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PubMedDate not supplied

Cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD) as second-line chemotherapy for ovarian adenocarcinoma.

Twenty women with recurrent ovarian adenocarcinoma received a monthly four-drug combination of cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin as second-line chemotherapy. There were no objective responses to this regimen. This is in contrast to the 49% response rate reported by Kane et al using these four drugs and the 63% response rate reported by Vogl et al using three of these drugs as second-line chemotherapy. The differences in the three regimens are reviewed; however, we could not identify reasons sufficient to account for the disparity in response rates.

Adenocarcinoma↗
PubMed2004

Analysis of the expression of chondroadherin in mouse ocular and non-ocular tissues.

PURPOSE: Chondroadherin (Chad) is a unique member of the small leucine rich repeat proteoglycan gene family. It is expressed at high levels in certain zones of cartilage and also has been detected in bone, tendon, bone marrow, and chondrosarcoma cells. Recently, we demonstrated that Chad is expressed in human and mouse lens and that its expression is decreased in the absence of mimecan/osteoglycin. This finding prompted us to explore the expression of Chad in other ocular and non-ocular tissues. METHODS: Reverse transcription-polymerase chain reaction amplification (RT-PCR), in situ hybridization (ISH), and immunohistochemistry (IHC) were used to determine the expression of Chad in human and mouse tissues. RESULTS: RT-PCR analysis showed strong expression of Chad in mouse brain, heart, lung, and embryo. Moderate expression was detected in mouse thymus, spleen, testis, and ovary, and very low expression in kidney and liver. Chad was highly expressed in human cornea, brain, and skeletal muscle, and moderately in human retina and lens. By ISH, Chad mRNA was detected in cornea, lens, and retina of postnatal day 21 mouse eyes. By IHC, immunostaining for Chad was seen in epithelial and endothelial layers of the cornea, as well as in lens, ciliary body, and retina of the adult mouse eye. Strong immunostaining was noted in retinal rod, cone, and plexiform layers. IHC analysis of tissue microarray demonstrated presence of Chad in brain (cerebellum), skeletal and cardiac muscles, lung, gastrointestinal tract, ovary, and cartilage. In most tissues, Chad expression was associated with either peripheral nerves and/or blood vessels. In the stomach and intestines, positive immunostaining was observed in Meissner's plexus and enteroendocrine cells. Intriguingly, positive immunostaining also was observed in Purkinje cells of the cerebellum and pancreatic islets. CONCLUSIONS: The present work establishes the expression and localization of Chad in several new locations including cornea, lens, ciliary body, retina, cerebellum, pancreatic islet, blood vessels, and peripheral nerves. The surprisingly broad expression pattern of Chad suggests potential roles for this protein in cell specific and/or tissues specific function(s). The results reported here are an essential prerequisite for future studies aimed at understanding the biological roles of Chad in health and disease.

Animals↗
PubMed2000

Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay.

Increased levels of advanced glycosylation end products (AGEs) have been reported in tissues in association with diabetes mellitus. Thus, we measured tissue AGE levels and detected an accumulation of AGEs in the kidney and liver from spontaneously diabetic Chinese hamsters (CHAD) to determine the relationship between AGEs and diabetes mellitus. Diabetic CHAD aged 12 to 13 months were studied together with age-matched nondiabetic CHAD. We used an AGE-specific noncompetitive enzyme-linked immunosorbent assay (ELISA) with polyclonal anti-AGE-bovine serum albumin (BSA) antibody to measure tissue AGE levels. The samples extracted from the kidney and liver obtained from diabetic and nondiabetic CHAD reacted with anti-AGE-BSA antibody. When the absorbance of standard AGE-BSA (0.1 microg/mL) was expressed as 1 U, AGE levels in the kidney and liver from diabetic CHAD were significantly increased as compared with nondiabetic CHAD (kidney, 0.26 +/- 0.05 v 0.10 +/- 0.03 U/microg protein, P< .01; liver, 0.20 +/- 0.03 v 0.09 +/- 0.02 U/microg protein, P< .01). Positive AGE staining was observed in the renal cortex, especially in the tubules of diabetic CHAD, but little AGE staining was observed in the glomerulus by the immunohistochemical study. AGE staining was diffuse in the hepatocytes. These AGE levels were significantly correlated with fasting plasma glucose and glycated hemoglobin (P < .01, respectively). In conclusion, we have confirmed that AGE structures were expressed in the kidney and liver from CHAD, and these AGE levels were increased in diabetic CHAD. AGE staining was observed in the renal tubules and hepatocytes. Tissue AGE levels were positively correlated with glycemic control in CHAD.

Animals↗
PubMed1994

Natural history of B-cell dysfunction in spontaneously diabetic Chinese hamsters.

To elucidate the pathogenesis of diabetes in spontaneously diabetic Chinese hamsters (CHAD strain), a longitudinal study from just after weaning to overt diabetic state was performed. Fasting and non-fasting plasma glucose, non-fasting plasma insulin and pancreatic hormone contents (insulin, glucagon and amylin) were measured, and light microscopic examination of pancreatic islets by immunohistochemical technique and pancreas perfusion study were performed. No insulitis was found in the islets of the CHAD strain. In animals aged 1 month, there was no significant difference in the percentage of B-cell area to islet area between the CHAD strain and the control. At this stage, hyperinsulinemia was observed despite normal plasma glucose levels both in fasting and non-fasting states. In the animals of the CHAD strain aged 2-4 months, insulin secretion from the pancreas, pancreatic insulin content and non-fasting plasma insulin level decreased in proportion to the decrease of B-cell mass. In animals aged about ten months, severe hyperglycemia and hypoinsulinemia were observed. We demonstrated the existence of amylin-like immunoreactivity in the B-cells of Chinese hamsters. However, no amyloid deposit was observed in the islets of the CHAD strain. After the onset of diabetes, amylin secretion from the pancreas and pancreatic amylin content in the CHAD strain were significantly lower than those in the control. We demonstrated the natural history of B-cell dysfunction in the CHAD strain. It could mean the process of B-cell exhaustion. The profile of the CHAD strain is similar to some types of human NIDDM. Therefore, the CHAD strain is a useful diabetic model in the study of NIDDM.

Amyloid↗
PubMed1993

Peripheral insulin resistance precedes the onset of hyperglycemia in spontaneously diabetic Chinese hamsters of Asahikawa colony.

To investigate the pathogenesis of spontaneously diabetic Chinese hamsters of Asahikawa colony (CHAD), hepatic glucose production (HGP) and glucose uptake of several tissues were determined before the onset of hyperglycemia (prediabetic state). HGP was calculated as glucose disposal in postabsorptive state using [3-3H]glucose. Glucose uptake of various tissues was assessed as glucose utilization index (R'g) by the 2-deoxyglucose method. Plasma insulin level was increased in prediabetic CHAD but not decreased in CHAD with short-term diabetes compared with control Chinese hamsters (non-diabetic strain). HGP of prediabetic CHAD was similar to that of control Chinese hamsters. However, after developing overt hyperglycemia (> 200 mg/100 ml), HGP increased linearly with plasma glucose level. R'g of adductor longus, extensor digitorum longus and triceps was significantly decreased in prediabetic CHAD. R'g of interscapular brown adipose tissue, white adipose tissue from inguinal, dorsal and epididymal sites were also decreased in prediabetic CHAD. Thus, peripheral insulin resistance precedes the development of hyperglycemia and may be a primary defect in CHAD. No significant difference of R'g in heart ventricle, diaphragm, tibialis anterior or brain was observed. In conclusion, insulin resistance in some muscles and brown and white adipose tissues precedes hyperglycemia and hepatic insulin resistance in CHAD. Hepatic overproduction of glucose (hepatic insulin resistance) is a major factor responsible for overt basal hyperglycemia and may play an important role in developing further diabetic state.

Adipose Tissue↗
PubMed1994

Urinary bladder dysfunction in spontaneously diabetic Chinese hamsters.

Urinary bladder dysfunction was investigated in spontaneously diabetic Chinese hamsters of the Asahikawa colony (CHAD). The wet weight of the urinary bladder was significantly increased in CHAD when compared with non-diabetic controls. In response to continuous infusion of physiological saline into the bladder under anesthesia, regular micturition was observed in controls. However, the threshold volume (i.e. the minimum volume at which rhythmic contraction appeared) was significantly increased and the amplitude of bladder contractions during micturition was decreased in CHAD aged 3-5 months (duration of diabetes, 0.6-2.2 months), leading to incomplete micturition. The frequency of micturition was also increased. Overflow incontinence was observed in all CHAD aged 13-15 months (duration of diabetes, 10-14 months). Acetylcholinesterase staining and activity in the urinary bladder walls were both significantly decreased in CHAD compared with controls. The in vitro increment of urinary bladder pressure caused by stimulation with bethanechol was not different between CHAD and controls. These findings suggest that CHAD have urinary bladder dysfunction which is caused by autonomic neuropathy and not by detrusor myopathy.

Acetylcholinesterase↗
PubMed1988

Immunochemistry of highly branched N-glycans. Terminal N-acetyl-D-glucosamine (GlcNAc) cluster antigens contain epitopes composed of terminal GlcNAc residues linked to mannose.

We have previously demonstrated by the immunoperoxidase method the presence of a chicken heterophile antigenic determinant (CHAD-1) in medullary lymphocytes of the bursa of Fabricius and thymus as well as in some nonlymphoid cells. It has been found that the anti-CHAD-1 antibody could be neutralized by absorption with several glycoproteins or glycopeptides containing highly branched, asparagine-linked oligosaccharides terminating in N-acetylglucosamine residues. In the present study, fetuin, desialo-fetuin, and a series of 27 highly purified oligosaccharides with well-defined structures were used to investigate the chemical composition and fine structure of the CHAD-1 epitope. It was shown that anti-CHAD-1 antibody binds to oligosaccharides with at least three terminal N-acetyl glucosamine residues at the nonreducing end. These residues may be linked beta 1-2, beta 1-4, or beta 1-6 to one, two, or three different mannose residues. The antibody combining site accommodates at least four carbohydrate residues. Oligosaccharides containing five or six terminal N-acetylglucosamine residues at the nonreducing end demonstrated the highest immunoreactivity with the anti-CHAD-1 antibody. Substitution of terminal N-acetylglucosamine residues with galactose, or with galactose and sialic acid, masks CHAD-1. On the basis of this work, epitopes that react with the anti-CHAD-1 antibody will be renamed terminal N-acetylglucosamine cluster antigens (TGCA). Anti-TGCA antibody has potential use in the monitoring of biosynthetic processing of asparagine-linked oligosaccharides and in studies of their cellular distribution and functions.

Acetylglucosamine↗
PubMedDate not supplied

[The probability of bipolarity among patients with recurrent depressive disorder].

UNLABELLED: Over the last few years researchers have paid a lot of attention to the problem of the correct diagnosis of affective disorders. Propositions have appeared regarding the widening of the officially accepted criteria to be used in diagnosis. AIM: The aim of the study was to assess the probability of various types of bipolar affective disorders (type 1 and 2 CHAD, as well as spectrum) among patients (n = 246) treated for recurrent depressive disorder (CHAJ). METHOD: The analysis was based on the broadened criteria for affective disorders introduced by Ghaemi et al. and Hirschfield's Questionnaire on affective disorders. RESULTS: The appearance in the past of strange, risky behaviour was associated with a greater risk of type 1 CHAD in comparison to CHAJ (OR=24.5), as did extreme, irrational expenditure (OR=21. 1), a lack of criticism with respect to one's own social behaviour (OR=20.3), increased interest in sex (OR=17.7), as well as extreme self confidence (OR=12). A lack of criticism with respect to one's own social behaviour and strange, risky behaviour was associated with a greater risk of type 2 CHAD (OR=12.7 and OR=10, respectively). The greatest risk of spectrum CHAD type disorders were associated with hypomania, including drug induced (OR=15.8). as well as a lack of criticism with respect to one's own social behaviour (OR=11.8). Panic attacks appeared more often in bipolar affective disorders in comparison to recurring depressive disorders, but their frequency was similar in all three groups (CHAD-I, CHAD-II, CHAD-S). The early occurrence of depression (before 25 years of age) increased the risk of each of the three types of bipolar affective disorders significantly (by a factor of 3 to 5). CONCLUSIONS: The findings indicate the necessity of discussion on sharp criteria of bipolar affective disorders. The results should be helpful in the diagnosis of such disorders, which could have important consequences for effective therapy.

Adult↗
PubMed1996

Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results--Eastern Cooperative Oncology Group Study E2878.

BACKGROUND: Following surgical debulking, most patients with international Federation of Gynecology and Obstetrics (FIGO) Stage III or IV carcinoma of the ovary receive treatment with combination chemotherapy. However, the optimal postsurgical therapy for ovarian carcinoma remains to be defined. METHODS: To define better the role of initial therapy with a cisplatin-based chemotherapy regimen, the Eastern (Cooperative Oncology Group (ECOG) initiated a randomized, Phase III trial, EST 2878, comparing initial therapy with a single, orally administered alkylating agent, melphalan, versus a complex regimen employing cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD). Women who failed treatment with melphalan were crossed-over to treatment with CHAD minus the cyclophosphamide (HAD). Study endpoints included response to therapy, time to treatment failure, and overall survival. RESULTS: Between October, 1978, and November, 1980, EST 2878 accrued 253 patients with advanced epithelial carcinoma of the ovary. There were 118 eligible patients initially treated with melphalan and 126 with CHAD. Two patients experienced lethal toxicities, including gastrointestinal hemorrhage (1 patient) and neutropenic sepsis (1 patient), and 22 patients experienced life-threatening toxicities, including hematologic toxicity (21 patients) and anaphylaxis (1 patient). Response to treatment and clinical complete response rates were higher in women receiving CHAD (60% and 38%, respectively) versus melphalan (42% and 21%, respectively) (P = 0.037 and P = 0.024, respectively), but these differences were confined to women older than 50 years of age. Likewise, time to treatment failure was significantly longer in women receiving CHAD (P = 0.014), but the difference was again confined to women older than 50 years of age and to women suboptimally debulked at the time of surgery. Survival did not differ between the two arms (median survivals of 17.5 months with initial melphalan therapy and 19.5 months with CHAD), probably because women treated initially with melphalan received salvage therapy with HAD). Twenty-three patients survived longer than 10 years. Among 18 long term survivors who had retrospective pathologic review, 8 had borderline tumors of the ovary. CONCLUSIONS: In women with advanced ovarian cancer, initial therapy with a cisplatin-based combination chemotherapy regimen resulted in higher clinical complete response rates and longer time to failure compared with initial therapy with a single, oral alkylating agent; however, the benefits of this approach were confined to women older than 50 years of age at diagnosis, and there was no significant difference in survival.

Adult↗