Patient may present with bone pain without known primary cancer and be found to have metastatic bone cancer. Patient may present with a pathologic fracture occurring in an area of bone weakened by cancer. There is no consensus as to the utility of PET scans in the clinical evaluation of bone metastases.
What are the radiological modes of presentation of secondary bone tumors in plain radiographs?
Indicates the net result of bone resorption and repair showing osteoblastic, osteolytic and mixed lesions, as well as defining the bone anatomy.
A skeletal survey (includes lateral skull, cervical spine, anteroposterior (AP) and lateral thoracic and lumbar spine, an AP pelvis and chest radiograph) is used as the primary investigation for bone metastases.
Radionuclide bone scanning is the preferred method for evaluating the entire skeleton for the presence of multiple lesions.
Reflects the metabolic reaction of bone to the disease process, with preferential uptake of the tracer at sites of active bone formation. Metastases are usually multiple, irregularly distributed foci of tracer that do not correspond to any single anatomic structure.
The probability that an abnormal scan represents metastatic tumor is directly related to the number of abnormal foci.
Bone scans are also limited by a lack of specificity, with most false-positive results due to trauma, whether recalled by the patient or not.
Also, it is reserved for patients with positive bone scans and negative radiographs in order to clarify pathology. MR: Even more sensitive than CT, especially for lesions involving the spine, because it can provide mutiplanar images and identify the nerve and spinal roots. Although whole body MRI has the potential to detect more lesions in the axial skeleton (particularly the spine) than bone scan, it is generally not feasible in most centers due to time constraints.
Whole body MRI techniques are rapidly advancing, and may replace technetium bone scanning in the future.
Yufeng Wang, Rong Lei, Xueqian Zhuang, Ning Zhang, Hong Pan, Gang Li, Jing Hu, Xiaoqi Pan, Qian Tao, Da Fu, Jianru Xiao, Y. Scientists have made a potentially life-saving discovery which could help prevent metastasis of breast cancer to the bone. According to researchers, metastasis affects roughly 85% of breast cancer patients with advanced tumours. The discovery is particularly important as once cancer spreads past this point, patients are "largely untreatable". The study by researchers at the Institute of Cancer Research found that an enzyme is released by a cancerous tumour before it spreads to the bones. They hope to block this enzyme, which is called LysYl Oxidase (LOX), and believe that doing so will prevent cancer from spreading. Once the cancer spreads to the bones, "osteolytic bone lesions" form which is essentially where bone is destroyed, the study explains. Researchers also discovered that treating mice with bisphosphonates could help treat patients with fragile bones and prevent cancer from spreading.
Co-author of the study, Dr Alison Gartland, from University of Sheffield said they were "really excited" by the findings.
Katherine Woods, senior research communications manager at Breast Cancer Campaign and Breakthrough Breast Cancer, told HuffPost UK Lifestyle: “By unveiling the role that the protein LOX is playing, these results open up a whole new avenue for research and treatments that could stop breast cancer spreading to the bone. AbstractPrevious studies have shown that Atp6v1c1, a regulator of the assembly of the V0 and V1 domains of the V-ATPase complex, is up-regulated in metastatic oral tumors.
The vacuolar H+-ATPase (V-ATPase) is believed to play an important role in tumor growth and metastasis by increasing H+ secretion, allowing tumor cells to survive in hypoxic conditions and the consequent acidic tumor microenvironment (1;2).
Atp6v1c1 knockdown inhibits primary 4T1 mouse mammary tumor metastasis and prolongs survival after xenograft in vivo.
Bone metastasis and lesions of primary mammary tumors derived from normal and Atp6v1c1-depleted 4T1 cells.
V-ATPases located at the plasma membrane of highly metastatic human breast cancer cells are involved in the acquisition of a more metastatic phenotype (3). Sennoune SR, Bakunts K, Martinez GM, Chua-Tuan JL, Kebir Y, Attaya MN, Martinez-Zaguilan R.
Martinez-Zaguilan R, Raghunand N, Lynch RM, Bellamy W, Martinez GM, Rojas B, Smith D, Dalton WS, Gillies RJ. De MA, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C, Perdicchio M, Matarrese P, Lugini L.
Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JWIII.
Bild AH, Yao G, Chang JT, Wang Q, Potti A, Chasse D, Joshi MB, Harpole D, Lancaster JM, Berchuck A.
Lelekakis M, Moseley JM, Martin TJ, Hards D, Williams E, Ho P, Lowen D, Javni J, Miller FR, Slavin J.
Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R.
Nam JS, Suchar AM, Kang MJ, Stuelten CH, Tang B, Michalowska AM, Fisher LW, Fedarko NS, Jain A, Pinkas J.
Stewart SA, Dykxhoorn DM, Palliser D, Mizuno H, Yu EY, An DS, Sabatini DM, Chen IS, Hahn WC, Sharp PA.
Joyce JA, Baruch A, Chehade K, Meyer-Morse N, Giraudo E, Tsai FY, Greenbaum DC, Hager JH, Bogyo M, Hanahan D. Kato Y, Lambert CA, Colige AC, Mineur P, Noel A, Frankenne F, Foidart JM, Baba M, Hata R, Miyazaki K. Taraboletti G, D'Ascenzo S, Giusti I, Marchetti D, Borsotti P, Millimaggi D, Giavazzi R, Pavan A, Dolo V.
2 clicks for more privacy: On the first click the button will be activated and you can then share the poster with a second click. Rapid bedside assessment of the renal function of patients undergoing contrast-enhanced CT. Tumors and pseudotumors of the spine: a review of the main aspects in computed tomography and magnetic resonance imaging. Meningiomas and nerve sheath tumors (intradural-extramedullary tumores) account for 30% and astrocytomas and ependymomas (intramedullary tumors) account for 10%. The use of paramagnetic contrast agent is very useful for the diagnosis of metastases in the spine. Hyperintense signal intensity on DWI was highly specific for the diagnosis of metastatic tumor infiltration of the spine (FIG 6). Optimal management requires proper patient selection to individualize the most appropriate treatment modality.
It?s an excessive accumulation of intraspinal fat causing cord compression and neurologic deficits. Included in this classification tumors that are inside the dural sac but outside the spinal cord.
NEUROFIBROMA: bulky multilevel spinal nerve root tumors in patient with stigmata of neurofibromatosis type I (NF1).
Among the intradural-intramedullary tumors the most frequent ones are ependymomas and astrocytomas. Neurofibromatosis Type 2-related ependymomas exhibit an indolent growth pattern with tumor progression limited to a minority of patients (FIG 29). Post-operative neurologic function determined largely by degree of pre-operative deficit (FIG.
Primary demyelination disease of central nervous system with multiple lesions disseminated over time and space. Less than half cross sectional area of spinal cord and less than two vertebral segments in length.
Acute disseminated encephalomyelitis: a review of the main aspects in the study with conventional MRI and using advanced techniques such as spectroscopy and diffusion.

Transabdominal ultrasound in the detection of gastroesophageal reflux disease in children: review of 500 cases. All published work is licensed under a Creative Commons Attribution 4.0 International License.
Bone metastases from prostate cancer are commonly osteoblastic and can result in disabling skeletal complications and affect quality of life. A 65-year-old African American man, with no past medical history or specific urologic symptoms, sought medical attention for non-specific pain symptoms. Prostate cancer is the second leading cause of cancer-related death in the United States among men and is one of the most commonly diagnosed cancer in American males.
A 65-year-old African American man with no past medical history presented with intermittent left gluteal pain for three months.
Computed tomography (CT) imaging of abdomen, pelvis and thorax showed diffuse osteolytic metastases involving the entire spine, ribs and pelvis, and there was an isolated expansile lytic lesion in the left iliac bone (Figures 1, 2). Figure 5: Post-treatment CT scan of the pelvis shows significant partial resolution of left iliac bone lesion.
Prostate biopsy revealed adenocarcinoma with a Gleason score of (4 + 3 = 7) which is associated with unfavorable outcome. Recent research studies have focused on the pathogenesis of bone metastasis to identify potential targets for therapeutic intervention. Bone is a common site for metastasis in patients with prostate adenocarcinoma and results in significant disabling complications like pathological fracture, spinal cord compression, severe bone pain and impaired mobility, unless intervened.
Zoledronic acid, an aminobisphosphonate, exerts potent inhibition of osteoclast adherence or activity and enhances osteoclast apoptosis; and it is currently used to prevent skeletal complications from bone metastases. For men who decide to be screened, it is suggested to begin at age 50 in average risk white men and at age 40-45 in black men, men with a positive family history, and men who are known or likely to have BRCA1 mutation (Grade 2B). Early detection and supportive treatment plays an integral role in reducing morbidity and preventing skeletal complications associated with bone metastases from prostate cancer. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. The research also adds weight to the growing body of evidence supporting the role of bisphosphonates in stopping secondary breast cancer in its tracks. Despite these studies, the function of Atp6v1c1 in tumor growth and metastasis is still unknown. Furthermore, studies of breast cancer have shown that V-ATPases located at the plasma membrane of highly metastatic human breast cancer cells are involved in the acquisition of a more metastatic phenotype and that V-ATPase inhibitors decreased the invasion and migration of highly metastatic cells (3). To identify the role of the C subunit in breast cancer biology, we first checked C1 or C2 expression in 4T1 cells using RT-PCR.
To confirm the results from our in vitro study, we used an orthotopic breast cancer mouse model.
Most advanced breast cancer patients develop osteolytic bone metastasis and lesions, which are a common cause of morbidity and sometimes mortality, causing extreme pain in advanced cancer patients (28). The C subunit, a component of V-ATPase, regulates V-ATPase enzymatic function through the control of a reversible dissociation of the V0 and V1 domains (9-12). 1: A 46 year old female patient, affected by breast cancer, underwent bone scintigraphy for disease stadiation. Post-treatment CT scan of pelvis showed considerable regression of left iliac lytic bone lesion (Figure 5). In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Atp6v1c1's expression in metastatic oral squamous cell carcinoma indicates that Atp6v1c1 has an important function in cancer growth and metastasis. In addition, functional expression of plasmalemmal V-ATPases in drug-resistant human breast carcinoma cell lines is also involved in drug-resistance (4). 24 hours after plating the lentivirus (Lenti-LacZ or Lenti-c1s3 (19)), generated using the pLB lentivirus system (Addgene, MA; plasmid #11619) (20), was added to cells for 8 hours of infection.
RT-PCR assays of three mouse tissues and 4T1 cells were performed with gene-specific primers for Atp6v1c1, Atp6v1c2, and β-actin.
Furthermore, ATP6v1c1 is the most strongly overexpressed gene in oral squamous cell carcinoma compared to other subunits of V-ATPase, it was recently suggested to control tumor growth and metastasis (13).
Comparison between the methods, demonstrating improved visualization of the lesion on T1 post-gadolinium sequence in the transverse plane, with the right neural foramen enlargement. The bones that are most commonly involvedy are vertebrae, sternum, pelvic bones, ribs, and femurs, and the characteristic radiologic appearance is osteoblastic but it can rarely present with predominantly osteolytic appearance. MRI spine showed significant resolution of lytic lesions with mild residual lesions involving several ribs and vertebrae, and no new lesions were detected. Post-treatment imaging studies confirmed significant regression of osteolytic lesions with no new metastatic bone lesions.
Other bisphosphonates like pamidronate and clodronate did not demonstrate an overall treatment benefit relative to placebo in these patients with advanced disease. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. We hypothesized that elevated expression of Atp6v1c1 is essential to cancer growth and metastasis and that Atp6v1c1 promotes cancer growth and metastasis through activation of V-ATPase activity.
Based on these findings, it is suggested that the V-ATPase complex is a potential target in breast cancer therapy and that it is an excellent candidate for anticancer drugs. Loose virus was washed off and media changed at 8 hours and cells were trypsinized 24 hours after infection and resuspended in culture media. Therefore, we hypothesized that Atp6v1c1, as a regulator of V-ATPase activity, plays a key role in breast cancer metastasis.In this study, we first found that C1, but not C2a or C2b, is expressed in the highly metastatic 4T1 mouse mammary cancer cell line as well as human cancer cell lines (Supp.
We are grateful for the assistance of Small Animal Bone Phenotyping Core and Histomorphometry and Molecular Analyses Core and Neuroscience Image Core and Neuroscience Molecular Detection Core Laboratory at the University of Alabama at Birmingham (P30 NS0474666). A range of options are available for treating skeletal metastases, including antineoplastic therapies that are directed at the tumor cells and other supportive or palliative therapies aimed at attenuating the skeletal complications, including bisphosphonates, radiotherapy, radiopharmaceuticals, surgery, vertebroplasty and kyphoplasty. To test this hypothesis, a Lentivirus-mediated RNAi knockdown approach was used to study the function of Atp6v1c1 in mouse 4T1 mammary tumor cell proliferation and migration in vitro and cancer growth and metastasis in vivo. The mean tumor diameter (TD) of tumors during the period between post-implantation day 0 and day 26. This paper was supported by National Natural Science Foundation of China Grant 30901525, Shanghai Natural Science Foundation Grant 09ZR1428900, Shanghai Education Commission Foundation Grant 10YZ39, and Talents Cultivation Plan of Shanghai Health System XYQ2011050 (all to S. In fact, the markers of bone resorption are elevated in patients with bone metastases from prostate cancer to a greater degree than bone metastases from any other malignancies.
Examination findings were normal, except for an ill-defined swelling in the left gluteal region and enlarged very hard prostate. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo.
Our data revealed that silencing of Atp6v1c1 in 4T1 cancer cells inhibited lysosomal acidification and severely impaired 4T1 cell growth, migration, and invasion through Matrigel in vitro. Therefore, defining the exact role and mechanism of V-ATPases in breast cancer cell growth and metastasis is very important, and may reveal a more specific therapeutic target and candidate for novel anticancer drugs.V-ATPases are composed of an ATP-hydrolytic domain (V1) and a proton-translocation domain (V0), as well as the accessory subunits ac45 and M8-9 (6). Number of mice bearing metastases in the lungs, liver, and bone from a primary mammary tumor based on H&E staining at day 33 (n=12 mice).
Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Shown are representative BLI images and H&E staining (F), BLI quantitation (G), and animal survival (H). We also show that Atp6v1c1 knockdown with Lenti-c1s3, a lentivirus targeting Atp6v1c1 for shRNA mediated knockdown, can significantly inhibit 4T1 xenograft tumor growth, metastasis, and osteolytic lesions in vivo. 3D, E) (n=12).Atp6v1c1 knockdown inhibits primary 4T1 mouse mammary tumor metastasis and prolongs survival after xenograft in vivo.
This is similar to previous findings in which the subunit Atp6v1c1 was ubiquitously expressed in various tissues in mice, but C2a and C2b were expressed specifically in the lungs and kidney respectively (29; 30). The V0 domain, an integral membrane bound domain, consists of a, c, c”, and d subunits in mammals (7-9). Visualized by white light (L) or by fluorescent light (FL) (primary magnification ×100).

To confirm the in vitro result that C1 knockdown inhibits 4T1 cells' migration and invasion, we also analyzed the metastasis in the primary mouse breast cancer model.
The V-ATPase is a tightly coupled enzyme that only exhibits activity when the enzyme is fully assembled with all subunits at the membrane; the C subunit is primarily responsible for its enzymatic function through the control of a reversible dissociation of the V0 and V1 domains (9-12) with Atp6v1c1 acting as a coordinating subunit which mediates V-ATPase assembly by interacting with actin as well as ATP6 subunits v0a, v1g and v1e (7). The cells between the red curves and marked by red arrows are the migration cells (primary magnification ×100).
There was metastatic osteolytic lesion in the femur from 4T1-c1s3-2 mice but no obvious metastatic osteolytic lesion in the tibia.
The Lenti-c1s3 lentivirus that we used here expressed shRNA, which has been previously shown in osteoclasts to specifically and efficiently target Atp6v1c1 (NM_025494.3) but not to target other genes (including subunits ATP6v0a3 and Atp6v1a (19)). Atp6v1c1, an isoform of the C subunit, was recently shown to be the most strongly overexpressed gene in oral squamous cell carcinoma in humans compared to other subunits, which suggests that pH regulation, which can facilitate tumor growth and metastasis, is mainly controlled by Atp6v1c1 (C1) (13).
Anti-Atp6v1c1 immunostaining of different 4T1 cells as indicated (primary magnification ×100).
Atp6v1c1 mRNA has also been shown to be expressed in breast cancer cell lines by microarray analysis (Supplementary Material: Fig.
All of these data suggest that C1 knockdown can significantly decrease 4T1 mammary tumor cell metastasis in vivo and that elevated C1 expression may be responsible for the higher risk of metastasis. The horseradish peroxidase avidin-biotin complex system (Rabbit Elite ABC Kit; Vector Laboratories) was used to visualize bound antibody. Atp6v1c1, Atp6v1a and Atp6L expression in different 4T1 cells as indicated by Western blotting. It was further confirmed that ATP6v1c1 knockdown resulted in increased xenograft survival (Fig. Bioluminescent Imaging (BLI) of mice as indicated (Red arrow indicates the metastatic site in BLI of mice and blue arrow indicates tumor necrosis).
Importantly, C1 knockdown in 4T1 cells significantly inhibits mammary tumor cell growth, migration and invasion in vitro.
However, the exact role and mechanisms of C1 in tumor growth and metastasis remain unknown. The experiments were performed in triplicate on three independent occasions.Reverse Transcription-PCR (RT-PCR). This result was further supported by our in vivo data that 4T1 cells with C1 knockdown have significantly less tumor volume and less metastasis to the lungs, liver, and bone.
Together, these findings suggest that the subunit C1 may play an important role in breast cancer cell growth, invasion, and metastatic osteolytic lesions through its role in the regulation of V-ATPases.To investigate the potential role of ATP6v1c1 in human cancers we used a mouse orthotopic xenograft model using mouse mammary tumor 4T1 (16). Meanwhile, there was no significant difference in Atp6v1a and Atp6L expression between c1-depleted cells and control cells (Fig. Quantification of Atp6v1c1 protein expression level in different 4T1 cells as indicated (normalized to the tubulin level) (n=3). These decreases in tumor growth and metastasis were confirmed to further result in an increase in tumor xenograft survival.
This data shows that C1 deficiency can effectively reduce 4T1 mammary tumor bone metastasis and metastatic bone lesions which may be attributed to a decrease in OCs or decreased OC activity in local bone metastases. However, this reduction in tumor metastasis may be a function of the significant reduction in tumor growth seen in the tumors with C1 knockdown although it is likely that the observed reduction in cancer cell motility and invasiveness is a major factor as well (Fig. This extensive homology between the murine and human ATP6v1c1 sequences indicates that they are likely to have similar functions within the cell and cellular milieu, and, further, that a mouse model of ATP6v1c1 knockdown may reasonably be used to recapitulate the human system (18). In addition, our data is similar to that produced by knockdown of ATP6L expression in hepatocellular carcinoma cells which can effectively retard cancer growth and suppress metastasis (26) and that knockdown of a3 in B16-F10 cells inhibited invasiveness and metastasis to lung and bone (34) which seems to support the hypothesis that extracellular acidification may play a major role in this effect.
To our knowledge, this is the first report that C1 deficiency can block breast cancer growth and metastasis. To our knowledge, this is the first report that C1 deficiency can block mammary tumor metastasis and growth.There are many potential causes which may underlie this change in tumor progression and growth in ATP6v1c1-knocked down mice, but previous literature suggests that the reduction in tumor growth and motility may be a function of a constellation of factors including, reductions in the function of low-pH dependent cathepsins, especially in the extracellular milieu, acting in invasion and angiogenesis, presumably to breakdown extracellular matrix (35-37) or via MMP9 which is known to be induced in acidic microenvironments (38-40). Migration was assessed in a wounded monolayer model using the scratch assay, as described (3). Five hours after injury of the monolayer, cell movement was captured under the microscope's medium magnification (100×). Alternatively, inhibition of V-ATPase activity through C1 may result in increased cell death through HIF-1a and increased autophagy (44) for which, perhaps, certain free factors of the V-ATPase may act as signaling vectors. The experiment was performed in triplicate on three separate occasions (n=3).Cell invasion assay.
Intriguingly, we have found that, in contrast to control 4T1-LacZ cells, ATP6v1c1-deficient cells are not induced to increase expression of RANKL by treatment with osteoclast conditioned media (Supp.
After 20 hours of incubation in 37°C, 5% CO2, cells that had migrated through the membrane where they were fixed with methanol and stained with hematoxylin. These results indicate that inhibition of C1 expression greater than 60% in 4T1 cells significantly decreases cell growth, migration, and invasion in vitro. 2) indicating that knockdown blocks at least one aspect of tumor-osteoclast crosstalk which is known to enhance both tumor growth and osteolysis.Eighty percent of patients with breast cancer develop bone metastases (45). Bone marrow is a primary site of metastasis, most likely due to its extensive blood supply, available growth factors, and other aspects of the microenvironment (45). Once a tumor lodges in the bone, progressive tumor growth leads to osteoclast-mediated bone loss, which causes debilitating pain and pathological fractures (45;46). Experiments were carried out on three separate occasions (n=3).Primary breast cancer mouse model.
In turn, bone resorption by osteoclasts releases growth factors from the bone matrix that stimulate tumor growth and bone destruction (47). All animals were maintained according to the Guide for the Care and Use of Laboratory Animals. This reciprocal interaction between breast cancer cells and the bone microenvironment results in a vicious circle that increases both bone destruction and the tumor burden. Notably, C1 knockdown in 4T1 cells effectively reduced primary 4T1 mammary tumor metastatic bone lesions (Fig.
During day 10 to day 26 after implantation, we monitored mean tumor diameter (TD) (23) then converted to volume under the assumption that the tumors are roughly spherical. Mice were euthanized after being exposed to X-ray (Faxitron X-ray) on day 28, and then perfused with 4% paraformaldehyde in PBS (pH 7.4). This may also be a factor of the decreased tumor growth in the ATP6v1c1 null tumors which could, via a mass effect, impact tumor cytokine production (e.g.
The ROI began 0.1 mm from the lowest point of the growth plate and moved distally for 300 slices. 2B-D) which are necessary for metastasis and which, when diminished, would reduce the efficiency of tumor cell metastasis.
Further, acidic microenvironments, such as those induced by tumors and osteoclasts, stimulate osteoclastogenesis through NFAT activity and recruitment of osteoclast precursors (42; 43).
These results may suggest that high expression of C1 is involved in 4T1 mammary tumor cell-mediated local immune reaction and inflammation in the bone microenvironment showed by less osteoclasts and osteolytic lesion, and that C1 deficiency may inhibit the vicious circle between breast-cancer cell growth and cytokine secretion and bone resorption by osteoclasts and decrease breast cancer's metastatic and osteolytic lesions.The results of our present study show, for the first time, that 4T1 mammary tumor cell V-ATPase-c1 knockdown can efficiently decrease breast cancer growth, metastasis, and formation of osteolytic lesions.
Further studies will be required to identify other molecules that might be involved in breast cancer metastasis and metastatic osteolytic lesions through C1 and confirm their roles.
Then the cells were injected into the left thoracic (#2) mammary fat pad in a 50μl volume.
Our results suggest that C1 would be a useful target for treating breast cancer and even other cancers such as oral squamous cell carcinoma (13) by blocking tumor growth, metastasis and, especially, tumor related osteolysis. For metastasis detection, we sectioned regions of the lungs, livers and knee joints from 12 mice per group using 5µm paraffin embedded sections of paraformaldehyde fixed tissues and EDTA decalcified bone, which were stained with hematoxylin and eosin (Azer Scientific, Morgantown, PA). Mice for whom metastatic mammary tumor cells were found on any slide of lung, liver, and bone sections were considered positive for metastasis as described (26).Statistical and data quantification analyses. Experimental data are reported as mean ± SEM (standard error of measurement) of three independent experiments, or more, as indicated in the respective figure legends and methods.
Data quantification analyses, including densitometry, were performed using the NIH ImageJ program (27). address
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