Cross neutralization of SARS-CoV-2 omicron subvariants after repeated doses of COVID-19 mRNA vaccines

We have measured the humoral response to messenger RNA (mRNA) vaccines in COVID-19 naïve and convalescent individuals. Third doses of mRNA COVID-19 vaccines induced a significant increase in potency and breadth of neutralization against SARS-CoV-2 variants of concern (VoC) including Omicron subvariants BA.1, BA.2, and BA.2.12.1, that were cross-neutralized at comparable levels and less for BA.4/5. This booster effect was especially important in naïve individuals that only after the third dose achieved a level that was comparable with that of vaccinated COVID-19 convalescents except for BA.4/5. Avidity of RBD-binding antibodies was also significantly increased in naïve individuals after the third dose, indicating an association between affinity maturation and cross neutralization of VoC. These results suggest that at least three antigenic stimuli by infection or vaccination with ancestral SARS-CoV-2 sequences are required to induce high avidity cross-neutralizing antibodies. Nevertheless, the circulation of new subvariants such as BA.4/5 with partial resistance to neutralization will have to be closely monitored and eventually consider for future vaccine developments.     

Sex selection may be inadvertently performed in in-vitro fertilization--embryo transfer programmes

The present study aims to ascertain whether sex selection maybe inadvertently performed in human in-vitro fertilization (IVF)and embryo transfer (IVF-embryo transfer) programmes when selectingfor high quality embryos (those with the fastest cleaving ratesand/or the best morphology) at the fresh transfer cycle. Allpatients entering into the study were treated with gonadotrophinsafter pituitary suppression with gonadotrophin-releasing hormoneagonists (GnRHa) and had intrauterine embryo transfer on day2 post-insemination. These patients were retrospectively dividedinto three groups according to whether the difference in meannumber of cells between embryos transferred and all embryosavailable for transfer in a given cycle was less than (negativeselection), equal to (no selection) or greater (positive selection)than zero. In cycles resulting in singleton births, the sexratio of the resulting babies was significantly (P 0.005) shiftedtoward the female (88.8%) and to the male (90.0%) in the negativeand positive selection groups respectively. No shift in sexratio was observed in cycles resulting in multiple births. Maternalage was another independent factor affecting sex ratio at birth.Sex ratio was significantly (P 0.05) skewed in favour of males(62.7%) and females (71.4%) in women <35 and 235 years ofage respectively. Maternal age, number of embryos transferredand the event of selecting or not selecting the slowest cleavingembryos for transfer were entered automatically in a three-groupdiscriminant model for distinguishing cycles resulting in onlyboys, both boys and girls, and only girls. These data suggestthat (i) sex selection may be inadvertently performed in IVF-embryotransfer programmes when selecting for high quality embryosat the fresh transfer cycles; (ii) human endometria may be favourable,indifferent or hostile to either fast cleaving or slow cleavingembryos depending on maternal age; and (iii) ‘natural’sex selection may be performed for social, psychological ormedical reasons.     

Influence of DNA Delivery Method on Gene Targeting Frequencies in Human Cells

Gene targeting can be used for genetic studies of human cell lines and has significant potential for somatic cell gene therapy. These applications are however restricted by the low frequency of homologous recombination in higher eukaryotes compared to the relatively efficient nonhomologous integration of transfected DNA into the genome. As part of our attempts to overcome this problem, we compared two widely used transfection methods for their efficiency in gene targeting. To our surprise we found that, for conditions that render similar frequencies of nonhomologous integrants, lipofection is much less efficient than electroporation in generating targeted clones. This suggests that nonhomologous and homologous recombination have different requirements for DNA delivery in human cells.     

Gastro-Gastric Fistulas and Marginal Ulcers in Gastric Bypass Procedures for Weight Reduction

Background: Gastro-gastric fistulas and marginal ulcers are frequent and serious complications of gastric compartmentalization procedures for obesity. Methods: The authors analyzed 810 patients after 911 operations for gastro-gastric fistulas and marginal ulcers over an 8-year period. All patients underwent a form of gastric bypass, in which a pouch is constructed along the lesser curvature of the stomach. The outlet of the pouch was restricted with a prosthetic band. In the first 189 patients (Group I), the pouch and stomach were stapled in continuity or partially divided. In the next 222 patients (Group II), segments were stapled and separated by transection. In the remaining 492 cases (Group III), in addition to transection of the stomach, a limb of jejunum was interposed between the pouch and excluded stomach. Stapled anastomoses were done in Group I and II patients and a portion of Group III patients. The remaining patients underwent hand-sewn anastomosis. Results: Gastro-gastric fistulas occurred in 49% of the patients in Group I, 2.6% of those in Group II, and 0% of those in Group III. In stapled anastomosis, the incidence of marginal ulceration in Groups I, II, and III were 8.5%, 5.4%, and 5.1%, respectively. In a subset of Group III patients, in whom a two-layer, hand-sewn anastomosis was done, the incidence was 1.6% when the outer layer was not absorbable and 0% when both layers were absorbable. Conclusions: Gastro-gastric fistulas and marginal ulcerations are likely the result of breakdown of the mucosa resulting from migrating staples and other foreign material. Lack of integrity of the gastric lining facilitates the action of the gastric digestive process. Transection of gastric segments with interposition of jejunum prevents gastro-gastric fistula formation. An intact serosa appears to block the digestion of bowel wall by gastric enzymes. Our early data suggest that the use of absorbable sutures at the gastrojejunostomy significantly decreases the incidence of marginal ulceration.     

Combining Clozapine with ECT

We describe the safe and effective use of the combination of clozapine and ECT in a patient with schizophrenia who had lost responsiveness to clozapine alone. We suggest further investigation to define the role of combined clozapine-ECT treatment in the management of treatment-resistant schizophrenia.     

Obesity Surgery Poly-parametric Patient Auto-evaluation

A simple auto-evaluation sheet is presented for the proper assessment of the patient's condition after surgery. Stress is put not only on weight loss, but on other important factors as well.     

Hemorrhagic activity of Bothrops venoms determined by two different methods and relationship with proteolytic activity on gelatin and lethality

The changes in hemorrhagic activity, proteolytic activity on gelatin and the lethal potency of four Bothrops venoms treated at different pH values or with EDTA were studied. Venoms from B. alternatus, B. jararaca, B. moojeni and B. neuwiedii of Argentina were preincubated at pH 5.8, 5.1 or 3.8 or with EDTA and the hemorrhagic activity expressed as size of the hemorrhagic lesion or as the amount of hemoglobin extracted, the proteolytic activity on gelatin and the lethal potency were determined. Although the MHDs recorded in rats were 19–56 fold higher than those recorded in mice, the A₅₅₀ extracted per gram of hemorrhagic haloes was very similar in rats or mice independent of the venom dose. Inhibition of proteolytic activity after preincubation at pH 5.1 or 3.8, agrees with the decreased amount of hemoglobin extracted from the hemorrhagic haloes, and with the increase in mean survival time after the i.p. injection to mice. Preincubation with EDTA resulted in 80% inhibition of hemorrhagic activity of B. jararaca venom and complete inhibition with the other Bothrops venoms tested. Measurement of the amount of hemoglobin extracted gives significant information in comparative studies, not available by measurement of the size of hemorrhagic haloes.     

Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.

PURPOSE: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. CONCLUSION: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.     

CD34+ cells from acute myeloid leukemia, myelodysplastic syndromes, and normal bone marrow display different apoptosis and drug resistance-associated phenotypes.

Myelodysplastic syndromes and acute myeloid leukemia (AML) are heterogeneous disorders in which conflicting results in apoptosis and multidrug resistance (MDR) have been reported. We have evaluated by multiparameter flow cytometry the expression of apoptosis- (APO2.7, bcl-2, and bax) and MDR-related proteins [P-glycoprotein (P-gp), multidrug resistance protein (MRP), and lung resistance protein (LRP)] specifically on bone marrow (BM) CD34+ cells, and their major CD32-/dim and CD32+ subsets, in de novo AML (n=90), high-risk myelodysplastic syndrome (n=9), and low-risk myelodysplastic syndrome (n=21) patients at diagnosis, and compared with normal BM CD34+ cells (n=6). CD34+ myeloid cells from AML and high-risk myelodysplastic syndrome patients displayed higher expression of bcl-2 (P <0.0001) and lower reactivity for APO2.7 (P=0.002) compared with low-risk myelodysplastic syndrome and normal controls. Similar results applied to the two predefined CD34+ myeloid cell subsets. No significant differences were found in the expression of P-gp, MRP, and LRP between low-risk myelodysplastic syndrome patients and normal BM, but decreased expression of MRP (P <0.03) in AML and high-risk myelodysplastic syndromes and P-gp (P=0.008) in high-risk myelodysplastic syndromes were detected. Hierarchical clustering analysis showed that low-risk myelodysplastic syndrome patients were clustered next to normal BM samples, whereas high-risk myelodysplastic syndromes were clustered together and mixed with the de novo AML patients. In summary, increased resistance to chemotherapy of CD34+ cells from both AML and high-risk myelodysplastic syndromes would be explained more appropriately in terms of an increased antiapoptotic phenotype rather than a MDR phenotype. In low-risk myelodysplastic syndromes abnormally high apoptotic rates would be restricted to the CD34- cell compartments.     

Preoperative uracil, tegafur, and concomitant radiotherapy in operable rectal cancer: a phase II multicenter study with 3 years' follow-Up.

PURPOSE: To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. PATIENTS AND METHODS: Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. RESULTS: All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. CONCLUSION: UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.