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12.5 kDa cystatin could be used to diagnose multiple sclerosis

12.5 kDa cystatin could be used to diagnose multiple sclerosis


Johns Hopkins researchers found that a protein found only in cerebrospinal fluid ( CSF ) that they say might be useful in identifying a subgroup of patients with multiple sclerosis or identifying those at risk for the debilitating autoimmune disorder.

Multiple sclerosis strikes over 10,000 Americans each year, most of whom are women, and causes weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. It is a disorder in which the immune system destroys myelin, the covering of nerves that helps transmit signals.

. According to Hopkins researchers, the study, published in the Annals of Neurology, is important because unlike other autoimmune diseases in which the body attacks its own tissues, multiple sclerosis cannot be diagnosed with a simple blood or other test.

“ There is the possibility now that the protein we identified, 12.5 kDa cystatin, can be used to diagnose multiple sclerosis, perhaps in its earliest stages, and also to monitor treatment by measuring its levels in CSF," says Avindra Nath, at The Johns Hopkins University School of Medicine and lead author of the study.

Working with human CSF, the Hopkins team showed that 12.5 kDa cystatin is a breakdown product of a larger protein called cystatin C or 13.4kDa, which in turn blocks activity of some enzymes, including cathepsin B.
Cathepsin B has been linked to demyelination.

" In fact, those patients who had more of the breakdown product of 12.5 kDa cystatin also seemed to have the highest cathepsin B inhibition," Nath said.

The investigators made their finding using a sophisticated technique called SELDI-time-of-flight mass spectroscopy that can find one specific protein in a complex mixture based on its weight.
They used it to examine CSF samples from 29 patients with multiple sclerosis or pre-multiple sclerosis symptoms such as numbness on one side; 27 patients with transverse myelitis; 50 infected with the AIDS virus ( which can cause nerve damage ); and 27 with other neurological diseases. The Hopkins researchers analyzed CSF instead of blood samples because CSF better represents local events in the brain than does blood, according to Nath. And the high concentrations of many proteins in the blood can mask proteins that might be biomarkers for multiple sclerosis, he added.

The team found that the 12.5kDa fragment of cystatin C occurred in CSF samples from two-thirds of patients with multiple sclerosis or the pre-multiple sclerosis conditions. Moreover, although total cystatin C levels in multiple sclerosis patients were not different from control patients without the disease, patients with multiple sclerosis had a larger proportion of the 12.5 kDa compared to 13.4 kDa cystatin C than did other patients. Thus, the presence of the 12.5 kDa fragment might identify a subgroup of multiple sclerosis patients.

Source: Johns Hopkins Medical Institutions, 2006


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Indietro

The U.S. Food and Drug Administration ( FDA ) has approved Gallium 68 PSMA-11 ( Ga 68 PSMA-11 ), the first drug for positron emission tomography ( PET ) imaging of prostate-specific membrane antigen ( PSMA ) positive lesions in men with prostate cancer.

Ga 68 PSMA-11 is indicated for patients with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy.
Ga 68 PSMA-11 is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen ( PSA ) levels.
Ga 68 PSMA-11 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.

Prostate cancer is the third most common form of cancer in the United States. It is estimated that there will be more than 190,000 new cases of prostate cancer and an estimated 33,000 deaths from this disease in 2020, according to the National Cancer Institute ( NCI ).
While computed tomography ( CT ) scans, magnetic resonance imaging ( MRI ) scans and bone scans are conventional methods commonly used to image patients with prostate cancer, these approaches are limited in detection of prostate cancer lesions.
F 18 Fluciclovine ( 18F-Fluciclovine ) and C 11 Choline ( 11C-Choline ) are two other PET drugs that are approved for prostate cancer imaging. However, they are only approved for use in patients with suspected cancer recurrence.

Once administered via injection, Ga 68 PSMA-11 binds to PSMA, which is an important pharmacologic target for prostate cancer imaging because prostate cancer cells usually contain elevated levels of the antigen.
As a radioactive drug that emits positrons, Ga 68 PSMA-11 can be imaged by PET to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body.

The safety and efficacy of Ga 68 PSMA-11 were evaluated in two prospective clinical trials with a total of 960 men with prostate cancer who each received one injection of Ga 68 PSMA-11.

In the first trial, 325 patients with biopsy-proven prostate cancer underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11.
These patients were candidates for surgical removal of the prostate gland and pelvic lymph nodes and were considered at higher risk for metastasis.
Among the patients who proceeded to surgery, those with positive readings in the pelvic lymph nodes on Ga 68 PSMA-11 PET had a clinically important rate of metastatic cancer confirmed by surgical pathology.
The availability of this information prior to treatment is expected to have important implications for patient care. For example, it may spare certain patients from undergoing unnecessary surgery.

The second trial enrolled 635 patients who had rising serum PSA levels after initial prostate surgery or radiotherapy, and thus had biochemical evidence of recurrent prostate cancer.
All of these patients received a single Ga 68 PSMA-11 PET/CT scan or PET/MR scan.
Based on the scans, 74% of these patients had at least one positive lesion detected by Ga 68 PSMA-11 PET in at least one body region ( bone, prostate bed, pelvic lymph node, or extra-pelvic soft tissue ).
In patients with positive Ga 68 PSMA-11 PET readings who had correlative tissue pathology from biopsies, results from baseline or follow-up imaging by conventional methods, and serial PSA levels available for comparison, local recurrence or metastasis of prostate cancer was confirmed in an estimated 91% of cases.
The second trial has demonstrated that Ga 68 PSMA-11 PET can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer, thereby providing important information that may impact the approach to therapy.

No serious adverse reactions were attributed to Ga 68 PSMA-11. The most common adverse reactions to Ga 68 PSMA-11 were nausea, diarrhea and dizziness.
There is a risk for misdiagnosis because Ga 68 PSMA-11 binding may occur in other types of cancer as well as certain non-malignant processes which may lead to image interpretation errors.
There are radiation risks because Ga 68 PSMA-11 contributes to a patient’s overall long-term cumulative radiation exposure, which is associated with an increased risk for cancer. ( Xagena )
Source: FDA, 2020

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