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Imaging techniques could replace the need for invasive tissue biopsies in helping rapidly determine whether cancer treatments are working effectively, according to researchers at the University of Cambridge.

In a study published in the journal Cancer Cell, researchers at the Cancer Research UK (CRUK) Cambridge Institute have shown how a new technique known as hyperpolarisation – which involves effectively magnetising molecules in a strong magnetic field – can be used to monitor how effective cancer drugs are at slowing a tumour’s growth.

In healthy tissue, cell proliferation is a tightly controlled process. When this process goes wrong, cell proliferation can run away with itself, leading to unchecked growth and the development of tumours.

All tissue needs to be ‘fed’. As part of this process – known as metabolism – our cells break down glucose and other sugars to produce pyruvate, which is in turn converted into lactate. This is important for producing energy and the building blocks for making new cells.

Imaging technique could replace tissue biopsies in assessing drug resistance

False colour image of a breast tumour (outlined) pre- and post-treatment with a PI3Ka inhibitor. Weaker colours post-treatment indicate that the drug is working. Credit: Brindle Lab

Tumours have a different metabolism to healthy cells, and often produce more lactate. This metabolic pathway is affected by the presence of a protein known as FOXM1, which controls the production of a metabolic enzyme that converts pyruvate into lactate.  FOXM1 also controls the production of many other proteins involved in cell growth and proliferation.

Around 70% of all cases of breast cancer are of a type known as estrogen-receptor (ER) positive. In many ER-positive breast cancer cases, an enzyme known as PI3Ka is activated. This leads to an abundance of FOXM1, enabling the cancer cells to grow uncontrollably – the characteristic sign of a tumour cell.

Drugs that inhibit PI3Ka are currently being tested in breast cancer patients. Such drugs should be able to decrease the amount of FOXM1 and check the tumour’s growth. However, a patient’s tumour may have an innate resistance to PI3Ka inhibitors, or can acquire resistance over time, making the drugs increasingly less effective.

Dr Susana Ros, first author from the CRUK Cambridge Institute, said: “Thanks to advances in cancer treatments, our medicines are becoming more and more targeted, but not all drugs will work in every case – some tumours are resistant to particular drugs. What we need are biomarkers – biological signatures – that tell us whether a drug is working or not.”

The researchers took breast cancer cells from patients and grew them in mouse ‘avatars’ to allow them to study the tumours in detail. They found that in tumours resistant to PI3Ka inhibitors, cancer cells continue to produce FOXM1 – meaning that this molecule could be used as a biomarker for drug resistance in patients with ER-positive breast cancer.

Checking whether a tumour is continuing to produce FOXM1 – and hence whether the PI3Ka inhibitor is still working – would usually involve an invasive tissue biopsy. However, researchers have used a new imaging technique to monitor this in real time and non-invasively.

The technique developed and used by the team is known as hyperpolarisation. First, the team produces a form of pyruvate whose carbon atoms are slightly heavier than normal carbon atoms (they carry an additional neutron and are hence known as carbon-13 molecules). The researchers then ‘hyperpolarise’ – or magnetise – the carbon-13 pyruvate by cooling it to around one degree above absolute zero (-272°C) and exposing it to extremely strong magnetic fields and microwave radiation. The frozen material is then thawed and dissolved into an injectable solution.

Patients are injected with the solution and then receive a regular MRI scan. The signal strength from the hyperpolarised carbon-13 pyruvate molecules is 10,000 times stronger than that from normal pyruvate, making the molecules visible on the scan. The researchers can use the scan to see how fast pyruvate is being converted into lactate – only the continued presence of FOXM1 would allow this to happen, and this would be a sign that the drugs are not working properly.

Dr Ros added: “We’ve been able to detect the presence of FOXM1, our biomarker, by using this new imaging technique in breast cancer models to look for a proxy – that is, how quickly pyruvate is converted to lactate.”

Professor Kevin Brindle, senior author of the study, commented: “In the future, this could provide us with a rapid assessment of how a breast cancer patient is responding to treatment without the need for invasive biopsies. This information could help put an end to giving treatments that are not working and the side effects that accompany them. Currently, patients can wait a long time to find out if a treatment is working. This technique could shorten this time, and help to tailor treatment for individual patients.”

Source: University of Cambridge




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How to install the FreeIPA identity and authorization solution on CentOS 8

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Jack Wallen walks you through the process of installing an identity and authorization platform on CentOS 8.

Image: CentOS

FreeIPA is an open source identity and authorization platform that provides centralized authorization for Linux, macOS, and Windows. This solution is based on the 389 Directory Server and uses Kerberos, SSSD, Dogtag, NTP, and DNS. The installation isn’t terribly challenging, and you’ll find a handy web-based interface that makes the platform easy to administer.

I’m going to walk you through the steps of getting FreeIPA up and running on CentOS 8. 

SEE: CentOS: A how-to guide (free PDF) (TechRepublic) 

What you’ll need

How to set your hostname

The first thing you must do is set your hostname. I’m going to be demonstrating with a LAN-only FQDN (which then must be mapped in /etc/hosts on any client machine that wants to access the server). 

Set your hostname with the command:

sudo hostnamectl set-hostname HOSTNAME

Where HOSTNAME is the FQDN of the server.

After you’ve set the hostname, you must add an entry in the server’s hosts file. Issue the command:

sudo nano /etc/hosts

Add a line at the bottom like this:

SERVER_IP HOSTNAME

Where SERVER_IP is the IP address of the server and HOSTNAME is the FQDN of the server.

Save and close the file.

How to install FreeIPA

The installation of FreeIPA starts with enabling the idm:DL1 repository with the command:

sudo module enable idm:DL1

When that command completes, sync the repository with the command:

sudo dnf distro-sync

Install FreeIPA with the command:

sudo dnf install ipa-server ipa-server-dns -y

How to set up FreeIPA Server

Next you have to run the configuration script for FreeIPA Server. To do that, issue the command:

sudo ipa-server-install

The first question you must answer is whether or not you want to install BIND for DNS. Accept the default (no) by pressing Enter on your keyboard. You must then confirm the domain and realm name, which will both be detected by the script. Once you’ve confirmed those entries, you’ll need to set a directory manager password, an IPA admin password for the web interface, and then accept the default (no) for the installation of chrony. 

After you’ve taken care of the above, you’ll be presented with the details of your installation (Figure A).

Figure A

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The details of my installation of FreeIPA Server.

Type y and hit Enter on your keyboard. The configuration will begin. This does take a bit of time, so either sit back and watch the text fly by or set about to take care of another task.

When the configuration completes, you’re ready to continue on.

How to access the web interface

Open a browser and point it to https://SERVER_IP (where SERVER IP is the IP address of the hosting server). You should be prompted for a username and password (Figure B). The username is admin and the password is the one you set for IPA admin during the configuration. 

Figure B

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The FreeIPA login screen.

Upon successful login, you’ll find yourself at the FreeIPA main window, where you can begin managing your centralized authentication server (Figure C).

Figure C

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The FreeIPA main window is ready to work.

And that’s all there is to getting FreeIPA installed on CentOS. You can now spend some time adding users and other bits to make your identity and authorization solution work for your business.

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Targeting Aging is the Way to Treat Diseases of Aging

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Near all work to date on the treatment of age-related disease has failed to consider or target underlying mechanisms of aging, the molecular damage that accumulates to cause pathology. It has instead involved one or another attempt to manipulate the complicated, disrrayed state of cellular metabolism in late stage disease, chasing proximate causes of pathology that are far downstream of the mechanisms of aging. This strategy has largely failed, and where it has succeeded has produced only modest benefits. Consider that statins, widely thought to be a major success in modern medicine, do no more than somewhat reduce and delay mortality due to atherosclerosis. They are not a cure. The mechanisms of aging are why age-related diseases such as atherosclerosis exist. They are the root cause of these diseases. Attempted therapies that continue to fail to target the mechanisms of aging will continue to fail to deliver meaningful benefits to patients. This must change.

Targeting Aging is the Way to Treat Diseases of Aging

Image credit: Pixabay (Free Pixabay license)

Aging doesn’t kill people – diseases kill people. Right? In today’s world, and in a country like the United States, most people die of diseases such as heart attack and stroke, cancer, and Alzheimer’s. These diseases tend to be complex, challenging, difficult, and extremely ugly to experience. And they are by nature chronic, caused by multifactorial triggers and predispositions and lifestyle choices. What we are only now beginning to understand is that the diseases that ultimately kill us are inseparable from the aging process itself. Aging is the root cause. This means that studying these diseases without taking aging into account could be dangerously misleading … and worst of all, impede real progress.

Take Alzheimer’s disease. To truly treat a disease like Alzheimer’s, we would need to identify and understand the biological targets and mechanisms that trigger the beginning of the disease, allowing us to intervene early – ideally, long before the onset of disease, to prevent any symptoms from happening. But in the case of diseases like Alzheimer’s, the huge problem is that we actually understand very little about those early targets and mechanisms. The biology underlying such diseases is incredibly complex. We aren’t sure what the cause is, we know for sure there isn’t only one target to hit, and all prior attempts to hit any targets at all have failed. When you start to think about how much of what we think we know about Alzheimer’s comes from very broken models – for example, mice, which don’t get Alzheimer’s naturally – it becomes totally obvious why we’re at a scientific stalemate in developing treatments for the disease, and that we’ve likely been coming at this from the wrong direction entirely.

The biggest risk factor for Alzheimer’s isn’t your APOE status; it’s your age. People in their twenties don’t get Alzheimer’s. But after you hit the age of 65, your risk of Alzheimer’s doubles every five years, with your risk reaching nearly one out of three by the time you’re 85. What if going after this one biggest risk factor is the best vector of attack? Maybe even the only way to truly address it? This isn’t about the vanity of staying younger, about holding on to your good looks or your ability to run an 8 minute mile. It’s about the only concrete possibility we have to cure these diseases. Instead of choosing targets for a single specific disease, i.e. a specific condition that arises in conjunction with aging, we can get out in front of disease by choosing targets that promote health. And we can identify these by looking at disease through the lens of the biology of aging.

Link: https://a16z.com/2020/10/07/aging-alzheimers-drug-discovery/

Source: Fight Aging!




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The Mandalorian Season 1 Recap Distills the Star Wars Series Into 89 Seconds

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Before The Mandalorian season 2 premieres Friday afternoon on Disney+ Hotstar (and Friday midnight on Disney+ in the US), Disney and Lucasfilm have given us an official 89-second recap of The Mandalorian season 1. That’s very brief, but it speaks to the fact that The Mandalorian wasn’t a narratively-heavy show on its debut last year.

Everything You Need to Know About The Mandalorian Season 2

The Mandalorian season 1 recap touches upon Mando’s (Pedro Pascal) profession (he’s a bounty hunter), his newest target (Baby Yoda), the people he meets along the way — Cara Dune (Gina Carano), Greef Karga (Carl Weathers), and Kuiil (voiced by Nick Nolte) — and the consequences of his decision to bring Baby Yoda under his wing.

“You have something I want. It means more to me than you will ever know,” the darksaber-wielding villain Moff Gideon (Giancarlo Esposito) says deep into The Mandalorian season 1 recap, as we are given a reminder of the Star Wars series’ action-heavy side. Gideon then declares: “It will be mine.”

The season 1 recap wraps by setting up The Mandalorian season 2, as tribe leader The Armorer (Emily Swallow) instructs Mando to reunite Baby Yoda “with its own kind”. Mando wonders: “You expect me to search the galaxy for the home of this creature?” Well, yes, otherwise what would we do in season 2, Mando.

In addition to Pascal, Carano, Weathers, and Esposito, The Mandalorian season 2 also stars Omid Abtahi as Dr. Pershing, Horatio Sanz as Mythrol, Rosario Dawson as Ahsoka Tano, Katee Sackhoff as Bo-Katan Kryze, Temuera Morrison as Boba Fett, Timothy Olyphant as former slave Cobb Vanth, Michael Biehn as a rival bounty hunter, and Sasha Banks in an undisclosed role.

Jon Favreau (The Lion King, Iron Man) created The Mandalorian and serves as showrunner and head writer on the Star Wars series. Favreau and Weathers are among the directors on season 2 alongside Dave Filoni, Rick Famuyiwa, Bryce Dallas Howard, Peyton Reed, and Robert Rodriguez.

The Mandalorian season 2 premieres October 30 on Disney+ Hotstar in India. Episodes will air weekly.

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