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Biomedical subjects

M Kuroki

Publications and source records attributed to M Kuroki.

At least 55 records · Page 3Linked to original sources
PubMed2000

[A case of mixed connective tissue disease with lupus-like manifestations of the central nervous system, successfully treated with cyclophosphamide combined with prednisolone].

A 29-year-old woman experienced Raynaud's phenomenon, swelling of her fingers, eruptions on her face, and muscle weakness in 1990. She was diagnosed as having mixed connective tissue disease (MCTD) and was treated with prednisolone (PSL) for 3 years. Most of her complaints disappeared after the treatment. In March 1997, she experienced fever, erythema, and lymphadenopathy. Although she was treated with PSL (20 mg/day) again, muscle weakness, mental disturbance, and recto-urinary disturbance appeared. When she was re-admitted to our hospital, increased levels of muscle-derived enzymes and positivity of anti-RNP antibody were found. High signal areas in her cerebrum were shown by magnetic resonance imaging, and slow and spike pattern was shown by electroencephalography. Hypoperfusion of the cerebral blood flow was suggested on single photon emission computed tomography. The number of mononuclear cells, amount of protein and level of interleukin-6 were found to be elevated in her cerebrospinal fluid (CSF). Her neurological manifestations were diagnosed as being due to MCTD, and showed characteristics similar to those of systemic lupus erythematosus. She was treated with PSL (60 mg/day) followed by steroid pulse therapy. Because the response to this treatment was partial, oral administration of cyclophosphamide (CPM) (100 mg/day) was added. Muscle weakness and neurological abnormalities as well as abnormal laboratory findings gradually improved over the following two months. We conclude that the treatment with CPM combined with PSL may be useful, when neurological manifestations of MCTD are serious and resistant to conventional therapy.

Adult↗
PubMed1999

Extracellular signal-regulated protein kinase (ERK)-dependent and ERK-independent pathways target STAT3 on serine-727 in human neutrophils stimulated by chemotactic factors and cytokines.

STAT3 (signal transducer and activator of transcription 3) is a latent transcription factor that is activated by tyrosine phosphorylation (Tyr-705) in cells stimulated with cytokines or growth factors. Recent studies suggest that one or more cytoplasmic serine kinases also phosphorylate STAT3 and are necessary for maximal gene activation. Here we demonstrate, with a site-specific antibody, that STAT3 is phosphorylated on Ser-727 in human neutrophils stimulated with chemotactic factors (N-formyl-methionyl-leucyl-phenylalanine and complement C5a), cytokines [granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF)], or a protein kinase C activator (PMA). (2-Amino-3'-methoxyphenyl)oxanaphthalen-4-one (PD 98059), an inhibitor of extracellular signal-regulated protein kinase (ERK) activation, blocked the serine phosphorylation of STAT3 induced by chemotactic factors or PMA. The drug was less effective on cytokines: it virtually abolished the response to GM-CSF that occurred 5 min after stimulation but only partly decreased those at 15-30 min and did not appreciably alter responses to G-CSF regardless of incubation time. 1-(5-Isoquinolinylsulphonyl)-2-methylpiperazine dihydrochloride (H7), an inhibitor of a putative STAT3 serine kinase, and 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580), an inhibitor of p38 mitogen-activated protein (MAP) kinase, did not dampen any of these serine phosphorylation responses. We propose that neutrophils use both ERK-dependent and ERK-independent pathways to phosphorylate Ser-727 on STAT3. The former pathway is recruited by all ERK-activating stimuli, whereas the latter pathway uses an undefined serine kinase and is recruited selectively by cytokines.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

Unresponsiveness of peripheral T cells induced by apoptotic bodies derived from autologous T cells.

Several reports described the dose-dependent effect of Staphylococcus aureus enterotoxin B (SEB) regarding both levels of apoptosis and anergy of T cells. We investigated here whether T-cell apoptosis induced with SEB causes unresponsiveness of naive T cells. Apoptotic bodies were isolated from human T cells stimulated with antigen-presenting cells (APCs) and SEB by the continuous density gradient centrifugation method. When naive T cells were stimulated with APCs and SEB in the presence of apoptotic bodies, their proliferation was dose dependently suppressed and their TCRs were less downregulated than those of T cells stimulated without apoptotic bodies. Furthermore, those T cells were predisposed not to respond to restimulation with fresh APCs and SEB in the absence of apoptotic bodies. These results, taken together with the observation of tight binding of apoptotic bodies to APCs, imply that T cells stimulated in the presence of apoptotic bodies may undergo unresponsiveness due to interruption of contact with APCs.

Adult↗
PubMed1999

Tumor-enhancement effect of a Mn3+ metalloporphyrin derivative (ATN-4T) in magnetic resonance imaging.

Magnetic resonance imaging is routinely used for tumor recognition in cancer diagnosis. The tumor image-enhancing characteristics of ATN-4T (THF-Mn-Asp), a Mn3+ metalloporphyrin derivative, were evaluated in rabbits. ATN-4T (10 mM) was diluted in gelatin to final concentrations ranging from 100 to 1 microM. Increasing concentrations of ATN-4T resulted in higher signal intensities. VX2 (squamous cell carcinoma) tumor-bearing rabbits were injected with 50 micromol/kg ATN-4T intravenously and T1 -weighted images were recorded continuously. Tumor images were compared with images of surrounding muscle tissue. T1-weighted images from ATN-4T-treated rabbits showed a marked enhancement of tumor contrast from 30 to 240 min postinjection. Microscopic examination revealed that carcinoma cells were scattered throughout the high contrast area of the tumor and were not seen in the surrounding muscles. ATN-4T appears useful for enhancing the intensity of tumors imaged by magnetic resonance.

Animals↗
PubMed1999

Tumor scintigraphy by the method for subtracting the initial image with technetium-99m labeled antibody.

The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.

Animals↗
PubMed1999

Enhanced antitumor activity of a combination treatment with a mouse/human chimeric anti-MK-1 antibody and lymphokine-activated killer cells in vitro and in a severe combined immunodeficient mouse xenograft model.

Mouse monoclonal antibody FU-MK-1, raised against a human gastric adenocarcinoma, recognizes a glycoprotein antigen (termed MK-1 antigen) present on most carcinomas and seems to be valuable in immunodiagnosis and immunotherapy of various cancers. In a recent study, we constructed a mouse/human chimeric antibody, designated Ch FU-MK-1, by fusing the FU-MK-1 V(H) and Vkappa genes to the human Cgamma1 and Ckappa genes, respectively. In the present study, we tested combination immunotherapy of Ch FU-MK-1 with human lymphokine-activated killer (LAK) cells in vitro and in mice with severe combined immunodeficiency (SCID) bearing human MK-1-expressing tumors. In in vitro experiments, Ch FU-MK-1 effectively mediated antibody-dependent cell-mediated cytotoxicity (ADCC) against MK-1-expressing MKN-74 cells, which was completely blocked by an anti-FcR antibody. Since the apoptotic pathway as well as the necrotic pathway have been shown to be utilized in various cytotoxic effector mechanisms, we investigated the role of apoptosis in ADCC mediated by LAK cells and Ch FU-MK-1 against MKN-74 cells. The implication of the apoptosis during ADCC was demonstrated by means of both a terminal-deoxynucleotidyltransferase-mediated dUTP-biotin nick-end-labeling assay and a propidium iodide staining method. In vivo antitumor activity of combination treatment with LAK cells and Ch FU-MK-1 was estimated using SCID mice inoculated s.c. with MKN-74 cells. The i.v. administration of LAK cells and i.p. administration of Ch FU-MK-1 and interleukin-2 (IL-2) produced a marked growth inhibition of MKN-74 tumors in SCID mice. When the actual tumor weights were measured 16 days after initiation of treatment, more than 70% reduction was observed in the group receiving LAK cells plus Ch FU-MK-1 plus IL-2 as compared to the control untreated group. Together these results suggest that Ch FU-MK-1 may serve as a potentially useful immunotherapeutic reagent for human MK-1-expressing tumors.

Animals↗
PubMed1999

The KOR-SA3544 antigen predominantly expressed on the surface of Philadelphia chromosome-positive acute lymphoblastic leukemia cells is nonspecific cross-reacting antigen-50/90 (CD66c) and invariably expressed in cytoplasm of human leukemia cells.

We previously reported a novel monoclonal antibody KOR-SA3544 which predominantly reacted with a surface antigen (sSA3544) expressed on Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia (ALL). In the present study, we demonstrate that the antibody specifically recognized nonspecific cross-reacting antigen (NCA)-50/90 (CD66c), one of the carcinoembryonic antigen (CEA)-related glycoproteins encoded by a member of the CEA gene family. In addition, we show that the SA3544 antigen (NCA-50/90) was invariably expressed in cytoplasm of all of the human leukemic cell lines examined (sSA3544-positive B-lymphoid two, sSA3544-negative T or B-lymphoid and non-lymphoid 24) regardless of the presence or absence of surface expression of this antigen. Immunoelectromicroscopic examination revealed that the cytoplasmic antigen was mainly present in granules in sSA3544-positive leukemia cells, whereas it was diffusely present in cytosol in sSA3544-negative leukemia cells. Thus, among members of the CEA family, NCA-50/90 was first demonstrated to be expressed not only on the surface of some leukemia cells, but also in cytoplasm of various types of leukemia cells.

Antibodies, Monoclonal↗
PubMed1999

Magnitude of activity in chronic hepatitis C is influenced by apoptosis of T cells responsible for hepatitis C virus.

BACKGROUND: The mechanisms of hepatitis C virus (HCV) persistence are unknown, but down-regulation of immune response in a host is likely to play a major role in it. METHODS: To investigate whether T cell apoptosis contributes to such down-regulation, we compared peripheral T cell apoptosis in patients with chronic hepatitis C (CHC) with the serum titre of HCV-RNA, serum alanine aminotransferase (sALT) levels and its change, or peripheral T cell proliferation to the recombinant core antigen of HCV, JCC-1. RESULTS: The percentage of apoptosis in T cells was 0.30 +/- 0.31% (mean +/- SD) in 44 patients with CHC and 0.10 +/- 0.05% in 10 normal volunteers (P < 0.05). In patients with CHC there was no statistical correlation between apoptosis in T cells and sALT levels, titre of HCV-RNA or T cell proliferation to JCC-1 antigen. But, in patients showing relatively more apoptosis in T cells (more than mean + 2SD of apoptosis in T cells from normal volunteers), sALT levels decreased. CONCLUSIONS: Thus, T cell apoptosis in patients with CHC is considered to cause a reduction in sALT, contributing to HCV persistence in patients with CHC.

Alanine Transaminase↗
PubMed1999

cDNA sequence analysis of monoclonal antibody FU-MK-1 specific for a transmembrane carcinoma-associated antigen, and construction of a mouse/human chimeric antibody.

Mouse monoclonal antibody (MAb) FU-MK-1, raised against a human gastric adenocarcinoma, recognizes a transmembrane antigen, GA733-2, present on most adenocarcinomas and seems to be of potential utility for immunodiagnosis and immunotherapy of those cancers. However, an inherent problem in their in vivo application is the human anti-mouse antibody response. In this study, we cloned and sequenced the variable region genes of the heavy and light chains (V(H) and Vkappa) of FU-MK-1 using the reverse transcription-polymerase chain reaction method. Then, we constructed a mouse/human chimeric antibody, designated as Ch FU-MK-1, by fusing the FU-MK-1 V(H) and Vkappa genes to the human Cgamma1 and Ckappa genes, respectively, and by ligating the chimeric H and L chain genes to each other in a mammalian cell expression vector. The final gene construct was transfected into mouse non-Ig-producing hybridoma cells by electroporation. The Ch FU-MK-1 antibody thus prepared bound to human adenocarcinoma cells and competitively inhibited the binding of the parental FU-MK-1 to the adenocarcinoma cells. Ch FU-MK-1 also showed a potent antibody-dependent cell-mediated cytotoxicity (ADCC) with human peripheral blood mononuclear cells as effectors against the adenocarcinoma cells, indicating that this chimeric antibody seems to be suitable for in vivo therapeutic approaches.

Adenocarcinoma↗
PubMed1999

Radioimmunotherapy for liver micrometastases in mice: pharmacokinetics, dose estimation, and long-term effect.

The pharmacokinetics of a therapeutic dose of 131I-labeled antibody and the absorbed dose in liver micrometastases of human colon cancer LS174T in female BALB/c nu/nu mice were investigated, along with the long-term therapeutic effect. Mice with liver micrometastases were given an intravenous injection of 131I-labeled anti-carcinoembryonic antigen (CEA) antibody F33-104 (8.88 MBq/ 40 microg). The biodistribution of the antibody was determined 1, 2, 4, 6, and 10 days later. The absorbed dose was estimated for three hypothetical tumor diameters; 1,000, 500, and 300 microm. Autoradiography showed a homogeneous distribution of radioactivity in the micrometastases, and a high uptake was maintained until day 6 (24.0 % injected dose (ID)/g on day 1 to 17.8 %ID/g on day 6), but decreased thereafter. The absorbed doses in the 1,000-, 500-, and 300-microm tumors were calculated to be 19.1, 12.0, and 8.2 Gy, respectively. The intravenous injection of the 131I-labeled antibody also showed a dose-dependent therapeutic effect (all mice of the nontreated group died, with a mean survival period of 4 weeks; 3 of the 8 mice that received 9.25 MBq survived up to 120 days with no sign of liver metastasis). These data give further evidence that micrometastasis is a good target of radioimmunotherapy, and that an absorbed dose of less than 20 Gy can effectively control small metastatic lesions.

Animals↗
PubMed1999

Effects of tirilazad mesylate on vasospasm and phospholipid hydroperoxides in a primate model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Tirilazad mesylate has been used in the attempt to prevent cerebral vasospasm after subarachnoid hemorrhage (SAH), although the actual targets of this agent in vivo have thus far been controversial. Chemiluminescence/high-performance liquid chromatography provided a new method for direct measurements of phosphatidylcholine hydroperoxide (PCOOH) and phosphatidylethanolamine hydroperoxide (PEOOH) in vivo and showed that phosphatidylcholine is the lipid class most susceptible to lipid peroxidation. In the present study we measured those levels in a primate model of SAH for determination of the effects of tirilazad on vasospasm. METHODS: Fourteen Macaca monkeys of both sexes were randomly assigned into 2 groups: a tirilazad group receiving a dosage of 0.3 mg/kg and a placebo group receiving only the vehicle in which tirilazad was delivered. After the induction of experimental SAH around the right middle cerebral artery on day 0, tirilazad or vehicle was administered intravenously every 8 hours for 6 days. On day 7, the animals were killed after angiography and regional cerebral blood flow measurements were performed. The levels of PCOOH and PEOOH were measured in the clots, bilateral parietal cortices, right frontal cortex contact with clots, cerebellar hemispheres, bilateral middle cerebral arteries, and basilar arteries. RESULTS: In the placebo group, a significant vasospasm occurred in the cerebral arteries on both sides, but most prominently on the right side. The degree of vasospasm in the cerebral arteries was significantly attenuated in the tirilazad group (P<0.005). There were no significant differences in regional cerebral blood flow, PCOOH, and PEOOH levels in the clots, cerebral cortices, and cerebellar hemispheres between the 2 groups. In contrast, the levels of PCOOH in the cerebral arteries were significantly higher in the placebo group than in the tirilazad group (P<0.025). It was remarkable that the tirilazad treatments eliminated PCOOH in any vascular territory after SAH. CONCLUSIONS: PCOOH in the artery wall may be an important indicator for vasospasm, and the inhibition of PCOOH may explain the efficacy of tirilazad on vasospasm.

Animals↗
PubMed1999

Heme oxygenase-1 gene induction as an intrinsic regulation against delayed cerebral vasospasm in rats.

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) causes cerebral ischemia and infarction. To date, the pathogenesis and gene expression associated with vasospasm remain poorly understood. The present study used fluorescent differential display to identify differentially expressed genes in a rat model of SAH. By using quantitative RT-PCR, we found that heme oxygenase-1 (HO-1) mRNA was prominently induced in the basilar artery and modestly in brain tissue in a rat vasospasm model. A significant correlation was observed between the degree of vasospasm and HO-1 mRNA levels in the basilar arteries exhibiting vasospasm. Intracisternal injection of antisense HO-1 oligodeoxynucleotide (ODN) significantly delayed the clearance of oxyhemoglobin and deoxyhemoglobin from the subarachnoid space and aggravated angiographic vasospasm. Antisense HO-1 ODN inhibited HO-1 induction in the basilar arteries but not in the whole brain tissue. This phenomenon was not observed in the nontreated, sense HO-1 ODN-treated, or scrambled ODN-treated arteries. We report the protective effects of HO-1 gene induction in cerebral vasospasm after SAH, a finding that should provide a novel therapeutic approach for cerebral vasospasm.

Animals↗
PubMed1999

[Role of advanced glycation end products (AGE) in the development of diabetic microangiopathies and the beneficial effects of AGE inhibitors].

Glucose or other reducing sugars in plasma or tissue fluids react with proteins by a nonenzymatic, post-translational process called glycation or Maillard reaction which leads to the formation of advanced glycation end products (AGEs). AGEs are implicated in the multiorgan complications of diabetes because of their multipotent bioactivities through their receptors as well as the functional and structural derangement of the AGE-bearing proteins. AGE inhibitors such as aminoguanidine have been shown to have beneficial effects on the progression of a full range of diabetic complications in animal models. Furthermore, a recent clinical study showed that aminoguanidine therapy resulted in significant improvements in several key measurements; it reduced urinary protein, LDL-cholesterol and triglycerides as well as blood pressure. A novel class of AGE-antagonists, AGE breakers have been also developed and waiting for the clinical evaluation.

Diabetic Angiopathies↗
PubMed1999

[Diabetic retinopathy--the mechanisms of the ocular neovascularization and the development of anti-angiogenic drugs].

Ocular neovascularization contributes to severe visual loss of the patients with diabetic retinopathy (DR) which is the leading cause of blindness on adults of working age. The mechanisms of ocular neovascularization are not fully understood. Several growth factors, particularly vascular endothelial growth factor (VEGF), vasoactive peptides such as angiotensin II and adhesion molecules such as integrins are considered to contribute to the ocular neovascularization. VEGF is believed to play the key role in the development of DR. Ischemic hypoxia of retina is well known to be the potent stimulus for the production of VEGF. In addition, we have reported that reactive oxygen intermediates, advanced glycation end products and insulin-like growth factor-1, also all, may participate in the pathogenesis of DR through their ability to increase VEGF production. The trials for anti-angiogenic drugs is developing now for the treatment of DR. VEGF may be the most suitable target for the inhibition of the ocular neovascularization.

Adult↗
PubMed1999

Intratumoral distribution of radiolabeled antibody and radioimmunotherapy in experimental liver metastases model of nude mouse.

UNLABELLED: The biodistribution and intratumoral distribution of radiolabeled anticarcinoembryonic antigen (CEA) monoclonal antibody in experimental liver metastases and the therapeutic effect of 131I-labeled anti-CEA antibody on the metastases were studied. METHODS: Three weeks after an intrasplenic injection of human colon cancer cells, mice received an intravenous injection of 125I- or 111In-labeled anti-CEA antibody F33-104. The biodistribution and tumor penetration of radiolabeled antibody were examined by using quantitative autoradiography. To evaluate the therapeutic effect, 5.55, 9.25 or 11.1 MBq (150, 250 or 300 microCi) 131I-labeled F33-104 were injected into groups of mice that had micrometastases smaller than 1 mm. Control groups were injected with phosphate-buffered saline or 131I-labeled control antibody. Mice were killed 3 wk later to determine the size of liver metastases. RESULTS: 1251-labeled F33-104 showed a high accumulation in the liver metastases (percentage of injected dose per gram of metastases [%ID/g] >24%, metastasis-to-liver ratio >9.8, metastasis-to-blood ratio >2.1); however, its accumulation was heterogeneous or peripheral in the nodules more than 1 mm in diameter. When the antibody dose was increased, antibody penetration was improved, but tumor uptake of radioactivity and specificity ratios decreased. In mice with large metastases, radioactivity in the normal tissue was lower than that in mice with small metastases, resulting in higher metastasis-to-background ratios. 111In-labeled antibody showed even higher tumor uptake than 125I-labeled antibody (>51 %ID/g). Metastases formation was suppressed in a dose-dependent manner by 131I-labeled F33-104 injection (5 of 8 mice had no macroscopic tumor after an injection of 5.55 MBq (150 microCi), and all mice had no visible metastasis after an injection of 9.25 or 11.1 MBq [250 or 300 microCi]), whereas tumor progression was seen in the control groups. CONCLUSION: Liver metastases had easy accessibility to the antibody. Micrometastases of less than 0.5 mm in diameter showed homogeneous intratumoral distribution of injected antibody and were successfully treated with 131I-labeled antibody. Very high uptake and satisfactory metastasis-to-liver ratios with 111In-labeled antibody suggest that the use of a radiometal with high beta-energy, such as 90Y or 188Re, is preferable for the successful radioimmunotherapy of metastases larger than 1 mm.

Animals↗
PubMed1999

In vitro and in vivo comparison of binding of 99m-Tc-labeled anti-CEA MAb F33-104 with 99m-Tc-labeled anti-CEA MAb BW431/26.

AIM: The purpose of this study was to assess the potential for radio-immunodetection (RAID) of murine anti-carcinoembryonic antigen (CEA) monoclonal antibody (MAb) F33-104 labeled with technetium-99m (99m-Tc) by a reduction-mediated labeling method. METHODS: The binding capacity of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA by means of in vitro procedures such as immunoradiometric assay and cell binding assay and the biodistribution of 99m-Tc-labeled anti-CEA MAb F33-104 in normal nude mice and nude mice bearing human colon adenocarcinoma LS180 tumor were investigated and compared with 99m-Tc-labeled anti-CEA MAb BW431/26. RESULTS: The in vitro binding rate of 99m-Tc-labeled anti-CEA MAb F33-104 with CEA in solution and attached to the cell membrane was significantly higher than 99m-Tc-labeled anti-CEA MAb BW431/261 (31.4 +/- 0.95% vs. 11.9 +/- 0.55% at 100 ng/mL of soluble CEA, 83.5 +/- 2.84% vs. 54.0 +/- 2.54% at 10(7) of LS 180 cells). In vivo, accumulation of 99m-Tc-labeled anti-CEA MAb F33-104 was higher at 18 h postinjection than 99m-Tc-labeled anti-CEA MAb BW431/26 (20.1 +/- 3.50% ID/g vs. 14.4 +/- 3.30% ID/g). 99m-Tc-activity in the kidneys of nude mice bearing tumor was higher at 18 h postinjection than at 3 h (12.8 +/- 2.10% ID/g vs. 8.01 +/- 2.40% ID/g of 99m-Tc-labeled anti-CEA MAb F33-104, 10.7 +/- 1.70% ID/g vs. 8.10 +/- 1.75% ID/g of 99m-Tc-labeled anti-CEA MAb BW431/26). CONCLUSION: 99m-Tc-labeled anti-CEA MAb F33-104 is a potential novel agent for RAID of recurrent colorectal cancer.

Adenocarcinoma↗