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Introduction: Patients with neuroendocrine neoplasms (NENs) may often develop other malignancies. This study aimed to identify the frequency at which these second malignancies occurred in England. Methods: Data were extracted from the National Cancer Registration and Analysis Service (NCRAS) on all patients diagnosed with a NEN at one of eight NEN site groups between 2012 and 2018: appendix, caecum, colon, lung, pancreas, rectum, small intestine, and stomach. WHO International Classification of Disease Edition-10 (ICD-10) codes were used to identify patients who had been diagnosed with an additional non-NEN cancer. Standardized incidence ratios (SIRs) for tumours diagnosed after the index NEN were produced for each non-NEN cancer type by sex and site. Results: A total of 20,579 patients were included in the study. The most commonly occurring non-NEN cancers after NEN diagnosis were the prostate (20%), lung (20%), and breast (15%). Statistically significant SIRs were observed for non-NEN cancer of the lung (SIR = 1.85, 95% CI: 1.55–2.22), colon (SIR = 1.78, 95% CI: 1.40–2.27), prostate (SIR = 1.56, 95% CI: 1.31–1.86), kidney (SIR = 3.53, 95% CI: 2.72–4.59), and thyroid (SIR = 6.31, 95% CI: 4.26–9.33). When stratified by sex, statistically significant SIRs remained for the lung, renal, colon, and thyroid tumours. Additionally, females had a statistically significant SIR for stomach cancer (2.65, 95% CI: 1.26–5.57) and bladder cancer (SIR = 2.61, 95% CI: 1.36–5.02). Conclusion: This study found that patients with a NEN experienced a metachronous tumour of the lung, prostate, kidney, colon, and thyroid at a higher rate than the general population of England. Surveillance and engagement in existing screening programmes are required to enable earlier diagnosis of second non-NEN tumours in these patients. [ABSTRACT FROM AUTHOR]

Haematological malignancies (HM) represent over 6% of the total cancer incidence in Europe and affect all ages, ranging between 45% of all cancers in children and 7% in the elderly. Thirty per cent of childhood cancer deaths are due to HM, 8% in the elderly. Their registration presents specific challenges, mainly because HM may transform or progress in the course of the disease into other types of HM. In the context of cancer registration decisions have to be made about classifying subsequent notifications on the same patient as the same tumour (progression), a transformation or a new tumour registration. Allocation of incidence date and method of diagnosis must also be standardised. We developed European Network of Cancer Registries (ENCR) recommendations providing specific advice for cancer registries to use haematology and molecular laboratories as data sources, conserve the original date of incidence in case of change of diagnosis, make provision for recording both the original as well as transformed tumour and to apply precise rules for recording and counting multiple diagnoses. A reference table advising on codes which reflect a potential transformation or a new tumour is included. This work will help to improve comparability of data produced by population-based cancer registries, which are indispensable for aetiological research, health care planning and clinical research, an increasing important area with the application of targeted therapies. [ABSTRACT FROM AUTHOR]

Zinc binding to the two Cys[SUB4] sites present in the DNA-binding domain (DBD) of nuclear hormone receptor proteins is required for proper folding of the domain and for protein activity. By utilizing Co[SUP2+] as a spectroscopic probe, we have characterized the metal-binding properties of the two Cys[SUB4] structural zinc-hindi ug sites found in the DBD of human estrogen receptor α. (hERα-DBD) and rat glucocorticoid receptor (GR-DBD). The binding affinity of Co[SUP2+] to the two proteins was determined relative to the binding affinity of Co[SUP2+] to the zinc finger consensus peptide, CP-1. Using the known dissociation constant of Co[SUP2+] from CP- 1, the dissociation constants of cobalt from hERα-DBD were calculated: K[SUBd1][SUPCo] = 2.2 (±1.0) × 10[SUP-7] M and K[SUBd2][SUPCo] = 6.1 (± 1.5) × 10[SUP-7] M. Similarly, the dissociation constants of Co[SUP2+] from GR-DBD were calculated: K[SUBd1][SUPCo] = 4.1 (± 0.6) × 10[SUP-7] M and K[SUBd2][SUPCo] = 1.7 (± 0.3) × 10[SUP-7] M. Metal-binding studies conducted in which Zn[SUP2+] displaces Co[SUP2+] from the metal-binding sites of hERα-DBD and GR-DB D indicate that Zn[SUP2+] binds to each of the Cys[SUB4] metal-binding sites approximately 3 orders of magnitude more tightly than Co[SUP2+] does: the stoichiometric dissociation constants are K[SUBd1][SUPZn]= 1 (± 1) × 10[SUP-10] M and K[SUBd2][SUPZn] = 5 (± 1) × 10[SUP-10] M for hERα-DBD and K[SUBd1][SUPZn] = 2 (± 1) × 10[SUP-10] M and K[SUBd2][Zn] = 3 (± 1) × 10[SUP-10] M for GR-DBD. These affinities are comparable to those observed for most other naturally occurring structural zinc-binding sites. [ABSTRACT FROM AUTHOR]

The article presents the authors' response to the article "Stage at diagnosis and colorectal cancer survival in six high-income countries: A population-based study of patients diagnosed during 2000 – 2007" by CAMILLE MARINGE and others published in a 2013 issue of the periodical. The topics discussed include different types of staging systems used in cancer studies, application of Marigne's method to colorectal carcinoma patients, and one year survival rate of cancer patients.

A letter to the editor is presented in response to an article about the diagnosis of Barrett's esophagus.

Background Providing detailed skin cancer statistics, including incidence and survival, by tumour type and patient characteristics is important for up-to-date epidemiological information. Objectives To create a new clinically relevant consensus-based classification for registered skin tumours using tumour type and patient characteristics and to describe its application to all registered tumours in England between 2013 and 2019. Methods Tumours with skin topographical codes (ICD-10) and morphology and behaviour (ICD-O3) were grouped together in an iterative process creating a hierarchical tree structure. The primary-level grouping partitioned skin tumours into skin cancer, melanoma in situ , extramammary Paget disease (EMPD) and tumours of uncertain malignant potential. Second-level groups split skin cancer into keratinocyte cancer (KC), melanoma and rare cancers. The third-level group split KC into basal cell carcinoma (BCC) and squamous cell carcinoma (cSCC). Further groups were split into genital or non-genital, first or subsequent tumour, age, gender, stage, or National Health Service (NHS) region. Incidence counts, Kaplan–Meier and net survival estimates and referral routes [two-week wait (TWW), general practitioner (GP), outpatient] categorisations were calculated for each grouping across all years. Results A total of 1 445 377 skin cancers and 49 123 precancerous lesions and undefined entities were registered in England between 2013 and 2019. Skin tumours and skin cancer incidence rates are increasing for most tumour types. The most common type of skin cancer was BCC with an incidence rate of 282.36 per 100 000 person-years (PYs) [ n = 158 934, 95% confidence interval (CI) 280.98–283.76] in 2019, followed by cSCC with an incidence rate of 85.24 per 100 000 PYs (n = 47 977, 95% CI 84.48–86.00) and melanoma with 27.24 (n = 15 332, 95% CI 26.81–27.67) per 100 000 PYs. Each year approximately 1800 rare skin cancers, 1500 genital cSCCs and 100 cases of EMPD are registered. Of 15 000 melanoma cases, 120 cases of melanoma occur in individuals aged < 25 years annually. One-year and five-year overall net survival varies by tumour type. cSCC 5-year net survival (89.8%, 95% CI 88.8–90.9) was comparable to the net survival of all melanomas (89.6%, 95% CI 88.7–90.6). BCC had excellent survival (overall net survival > 100%). Patients with late-stage melanoma, Merkel cell carcinoma and genital cSCC have a 5-year net survival < 60%. Older patients received fewer TWW referrals than their younger counterparts with the same tumour type at the same location. Patients with acral lentiginous melanoma had fewer TWW referrals and more standard GP referrals than patients with common melanomas. Conclusions 'Get Data Out' Skin provides detailed and up-to-date statistics on all registrable skin tumours in England, including for the first time precancerous lesions and rare subtypes of common cancers. These data can be used by clinicians, researchers and commissioners to better understand skin cancer and improve resource allocation. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a retrospective, population-based study comparing overall survival (OS) between males and females with neuroendocrine neoplasia (NEN). In total, 14,834 cases of NEN recorded in England's National Cancer Registry and Analysis Service (NCRAS)), were analysed. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Females displayed increased survival irrespective of the stage, morphology or level of deprivation, which was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). Stage of tumour mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. Females diagnosed with NEN tend to survive longer than males, and stage at presentation only accounts for part of this effect. Future research in NEN, as well as prognostication and treatment, should consider sex as an important factor. Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England's National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73–5.90) to 10.26 (6.6–14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor. [ABSTRACT FROM AUTHOR]

The International Federation of Gynaecology and Obstetrics (FIGO) updated its staging system for endometrial cancer in June 2023. The new system includes nonanatomic histological parameters and molecular classification, which are not traditionally part of staging systems. In August 2023, a survey was conducted among pathologists and clinicians to determine their views on adopting the FIGO 2023 system in the UK. The results showed no consensus on whether to incorporate the new parameters into staging, and only 34% of respondents favored adopting FIGO 2023. Access to timely molecular testing was identified as a factor that correlated with support for adoption. The British Association of Gynaecological Pathologists (BAGP) and British Gynaecological Cancer Society (BGCS) currently do not recommend adopting FIGO 2023 in the UK due to controversies and limited access to molecular classification. [Extracted from the article]

Summary: This analysis is the largest population‐based study to date to provide contemporary and comprehensive epidemiological estimates of all third edition of the International Classification of Diseases for Oncology (ICD‐O‐3) coded Langerhans cell histiocytosis (LCH) from England. People of all ages were identified from the National Cancer Registration Dataset using ICD‐O‐3 morphologies 9751–9754 for neoplasms diagnosed in 2013–2019. A total of 658 patients were identified, of whom 324 (49%) were children aged <15 years. The age‐standardised incidence rate was 4.46 (95% confidence interval [CI] 3.99–4.98) per million children and 1.06 (95% CI 0.94–1.18) per million adults aged ≥15 years. Prevalence of LCH was 9.95 (95% CI 9.14–10.81) per million persons at the end of 2019. The 1‐year overall survival (OS) was 99% (95% CI 97%–100%) for children and 90% (95% CI 87%–93%) for adults. Those aged ≥60 years had poorer OS than those aged <15 years (hazard ratio [HR] 22.12, 95% CI 7.10–68.94; p < 0.001). People in deprived areas had lower OS than those in the least deprived areas (HR 5.36, 95% CI 1.16–24.87; p = 0.03). There will inevitably be other environmental factors and associations yet to be identified, and the continued standardised data collection will allow further evaluation of data over time. This will be increasingly important with developments in LCH management following the large collaborative international trials such as LCH IV. [ABSTRACT FROM AUTHOR]

Summary: Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer worldwide with relatively low metastatic potential (2–5%). Developments in therapeutic options have highlighted the need to better identify high‐risk patients who could benefit from closer surveillance, adjuvant therapies and baseline/follow‐up imaging, while at the same time safely omitting low‐risk patients from further follow‐up. Controversy remains regarding the predictive performance of current cSCC staging systems and which methodology to adopt. Objectives: To validate the performance of four cSCC staging systems [American Joint Committee on Cancer 8th edition (AJCC8), Brigham and Women's Hospital (BWH), Tübingen and Salamanca T3 refinement] in predicting metastasis using a nationwide cohort. Methods: A nested case–control study using data from the National Disease Registration Service, England, 2013–2015 was conducted. Metastatic cSCC cases were identified using an algorithm to identify all potential cases for manual review. These were 1 : 1 matched on follow‐up time to nonmetastatic controls randomly selected from 2013. Staging systems were analysed for distinctiveness, homogeneity, monotonicity, specificity, positive predictive value (PPV), negative predictive value (NPV) and c‐index. Results: We included 887 metastatic cSCC cases and 887 nonmetastatic cSCC controls. The BWH system showed the highest specificity [92.8%, 95% confidence interval (CI) 90.8–94.3%, PPV (13.2%, 95% CI 10.6–16.2) and c‐index (0.84, 95% CI 0.82–0.86). The AJCC8 showed superior NPV (99.2%, 95% CI 99.2–99.3), homogeneity and monotonicity compared with the BWH and Tübingen diameter and thickness classifications (P < 0.001). Salamanca refinement did not show any improvement in AJCC8 T3 cSCC staging. Conclusions: We validated four cSCC staging systems using the largest nationwide dataset of metastatic cSCC so far. Although the BWH system showed the highest overall discriminative ability, PPV was low for all staging systems, which shows the need for further improvement and refining of current cSCC staging systems. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of a widely accepted and comparable animal cancer registration system lacks standardized animal cancer coding. The GIVCS group have developed a comparative coding system for canine neoplasms—Vet-ICD-O-canine-1—compatible with the human ICD-O-3.2 and consistent with the currently recognized classification schemes for canine tumors. This system comprises 335 topography codes and 534 morphology codes allowing the collection of consistent epidemiologic canine cancer data and offering a robust framework for comparative oncology studies. Cancer registries are fundamental tools for collecting epidemiological cancer data and developing cancer prevention and control strategies. While cancer registration is common in the human medical field, many attempts to develop animal cancer registries have been launched over time, but most have been discontinued. A pivotal aspect of cancer registration is the availability of cancer coding systems, as provided by the International Classification of Diseases for Oncology (ICD-O). Within the Global Initiative for Veterinary Cancer Surveillance (GIVCS), established to foster and coordinate animal cancer registration worldwide, a group of veterinary pathologists and epidemiologists developed a comparative coding system for canine neoplasms. Vet-ICD-O-canine-1 is compatible with the human ICD-O-3.2 and is consistent with the currently recognized classification schemes for canine tumors. It comprises 335 topography codes and 534 morphology codes. The same code as in ICD-O-3.2 was used for the majority of canine tumors showing a high level of similarity to their human counterparts (n = 408). De novo codes (n = 152) were created for specific canine tumor entities (n = 126) and topographic sites (n = 26). The Vet-ICD-O-canine-1 coding system represents a user-friendly, easily accessible, and comprehensive resource for developing a canine cancer registration system that will enable studies within the One Health space. [ABSTRACT FROM AUTHOR]

Background: The serum biomarker cancer antigen 125 (CA125) is widely used as an investigation for possible ovarian cancer in symptomatic women presenting to primary care. However, its diagnostic performance in this setting is unknown. We evaluated the performance of CA125 in primary care for the detection of ovarian and non-ovarian cancers.Methods and Findings: We studied women in the United Kingdom Clinical Practice Research Datalink with a CA125 test performed between 1 May 2011-31 December 2014. Ovarian and non-ovarian cancers diagnosed in the year following CA125 testing were identified from the cancer registry. Women were categorized by age: <50 years and ≥50 years. Conventional measures of test diagnostic accuracy, including sensitivity, specificity, and positive predictive value, were calculated for the standard CA125 cut-off (≥35 U/ml). The probability of a woman having cancer at each CA125 level between 1-1,000 U/ml was estimated using logistic regression. Cancer probability was also estimated on the basis of CA125 level and age in years using logistic regression. We identified CA125 levels equating to a 3% estimated cancer probability: the "risk threshold" at which the UK National Institute for Health and Care Excellence advocates urgent specialist cancer investigation. A total of 50,780 women underwent CA125 testing; 456 (0.9%) were diagnosed with ovarian cancer and 1,321 (2.6%) with non-ovarian cancer. Of women with a CA125 level ≥35 U/ml, 3.4% aged <50 years and 15.2% aged ≥50 years had ovarian cancer. Of women with a CA125 level ≥35 U/ml who were aged ≥50 years and who did not have ovarian cancer, 20.4% were diagnosed with a non-ovarian cancer. A CA125 value of 53 U/ml equated to a 3% probability of ovarian cancer overall. This varied by age, with a value of 104 U/ml in 40-year-old women and 32 U/ml in 70-year-old women equating to a 3% probability. The main limitations of our study were that we were unable to determine why CA125 tests were performed and that our findings are based solely on UK primary care data, so caution is need in extrapolating them to other healthcare settings.Conclusions: CA125 is a useful test for ovarian cancer detection in primary care, particularly in women ≥50 years old. Clinicians should also consider non-ovarian cancers in women with high CA125 levels, especially if ovarian cancer has been excluded, in order to prevent diagnostic delay. Our results enable clinicians and patients to determine the estimated probability of ovarian cancer and all cancers at any CA125 level and age, which can be used to guide individual decisions on the need for further investigation or referral. [ABSTRACT FROM AUTHOR]

The study aims to evaluate the differences in ovarian cancer survival by age and stage at diagnosis within and across seven high-income countries. We analyzed data from 58,161 women diagnosed with ovarian cancer during 2010–2014, followed until 31 December 2015, from 21 population-based cancer registries in Australia, Canada, Denmark, Ireland, New Zealand, Norway, and United Kingdom. Comparisons of 1-year and 3-year age- and stage-specific net survival (NS) between countries were performed using the period analysis approach. Minor variation in the stage distribution was observed between countries, with most women being diagnosed with 'distant' stage (ranging between 64% in Canada and 71% in Norway). The 3-year all-ages NS ranged from 45 to 57% with Australia (56%) and Norway (57%) demonstrating the highest survival. The proportion of women with 'distant' stage was highest for those aged 65–74 and 75–99 years and varied markedly between countries (range:72–80% and 77–87%, respectively). The oldest age group had the lowest 3-year age-specific survival (20–34%), and women aged 65–74 exhibited the widest variation across countries (3-year NS range: 40–60%). Differences in survival between countries were particularly stark for the oldest age group with 'distant' stage (3-year NS range: 12% in Ireland to 24% in Norway). International variations in ovarian cancer survival by stage exist with the largest differences observed in the oldest age group with advanced disease. This finding endorses further research investigating international differences in access to and quality of treatment, and prevalence of comorbid conditions particularly in older women with advanced disease. • The study demonstrates marked stage- and age-specific survival differences internationally • Largest survival difference was observed in older women with advanced stage • This study encourages further research on factors driving international differences in ovarian cancer survival [ABSTRACT FROM AUTHOR]

Context.-- Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). Objective.-- To develop standardized templates for brain tumor diagnostic pathology reporting. Design.-- As a response to the 2016 updated 4th edition of the WHO (World Health Organization) Classification of Tumours of the Central Nervous System (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. Results.-- The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. Conclusions.-- The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world. [ABSTRACT FROM AUTHOR]

Background: The diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities.Methods: Age-standardised incidence rate (ASR), 1-year overall survival, hazard ratios and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013-2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology.Results: A total of 15,222 NENs were identified, with an ASR (2013-2015 combined) of 8.6 per 100,000 (95% CI 8.5-8.7); 4.6 per 100 000 (95% CI, 4.5-4.7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73.9-75.4) varying significantly by sex. Site and morphology were prognostic. NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs.Conclusion: Advanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement. [ABSTRACT FROM AUTHOR]

Objective: To quantify geographic variation in the use of lymphadenectomy and/or external-beam radiotherapy (EBRT) for endometrial cancer in England.Design: Cross-sectional analysis of population-based data.Setting: English cancer registry data, linked to chemotherapy, radiotherapy and hospital episodes statistics data.Population: Twenty-two thousand four hundred and eighty-three women with endometrial cancer presenting without clinical or radiological evidence of distant metastatic spread, diagnosed in England from 2013 to 2016.Methods: Proportions of patients receiving lymphadenectomy and/or EBRT were compared across 19 Cancer Alliances, to identify variations in clinical practice. Two separate logistic regression models assessed the impact on variation of adjustment for tumour and patient characteristics.Main Outcome Measures: Receipt of lymphadenectomy, receipt of EBRT.Results: There was substantial variation by Cancer Alliance in the adjusted proportion of women with endometrial cancer receiving lymphadenectomy (range 5% [95% CI 4-6%] to 48% [95% CI 45-52%]) and EBRT (range 10% [95% CI 7-12%] to 31% [95% CI 28-33%]), after adjusting for variation in pathological grade, age, comorbidities, deprivation, ethnic group and (EBRT only) FIGO stage. Different approaches to clinical practice were identified; (i) one Cancer Alliance had significantly higher than average lymphadenectomy and significantly lower than average EBRT use, (ii) three had high use of both lymphadenectomy and EBRT, (iii) one had low lymphadenectomy use and high EBRT use, and (iv) three had low use of both lymphadenectomy and EBRT.Conclusions: Lymphadenectomy is probably used to triage for EBRT when lymphadenectomy use is high and EBRT use is low. This is probably a result of variation in local endometrial cancer management guidelines, suggesting that UK recommendations should be clarified.Tweetable Abstract: There is geographic variation in England in the use of lymphadenectomy and radiotherapy to treat endometrial cancer. [ABSTRACT FROM AUTHOR]

The author comments on TNM clinical staging of prostate cancer. Topics discussed include Clinical staging is important in assessing the spread of prostate cancer because a final pathological stage would be available only in those patients who undergo radical prostatectomy; issue within the TNM system related to the sub-categorization of cT2 prostate cancer by magnetic resonance imaging; and difference between the Union for International Cancer Control and American Joint Committee on Cancer.

Any practicing clinician who sees CC cases can confirm perihilar CC make up a much larger proportion of CC than 1-7%. ICD versions have separate codes for ICC and ECC, but neither ICD-10 nor any previous version of ICD has had a separate code for perihilar CC. IARC (Lyon) is the specialized cancer agency of the WHO, and has a separate ICD for Oncology (ICD-O) which exists for cancers only. In all 3 versions of the ICD-O so far, "Klatskin" CC could have been cross-referenced to either ICC (C22.1) or ECC (C24.0). [Extracted from the article]

Recent studies suggest that the developmental toxicity associated with childhood lead poisoning may be attributable to interactions of Pb(II) with proteins containing thiol-rich structural zinc-binding sites. Here, we report detailed structural studies of Pb(II) in such sites, providing critical insights into the mechanism by which lead alters the activity of these proteins. X-ray absorption spectroscopy of Pb(II) bound to structural zinc-binding peptides reveals that Pb(II) binds in a three-coordinate Pb(II)-S3 mode, while Zn(II) is known to bind in a four-coordinate mode in these proteins. This Pb(II)-S3 coordination in peptides is consistent with a trigonal pyramidal Pb(II)-S3 model compound previously reported by Bridgewater and Parkin, but it differs from many other reports in the small molecule literature which have suggested Pb(II)-S4 as a preferred coordination mode for lead. Reexamination of the published structures of these "Pb(II)-S4" compounds reveals that, in almost all cases, the coordination number of Pb is actually 5, 6, or 8. The results reported herein combined with this new review of published structures suggest that lead prefers to avoid four- coordination in sulfur-rich sites, binding instead as trigonal pyramidal Pb(II)-S3 or as Pb(II)-S5-8. In the case of structural zinc-binding protein sites, the observation that lead binds in a three-coordinate mode, and in a geometry that is fundamentally different from the natural coordination of zinc in these sites, explains why lead disrupts the structure of these peptides and thus provides the first detailed molecular understanding of the developmental toxicity of lead. [ABSTRACT FROM AUTHOR]

The adaptor protein complex AP-3 is involved in the sorting of lysosomal membrane proteins to late endosomes/lysosomes. It is unclear whether AP-3-containing vesicles form at thetrans-Golgi network (TGN) or early endosomes. We have compared the trafficking routes of endolyn/CD164 and‘typical’ lysosomal membrane glycoproteins (lgp120/lamp-1 and CD63/lamp-3) containing cytosolic YXXΦ-targeting motifs preceded by asparagine and glycine, respectively. Endolyn, which has a NYHTL-motif, is concentrated in lysosomes, but also occurs in endosomes and at the cell surface. We observed predominant interaction of the NYHTL-motif with theμ-subunits of AP-3 in the yeast two-hybrid system. Endolyn was mislocalized to the cell surface in AP-3-deficientpearlcells, confirming a major role of AP-3 in endolyn traffic. However, lysosomal delivery of endolyn (or a NYHTL-reporter), but not GYXXΦ-containing proteins, was practically abolished when AP-2-mediated endocytosis or traffic from early to late endosomes was inhibited in NRK and 3T3 cells. This indicates that endolyn is mostly transported along the indirect lysosomal pathway (via the cell surface), rather than directly from the TGN to late endosomes/lysosomes. Our results suggest that AP-3 mediates lysosomal sorting of some membrane proteins in early endosomes in addition to sorting of proteins with intrinsically strong AP-3-interacting lysosomal targeting motifs at the TGN. [ABSTRACT FROM AUTHOR]