Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

Photoprotection of the future: challenges and opportunities.

The use of sunscreens is an important and essential component of photoprotection. Since their introduction during the first half of the last century, sunscreens have benefited enormously from major technological advances such as the development of novel UV filters; as a result, their efficacy in preventing UV-induced erythema is unequivocal. More recently, however, new challenges have appeared, which have prompted a robust discussion about the safety of sunscreens. These include topics directly related to photoprotection of human skin such as improved/alternative methods for standardization of assessment of the efficacy of sunscreens, but also many others such as photoprotection beyond UV, concerns about human toxicity and ecological safety, the potential of oral photoprotective measures, consequences of innovative galenic formulations. On a first glance, some of these might raise questions and doubts among dermatologists, physicians and the general public about the use sunscreens as a means of photoprotection. This situation has prompted us to critically review such challenges, but also opportunities, based on existing scientific evidence. We conclude by providing our vision about how such challenges can be met best in the future in an attempt to create the ideal sunscreen, which should provide adequate and balanced protection and be easy and safe to use.

Feedback on the usefulness of an illustrated guidebook in an anatomical dissection course.

PURPOSE: Dissection provides direct experience in anatomy, which constitutes an essential discipline for medical students. For this purpose, we created a dissection guide for students in the 2nd-year of medical studies at the Grenoble University School of Medicine. The objective was to evaluate this tool of reverse pedagogy in terms of student satisfaction and educational interest. METHODS: Every 2nd-year student takes four sessions of limb dissection. To assist this dissection course, we developed a photographic guide launched in 2013. It includes an introduction presenting a methodology for dissection, followed by detailed protocols for each dissection area. Each step is illustrated with captioned photographs associated with a concise explanatory text. A questionnaire was then sent to 242 students to assess the impact of this tool and their overall satisfaction. RESULTS: Overall student satisfaction with this guidebook was rated 8.1 out of 10 with a 93.2% with significant improvement (p = 0.0137) and 78.7% of them declaring they had a better understanding of anatomy and mastery of the dissection techniques, respectively. In addition, students assessed the usefulness of the dissection guide at 3.6 out of 4 with the relevance of the content and presentation judged at 3.4 out of 4. Finally, the exam scores increased significantly with use of the guidebook (p < 0.0001). CONCLUSIONS: Students deemed the organization of this anatomy tutorial as highly satisfactory, and using the guidebook as a reference in dissection sessions allowed students to prepare for the dissection and improve their knowledge of anatomy, as demonstrated by improved exam scores.

Application of Tetrameric Recombinant Human Butyrylcholinesterase as a Biopharmaceutical for Amelioration of Symptoms of Acute Organophosphate Poisoning.

We present a procedure for optimizing the expression of recombinant tetrameric butyrylcholinesterase that enables large-scale production with the yield >30 mg/liter (>90 mg/roller bottle). Intravenous injection of the preparation significantly increased survival and decreased the severity of symptoms of poisoning with paraoxon, an organophosphorus toxin.

Morphological, structural and biophysical properties of French and Brazilian photoaged skin.

BACKGROUND: Knowledge of skin biology and its alterations in different populations is very important for the development of appropriate skincare strategies. OBJECTIVES: To evaluate and compare morphological, structural and biophysical properties of photoaged skin in French and Brazilian populations, using biophysical and skin-imaging techniques. METHODS: Forty-one French and 41 Brazilian healthy, female volunteers aged between 40 and 65 years were enrolled. Each participant completed a questionnaire concerning habits related to cosmetic use, sun exposure and sun protection during different life periods. Skin on the face and volar forearm was evaluated using noninvasive techniques, to determine skin colour, transepidermal water loss (TEWL), stratum corneum water content, skin microrelief, skin viscoelasticity and dermis structure. Reflectance confocal microscopy was used to measure epidermal layer thickness and epidermal morphological and structural characteristics. RESULTS: Compared with Brazilian skin, French skin was more hydrated, had a lower TEWL and presented a distinct viscoelastic profile on the forearms and face. Brazilian facial skin was more wrinkled, and the dermis was less echogenic on the forearms and face. The French participants had thicker stratum corneum. Brazilian facial skin presented a higher prevalence of rete ridge effacement, low interkeratinocyte reflectance, huddled collagen and solar elastosis. CONCLUSIONS: Morphological, structural and biophysical differences were found when assessing the skin of the Brazilian and French participants, who were exposed to different environmental factors.

Representing virus-host interactions and other multi-organism processes in the Gene Ontology.

BACKGROUND: The Gene Ontology project is a collaborative effort to provide descriptions of gene products in a consistent and computable language, and in a species-independent manner. The Gene Ontology is designed to be applicable to all organisms but up to now has been largely under-utilized for prokaryotes and viruses, in part because of a lack of appropriate ontology terms. METHODS: To address this issue, we have developed a set of Gene Ontology classes that are applicable to microbes and their hosts, improving both coverage and quality in this area of the Gene Ontology. Describing microbial and viral gene products brings with it the additional challenge of capturing both the host and the microbe. Recognising this, we have worked closely with annotation groups to test and optimize the GO classes, and we describe here a set of annotation guidelines that allow the controlled description of two interacting organisms. CONCLUSIONS: Building on the microbial resources already in existence such as ViralZone, UniProtKB keywords and MeGO, this project provides an integrated ontology to describe interactions between microbial species and their hosts, with mappings to the external resources above. Housing this information within the freely-accessible Gene Ontology project allows the classes and annotation structure to be utilized by a large community of biologists and users.

Pressure-induced molten globule state of human acetylcholinesterase: structural and dynamical changes monitored by neutron scattering.

We used small-angle neutron scattering (SANS) to study the effects of high hydrostatic pressure on the structure of human acetylcholinesterase (hAChE). At atmospheric pressure, our SANS results obtained on D11 at ILL (Grenoble, France) give a radius of gyration close to that calculated for a mixture of monomers, dimers and tetramers of the enzyme, suggesting a good agreement between hAChE crystal structure and its conformation in solution. Applying high pressure to the sample we found a global compression of about 11% of the enzyme up to a pressure of 900 bar and then again an extension up to 2.1 kbar indicating unfolding of the tertiary structure due to a molten globule (MG) state. On the other hand, we studied the influence of pressure up to 6 kbar on the dynamics of this enzyme, on the backscattering spectrometer IN13 at ILL. For the first time, we used elastic incoherent neutron scattering (EINS) to probe the differences between hAChE in its folded state (N), its high-pressure induced MG state and its unfolded state (U). Especially around the MG state at 1750 bar we found a significant increase in the dynamics, indicating a partial unfolding. A four-step-model is suggested to describe the changes in the protein.

Risk factors for early mortality from lung cancer: evolution over the last 20 years in the French nationwide KBP cohorts.

BACKGROUND: The impact of the most recent advances, including targeted therapies and immune checkpoint inhibitors, on early (3-month) mortality in lung cancer is unknown. The aims of this study were to evaluate the real-world rate of and risk factors for early mortality, as well as trends in early mortality over the last 20 years. MATERIALS AND METHODS: The KBP prospective observational multicenter studies have been conducted every 10 years since 2000. These studies collect data on all newly diagnosed patients with lung cancer (all stages and histologies) over 1 year in non-academic public hospital pulmonology or oncology units in France. In this study, we analyzed data on patient and tumor characteristics from participants in the KBP-2020 cohort and compared the characteristics of patients who died within 3 months of diagnosis with those of all other patients within the cohort. We also carried out a comparative analysis with the KBP-2000 and KBP-2010 cohorts. RESULTS: Overall, 8999 patients from 82 centers were included in the KBP-2020 cohort. Three-month survival data were available for 8827 patients, of whom 1792 (20.3%) had died. Risk factors for early mortality were: male sex, age >70 years, symptomatic disease at diagnosis, ever smoker, weight loss >10 kg, poor Eastern Cooperative Oncology Group performance status (≥1), large-cell carcinoma or not otherwise specified, and stage ≥IIIC disease. The overall 3-month mortality rate was found to have decreased significantly over the last 20 years, from 24.7% in KBP-2000 to 23.4% in KBP-2010 and 20.3% in KBP-2020 (P < 0.0001). CONCLUSION: Early mortality among patients with lung cancer has significantly decreased over the last 20 years which may reflect recent improvements in treatments. However, early mortality remained extremely high in 2020, particularly when viewed in light of improvements in longer-term survival. Delays in lung cancer diagnosis and management could contribute to this finding.

Consistency and completeness of reported outcomes in randomized trials of primary immunosuppression in kidney transplantation.

Inconsistent and incomplete outcome reporting may make estimates of treatment effects from published randomized trials unreliable. We aimed to determine outcome reporting practices and source of differences in reporting quality among randomized trials of primary immunosuppression in kidney transplantation. We searched the Cochrane Renal Group's Specialized Register, 2000-2012, specified four core outcomes we expected trials to report, and recorded if and how completely each was reported. We identified 179 trials. One hundred sixty-eight (94%) reported death, 145 (81%) as number dead and 119 (66%) as time to death. One hundred sixty-five (92%) reported graft loss, 158 (88%) as number with graft loss and 127 (71%) as time to graft loss. One hundred twenty-one (68%) reported creatinine and 114 (64%) estimated GFR (eGFR). One hundred forty-one (79%) provided complete reports of number dead, 95 (53%) censored and 99 (55%) uncensored number with graft loss. Seventy-three (41%) provided complete reports of time to death, 67 (37%) censored and 31 (17%) uncensored time to graft loss. Complete reporting of graft function was infrequent: 62 (35%) eGFR and 50 (28%) creatinine. All four outcomes were reported in any form in 61 (34%) and completely in 28 (16%) trials. No single trial or journal characteristic was consistently associated with complete outcome reporting. Outcome reporting in kidney transplant trials is inconsistent and frequently incomplete, and published estimates of treatment effects may be unreliable.

Biomedical Nanosystems for In Vivo Detoxification: From Passive Delivery Systems to Functional Nanodevices and Nanorobots.

The problem of low efficiency of nanotherapeutic drugs challenges the creation of new alternative biomedical nanosystems known as robotic nanodevices. In addition to encapsulating properties, nanodevices can perform different biomedical functions, such as precision surgery, in vivo detection and imaging, biosensing, targeted delivery, and, more recently, detoxification of endogenous and xenobiotic compounds. Nanodevices for detoxification are aimed at removing toxic molecules from biological tissues, using a chemical- and/or enzyme-containing nanocarrier for the toxicant to diffuse inside the nanobody. This strategy is opposite to drug delivery systems that focus on encapsulating drugs and releasing them under the influence of external factors. The review describes various kinds of nanodevices intended for detoxification that differ by the type of poisoning treatment they provide, as well as the type of materials and toxicants. The final part of the review is devoted to enzyme nanosystems, an emerging area of research that provides fast and effective neutralization of toxins in vivo.

Time-dependent kinetic complexities in cholinesterase-catalyzed reactions.

Cholinesterases (ChEs) display a hysteretic behavior with certain substrates and inhibitors. Kinetic cooperativity in hysteresis of ChE-catalyzed reactions is characterized by a lag or burst phase in the approach to steady state. With some substrates damped oscillations are shown to superimpose on hysteretic lags. These time dependent peculiarities are observed for both butyrylcholinesterase and acetylcholinesterase from different sources. Hysteresis in ChE-catalyzed reactions can be interpreted in terms of slow transitions between two enzyme conformers E and E'. Substrate can bind to E and/or E', both Michaelian complexes ES and Ε'S can be catalytically competent, or only one of them can make products. The formal reaction pathway depends on both the chemical structure of the substrate and the type of enzyme. In particular, damped oscillations develop when substrate exists in different, slowly interconvertible, conformational, and/or micellar forms, of which only the minor form is capable of binding and reacting with the enzyme. Biphasic pseudo-first-order progressive inhibition of ChEs by certain carbamates and organophosphates also fits with a slow equilibrium between two reactive enzyme forms. Hysteresis can be modulated by medium parameters (pH, chaotropic and kosmotropic salts, organic solvents, temperature, osmotic pressure, and hydrostatic pressure). These studies showed that water structure plays a role in hysteretic behavior of ChEs. Attempts to provide a molecular mechanism for ChE hysteresis from mutagenesis studies or crystallographic studies failed so far. In fact, several lines of evidence suggest that hysteresis is controlled by the conformation of His438, a key residue in the catalytic triad of cholinesterases. Induction time may depend on the probability of His438 to adopt the operative conformation in the catalytic triad. The functional significance of ChE hysteresis is puzzling. However, the accepted view that proteins are in equilibrium between preexisting functional and non-functional conformers, and that binding of a ligand to the functional form shifts equilibrium towards the functional conformation, suggests that slow equilibrium between two conformational states of these enzymes may have a regulatory function in damping out the response to certain ligands and irreversible inhibitors. This is particularly true for immobilized (membrane bound) enzymes where the local substrate and/or inhibitor concentrations depend on influx in crowded organellar systems, e.g. cholinergic synaptic clefts. Therefore, physiological or toxicological relevance of the hysteretic behavior and damped oscillations in ChE-catalyzed reactions and inhibition cannot be ruled out.

Fertility preservation in the male: from childhood to adulthood.

Approximately 50% of males will develop cancer during their lifetime. In the past, oncologic therapies have largely been focused primarily on cure of the underlying malignancy. With improvements in both diagnostic modalities and treatments, pediatric and adult cancer patients are routinely surviving their disease. For this large group of patients, survivorship issues have become a major concern. Central among these survivorship issues is fertility. For males diagnosed with a malignancy, impaired reproductive potential is often noted even before any cancer therapy has been initiated. Furthermore, cancer treatments, in the form of chemotherapy, radiation therapy, and surgery, can all have potentially deleterious and lasting effects on male reproductive capability. For these reasons, a change in oncologic treatment paradigms has occurred. Now, the offer of fertility preservation to males diagnosed with cancer is a key component of comprehensive oncologic care.

Correlation-based ultrasound imaging of strong reflectors with phase coherence filtering.

Two main metrics are usually employed to assess the quality of medical ultrasound (US) images, namely the contrast and the spatial resolution. A number of imaging algorithms have been proposed to improve one of those metrics, often at the expense of the other one. This paper presents the application of a correlation-based ultrasound imaging method, called Excitelet, to medical US imaging applications and the inclusion of a new Phase Coherence (PC) metric within its formalism. The main idea behind this algorithm, originally developed and validated for Non-Destructive Testing (NDT) applications, is to correlate a reference signal database with the measured signals acquired from a transducer array. In this paper, it is shown that improved lateral resolutions and a reduction of imaging artifacts are obtained over the Synthetic Aperture Focusing Technique (SAFT) when using Excitelet in conjunction with a PC filter. This novel method shows potential for the imaging of specular reflectors, such as invasive surgical tools. Numerical and experimental results presented in this paper demonstrate the benefit, in terms of contrast and resolution, of using the Excitelet method combined with PC for the imaging of strong reflectors.

Tropical to mid-latitude snow and ice accumulation, flow and glaciation on Mars.

Images from the Mars Express HRSC (High-Resolution Stereo Camera) of debris aprons at the base of massifs in eastern Hellas reveal numerous concentrically ridged lobate and pitted features and related evidence of extremely ice-rich glacier-like viscous flow and sublimation. Together with new evidence for recent ice-rich rock glaciers at the base of the Olympus Mons scarp superposed on larger Late Amazonian debris-covered piedmont glaciers, we interpret these deposits as evidence for geologically recent and recurring glacial activity in tropical and mid-latitude regions of Mars during periods of increased spin-axis obliquity when polar ice was mobilized and redeposited in microenvironments at lower latitudes. The data indicate that abundant residual ice probably remains in these deposits and that these records of geologically recent climate changes are accessible to future automated and human surface exploration.

An exploratory study of eating disorder psychopathology among Overeaters Anonymous members.

Overeaters Anonymous (OA) is a widely available, 12-step, self-help treatment program primarily used for weight loss that also offers to address eating disorder (ED) symptoms. However, because of OA's tradition of avoiding contact with "outside enterprises," little research has examined eating pathology among OA members. The present, uncontroled study examined current, self-reported ED psychopathology with the Eating Disorder Examination Questionnaire among 20 self-selected OA members. Consistent with OA's aim to address compulsive overeating, rates of subjective and objective bulimic episodes and eating concern were significantly elevated among OA members relative to norms for adult women, demonstrating medium effects, and restraint showed a significant, small effect. Other ED symptoms, including weight concern and compensatory behaviors, were not statistically different from norms, yet demonstrated small effect sizes. We conclude that many OA members may experience ED psychopathology that extends beyond binge eating.

Age-dependent production of IgA and IgM autoantibodies against IgG2a in a colony of 129/Sv mice.

Although much of the basic immunological work has been done with mice, little is known about anti-IgG autoantibodies in this species. Dresser (1, 2) has reported the occurrence, in CBA mice, of anti-IgG antibody (Ab)(1) detected by a hemolytic-plaque assay after stimulation with endotoxin or immunization against sheep erythrocytes. IgM rheumatoid factor has also been described in various strains of mice with a systemic lupus erythematosus-like disease (3). Recently, we have tried to induce anti-IgG in mice of the 129/Sv strain by inoculating autologous IgG. To our surprise, we found that the sera of all the animals had, before any inoculation, anti-IgG detectable by agglutination of particles coated with autologous IgG. The possibilities to investigate the mechanism of production and the biological role of this kind of Ab prompted us to undertake a study of the nature and specificity of the mouse anti-IgG.

The effect of complement on the ingestion of soluble antigen-antibody complexes and IgM aggregates by mouse peritoneal macrophages.

Complement was found to stimulate markedly the ingestion of soluble antigen-antibody complexes by mouse peritoneal macrophages. This was shown indirectly by measuring the release of degradation products when the complexes were labeled with 125I, or directly when the antigen, that was human transferrin, was labeled with 59Fe. In this case, the metal which was released from human transferrin inside the cells was not excreted, and its accumulation in the macrophages was a direct index of the uptake of immune complexes. The decay of radioactivity in macrophages after ingestion of 125I-labeled complexes was similar when they were taken up with or without complement, indicating that complement acts primarily on ingestion and not on digestion or excretion. The ingestion of complexes was morphologically confirmed using fluorescein-labeled antigen in the immune complexes. The opsonic effect of complement was also observed with IgM aggregates indicating that soluble complexes can be ingested through complement receptors without involvement of Fc-receptors, as required for particulate antigen-antibody complexes.

The binding of human lactoferrin to mouse peritoneal cells.

Human iron-saturated Lf (FeLf), which was labeled with 125I or 50Fe, was found to combine with the membrane of mouse peritoneal cells (MPC) which consisted of 70% macrophages. The following experimental data suggested the involvement of a specific receptor. (a) The binding of FeLf to MPC reached a saturation point. (b) The binding of radioactive FeLf was inhibited by preincubating the cells with cold FeLf but not with human Tf, human aggregated and nonaggregated IgG, or beef heart cytochrome c (c) Succinylation and carbamylation of FeLf resulted in a loss of its inhibiting activity on the binding of radioactive FeLf. Removal of neuraminic acid from FeLf increased its inhibitory activity. (d) The ability of apoLf to inhibit the binding of FeLf to MPC was significantly lower than that of FeLf. The existence of a Lf receptor capable of concentrating Lf released from neutrophils on the membrane of macrophages could explain the apparent blockade of the release of iron from the reticuloendothelial system, which accounts for the hyposideremia of inflammation. A receptor for FeLf was also found on mouse peritoneal lymphocytes. The affinity constant of FeLf for both lymphocytes and macrophages was 0.9 X 12(6) liter/mol. Howerver, macrophages bound three times more FeLf molecules (20 X 10(6)) per cell than did lymphocytes (7 X 10(6)).

Incidence and specificities of IgA and IgM anti-AgG autoantibodies in various mouse strains and colonies.

Mice, greater than 20 wk old, were tested for the presence of anti-IgG autoantibodies by agglutination and radioimmunoassay. IgA and IgM anti-IgG were found in the 129/Sv, C57BL/6, and DBA/2 strains from the local colony at the International Institute of Cellular and Molecular Pathology (ICP), at the Institut Pasteur de Paris (IP), and in the endotoxin-resistant C3H/He strain of ICP. These strains were negative at Iffa Credo (IC), and at The Jackson Laboratory (JL). Among 33 strains from the latter colony, 129/J, AKR/J, CBA/J, C57L/J, and NZB/BinJ were positive. All were specific pathogen-free and, excepting the NZB/BinJ, are not known to develop systemic autoimmune disorders. These differences between colonies suggest an influence of the environment on the production of anti-IgG. Evidence for the role of an infectious agent was provided by the fact that germ-free DBA/2 were negative in contrast to their SPF relatives. Strains which were positive at ICP and IP for anti-IgG had four-times higher serum levels of total IgA and two-times higher levels of total IgG than the corresponding negative strains from IC and JL. The anti-IgG titers differed markedly from one strain to the other in the same environment; e.g., in mice from ICP, BALB/c mice produced 40-times less anti-IgG than 129/Sv. IgA anti-IgG occurred only in high producers of anti-IgG. In these animals, the proportion of IgA vs. IgM anti-IgG was very different from one group to the other; C57BL/6 had mainly IgM anti-IgG, DBA/2 mainly IgA anti-IgG, and 129/Sv both IgM and IgA anti-IgG. The IgA anti-IgG from 129/Sv, 129/J, NZB/BinJ, C57L/J, DBA/2, and C3H/He had restricted hetero-, iso-, and allotypic specificities. It reacted only with mouse IgGa2, but not with the Ig-1b allotype. C57BL/6 also had IgA anti-IgG with a narrow specificity, but directed against IgG1 without allotypic restriction. In contrast to the specificity of IgA anti-IgG, the antibody activity of IgM anti-IgG was much broader, except in the 129/Sv and 129/J strains where IgM anti-IgG shared the same narrow specificity with IgA.

Lactoferrin, an iron-binding protein in neutrophilic leukocytes.

Lactoferrin, an iron-binding protein previously shown to occur in many external secretions, is identified as one of the major proteins present in human and guinea pig neutrophilic polymorphonuclear leukocytes. The identification of this protein in leukocyte extracts was based upon a comparison of its electrophoretic, antigenic, and iron-combining properties with the corresponding properties of the same protein isolated from human and guinea pig milk. Immunochemical quantitations showed that lactoferrin occurs in human neutrophilic leukocytes at the concentration of 3 microg per 10(6) cells. Tissue cultures from guinea pig bone marrow and spleen actively synthesized the protein, as shown both by net production of lactoferrin and incorporation of labeled amino acids into the protein. Immunohistochemical data indicate that lactoferrin first appears in myeloid cells at the stage of the promyelocyte.