Reduction Of Tumor Mass Research Articles

The Outcome of Surgical and Radiotherapy in Central Neurocytoma: A Case Report

BACKGROUND: Central neurocytoma (CN) is an infrequent and non-malignant neuro-epithelial tumor. CN is mostly found in lateral ventricle and may generate obstructive hydrocephalus. Surgical-radiation can increase patient survival and prognosis. This case report presented a rare case about 30-year-old female with CN. CASE PRESENTATION: 30-year-old female came to the hospital with severe headache and vomiting. Brain MRI showed a heterogeneous mass in right lateral ventricle causing obstructive hydrocephalus. The patient undergone partial resection. CN confirmed from histopathological analysis. Afterward, patient received 54 Gy conventional radiotherapy. 3 months after radiation, patient remain asymptomatic and no neurological deficit. Brain MRI evaluation showed slightly reduction of tumor mass (from 4,09 x 3,01 x 4,13 cm before radiation to 4,00 x 3,86 x 3,63 cm after radiation). DISCUSSION: This case report was consistent clinically, radiologically, and histopathologically with intraventricular CN. Headache and vomiting in patient due to the raised intracranial pressure from tumor mass and obstructive hydrocephalus. Headache is a significant and most frequent symptom in intraventricular tumors, may be caused by traction or compression of the pain-sensitive structures such as meningen and intracranial vasculature. Optimal management of CN still remains controversial due to their rarity. However, surgical management with gross total resection is the gold standard of treatment modality, associated with good prognosis and longer progression-free survival. CONCLUSION: Based on clinical characteristic, radiographic finding and histopathological features; this case was consistent with CN of the lateral ventricle. Surgical as the treatment option followed by radiation has led to good clinical outcome in this patient. KEYWORDS: central neurocytoma, hydrocephalus, neuro-epethelial tumor, radiotherapy

FROM ALLOGENIC TRANSPLANTATION TO PRECISION IMMUNE THERAPY

Allogeneic stem cell transplantation (ASCT) represents a model for immune cellular therapy leading to Immune Precision Medicine. The pioneers Georges Mathé in Paris and E. Donall Thomas (Nobel Prize in 1990) in Cooperstown, New York, pioneered ASCCT in the clinical field. In 1958, the first 4 survivors were seen in patients after accidental exposure to lethal or near lethal dose of TBI, in Paris. However, they were subsequently shown to have autologous recovery. Understanding of ABMT immune support begun in 1954 with 1980 Nobel Prize Jean Dausset. The first ABMTs were performed in severe combined immunodeficiencies with the first success observed in 1968 (syngeneic donor), followed in 1973 by unrelated donor ABMT in London. This was also the time of the initiation of registries. Development time in hematological malignancies The first success of ABMT in acute leukemia was observed in 1976 in Seattle with a related donor and in 1976 with an unrelated donor. Thereafter, the evolution will take place within the framework of the risk-benefit balance with reduction of the intensity of the conditioning regimen, the graft versus leukemia (GVL)/graft versus host disease (GVH) balance and the donor extension with umbilical cord blood and more recently the haplo-identical allogeneic ASTC. Autologous SCT was introduced at the beginning of the 80s to amplify reduction in tumor mass, particularly in lymphoid malignancies. Stem cell transplantation as an immune therapy platform Whatever the autologous or allogeneic context, the hematopoietic SCT is an exceptional platform for combining, modulating immunotherapy. In an allogeneic context, by modifying lymphocyte subpopulations, such as the supply of cytotoxic T-cells, the modulation of Tregs, the addition or activation of NK cells have an impact on GVH/GVL balance. The enhancement of anti-tumor cytotoxicity can be brought about using monoclonal antibodies (moAb), the addition of cancer vaccines. In an autologous context, there are some windows of opportunity, in the aplasia period due to the accessibility to stressed cancer cells, and cytokine burst approximately at D15, to add cell-drugs such as NK, γδ T-cells or anti-cancer moAbs, or to associate chimeric antigen receptor (CAR) immune cells such as CAR-NK, as well as immune checkpoint inhibitors depending on the risks. This paves the way for a real dynamic personalized medicine and should cause the methodology for developing these therapeutic strategies to be rethought. Obtaining an optimization of the clinical efficiency which must be preceded by a reflection of biological efficiency can be helped by mathematical models or AI. We have thus developed a mathematical model for the optimization of the use of anti-IL-6. There is a modeling of use of cytotoxic cells. In cellular therapy, the concept of cell-drugs orients towards non-MHC dependent allogenic cells such as NK and γδ T-cells, as well as obtaining them in large batches to reduce production costs. We are entering a new medical era, with new notions such as dynamic, globalized vision, the use of new tools resulting from the digital revolution, new targeted therapies, immunotherapy, the combination of strategies for better efficiency: the Immune Precision Medicine.

Radiotherapy Protocol of Central Neurocytoma for Resource-limited Settings in the Absence of Official Guidelines: A Case Report and Review of the Literature

BACKGROUND: Central neurocytoma (CN) is one of the rarest brain tumors which can cause considerable threats to the patient. Studies and trials regarding its treatment are scarce, and no official guidelines are dedicated to this disease. The main principle of treatment generally consists of surgery and radiotherapy. The choice of radiotherapy is divided into conventional fractionated radiotherapy and stereotactic radiosurgery (SRS). However, access to SRS in developing countries such as Indonesia is still limited. AIM: We report a case delineating the timeline and process of treatment in CN with a review of the literature. METHODS: We report the case of a 29-year-old woman with a solid inhomogeneous mass (AP 5.63 × CC 5.36 × LL 5.16 cm) in the right ventricle, attached to the septum pellucidum, as displayed on the magnetic resonance imaging (MRI). The patient had been vomiting for the past three weeks and presented with bidirectional horizontal nystagmus. RESULTS: Cognitive evaluation with Montreal Cognitive Assessment (MoCA-Ina) demonstrated a mild cognitive impairment. Biopsy was performed, and pathology analysis revealed some cells with fibrillary background and some with a honeycomb-like appearance. The immunohistochemistry staining showed positive results with synaptophysin and neuronal nuclear protein. According to the WHO classification of the central nervous system tumors, the profile favored CN Grade II. Subtotal resection (STR) was performed to reduce the tumor mass, which was measured with MRI 2-month post-surgery (AP 4.09 × CC 3.01 × LL 4.13 cm) and then followed by an external radiation program. Using intensity modulated radiation therapy (IMRT), a total dose of 54 Gy was given in 27 fractions, with the average planning target volume of 54.3 Gy. There was a minuscule reduction in tumor mass as seen in post-radiotherapy MRI (AP 4.00 × CC 3.86 × LL 3.63 cm). After the last session and at the 18-month follow-up, the patient did not have any complaints or abnormalities during clinical assessment. Reevaluation using MoCA-Ina showed an improved cognitive function. CONCLUSIONS: In line with recent evidence, we demonstrated that STR followed by IMRT with the dosage of 54 Gy in 27 fractions was a feasible treatment strategy for CN that resulted in cognitive improvement, with no side effects.

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

Effects of Non-Opioid Analgesics on the Cell Membrane of Skin and Gastrointestinal Cancers.

Skin and gastrointestinal cancer cells are the target of research by many scientists due to the increasing morbidity and mortality rates around the world. New indications for drugs used in various conditions are being discovered. Non-opioid analgesics are worth noting as very popular, widely available, relatively cheap medications. They also have the ability to modulate the membrane components of tumor cells. The aim of this review is to analyze the impact of diclofenac, ibuprofen, naproxen, acetylsalicylic acid and paracetamol on skin and gastrointestinal cancers cell membrane. These drugs may affect the membrane through topical application, at the in vitro and in vivo level after oral or parenteral administration. They can lead to up- or downregulated expression of receptors, transporters and other molecules associated with plasma membrane. Medications may also alter the lipid bilayer composition of membrane, resulting in changes in its integrity and fluidity. Described modulations can cause the visualization of cancer cells, enhanced response of the immune system and the initiation of cell death. The outcome of this is inhibition of progression or reduction of tumor mass and supports chemotherapy. In conclusion, non-opioid analgesics may be used in the future as adjunctive therapy for the treatment of these cancers.

Improvement of Kiteplatin Efficacy by a Benzoato Pt(IV) Prodrug Suitable for Oral Administration.

Kiteplatin, [PtCl2(cis-1,4-DACH)] (DACH = diaminocyclohexane), contains an isomeric form of the oxaliplatin diamine ligand trans-1R,2R-DACH and has been proposed as a valuable drug candidate against cisplatin- and oxaliplatin-resistant tumors, in particular, colorectal cancer. To further improve the activity of kiteplatin, it has been transformed into a Pt(IV) prodrug by the addition of two benzoato groups in the axial positions. The new compound, cis,trans,cis-[PtCl2(OBz)2(cis-1,4-DACH)] (1; OBz = benzoate), showed cytotoxic activity at nanomolar concentration against a wide panel of human cancer cell lines. Based on these very promising results, the investigation has been extended to the in vivo activity of compound 1 in a Lewis Lung Carcinoma (LLC) model and its suitability for oral administration. Compound 1 resulted to be remarkably stable in acidic conditions (pH 1.5 to mimic the stomach environment) undergoing a drop of the initial concentration to ~60% of the initial one only after 72 h incubation at 37 °C; thus resulting amenable for oral administration. Interestingly, in a murine model (2·106 LLC cells implanted i.m. into the right hind leg of 8-week old male and female C57BL mice), a comparable reduction of tumor mass (~75%) was observed by administering compound 1 by oral gavage and the standard drug cisplatin by intraperitoneal injection, thus indicating that, indeed, there is the possibility of oral administration for this dibenzoato prodrug of kiteplatin. Moreover, since the mechanism of action of Pt(IV) prodrugs involves an initial activation by chemical reduction to cytotoxic Pt(II) species, the reduction of 1 by two bioreductants (ascorbic acid/sodium ascorbate and glutathione) was investigated resulting to be rather slow (not complete after 120 h incubation at 37 °C). Finally, the neurotoxicity of 1 was evaluated using an in vitro assay.

Improvement of STING-mediated cancer immunotherapy using immune checkpoint inhibitors as a game-changer.

Various cancer therapies, such as surgery, radiotherapy, chemotherapy, and immunotherapy, have been used to treat cancer. Among cancer immunotherapies, stimulators of interferon genes (STING) activate various immune cells and induce them to attack cancer cells. However, the secretion of type I interferon (IFN α and β) increases after stimulation of the immune cell as a side effect of STING agonist, thereby increasing the expression of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Therefore, it is necessary to reduce the side effects of STING agonists and maximize cancer treatment by administering combination therapy. Tumor-bearing mice were treated with cisplatin, tumor-specific peptide, neoantigen, DMXAA (STING agonist), and immune checkpoint inhibitor (ICI). The combination vaccine group showed a reduction in tumor mass, an increased survival rate, and IFN-γ+ (interferon gamma) CD8+ (cluster of differentiation 8) T cells in the spleen and TME. The distribution of immune cells in the spleen and TME was confirmed, and the number of active immune cells increased, whereas that of immunosuppressive cells decreased. When measuring cytokine levels in the tumor and serum, the levels of pro-inflammatory cytokines increased and anti-inflammatory cytokines decreased. This study demonstrated that when various cancer therapies are combined to treat cancer, it can lead to an anticancer immune synergistic effect by increasing the immune response and reducing side effects.

Ex Vivo Irradiation of Lung Cancer Stem Cells Identifies the Lowest Therapeutic Dose Needed for Tumor Growth Arrest and Mass Reduction In Vivo.

Radiotherapy represents a first-line treatment for many inoperable lung tumors. New technologies offer novel opportunities for the treatment of lung cancer with the administration of higher doses of radiation in smaller volumes. Because both therapeutic and toxic treatment effects are dose-dependent, it is important to identify a minimal dose protocol for each individual patient that maintains efficacy while decreasing toxicity. Cancer stem cells sustain tumor growth, promote metastatic dissemination, and may give rise to secondary resistance. The identification of effective protocols targeting these cells may improve disease-free survival of treated patients. In this work, we evaluated the existence of individual profiles of sensitivity to radiotherapy in patient-derived cancer stem cells (CSCs) using both in vitro and in vivo models. Both CSCs in vitro and mice implanted with CSCs were treated with radiotherapy at different dose intensities and rates. CSC response to different radiation doses greatly varied among patients. In vitro radiation sensitivity of CSCs corresponded to the therapeutic outcome in the corresponding mouse tumor model. On the other side, the dose administration rate did not affect the response. These findings suggest that in vitro evaluation of CSCs may potentially predict patients’ response, thus guiding clinical decision.

Role of aerobic exercise training on tumor‐infiltrated immune cells

BackgroundDespite the remarkable treatment progress in the last decades, cancer remains the second leading cause of death in the world. Therefore, strategies capable of attenuating tumor initiation, progression and aggressiveness are important for reducing incidence and mortality caused by cancer. Considering this, it is well known that aerobic exercise training (AET) promotes several beneficial adaptations in the body, and it has emerged as a possible strategy to attenuate tumor progression. However, the mechanisms underlining the beneficial effects of AET on tumor progression are still unclear. Aim: Therefore, this study intended to evaluate whether AET could positively modify the tumor microenvironment, favoring infiltration of “antitumor” immune cells, and/or reducing the amount of “protumor” immune cells, consequently attenuating tumor progression.MethodsTo test this, Balb/c mice were submitted to a moderate intensity AET (60% of maximal aerobic capacity, 5 days/week, 1 hour/day, in a treadmill) for 1 month before being inoculated with 1x106 CT26 colon carcinoma cells (subcutaneous injection). The AET protocol was maintained during tumor progression, and the last exercise session was performed 48 hours before animals were sacrificed (9 days after tumor cells inoculation). Tumor volume and body weight were measured daily. Experimental groups were divided into control (healthy sedentary mice), CT26 SED (sedentary tumor‐bearing mice) and CT26 TR (trained tumor‐bearing mice). Tumors were harvested at day 9 and digested with collagenase IV and DNAse. After that, tumor leukocytes were separated by a Percoll gradient. Tumor‐infiltrated dendritic cells, macrophages, natural killer cells (NK), and T lymphocytes were measured by flow cytometry. Statistical analysis: Anova One‐way, Duncan post hoc, p<0.05. Ethical committee approval: CEUA EEFE‐USP 2017/02.ResultsTumor‐bearing mice submitted to AET presented an attenuated tumor progression when compared with CT26 SED group, with significant reduction in tumor volume and mass (ex vivo). AET significantly increased the total amount of tumor‐infiltrated leukocytes (CD45+), which included an increase in the percentage of NK cells, total, activated and effector memory CD8+ T cells, and effector memory CD4+ T cells in CT26 TR when compared to CT26 SED. Although there were no significant changes in the tumor amount of total and activated CD4+ T cells, the CD4+/CD8+ ratio was significantly reduced in CT26 TR comparing with CT26 SED mice, suggesting that the balance between CD4+ and CD8+ T cells in trained mice tumors favored a cytotoxic/effector T lymphocyte profile. Moreover, the percentage of tumor‐infiltrated regulatory T cells (Tregs) in CT26 TR was significantly decreased when compared to CT26 SED mice. No significant changes were found for dendritic cells and macrophages (types M1 and M2).ConclusionAET increases tumor‐infiltrated amounts of cytotoxic/effector immune cells, such as NK and CD8+ T cells, while decreasing the percentage of Tregs in a colon cancer animal model. These data suggest that AET can attenuate tumor growth by modulation of tumor‐infiltrated immune cells number and profile.

Juglone and KPT6566 Suppress the Tumorigenic Potential of CD44+CD133+ Tumor-Initiating Caco-2 Cells In Vitro and In Vivo.

Pin1, a cis/trans isomerase of peptidyl-prolyl peptide bonds, plays a crucial role in the pathogenesis of many human cancers. Although chemical inhibitors of Pin1 show potent antitumor therapeutic properties against various cancers, their effect on colorectal cancer, especially colorectal tumor-initiating cells, remains unknown. Here, we investigated the effect of Juglone and KPT6566 on Caco-2 cells and tumor-initiating Caco-2 cells. Juglone and KPT6566 inhibited cell growth and colony formation, and induced apoptosis of Caco-2 cells. We also found that Juglone and KPT6566 downregulated expression of G1-phase-specific cyclins and cyclin-dependent kinases in a time-dependent manner, consistent with suppression of Caco-2 cell proliferation and colony formation. Although tumor-initiating cells are thought to be responsible for resistance to traditional chemotherapeutic drugs, our experiments demonstrate that Juglone or KPT6566 kill both tumor-initiating and non-tumor-initiating Caco-2 cells with equal or similar efficacy. Finally, when CD44+CD133+ tumor-initiating Caco-2 cells were injected into NSG mice, Juglone or KPT6566 led to a meaningful reduction in tumor volume and mass compared with tumors isolated from mice that received control treatment. Overall, these results indicate that chemical Pin1 inhibitors may be a valuable therapeutic option against colorectal tumor-initiating cancer cells.

HOA-DN30: a highly effective humanized single-arm MET antibody inducing remission of ‘MET-addicted’ cancers

BackgroundThe tyrosine kinase receptor encoded by the MET oncogene is a major player in cancer. When MET is responsible for the onset and progression of the transformed phenotype (MET-addicted cancers), an efficient block of its oncogenic activation results in potent tumor growth inhibition.MethodsHere we describe a molecular engineered MET antibody (hOA-DN30) and validate its pharmacological activity in MET-addicted cancer models in vitro and in vivo. Pharmacokinetics and safety profile in non-human primates have also been assessed.ResultshOA-DN30 efficiently impaired MET activation and the intracellular signalling cascade by dose and time dependent removal of the receptor from the cell surface (shedding). In vitro, the antibody suppressed cell growth by blocking cell proliferation and by concomitantly inducing cell death in multiple MET-addicted human tumor cell lines. In mice xenografts, hOA-DN30 induced an impressive reduction of tumor masses, with a wide therapeutic window. Moreover, the antibody showed high therapeutic efficacy against patient-derived xenografts generated from MET-addicted gastric tumors, leading to complete tumor regression and long-lasting effects after treatment discontinuation. Finally, hOA-DN30 showed a highly favorable pharmacokinetic profile and substantial tolerability in Cynomolgus monkeys.ConclusionshOA-DN30 unique ability to simultaneously erase cell surface MET and release the ‘decoy’ receptor extracellular region results in a paramount MET blocking action. Its remarkable efficacy in a large number of pre-clinical models, as well as its pharmacological features and safety profile in non-human primates, strongly envisage a successful clinical application of this novel single-arm MET therapeutic antibody for the therapy of MET-addicted cancers.

Coumarin-Palladium(II) Complex Acts as a Potent and Non-Toxic Anticancer Agent against Pancreatic Carcinoma Cells.

Pancreatic carcinoma still represents one of the most lethal malignant diseases in the world although some progress has been made in treating the disease in the past decades. Current multi-agent treatment options have improved the overall survival of patients, however, more effective treatment strategies are still needed. In this paper we have characterized the anticancer potential of coumarin-palladium(II) complex against pancreatic carcinoma cells. Cells viability, colony formation and migratory potential of pancreatic carcinoma cells were assessed in vitro, followed by evaluation of apoptosis induction and in vivo testing on zebrafish. Presented results showed remarkable reduction in pancreatic carcinoma cells growth both in vitro and in vivo, being effective at micromolar concentrations (0.5 μM). Treatments induced apoptosis, increased BAX/BCL-2 ratio and suppressed the expression of SOX9 and SOX18, genes shown to be significantly up-regulated in pancreatic ductal adenocarcinoma. Importantly, treatments of the zebrafish-pancreatic adenocarcinoma xenografts resulted in significant reduction in tumor mass, without provoking any adverse toxic effects including hepatotoxicity. Presented results indicate the great potential of the tested compound and the perspective of its further development towards pancreatic cancer therapy.

Profile and Clinical Outcome of Children with Wilms' Tumor treated at a Tertiary Care Centre, India.

Pritanjali SinghBackground Wilms' tumor (WT) is the most common kidney tumor of the pediatric age group. The outcome of WT has improved due to the evolution of the treatment approach. A prospective observational study was conducted at All India Institute of Medical Sciences (AIIMS), Patna, to analyze the clinical profile along with the response and outcome to neoadjuvant chemotherapy according to the International Society of Pediatric Oncology (SIOP) protocol. Materials and Methods In total, 28 patients of WT visited the radiotherapy department from January 2015 to December 2019. Results Gender distribution showed male preponderance with a median age at diagnosis was 31 months. The abdominal lump was the dominant clinical presentation. The median volume of tumor at diagnosis was 359.48 mL (52.67-1805.76). Radiological staging workup shows that stage I, II, III, IV, and V were 7.1%, 39.3%, 39.3%, 10.7%, and 3.6% respectively. Neoadjuvant chemotherapy (NACT) was received by all patients. Also, 71.4% of patients showed > 50% of tumor volume reduction, while 28.6% of patients showed < 50% of tumor mass reduction. There was a statistically significant decrease in the tumor volume reduction following neoadjuvant chemotherapy ( p < 0.001). There was a statistically significant stage down ( p = 0.018) of the disease. Bivariate correlation studies showed recurrence was correlating statistically significantly with age < 24 months ( p = 0.049), locoregional lymph nodes ( p = 0.008), histopathological subtypes ( p < 0.001), stage of the disease ( p = 0.003), and risk groups ( p < 0.001). In addition, 25% of patients developed recurrence during the median follow-up of 25 months. The median disease-free survival (DFS) and overall survival (OS) were not reached. The mean DFS and OS were 48 and 59.13 months, respectively. One- and 3-year DFS were 100% and 64.1%, respectively. One- and 3-year OS were 100% and 75% respectively. Conclusion Our study suggests that most of the patients presented at an advanced stage, thus rendering most of the cases difficult to undergo surgery at presentation. Neoadjuvant chemotherapy followed by surgery may be considered a well-balanced approach with a comparable response and survival outcomes.

In Vitro and In Vivo Evaluation of a Cyclic LyP-1-Modified Nanosystem for Targeted Endostatin Delivery in a KYSE-30 Cell Xenograft Athymic Nude Mice Model.

This work investigated the use of LyP-1 as a homing peptide for p32 receptor targeting on the surface of an endostatin (ENT)-loaded chitosan-grafted nanosystem intended for intracellular delivery of ENT and mitochondrial targeting in a squamous cell carcinoma (SCC) cell line (KYSE-30) model. The angiogenic factors for VEGF-C and MMP2 were assessed with in vivo evaluation of the nanosystem upon ENT release and tumor necrosis in nude mice with a KYSE-30 cell xenograft. The LyP-1-modified nanosystem revealed a three-fold decrease in proliferation at 1000 µg/mL compared with the control and facilitated receptor-mediated cellular uptake and internalization. In addition, targeting of the Lyp-1-functionalized nanosystem to mitochondrial and nuclear proteins in vitro and in vivo was achieved. Up to 60% inhibition of KYSE-30 cell migration was observed and the expressions of VEGF-C and MMP-2 as angiogenic markers were reduced 3- and 2-fold, respectively. A marked reduction in tumor mass was recorded (43.25%) with the control, a 41.36% decrease with the nanoparticles and a 61.01% reduction with the LyP-1-modified nanosystem following treatment in mice. The LyP-1-functionalized nanosystem targeted tumor lymphatics, instigated nuclear rupture and mitochondrial distortion, and decreased cell proliferation and migration with inhibition of VEGF-C and MMP2 expression.

Antitumor Effect of Manool in a Murine Melanoma Model.

The manool diterpene, found in abundance in Salvia officinalis L., showed a selective cytotoxic effect against murine melanoma cells. Therefore, the present study aimed to evaluate the antitumor potential of manool in a murine melanoma model, administered by three routes: oral, subcutaneous, and intraperitoneal. In addition, the antimelanoma effect of manool (orally) combined with cisplatin (subcutaneous) was evaluated. The results obtained revealed that manool, administered by the three routes, was able to significantly decrease the mass and frequency of mitosis of the tumor tissue. The data obtained revealed that manool, at a dose of 20 mg/kg, was able to significantly decrease the tumor mass when administered by the three routes, with the percentages of reduction being equivalent to 62.4% (oral), 48.5% (intraperitoneal), and 38.8% (subcutaneous), without toxic effects. The treatment of manool plus cisplatin led to 86.7% reduction in tumor mass, higher than that observed in treatment with manool or cisplatin alone (50.7%), although signs of toxicity have been observed. The results also showed that treatments with manool (20 mg/kg orally) and/or cisplatin did not alter the activity of caspase 3 cleaved in tumor tissue. Therefore, manool revealed a promising antimelanoma effect, but without involvement of the caspase 3 cleaved pathway.

Potential of Mycobacterium tuberculosis chorismate mutase (Rv1885c) as a novel TLR4-mediated adjuvant for dendritic cell-based cancer immunotherapy

ABSTRACT For clinical application by dendritic cell (DC)-based cancer immunotherapy, a proper adjuvant system to elicit a strong anticancer immune response is needed. Here, we investigated the potential of chorismate mutase (TBCM, Rv1885c), a putative Mycobacterium tuberculosis (TB) virulence factor, as an immunoadjuvant in DC-based tumor immunotherapy. First, we found that TBCM functionally activated DCs by upregulating costimulatory molecules, increasing the secretion of proinflammatory cytokines, enhancing migration and inducing the Th1-type immune response in a dose-dependent manner via TLR4-mediated signaling. In addition, subcutaneous injection of TBCM-activated DCs loaded with cell lysates led to reduced tumor mass, enhanced mouse survival and lowered tumor incidence in lung carcinoma (LLC) cell-bearing mice. This is mainly mediated by functional cytotoxic T lymphocyte-mediated oncolytic activity and inhibition of cancer proliferation- and metastasis-related genes. Moreover, TBCM-induced DCs can also generate memory CD4 T cells and exert long-term tumor prevention effects. In conclusion, our findings suggest that TBCM (Rv1885c), a novel TLR4 agonist, could be used as an immunoadjuvant for DC-based cancer immunotherapy.

Combination of Photodynamic Therapy and Therapeutic Vaccination.

Tumor ablation by photodynamic therapy (PDT) results in a strong reduction in tumor mass and can lead to improved recognition of tumor cells by the immune system. This supports combinations of PDT and immunotherapy for the treatment of advanced tumors. Therapeutic vaccination is a tumor-specific type of cancer immunotherapy that aims to directly strengthen the immune response against tumor antigens. In this chapter, we describe the combination of PDT and therapeutic vaccination using a peptide tumor antigen vaccine.

Tumor venéreo transmissível canino com remissão espontânea: estudo de caso com ênfase aos exames clínico e citopatológico para monitoramento da evolução tumoral

Abstract The canine transmissible venereal tumor (TVTC) is a neoplasm transmitted mainly through copulation and with a high incidence in stray dogs in Brazil. In the process of tumor evolution of TVTC, the progression, stationary and regression phases are recognized. The host immunity is related to the disease’s biological behavior, however, spontaneous regression observation in cases of naturally occurring TVTC is uncommon. A canine patient was attended, after beeing rescued from the street, due to an ulcerated mass in the external genitália and tick infestation. Cytopathological examination, which diagnosed TVTC, and laboratory tests that showed mild anemia and severe thrombocytopenia were performed. In view of the impossibility of carrying out other exams, it was made the presumptive diagnosis of canine monocytic ehrlichiosis (CME), and treatment was instituted. During follow-up it was observed quick improvement in clinical signs and laboratory changes, as well as a reduction in tumor mass. A new cytopathological evaluation was carried out, and was verified increase in mature lymphocytes and plasmocytes in the midst of the tumor cells, finding compatible with the stationary phase of the disease. From that moment on, it was decided to perform only clinical and cytopathological follow-up. In the following evaluations, continuous clinical remission and cytopathological findings compatible with those described in the regression phase were observed, until its complete remission. It is considered that the improvement in the general health of the patient after the treatment of CME is related to the spontaneous regression of TVTC, and that simultaneous performance of serial clinical and cytopathological exams may be feasible and useful for monitoring the stages of evolution of TVTC.

Effect of Astragali Radix-Curcumae Rhizoma compatibility combined with 5-fluorouracil on Th17/Treg balance and tumor-related mRNA and protein expression in orthotopic xenograft model mice of CT26.WT colorectal carcinoma

Astragali Radix-Curcumae Rhizoma(AR-CR) is a combination commonly used in the clinical treatment of tumors. Based on the T helper 17(Th17)/regulatory T cell(Treg) balance, the present study explored the possible mechanism of AR-CR combined with 5-fluorouracil(5-FU) on the tumor growth of orthotopic xenograft model mice of colorectal carcinoma. Ninety male BALB/c mice were randomly divided into nine groups, i.e., a blank group, a model group, a 5-FU group, high-, medium-, and low-dose AR-CR(2∶1) groups, and high-, medium-, and low-dose AR-CR+5-FU groups, with 10 mice in each group. The orthotopic xenograft model of CT26.WT colorectal carcinoma was induced in mice except those in the blank group. Twenty-four hours after the ope-ration, mice in the blank group and the model group received normal saline by gavage(10 mL·kg~(-1), once per day), and those in the 5-FU group received 5-FU by intraperitoneal injection(25 mg·kg~(-1), once every other day). Mice in the AR-CR groups received AR and CR decoctions by gavage(12, 6, and 3 g·kg~(-1), once a day) and those in the combination groups received AR and CR decoctions and 5-FU(doses and administration methods were the same as above). After intervention for three weeks, all mice were sacrificed and tumor tissues were collected. The tumor mass was weighed and the average tumor weight was calculated. The changing trend of Th17/Treg(%) in the CD4~+T lymphocytes of the spleen tissues of the mice in each group was detected. The mRNA expression in the blood and protein expression in the tumor tissues of transforming growth factor-β(TGF-β), tumor necrosis factor-α(TNF-α), interferon-γ(IFN-γ), Smad4, N-cadherin, matrix metalloproteinase-7(MMP-7) were detected. The experimental results revealed that compared with the model group, the groups with drug intervention showed reduced tumor mass(P&lt;0.01), decreased CD4~+IL-17~+ in the spleen tissues to varying degrees(P&lt;0.001), and increased proportion of CD4~+Foxp3~+(P&lt;0.001 or P&lt;0.05), indicating that Th17/Treg maintained dynamic balance, and the effect of the combination groups was predominant. Additionally, the mRNA expression in the blood and protein expression in the tumor tissues of TGF-β, TNF-α, IFN-γ, Smad4, N-cadherin, and MMP-7 declined to varying degrees in a dose-dependent manner(P&lt;0.01 or P&lt;0.001). The AR-CR combined with 5-FU can inhibit the tumor growth of orthotopic xenograft model mice of CT26.WT colorectal carcinoma. The mechanism may be related to maintenance of Th17/Treg dynamic balance in the body and down-regulation of TGF-β, TNF-α, IFN-γ, Smad4, N-cadherin, and MMP-7 expression.

SIRT5 promotes non-small cell lung cancer progression by reducing FABP4 acetylation level.

This study evaluates the role of SIRT5 in non-small cell lung cancer (NSCLC) progression and explores the underlying mechanism. The expression and correlation of SIRT5 and FABP4 in lung cancer were analyzed by the GEPIA database. The expression levels of SIRT5 and FABP4 in NSCLC cells were measured by qRT-PCR and western blot. The effect of SIRT5 and FABP4 on NSCLC cell development was determined. The interaction between SIRT5 and FABP4 was analyzed by co-immunoprecipitation (Co-IP). Tumor mass and volume were measured in nude mice to study the effect on the growth of NSCLC transplanted tumors. GEPIA database analysis showed that SIRT5 was highly expressed, while FABP4 was lowly expressed in lung cancer, which was consistent with the detection results of SIRT5 and FABP4 expressions in NSCLC cell lines. The expression of SIRT5 was negatively correlated with FABP4. Transfection of sh-SIRT5 in NSCLC cells led to a decrease in NSCLC cell malignancy, which was counteracted by sh-FABP4 transfection. Western blot and Co-IP showed that SIRT5 reduced FABP4 expression by inducting the deacetylation of FABP4. Nude mice in the sh-SIRT5 + sh-FABP4 group had significantly reduced tumor mass and volume compared with those in the sh-FABP4 group, while the tumor mass and volume in the sh-SIRT5 + sh-FABP4 group were increased in comparison to those in the sh-SIRT5 group. To conclude, collected evidence showed that SIRT5 promoted NSCLC cell development by reducing FABP4 acetylation level.