David Reese

Abstract IA03: Molecular engineering in the era of artificial intelligence

Converging effects of cannabis and psychosis on the dopamine system: A longitudinal neuromelanin-sensitive MRI study in cannabis use disorder and first episode schizophrenia

Importance Despite evidence that individuals who use cannabis early in life are at elevated risk of psychosis and that the neurotransmitter dopamine has a role in both conditions, the mechanism linking the two conditions remains unclear. Objective To use neuromelanin-sensitive MRI (neuromelanin-MRI), a practical, proxy measure of dopamine function, to assess whether a common alteration in the dopamine system may be implicated in cannabis use and psychosis and whether this alteration can be observed in cannabis users whether or not they have a diagnosis of first-episode schizophrenia. Design, Setting, and Participants This longitudinal observational study recruited participants from 2019 to 2023 from an early intervention service for psychosis in London, Ontario, Canada. The sample consisted of 25 participants with cannabis use disorder (CUD) and 36 participants without CUD (nCUD), of which 28 had first-episode schizophrenia (FES). One-year follow-up was completed for 12 CUD and 25 nCUD participants. Main Outcomes and Measures Neuromelanin-MRI contrast within the substantia nigra (SN) and within a subregion previously linked to psychosis severity (a priori psychosis region of interest) and diagnoses of schizophrenia-spectrum disorder and cannabis use disorder derived from the Structured Clinical Interview for DSM-5. Linear mixed effects analyses were performed relating neuromelanin-MRI contrast to clinical measures. Results We found that CUD was associated with elevated neuromelanin-MRI signal in a cluster of ventral SN voxels (387 of 2060 SN voxels, p corrected =0.027, permutation test). Furthermore, CUD was associated with elevated neuromelanin-MRI signal in an SN subregion previously documented to have elevated signal in relation to untreated psychotic symptoms (t 92 =2.12, p=0.037). In contrast, FES was not associated with a significant alteration in neuromelanin-MRI signal (241 SN voxels had elevated signal, p corrected =0.094). Conclusions and Relevance These findings suggest that elevated dopamine function in a critical SN subregion may contribute to the risk of psychosis in people with CUD. Thus, cannabis affects the long-suspected ‘final common pathway’ for the clinical expression of psychotic symptoms. Imaging the dopamine system with neuromelanin-MRI may index long-term dopamine turnover. Key Points Question Is the same midbrain dopamine pathway impacted by cannabis as in psychosis? Findings Cannabis use disorder participants had elevated neuromelanin-MRI signal in a cluster of ventral substantia nigra voxels and in a subregion previously documented to have elevated signal in relation to untreated psychotic symptoms. Meaning Increased dopamine functioning in the ventral substantia nigra may contribute to the risk of psychosis in people with cannabis use disorders.

Advantages of a Truly Open-Access Data-Sharing Model

There are many models for sharing clinical-trial data. These investigators provide their viewpoint on why an open-data model has value over others.

Massively Parallel Tumor Multigene Sequencing to Evaluate Response to Panitumumab in a Randomized Phase III Study of Metastatic Colorectal Cancer

PURPOSE: To investigate whether EGF receptor (EGFR) pathway mutations predicted response to monotherapy with panitumumab, an anti-EGFR monoclonal antibody, in a randomized phase III study of metastatic colorectal cancer. EXPERIMENTAL DESIGN: Using massively parallel multigene sequencing, we analyzed 320 samples for 9 genes, with multigene sequence data from 288 (90%) samples. RESULTS: Mutation rates were: KRAS (45%), NRAS (5%), BRAF (7%), PIK3CA (9%), PTEN (6%), TP53 (60%), EGFR (1%), AKT1 (<1%), and CTNNB1 (2%). In the randomized study and open-label extension, 22 of 138 (16%) wild-type KRAS (codons 12/13/61) patients versus 0 of 103 mutant KRAS (codons 12/13) patients had objective responses. Of 6 mutant KRAS (codon 61) patients, 1 with a Q61H mutation achieved partial response during the extension. Among wild-type KRAS (codons 12/13/61) patients, 0 of 9 patients with NRAS mutations, 0 of 13 with BRAF mutations, 2 of 10 with PIK3CA mutations, 1 of 9 with PTEN mutations, and 1 of 2 with CTNNB1 mutations responded to panitumumab. No patients responded to best supportive care alone. Panitumumab treatment was associated with longer progression-free survival (PFS) among wild-type KRAS (codons 12/13/61) patients [HR, 0.39; 95% confidence interval (CI), 0.28-0.56]. Among wild-type KRAS patients, a treatment effect for PFS favoring panitumumab occurred in patients with wild-type NRAS (HR, 0.39; 95% CI, 0.27-0.56) and wild-type BRAF (HR, 0.37; 95% CI, 0.24-0.55) but not mutant NRAS (HR, 1.94; 95% CI, 0.44-8.44). CONCLUSIONS: These results show the feasibility and potential clinical use of next-generation sequencing for evaluating predictive biomarkers.

SoriaJournal of Clinical Oncology

Phase 1b Study of Dulanermin (recombinant human Apo2L/TRAIL) in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Patients With Advanced Non-Squamous Non–Small-Cell Lung Cancer

PURPOSE: To determine the safety, pharmacokinetics (PK), and maximum-tolerated dose (MTD) up to a prespecified target dose of dulanermin in combination with paclitaxel, carboplatin, and bevacizumab (PCB) in patients with previously untreated, nonsquamous, stage IIIb (with pleural effusion)/IV or recurrent non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this phase 1b study, patients (n = 24) received PCB on day 1 of each 21-day cycle then dulanermin at 4 or 8 mg/kg/d for 5 consecutive days or 15 or 20 mg/kg/d for 2 consecutive days per assigned treatment cohort. Incidence of dose-limiting toxicities (DLTs), adverse events, and antidulanermin antibodies were assessed. PK parameters were recorded for each agent. Tumor response was measured by modified Response Evaluation Criteria in Solid Tumors. RESULTS: Twenty-four patients received at least one dose of dulanermin plus PCB, six in each treatment cohort. There were no DLTs. An MTD was not reached, and the drug combination was well tolerated. Treatment-emergent adverse events were generally as expected for the PCB regimen. Adverse events attributed to dulanermin were grade 1/2; no significant hepatotoxicity occurred. There was minimal impact of PCB on the PK of dulanermin. There was one confirmed complete response and 13 confirmed partial responses. The overall response rate was 58% (95% CI, 37 to 78). Median progression-free survival was 7.2 months (95% CI, 4.7 to 10.3). CONCLUSION: Dulanermin plus PCB was well tolerated with no occurrence of DLTs and demonstrated antitumor activity in this patient population. Dulanermin at 8 mg/kg/d for 5 days and 20 mg/kg/d for 2 days every 3 weeks in combination with PCB is being studied in a phase II trial.

Results of Two Open-Label, Multicenter Phase II Studies of Docetaxel, Platinum Salts, and Trastuzumab in HER2-Positive Advanced Breast Cancer

BACKGROUND: Preclinical data indicate that docetaxel, platinum salts, and the combination of both drugs are highly synergistic with the anti-HER2 antibody trastuzumab. The University of California at Los Angeles-Oncology Research Network (UCLA-ORN) and the Breast Cancer International Research Group (BCIRG) have conducted two phase II studies to evaluate docetaxel and trastuzumab in combination with either cisplatin or carboplatin for the treatment of women with advanced breast cancer that overexpresses HER2. METHODS: Each study enrolled 62 patients with HER2-overexpressing tumors. Patients received a median of six cycles of docetaxel at 75 mg/m2 of body surface area and cisplatin (BCIRG 101 study) at 75 mg/m2 or carboplatin (UCLA-ORN study) at AUC = 6 mg/mL. min given on day 1 and then every 21 days. Trastuzumab was given on day 1, cycle 1 (4 mg/kg) and then continued weekly at 2 mg/kg for 1 year or until disease progression. Tumor measurements were obtained at baseline, after three cycles of chemotherapy, and then every 3 months. HER2 gene amplification was determined by fluorescence in situ hybridization. RESULTS: Patient characteristics were comparable between trials with the exception that 15% of the patients in the UCLA-ORN study had received previous adjuvant taxane therapy. Both regimens were well tolerated, with manageable toxicities. Hematologic toxicities were more frequent in patients in the UCLA-ORN study than in patients in the BCIRG 101 study, whereas the reverse pattern was observed for non-hematologic toxicities. One patient in each study developed reversible congestive heart failure. Responses were observed in 49 of 62 patients in the BCIRG 101 study (overall response rate = 79%, 95% confidence interval [CI] = 66% to 89%) and in 34 of 59 evaluable patients in the UCLA-ORN study (overall response rate = 58%, 95% CI = 44% to 70%). Median times to progression were 9.9 months (95% CI = 8.3 to 13.1 months) and 12.7 months (95% CI = 8.6 to 15.5 months) for patients in the BCIRG 101 and UCLA-ORN studies, respectively. Overall response rates were higher and median time to progression was longer in the subset of patients whose tumors harbored HER2 gene amplification. CONCLUSION: Combinations of docetaxel, a platinum salt, and trastuzumab are feasible and active in patients with advanced breast cancers that overexpress HER2. The BCIRG is conducting ongoing randomized studies of the three-drug combination in both the metastatic and adjuvant settings.

Combination chemotherapy for metastatic breast cancer

Despite more than four decades of effort, the improvement in survival in metastatic breast cancer has been modest. Recently, however, new drugs such as the taxanes have emerged as pivotal agents in the treatment of metastatic disease and they are now being investigated in the adjuvant setting. In addition, the introduction of molecularly targeted therapies such as trastuzumab provides a new paradigm for the development of biologic treatments. The incorporation of trastuzumab into new combination regimens based on potential molecular synergies is a focus of current research.

HER2 Protein Expression and Gene Amplification in Androgen-Independent Prostate Cancer

The role of the HER2 receptor remains uncertain in the pathogenesis and progression of human prostate cancer. Previous studies have reported widely divergent rates for HER2 expression in primary prostate tumors, probably owing to significant methodologic differences in the studies. Few data exist about the frequency of HER2 protein overexpression and gene amplification in androgen-independent prostate cancer (AIPC), although recent xenograft models suggest HER2 expression may be up-regulated in the transition from androgen-dependent to androgen-independent disease. We studied the role of HER2 protein in AIPC by immunohistochemical and fluorescence in situ hybridization (FISH) analyses on AIPC specimens using well-characterized and validated reagents. Fourteen (36%) of 39 specimens expressed HER2; however, only 2 (5%) had moderate (2+) expression, and 2 (5%) had high-level (3+) expression. Two (6%) of 36 specimens had gene amplification by FISH. These data suggest that HER2 protein overexpression and gene amplification are relatively uncommon in AIPC.

A Phase II Trial of Humanized Anti‐Vascular Endothelial Growth Factor Antibody for the Treatment of Androgen‐Independent Prostate Cancer

Objective: Vascular endothelial growth factor (VEGF) is a glycoprotein that is important in promoting tumor angiogenesis. Recombinant humanized anti (rhuMAb)‐VEGF is a humanized murine monoclonal antibody that neutralizes VEGF activity and has shown promise in animal tumor models. Methods: To evaluate the efficacy and safety of single‐agent rhuMAb VEGF in metastatic androgen‐independent prostate cancer (AIPC), we treated 15 patients with 10 mg/kg rhuMAb VEGF every 14 days for six infusions (one cycle), followed by additional treatment for selected patients who had a response or were stable. Results: After one cycle, none of the 15 patients who were evaluable for tumor response had an objective complete or partial response. Three possible mixed responses were observed. No patient achieved a >50% decrease in serum prostate specific antigen (PSA) level after one cycle. Four patients (27%) had a PSA decline of <50%, three patients (20%) had a PSA level increase of <50%, and eight patients (53%) had a PSA increase of >50%. The median time to objective progression was 118 days, and the median time to PSA progression was 57 days. Toxicity was generally mild, with asthenia present in 6 (40%) of 15 patients. Severe hyponatremia developed in two patients, although the association with rhuMAb VEGF was unclear. Conclusions: We concluded that single‐agent rhuMAb VEGF in this dose and with this schedule did not produce significant objective responses in patients with AIPC. Further development of this agent in patients with prostate cancer should focus on earlier stage disease or should evaluate it in combination with other therapies.

SmallJournal of Clinical Oncology

Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells

PURPOSE: Provenge (Dendreon Corp, Seattle, WA) is an immunotherapy product consisting of autologous dendritic cells loaded ex vivo with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP) linked to granulocyte-macrophage colony-stimulating factor. Sequential phase I and phase II trials were performed to determine the safety and efficacy of Provenge and to assess its capacity to break immune tolerance to the normal tissue antigen PAP. PATIENTS AND METHODS: All patients had hormone-refractory prostate cancer. Dendritic-cell precursors were harvested by leukapheresis in weeks 0, 4, 8, and 24, loaded ex vivo with antigen for 2 days, and then infused intravenously over 30 minutes. Phase I patients received increasing doses of Provenge, and phase II patients received all the Provenge that could be prepared from a leukapheresis product. RESULTS: Patients tolerated treatment well. Fever, the most common adverse event, occurred after 15 infusions (14.7%). All patients developed immune responses to the recombinant fusion protein used to prepare Provenge, and 38% developed immune responses to PAP. Three patients had a more than 50% decline in prostate-specific antigen (PSA) level, and another three patients had 25% to 49% decreases in PSA. The time to disease progression correlated with development of an immune response to PAP and with the dose of dendritic cells received. CONCLUSION: Provenge is a novel immunotherapy agent that is safe and breaks tolerance to the tissue antigen PAP. Preliminary evidence for clinical efficacy warrants further exploration.

SmallJournal of Clinical Oncology

Prospective Trial of the Herbal Supplement PC-SPES in Patients With Progressive Prostate Cancer

PURPOSE: PC-SPES is an herbal supplement for which there are anecdotal reports of anti-prostate cancer activity. This phase II study was undertaken to assess the efficacy and toxicity of PC-SPES in prostate cancer patients. PATIENTS AND METHODS: Thirty-three patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgen-independent prostate cancer (AIPCa) were treated with PC-SPES at a dose of nine capsules daily. Clinical outcome was assessed with serial serum prostate-specific androgen (PSA) level measurement and imaging studies. RESULTS: One hundred percent of ADPCa patients experienced a PSA decline of >/= 80%, with a median duration of 57+ weeks. No patient has developed PSA progression. Thirty-one patients (97%) had declines of testosterone to the anorchid range. Two ADPCa patients had positive bone scans; both improved. One patient with a bladder mass measurable on computed tomography scan experienced disappearance of this mass. Nineteen (54%) of 35 AIPCa patients had a PSA decline of >/= 50%, including eight (50%) of 16 patients who had received prior ketoconazole therapy. Median time to PSA progression was 16 weeks (range, 2 to 69+ weeks). Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease, and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events (n = 3) and allergic reactions (n = 3). Other frequent toxicities included gynecomastia/gynecodynia, leg cramps, and grade 1 or 2 diarrhea. CONCLUSION: PC-SPES seems to have activity in the treatment of both ADPCa and AIPCa and has acceptable toxicity. Further study is required to determine whether its effects exceed those expected with estrogen therapy.

Infusional floxuridine-based therapy for patients with metastatic renal cell carcinoma

BACKGROUND: The treatment of patients with metastatic renal cell carcinoma (RCC) continues to pose a major clinical challenge. Previous studies have suggested that infusional floxuridine (FUDR) has antitumor efficacy and is well tolerated. To the authors knowledge the combination of infusional FUDR with biologic response modifiers (BRMs) has not been evaluated extensively in patients with metastatic RCC. METHODS: Thirty-nine previously untreated patients with metastatic RCC were treated with infusional FUDR at 0.075 mg/kg/day for 14 days of a 28-day cycle. Beginning with the second cycle of FUDR, 24 patients received subcutaneous interferon-alpha-2b (3 million U 3 times a week for Weeks 1 and 2) and 15 received subcutaneous interleukin-2 (IL-2) (5 million U/m(2) 5 days a week for 3 weeks, followed by 1 week off). The dose of FUDR was increased by 0.025 mg/kg each cycle until the maximum tolerated dose for each patient was reached. RESULTS: Five patients receiving FUDR plus interferon achieved a partial response and 1 achieved a complete response whereas 3 patients receiving FUDR plus IL-2 achieved a partial response, for an overall response rate of 23%. The median survival for all patients was 21 months, and 8 patients still were alive 6-57+ months after the initiation of therapy. Toxicity was mild to moderate, and was comprised primarily of fatigue, diarrhea, dacryocystitis, and fluid retention (in the IL-2 cohort). CONCLUSIONS: FUDR in conjunction with IL-2 or interferon appears to produce response rates comparable to those observed with other programs utilizing BRMs and generally is well tolerated. FUDR regimens may be useful in the treatment of metastatic RCC in the outpatient community setting.

Special Departments

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2000.18.2.448 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 10637263 Mack Roach IIIxMack Roach IIISearch for articles by this author , David ReesexDavid ReeseSearch for articles by this author , Vivian WeinbergxVivian WeinbergSearch for articles by this author , Eric J. SmallxEric J. SmallSearch for articles by this author , Peter R. CarrollxPeter R. CarrollSearch for articles by this author Francesco BoccardoxFrancesco BoccardoSearch for articles by this author , Alessandra RubagottixAlessandra RubagottiSearch for articles by this author Show More University of CaliforniaSan Francisco San Francisco, CAOn behalf of the Italian Prostate Cancer Project University and National Cancer Institute GenoaItaly https://doi.org/10.1200/JCO.2000.18.2.448 First Page Full Text PDF Figures and Tables © 2000 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01012000In Reply:While we share the caution expressed by Roach et al, we disagree with most of the points raised by them.First, we never used the term equivalent to define the results achieved by bicalutamide monotherapy in our trial. This is a misinterpretation of our conclusions. We just limited to recognize that the results achieved by bicalutamide were comparable to those achieved by maximum androgen deprivation.Roach et al are correct in saying that trial amendment (which was required for ethical reasons) did further weaken the power of the trial. However, they are probably wrong in stating that “trial design was altered” and that amendment “led to potential biases in interpretation.” In fact, as it is clearly stated in the article,1 different lists of randomization were available by disease stage. Moreover, only 11 patients with stage C disease were entered since the date of amendment.There is no doubt that there are marked differences in the prognosis of patients with stage C and those with stage D. For this reason, separate analyses by stage were provided in the article (Fig 4 and Table 2) together with an analysis of all patients.1 The imbalances in treatment arms recalled by Roach et al were not significant and were “corrected” through multivariate analysis. As it is clearly stated in the article, patient age, initial alkaline phosphatase level, and baseline hemoglobin level were included in the model in addition to baseline prostate-specific antigen level, disease stage, and tumor grade.1 The analysis of paired data for changes in hemoglobin level relative to the patients for whom baseline, 3-month, and 6-month data were available are reported in Table 1. Hemoglobin Levels at the Start of Treatment and at 3 and 6 Months after Treatment (paired data)Hemoglobin Levels at the Start of Treatment and at 3 and 6 Months after Treatment (paired data)No. of PatientsHemoglobin Levels (g/dL)T0T3T6NOTE. Data are expressed as mean ± SE.Abbreviation: NS, not significant.Bicalutamide4813.7 ± 0.3113.7 ± 0.2313.8 ± 0.22Goserelin + flutamide5613.8 ± 0.2512.7 ± 0.2112.8 ± 0.21PNS.003.002Findings are almost identical to those reported in Table 4 in the article1 and in our opinion do not require further comment.Evaluation of QoL was not the primary end point of this study, and we already recognized that “the reliability of QoL analysis might be biased by the low compliance of patients.” However, our results are enforced by those reported on in this regard in the previous trials comparing bicalutamide monotherapy with castration.2,3 Moreover, data on sexual functioning were drawn after all patients were interviewed, and there is no doubt that fewer patients in the bicalutamide group complained of loss of libido and erectile dysfunction. This finding is common to the majority of previous trials reporting on pure antiandrogen monotherapy.2-5Loss of sexual potency has proved to be of special concern for younger men. An estimation of the perception of sexual dysfunction as an event negatively influencing QoL comes from the studies performed in men treated either with surgery or with radiotherapy for localized or locally advanced disease. Comparative trials have shown that the decline in sexual function was the most common cause of disease-specific stress among men with prostate cancer.6 Singer et al7 reported that of a sample of 50 men without known prostate cancer, 68% were willing to trade a 10% or greater advantage in 5-year survival in order to maintain sexual potency. A larger trial of 230 men in a general medicine clinic supported this finding, with 67% of men stating they would be willing to trade an increase of 14% in survival time in order to prevent impotence.8If it is acceptable, at least in principle, that men who are virtually candidates for cure might trade an increase of 10% or more in expected survival in order to prevent impotence, why should we not accept that men who are no longer candidates to be cured of their disease, like those with locally advanced or metastatic disease, could be willing to trade a modest (42 days in the trials of bicalutamide v castration,2) deficit in expected survival to achieve the same goal? Of course, the balance of risk and benefit should be integral to the discussion between the patient and the physician. However, not informing patients about the possible alternatives to androgen deprivation could limit their ability to choose. It has been said that a distinguished Italian surgeon in the 1970s chose to die of his prostate cancer because he did not want to accept the consequences of androgen deprivation. Let’s believe that should this gentleman be born 20 years later, he would probably live longer (and maybe die of a competing cause!) and benefit from a more appropriate palliation of his disease thanks to antiandrogen monotherapy.7. Boccardo F, Rubagotti A, Barichello M, et al: Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients: Results of an Italian Prostate Cancer Project study. J Clin Oncol 17::2027,1999-2038, Link, Google Scholar7. Tyrrell CJ, Kaisary AV, Iversen P, et al: A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 33::447,1998-456, Crossref, Medline, Google Scholar7. Iversen P, Tyrrell CJ, Kaisary AV, et al: Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: Results from two multicenter randomized trials at a median follow-up of 4 years. Urology 51::389,1998-396, Crossref, Medline, Google Scholar7. Kaisary AV: Antiandrogen monotherapy in the management of advanced prostate cancer. Eur Urol 31::14,1997-19, (suppl 2) Crossref, Medline, Google Scholar7. Migliari R, Muscas G, Usai E: Effect of Casodex on sleep-related erections in patients with advanced prostate cancer. J Urol 148::338,1992-341, Crossref, Medline, Google Scholar7. Helgason AR, Adolfsson J, Dickman P, et al: Sexual desire, erection, orgasm and ejaculatory functions and their importance to elderly Swedish men: A population-based study. Age Ageing 25::285,1996-291, Crossref, Medline, Google Scholar7. Singer PA, Tasch ES, Stocking C, et al: Sex or survival: Trade-offs between quality and quantity of life. J Clin Oncol 9::328,1991-334, Link, Google Scholar7. Mazur DJ, Hickham DH: Patient preferences: Survival versus quality of life. J Gen Intern Med 8::374,1993-377, Crossref, Medline, Google Scholar

Neurite Growth Patterns Leading to Functional Synapses in an Identified Embryonic Neuron

We explored the relationship between neurite outgrowth and the onset of synaptic activity in the central neuropil of the leech embryo in vivo. To follow changes in early morphology and the onset of synaptic activity in the same identified neuron, we obtained whole-cell patch-clamp recordings and fluorescent dye fills from dorsal pressure-sensitive (P) cells, the first neurons that could be reliably identified in the early embryo. We followed the development of the P cell from the first extension of neurites to the elaboration of an adult-like arbor. After the growth of primary neurites, we observed a profuse outgrowth of transient neurites within the neuropil. Retraction of the transient neurites left the primary branches studded with spurs. After a dormant period, stable secondary branches grew apparently from the spurs and became tipped with terminals. At this time, neurites of the Retzius (R) cell, a known presynaptic partner in the adult, were observed to apparently contact the terminals. Although voltage-dependent currents were seen in the P cell at the earliest stage, spontaneous synaptic activity was only observed when terminals had formed. Spontaneous release was observed before evoked release could be detected from the R cell. Our results suggest that transient neurites are formed during an exploratory phase of development, whereas the more precisely timed outgrowth of stable neurites from the spurs signals functional differentiation during synaptogenesis. Because spurs have also been observed in neurons of the mammalian brain, they may constitute a primordial synaptic organizer.

Oncogenic Osteomalacia Associated With Prostate Cancer

No AccessJournal of UrologyClinical Urology: Case Reports1 Sep 1997Oncogenic Osteomalacia Associated With Prostate Cancer David M. Reese and Peter J. Rosen David M. ReeseDavid M. Reese and Peter J. RosenPeter J. Rosen View All Author Informationhttps://doi.org/10.1016/S0022-5347(01)64351-9AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Oncogenic Osteomalacia Associated With Prostate Cancer." The Journal of Urology, 158(3), p. 887 References 1 : Neoplastic pathology of oncogenic osteomalacia/rickets.. Cancer1985; 55: 1691. Google Scholar 2 : Oncogenous osteomalacia. Review of the world literature of 42 cases and report of two new cases.. Amer. J. Med.1984; 77: 501. Google Scholar 3 : Brief report: inhibition of renal phosphate transport by a tumor product in a patient with oncogenic osteomalacia.. New Engl. J. Med.1994; 330: 1645. Google Scholar 4 : Oncogenic osteomalacia: evidence for a humoral phosphaturic factor.. J. Clin. Endocr. Metab.1995; 80: 1628. Google Scholar 5 : Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphatemia and tumor extracts inhibit renal 25-hydroxyvitamin D1-hydroxylase activity.. J. Clin. Endocr. Metab.1988; 67: 46. Google Scholar From the Division of Hematology-Oncology, Department of Medicine, UCLA School of Medicine, Los Angeles, California.© 1997 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 158Issue 3September 1997Page: 887 Advertisement Copyright & Permissions© 1997 by American Urological Association, Inc.MetricsAuthor Information David M. Reese More articles by this author Peter J. Rosen More articles by this author Expand All Advertisement PDF downloadLoading ...

HER‐2/ neu Signal Transduction in Human Breast and Ovarian Cancer

The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor tyrosine kinase with significant sequence homology to other members of the class I receptor tyrosine kinase family. The HER-2/neu gene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and overexpression of the receptor is associated with poor prognosis. Tyrosine phosphorylation and activation of the HER-2 receptor lead to activation of specific signal transduction pathways in breast and ovarian cancer cells, including the ras/MAP kinase cascade, phosphatidylinositol 3-kinase, and phospholipase C-gamma. HER-2/neu signal transduction pathways ultimately converge on the cell nucleus, where the expression of diverse genes is induced after activation of the receptor. A more complete understanding of HER-2/neu signal transduction pathways may allow the development of specific therapeutics for the treatment of those human breast and ovarian cancers containing this alteration.

Expression of the c-kit Proto-Oncogene and Its Ligand Stem Cell Factor (SCF) in Normal and Malignant Human Testicular Tissue

Recent findings suggest an important role of the proto-oncogene c-kit, a surface membrane receptor of the tyrosine kinase family, and its ligand stem cell factor (SCF) in normal spermatogenesis and possibly in the pathogenesis of certain testicular germ cell tumors. To further investigate this potential role, the expression of c-kit and SCF was studied in normal and malignant human testicular tissue specimens at the mRNA and protein level by Northern blot analysis and immunohistochemistry, respectively. The detection of the c-kit receptor in normal human germ cells and its natural ligand SCF in Sertoli cells suggests the presence of a local trophic regulatory system that may be active in human spermatogenesis. Additionally, c-kit expression was detected in the seminoma but not in the nonseminoma subtype of human testicular germ cell tumors (GCT). Stem cell factor was not expressed at the mRNA level in tissue from either subtype of GCT as determined by Northern blot analysis; however, the protein was detected immunohistochemically in the cytoplasm of rare tumor cells.