[Analysis and prediction of thyroid cancer morbidity and mortality trends in China].

Objective: To analyze the morbidity and mortality trends of thyroid cancer in China from 1990 to 2019, explore the causes of the trends, and predict morbidity and mortality in the future. Methods: The morbidity and mortality data of thyroid cancer in China from 1990 to 2019 were collected from the 2019 Global Burden of Disease database. The Joinpoint regression model was used to describe the change trends. Based on the morbidity and mortality data from 2012 to 2019, a grey model GM (1,1) was constructed to predict the trends in the next ten years. The model was tested by the posterior error method and residual test method. Results: In all populations, men and women, the AAPC values of the crude morbidity rates were 4.15% (95%CI: 3.86%-4.44%, P<0.001), 5.98% (95%CI: 5.65%-6.31%, P<0.001) and 3.23% (95%CI: 2.94%-3.53%, P<0.001) respectively, the AAPC values of age-standardized morbidity rates were 2.47% (95%CI: 2.12%-2.83%, P<0.001), 3.98% (95%CI: 3.68%-4.29%, P<0.001), 1.65% (95%CI: 1.38%-1.93%, P<0.001), the AAPC values of crude mortality rates were 2.09% (95%CI: 1.92%-2.25%, P<0.001), 3.68% (95%CI: 3.45%-3.90%, P<0.001), 0.60% (95%CI: 0.50%-0.71%, P<0.001). The age-standardized mortality rates in men showed a fluctuating trend of first decrease (1990-1994), then increase (1994-2012), and then decrease (2012-2019) (AAPC=1.35%, 95%CI: 1.16%-1.53%, P<0.001). The age-standardized mortality rate in women continuously decreased (AAPC=-1.70%, 95%CI: -1.82%- -1.58%, P<0.001). The GM (1,1) models can be used for medium and long-term predictions. The results of the residual test show that the average relative error values of all models are less than 10.00%, the prediction accuracy values are more than 80.00%, and the prediction effects are good. The results of the posterior error method show that all the prediction results are good except the qualified prediction of the age-standardized morbidity rate in men. In 2029, the crude morbidity rates would increase to 3.57/100 000, 2.78/100 000, and 4.40/100 000, respectively, and the age-standardized incidence rates would increase to 2.38/100 000, 1.89/100 000, and 2.88/100 000, respectively, the crude mortality rates would increase to 0.57/100 000, 0.62/100 000 and 0.53/100 000, and the age-standardized mortality rates would decrease to 0.33/100 000, 0.42/100 000 and 0.27/100 000 in all population, men and women in China. Conclusions: The overall, gender- specific age-standardized mortality rates showed downward trends in the last decade or so, and the prediction results showed that it might further decline. However, the crude morbidity rates, age-standardized and crude mortality rates have been on the rise, and the population aging is becoming increasingly serious in China, which requires close attention and targeted prevention and control measures.

Bombesin stimulates in vitro growth of human breast cancer independent of estrogen receptors status.

BACKGROUND: Approximately 180,000 women will be found to have breast cancer this year in the United States. Chemotherapy has limited success in advanced disease and the effect of tamoxifen appears to require a functional estrogen-receptor (ER). Our aim was to determine whether bombesin (BBS) regulates growth of human breast cancer cells. METHODS: Estrogen-dependent (MCF-7), estrogen-responsive (ZR-75-1) and estrogen-independent (MDA-MB-231) human breast cancer cells were studied. Receptors were identified by cross-linking methods and radioligand binding assays; intracellular calcium ([Ca2+]i) was measured after BBS treatment to confirm functional status of the receptor; and the effect of BBS on cell growth was measured directly. RESULTS: All three cell lines had a high affinity BBS receptor (Kd = 1-7 nM; molecular weight 75 kDa). BBS stimulated [Ca2+]i levels as well as cell growth in all three cell lines; the trophic effect was blocked by BBS receptor antagonists. CONCLUSIONS: We conclude that BBS is trophic for human breast cancers independent of ER status, and that antagonism of the BBS receptor may be a useful target for hormonal therapy in ER-negative breast cancer.

Human monoclonal antibody against colon cancer.

The purpose of the study was to produce human monoclonal antibodies (hMcAb) against human colon cancer for use in radioimmunoimaging. Human-mouse heterohybridomas were developed by fusing SHM-D33 mouse-human hybrid heteromyeloma cells with human lymphocytes from colon cancer tumor-draining lymph nodes. The hybridomas capable of secreting human monoclonal antibodies were screened by using human colon cancer cell lines and pathological biopsies with ELISA and immunohistochemical methods. hMcAb clone H11 was selected for a large-scale antibody production, which was purified from mouse ascites. Biodistribution study demonstrated that specific uptake of 125I-hMcAb H11 by human colon cancer xenografts was significantly higher than by normal tissues. Radioimmunoimaging of human colon cancer xenografts exhibited distinct tumor visualization during the period of 72-96 hr after intraperitoneal injection of 125I-hMcAb H11. The development of human monoclonal antibodies such as hMcAb H11 may be useful for radioimmunodetection and therapy of colon cancer.

Growth of mouse hepatocytes is stimulated by gastrin.

Hepatocyte growth is regulated by various growth factors, including epidermal growth factor (EGF) and insulin. Recently, several additional peptide hormones have been shown to stimulate growth of hepatocyte only in the presence of EGF or insulin and are thus termed secondary mitogens. Gastrin regulates growth of normal and neoplastic gastrointestinal tissues, but the effect on growth of hepatocyte is unknown. We examined the effect of gastrin on growth of a normal mouse hepatocyte (NMH) line established in our laboratory. Effect of gastrin-17 (G-17) (10(-8) to 10(-6) M) on growth of NHM cells was examined in either the presence or absence of EGF in the culture medium. Growth of NMH cells was evaluated by incorporation of either bromodeoxyuridine (BrdU) or 3H-thymidine and by counting cells. Presence of a cell-surface receptor for G-17 was determined by Scatchard analysis using 125I-G-17. In the presence of EGF, gastrin stimulated growth of NMH cells; in the absence of EGF, gastrin did not affect growth. The stimulatory effect of gastrin on NMH cells was blocked by JMV 320, a CCK-B type receptor antagonist. NMH cells possess a single, high affinity binding site for gastrin (Kd = 1.2 nM); EGF increased the gastrin binding capacity compared to non-treated cells (3.5 +/- 0.4 vs. 2.2 +/- 0.6 fmol/10(6) cells). G-17 stimulated growth of NMH cells through a single high affinity receptor for G-17 which pharmcologically appears to be the CCK-B type only in the presence of EGF and thus can be considered a secondary mitogen.

Cytocidal effect of high energy shock wave on tumour cells enhanced with larger dose and multiple exposures.

Cultured LLC-WRC256 (Walker rat carcinoma) cells were exposed to different doses of high energy shock waves (HESW). The immediate viabilities were 98% in the control cells, and 74%, 53% and 18% following 400, 800, and 1500 HESW treatment, respectively. Surviving cells in the 400 and 800-treated HESW demonstrated delayed upward growth rate curves, and the 1500 HESW-treated a downward curve. Agar clonogenic efficiencies for surviving cells were 36% (control), 20% (400 HESW), 15% (800 HESW) and 3% (1500 HESW). LLC-WRC256 tumours in Wistar rats were treated once every other day with 1500 HESW on a total of three occasions. Tumours treated with HESW grew more slowly (4.9 cm3) than those in the control (13.5 cm3). HESW fragmented cells and destroyed cell membranes and intracellular organelles. A histological examination of tumours treated with HESW demonstrated local haemorrhage with necrosis in the HESW focus area. Damage to the surrounding skin and soft tissue was slight and transient. These findings suggest that the growth of tumour cells can be suppressed in vitro and in vivo by treatment with HESW.

Radioimmunoimaging of xenograft pancreatic cancer with 131I-monoclonal antibody P2.

Monoclonal antibodies (McAbs) to pancreatic cancer were developed by fusing SP2/0 cells and splenocytes from Balb/c mice immunized with CH-2 cells. The specific binding rates of McAb P1 and P2 were 40.1 and 43.8%, respectively, shown by binding radioreactivity assay in vitro, which were in sharp contrast with those of control groups (p < 0.05). The biodistribution of radioiodinated McAb P2 was studied by measuring parameters of tumor-specific radioreactivity in nude mice bearing CH-2 tumors. The ratios of tumors to nontumors were all > 2 at 48 h. The localization index of cancer and the ratio of tumor to pancreas were 4.05 and 4.16, respectively, at 72 h. Therefore, 131I-McAbs may be useful for radioimmunoimaging (RII) of pancreatic cancer. After intraperitoneal injection of 131I-McAb P2 into tumor-bearing nude mice, imaging of xenograft pancreatic cancer became increasingly distinct with the nonspecific background fading, especially in the period of 72-96 h. Examination of pancreatic cancer tissues by immunohistochemical methods revealed that McAb P2 was strongly positive (86%) in comparison with other tumors and normal tissues. The results demonstrated that clinical RII of pancreatic cancer was feasible with McAb P2.

Successful intracerebroventricular allotransplantation of parathyroid tissue in rats without immunosuppression.

The lateral ventricle of the brain may be an immunoprivileged site for viable allografts. Allotransplanted parathyroid tissue from histoincompatible ACI rats survived and remained functional for more than 3 months in the cerebroventricles of recipient F344 rats. Microscopic examination proved that the allotransplanted parathyroid tissues retained normal histological features. In sharp contrast, when the parathyroid was placed beneath the renal capsule the allografted parathyroid tissue uniformly lost its capacity to liberate parathyroid hormone within one month, and only residual scar tissue remained at the transplantation site. After allotransplantation of parathyroid tissue into the cerebroventricle, the serum concentrations of both Ca++ and parathyroid hormone were maintained at levels similar to those before parathyroidectomy, until the time of sacrifice. During the 3-month period of post-transplantation observation, no neurological symptoms were noted in any of the F344 rats.

Early stages of gallstone formation in guinea pig are associated with decreased biliary sensitivity to cholecystokinin.

The purpose of this study was to measure differences in gallbladder sensitivity to cholecystokinin (CCK) in vivo during the early stages of gallstone formation and to correlate these findings to gallbladder CCK receptors. Guinea pigs were placed on either a normal diet or a two-week cholelithogenic diet, after which gallbladder emptying pressure to exogenously administered CCK was measured in vivo, according to the presence or absence of gallstones. At all doses of CCK tested (except 10(-10) mol/kg), the gallbladder response to CCK of guinea pigs that did not develop gallstones (on the cholelithogenic diet) was more sensitive than that of guinea pigs that did develop gallstones. Neither group was different from guinea pigs on a normal diet. In a second experiment, CCK receptors were measured on gallbladder muscularis from guinea pigs after two weeks on the same diet as in the first experiment. Those guinea pigs that did not develop gallstones had greater concentrations of CCK receptors (149 +/- 9 fmol/mg protein) than those that did develop gallstones (70 +/- 23 fmol/mg protein). Neither group was different from normal diet guinea pigs (119 +/- 57 fmol/mg protein). At the time point measured, there were no differences in the lipid chemistry or protein concentrations of gallbladder bile between the guinea pigs on the cholelithogenic diet that did or did not develop gallstones, or those on normal guinea pig chow. We conclude that the early stages of gallstone formation in guinea pigs are associated with decreased gallbladder sensitivity to CCK and that this change may be due to a lower concentration of CCK receptors on the gallbladder smooth muscle.

[Culture and characterization of normal human hepatocytes].

Small pieces of normal liver tissues were obtained from patients with gallstones undergoing cholecystectomy, and hepatocytes were isolated from these tissues. They were cultured in a medium of DFH containing several growth factors and hormones, successively for more than two years over 60 passages. They showed doubling time about 25 hours, peak mitotic index near 4% and heteroploid karyotype. They kept secreting some enzymes and albumin, that are usually produced by normal liver tissue. In contrast with hepatoma cells, the cultured normal hepatocytes failed to form xenograft tumor in nude mice and their proliferation was depended upon exogenous growth-factors in vitro. The cultured hepatocytes can be used as a cell model for study of carcinogenic process and stored as a cell-pool for clinical cell transplantation in the coming years.

Effect of age and sensitivity to cholecystokinin on gallstone formation in the guinea pig.

The purpose of this study was to evaluate the effect of age and the role of cholecystokinin therapy on gallstone formation in guinea pigs. Guinea pigs (31 1-mo-old, 31 1-yr-old, and 23 3-yr-old) were placed on a cholelithogenic diet for 2 wk while another 10 guinea pigs of each age group remained on regular chow. Half of each group received a daily injection of cholecystokinin (0.5 nmol/kg). After 2 wk, guinea pigs were killed and the gallbladders were examined for gallstones. The concentrations of bile constituents were determined. The prevalence of gallstones was: 1-mo-old, control 0 out of 16, cholecystokinin 1 out of 15; 1-yr-old, control 3 out of 14, cholecystokinin 5 out of 16; 3-yr-old, control 10 out of 11, cholecystokinin 3 out of 8. Gallstone formation was significantly greater in 3-yr-old controls than in the two younger control groups, and cholecystokinin treatment significantly reduced the incidence of gallstones to near the level seen in younger guinea pigs. In the two younger age groups (but not in the 3-yr-old group), the cholelithogenic diet significantly reduced the concentration of bile salts in bile below that of guinea pigs on a normal diet. The cholelithogenic diet and treatment with cholecystokinin did not alter the relative compositions of bile lipids from that of guinea pigs on a normal diet in any of the three ages studied. In the second experiment we measured gallbladder emptying in response to exogenous infusion of cholecystokinin-8 (100 fmol/kg/h-100 nmol/kg/h) in the same three age groups of guinea pigs in vivo that had been maintained on regular chow. There was no difference in cholecystokinin sensitivity between the two younger age groups, but both were significantly more sensitive to cholecystokinin than the 3-yr-old guinea pigs in rate of gallbladder emptying in the dose range 1 pmol/kg/h-1 nmol/kg/h. We conclude that a major factor in the increased incidence of gallstone formation in the aged guinea pig gallstone model is decreased gallbladder emptying due to decreased gallbladder sensitivity to cholecystokinin.

[Preparation of monoclonal antibodies for radioimmunoimaging of xenografted pancreatic cancer].

Monoclonal antibodies (McAb) to pancreatic cancer were developed by fusing SP2/0 cells and splenocytes from Balb/C mouse immunized with Pan-2 cells. The specific binding rate of McAb P1 and McAb P2 were 40.1% and 43.8% respectively when shown by binding radioactivity assay in vitro, which were in sharp contrast with control groups (less than 5%). The biodistribution of radioiodinated McAb P2 was studied by measuring parameters of tumor specific radioactivity in nude mice bearing Pan-2 tumor. The ratios of tumor to non-tumor (T/NT) were all more than 2 at 48-hour. Localization index (LI) of cancer and the ratio of Tumor/Pancreas were 4.05 and 4.16 respectively at 72-hour. So 131I McAbs may be useful for radioimmunoimaging of pancreatic cancer. After intraperitoneal injection of 131I-McAb P2 into tumor-bearing nude mice, imaging of xenograft pancreatic cancer became increasingly distinct with nonspecific background fainting, especially in the period of 72-96 hours. Pancreatic cancer tissues were examined by immunohistochemistry with McAb P2 and revealed strongly positive (86%), in comparison with other tumors and normal tissues. The results demonstrated that clinical radioimmunoimaging of pancreatic cancer was feasible with McAb P2.

Intracerebroventricular administration of bombesin inhibits biliary and gastric secretion in the rat.

The effect of intracerebroventricular (ICV) bombesin on bile and gastric acid secretion was examined in the rat. ICV bombesin (10 micrograms in 10 microliters) inhibited basal biliary volume by 27% and bile bicarbonate by 52% of control values, while gastric acid secretion was decreased by 75%. These results provide evidence for central mechanisms for the control of gastrointestinal function.

[Inhibition by VIP of the proliferation of pancreatic cancer cells].

The molecular biological mechanism of the inhibition by VIP (vasoactive intestinal peptide) on proliferation of pancreatic cancer cells was studied by identifying hormone receptor and using tumor model in vivo. Inhibition appears only in those cells with VIP receptor. Cell-membrane receptors may change during carcinogenesis process. The inhibition of VIP (at certain concentration) on proliferation of tumor cells is remarkable, but, on the other hand, negligible on that of normal cells. These results suggested the feasibility of clinical application of VIP to the treatment of human pancreatic cancer.

Age-related changes in gallbladder contractility and gallbladder cholecystokinin receptor population in the guinea pig.

We have examined the effects of aging on guinea pig biliary motility both in vitro and in vivo. The first experiment compared contractile tension of gallbladder strips from young adult (6-12 months old) and 3-year-old guinea pigs in vitro. Contraction of gallbladder strips from the young guinea pigs was twice as forceful and was more sensitive to octapeptide of cholecystokinin (CCK-8) stimulation than the gallbladder strips from the older guinea pigs. The two groups were also studied in vivo by measuring changes in the intraluminal pressure of the gallbladder in response to exogenously administered doses of CCK-8. Young adult guinea pigs were more sensitive to CCK-8 at the lower doses tested and demonstrated gallbladder contractions that were more forceful than that of the old guinea pigs. CCK receptors were measured on gallbladder muscularis membranes from young adult and old guinea pigs. The number of receptors on gallbladder membranes decreased with age: 65.0 +/- 17.7 fmoles/mg protein on membranes from 1 year old; 7.9 +/- 2.0 fmoles/mg protein on membranes from 3 years old. The binding affinity of CCK receptors on gallbladder muscularis membranes for binding to CCK-8 was not significantly different in the two age groups studied. We conclude that age-related decreases in gallbladder responses to CCK-8 may be due to decreased concentrations of CCK receptors on gallbladder muscle cells.

Role of vagal hyperactivity in gastric stress ulceration after acute injury to the cervical cord.

The role of vagal hyperactivity in the pathogenesis of gastric stress ulceration that occurs after acute trauma to the cervical cord is controversial. We have used a rat model of transection of the cervical cord to induce gastric stress ulceration and to examine the cause of the ulcers. Cervical cord transection did not increase gastric acid output or plasma levels of gastrin or pancreatic polypeptide, either immediately or up to eight hours later. However, gastric stress ulceration showed a time-related increase in ulceration. Vagal stimulation with 2-deoxy-glucose enhanced the gastric acid output in rats with cervical cord transection but failed to change the quantity or characteristics of the gastric ulceration. We conclude that there is no evidence to support the vagal hyperactivity hypothesis in the pathogenesis of gastric stress ulceration after acute cervical cord injury.

Vasoactive intestinal peptide inhibits the growth of hamster pancreatic cancer but not human pancreatic cancer in vivo.

We have previously shown that hamster H2T pancreatic ductal cancer has a receptor for vasoactive intestinal peptide (VIP) which is not present on a cell line of human pancreatic ductal cancer (MIA). The purpose of this study was to examine the effect of chronic administration of VIP on the growth of both H2T hamster pancreatic carcinoma and MIA human pancreatic carcinoma in vivo. The growth of H2T was studied in hamsters; a control group of six hamsters received 0.1% bovine serum albumin (BSA) in saline, and two treatment groups of six hamsters each received VIP (1 and 10 nmol/kg), all administered three times a day by i.p. injection for 35 days. Both doses of VIP inhibited the growth of H2T tumor (tumor area, weight, DNA, RNA, and protein content). The growth of MIA was studied in athymic Balb/c mice, one group of 10 received 0.1% BSA and the other 10 received VIP (1 nmol/kg), both three times a day by i.p. injection for 3 months. There was no difference in tumor growth rate between the two groups. Treatment with VIP did not have any effect on body weight or size of the normal pancreas in either the hamsters or the mice. We conclude that the differential response of hamster and human pancreatic cancer to VIP treatment may be due to the presence or absence of VIP receptors.