Clinical significance and new detection system of autoantibodies in myositis with interstitial lung disease.

Anti-aminoacyl-tRNA synthetase (ARS) and anti-melanoma differentiation-associated gene 5 (MDA5) antibodies are closely associated with interstitial lung disease in polymyositis and dermatomyositis. Anti-ARS-positive patients develop common clinical characteristics termed anti-synthetase syndrome and share a common clinical course, in which they respond well to initial treatment with glucocorticoids but in which disease tends to recur when glucocorticoids are tapered. Anti-MDA5 antibody is associated with rapidly progressive interstitial lung disease and poor prognosis, particularly in Asia. Therefore, intensive immunosuppressive therapy is required for anti-MDA5-positive patients from the early phase of the disease. New enzyme-linked immunosorbent assays to detect anti-ARS and anti-MDA5 antibodies have recently been established and are suggested to be efficient and useful. These assays are expected to be widely applied in daily practice.

The effect of competition on the neutral intraspecific diversity of invasive species.

This paper deals with the effect of interspecific competition on the dynamics of neutral genetic diversity in a range-expanding population. The spread of an invasive species in an environment already hosting a resident competitor is described by a traveling wave solution with minimal speed, u(t,x) = U(x - c ∗ t), of a diffusive Lotka-Volterra competition model. The description of the dynamics of neutral genetic fractions in this wave is based on a decomposition of the wave into several components, as proposed by Roques et al. (Proc Natl Acad Sci USA 109(23):8828-8833, 2012). Our analytical results reveal that the wave can be either the pulled type, corresponding to strong erosion of the diversity, or the pushed type, corresponding to maintenance of the initial diversity. The pulled/pushed nature of the wave depends on the linear or nonlinear nature of the speed c *. Our results show that, for sufficiently strong competition, the speed is nonlinear, and therefore all of the genetic diversity in the invasive population is maintained. Conversely, in the absence of competition, or when competition is mild, the speed is linear, which means that only the furthest forward fraction in the initial invasive population eventually remains in the colonization front. Our numerical results also show that the sufficient conditions of Lewis et al. (J Math Biol 45(3):219-233, 2002) and Huang (J Dyn Differ Equ 22(2):285-297, 2010) for the linearity of the speed c * can still be improved, and they show that nonlinear speeds occur across a wide region of the parameter space, providing a counterpoint to recent analytical results suggesting that nonlinear speeds only occur in certain limiting cases.

Multiple intra-articular injections with adipose-derived stem cells for knee osteoarthritis cause severe arthritis with anti-histone H2B antibody production.

Introduction: Osteoarthritis (OA) is the most common form of arthritis. OA results from the breakdown of cartilage, which leads to deterioration of the entire joint and the connective tissue that holds the joint together, and gradually and irreversibly worsens over time. Adipose-derived stem/stromal cells (ADSCs) have been used in the treatment of knee OA. However, the safety and efficacy of ADSC treatment of OA remain unclear. In this study, we investigated the pathophysiology of severe knee arthritis that occurred after ADSC treatment by screening for autoantibodies in synovial fluid from patients who received ADSC treatment. Methods: Adult Japanese patients with OA who received ADSC treatment at Saitama Cooperative Hospital between June 2018 and October 2021 were enrolled. Antibodies (Abs) were screened using immunoprecipitation (IPP) with [35S]-methionine-labeled HeLa cell extracts. The detected protein was identified by liquid chromatography coupled with time-of-flight mass spectrometry (MS) and ion trap MS, and the corresponding proteins were confirmed as autoantigens using immunoblotting. Ab titers were measured using an enzyme-linked immunosorbent assay. Results: A total of 113 patients received ADSC treatment, and 75% (85/113) received ADSC injection at least twice with a 6-month interval between. No obvious abnormalities were observed in any patient after their first treatment; by contrast, 53% (45/85) of patients who received their second or third ADSC injection showed severe knee arthritis. IPP detected a common anti-15 kDa Ab in synovial fluid of 62% (8/13) of the samples analyzed from patients who showed severe arthritis. This Ab was not detected in synovial fluid obtained from the same joints before treatment. The corresponding autoantigen was identified as histone H2B. All available synovial samples from patients who tested positive for anti-histone H2B Ab were newly positive after the treatment; that is, none had been positive for anti-histone H2B Ab before treatment. Conclusions: Multiple ADSC injections for OA induced severe arthritis in a high percentage of patients, particularly after the second injection. Synovial fluid from some patients with knee arthritis contained Ab to histone H2B that appeared only after ADSC treatment. These findings provide new insights into the pathogenesis of ADSC treatment-induced severe arthritis.

Effects of angiotensin on the expression of fibrosis-associated cytokines, growth factors, and matrix proteins in human lung fibroblasts.

BACKGROUND AND OBJECTIVES: Angiotensin (Ang) II plays an important role in fibrogenesis in various organs, including the lung. The aim of this study is to elucidate (i) the effects of Ang II on the expression of cytokines, growth factors or matrix proteins in normal human lung fibroblasts, and (ii) the inhibitory effects of an Ang II type 1 (AT1) receptor blocker, candesartan. METHODS: Normal human adult lung fibroblasts were cultured. Candesartan was added and the cells were incubated. All the cells in culture dishes were collected at day 0 and 2, and the cell numbers were counted using a Neubauer haemocytometer (Clay-Adams, Parsippany, NJ, USA). The cell proliferation rates at day 2 were calculated in comparison to those at day 0. Total cellular RNA was extracted for real-time quantitative PCR, or the culture supernatant was collected for either a Sircol assay or enzyme-linked immunosorbent assay (ELISA). Laser scanning confocal microscopy was used for analyzing the cells with and without prior exposure to candesartan. Comparisons between the means of multiple groups were analyzed by one-way analysis of variance (ANOVA) followed by Tukey's test or Games-Howell's test. Values of P < 0*05 were considered to be statistically significant. RESULTS: Among the 12 fibrosis-associated cytokines and growth factors, mRNA expressions of interleukin (IL)-4, IL-7, and platelet-derived growth factor-D were significantly modulated by Ang II, and suppressed by candesartan. Soluble collagen and elastin levels were significantly elevated by Ang II, and suppressed by candesartan. Under confocal microscopy, the intracellular distribution of elastin was significantly increased by Ang II, and suppressed by candesartan. CONCLUSION: These data indicate that Ang II promotes lung fibrosis by increasing the matrix formation, which was suppressed by AT1 receptor blocker.

p21 expression as a predictor for favorable prognosis in squamous cell carcinoma of the lung.

Although p21 WAF1/Cip1 expression has been detected immunohistochemically in non-small cell lung cancer (NSCLC), the associations between p21 expression and clinical characteristics are unknown. To determine the association between p21 expression and clinical features, p21 expression was immunohistochemically analyzed in paraffin-embedded tumor samples from 137 patients with curatively resected NSCLC. p21 expression, indicating normal p21 function, was detected in 48 (35.0%) of the 137 patients with curatively resected NSCLC and was detected more frequently in patients with stage I or II disease (40.2%) than in those with stage IIIA disease (22.5%; P = 0.0483). There was no difference in the positive rate between squamous cell carcinoma [SCC; 15 of 48 (31.3%)] and adenocarcinoma [30 of 77 (39.0%)]. For SCC, patients with tumors expressing p21 survived longer than did those with tumors negative for p21 expression; however, the corresponding survival time was not significant for adenocarcinoma. On the other hand, p53 expression, detected in 58 (42.3%) of these patients, did not act as any predictor for prognosis in either SCC or adenocarcinoma. Our findings suggest that the presence of p21 expression is associated with favorable prognosis in SCC and may be useful in obtaining candidates for adjuvant therapies from among patients with SCC.

Phosphorylation of retinoblastoma protein at apoptotic cell death in rat neuroblastoma B50 cells.

Phosphorylation of the retinoblastoma protein (RB) was observed during apoptosis of B50 neuroblastoma cells following induction by dibutyryl cAMP, after differentiation into neurons, or by cycloheximide during proliferation. A weak but distinct increase in a RB and histone H1 kinase activity was detected at the time of RB phosphorylation. However, the RB kinase appeared to correspond to neither p34cdc2 kinase, CDK2 nor CDK5 because it was not inhibited by butyrolactone I, an inhibitor for them. Expression of CDK4 and 6 along with several cyclins also did not coincide with the appearance of phosphorylated RB in the apoptotic process.

Prognostic significance of serum p53 antibodies in squamous cell carcinoma of the lung.

BACKGROUND: The prognostic significance of serum p53-Abs positivity for non-small cell lung cancer (NSCLC) is still unknown. PATIENTS AND METHODS: To determine the prognostic value of serum p53-Abs status, we determined serum p53-Abs and immunohistochemistry in 140 patients with stage I-IIIA NSCLC. RESULTS: p53-Abs were detected in 12.1% of all patients and in 17.6% of those with squamous cell carcinoma (SCC). Neither p53-Abs nor p53 overexpression alone was correlated with survival for all patients. When these factors were combined for SCC, seronegative patients with tumors overexpressing p53 survived significantly longer than did those with p53-Abs or p53-nonexpressing tumors. In multivariate analysis, p53-Abs status and p53 overexpression were independent prognostic factors for SCC (p = 0.0337). CONCLUSIONS: These findings suggest that the combination of p53Abs seropositivity and p53 overexpression may be a prognostic factor for SCC.

Extraneural metastasis of pineal tumor.

The case of an eight-year old male with a pineal tumor is reported, in which metastases occurred to extraneural organs. The pineal tumor consisted of portions of benign teratoma, malignant ependymoma and embryonal carcinoma. Only the embryonal carcinoma metastasized. The intracanial and spinal subarachnoid space alos was invaded by disseminated embryonal carcinoma. There have been seven other similar cases reported. All patients were males from five to 34 years of age.

[A case of multiple liver metastases from sigmoid colon cancer effectively treated by hepatic intra-arterial administration of levoforinate and 5-fluorouracil].

A 62-year-old female patient, who was diagnosed with sigmoid colon cancer with multiple liver metastases, was admitted to our hospital. She underwent sigmoidectomy with D3 lymph node dissection on January 31, 2000. In addition to that, she received hepatic intra-arterial infusion of levoforinate (l-LV) 250 mg and 5-fluorouracil (5-FU) 500 mg for combined multiple hepatic metastases starting on postoperative day 14, and these medications were administered over 48 hours once weekly by infuser pump. The tumor diminished by 59% 2 months after the start of administration and further diminished at 4 months. PR was achieved. Cancer metastasis to the cerebellum and metastasis to the lung were detected at month 9 and month 11, respectively, but the liver metastatic tumor continued to diminish in size, ultimately becoming undetectable by CT scan at month 10. Surgery and radiotherapy were performed for the cerebellar metastasis, and intravenous administration of a combination of l-LV and 5-FU was performed systemically for the pulmonary metastatic tumor. At present, the patient receives regular outpatient treatment continuously. To our knowledge, there has been no report on the combination therapy with l-LV and 5-FU through the hepatic artery. Since good antitumor efficacy was demonstrated in the present patient, this case is described in this report together with four other cases of hepatic metastasis from colorectal cancer.

[Arterial infusion therapy with implantable port for inoperable hepatobiliary tumors].

PURPOSE: To assess the clinical utility of arterial infusion therapy with implantable port for inoperable malignant hepatobiliary tumors. MATERIALS AND METHODS: Twenty-seven patients with advanced hepatobiliary tumors (M:F = 14:13, mean age 63.6, 11 cases with metastases from colon cancer, 4 cases from gastric cancer, 5 cases with gallbladder cancer, 3 cases with cholangiocarcinoma, 2 cases with cholangiocellularcarcinoma, 1 case with hepatocellular carcinoma and 1 with pancreatic cancer) were treated with arterial infusion ports which were placed via left subclavian artery or femoral artery. The regimens used were FEM for 5 cases, EEP for 2 cases and FP for 20 cases. RESULTS: Overall mean survival date was 241.8 days. The numbers of cases with CR, PR, NC and PD were 1, 6, 10 and 10, respectively, and the effective rate was 25.9%. Mean survivals of cases with cholangiocellularcarcinoma, metastases from gastric cancer and colon cancer were 715 days, 324.3 days and 245.9 days, respectively. Severe gastrointestinal side effects (> grade 3) were not observed. Serious bone marrow suppressions were frequently observed with FEM and EEP, but were rare with FP (10%). DISCUSSION: Arterial infusion therapy with implantable port is clinically useful for advanced cholangiocancer and metastases from the gastrointestinal system. This system contributes to the quality of life of patients, since the infusion procedure is simple and can be archived in the outpatient clinics.

Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers.

Small-cell lung cancer (SCLC) is a highly aggressive disease that exhibits rapid growth and genetic instability. We found earlier frequent overexpression of the miR-17-92 microRNA cluster, and showed that SCLC cells were addicted to continued expressions of miR-17-5p and miR-20a, major components of this microRNA cluster. In this study, we identified the frequent presence of constitutively phosphorylated H2AX (gamma-H2AX), which reflects continuing DNA damage, preferentially in SCLC. Knockdown of RB induced gamma-H2AX foci formation in non-small cell lung cancer (NSCLC) cells with wild-type RB, in association with growth inhibition and reactive oxygen species (ROS) generation, which was canceled by overexpression of miR-17-92. Conversely, induction of gamma-H2AX was observed in a miR-17-92-overexpressing SCLC cell line with miR-20a antisense oligonucleotides. These findings suggest that miR-17-92 overexpression may serve as a fine-tuning influence to counterbalance the generation of DNA damage in RB-inactivated SCLC cells, thus reducing excessive DNA damage to a tolerable level and consequently leading to genetic instability. Therefore, miR-17-92 may be an excellent therapeutic target candidate to elicit excessive DNA damage in combination with DNA-damaging chemotherapeutics.

[Blood coagulation and fibrinolysis in cord blood with reference to birth weight].

To clarify the hemocoagulative and fibrinolytic dynamics of the perinatal period and also to seek the cause of SGA (small for gestational age) baby birth, the coagulation and fibrinolysis of the cord blood were examined, and moreover a comparison with the maternal blood, discussion on the difference in birth weight, and an examination of the difference due to the sex of babies were made in 68 cases with full-term, vaginal, spontaneous delivery, and the following conclusions were reached. In comparison with maternal blood, cord blood significantly showed any of the following: Prolongations of the prothrombin time, and the activated partial thromboplastin time, a decrease in fibrinogen, and a decrease in the platelet aggregation, antithrombin III, and plasminogen. In addition, high values for thromboxane B2 and 6-ketoprostaglandin F1 alpha were observed. In the SGA group, significant decreases were observed in the platelet count, antithrombin III, plasminogen, and alpha 2-plasmin inhibitor as compared with the AGA (appropriate for gestational age) and LGA (large for gestational age) baby groups. No sex difference was observed in the hemocoagulative and fibrinolytic capacities of the cord blood. These hemocoagulative and fibrinolytic capacities, particularly changes in the fibrinolytic system observed in the SGA group, seem to be attributable to chronic DIC (disseminated intravascular coagulation) and mild acidosis due to various stresses during pregnancy and at parturition, in turn due to immaturity of the liver in babies.

[A study of blood coagulation and fibrinolysis in a small-for- gestational-age infant birth group].

In order to approach from the aspect of blood coagulation and fibrinolysis the reason for the birth of SGA (small for gestational age) infants, we studied the blood coagulation and fibrinolysis capacity of maternal venous blood in the 36th and 37th weeks after conception employing 54 cases in which were no abnormality was seen during pregnancy up to delivery, and we also studied the relationship of the body weight at delivery and arrived at the following conclusions. In the SGA infant birth group there was a tendency toward acceleration of blood coagulation, acceleration of blood platelet aggregation and inhibition of fibrinolysis when compared with two other groups i.e. AGA (appropriate for gestational age) and LGA (large for gestational age) infant birth groups. In the SGA infant birth group in particular there was seen a statistically significant reduction in prothrombin time (p less than 0.002) when compared with the other two groups. A correlation was noted between prothrombin time for maternal blood and the infant's body weight at birth (r = 0.38446, p less than 0.01), and the shorter the prothrombin time for maternal blood in the late stage of pregnancy, the lower the infant's body weight tended to be at birth. The results indicate that these changes in blood coagulation and fibrinolysis may influence the decrease in the blood output of the uterine placenta, and it may be assumed that this causes the birth of SGA infants. Furthermore, the prothrombin time values become one of the parameters used in forecasting an SGA infant's birth, and this should to be considered as a new fibrinolytic therapy for SGA infants.

Experimental studies on intestinal absorption following Martin's operation.

Experimental studies were done on rats on compensatory absorptive capacity following Martin's operation for extensive aganglionosis. Experimental aganglionosis was produced in the descending colon of rats by serosal application of 0.1% benzalkonium chloride solution. Wide side-to-side anastomosis was performed between the aganglionic colon and the distal ileum, removing the remaining colon. As to absorptive capacity of water and electrolytes, this experimental intestine was compared, with other intestines, especially control intestine, in which similar side-to-side anastomosis was done between the normal colon and the normal ileum. "Experimental" as well as control intestine showed higher absorptive capacities of water, Na and Cl per unit length than did summed up values of the ileum and the colon per unit length. Postoperative body weight curves showed fairly good increases and appearance of feces showed a fair improvement in the experimental group. Autopsy of experimental intestine revealed marked dilatation of the anastomosed ileum and mucosal hypertrophy of the anastomosed colon. These results suggested a favorable compensatory absorptive capacity following Martin's operation.

Pulsatile secretion of prolactin and oxytocin during nursing in the lactating rat.

The secretory profile of prolactin and oxytocin in response to suckling stimuli by litters was studied in unanesthetized and urethane-anesthetized lactating rats. Serum prolactin levels were determined by radioimmunoassay. Oxytocin released at milk-ejection reflex was monitored by the changes in the intramammary pressure and/or the characteristic pup's reaction associated with the milk ejection. Serum prolactin concentrations began to rise earlier than the first milk ejection in unanesthetized rats, but they were never elevated without the appearance of milk ejections in urethane-anesthetized rats. Pulsatile fluctuation in serum prolactin levels at 6-15 min intervals was observed in the nursing period when 10 pups were suckling continually. The intermittent milk-ejection reflex occurred not always but preponderantly (64-91%) when the serum prolactin levels were at the nadir of the fluctuation. Injection of an estimated dose of oxytocin released at each milk ejection (1 mU) did not change the serum prolactin levels. These results indicate that the mechanism for prolactin release may be more susceptible to the effects of anesthesia than that for oxytocin release in response to the suckling stimuli and that the release of both the hormones is pulsatile in nature and be influenced by a common biological clock during the nursing period.

Detection of large cell component in small cell lung carcinoma by combined cytologic and histologic examinations and its clinical implication.

BACKGROUND: In the classification recently proposed by the Pathology Committee of International Association for the Study of Lung Cancer, small cell lung carcinoma (SCLC) was divided into three subtypes: pure SCLC, mixed small cell/large cell carcinoma (mixed SC/LC), and combined SCLC. METHODS: To examine the clinical utility of this classification, histologic specimens, cytologic specimens obtained by brushing or fine-needle aspiration, and sputum cytologic specimens from 430 patients with SCLC were reviewed. RESULTS: When the subtype of SCLC was determined from the biopsy specimen, cytologic specimen obtained by brushing or fine-needle aspiration, and sputum cytologic specimen, the frequency of mixed SC/LC was 25 of 299 (8.4%), 75 of 400 (18.8%), and 8 of 232 (3.4%), respectively. Whatever the diagnostic method, patients with mixed SC/LC showed a poorer response to treatment and worse prognosis than those with pure SCLC: a median survival of 144 days versus 285 days when classified with the use of biopsy specimens; 160 days versus 275 days with cytologic specimens obtained by brushing or fine-needle aspiration; and 47 days versus 259 days with sputum cytologic specimens, respectively. CONCLUSIONS: These findings showed that mixed SC/LC should be separated from pure SCLC as a distinctive group and that cytologic studies of specimens obtained by brushing or fine-needle aspiration were sensitive and useful procedures for this purpose.

[Monthly changes in serum alpha 2-globulin and immunoglobulin levels in chronic hemodialysis patients--with special reference to the occurrence of cancer and blood transfusion].

Thirty-eight patients with chronic renal failure who were treated by hemodialysis more than 100 times each, including 13 cancer patients, were examined for serum alpha 2-globulin and immunoglobulin values monthly, the relationship between the possibility of cancer occurrence and the frequency of blood transfusion during hemodialysis was discussed. The alpha 2-globulin value of the patients treated with blood transfusion more than 20 times was significantly higher than that of the patients not receiving blood transfusion. Moreover, the IgA value was reduced and the IgM value was increased. The IgA values of cancer patients found before or during hemodialysis were significantly higher than those of patients without cancer. There was no significant difference between the group who had undergone hemodialysis more than 500 times those who had received it less than 500 times.