Psychological and professional impact of COVID-19 lockdown on French dermatologists: Data from a large survey.

AIM: To evaluate the extent to which COVID-19-related lockdown affected dermatologists. METHODS: An anonymous online survey was proposed to all French dermatologists and dermatology residents to assess the impact of COVID-19 lockdown on their professional activity, their level of stress and their psychological state, as well as their coping strategies. RESULTS: Exactly 800 dermatologists completed the survey. The respondents noted changes in behaviour in their professional and personal environment. The number of cancelled or rescheduled appointments was very high, with a huge financial impact for private practitioners. Stigmatisation was also reported. Anxiety and a feeling of increased stress were very frequent. Increased substance use was also reported. CONCLUSION: The impact of the COVID-19 pandemic and lockdown was significant for French dermatologists, with risks to their own health, profound changes in their practice, and financial and psychological impact, but also the development of new consultation and evaluation strategies to improve their work-life balance.

[The therapeutic contribution of proteomic approaches in cancers]. / L'apport thérapeutique des approches protéomiques dans les cancers.

Up to now, there are no protein tumor markers with a specificity and sensitivity sufficient to have a utility in prognosis and early diagnosis of cancer. Recent advances in proteomics approaches have led to the identification of novel tumor markers of cancer that may have a utility in screening strategies and treatment. The purpose of the current review is to describe the major advances in cancer proteomics, especially those related to the study of serum biomarkers, immune-related responses (autoantibodies) and alterations in cellular proteins.

The oncofetal protein, 5T4, is a suitable target for antibody-guided anti-cancer chemotherapy with calicheamicin.

The oncofetal protein, 5T4, is a tumor-associated protein displayed on the cell membrane of various carcinomas. This molecule is a promising target for anti-tumor vaccine development and for targeted therapy with staphylococcus exotoxin. The potential use of 5T4 as a target for antibody-guided chemotherapy has not been demonstrated. We report oncolytic efficacy and selectivity in vitro and in vivo with immuno-conjugates of calicheamicin (CM) and the anti-5T4 antibody, H8. CM is a potent cytotoxic drug that causes double strand breaks in DNA. Conjugates of CM and H8 were constructed with acid-labile as well as acid-stabile linkers. In vitro, when applied to monolayers of 5T4(+) cells, CM-conjugates targeting 5T4 were consistently more toxic than either free drug or a non-binding control CM-conjugate. This difference was less pronounced on 5T4-deficient cells. In vivo, four 5T4-positive subcutaneous tumor models were treated with conjugates. Efficacy was demonstrated by reduction of tumor growth relative to controls treated with drug vehicle. To evidence selectivity, the efficacy of the anti-5T4 conjugates was compared to the efficacy of H8, a mixture of H8 and calicheamicin, calicheamicin alone or calicheamicin conjugated to the anti-CD33 antibody, hP67.6. In addition, the efficacy and selectivity of an acid-labile conjugate of H8 was evaluated in an orthotopic model for 5T4(+) lung cancer. Increased survival following treatment was used as a parameter of efficacy. Calicheamicin conjugates of H8 were effective and selective in all the examined tumor models. Differences in efficacy between the acid-labile and acid-stabile conjugates depended on the investigated tumor model.

Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage.

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining cells undergo Schwann cell-like differentiation. Like other neural crest and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultures contain cells of neural (N-type) and epithelial (substrate-adherent, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma and glioma cell lines, we demonstrate that the determinants of the response to DNA cleavage are intrinsic properties of the cell. Furthermore, using a series of analogues of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show that the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteristics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damaging agent used, and not the specific characteristics of the damage it produces, is the trigger for production of the cellular response. Response type does not correlate with previously published values for expression of the apoptosis modulators Bcl-2, Bcl-XL, wildtype p53, or, in medulloblastoma lines, p75.

Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioimmunoconjugates by cancer cells.

Radiolabeled antibodies have produced encouraging remissions in patients with chemotherapy-resistant hematological malignancies; however, the selection of therapeutic radionuclides for clinical trials remains controversial. In this study, we compared the internalization, lysosomal targeting, metabolism, and cellular retention of radiolabeled murine and humanized monoclonal antibodies targeting the CD33 antigen (monoclonal antibodies mP67 and hP67, respectively) on myeloid leukemia cell lines (HEL and HL-60) and of anti-carcinoma antibodies (monoclonal antibodies hCTM01 and hA33) targeting breast cancer and colorectal carcinoma cell lines (MCF7 and Colo 205, respectively). Each antibody was labeled with 125I (by the IodoGen method) and with 111In and 90Y using macrocyclic chelation technology. Targeted tumor cells were analyzed for retention and metabolism of radioimmunoconjugates using cellular-radioimmunoassays, Percoll gradient fractionation of cell organelles, SDS-PAGE, and TLC of cell lysates and culture supernatants. Our results suggest that antibodies are routed to lysosomes after endocytosis, where they are proteolytically degraded. [125I]monoiodotyrosine is rapidly excreted from cells after lysosomal catabolism of antibodies radioiodinated by conventional methods, whereas small molecular weight 111In and 90Y catabolites remain trapped in lysosomes. As a consequence of the differential disposition of small molecular weight catabolites, 111In and 90Y conjugates displayed superior retention of radioactivity compared with 125I conjugates when tumor cells were targeted using rapidly internalizing antibody-antigen systems (e.g., hP67 with HEL cells and hCTM01 with MCF7 cells). When tumor cells were targeted using antibody-antigen systems exhibiting slow rates of endocytosis (e.g., hP67 on HL-60 cells and hA33 on Colo 205 cells), little differences in cellular retention of radioactivity was observed, regardless of whether 125I, 111In, or 90Y was used.

Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics.

The calicheamicin family of antitumor antibiotics are capable of producing double-stranded DNA breaks at sub-picomolar concentrations. Their potency suggested that the calicheamicins would be excellent candidates for targeted delivery and a hydrazide prepared from the most potent and abundant of the naturally occurring derivative, gamma 1I, was linked to oxidized sugars on CT-M-01, an internalizing anti-polyepithelial mucin antibody. The conjugates retained the immunoreactivity of the unmodified antibody and were specifically cytotoxic toward antigen positive tumor cells in vitro and in vivo. Hydrazide analogues of less potent calicheamicin derivatives were also prepared and conjugated to CT-M-01. Comparison of the therapeutic efficacy of the conjugates against the MX-1 xenograft tumor implanted s.c. in nude mice showed that conjugates of derivatives missing the rhamnose, a sugar residue that is part of the DNA binding region of the drug, were not as promising as antitumor therapies. However, conjugates of two derivatives, alpha 3I and N-acetyl-gamma 1I, in which the rhamnose residue is present but the amino sugar residue of the parent drug is either missing or modified, significantly inhibited tumor growth over a 4-fold dose range and produced long-term tumor-free survivors. Sterically hindering methyl groups adjacent to the disulfide in the linker further increased the therapeutic window of these potent conjugates.

Aortic valve replacement with stentless xenografts.

Between 15th June 1991 and 15th August 1992, 40 patients underwent aortic valve replacement with the newly designed Edwards stentless aortic bioprosthesis 2500. The patients' ages ranged from 24 years to 80 years (mean 60.3 years). Preoperatively, 17 patients presented with pure aortic stenosis, three with aortic regurgitation and 20 with mixed lesion. The operations were performed with normothermic extracorporeal cardiopulmonary bypass and cold cardioplegic arrest. The implanted valves ranged in diameter from 21 mm to 27 mm. Ten patients received a subcoronary implantation, with the lower row of sutures being interrupted and the upper being continuous. The so-called miniroot technique was used in the other 30, also involving lower interrupted and running upper sutures after adaptation of the coronary ostia to the preformed openings in the graft. The aortic cross-clamp time ranged from 51 minutes to 94 minutes (mean 71 minutes). There was no operative mortality but three patients died early after the operation due to cardiac tamponade, sepsis and pneumonia. There was no late mortality or morbidity in the surviving patients up to 16 months postoperatively. Echocardiography, performed at discharge and twice a year thereafter showed no signs of significant valve incompetence in any patient, and continuous wave Doppler measurements indicated that resting pressure gradients across the aortic valve were low or absent. Our preliminary experience with the stentless aortic xenograft shows improved hemodynamic function as compared to stent mounted xenografts or mechanical prostheses. Further studies are needed, however, to establish the long-term performance of this device.

Aortic annular enlargement with the use of a homograft valve.

A technique of annular enlargement for use in homograft aortic valve surgery is described. Potential advantages of this technique, that allows convenient valve sizes in small aortic annuli, lie in the pediatric group of patients requiring aortic valve replacement.

Matrix-assisted UV-laser desorption/ionization mass spectrometric analysis of monoclonal antibodies for the determination of carbohydrate, conjugated chelator, and conjugated drug content.

The chemically averaged molecular weights of a variety of native and conjugated monoclonal antibodies, approximately 150,000, were measured by matrix-assisted UV-laser desorption/ionization mass spectrometry. The average mass of the carbohydrate present in a monoclonal antibody was estimated from the difference between the measured mass of the monoclonal antibody and the mass of the protein present in the monoclonal antibody computed from the amino acid translation of the DNA sequence. The loading of chelators and anticancer drugs conjugated to a monoclonal antibody was quantitated from the difference in the measured masses for the conjugated and untreated monoclonal antibody relative to the expected mass change upon conjugation of 1 mol of chelator or drug. The loading results obtained by mass spectrometry were consistent in most cases with measurements obtained by radioactivity trace assay or UV spectrometry. Similar matrix-assisted UV-laser desorption/ionization mass spectrometric studies were also made after reducing untreated and conjugated monoclonal antibodies with dithiothreitol to determine the distribution of carbohydrate and chelator between the light and heavy chains of the molecules. Matrix-assisted UV-laser desorption/ionization mass spectra were used to compute loading values for covalently bound drugs and proteins, while the loading values obtained by use of gel-filtration HPLC and UV spectrometry cannot distinguish between covalently and noncovalently bound drugs and proteins.

Synthesis and structure of the platelet aggregation factor thromboxane A2.

In 1975, Hamberg et al. reported evidence for the existence of an unstable platelet-aggregating factor which they named thromboxane A2 (TXA2) and for which they proposed a novel bicyclic oxetane structure (1, below) based on the short half-life of the factor (t1/2 (37 degrees C) = 32 s at pH 7.4) and the isolation of degradation products related to thromboxane (TXB2) (2, below). As natural TXA2 has not yet been isolated and characterized as a pure compound, we have synthesized the proposed structure (1) from TXB2 and compared its biological properties with those of authentic, biologically generated material. Here we present evidence that synthetic material having structure (1) is indistinguishable from platelet-derived TXA2 in various biological assays and that the proposed structure (1) for TXA2 is correct.

[Secondary prevention of gastric cancer in a risk group of persons without gastric acid. 2nd communication (author's transl)]. / rärvention

More than 6,000 predominant unselected persons were examined by tubeless gastric acid test using the "Desmoidpille" and by simultaneous determination of uropepsin according to West et al. About 1,000 probands demonstrating a lacking acid secretion were recognized as risk group and taken into supervision over several years since 1972. In this risk group 20 cases of gastric cancer were detected, 9 of them already by first investigation. 5 gastric cancers were found during the follow-up as true early gastric cancers. In 5,200 probands without risk signs (normal acid test) only 6 cases of gastric cancer were observed during time of follow-up. So it is a high risk group indeed, we have selected. Regarding the casuistry of 7 persons, younger than 70 years of age, with gastric cancer detected during follow-up, 4 of them survived, such a dispensaire included in a general geriatric care seems useful to practice.

Lung biopsy through the flexible fiberoptic bronchoscope.

Peripheral lung lesions are a difficult diagnostic problem. The technique of forceps lung biopsy through the flexible fiberoptic bronchoscope provides potential access to the entire lung. Experience to date documents the procedure's safety and high yield of helpful information.