In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Effect of SARS and COVID-19 outbreaks on urology practice and training.

INTRODUCTION: The objective was to investigate the changes in urology practice during coronavirus disease 2019 (COVID-19) pandemic with a perspective from our experience with severe acute respiratory syndrome (SARS) in 2003. METHODS: Institutional data from all urology centres in the Hong Kong public sector during the COVID-19 pandemic (1 Feb 2020-31 Mar 2020) and a non-COVID-19 control period (1 Feb 2019-31 Mar 2019) were acquired. An online anonymous questionnaire was used to gauge the impact of COVID-19 on resident training. The clinical output of tertiary centres was compared with data from the SARS period. RESULTS: The numbers of operating sessions, clinic attendance, cystoscopy sessions, prostate biopsy, and shockwave lithotripsy sessions were reduced by 40.5%, 28.5%, 49.6%, 44.8%, and 38.5%, respectively, across all the centres reviewed. The mean numbers of operating sessions before and during the COVID-19 pandemic were 85.1±30.3 and 50.6±25.7, respectively (P=0.005). All centres gave priority to cancer-related surgeries. Benign prostatic hyperplasia-related surgery (39.1%) and ureteric stone surgery (25.5%) were the most commonly delayed surgeries. The degree of reduction in urology services was less than that during SARS (47.2%, 55.3%, and 70.5% for operating sessions, cystoscopy, and biopsy, respectively). The mean numbers of operations performed by residents before and during the COVID-19 pandemic were 75.4±48.0 and 34.9±17.2, respectively (P=0.002). CONCLUSION: A comprehensive review of urology practice during the COVID-19 pandemic revealed changes in every aspect of practice.

Efficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease.

The emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents the growth of ascomycetous mold species via inhibition of de novo pyrimidine biosynthesis, a mechanism of action distinct from that of currently available antifungal drugs. We studied the in vivo efficacy of olorofim intraperitoneal therapy (15 mg/kg of body weight every 8 h for 9 days) against infection with A. fumigatus, A. nidulans, and A. tanneri in both neutropenic CD-1 mice and mice with chronic granulomatous disease (CGD) (gp91-/-phox mice). In the neutropenic mouse model, 80% to 88% of treated mice survived for 10 days, and in the CGD group, 63% to 88% of treated mice survived for 10 days, depending on the infecting species, while less than 10% of the mice in the control groups survived for 10 days. In the olorofim-treated groups, galactomannan levels were significantly suppressed, with lower organ fungal DNA burdens being seen for all three Aspergillus spp. Histopathological slides revealed a limited number of inflammatory foci with or without detectable fungal elements in the kidneys of neutropenic CD-1 mice and in the lungs of CGD mice. Furthermore, the efficacy of olorofim was unrelated to the triazole MICs of the infecting Aspergillus spp. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.

In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates.

Background: F901318 is a new antifungal agent with a novel mechanism of action with activity against Aspergillus species. We investigated the in vitro activity of F901318 against a collection of Aspergillus isolates. Methods: A total of 213 Aspergillus isolates were used in this study. A total of 143 Aspergillus fumigatus sensu stricto isolates were used, of which 133 were azole resistant [25 TR34/L98H; 25 TR46/Y121F/T289A; 33 A. fumigatus with cyp51A-associated point mutations (25 G54, 1 G432 and 7 M220); and 50 azole-resistant A. fumigatus without known resistance mechanisms]. Ten azole-susceptible A. fumigatus isolates were used as WT controls. The in vitro activity was also determined against Aspergillus calidoustus (25 isolates), Aspergillus flavus (10), Aspergillus nidulans (10) and Aspergillus tubingensis (25). F901318 activity was compared with that of itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B and anidulafungin. Minimum effective concentrations and MICs were determined using the EUCAST broth microdilution method. Results: F901318 was active against all tested isolates: A. fumigatus WT, MIC90 0.125 mg/L (range 0.031-0.125); TR34/L98H,TR46/Y121F/T289A and azole resistant without known resistance mechanisms, MIC90 0.125 mg/L (range 0.031-0.25); A. fumigatus with cyp51A-associated point mutations, MIC90 0.062 mg/L (range 0.015-0.125); and other species, A. calidoustus MIC90 0.5 mg/L (range 0.125-0.5), A. flavus MIC90 0.062 mg/L (range 0.015-0.62), A. nidulans MIC90 0.125 mg/L (range 0.062-0.25) and A. tubingensis MIC90 0.062 mg/L (range 0.015-0.25). Conclusions: F901318 showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms, suggesting no significant implications of azole resistance mechanisms for the mode of action of F901318.

Intraoperative dexamethasone alters immune cell populations in patients undergoing elective laparoscopic gynaecological surgery.

BACKGROUND: Anaesthetists use dexamethasone principally for its anti-emetic effect. The purpose of this study was to characterize the effects of a single intraoperative dose of dexamethasone on cellular and metabolic components of the immune system in patients undergoing laparoscopic surgical procedures. METHODS: In this prospective double-blind trial, female patients undergoing elective major laparoscopic surgery were randomized to receive saline (Control group, n =16) or dexamethasone 4 mg (Dexamethasone group, n =16) i.v. after the induction of anaesthesia. Inflammatory markers and immune cell counts were examined at 24 and 48 h and 6 weeks after surgery. The changes from baseline preoperative values were compared between groups using a Mann-Whitney U -test, and linear mixed models were used to validate the findings. RESULTS: No differences in concentrations of serum glucose and interleukin-6 were observed between groups after surgery. The increase in C-reactive protein concentration at 24 h after surgery was greater in the control group [median (interquartile range), 33 (25-65) vs 17 (7-26) mg dl -1 ; P =0.018]. Extensive changes in the counts of white cells, including most lymphocyte subsets, were observed 24 h after surgery, and dexamethasone appeared to attenuate most of these changes. Changes at 48 h and 6 weeks did not differ between groups. CONCLUSIONS: In female patients undergoing elective laparoscopic gynaecological surgery, dexamethasone administration appears to attenuate inflammation and to alter immune cell counts at 24 h, with no effects identified after this time. The importance of these changes for postoperative immune function is unknown. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ACTRN12608000340336).

A phase I trial of bortezomib in combination with epirubicin, carboplatin and capecitabine (ECarboX) in advanced oesophagogastric adenocarcinoma.

PURPOSE: The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. DESIGN: A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. RESULTS: 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. CONCLUSIONS: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome.

Ulnar-mammary syndrome is a rare pleiotropic disorder affecting limb, apocrine gland, tooth and genital development. We demonstrate that mutations in human TBX3, a member of the T-box gene family, cause ulnar-mammary syndrome in two families. Each mutation (a single nucleotide deletion and a splice-site mutation) is predicted to cause haploinsufficiency of TBX3, implying that critical levels of this transcription factor are required for morphogenesis of several organs. Limb abnormalities of ulnar-mammary syndrome involve posterior elements. Mutations in TBX5, a related and linked gene, cause anterior limb abnormalities in Holt-Oram syndrome. We suggest that during the evolution of TBX3 and TBX5 from a common ancestral gene, each has acquired specific yet complementary roles in patterning the mammalian upper limb.

Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family.

Holt-Oram syndrome is a developmental disorder affecting the heart and upper limb, the gene for which was mapped to chromosome 12 two years ago. We have now identified a gene for this disorder (HOS1). The gene (TBX5) is a member of the Brachyury (T) family corresponding to the mouse Tbx5 gene. We have identified six mutations, three in HOS families and three in sporadic HOS cases. Each of the mutations introduces a premature stop codon in the TBX5 gene product. Tissue in situ hybridization studies on human embryos from days 26 to 52 of gestation reveal expression of TBX5 in heart and limb, consistent with a role in human embryonic development.

Assessing graduating dental students' competencies: the impact of classroom, clinic and externships learning experiences.

OBJECTIVES: The present study assessed recent dental graduates' educational experiences with regard to competency development in different learning contexts and preparedness for independent professional performance. METHODS: The present study employed a questionnaire examining University of Manitoba graduating dental students' confidence and perceived importance of 47 competencies expected by the ACFD/CDA by requiring students to rate each competency on a five-point Likert scale. In addition, contribution of each of the three learning environments (classroom, clinic, and externship) towards competency development was assessed. RESULTS: Recent graduates reported most confidence in areas of basic clinical procedures involving radiographic, pharmacologic and caries management, with least confidence in implantology, orofacial pain, trauma and surgical management. Most importance was attributed to interpersonal-communication and basic clinical skills, with least importance in scientific research, implantology and prosthetic laboratory aspects. Overall, graduates felt that clinical setting contributed the most to competency development, followed by classroom and then externship contexts. CONCLUSION: Graduating students' professional preparedness can reflect the quality of dental programme. However, the amount of importance that graduates place on each competency might impact their confidence in the associated competencies and vice versa. In addition, learning settings must be effectively utilised for particular competencies' development.

Activation of rat T lymphocytes by anti-CD2 monoclonal antibodies.

Rat T cells and thymocytes were induced to proliferate by a pair of mAbs, MRC OX-54 and MRC OX-55, directed against rat CD2. Accessory cells were required but their role was not simply for crosslinking of the two mAbs, as neither MRC OX-54 nor MRC OX-55 alone, in the presence of a crosslinking second antibody, caused T cell mitogenesis. Nor could the phorbol ester PMA replace either antibody. The two mAbs recognized distinct epitopes on rat CD2; however, MRC OX-54 could partially block MRC OX-55 binding whereas the reverse situation was not seen. A further CD2 epitope was recognized by two mutually competitive mAbs, MRC OX-34 and MRC OX-53, which were not mitogenic. Neither MRC OX-34 nor MRC OX-53 affected the binding of MRC OX-54 or MRC OX-55, yet they prevented the mitogenic effect induced by these mAbs. The presence of mAbs against CD4 and the IL-2-R also abrogated this mitogenesis, whereas an anti-CD5 mAb augmented the CD2-induced proliferation.

Myofibrils bear most of the resting tension in frog skeletal muscle.

The tension that develops when relaxed muscles are stretched is the resting (or passive) tension. It has recently been shown that the resting tension of intact skeletal muscle fibers is equivalent to that of mechanically skinned skeletal muscle fibers. Laser diffraction measurements of sarcomere length have now been used to show that the exponential relation between resting tension and sarcomere length for whole frog semitendinosus muscle is similar to that of single fibers. Slack sarcomere lengths and the rates of stress relaxation in these muscles were similar to those in skinned fibers, and sarcomere length remained unchanged during stress relaxation, as in skinned fibers. Thus, in intact semitendinosus muscle of the frog up to a sarcomere length of about 3.8 micrometers, resting tension arises, not in the connective tissue as is commonly thought, but in the elastic resistance of the myofibrils.

Concerted nonsyntenic allelic loss in human colorectal carcinoma.

Familial polyposis coli (FPC) is caused by an autosomal dominant gene on chromosome 5, and it has been proposed that colorectal cancer in the general population arises from loss or inactivation of the FPC gene, analogous to recessive tumor genes in retinoblastoma and Wilms' tumor. Since allelic loss can be erroneously scored in nonhomogeneous samples, tumor cell populations were first microdissected from 24 colorectal carcinomas, an additional nine cancers were engrafted in nude mice, and nuclei were flow-sorted from an additional two. Of 31 cancers informative for chromosome 5 markers, only 6 (19%) showed loss of heterozygosity of chromosome 5 alleles, compared to 19 of 34 (56%) on chromosome 17, and 17 of 33 (52%) on chromosome 18. Therefore, it appears that (i) FPC is a true dominant for adenomatosis but not a common recessive gene for colon cancer; and (ii) simple Mendelian models involving loss of alleles at a single locus may be inappropriate for understanding common human solid tumors.

Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor.

The Wilms tumor locus on chromosome 11p13 has been mapped to a region defined by overlapping, tumor-specific deletions. Complementary DNA clones representing transcripts of 2.5 (WIT-1) and 3.5 kb (WIT-2) mapping to this region were isolated from a kidney complementary DNA library. Expression of WIT-1 and WIT-2 was restricted to kidney and spleen. RNase protection revealed divergent transcription of WIT-1 and WIT-2, originating from a DNA region of less than 600 bp. Both transcripts were present at high concentrations in fetal kidney and at much reduced amounts in 5-year-old and adult kidneys. Eleven of 12 Wilms tumors classified as histopathologically heterogeneous exhibited absent or reduced expression of WIT-2, whereas only 4 of 14 histopathologically homogeneous tumors showed reduced expression. These data demonstrate a molecular basis for the pathogenetic heterogeneity in Wilms tumorigenesis.

Wilms tumor locus on 11p13 defined by multiple CpG island-associated transcripts.

Wilms tumor is an embryonal kidney tumor involving complex pathology and genetics. The Wilms tumor locus on chromosome 11p13 is defined by the region of overlap of constitutional and tumor-associated deletions. Chromosome walking and yeast artificial chromosome (YAC) cloning were used to clone and map 850 kilobases of DNA. Nine CpG islands, constituting a "CpG island archipelago," were identified, including three islands that were not apparent by conventional pulsed-field mapping, and thus were at least partially methylated. Three distinct transcriptional units were found closely associated with a CpG island within the boundaries of a homozygous DNA deletion in a Wilms tumor.

B-cell antigen receptor motifs have redundant signalling capabilities and bind the tyrosine kinases PTK72, Lyn and Fyn.

BACKGROUND: The 13 cell antigen receptor (BCR) is a multimeric protein complex consisting of an antigen recognition structure (membrane immunoglobulin) and two associated proteins, lg-alpha and Ig-beta It has been proposed that signalling through the BCR involves Ig-alpha and Ig-beta. Both of these proteins contain within their cytoplasmic domains an amino-acid motif that is present in a number of immune recognition receptors, including the BCR, T-cell antigen receptor and Fc receptor complexes. This motif, termed the antigen-receptor homology motif (ARH1), appears to have signal transduction ability. RESULTS: We now show that the presence of cytoplasmic regions containing the ARM motif from either Ig-alpha or Ig-beta is sufficient to confer signalling capability on an otherwise non-functional fusion protein. Both Ig-alpha- and Ig-beta-containing chimeras induced, in an apparently redundant fashion, signalling events seen upon membrane immunoglobulin crosslinking, including tyrosine phosphorylation of particular proteins, phosphoinositicle breakdown and calcium mobilization. Furthermore, crosslinking of the chimeras resulted in tyrosine phosphorylation of the Ig-alpha and Tg-beta tails and their association with the tyrosine kinases PTK72, p53/56(lyn) and p59(fyn). CONCLUSIONS: These observations indicate that Ig-alpha and Ig-beta are responsible for coupling membrane immunoglobulin to intracellular signalling components. Moreover, they demonstrate that a number of tyrosine kinases associate directly with the cytoplasmic domains of both Ig-alpha and Ig-beta. Stimulation of the chimeras, which results in tyrosine phosphorylation of the ig-alpha and Ig-beta tails, is a prerequisite for some of these associations. The implications of these findings for the mechanism by which the BCR initiates the signalling reactions are discussed.

The SPS100 gene of Saccharomyces cerevisiae is activated late in the sporulation process and contributes to spore wall maturation.

We previously described the use of a differential hybridization screen of a genomic DNA library of Saccharomyces cerevisiae to identify sporulation-specific (SPS) genes (A. Percival-Smith and J. Segall, Mol. Cell. Biol. 4:142-150, 1984). This initial screen identified 14 SPS genes that are first expressed 6 to 8 h after transfer of cells to sporulation medium. Accumulation of transcripts corresponding to these genes becomes maximal at 8 to 12 h of sporulation, the time at which meiotic events are nearing completion, and by 15 h of sporulation, transcript levels are beginning to decrease. In the present study two additional SPS genes, first expressed at 12 h of sporulation, were isolated. The steady-state level of transcripts corresponding to these two genes, termed SPS100 and SPS101, remains unchanged from 15 to 35 h, a time coincident with spore wall maturation. The nature of the putative 34.2-kilodalton protein encoded by the SPS100 gene is consistent with its being a component of the glycoprotein matrix of the spore wall; the protein contains a potential signal sequence and cleavage site and numerous sites for potential glycosylation. A MATa sps100/MAT alpha sps100 strain was found to be indistinguishable from the wild-type strain when assessed for efficiency of ascus formation and spore viability. However, a more detailed analysis of the mutant strain revealed that the SPS100 gene product serves a protective role during the early stages of spore wall formation. The time at which resistance to ether could first be detected in developing spores was delayed by 5 h in the mutant strain relative to the wild-type strain. This phenotype is presumably a reflection of a defect in spore wall maturation. This study has confirmed that temporally distinct classes of sporulation-specific genes are sequentially activated during the process of meiosis and spore formation and has shown that the SPS100 gene, identified on the basis of its developmental-specific expression pattern, contributes to spore development.

iPTF16geu: A multiply imaged, gravitationally lensed type Ia supernova.

We report the discovery of a multiply imaged, gravitationally lensed type Ia supernova, iPTF16geu (SN 2016geu), at redshift z = 0.409. This phenomenon was identified because the light from the stellar explosion was magnified more than 50 times by the curvature of space around matter in an intervening galaxy. We used high-spatial-resolution observations to resolve four images of the lensed supernova, approximately 0.3 arc seconds from the center of the foreground galaxy. The observations probe a physical scale of ~1 kiloparsec, smaller than is typical in other studies of extragalactic gravitational lensing. The large magnification and symmetric image configuration imply close alignment between the lines of sight to the supernova and to the lens. The relative magnifications of the four images provide evidence for substructures in the lensing galaxy.

Influence of solid phase and formulation processing on stability of Abbott-232 tablet formulations.

Abbott-232 is a chemically stable, highly water soluble non-hygroscopic compound selected for development as a potent uroselective alpha(1A) agonist. An anhydrate, a monohydrate, and an amorphous phase were isolated. The anhydrate was chosen for formulation development based on solid-state characterization. Excipients for immediate release (IR) tablet formulations were selected according to compatibility studies. However, the prototype IR tablets designed for clinical trials were found to be chemically unstable. Thus, process-induced phase transformation was investigated as the likely cause of the observed instability. Since the drug loading in the formulations was low (1%), model granulations containing 30% drug were evaluated to test this hypothesis. Investigation using a variety of analytical techniques indicated that the observed degradation was, indeed, a result of a solution-mediated phase transformation from anhydrate to amorphous Abbott-232 during wet granulation. A new direct compression formulation was, therefore, developed to prevent the solution-mediated process induced phase transition. Since the drug loading was low, a polarized light microscope (PLM) method was used to evaluate the solid phase in the new formulation. PLM confirmed that the original anhydrate form remained unchanged in tablets manufactured by the dry process. Stability studies confirmed that both IR and extended release (ER) tablets of Abbott-232 were successfully developed for clinical trials using direct compression.

Oxygen alert cards and controlled oxygen: preventing emergency admissions at risk of hypercapnic acidosis receiving high inspired oxygen concentrations in ambulances and A&E departments.

BACKGROUND: Appropriate resuscitation of hypoxic patients is fundamental in emergency admissions. To achieve this, it is standard practice of ambulance staff to administer high concentrations of oxygen to patients who may be in respiratory distress. A proportion of patients with chronic respiratory disease will become hypercapnic on this. OBJECTIVES AND METHODS: A scheme was agreed between the authors' hospital and the local ambulance service, whereby patients with a history of previous hypercapnic acidosis with a Pao2 >10.0 kPa--indicating that oxygen may have worsened the hypercapnia--are issued with "O2 Alert" cards and a 24% Venturi mask. The patients are instructed to show these to ambulance and A&E staff who will then use the mask to avoid excessive oxygenation. The scheme was launched in 2001 and this paper present the results of an audit of the scheme in 2004. RESULTS: A total of 18 patients were issued with cards, and 14 were readmitted on 69 occasions. Sufficient documentation for auditing purposes was available for 52 of the 69 episodes. Of these audited admissions, 63% were managed in the ambulance, in line with card-holder protocol. This figure rose to 94% in the accident and emergency department. CONCLUSION: These data support the usability of such a scheme to prevent iatrogenic hypercapnia in emergency admissions.

A third Wilms' tumor locus on chromosome 16q.

Loss of heterozygosity studies have been used to identify chromosomal regions which are frequently deleted and thus indicate areas which may harbor tumor suppressor genes. As a result, both the WT1 gene located in chromosome 11p13 and an unidentified gene(s) within chromosome 11p15 have been implicated in Wilms' tumorigenesis. Cytogenetic and linkage studies suggest that additional non-chromosome 11 sites are involved in Wilms' tumor. Because these sites may also involve loss of heterozygosity, loci on 33 autosomal arms were screened for allele loss in a series of Wilms' tumors. We found that in addition to loss on chromosome 11p (11 of 25 informative tumors) there was significant loss on chromosome 16q (9 of 45 informative tumors), while the total frequency of allele loss excluding these loci was low (9 of 426 total informative loci). These data indicate that losses of both chromosome 11p and 16q alleles are nonrandom events and suggest that 16q is the location of a third tumor suppressor gene underlying Wilms' tumorigenesis. The parental origin of the lost chromosome 16q allele was determined in eight sporadic tumors. Alleles of paternal and of maternal origin were each lost in four sporadic tumors indicating that, unlike chromosome 11p, alleles of either parental origin are lost on 16q.