The exploitation of the physiologic processing and presenting machinery of dendritic cells (DCs) by in vivo loading of tumor-associated antigens may improve the immunogenic potential and clinical ...efficacy of DC-based cancer vaccines. The approach developed by our group was based on the clinical observation that some patients treated with the infusion of donor lymphocytes transduced to express the HSV-TK suicide gene for relapse of hematologic malignancies, after allogeneic hematopoietic stem cell transplantation, developed a T cell-mediated immune response specifically directed against the HSV-TK gene product.We demonstrated that lymphocytes genetically modified to express HSV-TK as well as self/tumor antigens, acting as antigen carriers, efficiently target DCs in vivo in tumor-bearing mice. The infusion of TRP-2-transduced lymphocytes induced the establishment of protective immunity and long-term memory in tumor-bearing mice by cross-presentation of the antigen mediated by the CD11c(+)CD8a(+) DCs subset. A similar approach was applied in a clinical setting. Ten patients affected by MAGE-3(+) metastatic melanoma were treated with autologous lymphocytes retrovirally transduced to express the MAGE-3 tumor antigen. In three patients, the treatment led to the increase of MAGE-3 specific CD8+ and CD4+ effectors and the development of long-term memory, which ultimately correlated with a favorable clinical outcome. Transduced lymphocytes represent an efficient way for in vivo loading of tumor-associated antigens of DCs.
Melanoma is the most lethal dermal tumor, and a high recurrence rate and skin defects are two main serious problems. An antimelanoma material,which effectively inhibits tumor recurrence and possesses ...excellent biocompatibility, is urgently needed to treat melanoma. In this study, we developed a novel antitumor Yb
Yb(NO
containing chitosan hydrogel (Yb-CS hydrogel) by dissolving Yb(NO
and chitosan in acetic acid solution and forming composite hydrogels by a freeze-drying process after adding NaOH to the mixed solution. In vitro studies demonstrated that the Yb
produces effect of inducing cell death in Yb-CS hydrogel. Moreover, we found that the Yb-CS hydrogel inhibited a focal adhesion kinase (FAK)-dependent signaling pathway and induced B-16 cell anoikis. However, the Yb-CS hydrogel was less effective on L929 normal mouse dermal cells. In vivo studies showed that the Yb-CS hydrogel inhibited the recurrence of melanoma in a mouse bare xenograft tumor model. We concluded that the Yb-CS hydrogel could potentially be used in the antimelanoma field, especially in the inhibition of melanoma recurrence.
Background
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Early treatment may improve any chances of preventing metastatic disease, but diagnosis of small UM is ...challenging. Up to 95 % of all UMs carry somatic mutations in the G-coupled proteins GNAQ and GNA11 promoting anchorage-independent growth and proliferation. About 50 % of UMs are fatal. Once metastatic, patients have limited options for successful therapy.
Methods
We have developed functionalized gold nanoparticles (AuNPs) to visualize transcripts of mutant GNAQ mRNA in living cells. In addition to their suitability as a specific tool for GNAQ mutation detection, we have developed a novel linker that enables conjugation of siRNAs to AuNPs allowing for greater and more rapid intracellular release of siRNAs compared to previously described approaches.
Results
Binding of modified AuNPs to matching target mRNA leads to conformational changes, resulting in a detectable fluorescent signal that can be used for mutation detection in living cells. Knockdown of GNAQ with siRNA-AuNPs effectively reduced downstream signals and decreased cell viability in GNAQ mutant uveal melanoma cells.
Conclusion
AuNPs may in future be developed to serve as sensors for mutations of vital importance. The new release system for siRNA-AuNP improves previous systems, which conceivably will be useful for future therapeutic gene regulatory approaches.
The electronic properties of vemurafenib (VB) provide a rational basis for understanding its strong UVA-induced phototoxicity. Thus, solvation of hydrophobic VB by hydrogen bonding solvents controls ...its photophysical, photochemical and photosensitizing properties. Addition of phosphate buffered saline (PBS) to methanol (MeOH) induces a bathochromic shift of the VB absorbance spectrum and a fluorescence emission (λmax = 450 nm, quantum yield (Φ) = 0.011). Phosphorescence (λmax = 461 nm) is observed at 77 K in MeOH. 308 nm laser flash spectroscopy demonstrates that the lifetimes (τ) and quantum yields of the VB triplet state ((3)T(*)(1)) in deaerated MeOH (τMeOH = 0.41 μs, λmax ∼ 380 nm), MeOH-PBS and HSA solutions markedly depend on the microenvironment. A long-lived radical (half-life >200 μs) is also formed. The state (3)T(*)(1) is quenched by O2 and electron donors (Cys and 2'-deoxyguanosine) at a rate constant >1 × 10(9) M(-1) s(-1). UVA-irradiation of VB in air-saturated MeOH or MeOH-PBS solutions produces a UVA-absorbing photoproduct (Φ ∼ 5 × 10(-4)). VB photosensitizes Trp destruction by type I (radical formation) and type II (singlet oxygen ((1)O2) formation) photodynamic reactions (Φ = 0.005). Singlet oxygen production is further demonstrated by the VB-photosensitized His oxidation (ΦMeOH = 0.006).
The unique characteristics of nanostructured chitosan composites provide a higher affinity for negatively charged biological site-specific targeting in delivery of drugs. The therapeutic applications ...of nanostructured chitosan composites in various types of cancers such as melanoma cancer, bladder cancer, breast cancer, lung cancer, colon cancer, pancreatic cancer, metastatic cancer, and prostate cancer are focused. Herein, nanostructured chitosan composites are potential vehicles for controlled drug release of drug. The therapeutic applications of nanostructured chitosan in safe delivery of cancer drugs in the present review may explore a new dimension in the area of biomedical applications of chitosan derivatives.
The use of mushroom extracts has been common practice in traditional medicine for centuries, including the treatment of cancer. Proteins called hydrophobins are very abundant in mushrooms. Here, it ...was examined whether they have antitumor activity. Hydrophobin SC3 of
Schizophyllum commune
was injected daily intraperitoneally starting 1 day after tumor induction in two tumor mouse models (sarcoma and melanoma). SC3 reduced the size and weight of the melanoma significantly, but the sarcoma seemed not affected. However, microscopic analysis of the tumors 12 days after induction revealed a strong antitumor effect of SC3 on both tumors. The mitotic activity of the tumor decreased 1.6- (melanoma) to 2.3-fold (sarcoma), while the vital mass decreased 2.3- (melanoma) to 4.3-fold (sarcoma) compared to the control. Treatment did not cause any signs of toxicity. Behavior, animal growth, and weight of organs were similar to animals injected with vehicle, and no histological abnormalities were found in the organs. In vitro cell culture studies revealed no direct cytotoxic effect of SC3 towards sarcoma cells, while cytotoxic activity was observed towards melanoma cells at a high SC3 concentration. Daily treatment with SC3 did not result in detectable levels of anti-SC3 antibodies in the plasma. Instead, a cellular immune response was observed. Incubation of spleen cells with SC3 resulted in a 1.5- to 2.5-fold increase in interleukin-10 and TNF-α mRNA levels. In conclusion, the nontoxic fungal hydrophobin SC3 showed tumor-suppressive activity possibly via immunomodulation and may be of benefit as adjuvant in combination with chemotherapy and radiation.
Metastatic Brain Tumors Hacıyakupoğlu, Ersin; Oktay, Kadir; Olguner, Semih Kıvanç ...
Çukurova Üniversitesi tip fakültesi dergisi,
06/2014
Journal Article
Metastatik tümör; orjinini Santral Sinir Sistemi (SSS) dışındaki dokulardan alan primer sistemik kanserlerin sekonder olarak SSS ne yayılmasıdır. Erişkinde SSS ne en sık metastaz sırasıyla akciğer, ...meme, malign melanom, renal hücreli Ca, kolon ve tiroid kanserinden gelir. Akciğer kanseri %30-60 oranında beyine metastaz yapar. Çocukta beyin metastazı oldukça azdır. En sık lösemi, lenfoma, osteogenik sarkom, rhabdamyosarkom ve germ hücreli tümörler beyne metastaz yaparlar. Malign melanom, akciğer, meme ve kolon kanserleri %50 oranında multipl metastaz yaparken renal tümörler tek metastaz yapmaya meyillidir. Akciğer kanseri tanı koyduktan 6-9 ay sonra beyne metastaz yaparken, renal kanser 1 yıl, kolon kanseri 2 yıl, meme kanseri ve malign melanom 3 yıl sonra beyine metastaz yapabilir. %6 olguda primer tümöre ait hiçbir bulgu yokken beyine metastaz olmaktadır. Tedavide verilen ilk ilaç kortikosteroiddir, daha sonra ameliyat, Radyoterapi (RT), Kemoterapi (KT) ve Stereotaktik Radyosurgery (SRS) yapılabilir. Küçük hücreli akciğer kanseri, lenfoma, germ hücreli tümörler RT ve KT"ye hassastırlar. Non small akciğer kanserleri, renal, kolon, malign melanom radiorezistandır. Eğer hastada 3-4 aydan uzun yaşam süresi bekleniyorsa agresif tedavi uygulanır. RT"de verilen dozun total miktarı ve veriliş süresi ile ilgili akut ve kronik komplikasyonlar meydana gelir. Metastatik tümörlerin ameliyatlarında amaç nörolojik defisit olmadan tümörün total çıkartılması, intrakranial basıncın azaltılması ve eğer postoperatuar RT yapılacaksa dozun mümkün olduğu kadar düşük tutulmasıdır. Önceleri multipl metastazlar opere edilmemekte idi ancak ne kadar çok metastaz alınırsa RT ve KT den o kadar çok cevap alındığından günümüzde ameliyat önemlidir. Anahtar Kelimeler: Metastatik beyin tümörleri, Stereotaktik radyosurgery, Malign melanom, Akciğer kanserleri, Renal hücreli karsinom, Radyoterapi, Kemoterapi
Metastatic tumor is secondary spread to the central nervous system of primer systemic cancers originating from tissues other than the central nervous system. In adults; there are metastases respectively from lungs, breasts, malign melanoma, renal cell carcinoma, colon and thyroid cancers. 30-60% of lung cancers metastasis to the brain. In children there are quite a few cerebral metastases. Most commonly leukemia, lymphoma, osteogenic sarcoma, rhabdomyosarcoma and germ cell tumors metastasis to the brain. %50 of malign melanoma, lung, breast and colon cancers intend to make multipl metastases but renal cell cancers intend to make solitary metastasis.While lung cancers metastasis to brain in 6-9 months after the definitive diagnosis, renal cancers in 1 year, colon cancers in 2 years, breast cancers and malign melanoma in 3 years metastasis to brain. In 6% of cases there are cerebral metastasis while there isn"t a symptom of a primary tumor. For treatment corticosteroids, surgery, Radiotherapy(RT), Chemotherapy(CT) and Stereotactic Radiosurgery(SRS) can be implemented. Small cell lung cancers, lymphoma, germ cell tumors are sensitive to RT and CT. Non small cell lung cancers, renal, colon cancers and malign melanoma are radioresistant. The purposes in the surgery of the metastatic brain tumors are; total resection of tumors without neurologic deficits, decreasing the intracranial pressure and decreasing the dose of postoperative radiotherapy. Key Words: Metastatic brain tumors, Stereotactic radiosurgery, Malign melanoma, Lung cancers, Renal cell carcinoma, Radiotherapy, Chemotherapy
Dendritic cells (DCs) form a complex network of cells that initiate and orchestrate immune responses against a vast array of pathogenic challenges. Developmentally and functionally distinct DC ...subtypes differentially regulate T-cell function. Importantly it is the ability of DC to capture and process antigen, whether from pathogens, vaccines, or self-components, and present it to naive T cells that is the key to their ability to initiate an immune response. Our typical isolation procedure for DC from murine spleen was designed to efficiently extract all DC subtypes, without bias and without alteration to their in vivo phenotype, and involves a short collagenase digestion of the tissue, followed by selection for cells of light density and finally negative selection for DC. The isolation procedure can accommodate DC numbers that have been artificially increased via administration of fms-like tyrosine kinase 3 ligand (Flt3L), either directly through a series of subcutaneous injections or by seeding with an Flt3L secreting murine melanoma. Flt3L may also be added to bone marrow cultures to produce large numbers of in vitro equivalents of the spleen DC subsets. Total DC, or their subsets, may be further purified using immunofluorescent labeling and flow cytometric cell sorting. Cell sorting may be completely bypassed by separating DC subsets using a combination of fluorescent antibody labeling and anti-fluorochrome magnetic beads. Our procedure enables efficient separation of the distinct DC subsets, even in cases where mouse numbers or flow cytometric cell sorting time is limiting.
Defining "intermittent UVR exposure" Bodekær, M; Philipsen, P A; Petersen, B ...
Photochemical & photobiological sciences,
01/2016, Letnik:
15, Številka:
9
Journal Article
Recenzirano
Cutaneous malignant melanoma (CMM) has been associated with "intermittent UVR exposure", which in previous studies has mainly been assessed by retrospective questionnaire data. Further, there is no ...uniform definition of the term "intermittent UVR exposure".
We aimed to define and quantify "intermittent UVR exposure" by an objective measure.
A broad study population of adults and children had data collected during a summer period. Data were personal UVR dosimetry measurements, from which the number of "intermittent days" was derived, sun behaviour diaries and retrospective questionnaires. Two definitions of intermittent UVR exposure were tested: (1) days when UVR dose exceeded 3 times individual average daily UVR dose, and (2) days when UVR dose exceeded individual constitutive skin type. Measures of nevi and lentigines were used as surrogates for CMM.
Using the first definition based solely on UVR dosimetry data we found 1241 "intermittent days" out of a total of 17 277 days (7.2%) among 148 participants. The numbers for nevi and lentigo density were significantly predicted by the number of intermittent days (R(2) = 0.15 and R(2) = 0.40, p < 0.001). The corresponding numbers for prediction of nevi and lentigo density by retrospective questionnaire data was lower (R(2) = 0.11, R(2) = 0.26, p < 0.001).
We introduce a well-defined objective measure of intermittent UVR exposure. This measure may provide a better prediction of solar skin damage and CMM than retrospective questionnaire data.
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