Light-manipulation combined cancer treatment in vitro

Cancers are emerging in an endless stream, leading to severe threat to human health [ 1 ]. To date, cancer treatment is still a worldwide problem and the eradication of cancers have been the lifelong pursuit of many scientists and physicians. Great efforts have been made to fight against cancers, and a large number of therapeutic approaches have been developed for clinical treatment of cancers, such as chemotherapy, gene therapy, radiotherapy, immunotherapy, and phototherapy [ 2 ].

However, it is still difficult to cure and eliminate cancer by relying solely on these techniques since the effectiveness of cancer treatment is strongly related to the stage at which the malignancy is detected. The tremendous progresses of nanotechnology and nanomaterials have paved new ways to address some pressing challenges in precise cancer diagnostics and therapy.

Nanomaterials with intelligent properties have enabled exciting opportunities for solving the traditional complex problems that cannot be reached with conventional methods [ 3456 ]. A variety of nanomaterials, such as magnetic nanobeads MNs [ 7 ], quantum dots QDs [ 8 ], upconverting nanomaterials UCNPs [ 9 ], hydrogel sheets [ 10 ], and gold nanoparticles AuNPs [ 11 ], have been rationally fabricated, leading to great revolution in nanomedicine.

These nanomedicine platforms that allow for precise and remote manipulation of nanoscale objects in biological environments have enabled exciting opportunities for precise diagnostics and therapy of cancers.

In order to achieve precise treatment of cancer, it is required that the nanoparticles are distributed at a reasonable time and space at the target site, so they can be efficiently taken up and released by the cells, which requires a reasonable construction of the delivery system to avoid multiple obstacles to transport to the tumor site.

The active propulsion of these motors plays a key role for their biomedical applications. To meet these demands of efficient energy harvesting and conversion, a wide variety of fabrication strategies have been developed, such as metallic thin films deposition, template-assistant metal electroplating, rolling-up methods, and self-assembly techniques [ 3132 ].

They can efficiently be moved by harnessing various fuels and various driving modes [ 454647 ]. Coincidentally, cancer cells have been found to generate oxidative stress by producing an elevated level of hydrogen peroxide H 2 O 2 and exhibit acidic pH levels.

For example, ultrasound-driven nanowires that harness energy to generate an asymmetric pressure gradient for propulsion were able to target tumors in an active targeting manner [ 49 ]. Wang et al. Such nanoswimmers are capable of actively targeting a single cell and opening the cell membrane, which could be utilized for intracellular drug delivery, artificial insemination, and subcellular surgery processes.

Currently, traditional delivery systems rely solely on circulation of body fluids and lack sufficient penetration and targeting, which makes it difficult for drugs to penetrate tissue and the interior of the lesion.

This seriously affects the therapeutic effect of the drug. Anticancer agents such as proteins, siRNAs, and plasmids exhibit excellent biological activity and therapeutic effects in the cytoplasm, and their emergence has brought new choices for advancing the treatment of cancer [ 53 ]. However, effectively delivering these agents to the cytoplasm while still ensuring their activity is still very difficult. Transfection techniques can be used to deliver them to cells via some biological vectors such as viral vectors or liposome complexes, but the use of biological vectors could introduce an uncontrolled risk of delivery.

In order to deliver the drug precisely to the target disease site, the drug carrier needs to have some unique capabilities, including propulsion, cargo and release, and penetration.If you feel you have been helped by this site, please share the message and take a look at the easy ways you can contribute at no financial cost.

Businessman Joe Tippens had small cell lung cancer that had metastasised all over his body. After treatment with conventional chemotherapy and radiation he was handed a death sentence three months to live in early Thanks to much research into alternative cancer treatments and a coincidence that led him to include the drug Fenbendazole in his self-treatment, he became a survivor.

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Fenbendazole, Mebendazole and related drugs are anthelmintics, i. Fenbendazole is approved for treating a range of animals including cats and dogs, Mebendazole for use in humans. A research paper from Fenbendazole acts as a moderate microtubule destabilizing agent and causes cancer cell death by modulating multiple cellular pathways showed this compound sold at Amazon as Panacur Canine Dewormer [1] to actually have anti-cancer properties.

Joe Tippens first learned about Fenbendazole's anticancer effects from a veterinarian friend. This friend told him about a scientist doing cancer research on mice who stumbled across a canine product Fenbendazole which killed many different types of cancer induced in mice in the laboratory. In six weeks, her brain tumor was gone. Since Joe Tippens had nothing to lose, it was a no-brainer for him to try Panacur himself. Every week, he took a dose of 1 gram per day containing approximately mg of Fenbendazole for three consecutive days, followed by four days off, then repeated the cycle.

He decided to complement this approach with three supplements: full-spectrum vitamin E containing four tocotrienols and tocopherols eachbio-available curcumin, and CBD oil.

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Within three months, the formerly terminally ill patient was clear of all cancer and metastases and has remained so to this day. He continues to religiously stick to this protocol. As he started spreading the news about his surprising DIY cancer cure [7]many positive and even sensational success stories came pouring in of cancer patients including stage 4 who were healed or improved using the same protocol.

These included. Joe Tippens of course "diluted" his Fenbendazole self-treatment with additional supplements - CBD oil by itself is a recognized alternative cancer treatment with successes under its belt, and vitamin E and curcumin both have many health and healing benefits.

Such additions - including dietary upgrades - should only be able to enhance the anticancer effect of Fenbendazole. Judging by the above-reported brain cancer success apparently using Fenbendazole alone and the quoted study that described Fenbendazole as a potential therapeutic agent with anti-neoplastic activity thanks to its effect on multiple cellular pathways resulting in the destruction of cancer cells, it would seem that this compound alone has powerful anti-cancer benefits.

Fenbendazole combination treatment: successes with terminal cancer

On the other hand, an animal study lymphoma in mice found the addition of vitamins necessary to impede tumor growth. In this study, Fenbendazole alone did not have an inhibitory effect. While the above-quoted successes in humans have been reached with Fenbendazole, studies are also finding potent anti-cancer effects of sister drugs such as Mebendazole.

For what it is worth, three animal studies showed fenbendazole and its sister drug Mebendazole to be of possible interest in treating brain cancer. Searching the medical database PubMed for "Mebendazole cancer", one finds many other papers showing anti-cancer effects of mebendazole on a variety of malignant tumors and cancers such as.

Another antihelminthic drug called Levamisole was used as an effective complementary treatment for colorectal carcinoma that normalized a depressed immune system. If you value this content and wish to support my work every dollar is gratefully appreciatedplease donate:. You can support this nothing-to-sell site at no extra cost to you by shopping through its international Amazon partner links. See Support this site.

The partner link to Amazon UK is Panacur at amazon. Unauthorized republishing of content is strictly forbidden.Charles River Laboratories International, Inc. This press release features multimedia. Charles River offers a range of cancer cell-based assays, including PDX assays and assays representing the entire tumor microenvironment TMEso therapies are not only tested for their effect on real patient materials, but also their interaction with the human immune systems.

Through this collaboration, Charles River will now have a critical new addition to our human oncology assay repertoire, allowing identification of therapeutics that overcome cancer immunotherapy resistance. The database is comprised of more than tumor models, including PDX, cell lines and cell line derived xenografts. These models have been extensively profiled for histological features, molecular data, and sensitivity to standard-of-care compounds, allowing a precise selection of suitable tumor models for preclinical anti-cancer agent testing.

The biological advantages of PDX include the retention of histological and genetic characteristics of the donor tumor and the preservation of cell-autonomous heterogeneity, which increase the translational relevance of the Cypre platform significantly. Approved Quotes. About Charles River. Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts.

Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit www.

About Cypre. We are now applying this approach with strategic partners for therapeutic discovery, lead validation, and precision medicine. To learn more about us, visit www. View source version on businesswire. By broadening our 3D in vitro services with this collaboration, we can provide our clients with a complete, integrated tumor model service platform.

We look forward to building this relationship and providing more customers with our unique solution that will improve targeted and immuno-therapeutic options for cancer patients. Sponsor Center.For several decades, cancer has been one of the most life-threatening diseases.

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For enhancing anticancer efficiency with minimum side effects, combination therapy is envisioned. The current manuscript reports for the first time the development of a methylene blue MB bound nanoplatform, which is capable of delivering targeted diagnostic and combined synergistic photothermal and photodynamic treatment of cancer. Experimental data found that, once the nanoparticle binds with the target cell surface, it can detect LNCaP human prostate cancer cell selectively using fluorescence imaging.

Our result shows that the therapeutic actions can be controlled with external NIR light. No cytotoxicity was observed in the absence of NIR light. Targeted photodynamic and photothermal treatment using nm NIR light indicates that the multimodal treatment enhances the possibility of destroying LNCaP prostate cancer cells in vitro dramatically.

We discuss the operating principle for the targeted imaging and possible mechanisms for combined therapeutic actions. Our experimental data show that NIR light activated combined therapy for cancer may become a highly effective treatment procedure in clinical settings.

Recent advances have been achieved with our better understanding of the signaling pathways and molecular underpinnings of cancer drug resistance. Our result shows that the cancer cells can be selectively separated, imaged, and destroyed significantly by illumination with nm near IR continuum light for a few minutes.

Experimental data demonstrated that, due to the synergistic effect, the therapeutic efficacy of the nanoplatform was enhanced significantly compared to PDT or PTT alone. Methylene blue is a well-known photodynamic therapy drug. The poor selectivity of methylene blue for the targeted tumor sites minimizes PDT efficacy in vivo and also increases the potential phototoxicity to normal tissues.

As shown in Scheme 1in our design, we have used methylene blue as a photodynamic therapy drug and as a fluorescence imaging probe. We have demonstrated that, in the nanoplatform, the magnetic core is capable of rare tumor cell isolation and enrichment using a small bar magnet. To make sure that the combined therapy using the nanoplatform delivers only to the malignant cells, we have demonstrated that, in our design, combined therapy is only activated in the presence of NIR light and no toxicity was observed without light exposure.

A SEM images of freshly prepared core—shell plasmonic nanopopcorn.

light-manipulation combined cancer treatment in vitro

C Absorption spectra of core—shell nanoparticle, methylene blue, and methylene blue conjugated nanoplatform. Nanoplatforms which can be used for selective imaging and combined therapy were developed via a several step process, as described in the Experimental Section.

At first, popcorn shape iron magnetic core—gold shell nanoparticles were prepared using our reported method. To find out whether the nanoplatform developed by us can be used for combined synergistic therapeutic action for cancer, we have used the LNCaP human prostate cancer cell line, which is well-known to overexpresses the prostate specific membrane antigen PSMA on the cell surface. Next, to separate nanoplatform attached cancer cells from the mixture, we used a bar. At the end, after magnetic separation, we used fluorescence image, TEM, and enzyme-linked immunosorbent assay kits for the characterization of cells that bind with nanoplatform and separated them by bar magnet.

Similarly, cells that did not bind with the nanoplatform were also characterized using microscopic and optical imaging technique as well as using enzyme-linked immunosorbent assay. Our enzyme-linked immunosorbent assay results indicate no PSMA presence in the fractions of cell suspensions that did not bind to the nanoplatform, which indicates the absence of LNCaP cells in cell suspension which are not separated by the magnet.

On the other hand, we find that PSMA was present in the nanoplatform attached cell suspension. Enzyme-linked immunosorbent assays results clearly indicate that LNCaP cells are attached to the nanoplatform. All the experimental results, described above, clearly indicate that the MB-bound A9-aptamer-conjugated nanoplatform developed by us is highly selective for binding with the LNCaP prostate cancer cell line, which overexpresses PSMA.

C Fluorescent images of cell suspension which are not separated by the magnet. D Bright-field image of cell suspension which are not separated by the magnet.

For fluorescence imaging, we used nm excitation and the fluorescence was collected between and nm. Next, to find out whether our design of core—shell nanoplatform can be used for multimodal therapy, after successful targeted prostate cancer LNCaP cell separation, we performed NIR irradiation experiments using nm excitation light.

For this purpose, at first, we performed a cytotoxicity experiment in the absence of NIR light to determine whether the nanoplatform developed by us is cytotoxic or not. Next, to determine if the combined therapy is much superior to single therapy, we designed several different experiments, which we discuss now.

For the cytotoxicity measurement, MB-bound nanoplatform attached LNCaP cells were incubated for 12 h without any laser light. For imaging we used nm excitation, and the fluorescence was collected between and nm. The bright-field image clearly shows that cancer cells are dead after combined therapy. The bright-field image clearly shows that cancer cells are alive after nm light exposure in the absence of nanoplatforms or MB. C Plot showing the percentage of cell viability in MB-bound nanoplatform attached LNCaP cells in the absence of laser light and in the presence of laser light.Abstract New incidence of prostate cancer is a major public health issue in the Western world, and has been rising in other areas of the globe in recent years.

In an effort to understanding the molecular pathogenesis of this disease, numerous cell models have been developed, arising mostly from patient biopsies.

The introduction of the genetically engineered mouse in biomedical research has allowed the development of murine models that allow for the investigation of tumorigenic and metastatic processes. Current challenges to the field include lack of an animal model that faithfully recapitulates bone metastasis of prostate cancer.

Keywords: prostate cancer, cell lines, intratibial injection, mouse models, xenograft. The incidence of prostate cancer PCa is one of the most prevalent cancer diagnoses throughout the world, and is one of the most intensely studied problems in human disease.

According to the American Cancer Society, in there were overnew cases of PCa diagnosed in the US, resulting in about 29deaths [ 1 ]. As cancer is a disease of aging, prostate lesions occur infrequently before the age of 40, with the peak incidence occurring between the age of 70—74 [ 2 ]. The etiology of PCa has remained a puzzling issue. A strong correlation exists with age, with increased relative risk for individuals with a family history [ 4 ].

Environmental risk factors, which have been quantified in adoption studies at 4. Smoking may also put individuals at increased risk for PCa, and sexually transmitted diseases have been identified as a risk factor [ 1011 ]. Inflammatory factors have been implicated in the development of PCa, such as bacterial toxins and exogenous carcinogens such as 2-aminomethylphenylimidazo 45-b pyridine or PhIP [ 1213 ].

There is a discussion in the field regarding the specificity of the prostate specific antigen PSA test as a useful prognostic indicator of potential metastatic castration resistant prostate cancer mCRPCwith some saying that widespread epidemiological screening does not justify the modest decrease in cancer death [ 14 - 16 ].

By far the most useful in vitro model that we have of PCa is cell culture. The sheer number of cell lines that are available for study is expansive, due to the fact that PCa can arise from one of several cell sources in the prostate. In addition to the information contained in this review, a good cell line database is available from the British Columbia BC Cancer Agency [ 17 ].

">In vitro and in vivo model systems used in prostate cancer research

A comprehensive and exhaustive two-part compendium of PCa cell lines is available from Sobel and Sadar [ 1819 ]. A summary is available in Table 1. DU cells were first isolated from a brain metastatic prostate tumor in [ 20 ]. The isolation of this line represented an answer to the criticism of then existing cell lines MA and EB 33, both of which represented cell isolated from admixtures of benign tumor or moderately differentiated adenocarcinoma.

This observation has brought this cell line into disfavor among investigators. The vast majority of human prostate tumors express AR, so some would contend that this is a model that does not faithfully mimic human disease [ 21 ]. This is an important consideration, as the selection of this cell line for experimentation such as studies that seek to test the effect of hormone status would be futile on this model. Phosphatase and tensin homolog PTEN expression is heterozygous [ 23 ].

This line contains marker chromosomes M 1M 2and M 3. An important consideration in the selection of a PCa cell model is growth rate and behavior as a xenograft. DU cells maintain phenotype and genotype when injected into mice and metastasize to a variety of organs, including spleen, lung, and liver [ 2526 ].

Tumor growth in SCID mice has a 7-day latency with a biphasic growth rate of 5. The response to growth factors is another important consideration to make when choosing a PCa cell line as growth factor independence via autocrine signaling has been defined as one of the hallmarks of cancer [ 28 ]. A substantial amount of work has been done on the effect of growth factors on this cell line.

Why Do Cancer Treatments Stop Working? Overcoming Treatment Resistance

More information on the growth factors and growth factor receptor expression profile is available in Table 1. Investigators have recently started to interrogate the role of energy metabolism in the role of PCa carcinogenesis. Recent work done on glucose deprivation and activation of AMP-activated protein kinase by vascular endothelial growth factor detected an absence of LKB1 in this cell line [ 33 ]. As a final note, one of the obvious goals of cancer treatment is to induce cancer cells into apoptosis and thus decreased tumor bulk.Many patients diagnosed with cancer have far more treatment options now than they did even a decade ago.

In some cases, these treatments can produce remarkable responses, completely eradicating tumors in patients whose cancer had spread throughout their body. But nearly all current treatments face the same problem: for many patients, they ultimately stop working. Commonly known as drug resistancethis phenomenon is one of the most challenging problems facing cancer researchers and patients today.

When cancer cells resist the effects of drugs used for treatment, they can grow and reform tumors, a process known as recurrence or relapse.

light-manipulation combined cancer treatment in vitro

Sometimes resistance develops quickly, within a matter of weeks of starting treatment. In other cases, it develops months, or even years, later. Resistance can occur when cancer cells—even a small group of cells within a tumor—contain molecular changes that make them insensitive to a particular drug before treatment even begins. Because cancer cells within the same tumor often have a variety of molecular changes, this so-called intrinsic resistance is common.

In other cases of resistance, cancer cells may adapt to the drug while it is being administered, acquiring molecular changes that allow them to escape its effects.

Molecular alterations that contribute to intrinsic or acquired treatment resistance include mutation of the drug's molecular target, changes in the way the drug interacts with the tumor, broad cellular changes, and changes in the tumor microenvironmentamong others. To complicate matters, many of these factors can be at play simultaneously in a single tumor. Researchers believe one possible way to overcome or delay the development of resistance is to treat patients with combinations of different drugs.

One combination treatment approach is to "co-administer drugs that work by different molecular mechanisms," Bissan Al-Lazikani, Ph. Another approach is to treat patients with drugs that block the particular mechanism of resistance their tumors have developed, and then treat them again with the drug to which they grew resistant. The idea is that this combination approach may "re-sensitize" the patients to the original treatment.

Scientists are pioneering many different methods to discover and test novel drug combinations that may be able to overcome multiple mechanisms of resistance or delay their emergence.

If these efforts are successful, it could potentially transform cancer for many patients. One way cancer cells resist treatment is by expelling cancer drugs. For example, healthy cells have proteins known as transporters that pump out toxic agents.

Michael Gottesman, M. More than 30 years ago, they discovered that "in some cases, when patients go from being sensitive to resistant to treatment, their cancer cells start to overexpress ABC transporters," he said.

In more recent studies, they analyzed DNA and RNA from tumors that are sensitive to or resistant to chemotherapy and found "increases in expression of one or more of these transporters in many different kinds of tumors," said Dr. When given in combination with other cancer therapies, drugs that block the activity of ABC transporters might allow greater amounts of anticancer drugs to accumulate in cancer cells, thereby boosting their effect, he explained.

Earlier versions of ABC transporter inhibitors did not hit their intended molecular targets specifically and caused serious side effects. A later generation of inhibitors were better at blocking the activity of these transporters but were also very toxic in clinical trials. Toxicity likely stems from the fact that ABC transporters also serve important roles in healthy cells, Dr.

Gottesman explained. Now scientists are working to develop new ABC transporter inhibitors that, they hope, strike a balance between increased efficacy and decreased toxicity. Importantly, one study showed that mice treated with osimertinib did not demonstrate weight loss, a sign of toxicity. Researchers also plan to take a precision medicine approach when designing clinical trials for new inhibitors by using genetic profiling to help determine which patients' tumors overexpress ABC transporters and are thus most likely to benefit from treatment that includes an ABC transporter inhibitor.

In addition to arising through genetic alterations, drug resistance can also emerge as a result of alterations in cancer cells' epigenetic codes—molecular modifications that, without altering the DNA code, turn genes on or off. A major difference between epigenetics and genetics is that the epigenetic code is reversible and can shift over time.Thalidomide is an anti-angiogenic agent that is used in the treatment of cancer. However, in many cases, particularly in patients with breast cancer, thalidomide treatment alone is insufficient and must be combined with other drugs or therapies.

In the clinical setting, thalidomide is most commonly used in combination with radiation therapy. However, the exact mechanisms of its effect are unkown. Radiotherapy alters the expression of substance P, which is considered a crucial pro-angiogenic peptide.

To determine whether thalidomide and radiotherapy in combination overcome the limitations of each as monotherapy, we examined the effects of the combination on the growth of breast cancer cells as well as on the expression of substance P in vitro. The levels of substance P in the conditioned media and in the cell lysates were determined by a substance P ELISA kit, and changes in the protein content were analyzed by Western blotting.

Thalidomide alone resulted in a significant inhibition in the growth of the 4T1 RT alone inhibited the growth of the 4T1 The combination therapy enhanced the growth inhibition noted in the 4T1 The expression of substance P in the conditioned media and in the cell lysates increased within 72 h of RT.

light-manipulation combined cancer treatment in vitro

This increase was significantly enhanced with the combination therapy. These data indicate that thalidomide inhibits breast cancer cell growth and potentiates the anti-tumor effects of radiation at appropriate doses.

Breast cancer is one of the most common neoplasms in women and is a leading cause of cancer-related mortality, resulting in approximatelydeaths worldwide annually 1. Surgery, radiotherapy and chemotherapy are widely used treatment methods for breast cancer. Despite significant improvements in cancer diagnosis and therapy, breast cancer remains a challenging disease to treat, and approximately one quarter of breast cancer patients succumb to the disease.

Thus, further investigations into the mechanisms of this disease are required to aid in the development of novel treatments 2. The formation of new blood vessels by the extension or elaboration of existing vasculature is called angiogenesis.

This mechanism plays a central role in both local tumor growth and distant metastasis in breast cancer 34. Angiogenesis is regulated by angiogenic and anti-angiogenic factors, and the expression levels of angiogenic factors reflect the aggressiveness of tumor cells.

Since the discovery of angiogenic inhibitors, the inhibition of tumor angiogenesis has become a promising strategy for the treatment of cancer, and thousands of patients have received anti-angiogenic therapy to date.

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Unfortunately, despite their theoretical effects, anti-angiogenic treatments have not proven beneficial in terms of long-term survival. Thus, there is clear need for a new comprehensive treatment strategy combining anti-angiogenic agents with conventional treatments, such as chemotherapy or radiotherapy, in the treatment of cancer 5 — 7. Thalidomide a derivative of glutamic acid that exists as an equal mixture of its enantiomers was introduced in Europe for the treatment of morning sickness in pregnant women.

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However, due to its teratogenicity, it was withdrawn from the market in the late s 8. Today, thalidomide is one of the most well-known teratogens in medical history and is clinically recognized as an efficient therapeutic agent for the treatment of various types of cancer; however, the anti-angiogenic mechanism of thalidomide remains unknown. Certain studies conducted in pre-clinical tumor models have documented the advantages of combining cytotoxic chemotherapeutic agents with radiation therapy.

Over the last few years, significant survival benefits for breast cancer patients have been achieved with the use of postoperative systemic therapies and radiotherapy 11 Currently, the majority of early breast cancer patients are routinely managed with breast-conserving surgery followed by radiation therapy and adjuvant systemic therapies, including chemotherapy and hormone therapy.

Despite the extensive use of radiotherapy and systemic treatments, the optimal strategy for their use in combination remains unclear, and their mechanisms are unkown 13 Recently, it was confirmed that neuroimmune mechanisms also play a role in the defense against cancer, as well as in its progression.

The involvement of the nervous system in the modulation of cancer development and its progression is indicated by clinical and experimental data from various studies. Several retrospective studies of patients who have undergone vagotomy suggest that the loss of various sensory nerve mediators, such as substance P SPleads to an increased risk of cancer development SP is generally accepted to be the major neuropeptide involved in neurogenic inflammation, and is the most important neuropeptide in cancer.

The PPT-A gene is expressed in many other cell types, such as monocytes, human fibroblasts, keratinocytes, lymphocytes, platelets and tumor cells.


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