Dimitrios Topalis ◽  
Graciela Andrei ◽  
Robert Snoeck
Keyword(s):  
Cell Cycle ◽  
Cell Carcinoma ◽  
Tumor Cells ◽  
Merkel Cell Carcinoma ◽  
Tumor Antigens ◽  
Therapeutic Option ◽  
Target Sequence ◽  
Merkel Cell ◽  
Guide Rna

Merkel cell carcinoma (MCC) is an aggressive type of skin cancer whose main causative agent is Merkel cell polyomavirus (MCPyV). MCPyV is integrated into the genome of the tumor cells in most MCCs. Virus-positive tumor cells constitutively express two viral oncoproteins that promote cell growth: the small (sT) and the large (LT) tumor antigens (TAs). Despite the success of immunotherapies in patients with MCC, not all individuals respond to these treatments. Therefore, new therapeutic options continue to be investigated. Herein, we used CRISPR/Cas9 to target the viral oncogenes in two virus-positive MCC cell lines: MS-1 and WAGA. Frameshift mutations introduced in the target sequence upon repair of the Cas9-induced DNA break resulted in decreased LT protein levels, which subsequently impaired cell proliferation, caused cell cycle arrest, and led to increased apoptosis. Importantly, a virus-negative non-MCC cell line (HEK293T) remained unaffected, as well as those cells expressing a non-targeting single-guide RNA (sgRNA). Thus, we presumed that the noted effects were not due to the off-target activity of the TAs-targeting sgRNAs. Additionally, WAGA cells had altered levels of cellular proteins involved in cell cycle regulation, supporting the observed cell cycle. Taken together, our findings provide evidence for the development of a CRISPR/Cas9-based therapeutic option for virus-positive MCC.

Comparison of Ceftriaxone and Antipseudomonal β-Lactam Antibiotics Utilized for Potential AmpC β-Lactamase-Producing Organisms

2020 ◽  
pp. 001857872093146
Author(s):  
David M. Peters ◽  
Jessica B. Winter ◽  
Christopher A. Droege ◽  
Neil E. Ernst ◽  
Siyun Liao
Keyword(s):  
Treatment Failure ◽  
Therapeutic Option ◽  
Primary Objective ◽  
Definitive Treatment ◽  
Failure Rates ◽  
Production Methods ◽  
Optimal Dosing ◽  
Definitive Therapy ◽  
Enterobacteriaceae Infections ◽  
Tract Infections

Background: Induction of antibiotic resistance is associated with increased morbidity and mortality in AmpC β-lactamase producing Enterobacteriaceae. The use of ceftriaxone is controversial for treatment of these organisms due to concerns for inducible resistance. This study was designed to compare treatment failure rates between ceftriaxone and antipseudomonal β-lactam antibiotics when used as definitive therapy for organisms most commonly associated with chromosomal AmpC β-lactamase production. Methods: A retrospective, single-center cohort study was performed enrolling patients hospitalized with monomicrobial Enterobacter, Citrobacter, or Serratia spp. infections. The primary objective compared proportion of treatment failure between groups. All patients received either ceftriaxone or an antipseudomonal β-lactam alone within 24 hours of culture finalization, and with a duration of at least 72 hours for definitive treatment. Treatment failure was defined as either clinical failure (abnormal white blood cell count or temperature on day 7 or 14 post-antibiotics) or microbiologic failure (regrowth of the same organism at same site within 14 or 21 days). Results: Of 192 total patients, treatment failure was observed in 24/71 patients (34%) receiving ceftriaxone and in 42/121 patients (35%) receiving antipseudomonal β-lactam ( P = .98). No difference was observed between clinical or microbiologic failure rates between groups. The ceftriaxone group had significantly more patients undergoing treatment for urinary tract infections (51% vs 17%, P < .001), but treatment failure rates remained similar between groups when comparing infections of all other sources. Conclusion: Ceftriaxone has comparable treatment failure rates to antipseudomonal β-lactams for susceptible Enterobacteriaceae infections and may be considered as a therapeutic option. Further, prospective research is needed to validate optimal dosing and application in all sites of infection.

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