Cancer “moderate” therapy will be come

Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines.

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 Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin-α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action.

Reference:

Gunjan Guha, Wanli Lu, et al. Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) PLOS ONE,2015. DOI: 10.1371/journal.pone.0125322.

Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury

Since been found, miRNA has drawn increasing attention for it plays an important role in a number of biological processes. A recent study pointed out that this small RNA molecules not only attribute to diagnosis and treatment of cancer and other diseases in a prominent, but also to predict long-term damage caused by radiation exposure in living organisms within 24 hours, and its estimated speed is much faster than existing radiation absorbed dose method.

This successful research published in the journal Science Translational Medicine on May 13th.

Researchers from the Dana-Farber Cancer Institute presented this novel blood test, before labor tests showed that the method can reveal the fate of victims of radiation accidents, as well as the dose of radiation received by them within 24 hours, which will caused severe bone damage, or damage to other organs. The researchers said this detection can “help prompt medical intervention and improve the overall living conditions of patients.”

From nuclear power plants, radioactive materials, nuclear and other high-energy radiation can cause radiation patients’ living tissue damage and even cancer and infections. The most susceptible to radiation toxicity are the hematopoietic system, which is composed of the composition of the blood and blood-forming organs. Damage required months or a few weeks to reflect after radiation exposure out, this will hinder timely medical treatment, and methods currently used to predict in vivo radiation dose to the patient are detecting the loss of white blood cells, damage DNA or chromosomal abnormalities which are often tedious and time-consuming.

Compared with the current methods, this method uses the unique blood biomarkers: miRNA. In the future, these molecules may serve as diagnostic biomarkers to guide the early treatment of radiation accident victims.

The researchers gave mice exposed to low, high, and lethal dose of total body irradiation and exposure to radiation is detected within 24 hours of miRNA concentration in blood. The change was found in the screening of 170 miRNAs in 68 kinds of serum miRNAs occurred before or after the emergence of radiation, and these serum miRNAs can serve as “a signal indicator of radiation dose”. These miRNAs can distinguish between lethal and non-lethal dose of radiation, and to accurately predict the overall survival.

At the same time researchers also analyzed the correlation between radiation therapy and miRNAs, they found that mice receiving radiation therapy before in contact with lethal doses of radiation, its RNA expression profiles reflect the protective effect of the drug, and can predict the serious injury suffered in a lesser extent. As for the lethal dose of radiation after bone marrow transplantation in mice, miRNAs have also identified the role.

These results indicate that, miRNA can be changed within 24 hours after radiation exposure, and therefore can be used as a biomarker for early diagnosis and treatment, the application and radiation therapy.

Mother, son both fighting cancer

In 2012, her 6-year-old son, Colin, was diagnosed with leukemia. That same year, her father died from ALS. In 2013, her house flooded and the family lost everything in the basement. And in 2014, the single mother of two was diagnosed with breast cancer.

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Cheryl thought that it wasn’t possible for both her and Colin to make it through cancer alive, but she hoped that her son would be the one to survive. Allowing Smith to take photos would ensure that the family was in photos together — that her children could remember her through the images and know that she fought to beat cancer and be there for them.

Smith gained Cheryl’s trust and began to visit regularly. He was there for the appointments, the treatments, the surgeries — and the very worst days after those treatments when Cheryl was in the kind of pain that she can only describe as “bone-melting.”

Cheryl had tried her hardest to make Colin’s leukemia navigable. By using pamphlets from the cancer care center, they had educated the teachers and children in his school about what Colin was enduring — and in turn, he became the school rock star rather than an outcast.

In a rare moment, as her hair, eyelashes and eyebrows began to disappear after the chemotherapy, Cheryl caught herself looking in the mirror and tearing up.

Cancer hotels home to China’s healthcare misery

A shabby row of two-story buildings in west Beijing, a few hundred meters from one of China’s top cancer treatment and research hospitals, they house untold misery. Known locally as “cancer hotels,” they provide a cheap, temporary accommodation for hundreds of patients in a country where a cancer diagnosis can be financially, as well as physically, devastating.

They have used one of the modest guesthouses as a place to wait for chemotherapy, surgery and radiotherapy at the nearby hospital since her diagnosis with cervical cancer in September 2014. There’s no nursing care in their lodgings, but a communal kitchen allows them to live cheaply as well as draw support from fellow sufferers.

The World Health Organization says cancer rates in China are growing “ferociously,” with 2.2 million men and women dying of cancer each year — many of which could be prevented. Lung cancer is the most common cancer diagnosed in men, breast cancer for women.

Bernhard Schwartlander, WHO Representative in China, told CNN that the cancer hotels that have sprung up around reputable hospitals in many major cities are a response to weaknesses in China’s healthcare system — most patients don’t have affordable access to good quality cancer treatment close to where they live, he said.

Cancer treatment can be very expensive and costs are insufficiently covered by basic health insurance, he said. “Paying out of pocket for the cancer drugs can be a huge financial drain on poor rural households.” “Therefore, there is a serious risk that for many people, a cancer diagnosis can be financially catastrophic — and push a household into poverty.”

Even though most county hospitals have cancer diagnosis and treatment capacity, some people believe the quality of care is better in cities, he said. But their decision to head to prestigious hospitals was not always the best course of action, he added. The real quality of care, once things like waiting times are taken into consideration, is not always better — although some rare cancers can only be treated by specialists in larger cities, he said.

UNC Lineberger study finds new potential melanoma drug target

UNC Lineberger Comprehensive Cancer Center researchers have identified a possible new drug target for a potentially deadly form of skin cancer that, when blocked in a pre-clinical study in mice, reduced the cancer’s growth.

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The researchers found high levels of a particular enzyme in melanoma samples that they believe is a driver of the cancer’s growth. The enzyme, called interleukin-2 inducible T-cell kinase, or ITK, has not previously been explored as a driver of solid tumors. Normally, it’s expressed in a subset of the body’s disease-fighting immune cells.

“ITK has been conceived of as a therapeutic target for inflammatory diseases such as chronic obstructive pulmonary disorder, but because ITK had not been noted in melanoma before, it has not been a target for its treatment,” Carson said. “I expect ITK to become an important therapeutic target for melanoma because of the expected minimal side effects, and the fact that ITK is found in so many of the melanomas we have investigated.”

Funded in part by the University Cancer Research Fund, the findings were the result of years of collaborative work involving multiple UNC Lineberger researchers and University of North Carolina School of Medicine departments.

New Tool Reveals Genetic Mutation Related to Disease

Scientists from University of Massachusetts Medical School have developed a new powerful tool which could reveal the character of human disease related genetic mutations. The study may help scientists describe the genome mutations hidden behind the complex polygenetic diseases. This study was published in Cell.

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Gene regulatory networks(GRN) comprising physical and functional interactions between transcription factors(TFs) and regulatory elements play a critical role in development and physiology. Consequently, inappropriate gene regulation underlies a variety of human diseases. Abroad variety of disease-associated mutations have been uncovered, including mutations in TF-encoding genes as well as mutations in non-coding sequences such as enhancers and promoters.

 

TF-DNA interactions can be mapped with either “TF-centered ” or “gene-centered” methods. Chromatin immunoprecipitation(ChIP) is the most widely used TF centered method to identify the DNA regions with which a TF interacts in vivo. Enhanced yeast one-hybrid(eY1H) assays provide a gene-centered method for the detection and identification of TF-DNA interactions. Briefly, eY1H assays measure TF-DNA interactions in the milieu of the yeast nucleus. DNA regions to be assayed are fused upstream of two reporter genes LacZ and HIS3, and integrated into the yeast genome, enabling their incorporation.

 

In this study, researchers test their human eY1H platform to identify TFs interacting with human enhancers and to determine protein-DNA interaction changes caused by mutant TFs as well as non-coding disease-associated mutations. They find that eY1H assays more effectively retrieve TFs with limited expression patterns or levels when compared to ChIP.

 

They provide examples of functional models of target sharing by TFs, including redundancy, which may provide robustness and opposing function, which can ascertain proper timing of enhancer activity during development. Finally, they demonstrate that eY1H assays can be effectively used to identify changes in TF binding conferred by disease-associated coding or non-coding mutations.

New Mechanism of Drug Resistance in Cancer Treatment

Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Scientists from Memorial Sloan Kettering Cancer Center have identified a new mechanism of the drug resistance in cancer treatment. A bunch of resistance cells are found to response to the huge changes in the micro-environment. The deep understanding of this process may help to promote the efficacy of targeted anti-cancer drugs. This study was published in Nature.

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Kinase inhibitors such as vemurafenib, erlotinib or crizotibib have shown clinical efficacy in melanoma with BRAF mutations, or in lung adenocarcinoma with EGFR mutations or ALK translocations, respectively. Although complete responses are rare, the vast majority of patients show partial tumour regression or disease stabilization. However, drug resistance invariably develops, and most patients progress within 6-12 months, representing a common complication of targeted therapies that hampers long-term treatment success.

In this study, researchers show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression.

The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafebib is driven by down-regulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signaling pathways, most prominently the AKT pathway.

Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cell, paradoxically establishing a tumour micro-environment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.

IBM’s Watson supercomputer to speed up cancer care

IBM’s supercomputer Watson will be used to make decisions about cancer care in 14 hospitals in the US and Canada, it has been announced.

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Using computers to trawl through vast amounts of medical data speeds up the diagnosis process. The system will help assess individual tumours and suggest which drug should be used to target them. Doctors have welcomed the new computer which will learn from each case it examines.

Most people currently diagnosed with cancer will receive surgery, chemotherapy or radiation treatment. But as genetic sequencing becomes increasingly accessible and affordable, some patients are starting to benefit from treatments that target their specific cancer-causing genetic mutations.

However the process is very time-consuming – a single patient’s genome represents more than 100 gigabytes of data – and this needs to be combined with other medical records, journal studies and information about clinical trials. What would take a clinician weeks to analyse can be completed by Watson in only a few minutes.

Sometimes it is impossible to identify the main mutation and, in other cases, no targeted therapy currently exists. Those collaborating with IBM include the Cleveland Clinic, the Fred & Pamela Buffett Cancer Centre in Omaha and the Yale Cancer Centre. Eleven others will join the programme by the end of 2015 and each will pay an undisclosed subscription fee to IBM.

New Achievement in Bladder Cancer Microenvironment Studies

Researchers from Stanford University have reported that CD14+ cancer cells could promote the development of bladder cancer. Their study was published in PNAS.

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Solid tumors represent a complex mass of tissue composed of multiple distinct cell types. Cells with the tumor produce a range of soluble factors to create a complex of signaling networking within the tumor microenvironment. Bladder cancer(BC) represents a growing number of solid tumors characterized by the infiltration of a significant number of solid tumors characterized by the infiltration of a significant number of myeloid cells in the neoplastic lesion.

In this study, scientists define the crucial role of CD14-high bladder cancer(BC) cells in orchestrating multiple hallmarks of cancer in the early stages of BC. Inflammatory factors produced by this subpopulation of tumor cells activate angiogenesis to support establishment and maintenance of an immune-suppressive, inflammatory tumor microenvironment. Additionally, this subpopulation is able to drive tumor growth by producing factors that drive autocrine and paracrine proliferative stimulation.

Here they show that a tumor-cell subpopulation establishes a tumor microenvironment orchestrating tumor-promoting inflammation and tumor-cell proliferation. Collectively, this study highlights the need to explore the broader role of CD14 expression is critical for IL6 secretion by these cells

Therefore, therapeutic targeting of CD14 might represent a strategy for treating cancer.

Reference:Cheah M T, Chen J Y, Sahoo D, et al. CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer[J]. Proceedings of the National Academy of Sciences, 2015, 112(15): 4725-4730.

TGF-β Plays Important Role along with microRNA Promotes Colon Cancer Metastasis

Researchers from University of Cornell have identified that microRNA-1269a could form a regenerative circuit which may promote the metastasis of colon cancer. Their study was published in Nature Communication.

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Many solid tumours progress through stages while accumulating genetic alterations and reprogramming microenvironments. Ranked among the most common cancers and a leading cause of cancer-related deaths, colorectal cancer(CRC) progresses through an adenomas to carcinoma sequence that eventually leads to metastasis.

microRNAs are small noncoding RNA molecules that suppress gene expression via the 3′ untranslated regions(UTRs) of target mRNAs. Individual microRNA can control many target genes and microRNA expression is often altered in cancer cells Among them, microRNAs that promote relapse metastasis are of particular interest as potential prognostic biomarkers and therapeutic targets.

In this study, scientists show that miR-1269a expression is upregulated in late-stage CRC and is associated with recurrence and metastasis of disease-free stage ⅡCRC patients. miR-1269a promotes CRC cells to undergo epithelial-mesenchymal transition(EMT) and to metastasize in vivo. Mechanistically, miR-1269 targets Smad7 and to metastasize in vivo. Mechanistically, miR-1269 targets Smad7 and HOXD10 to enhance transforming growth factor (TGF)-β Signaling, which in turn upregulates miR-1269 via Sox4.

Their findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for patients and a potential therapeutic target to deter metastasis.