Signal transducer and activator of transcription (STAT) 1 and STAT3 are expressed in the human ovary and have Janus kinase 1-independent functions in the COV434 human granulosa cell line.

Ovarian granulosa cells are fundamental for oocyte maintenance and maturation. Recent studies have demonstrated the importance of members of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathway in the granulosa cell population of mouse and horse ovaries, with perturbation of JAK1 signalling in the mouse shown to impair oocyte maintenance and accelerate primordial follicle activation. The presence and role of the JAK/STAT pathway in human granulosa cells has yet to be elucidated. In this study, expression of JAK1, STAT1 and STAT3 was detected in oocytes and granulosa cells of human ovarian sections from fetal (40 weeks gestation) and premenopausal ovaries (34-41 years of age; n=3). To determine the effects of JAK1 signalling in granulosa cells, the human granulosa-like cell line COV434 was used, with JAK1 inhibition using ruxolitinib. Chemical inhibition of JAK1 in COV434 cells with 100nM ruxolitinib for 72h resulted in significant increases in STAT3 mRNA (P=0.034) and p-Y701-STAT1 protein (P=0.0117), demonstrating a role for JAK1 in modulating STAT in granulosa cells. This study implicates a conserved role for JAK/STAT signalling in human ovary development, warranting further investigation of this pathway in human granulosa cell function.

Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy.

PURPOSE: We investigated the ability of In-111-capromab pendetide to separate patients who have failed radical prostatectomy into categories of those who would versus those who would not respond to salvage radiotherapy. METHODS: Prostate-specific antigen (PSA) levels in 32 men with prostate cancer who had failed radical prostatectomy and had undergone a whole-body In-111-capromab pendetide scan were followed-up for 13 months (median) after salvage radiotherapy to the pelvis. A logistic regression model was used to determine whether the scan findings, as well as other clinical variables, were associated with a durable complete response (DCR), a nondurable response (NDR), or no response (NR). RESULTS: Sixteen of 23 (70%) men with a normal scan outside the prostatic fossa achieved a DCR after salvage radiotherapy versus two of nine (22%) who had a positive scan outside the prostate fossa and pelvis (P = .0225, Fisher's exact test). Predicted probability (95% confidence interval [CI]) that a DCR would be obtained with a normal scan was 0.88 (0.55 to 0.98); for men with a positive scan limited to the prostatic fossa it was 0.62 (0.42 to 0.79); and for men with a positive scan outside the pelvis it was 0.27 (0.09 to 0.58). No other variables before radiotherapy showed a significant association with the DCR rate. CONCLUSION: Salvage radiotherapy is statistically more likely to lead to a durable complete PSA response in men with prostate cancer who have failed radical prostatectomy and have a negative In-111-capromab pendetide scan outside the pelvis as compared with those who have a positive scan.

Radioimmunodetection of occult carcinoembryonic antigen-producing cancer.

This study evaluates the ability of 111In-labeled anti-carcinoembryonic antigen (CEA) monoclonal antibody (Mab) ZCE-025 to detect sites of occult cancer in patients with elevated serum CEA who have negative or equivocal CT scans. One hundred forty patients suspected of having occult cancer were evaluated. Except for elevated CEA levels, all had negative work-ups, including negative or inconclusive CT scans. Eighty-two patients (59%) had positive scans and 58 (41%) had negative scans. Seventy-five of the 82 patients with positive scans had confirmation of at least one Mab-positive lesion (91% positive predictive value). Thirty-eight of the 58 patients with negative scans had negative follow-up (66% negative predictive value). The Mab scan correctly identified at least one site of tumor in 75 of the 95 patients with recurrent or metastatic disease (79% sensitivity) and correctly predicted the absence of disease in 38 of 45 patients (84% specificity).

Auditory brainstem and middle latency responses in non-human primates.

Auditory brainstem (ABR) and middle latency responses (MLR) were obtained from each ear in 8 crab-eating macaques, 4 white-handed gibbons, 4 siamangs and 2 orangutans. Macaques ranged in age from 5 days to 15 years with the 6 older animals in age-matched, male-female pairs. From each animal, latency-intensity functions were obtained and multiple MLR recordings were measured at 60 and 70 dB. Latency-intensity functions, interwave intervals, thresholds and percent detectability were calculated for ABR waveforms. Waves II and IV were largest in amplitude and were most consistently detected at low stimulus intensities in all species tested. Waves I and II had adult latencies in the youngest animal tested (5-day-old macaque), while waves III and IV were prolonged in comparison to the 15-month-old macaque, in whom latencies had reached adult values. There were no apparent sex differences in evoked potentials in the age-matched, male-female pairs. A broad, negative MLR at 7-13 ms was observed in all animals. Longer latency MLRs varied among animals of the same species, but were replicable in some individuals, including the youngest macaque (5 days) and orangutan (7 months). These data were compared to responses obtained in humans, other primates and other vertebrates.

Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen. Positron emission tomography and biopsy correlation.

The utility of monoclonal antibody (MAb) imaging for detection of occult recurrent prostate cancer was investigated in 14 patients with elevated serum prostate-specific antigen at least 3 months after therapy. All were imaged with capromab pendetide (CYT-356) and subsequently had biopsies of the prostate bed. Ten also had PET scans with F-18 fluorodeoxyglucose. Ten MAb scans were positive for tumor in the prostate bed and eight showed lymph node metastases. Six of the seven patients with positive biopsies had positive MAb scans, one had a negative scan. Three of the seven patients with negative biopsies had negative MAb scans, four had positive scans. Of the six patients with positive biopsies who had PET scans, one was positive, five were negative. Two of four patients with negative biopsies had negative positron emission tomography scans, two were positive. MAb imaging is superior to PET scan for identifying recurrent disease in the prostate bed. Assuming no false-negative biopsies, the positive predictive values for MAb and PET scan are 60% and 33%, negative predictive values are 75% and 29% and sensitivities are 86% and 17%. Additional investigation is necessary to determine if MAb uptake in lymph nodes is predictive of metastatic disease.

Auditory middle latency responses in children: effects of age and diagnostic category.

The nature of auditory middle latency responses (MLRs) in children has been the subject of considerable debate. In order to study MLRs as a function of age, MLRs were obtained in 217 subjects ranging in age from 6 days to 20 years, all with normal auditory brain-stem responses (ABRs). Subjects were classified into several diagnostic categories: normal; communicative disorders (language delay, learning disability); mentally retarded, multiply handicapped; and post-meningitic. Age effects, the effects of diagnostic category, and possible differences in MLRs of males vs. females and right vs. left ears were examined. The detectability of both Na and Pa was found to increase significantly as a function of age. Detection of these MLR components became similar to adult values (approaching 100% detectability) at approximately 10 years of age. No significant differences were found among diagnostic categories. There were also no significant differences in the detectability of MLRs in males as compared to females, and there were no right vs. left ear differences. The strong age effect which appears to exist in the MLR influences their clinical use. When responses are present, they may be useful indicators of hearing sensitivity, but the absence of MLRs in children cannot be taken as an indication of hearing loss. Similarly, absent or abnormal MLRs cannot be interpreted as a manifestation of auditory pathway dysfunction, since there appears to be little difference in MLRs in normal subjects and MLRs in patients with a wide range of neurologic, cognitive, and speech and language disorders.

Auditory brain-stem responses in hydrocephalic patients.

Auditory brain-stem response (ABR) was measured in 40 patients (80 ears) with confirmed hydrocephalus. Eighty-eight percent of these patients showed some form of ABR abnormality. Responses indicative of brain-stem dysfunction consisted of prolonged I-V interwave latency (38%), reduced V/I amplitude ratio (33%), and abnormalities in wave-shape of components III (27%) and V (53%). In addition, 70% of the patients had elevated ABR thresholds; 45% had responses in excess of 20 dB HL and the remaining 25% had no ABR activity. The etiology of the hydrocephalus, head circumference and brain-stem symptoms were not associated with particular ABR abnormalities. Communicating hydrocephalus correlated significantly with both prolonged I-V conduction time and absence of ABR activity, compared with non-communicating hydrocephalus. Four of the 9 patients retested showed ABR improvement on follow-up; one patient showed deterioration. The results were compared to our prior studies of ABR in 60 post-meningitic patients and in 100 severely neurologically impaired institutionalized children in whom the incidence of intrinsic brainstem abnormalities was one-third and two-thirds that of the hydrocephalic group, respectively. The results of this study suggest that ABR can be used to document clinically unsuspected brain-stem pathology that may accompany hydrocephalus. Auditory brain-stem dysfunction is likely to complicate the assessment of hearing sensitivity in hydrocephalic patients.